Pharmacology Comprehensive Study Guide: Section 2

GABAA receptors are ligand-gated ion channels, more specifically members of the...

"Cys-loop" superfamily that also includes nicotinic acetylcholine (nAChR), glycine, and serotonin type 3 (5-hydroxytryptamine type 3, or 5-HT3) receptors. Each of these receptors is formed as a pentameric combination of transmembrane protein subunits.

Tactile evaluation of double burst stimulation may be better to differentiate...

"fade" than TOF

Myasthenia Gav(MG), the most common and well studied postsynaptic neuromuscular transmission disorder, is caused by antibody-mediated reduction in the number of functioning...

"postsynaptic" AChRs. This complement-mediated destruction is caused by a variety of actions including antibodies directed against the AChR.

Lambert-Eaton myasthenic syndrome (LEMS) is an acquired...

"presynaptic" disorder of neuromuscular transmission caused by autoantibodies directed against voltage-gated Ca2 + channels in the motor nerve terminal resulting in down-regulation by endocytosis.

When given in very high doses, thiopental can even exhibit...

"zero order kinetics," wherein metabolic capacity is saturated, grossly prolonging the duration of action.

Antagonism of nondepolarizing neuromuscular blockade by acetylcholinesterase inhibitors depends primarily on five factors:

(1) Depth of the blockade when reversal is attempted (2) Anticholinesterase used (3) Dose administered (4) Rate of spontaneous clearance of the neuromuscular blocker from plasma (5) Choice of anesthetic drugs and the depth of anesthesia

There are three main classes of α2 agonists:

(1) Phenylethylates (α-methyl DOPA, guanabenz) (2) Imidazolines (clonidine, dexmedetomidine, mivazerol) (3) Oxaloazepines

Anticholinesterase drugs are classified according to the mechanism by which they inhibit the activity of acetylcholinesterase:

(a) Reversible inhibition (b) Formation of carbamyl esters (c) "Irreversible" inactivation by organophosphates

Edrophonium is used to:

(a) antagonize the effects of nondepolarizing neuromuscular-blocking drugs b) diagnose and assess therapy of myasthenia gravis and cholinergic crisis (c) evaluate the presence of dual blockade produced by succinylcholine.

PROPOFOL (Diprivan): Dose

**Base on LBW (IBW + 20%) *Induction: 1-2.5mg/kg, Pedi: 2.5-3.5mg/kg *Infusion: 25-200 mcg/kg/hr

Endogenous Ligand: Mu (μ)

**Endorphins *β-Endorphin *Endomorphin

Endogenous Ligand: Delta (δ)

**Enkephalins *Leu-enkephalin *Met-enkephalin

ALFENTANIL (Alfenta): MOA

**G Protein-Coupled Receptor *Inhibits the activity of adenylate cyclase *Mu agonist *Kappa agonist *Delta agonist *Serotonin Reuptake Inhibitor

MORPHINE: MOA

**G Protein-Coupled Receptor *Mu agonist *Delta agonist *Kappa agonist *Inhibits the activity of adenylate cyclase

HYDROMORPHONE (Dilaudid): MOA

**G Protein-Coupled Receptor *Mu agonist *Kappa agonist *Delta agonist *Inhibits the activity of adenylate cyclase

METHADONE (Dolophine): MOA

**G Protein-Coupled Receptor *Mu agonist *Kappa agonist *Delta agonist *NMDA Antagonist *Serotonin Reuptake Inhibitor *Norepinephrine Reuptake Inhibitor *Inhibits the activity of adenylate cyclase

FENTANYL (Sublimaze): MOA

**G Protein-Coupled Receptor *Mu agonist *Kappa agonist *Delta agonist *Serotonin Reuptake Inhibitor *Inhibits the activity of adenylate cyclase

REMIFENTANIL (Ultiva): MOA

**G Protein-Coupled Receptor *Mu agonist *Kappa agonist *Delta agonist *Serotonin Reuptake Inhibitor *Inhibits the activity of adenylate cyclase

SUFENTANIL (Sufenta): MOA

**G Protein-Coupled Receptor *Mu agonist *Kappa agonist *Delta agonist *Serotonin Reuptake Inhibitor *Inhibits the activity of adenylate cyclase

MEPERIDINE (Demerol): MOA

**G Protein-Coupled Receptor *Mu agonist *Kappa agonist *Delta agonist *mACh Antagonist *Alpha2b agonist (possibly) *Sodium Channel Antagonist *Serotonin Reuptake Inhibitor *Inhibits the activity of adenylate cyclase

NALBUPHINE (Nubain): MOA

**G Protein-Coupled Receptor *Mu antagonist *Kappa partial-agonist *Delta Agonist

NALOXONE (Narcan): MOA

**G Protein-Coupled Receptor *Mu antagonist (high) *Delta antagonist (moderate) *Kappa antagonist (moderate) *Inhibits the activity of adenylate cyclase

BUTORPHANOL (Stadol): MOA

**G Protein-Coupled Receptor *Partial Kappa agonist *Competitive Kappa antagonist *Partial Mu agonist *Competitive Mu antagonist

CODEINE: MOA

**G Protein-Coupled Receptor *Prodrug *Mu agonist *Kappa agonist *Delta agonist *Inhibits the activity of adenylate cyclase

HYDROCODONE: MOA

**G Protein-Coupled Receptor *Prodrug *Mu agonist *Kappa agonist *Delta agonist *Inhibits the activity of adenylate cyclase

OXYCODONE: MOA

**G Protein-Coupled Receptor *Prodrug *Mu agonist *Kappa2b agonist *Delta agonist *Inhibits the activity of adenylate cyclase

BUPRENORPHINE (Buprenex, Subutex, Suboxone, Butrans): MOA

**G-Protein Coupled Recepter *Inhibits the activity of adenylate cyclase *Partial μ-opioid agonist displaying high affinity for and slow dissociation from the μ-opioid receptor *Considered to be a partial Mu agonist (e.g., has limited intrinsic activity) and accordingly can display antagonism when used in conjunction with a full agonist *Kappa Antagonist *Delta Antagonist

TRAMADOL (Ultram): MOA

**G-Protein Coupled Recepter *Inhibits the activity of adenylate cyclase *Supplied as a racemic mixture *Mu agonist (M1 metabolite binds to Mu greater than parent drug) *Inhibits Serotonin reuptake *Inhibits Norepinephrine uptake *α2 Agonist *NMDA receptor antagonist *5-HT2C receptor antagonist *Nicotinic Acetylcholine receptor antagonist *Muscarinic(M1/M3) Acetylcholine receptor antagonist *TRPV1 receptor agonist

DIAZAPAM (Valium): Onset/Half-life/DOA

**Onset *1-5 min IV *30-60 min PO/PR **Peak *15-60 min IV *1-2 hr PO/PR *HL: 20-50 hr **DOA: 3 hr

LORAZEPAM (Ativan): Onset/Half-life/DOA

**Onset: *1-5 min IV *20-30 min PO **Peak *15-20 min IV *2 hr PO *HL: 10-20 hr IV **DOA: 6-10 hr

CATAPRES (Clonidine): Onset/Peak/Half-life/DOA

**Onset: *< 1min IV * min PO **Peak * min IV *1-3 hr PO *DHL: 7-15min **EHL: * IV *6-24 hr PO **DOA: *min IV *hr PO

MIDAZOLAM (Versed): Onset/Half-life/DOA

**Onset: *< 1min IV *10min PO *15min IM **Peak *10 min IV *20-30 min PO *HL: 1-4 hr IV **DOA: *15-90min IV *2-6hr PO *15-90min IM

TRAMADOL (Ultram): Dose

**PO *Immediate Release: 25-400 mg/day in 4 doses *Extended Release: 100-300 mg/day in 1 dose

PYRIDOSTIGMINE (Mestinon, Regonol): Dose/Onset/Peak/HL/DOA/VD

*0.1-0.4 mg/kg *Onset: 2-4 min *Peak: 15 min *HL: 90 min *DOA: 90-180 min *VD: 1.1 L/KG *Poor lipid solubility

C Sympathetic Fiber: Diameter

*0.3-1.3 μm

C Dorsal Root Fiber: Diameter

*0.4-1.2 μm

TOF: Established anesthesia

*1-2 twitches

Aδ Fiber: Diameter

*1-4 μm

LORAZEPAM (Ativan): Dose

*1-4mg IV

Dosing for lipid emulsion therapy?

*1.5mL/kg 20% bolus followed by 0.25ml/kg/min for at least 10 minutes after circulatory stability. If circulatory stability is not attained consider another bolus and increasing infusion to 0.5ml/kg/min.

MEPERIDINE (Demerol): Considerations

*1/10 as strong at Morphine *May cause dilated pupils *May increase heart rate and decrease cardiac contractility *Structurally similar to atropine (vagolytic properties) *Associated with more euphoria, difficulty concentrating, confusion, and impaired psychomotor and cognitive performance

TRAMADOL (Ultram): Considerations

*1/6000 the Mu activity of Morphine

KETAMINE (Ketalar): PharmacoKINETICS

*10% protein binding - leaves the plasma quickly *Rapid CNS effects R/T extremely high lipid solubility and large unbound fraction *Rapid redistribution from brain out of the central circulation to peripheral tissues accounts for rapid re-awakening after a single dose

ATRACURIUM BESYLATE (Tracrium): Metabolism

*10-40% Hofmann elimination *Enzymatic ester hydrolysis and renal elimination have lesser roles (some studies suggest up to 65%). *Laudanosine metabolite excreted in urine *The Ester hydrolysis involved in atracurium metabolism is catalyzed by a nonspecific esterase distinct from the butyrylcholinesterase responsible for hydrolysis of succinylcholine and mivacurium.

LIDOCAINE (Xylocaine): EHL

*100 min

PRILOCAINE (Citanest): EHL

*100 min

FENTANYL (Sublimaze): Considerations

*100X strong as Morphine *Produce a slowing of heart rate by directly increasing vagal nerve tone in the brainstem

REMIFENTANIL (Ultiva): Considerations

*100X strong as Morphine (Same as Fentanyl) *Produce a slowing of heart rate by directly increasing vagal nerve tone in the brainstem

ROPIVICAINE (Naropin): EHL

*110 min

MEPIVICAINE (Carbocaine, Polocaine): EHL

*115 min

PROCAINE (Novocaine): Max Dose

*14 mg/kg

CODEINE: Dose

*15mg PO (antitussive) *60mg PO (Analgesia)

BUPIVICAINE (Marcaine, Sensorcaine): Metabolism

*1st pass lung (lipophilic drugs taken quickly into lungs which are the 1st vascular bed after heart) *Hepatic Metabolism *Renal excretion

LIDOCAINE (Xylocaine): Metabolism

*1st pass lung (lipophilic drugs taken quickly into lungs which are the 1st vascular bed after heart) *Hepatic P450, CYP3A4/5 *Dealkylated to monoethylglycine xylidide and glycine xylidide, which can be metabolized further to monoethylglycine and xylidide. *Both monoethylglycine xylidide and glycine xylidide retain local anesthetic activity. *∼75% of the xylidide is excreted in the urine as the further metabolite 4-hydroxy-2, 6-dimethylaniline

ROPIVICAINE (Naropin): Metabolism

*1st pass lung (lipophilic drugs taken quickly into lungs which are the 1st vascular bed after heart) *Hepatic P450, CYP3A4/5 *Metabolized to 2,6-pipecoloxylidide and 3-hydroxyropivacaine *Renal excretion

The postjunctional nicotinic acetylcholine receptor is a pentameric member of the superfamily of ligand-gated ion channels. This mature form consists of five subunits:

*2 alpha (α) *1 delta (δ) *1 beta (β) *1 epsilon (ε) **In the immature (fetal) form, the ε subunit is replaced by a gamma (γ) subunit.

The NMJ contains three types of nicotinic cholinergic receptors (nAChRs):

*2 are postsynaptic on the skeletal muscle surface -1 Junctional -1 Extrajunctional *And 1 is presynaptic on the nerve ending

DIAZAPAM (Valium): Dose

*2-10mg IV

MIDAZOLAM (Versed): Considerations

*2-4X as strong as Diazapam

BUPIVICAINE (Marcaine, Sensorcaine): EHL

*210 min

BUPRENORPHINE (Buprenex, Subutex, Suboxone, Butrans): Considerations

*25-50X Strong as Morphine *Thus, care should be taken in treating patients who also are taking known inhibitors of CYP3A4 (e.g., azole antifungals, macrolide antibiotics, and HIV protease inhibitors), as well as drugs that induce CYP3A4 activity (e.g., certain anticonvulsants and rifampin). *Unable to be reversed by Narcan d/t strong Mu binding

TOF: Attempting reversal of neuromuscular blockage

*3-4 twitches

Aγ Fiber: Diameter

*3-6 μm

COCAINE: EHL

*30-90 mins

Train-of-four

*4 impulses at 2 Hz every 1/2 seconds for 2 seconds *Most common used *Does not require baseline

COCAINE: Max Dose

*4% Topical: 3 mg/kg (200mg total)

Structure of nAChR

*5 glycoprotein subunits: -2 alpha -1 beta -1 delta -1 epsilon *arrainged in cylindrical fashion and the center is an ion channel *pre & postjunctional receptors have different affinities for ACh

ALFENTANIL (Alfenta): Considerations

*5-10X strong as Morphine *1/5 - 1/10X strong as Fentanyl *Produce a slowing of heart rate by directly increasing vagal nerve tone in the brainstem

HYDROMORPHONE (Dilaudid): Considerations

*5-8X Strong as Morphine *Less nausea and pruritis than morphine? *May have hypotension/Histamine release

NEOSTIGMINE (Prostigmin, Vagostigmin): Metabolism

*50% hydrolyzed by plasma esterases and hepatic metabolism to 3-hydroxyphenyltrimethyl ammonium (3-OH PPM) and conjugated 3-OH PPM. *Renal excretion, 50% unchanged in urine *Use cautiously in renal failure

SUFENTANIL (Sufenta): Considerations

*500-1000X strong as Morphine *5-10X strong as Fentanyl *Produce a slowing of heart rate by directly increasing vagal nerve tone in the brainstem

BUTORPHANOL (Stadol): Considerations

*5X strong as Morphine *Analgesic doses of butorphanol produce an increase in pulmonary arterial pressure and in the work of the heart; systemic arterial pressure is slightly decreased *Major side effects of butorphanol are drowsiness, weakness, sweating, feelings of floating, and nausea *While the incidence of psychotomimetic side effects is lower than that with equianalgesic doses of pentazocine, they are qualitatively similar

Aα Fiber: Diameter

*6-22 μm

Aβ Fiber: Diameter

*6-22 μm

VECURONIUM BROMIDE (Norcuron): Metabolism

*60% Liver *40% Renal

CHLOROPROCAINE (Nesacaine): EHL

*7 min

AMITRIPTYLINE (Elavil): Dose

*75 mg PO QD, may increase up to 150-300 mg PO per day

CISATRACURIUM BESYLATE (Nimbex): Metabolism

*75% Hofmann elimination *15% Renal eliminated *Laudanosine metabolite excreted in urine *Unlike Atracurium, "Not" metabolized by enzymatic ester hydrolysis

EDROPHONIUM (Tensilon, Enlon): Metabolism

*75% Renal excretion, although in the absence of renal function, hepatic metabolism accounts for the inactivation of 30%

ROCURONIUM (Zemuron): Metabolism

*80% Liver *20% Renal *Excretion is biliary (50%-70%) & Renal (10-25%)

PANCURONIUM BROMIDE (Pavulon): Metabolism

*85% Renal *15% Liver

PROCAINE (Novocaine): EHL

*9 min

B Fiber: Diameter

*<3 μm

BENZOCAINE (Anbesol, Cepacol, Lanacane, Hurricaine): Dose

*A brief spray of 20% benzocaine delivers the recommended dose of 200 to 300 mg.

What are the chemical structural requirements for a drug to be a local anesthetic?

*A lipophilic end *A hydrophilic end *An intermediate chain which is either an "Este" or an "Amide"

Single Twitch

*A single electrical pulse is delivered at 1 Hz *Requires a baseline before muscle relaxation *The ratio of the evoked twitch is compared with the twitch before muscle relaxation (control twitch) *Gives a crude indication of neuromuscular blockade. If they have any twitch they are not 100% relaxed *Used with depolarizing muscular relaxants *Degree of twitch depression used to calculate level of blockade

Ionotropic glutamate receptors (iGluR) (4):

*AMPA *Kainate *NMDA *Orphin

PHYSOSTIGMINE (Antilirium): Class

*Acetylcholine Inhibitor *Anticholinesterase *Parasympathomimetic *Naturally Occurring Tertiary Amine *Monomethylcarbamate

EDROPHONIUM (Tensilon, Enlon): Class

*Acetylcholine Inhibitor *Anticholinesterase *Parasympathomimetic *Synthetic Quaternary Ammonium Agent

NEOSTIGMINE (Prostigmin, Vagostigmin): Class

*Acetylcholine Inhibitor *Anticholinesterase *Parasympathomimetic *Synthetic Quaternary Ammonium Agent

PYRIDOSTIGMINE (Mestinon, Regonol): Class

*Acetylcholine Inhibitor *Anticholinesterase *Parasympathomimetic *Synthetic Quaternary Ammonium Agent *Dimethylcarbamate

What factors increase the likelihood of local anesthetic systemic toxicity?

*Advanced age *Heart failure *Ischemic heart disease *Conduction abnormalities *Metabolic disease *Liver disease *Low plasma protein concentration *Acidosis *Medications that inhibit sodium channels *Severe cardiac dysfunction with low ejection fraction

Aβ Fiber: Location

*Afferent from skin and joints

How do you treat local anesthetic systemic toxicity

*Airway first *Halt seizures - avoiding large doses of propofol for its cardiac effects, benzodiazepines are primary *Use succinylcholine if there is nothing else *Start ACLS with lower doses of epi *No vasopressin, no calcium channel or beta blockers *Lipid emulsion therapy *Cardiopulmonary bypass

PROPOFOL (Diprivan): Class

*Alkyphenol (2, 6 diisopropylphenol)

Common NMDA receptor antagonists include:

*Amantadine (Symmetrel) *Ketamine *Methoxetamine *Phencyclidine (PCP) *Nitrous oxide *Xenon *Dextromethorphan and dextrorphan *Ethanol *Riluzole (Rilutek)(used in ALS) *Lead (Pb2+)[25]

How do you identify Amide and Ester local anesthetics by their names?

*Amides contain 2 of the letter "I" in their name *Esters have only 1

KETOROLAC (Toradol): Indications

*Analgesic *Antipyretic *Anti-inflammatory

IBUPROFEN (Motrin, Advil): Indications

*Analgesic *Antipyretic *Anti-inflammatory *Rheumatoid arthritis *Osteoarthritis *Acute gouty arthritis *Migraine *Antagonizes Niacin flush *Dysmenorrhea

ACETAMINOPHEN (Tylenol): Indications

*Analgesic *Antipyretic *Migraine

DIAZAPAM (Valium): Indications

*Anxiety, ETOH withdrawal *Status epilepticus *Sedation *Relief of muscle spasms, paraplegia

LORAZEPAM (Ativan): Indications

*Anxiety, ETOH withdrawal *Status epilepticus *Sedation *Relief of muscle spasms, paraplegia

MIDAZOLAM (Versed): Indications

*Anxiety, ETOH withdrawal *Status epilepticus *Sedation *Relief of muscle spasms, paraplegia

Post-tetanic Count

*Apply 5 seconds of 5oHz tetany *Wait 3 seconds, then count eight 1 Hz twitches *Can give an pproximate time until return of response to single twitches *Permits assessment of block too deep for any other techninqu *A Post-tetanic Count (PTC) of 2 by palpation suggests no twitch response for about 20-30 minutes *PTC of 5 about 10-15 minutes

KETAMINE (Ketalar): Class

*Arylcyclohexylamine (Phencyclidine (PCP) derivative)

Current use of anti-AChE agents is limited to four conditions in the periphery:

*Atony of the smooth muscle of the intestinal tract and urinary bladder *glaucoma *myasthenia gravis *reversal of the paralysis of competitive neuromuscular blocking drugs

B Fiber: Function

*Autonomic Function *Vasomotor *Visceromotor *Sudomotor *Pilomotor

METHOHEXITAL SODIUM (Brevital): Class

*Barbiturate (N-methylated oxybarbiturate)

THIOPENTAL SODIUM (Pentothal): Class

*Barbiturate (Thiobarbiturate)

DIAZAPAM (Valium): Class

*Benzodiazepine

LORAZEPAM (Ativan): Class

*Benzodiazepine

MIDAZOLAM (Versed): Class

*Benzodiazepine -Imidazole ring

ROMAZICON (Flumazenil): Class

*Benzodiazepine Antagonist -Imidazole ring

ROMAZICON (Flumazenil): Indications

*Benzodiazepine reversal *Ambien Reversal *β-carboline Reversal

Remifentanil's ester structure renders it susceptible to hydrolysis by nonspecific plasma and tissue esterases to inactive metabolites. This unique pathway of metabolism imparts to remifentanil:

*Brevity of action *Precise and rapidly titratable effect due to its rapid onset (similar to that of alfentanil) and offset *Noncumulative effects *Rapid recovery after discontinuation of its administration

Although all local anesthetics block the cardiac conduction system through a dose-dependent block of Na+ channels, two features of bupivacaine's Na+-channel blocking abilities may enhance its cardiotoxicity:

*Bupivacaine exhibits a much stronger binding affinity to resting and inactivated Na+ channels than lidocaine. *Local anesthetics bind to Na+ channels during systole and dissociate during diastole. Bupivacaine dissociates from Na+ channels during cardiac diastole much more slowly than lidocaine. Indeed, bupivacaine dissociates so slowly that the duration of diastole at physiologic heart rates (60-180 beats per minute) does not allow enough time for complete recovery of Na+ channels and bupivacaine conduction block accumulate.

BUPRENORPHINE (Buprenex, Subutex, Suboxone, Butrans): Metabolism

*Buprenorphine is metabolized to norbuprenorphine by CYP3A4. *Thus, care should be taken in treating patients who also are taking known inhibitors of CYP3A4 (e.g., azole antifungals, macrolide antibiotics, and HIV protease inhibitors), as well as drugs that induce CYP3A4 activity (e.g., certain anticonvulsants and rifampin). *Both N-dealkylated and conjugated metabolites are detected in the urine (10-30%), but most of the drug is excreted unchanged in the feces (70-90%).

DIAZAPAM (Valium): Considerations

*Burns on injection *May induce ALA synthetase activity precipitating an acute porphyria attack

TETRACAINE (Pontocaine): Spinal Dose

*C-Section: 8mg *Abdominal Surgery: <5'6": 12mg 5'6"-6': 15mg >6": 18mg

LIDOCAINE (Xylocaine): Considerations

*CES *TNS *Most potent vasodilator *Metabolites can accumulate in liver disease causing toxicity

ACETAMINOPHEN (Tylenol): Class

*COX Inhibitor

KETOROLAC (Toradol): MOA

*COX Inhibitor *Inhibition of cyclooxygenase (COX) activity resulting in a decrease in the peripheral synthesis of prostaglandins. This inhibition of prostaglandins decreases the inflammatory response to surgical trauma and peripheral nociception and pain perception

IBUPROFEN (Motrin, Advil): MOA

*COX Inhibitor (equipotent of COX-1 & COX-2) *Inhibition of cyclooxygenase (COX) activity resulting in a decrease in the peripheral synthesis of prostaglandins. This inhibition of prostaglandins decreases the inflammatory response to surgical trauma and peripheral nociception and pain perception

ACETAMINOPHEN (Tylenol): MOA

*COX Inhibitor (highly selective for COX-2) *Inhibition of cyclooxygenase (COX) activity resulting in a decrease in the peripheral synthesis of prostaglandins. This inhibition of prostaglandins decreases the inflammatory response to surgical trauma and peripheral nociception and pain perception

ETOMIDATE (Amidate): Class

*Carboxylated Imidazole derivative

LIDOCAINE (Xylocaine): Dose

*Cardiac: 1-1.5mg/kg *Infusion: 1-4mg/min *PNB: 4mg/kg, 7mg/kg w/epi *Epi: 4mg/kg *SAB: 1.5mg/kg *Bier Block: 200mg in 10-40ml (0.5%, 1% or 2%)

Esters: Metabolism

*Catalyzed by plasma and tissue cholinesterase via hydrolysis - it occurs throughout the body and is rapid

KETAMINE (Ketalar): Physiologic Effects

*Causes mydriasis, nystagmus, salivation, lacrimation, and increased skeletal muscle tone after administration *↑HR, SV, DBP, SVR, LVEDP, PAP, RAP, cardiac O2 requirements *Great for hypovolemic patients or patients who can not endure big drop in pressure *BAD for CAD pts because of negative balance between myocardial oxygen supply and demand- propofol or midazolam can attenuate the cardiovascular effects if given prior *Potent analgesic *DOC for active bronchospasm = bronchodilates *Beneficial d/t minimal depressant effects on respiratory rate and airway skeletal muscle tone, pharyngeal and laryngeal reflexes *Can cause apnea w/ induction and increased secretions usually require glycopyrrolate *Avoid atropine or droperidol because they act centrally on the brain and increase SNS activity by blocking the PNS *Myoclonic activity after induction **CNS depression w/ undesirable psychological reactions, which occur during awakening- termed emergence reactions. Occurs in 5-30% of patients and is dose dependent at >2mg/kg. Occur about 1 hour after emergence. Common manifestations of these reactions, which vary in severity and classification, are vivid dreaming, extracorporeal experiences & illusions *Using versed pre-op may block the effects *Subsequent doses usually diminished this problem and you see it more in children, women, and people with a hx of nightmares *Administration of ketamine can prevent hyperalgesia with opioids, which is thought to be due to NMDA activation and spinal sensitization to glutamate and substance p.

PHYSOSTIGMINE (Antilirium): Indications

*Central Anticholinergic Syndrome (CAS) *Glaucoma *Postoperative shivering *Alzheimer's disease *Delayed gastric emptying. *Orthostatic hypotension *Central nervous system effects of atropine, scopolamine and other anticholinergic drug overdoses. *Antidote of choice for Datura stramonium & Atropa belladonna poisoning *Antidote for GHB poisoning *May reverse delirium in babiturate overdose

Antagonism of neuromuscular blockade by anticholinesterase drugs may be inhibited or even prevented by:

*Certain antibiotics *Hypothermia *Respiratory acidosis associated with a PaCO2 of > 50 mm Hg *Hypokalemia and metabolic acidosis

METHADONE (Dolophine): Indications

*Chronic pain *Tx of opioid abstinence syndromes *Tx of heroin users

GABAPENTIN (Neurontin): Class

*Cyclic Analog of GABA

LGICs are classified into three superfamilies which lack evolutionary relationship:

*Cys-loop receptors *Ionotropic glutamate receptors (iGluR) *ATP-gated channels

All three subtypes of the α2-AR share the same signaling pathways in native cells:

*Decrease in adenylyl cyclase activity *Suppression of voltage-gated Ca++ currents *Activation of receptor-operated K+ currents and MAP kinase activity

THIOPENTAL SODIUM (Pentothal): Considerations

*Decreased CBF, CMRO2 and ICP, without compromising CPP *Hypotension d/t peripheral vasodilation w/ reflex tachycardia. There is a decrease in contractility and CO. Mild, transient BP reductions in euvolemia, but decreased CO, systemic vascular resistance, and PVR if hypovolemic = decreased preload in shock patient could lead to death *Liver enzyme induction and decreased hepatic blood flow, but usually only w/ sustained drug delivery (2-7 days) *Anticonvulsant activity *Acute tolerance occurs quickly R/T liver enzyme induction and may require doses up to 6x higher. Physical dependence can occur w/ sustained infusions *Dose dependent resp depression w/ decreased response to hypercarbia and hypoxemia *Airway reflexes intact with smaller doses, but apnea with large doses. Salivation requires treatment *Decreases IOP *Stimulates the release of histamine and may cause allergic rxns *Hang-over, tiredness, N/V, some pain on injection *ASA and coumadin will potentiate thiopental as they compete for the metabolic binding sites *Prolonged elimination in obese *May have anti-analgesic effects

PROPOFOL (Diprivan): Considerations

*Decreases CMRO2, ICP, and CBF.; however also decreases MAP and there for CPP (head injured patients are at risk for hypoperfusion. Decreases IOP) *Myoclonic activity after induction, but has anticonvulsant properties *Dose dependent resp depression *Some bronchodilatory effects *Decreases responsiveness to hypoxia and hypercarbia with a concomitant decrease in pH and increase in PaCO2 *Mild attenuation of HPV *25- 40% decrease in ABP & SVR w/ peripheral arterial and venous dilation causing profound hypotension. There is no reflex bradycardia due to baroreceptor inhibition *Pain on injection very common. Use large IV and vein w/ 1% lidocaine and open fluids *Supports bacterial growth so discard after 6 hours *Propofol infusion syndrome is a rare but lethal syndrome associated with infusion of propofol at 4 mg/kg/hr or more for 48 hours or longer. Rhabdo, hypoxemia, hyperlipidemia, metabolic acidosis, and fatty liver are signs *Agent of choice in suspected malignant hyperthermia *Anti-emetic properties (DOC if high hx of PONV) *Direct suppression of SNS w/ reports of bradycardia and asystole after induction - pre-hydrate to avoid *Prolonged infusions w/ green urine (phenols) and increased uric acid excretion and crystallization in the urine. May see cloudy urine at low pH *Treats opioid induced pruritus and nausea at 10mg w/o reversing analgesia.

SUCCINYLCHOLINE (Anectine, Quelicin): Class

*Depolarizing Agent

Why do we need neuromuscular monitoring?

*Determination of the exact point for intubation *Intraoperative titration of muscle relaxants *determining the exact point for extubation *avoid reversal of muscle relaxants *avoid residual neuromuscular block *avoid possible post operative complications *reduce cost (OR time and medications)

LA Neuroaxial MOA:

*Diffuses through the axolemma, across the dura in an uncharged form to act on nerve roots and the spinal cord. Once inside the neuron, where the pH is lower, the drug becomes protonated and binds to the Na+ channel on the cytoplasm side. It blocks initiation and transmission of nerve impulses by inhibiting passage of sodium ions through inner portion of ion-selective sodium channels in nerve membranes. Inhibition of sodium permeability slows the rate of depolarization so that threshold potential is not reached.

CATAPRES (Clonidine): Considerations

*Do not withhold prior to surgery d/t rebound HTN *Significant hypotension is more likely in patients with high sympathetic tone such as diabetics, the elderly, and those with hypovolemia. *Benefits include anesthesia include preoperative sedation and anxiolysis, drying of secretions (antisialagogue effects), and analgesia *Antishivering effects (α2B)

CARBAMAZEPINE (Tegretol, Equetro): Dose

*Dosing starts at 100 mg PO BID and is increased up to 400-800 mg/day

CATAPRES (Clonidine): Side effects

*Dry mouth *Sedation *Bradycardia *Sexual dysfunction

Protein Binding best indicates...

*Duration of Action

Endogenous Ligand: Kappa (κ)

*Dynorphin

PANCURONIUM BROMIDE (Pavulon): Dose/ED95

*ED95: 0.05mg/kg *Intubating Dose (X ED95): 1-1.5

VECURONIUM BROMIDE (Norcuron): Dose/ED95

*ED95: 0.05mg/kg *Intubating Dose (X ED95): 2-4

CISATRACURIUM BESYLATE (Nimbex): Dose/ED95

*ED95: 0.05mg/kg *Intubating Dose (X ED95): 3-5

ATRACURIUM BESYLATE (Tracrium): Dose/ED95

*ED95: 0.25mg/kg *Intubating Dose (X ED95): 2

ROCURONIUM (Zemuron): Dose/ED95

*ED95: 0.3mg/kg *Intubating Dose (X ED95): 2-4

SUCCINYLCHOLINE (Anectine, Quelicin): Dose/ED95

*ED95: 0.3mg/kg *Intubating Dose (X ED95): 3-5 *Adult: 1-1.5mg/kg *Pediatric: 1-2mg/kg IV and IM: 4mg/kg *Infants: 2-3mg/kg IV *Laryngospasm: 0.1-0.5mg/kg IV or 4-6mg/kg IM *Dosing: TBW

Aγ Fiber: Location

*Efferent to muscle spindles

Aα Fiber: Location

*Efferent to muscles

SUCCINYLCHOLINE (Anectine, Quelicin): Contraindications/Precautions

*Elevated serum potassium levels & cardiac arrest - burns, crush injuries, de-enervation, immobility, spinal cord transections, stroke, trauma, upper motor neuron injury due to up-regulation of extra-junctional receptors, which are very sensitive to succ *<10 y/o *Personal/familial MH *Myopathies, elevated CPK, narrow angle glaucoma, penetrating eye injuries *Atypical pseudocholinesterase patients *Myotonia is an abnormal delay in relaxation after contraction and the use of Succ will result in difficult ventilating conditions so it should be avoided *Echothiophate & Isoflurophate drops (glaucoma) because it depresses plasma cholinesterase activity and inhibits acetylcholinesterase

Nerve axons are further organized within three layers of connective tissue:

*Endoneurium *Perineurium *Epineurium

NALBUPHINE (Nubain): Considerations

*Equipotent to Morphine 1:1 *Less likely to produce dysphoric side effects than is pentazocine *Depresses respiration as much as do equianalgesic doses of morphine; however, exhibits a ceiling effect such that increases in dosage beyond 30 mg produce no further respiratory depression as well as no further analgesia *Does not produce an increase in cardiac index, pulmonary arterial pressure, or cardiac work, and systemic blood pressure

Order of Paralysis for NMB

*Eyes *Extremities *Trunk (from neck down through intercostals) *Abdominal muscles *Diaphragm

CHLOROPROCAINE (Nesacaine): Considerations

*Fast onset *Fast offset *Lowest PB *Neurotoxic with SAB

Aδ Fibers: General

*Fast/Sharp Pain *Synapse at Rexed lamina 1 & 5 *First order neurons form A-delta fibers communicate with second order neuron in Rexed lamina 1 & 5. *The major neurotransmitter released from A-delta fibers is Glutamate which binds to AMPA receptors on the post synaptic membrane of A-delta interneurons.

The ketorolac package insert advises the following intravenous dosing protocol:

*For a single dose, 30 mg IV or 15 mg if patient age is greater than 65 or body weight less than 50 kg. *For multiple dosing, patients should be commenced on 30 mg q6 hrs, not to exceed 120 mg in a 24-hour period; in those older than 65 yrs or weighing less than 50 kg, the dosing should be 15 mg every 6 hrs, not to exceed 60 mg in 24 hrs. *In no circumstance should dosing go beyond 5 days of therapy.

GABAPENTIN (Neurontin): MOA

*G Protein-Coupled Receptor *Ion Channel Gated Ion *Ca2+ Channel Antagonist *NMDA Receptor Inhibitor *Alpha2 Adrenergic Receptor Agonist *Adenosine A1 Receptor Agonist *Analgesic effects may be related to calcium influx inhibition as well as inhibition of the release of excitatory neurotransmitters in spinal and supraspinal pathways *Interacts with voltage-sensitive calcium channels in cortical neurons. *Increases the synaptic concentration of GABA, enhances GABA responses at non-synaptic sites in neuronal tissues, and reduces the release of mono-amine neurotransmitters *Reduction of the axon excitability measured as an amplitude change of the presynaptic fibre volley (FV) in the CA1 area of the hippocampus

CATAPRES (Clonidine): MOA

*G-protein coupled receptors *α2 Receptor Agonist *α1 Receptor Agonist *I1 (Imidazoline) Receptor agonist *α2:α1-receptor affinity of 220:1

PRECEDEX (Dexmedetomidine): MOA

*G-protein coupled receptors *α2 Receptor Agonist *α1 Receptor Agonist *α2:α1-receptor affinity of 1620:1 *Acts presynaptically and postsynaptically *Leads to hyperpolarization via K+ influx with a subsequent decrease in neuronal firing as well as reduced norepinephrine release mediated by inhibitory presynaptic autoreceptors. It also decreases cAMP concentration by inhibiting adenylyl cyclase. *Decreases sympathetic tone by inhibition of Ca2+ influx in locus ceruleus neurons *Sedative effects are produced by actions in the "locus ceruleus"

Anionic Cys-loop Receptors (2):

*GABAA *Glycine (GlyR)

Signs of Recovery from Neuromuscular Blockers

*Good TV and RR *Resp. smooth and unlabored *Opens eyes widely *Sustained protrusion and purposeful movement of tongue *Swallows effectively *Head lift for 5 seconds *Strong/constant hand grip *effective cough *VC of 15mml/kg *Inspiratory force of 25-30cm H2O *Sustained tet response to 50Hz for 5 sec *TOFR >0.9 w/o fade *No fade to double burst stimulation (DBS)

G-proteins: The α subunit may be "Stimulatory" or "Inhibitory"...

*Gsα stimulates adenylate cyclase and increases cyclic AMP production *Giα decreases cyclic AMP production.

AMITRIPTYLINE (Elavil): HL

*HL: 22 hrs (26 hr for active metabolite, nortriptyline)

NALBUPHINE (Nubain): Half-life

*HL: 3 hrs

CATAPRES (Clonidine): Indications

*HTN *Preoperative sedation and anxiolysis *Tx of diarrhea in diabetics *Differential Dx in pheochromocytoma *Treating and preparing addicted subjects for withdrawal from narcotics, alcohol, and tobacco *Additive for prolongation of regional anesthesia *Other off-label uses are: -Atrial fibrillation -ADHD -Constitutional growth delay in children -Cyclosporine-associated nephrotoxicity -Tourette's syndrome -Hyperhidrosis -Mania -Posthepatic neuralgia -Psychosis -Restless leg syndrome -Ulcerative colitis -Allergy-induced inflammatory reactions in patients with extrinsic asthma

KETOROLAC (Toradol): Metabolism

*Hepatic *Metabolized principally by glucuronic acid conjugation. *Renal excretion (40% as metabolites and 60% unchanged)

HYDROMORPHONE (Dilaudid): Metabolism

*Hepatic *Metabolized to Hydromorphone-3-Glucoronide which is potentially neurotoxic in high doses (may accumulate in renal failure)=dose not have any analgesic properties *Renal excretion

MEPERIDINE (Demerol): Metabolism

*Hepatic 90% *Hydrolyzed to meperidinic acid, which in turn is partially conjugated. *Also N-demethylated to normeperidine, which then may be hydrolyzed to normeperidinic acid and subsequently conjugated. *Active metabolite normeperidine (which has HL of 15-20hrs) *First pass pulmonary uptake exceeds 65% of first dose *Excreted in urine

MEPIVICAINE (Carbocaine, Polocaine): Metabolism

*Hepatic Metabolism *Renal excretion

PRILOCAINE (Citanest): Metabolism

*Hepatic Metabolism *Renal excretion

METHOHEXITAL SODIUM (Brevital): Metabolism

*Hepatic Metabolism *Renal excretion of inactive metabolites

ACETAMINOPHEN (Tylenol): Metabolism

*Hepatic Metabolism (>90%) *3 metabolic pathways are notable: *Glucuronidation in 40-66% *Sulfation (sulfate conjugation) in 20-40% *N-hydroxylation and rearrangement, then GSH conjugation, accounts for less than 15%. P450 (CYP2E1, CYP1A2 & CYP2D6) metabolism forms a minor yet significant alkylating metabolite known as NAPQI (N-acetyl-p-benzo-quinone imine)(also known as N-acetylimidoquinone). NAPQI is then irreversibly conjugated with the sulfhydryl groups of glutathione. *Renal Excretion

CARBAMAZEPINE (Tegretol, Equetro): Metabolism

*Hepatic P45, CYP3A4, to active epoxide form (carbamazepine-10,11 epoxide) *Excretion via Renal (70%) and Feces (30%)

IBUPROFEN (Motrin, Advil): Metabolism

*Hepatic P450, CYP2C9 *90% is metabolized to hydroxylate or carboxylate derivatives *Renal excretion of metabolites

CODEINE: Metabolism

*Hepatic P450, CYP2D6 *Metabolized in part by O-demethylation into morphine, a metabolic process mediated by the liver P450 isoform CYP2D6. *Patients who lack CYP2D6 because of deletion, frame shift, or splice mutations (approximately 10% of the Caucasian population) or whose CYP2D6 is inhibited (e.g., patients taking quinidine) do not respond normally to codeine even though they exhibit a normal response to morphine. *Effective orally d/t decreased 1st pass metabolism *Conversely, certain ethnic groups (e.g., Ethiopians) carry frequently duplicated, functional CYP2D6 genes, resulting in the ultra rapid conversion of codeine to morphine, and are thought to be particularly susceptible to the effects of codeine. *Renal Excretion **Prodrug to "Morphine" (10%) and "Hydrocodone" (1%)

AMITRIPTYLINE (Elavil): Metabolism

*Hepatic P450, CYP2D6 *Renal Excretion

OXYCODONE: Metabolism

*Hepatic P450, CYP2D6 & CYP3A *Oxidized to Oxymorphone by CYP2D6 and N-demethylated by CYP3A to norOxycodone. *Effective orally d/t decreased 1st pass metabolism *Renal (and sweat) excretion of drug and metabolites **Prodrug to "Oxymorphone"

HYDROCODONE: Metabolism

*Hepatic P450, CYP2D6 & CYP3A4 *Metabolized by CYP2D6 to Hydromorphone *A major metabolite, norhydrocodone, is predominantly formed by CYP3A4-catalyzed oxidation *Renal excretion of drug and metabolites *Prodrug to "Hydromorphone"

ALFENTANIL (Alfenta): Metabolism

*Hepatic P450, CYP3A4 *Alfentanil is metabolized predominantly by two independent pathways: -Piperidine N-dealkylation to noralfentanil -Amide N-dealkylation to N-phenylpropionamide *10% pulmonary first-pass uptake *Noralfentanil is the major metabolite recovered in urine, with < 0.5% of an administered dose of alfentanil being excreted unchanged. *Efficiency of hepatic metabolism is emphasized by clearance of about 96% of alfentanil from the plasma within 60 minutes of its administration.

SUFENTANIL (Sufenta): Metabolism

*Hepatic P450, CYP3A4 *Significant 1st pass lungs, hepatic extractions *Weak active metabolite *Excretion of metabolites in urine and feces

FENTANYL (Sublimaze): Metabolism

*Hepatic P450, CYP3A4 *n-demethylation to norfentanil *75% First pass pulmonary uptake *Excreted in urine (metabolites), less than 10% unchanged

METHADONE (Dolophine): Metabolism

*Hepatic P450, CYP3A4 as well as CYP2B6, CYP2D6, CYP1A2 & CYP2C19 *Undergoes extensive biotransformation in the liver *A substrate for the P-Glycoprotein efflux protein in intestine and brain *Bioavailability and elimination half-life of methadone is subject to substantial inter-individual variability *N-demethylation and cyclization to form pyrrolidines and pyrroline, are excreted in the urine and the bile along with small amounts of unchanged drug. *Amount of methadone excreted in the urine is increased when the urine is acidified.

LORAZEPAM (Ativan): Metabolism

*Hepatic conjugation with glucuronic acid, inactive metabolites *Renal excretion, 80% unchanged in urine *d/t less hepatic metabolism, may be safe in liver failure

KETAMINE (Ketalar): Metabolism

*Hepatic cytochrome P450 enzymes (especially CYP3A4) metabolize ketamine to norketamine by N-methylation in a perfusion-limited manner. *norketamine is 1/3 as potent as Ketamine *These products are conjugated to water-soluble glucuronide derivatives and are excreted in the urine *Renal >90%, but less than 4% unchanged

TRAMADOL (Ultram): Metabolism

*Hepatic demethylation and glucuronidation via: -CYP2D6 -CYP3A4 -Conjugation with subsequent renal excretion (90%). *The rate of formation of the active metabolite is dependent on CYP2D6 and therefore is subject to both metabolic induction and inhibition.

ROMAZICON (Flumazenil): Metabolism

*Hepatic metabolism by microsomal enzymes to inactive metabolites *Renal excretion, 90% in urine unchanged

DIAZAPAM (Valium): Metabolism

*Hepatic using an oxidative pathway of N-demethylation. The two principal metabolites of diazepam are desmethyldiazepam and oxazepam, with a lesser amount metabolized to temazepam *Renal excretion of metabolites *CYP3A4-5, CYP1A2 and CYP2C19

MORPHINE: Metabolism

*Hepatic via glucuronidation by phase II metabolism enzyme UDP-glucuronosyl transferase-2B7 (UGT2B7) *Morphine-6-glucoronide (can produce its own resp depression & analgesia) - adjust dose for renal pts *Morphine-3-glucoronide (Relatively benign, can produce CNS excitatory effects...ie. Clonus, Seizures) *Metabolites excreted in urine

MIDAZOLAM (Versed): Metabolism

*Hepatic: Extensive hydroxylation by cytochrome P-450/CYP3A4-5 to 1-hydroxymidazolam, >50% 1st pass *Affected by changes in hepatic blood flow and drugs that alter cytochrome P-450A *Renal excretion *Not altered by renal failure.

THIOPENTAL SODIUM (Pentothal): Metabolism

*Hepatic: Oxidative metabolism to hydroxythiopental and carboxylic acid in the liver *Slow metabolism related to redistribution and its high affinity for adipose tissue *30% of the dose remains in 24 hours

NALOXONE (Narcan): Metabolism

*Hepatic: metabolized in the liver primarily by conjugation with glucuronic acid to form naloxone-3-glucuronide; other metabolites are produced in small amounts. *Renal excretion

SUCCINYLCHOLINE (Anectine, Quelicin): Metabolism

*Hepatically metabolized by plasma cholinesterase (pseudocholinesterase, butyrylcholinesterase) before reaching the NMJ and renally excreted *Succinylcholine --> succinylmonocholine + choline (plasma cholinesterase) *Succinylmonocholine --> succinic acid + choline (plasma cholinesterase)

PENTAZOCINE (Talwin): Considerations

*High doses cause an increase in blood pressure and heart rate *Higher doses of pentazocine (60-90 mg) elicit dysphoric and psychotomimetic effects *Does not antagonize the respiratory depression produced by morphine *Ceiling effects for analgesia and respiratory depression are observed at doses above 50-100 mg of pentazocine

BUPIVICAINE (Marcaine, Sensorcaine): Considerations

*Highest risk for cardiotoxicity *Concentrations >0.5% contraindicated in OB *Not for Bier Blocks or trans-art Axillary blocks

MORPHINE: Considerations

*Histamine Release *Morphine-6-glucoronide (can produce its own resp depression & analgesia) - adjust dose for renal pts *Stimulates vasopressin secretion in high doses *Inhibits vasopressin secretion in low doses

ATRACURIUM BESYLATE (Tracrium): Precautions

*Histamine release- avoid in asthmatics, prone to bronchospasm *Laudanosine is a metabolite that can cause CNS excitation and CV disturbances

PHYSOSTIGMINE (Antilirium): Metabolism

*Hydrolyzed by AChE *Mainly by hydrolytic cleavage by plasma esterases *Renal excretion plays only a minor role in its elimination

How is spinal bioavailability of the opioids affected by their ionization?

*Hydrophilic drugs like morphine or dilaudid are less available than lipophilic opioids such as fentanyl or sufentanil

Two types of nonadrenergic imidazoline receptors have been identified:

*I1 receptors in brain *I2 receptors in brain, pancreas, and kidney **A number of the α2 agonists also have activity at I1 receptors.

NALOXONE (Narcan): Dose

*IV/IM/SQ/IL: 0.4-4 mg or 1-4 mcg/kg *Larger doses of 5-20 mg may be needed for specific agents *Pedi: 10 mcg/kg *Infusion:

BUPRENORPHINE (Buprenex, Subutex, Suboxone, Butrans): Dose

*IV/IM: 0.3 mg q6 hrs *SL: 0.4-0.8 mg

BUTORPHANOL (Stadol): Dose

*IV/IM: 1-4 mg q3-4 hrs

NALBUPHINE (Nubain): Dose

*IV/IM: 10 mg q3-6 hrs

PENTAZOCINE (Talwin): Dose

*IV/IM: 30 mg q3-4 hrs

PHYSOSTIGMINE (Antilirium): Dose

*IV: 0.01-0.03 mg/kg *IV: 15-60 mcg/kg for CAS (central anticholinergic syndrome)

NEOSTIGMINE (Prostigmin, Vagostigmin): Dose

*IV: 0.025-0.075 mg/kg

ROMAZICON (Flumazenil): Dose

*IV: 0.2mg (8-15mcg/kg), may repeat 0.1mg q1min to a total dose of 1mg. May give up to 3mg/hr. Consider other causes if 5mg administered w/o effect

HYDROMORPHONE (Dilaudid): Dose

*IV: 0.4-2 mg or 0.01-0.04 mg/kg

ALFENTANIL (Alfenta): Dose

*IV: 0.5-1 mg (aka. 500-1000 mcg)

EDROPHONIUM (Tensilon, Enlon): Dose

*IV: 0.5-1 mg/kg *Tensilon test: 2mg IV, followed 45 sec later by an additional 8mg if the first dose is without effect

REMIFENTANIL (Ultiva): Dose

*IV: 1 mcg/kg *Infusion: 0.05-2 mcg/kg/min

LIDOCAINE (Xylocaine): Onset

*IV: 1 min *PNB: 5 min/1-3 hrs *Epi: 5 min/1-2 hrs *SAB: <5 min/ 30-60 mins

MEPERIDINE (Demerol): Dose

*IV: 12.5-100 mg *Epidural: 25-50mcg, 5-20mg/hr *Spinal: 10mcg

MORPHINE: Dose

*IV: 2-10 mg or 0.1 mg/kg *Epidural: 2-5mg, 0.1-1mg/hr *Spinal: 0.1-0.3mg *PCA: 1mg/ml, bolus 0.5-3 mg Q5-10 min; Infusion 0.5-10 mg; LO 1-2 mg Q10-15 min

SUFENTANIL (Sufenta): Dose

*IV: 2.5-10 mcg *Induction 2.5-25 mcg *Infusion 0.1-0.5 mcg/kg/min *Epidural: 25-50mcg, 10-50mcg/hr *Spinal: 5-10mcg

FENTANYL (Sublimaze): Dose

*IV: 25-100 mcg or 0.5-2 mcg/kg *IV Induction as sole agent: 5-50 mcg/kg *Epidural: 50-100 mcg, 25-100 mcg/hr *Spinal: 10-25 mcg

KETOROLAC (Toradol): Dose

*IV: 30 mg followed by 15 mg q6hrs (60 mg/day max) -1/2 dose if >65 yrs or <50kg *Pedi: 0.5 mg/kg/day one time dose IV

PRECEDEX (Dexmedetomidine): Considerations

*If bolus administered rapidly the peripherally mediated α2B receptors will dominate prior to the centrally acting α2A receptors causing hypertension. Typical hypotensive effects occur as a result of α2A stimulation. *Significant hypotension is more likely in patients with high sympathetic tone such as diabetics, the elderly, and those with hypovolemia. *Infusions longer than 24hrs could be associated with rebound hypertension/withdrawl *Benefits include anesthesia include preoperative sedation and anxiolysis, drying of secretions (antisialagogue effects), and analgesia *Antishivering effects (α2B) *Maintains resp drive *Mimics real sleep more and any other anesthetic

CARBAMAZEPINE (Tegretol, Equetro): Class

*Iminostilbene derivative

CARBAMAZEPINE (Tegretol, Equetro): MOA

*Increases limbic GABAB receptors and has effects on inositol cycling. It has unique effects at peripheral-type benzodiazepine receptors, increases stimulatory G protein alpha subunits (Gsα), and decreases inhibitory G protein subunits (Giα). It appears to lack the effects on GSK-3 and protein kinase C possessed by lithium and valproate. It has anticholinergic, antidiuretic, and muscle relaxant properties.

ETOMIDATE (Amidate): Dose

*Induction: 0.1-0.4mg/kg

METHOHEXITAL SODIUM (Brevital): Dose

*Induction: 1-2mg/kg

KETAMINE (Ketalar): Dose

*Induction: 1-4 mg/kg IV, 4-6 mg/kg IM *Infusion: 15-45 mcg/kg/min (1-3 mg/min)

THIOPENTAL SODIUM (Pentothal): Dose

*Induction: 3-5 mg/kg

2 mechanisms underlying the potent analgesic effects of intrathecally or epidurally applied opioids:

*Inhabition of Ca2+ influx of incoming peripheral sensory neurons and the subsequent spinal release of glutamate and neuropeptides such as substance P *Open G-protein-coupled inwardly rectifying K+ (GIRK) channels and hyperpolarize the membrane

Anticholinesterase agents: mechanism of action

*Inhibiting activity of acetylcholinesterase *More ACh available at NMJ, compete for nAChRs *Actions at mAChRs -bradycarda -hypersecretion -increased intestinal tone

IBUPROFEN (Motrin, Advil): Considerations

*Inhibition of platelet production & aggregation *Bronchospasm in pts with nasal polyps, asthma, & ASA sensitivity (sampter's triad) *Renal toxicity *GI upset

KETOROLAC (Toradol): Considerations

*Inhibition of platelet production & aggregation *Bronchospasm in pts with nasal polyps, asthma, & ASA sensitivity (sampter's triad) *Renal toxicity *GI upset

GABAPENTIN (Neurontin): Dose

*Initial dose: 300 mg PO on day 1, 300 mg PO twice a day on day 2, then 300 mg PO 3 times a day on day 3 *Dose may be titrated up as needed for pain relief to a daily dose of 1800 mg. *Maintenance dose: 900-1800 mg PO in 3 divided doses...up to 3600mg per day may occur

What is the downside to adding bicarbonate sodium to local anesthetics?

*It reduces the onset but can induce hypotension during the administration of epidural anesthesia

What is the onset for local anesthetic toxicity?

*It varies *If under 60 seconds, it implies intravascular injection *If 60-300 seconds, it implies partial intravascular - but can occur up to 30 minutes after injection

Local Anesthetic MOA:

*LA blocks voltage gated NA+ channels. The unionized form of the LA diffuses through the nerve axon into the axolemma. A lower pH inside the neuron/axolemma causes nonionized portion to split into ionized/unionized portions; the ionized portion binds to a receptor on the sodium channel when the channel is in the inactivated state. When the sodium channel is inactivated, action potentials cannot be generated. *2-3 nodes of Ranvier must be blocked to stop nerve conduction *Conduction block is frequency dependent=>the greater the frequency of action potentials, the faster the nerve is blocked by LA and LA must attach to sodium channel when it is in the inactivated/closed (yet open)/absolute refractory state, thus the faster the nerve fires, the more opportunities for LA to catch the sodium channel in inactivated state and sensory fibers fire at greater frequency than motor fibers thus more likely to be blocked; both unionized and ionized forms of the LA are required for conduction block. *Local anesthetics, once bound to the inside of the voltage-gated sodium channel, stabilize and prolong the duration of the inactivated state, thus inhibiting VGSC opening during further depolarization. This inhibits neuronal conduction.

CISATRACURIUM BESYLATE (Nimbex): Precautions

*Laudanosine is a metabolite that can cause CNS excitation and CV disturbances *Some renal elimination that can account for slightly prolonged DOA in renal failure patients

SUCCINYLCHOLINE (Anectine, Quelicin): MOA

*Ligand-gated ion channel *nAChR Agonist (α-subunit) *mAChR Agonist in subsequent doses and in children *Only depolarizing neuromuscular blocking agent **Phase I Block: Binds to the 2 alpha subunits of the post-synaptic nAchR, causing an opening in the center of the rosette and allowing entrance of sodium ions and exit of potassium ions, causing depolarization of the post-junctional membrane at the motor endplate *Not degraded by acetylcholinesterase at the NMJ, so it will continue to bind the alpha subunits rendering the site inactive to further Ach release *Sustained depolarization causes muscle paralysis - essentially a very long refractory period *Inactivation of sodium channels in the junctional and peri-junctional areas, which prevents the propagation of the action potential *No TOF or fade observed because succinylcholine has no effect on the presynaptic receptors that release Ach **Phase II Block: After 7-10mg/kg or 30-60 min, TOF and tetanic fade become evident, indicating overdose. Neostigmine and edrophonium can antagonize this block.

VECURONIUM BROMIDE (Norcuron): MOA

*Ligand-gated ion channel *nAChR Antagonist (Predominately post-junctional, some pre-junctional) *Intermediate acting NMBA *"Competitively" antagonizes/blocks ACh from binding to the motor endplate receptors thus preventing depolarization *Binds to one of the 2 alpha subunits on the Nicotinic Ach post-synaptic receptor, preventing access to the receptor by Ach such that the receptor does not open for the transmission of sodium ions, which blocks the action potential that leads to contraction. Non-depolarizing NMB produce a characteristic TOF and tetanic fade by blocking presynaptic nicotinic Ach receptors, preventing the mobilization of more of the stored Ach vesicles. Onset of action is inversely proportional to potency. Only around 25% of Ach receptors need to be filled to initiate contraction; however, NMB agents must block around 75% of the receptors to stop the impulse so there is a wide margin of safety.

ATRACURIUM BESYLATE (Tracrium): MOA

*Ligand-gated ion channel *nAChR Antagonist (Predominately post-junctional, some pre-junctional) *Intermediate acting NMBA *"Competitively" antagonizes/blocks ACh from binding to the motor endplate receptors thus preventing depolarization *Binds to one of the 2 alpha subunits on the post-synaptic nAchRs, preventing access to the receptor by Ach such that the receptor does not open for the transmission of sodium ions, which blocks the action potential that leads to contraction. Non-depolarizing NMB produce a characteristic TOF and tetanic fade by blocking presynaptic nAchRs, preventing the mobilization of more of the stored Ach vesicles. Onset of action is inversely proportional to potency. Only around 25% of Ach receptors need to be filled to initiate contraction; however, NMB agents must block around 75% of the receptors to stop the impulse so there is a wide margin of safety.

CISATRACURIUM BESYLATE (Nimbex): MOA

*Ligand-gated ion channel *nAChR Antagonist (Predominately post-junctional, some pre-junctional) *Intermediate acting NMBA *"Competitively" antagonizes/blocks ACh from binding to the motor endplate receptors thus preventing depolarization *Binds to one of the 2 alpha subunits on the post-synaptic nAchRs, preventing access to the receptor by Ach such that the receptor does not open for the transmission of sodium ions, which blocks the action potential that leads to contraction. Non-depolarizing NMB produce a characteristic TOF and tetanic fade by blocking presynaptic nAchRs, preventing the mobilization of more of the stored Ach vesicles. Onset of action is inversely proportional to potency. Only around 25% of Ach receptors need to be filled to initiate contraction; however, NMB agents must block around 75% of the receptors to stop the impulse so there is a wide margin of safety.

ROCURONIUM (Zemuron): MOA

*Ligand-gated ion channel *nAChR Antagonist (Predominately post-junctional, some pre-junctional) *mAChR Agonist minimally in cardiac muscle *Intermediate acting NMBA *"Competitively" antagonizes/blocks ACh from binding to the motor endplate receptors thus preventing depolarization *Binds to one of the 2 alpha subunits on the post-synaptic nAchRs, preventing access to the receptor by Ach such that the receptor does not open for the transmission of sodium ions, which blocks the action potential that leads to contraction. Non-depolarizing NMB produce a characteristic TOF and tetanic fade by blocking presynaptic nAchRs, preventing the mobilization of more of the stored Ach vesicles. Onset of action is inversely proportional to potency. Only around 25% of Ach receptors need to be filled to initiate contraction; however, NMB agents must block around 75% of the receptors to stop the impulse so there is a wide margin of safety. *Rapid onset of action similar to succyncholine, but longer duration of action

PANCURONIUM BROMIDE (Pavulon): MOA

*Ligand-gated ion channel *nAChR Antagonist (Predominately post-junctional, some pre-junctional) *mAChR Agonist modestly in cardiac muscle *Long acting NMBA *"Competitively" antagonizes/blocks ACh from binding to the motor endplate receptors thus preventing depolarization *Binds to one of the 2 alpha subunits on the post-synaptic nAchRs, preventing access to the receptor by Ach such that the receptor does not open for the transmission of sodium ions, which blocks the action potential that leads to contraction. Non-depolarizing NMB produce a characteristic TOF and tetanic fade by blocking presynaptic nAchRs, preventing the mobilization of more of the stored Ach vesicles. Onset of action is inversely proportional to potency. Only around 25% of Ach receptors need to be filled to initiate contraction; however, NMB agents must block around 75% of the receptors to stop the impulse so there is a wide margin of safety.

KETAMINE (Ketalar): MOA

*Ligand-gated ion channels *G-protein coupled receptors *NMDA Receptor Antagonist *GABAA Receptor Agonist (weak) *nAChR Antagonist *mAChR Antagonist *Na+ Channel Blocker *µ-opioid Receptor Antagonist *κ-opioid Receptor Agonist *5-HT Receptor Agonist *Monoaminergic Receptors (antinociceptive action may involve descending inhibitory monoaminergic pain pathways). *Depresses function in the cortex and thalamus, while stimulating the limbic system *Produces a functional dissociation between the thalamocortical and limbic systems, a state termed "dissociative anesthesia." *NMDAR antagonism prevents central sensitization and tolerance *mAChR antagonism causes salivation & lacrimation *Depresses transmission in the reticular formation, which affects the affective component of pain

METHOHEXITAL SODIUM (Brevital): MOA

*Ligand-gated ion channels *GABAA Agonist (δ and β subunits are possible sites of action) *AMPA Antagonist *Kainate Antagonist *nAChR Antagonist *Binds to the barbiturate receptor on the GABAA complex and at low concentrations, it enhances the effects of GABA at the GABAA complex *Decreases the rate of dissociation of GABA from the complex and increases the duration of GABA activated chloride channels *Net effect is hyper-polarization of the cell membrane and an increased threshold of excitability *At higher concentration, it directly stimulates the GABAA receptor complex, resulting in barbiturate anesthesia *Depression of the RAS

THIOPENTAL SODIUM (Pentothal): MOA

*Ligand-gated ion channels *GABAA Agonist (δ and β subunits are possible sites of action) *AMPA Antagonist *Kainate Antagonist *nAChR Antagonist *Binds to the barbiturate receptor on the GABAA complex and at low concentrations, it enhances the effects of GABA at the GABAA complex *Decreases the rate of dissociation of GABA from the complex and increases the duration of GABA activated chloride channels *Net effect is hyper-polarization of the cell membrane and an increased threshold of excitability *At higher concentration, it directly stimulates the GABAA receptor complex, resulting in barbiturate anesthesia *Depression of the RAS

PROPOFOL (Diprivan): MOA

*Ligand-gated ion channels *GABAA Receptor Agonist *Glycine Receptor Agonist *NMDA Receptor Antagonist *AMPA Receptor Antagonist *5-HT Receptor Antagonist *GABAA-binds to β subunit, though there is now evidence that α, β, and γ subunits all contribute to GABAA sensitivity to propofol *Binds to the B subunit of the GABAA receptor, enhancing GABA induced chloride currents, inhibiting Ach release in the hippocampus and pre-frontal cortex and hyper-polarizing the cell *Decreases the rate of dissociation of GABA from the GABAA receptor *Possesses ion-channel blocking effects at the cerebral cortex and at the nicotinic Ach receptors *May inhibit NMDA glutamate receptors through modulation of channel gating

DIAZAPAM (Valium): MOA

*Ligand-gated ion channels *GABAA Receptor Agonist (Indirect) *Benzodiazepines do not activate the GABAA receptors by themselves; rather, they promote the binding of the major inhibitory neurotransmitter γ-aminobutyric acid (GABA) to the GABAA subtype of GABA receptors. *Believed to bind at the interface between α and γ subunits

LORAZEPAM (Ativan): MOA

*Ligand-gated ion channels *GABAA Receptor Agonist (Indirect) *Benzodiazepines do not activate the GABAA receptors by themselves; rather, they promote the binding of the major inhibitory neurotransmitter γ-aminobutyric acid (GABA) to the GABAA subtype of GABA receptors. *Believed to bind at the interface between α and γ subunits

MIDAZOLAM (Versed): MOA

*Ligand-gated ion channels *GABAA Receptor Agonist (Indirect) *Benzodiazepines do not activate the GABAA receptors by themselves; rather, they promote the binding of the major inhibitory neurotransmitter γ-aminobutyric acid (GABA) to the GABAA subtype of GABA receptors. *Believed to bind at the interface between α and γ subunits

ETOMIDATE (Amidate): MOA

*Ligand-gated ion channels *GABAA Receptor Agonist (β1 subunit) *Glycine Receptor Agonist *2PK Receptor Agonist *Of all of the clinically used intravenous anesthetics, etomidate exhibits the greatest selectivity for GABAA receptors and has the fewest relevant interactions with other ion channels *Binds to the B subunit of the GABAA receptor, enhancing GABA induced chloride currents, inhibiting Ach release in the hippocampus and pre-frontal cortex and hyper-polarizing the cell *Decreases the rate of dissociation of GABA from the GABAA receptor *Possesses ion-channel blocking effects at the cerebral cortex and at the nicotinic Ach receptors

ROMAZICON (Flumazenil): MOA

*Ligand-gated ion channels *GABAA Receptor Antagonist (Indirect) *Competitive antagonist *Reverses "all" the agonist effects of benzodiazepines in a dose dependent manner *Minimal agonist activity

NEOSTIGMINE (Prostigmin, Vagostigmin): MOA

*Ligand-gated ion channels (for nAChRs) *G-protein coupled receptors (for mAChRs) *nAChR Agonist *mAChR Agonist (effects are prominent) *Primary actions are post-synaptic *Produce "reversible" inhibition of acetylcholinesterase by forming a carbamyl ester complex at the esteratic site of ACh

EDROPHONIUM (Tensilon, Enlon): MOA

*Ligand-gated ion channels (for nAChRs) *G-protein coupled receptors (for mAChRs) *nAChR Agonist *mAChR Agonist (least of of all the anticholinesterases) *Primary actions are presynaptic *Produces "reversible" inhibition of acetylcholinesterase by electrostatic attachment to the anionic site and hydrogen bonding at the esteratic site of the enzyme.

PHYSOSTIGMINE (Antilirium): MOA

*Ligand-gated ion channels (for nAChRs) *G-protein coupled receptors (for mAChRs) *nAChR Agonist *mAChR Agonist (peripheral effects are prominent) *Primary actions are post-synaptic *Produce "reversible" inhibition of acetylcholinesterase by forming a carbamyl ester complex at the esteratic site of ACh *Only anticholinesterase that crosses the blood brain barrier (because the quaternary amine is replaced by a smaller tertiary amine), causes increase in central ACh levels

PYRIDOSTIGMINE (Mestinon, Regonol): MOA

*Ligand-gated ion channels (for nAChRs) *G-protein coupled receptors (for mAChRs) *nAChR Agonist *mAChR Agonist (prominent, yet less than neostigmine) *Primary actions are post-synaptic *Produce "reversible" inhibition of acetylcholinesterase by forming a carbamyl ester complex at the esteratic site of ACh

NALBUPHINE (Nubain): Metabolism

*Liver

PENTAZOCINE (Talwin): Metabolism

*Liver

BUTORPHANOL (Stadol): Metabolism

*Liver *Renal excretion (75%)

PRECEDEX (Dexmedetomidine): Dose

*Loading: 0.5-1 mcg/kg over 10 min *Infusion: 0.2-0.7 mcg/kg/hr, may use as high as 0.1 mcg/kg/hr

EMLA Cream: Class

*Local Anesthetic

ARTICAINE (Septocaine): Class

*Local Anesthetic *Aminoamide

LIDOCAINE (Xylocaine): Class

*Local Anesthetic *Aminoamide

PRILOCAINE (Citanest): Class

*Local Anesthetic *Aminoamide

BUPIVICAINE (Marcaine, Sensorcaine): Class

*Local Anesthetic *Aminoamide -pipecoloxylidide

MEPIVICAINE (Carbocaine, Polocaine): Class

*Local Anesthetic *Aminoamide -pipecoloxylidide

ROPIVICAINE (Naropin): Class

*Local Anesthetic *Aminoamide -pipecoloxylidide

BENZOCAINE (Anbesol, Cepacol, Lanacane): Class

*Local Anesthetic *Aminoester

CHLOROPROCAINE (Nesacaine): Class

*Local Anesthetic *Aminoester

PROCAINE (Novocaine): Class

*Local Anesthetic *Aminoester

TETRACAINE (Pontocaine): Class

*Local Anesthetic *Aminoester

COCAINE: Class

*Local Anesthetic *Aminoester -ester of benzoic acid,

BENZOCAINE (Anbesol, Cepacol, Lanacane, Hurricaine): Class

*Local Anesthetic *Aminoester -the ethyl ester of p-aminobenzoic acid (PABA)

The respiratory depression associated with local anesthetic overdose results in hypoxia and acidosis - what are the CNS implications?

*Local anesthetic accumulation in the fetal circulation is enhanced by the fact that fetal pH is lower than maternal pH. This may result in high fetal levels of local anesthetics

PRECEDEX (Dexmedetomidine): Indications

*MAC anesthetic cases *Adjunct to GA when cardiovascular stability decreased analgesics are desired

KETAMINE (Ketalar): Indications

*MAC anesthetics *GA induction when adrenergic stability or bronchodilation are desired *Chronic Pain *Depression *Bi-polar disorder

MEPERIDINE (Demerol): Contraindications

*MAOI's or within 14 days of use

CHLOROPROCAINE (Nesacaine): Max Dose

*MAX DOSE: 14mg/kg *PNB: 10 mg/kg *EPI: 10 mg/kg

TETRACAINE (Pontocaine): Dose

*MAX DOSE: 1mg/kg

MEPIVICAINE (Carbocaine, Polocaine): Dose

*MAX DOSE: 7mg/kg *PNB: 5 mg/kg *Epi: 5 mg/kg *SAB: 1.5 mg/kg

PRILOCAINE (Citanest): Dose

*MAX DOSE: 8.5mg/kg

TRAMADOL (Ultram): Precautions

*May cause Serotonin Syndrome in pts taking TCA's or SSRI's *Can lower seizure threshold

METHOHEXITAL SODIUM (Brevital): Considerations

*May induce ALA synthetase activity precipitating an acute porphyria attack *Can increase ictal activity, and seizures have been described in patients who received doses sufficient to produce burst suppression of the EEG. This property makes it a good choice for anesthesia in patients who undergo electroconvulsive therapy.

KETAMINE (Ketalar): Contraindications/Precautions

*May induce ALA synthetase activity precipitating an acute porphyria attack *Co-administration with Theophylline will cause seizures *Gluacoma (increases IOP) *Pts who require stable ICP. It increases ICP, CMRO2, CBF, and brain metabolism R/T cerebral vasodilation and sympathimimetic qualities *Pt with ischemic heart disease or who can't tolerate increased myocardial oxygen demand *Pts w/ psychiatric disorders

MIDAZOLAM (Versed): Precautions/Adverse Reactions

*May induce ALA synthetase activity precipitating an acute porphyria attack *HOTN *Tachycardia *Vasovagal *PVCs *Bronchospasms *Laryngospasm *Respiratory depression *Apnea *Euphoria *Delirium *Prolonged emergence *N/V *Salivation *Rash *Puritus, *Pain at injection site.

PROPOFOL (Diprivan): Contraindications/Precautions

*May induce ALA synthetase activity precipitating an acute porphyria attack *Hypersensitivity/allergy to propofol or its components, egg, soybean, soy products *Allergies related to phenyl nucleus and diisoprpyl side chain *Sodium sulfite preparation may cause anaphylaxis *Caution in people with multiple drug allergies *Pt's who can not sustain a large drop in BP *Does not release histamine- only barbiturates do!

ETOMIDATE (Amidate): ETOMIDATE (Amidate): Contraindications/Precautions

*May induce ALA synthetase activity precipitating an acute porphyria attack *Relative contraindications for pts with adrenal insufficiency. *Suppresses adrenal steroid synthesis after a single dose up to 8 hours by inhibiting 11-B hydroxylase, which inhibits ascorbic acid re-synthesis that is necessary for corticosteroid and mineralocorticoid production. The effect is usually very short lived and studies indicate it is not clinically significant, though it should probably be avoided in at risk patients *Avoid in focal epilepsy as it may stimulate seizure activity.

THIOPENTAL SODIUM (Pentothal): Contraindications/Precautions

*May induce ALA synthetase activity precipitating an acute porphyria attack *Respiratory obstruction or an inadequate airway *Severe cardiovascular instability or shock *Status asthmaticus *Porphyria may be precipitated or acute attacks may be accentuated by the administration of thiopental. This is a disorder of the metabolism of the heme precurors, which are toxic when they accumulate. The urine may turn black, HTN, renal dysfunction. Give pre-op versed and hydrate *Hepatic Failure *Intra-arterial injections is BAD - it will vasoconstrict the arteries and causes vasospasm and pain down the arm, blanching of skin with loss of distal pulses, and gangrene. It must be diluted with saline ASAP and treated w/ papaverine (40-80mcg), phentolamine (alpha 1, 2 blocker), lidocaine and heparinization and brachial plexus block

MEPIVICAINE (Carbocaine, Polocaine): Considerations

*May induce ALA synthetase activity resulting in acute porphyria attack *Not used in OB *Lacks vasodilator properties

ROMAZICON (Flumazenil): Considerations

*May precipitate seizures in benzo dependent patients *Caution in concurrent TCA overdose

How does preeclampsia change the accumulation of local anesthetics?

*May result in a greater accumulation of the drug

ACETAMINOPHEN (Tylenol): Considerations

*Metabolite p-aminophenol=nephrotoic *Acetlylcysteine=antioxidant scavenger for OD *Analgesic ceiling at 1000 mg *Contra/Caution in Hepatic disease *May potentiate coumadin

Amides: Metabolism

*Metabolized in the liver by enzymes. A significant blood level may develop.

ETOMIDATE (Amidate): Metabolism

*Metabolized in the liver primarily by hepatic microsomal enzymes and plasma esterases into the corresponding carboxylic acid (ester hydrolysis). *Main metabolite is inactive *Excreted by the kidneys (80%) and Biliary (20%)

Dual opioid and NMDA receptor antagonists:

*Methadone *Dextropropoxyphene *Tramadol *Kratom alkaloids

BENZOCAINE (Anbesol, Cepacol, Lanacane, Hurricaine): Considerations

*Methemoglobinemia

EMLA Cream: Considerations

*Methemoglobinemia

AMITRIPTYLINE (Elavil): Indications

*Migraine prophylaxis *Neuropathic pain disorders *Fibromyalgia *Vulvodynia *Nocturnal enuresis *IBS *ADHD *Pseudobulbar affect *Insomnia *Cyclic vomiting syndrome *Tinnitus *Chronic cough *Interstitial cystitis *Preventive for pts w/ recurring biliary dyskinesia (sphincter of Oddi dysfunction)

Benzylisoquinoliniums

*Mivacurium *cis-atracurium *Atricurium

ROPIVICAINE (Naropin): Considerations

*More motor sparing than Bupivacaine *Less cardiotoxic than Bupivicaine *S Enantiomer *Favored in OB as "walking" epidurals

TETRACAINE (Pontocaine): Considerations

*Most potent *Most Toxic ester LA *No IV injection *Max topical 100 mg *Avoided for PNB

Aα Fiber: Function

*Motor

Aγ Fiber: Function

*Muscle tone

Events associated with up-regulation of nAChRs:

*Myasthenia Gravis *Anticholinesterase overdose *Organophosphate overdose

There are three known mammalian tachykinin receptors termed:

*NK1 *NK2 *NK3

KETOROLAC (Toradol): Class

*NSAID -heteroaryl acetic acid derivative

IBUPROFEN (Motrin, Advil): Class

*NSAID -propionic acid class

PAPAVERINE: Class

*Naturally Occurring Opium Alkaloid (Benzylisoquinoline derivative)

CODEINE: Class

*Naturally Occurring Opium Alkaloid (Phenanthrene Derivative)

MORPHINE: Class

*Naturally Occurring Opium Alkaloid (Phenanthrene Derivative)

GABAPENTIN (Neurontin): Indications

*Neuropathic pain *Epilepsy

REMIFENTANIL (Ultiva): Metabolism

*Non specific plasma esterases (not prolonged in cholinesterase deficiency) *Excreted in urine

PANCURONIUM BROMIDE (Pavulon): Class

*Nondepolarizing Agent (Aminosteroid)

ROCURONIUM (Zemuron): Class

*Nondepolarizing Agent (Aminosteroid)

VECURONIUM BROMIDE (Norcuron): Class

*Nondepolarizing Agent (Aminosteroid)

ATRACURIUM BESYLATE (Tracrium): Class

*Nondepolarizing Agent (Benzylisoquinoline)

CISATRACURIUM BESYLATE (Nimbex): Class

*Nondepolarizing Agent (Benzylisoquinoline)

COCAINE: MOA

*Norepinephrine Reuptake Inhibitor *Dopamine Reuptake Inhibitor *Serotonin Reuptake Inhibitor

GABAPENTIN (Neurontin): Metabolism

*Not appreciably metabolized *Renal excretion-excreted unchanged in the urine with 10% to 23% excretion in the feces.

Acute Porphyria Attack: Treatment

*O2 *Discontinue precipitating agent *Initiate a glucose 10% infusion *Hematin (trade name Panhematin) is the drugs of choice in acute porphyria *Any sign of low blood sodium (hyponatremia) or weakness should be treated as these are signs of impending syndrome of inappropriate antidiuretic hormone (SIADH) or peripheral nervous system involvement that may be localized or severe progressing to bulbar paresis and respiratory paralysis. *Cimetidine has also been reported to be effective for acute porphyric crisis and possibly effective for long term prophylaxis *Pain should be treated as early as medically possible, due to its severity

Anticholinesterases are typically given only once spontaneous recovery of neuromuscular function has begun. Under these circumstances, recovery of neuromuscular transmission is the function of primarily two processes:

*Ongoing spontaneous recovery of neuromuscular function as the NMBA is eliminated from the neuromuscular junction *The increase in acetylcholine at the neuromuscular junction due to the effect of the anticholinesterase

COCAINE: Metabolism

*Only LA that metabolized by both liver and pseudocholinesterase *Hepatic P450, CYP3A4 *Plasma pseudocholinesterase *1% excreted unchanged in the urine *Renal metabolites are benzoylecgonine and ecgonine methyl ester

COCAINE: Considerations

*Only vasoconstrictor, *High PB *SE: HTN, Tachy, coronary vasospasm, V-fib, MI, *Caution with TCAs, EPI, ketamine& Pancuronuim

TRAMADOL (Ultram): Onset/Peak/Half-life/DOA

*Onset: 1 min *Peak: *HL: 5-7 hrs *DOA:

MORPHINE: Onset/Peak/Half-life/DOA (IV)

*Onset: 1 min *Peak: 45-90 min *HL: 2-3hrs *DOA: 4 hrs

BUPRENORPHINE (Buprenex, Subutex, Suboxone, Butrans): Onset/Peak/Half-life/DOA

*Onset: 1 min *Peak: 5 min *HL: 20-75 hrs *DOA:

ROMAZICON (Flumazenil): Onset/Half-life/DOA

*Onset: 1-2 min *HL: 1 hr *DOA: 45-90 min

ROCURONIUM (Zemuron): Onset/Peak/HL/DOA

*Onset: 1-2 min *Peak: 2 min *HL: 70 min *DOA: 30-60min

SUFENTANIL (Sufenta): Onset/Peak/Half-life/DOA

*Onset: 1-3 min *Peak: 3-5 min *HL: 2-4 hrs *DOA: 30-60 min: Dose dependent

OXYCODONE: Onset/Half-life/DOA (PO)

*Onset: 15 min *HL: 4 hrs *DOA: 4 hrs

HYDROCODONE: Onset/Half-life/DOA

*Onset: 15-30 min *HL: 4-6 hrs *DOA: 4-8 hrs

IBUPROFEN (Motrin, Advil): Onset/Peak/DOA/HL

*Onset: 15-30 mins *Peak: 1-2 hrs *DOA: 4-8 hrs *HL: 2 hrs

ETOMIDATE (Amidate): Onset/Peak/Half-life/DOA

*Onset: 15-45 sec *Peak: 1 min *DHL: 2-4 min *EHL: 2-5 hr *DOA: 5-10 min

REMIFENTANIL (Ultiva): Onset/Peak/Half-life/DOA

*Onset: 1min *Peak: 1-2 min *HL: 10 min *DOA: 5-10min

NALOXONE (Narcan): Onset/Half-life/DOA

*Onset: 2 min *HL: 11 hrs *DOA: 20-60min

PENTAZOCINE (Talwin): Onset/Half-life/DOA

*Onset: 2-3mins *HL: 2-3hrs *DOA: 2-3hrs

CISATRACURIUM BESYLATE (Nimbex): Onset/Peak/HL/DOA

*Onset: 2-4 min *Peak: 5 *HL: 22 mins *DOA: 30-60min

CARBAMAZEPINE (Tegretol, Equetro): Onset/Peak/HL

*Onset: 2-4 weeks *Peak: 2-6 weeks *HL: 36 hrs

PANCURONIUM BROMIDE (Pavulon): Onset/HL/DOA

*Onset: 2-4min *HL: 130min *DOA: 60-90min

VECURONIUM BROMIDE (Norcuron): Onset/Peak/HL/DOA

*Onset: 2-4min *Peak: 5 *HL: 70min *DOA: 30-60min

ATRACURIUM BESYLATE (Tracrium): Onset/Peak/HL/DOA

*Onset: 2-4min *Peak: 5 min *HL: 20 min *DOA: 30-60min

PRECEDEX (Dexmedetomidine): Onset/Half-life/DOA

*Onset: 2-5 min *DHL: 6 mins *EHL: 2 hrs *DOA: 1-2 hrs

FENTANYL (Sublimaze): Onset/Peak/Half-life/DOA (IV)

*Onset: 2-5 min *Peak: 3-5 min *HL: 2-6hr *DOA: 30-60min

FENTANYL (Sublimaze): Onset/Half-life/DOA (Epidural)

*Onset: 20-30min *HL: 2-4hrs *DOA: 2-3hrs

THIOPENTAL SODIUM (Pentothal): Onset/Half-life/DOA

*Onset: 30 Sec *Peak: <1 min *DHL: 2-4 min *EHL: 12 hr *DOA: 5-10 min

PROPOFOL (Diprivan): Onset/Peak/Half-life/DOA

*Onset: 30 sec *Peak: 1 min *DHL: 2-4 min *EHL: 2 hr *DOA: 5-10 min

KETAMINE (Ketalar): Onset/Half-life/DOA

*Onset: 30-60 sec **Peak *1 min IV *10-15 min IM *15-30 min PO *DHL: 11-17 min *EHL: 2-3 hr *DOA: 10-15 min

METHADONE (Dolophine): Onset/Half-life/DOA (PO)

*Onset: 30-60min *HL: 15-30hrs *DOA: 6-8hrs

CODEINE: Onset/Half-life/DOA (PO)

*Onset: 30-60min *HL: 4-6hr *DOA: 2.5-3.5hr

SUCCINYLCHOLINE (Anectine, Quelicin): Onset/Peak/HL/DOA

*Onset: 30-60sec *Peak: 1 min *HL: 1-2 min *DOA: 5-10 min

PHYSOSTIGMINE (Antilirium): Onset/DOA/VD

*Onset: 5 min *DOA: 1-2 hrs *VD: 2.4 L/kg *High lipid solubility

NEOSTIGMINE (Prostigmin, Vagostigmin): Dose/Onset/Peak/HL/DOA/VD/PB

*Onset: 5 min *Peak: 10 min *HL: 75 min *DOA: 30-120 min *VD: 0.7 L/kg *PB: 20%

EMLA Cream: Onset/Peak

*Onset: 5 min *Peak: 30-45 mins

MORPHINE: Onset/Half-life/DOA (Epidural)

*Onset: 60-90min *HL: 3-5hrs *DOA: 8-24hrs

MEPERIDINE (Demerol): Onset/Peak/Half-life/DOA (IV)

*Onset: <1 min *Peak: 5-20 min *HL: 3-5 hrs *DOA: 2-4hrs

METHOHEXITAL SODIUM (Brevital): Onset/Half-life/DOA

*Onset: <1min *DHL: 5 min *EHL: 4 hr *DOA: 10-15 min

HYDROMORPHONE (Dilaudid): Onset/Half-life/DOA

*Onset: <1min *Peak: 30-60min *HL: 1-3hr *DOA: 4-5hr

EDROPHONIUM (Tensilon, Enlon): Onset/Peak/HL/DOA/VD

*Onset: <2 min *Peak: 1-5 min *HL: 110 min *DOA: 30-60 min *VD: 1.1 L/KG *Poor lipid solubility

KETOROLAC (Toradol): Onset/Peak/HL

*Onset: IV- 5 mins IM- 20 mins *Peak: 2-3 hrs *HL: 4-6 hrs

COCAINE: Onset/Peak/DOA

*Onset: IV-Immediate Intranasal- *Peak: IV- 5 mins Intranasal- 15 mins *DOA: IV-30 min after peak Intranasal- 60 mins after peak

BUTORPHANOL (Stadol): Onset/Half-life/DOA

*Onset: Immediate *HL: 2.5-3hrs *DOA: 3-4hrs

ALFENTANIL (Alfenta): Onset/Peak/Half-life/DOA

*Onset: Immediate *Peak: 5 min *HL: 1.5 hr *DOA: 1-3 hrs

BENZOCAINE (Anbesol, Cepacol, Lanacane, Hurricaine): Onset/Peak/DOA/HL

*Onset: Rapid *DOA: 30-60 mins

PRILOCAINE (Citanest): Onset/DOA

*PNB: 10 min/1-2 hrs *Spinal: 5 min *Epidural: 5-15 min

BUPIVICAINE (Marcaine, Sensorcaine): Onset/DOA

*PNB: 15 min/4-14 hrs *Epi: 10 min/2-5 hrs *SAB: 5 min/1-6 hrs

ROPIVICAINE (Naropin): Onset/DOA

*PNB: 15 min/5-8 hrs *Epi: 10 min/2-6 hrs *SAB: 5 min

BUPIVICAINE (Marcaine, Sensorcaine): Dose

*PNB: 2.5 mg/kg *Epi: 2 mg/kg *SAB: 0.3 mg/kg

ROPIVICAINE (Naropin): Dose

*PNB: 3.5 mg/kg *Epi: 3 mg/kg

MEPIVICAINE (Carbocaine, Polocaine): Onset/DOA

*PNB: 5 min/2-4 hrs *Epidural: 15 min/1-3 hrs *SAB: 10 min/1-2 hrs

CHLOROPROCAINE (Nesacaine): Onset

*PNB: 5 min/30-60 min *Epi: 5 min/30-60 min

TETRACAINE (Pontocaine): Onset/DOA

*PNB: 7-10 min/1-3 hrs *Spinal: 7-10 min

CATAPRES (Clonidine): Dose

*PO: 0.1-0.6 mg in 2-3 doses *IV: 10 mcg/kg *Shivering: 75 mcg IV

HYDROCODONE: Dose

*PO: 2.5-10 mg -normally mixed with tylenol

METHADONE (Dolophine): Dose

*PO: 20-30 mg starting dose (0.1-0.5 mg/kg) *IV: 20 mg *Epidural: 5mg, 0.3-0.5mg/hr

ACETAMINOPHEN (Tylenol): Dose

*PO: 325-650mg Q 4-6º or 15mg/kg , Max 4 gm/day *Pedi: 10-15 mg/kg q6-8 hrs *PR: 20-60 mg/kg *IV (OFIRMEV ): give over 15 minutes Adults >50 kg: 1000 mg q6 hrs or 650 mg q4 hrs, with a maximum single dose of OFIRMEV of 1000 mg, a minimum dosing interval of 4 hours, and a maximum daily dose of acetaminophen of 4000 mg per day. Adults <50 kg: 15 mg/kg q6 hrs or 12.5 mg/kg q4 hrs, with a maximum single dose of OFIRMEV of 15 mg/kg, a minimum dosing interval of 4 hours, and a maximum daily dose of acetaminophen of 75 mg/kg per day.

IBUPROFEN (Motrin, Advil): Dose

*PO: 400-800 mg QID *Pedi: 7.5-10 mg/kg QID

OXYCODONE: Dose

*PO: 5-30 mg

CODEINE: Indications

*Pain *Cough

HYDROCODONE: Indications

*Pain *Cough

HYDROMORPHONE (Dilaudid): Indications

*Pain *Epidural analgesia *PCA

MEPERIDINE (Demerol): Indications

*Pain *Epidural analgesia *PCA *Shivering/Rigors

Aδ Fiber: Function

*Pain *Temperature *Touch

C Dorsal Root Fiber: Function

*Pain *Temperature *Touch

ETOMIDATE (Amidate): Physiologic Effects

*Pain on injection (85%) due to propylene glycol solution - give in a large catheter in a large vein with fluids wide open and an analgesic *Highest incidence of nausea and vomiting among agents *May cause initial hyperventilation *Apnea usually only occurs in conjunction with opioids and benzos *Ventilatory response to carbon dioxide is diminished. Less depressant effects than thiopental *Myoclonic activity after induction mimics seizure - give opioid or versed to diminish *Decreases ICP, CBF, and cerebral metabolism R/T cerebral vasoconstriction without a decrease in MAP or CPP *Lowers plasma cortisol and depresses the immune response.

OXYCODONE: Indications

*Pain, post-operative, chronic, cancer

Aminosteroids

*Pancuronium *Vercuronium *Rocuronium

PENTAZOCINE (Talwin): MOA

*Partial Mu agonist *Weaker Mu antagonist *Kappa agonist

GABAPENTIN (Neurontin): Peak/HL

*Peak: 1.5-4 hrs *HL: 5-7 hrs

ACETAMINOPHEN (Tylenol): Peak/HL

*Peak: 30-60 mins *HL: 2 hrs

GABAA receptors have the important ability to convey two different types of inhibition within the brain:

*Phasic inhibition involves temporally and spatially precise responses to very brief, high levels of synaptic GABA *Synaptic spillover produces prolonged low levels of GABA in the extrasynaptic space that activate highly sensitive GABAA receptor subtypes, thereby producing a tonic inhibitory current.

Peripheral nerves are covered by a nerve sheath while axial nerves are encased in three layers of meninges:

*Pia matter *Arachnoid *Dura matter

PYRIDOSTIGMINE (Mestinon, Regonol): Metabolism

*Plasma Esterases *25% is metabolized by the hepatic microsomal enzyme system to 3-hydroxy-methyl pyridinium, its major metabolite, and six other minor metabolites. All of these metabolites are excreted in the urine. *Renal excretion, 75% unchanged in urine *use cautiously in renal failure

PROCAINE (Novocaine): Metabolism

*Plasma cholinesterases *Metabolite is PABA

TETRACAINE (Pontocaine): Metabolism

*Plasma cholinesterases *Metabolite is PABA

CHLOROPROCAINE (Nesacaine): Metabolism

*Plasma cholinesterases *Resulting pharmacologically inactive metabolites of chloroprocaine are 2-chloro-aminobenzoic acid and 2-diethylaminoethanol. *Metabolite is PABA

C Sympathetic Fiber: Location

*Postganglionic sympathetic

Lipid Solubility best indicates...

*Potency

PANCURONIUM BROMIDE (Pavulon): Precautions

*Potential for arrhythmias d/t release of catecholemines *Use caution w/ TCA's and Halothane *Caution in CAD and unwanted tachycardia

B Fiber: Location

*Preganglionic sympathetic

How does pregnancy affect the effects of local anesthetics?

*Pregnancy enhances their effect *Due to progesterone's effects on the susceptibility of nerves to conduction blockade and probably partly due to venous dilation

Opioids bind to presynaptic and postsynaptic receptor sites, which selectively blocks transmission of afferent nociceptive stimuli from Aδ and C fibers:

*Presynaptic effects include release of spinal adenosine, which seems to be an important mediator specific for spinally mediated analgesia, as well as inhibition of Ca2+ influx and the subsequent release of glutamate and neuropeptides (such as substance P) from primary afferent terminals *Postsynaptic effects include an increase in K+ conductance, hyperpolarizing ascending second-order projecting neurons without affecting somatosensory or motor evoked potentials

There are two necessary components of LTP:

*Presynaptic glutamate release *Postsynaptic depolarization

CATAPRES (Clonidine): Metabolism

*Primarily in Liver by glucuronidation with a small portion undergoing hydroxylation by CYP2A6. *Undergoes rapid hepatic metabolism involving conjugation, N-methylation, and hydroxylation, followed by conjugation. *Metabolites are excreted in the urine and bile

PRECEDEX (Dexmedetomidine): Metabolism

*Primarily in Liver by glucuronidation with a small portion undergoing hydroxylation by CYP2A6. *Undergoes rapid hepatic metabolism involving conjugation, N-methylation, and hydroxylation, followed by conjugation. *Metabolites are excreted in the urine and bile.

HYDROCODONE: Considerations

*Prodrug (CYP2D6) *1.5 times less potent as oxycodone

CODEINE: Considerations

*Prodrug (CYP2D6) *60% as effective as morphine.

OXYCODONE: Considerations

*Prodrug (CYP2D6) *Accumulation of metabolites during renal failure *1.5 times as potent as Hydrocodone

Using opioids in administration of neuraxial anesthesia does what exactly?

*Produces analgesia without loss of sensation or proprioception *When combined with a local anesthetic it increases block density and allows for lower doses of local anesthetic

METHADONE (Dolophine): Considerations

*Prolongs QTi (females>males)

How does the addition of epinephrine affect local anesthetics?

*Provides a marker for inadvertent intravascular injection *Decreases the rate of vascular absorption *Decreases onset time *Decreases peak concentration *Increases blockade *Increases duration of action *Increases area of blockade

All NSAIDs, including aspirin, can induce hypersensitivity reactions of two general types, both likely related to the inhibition of prostaglandin synthesis:

*Provocation of asthmatic attacks in patients with vasomotor rhinitis and nasal polyposis is likely related to inhibition of normal production of the bronchodilator PGE2. *NSAIDs also rarely induce the syndrome of urticaria and angioedema related to inhibition of prostaglandin effects that normally stabilize histamine stores in mastocytes and inhibit the inflammatory response.

What are the most common side effects of neuraxial opioid administration in obstetrics?

*Pruritus & N/V *Fetal bradycardia and maternal respiratory depression are the most serious complications

NALOXONE (Narcan): Considerations

*Pts on chronic opioid therapy *Pts with cardiovascular disease *Opioid tolerant parturients

PROPOFOL (Diprivan): Metabolism

*Rapidly metabolized in the liver by conjugation to glucuronide and sulfate --> inactive water soluble metabolites *It is excreted by the kidneys, but propofol clearance exceeds hepatic blood flow *The lungs are responsible for 30% of the uptake and first pass elmination *Rapid renal clearance of 75% in first 24 hours

METHOHEXITAL SODIUM (Brevital): Contraindications/Precautions

*Respiratory obstruction or an inadequate airway *Severe cardiovascular instability or shock *Status asthmaticus *Porphyria may be precipitated or acute attacks may be accentuated by the administration of thiopental. This is a disorder of the metabolism of the heme precurors, which are toxic when they accumulate. The urine may turn black, HTN, renal dysfunction. Give pre-op versed and hydrate *Hepatic Failure *Stimulates the release of histamine and may cause allergic rxns *Intra-arterial injections is BAD - it will vasoconstrict the arteries and causes vasospasm and pain down the arm, blanching of skin with loss of distal pulses, and gangrene. It must be diluted with saline ASAP and treated w/ papaverine (40-80mcg), phentolamine (alpha 1, 2 blocker), lidocaine and heparinization and brachial plexus block

NALOXONE (Narcan): Indications

*Reversal of Opioid induced respiratory depression *Reversal of pruritus associated with opioids *Reversal of intraoperative sphincter of oddi spasm *Drug addiction/rehab tx programs

PYRIDOSTIGMINE (Mestinon, Regonol): Indications

*Reversal of the paralysis of competitive neuromuscular blocking drugs *Atony of the smooth muscle of the intestinal tract and urinary bladder *Myasthenia gravis *Combat the effects of curariform drug toxicity *Sometimes is used to treat orthostatic hypotension *May be of benefit in chronic axonal polyneuropathy *Prescribed "off-label" for the postural tachycardia syndrome

NEOSTIGMINE (Prostigmin, Vagostigmin): Indications

*Reversal of the paralysis of competitive neuromuscular blocking drugs *Atony of the smooth muscle of the intestinal tract and urinary bladder *myasthenia gravis

EDROPHONIUM (Tensilon, Enlon): Indications

*Reversal of the paralysis of competitive neuromuscular blocking drugs *Tensilon Test: Used to differentiate myasthenia gravis from cholinergic crisis and Lambert-Eaton myasthenic syndrome

EMLA Cream: Dose

*Roughly 2.5 g of the cream applied over a 25 cm2 area of skin. *Lidocaine 2.5%/Prilocaine 2.5% *Apply 1 hr prior and no longer than 4 hrs

PROCAINE (Novocaine): Onset/DOA

*SAB: 2-5 min/30-60 min

MIDAZOLAM (Versed): Dose

*Sedation: 1.0-2.5mg IV *Induction: 0.1-0.2 mg/kg IV *Anxiolysis: 0.5-5 mg IV *0.5 mg/kg PO kids

BUTORPHANOL (Stadol): Class

*Semi-Synthetic Opioid (Phenanthrene Derivative)

HEROIN: Class

*Semisynthetic Derivative of Opium Alkaloid (Morphine Derivative)

BUPRENORPHINE (Buprenex, Subutex, Suboxone, Butrans): Class

*Semisynthetic Derivative of Opium Alkaloid (Thebaine Derivative)

OXYCODONE: Class

*Semisynthetic Derivative of Opium Alkaloid (Thebaine Derivative)

HYDROMORPHONE (Dilaudid): Class

*Semisynthetic Derivative of Opium Alkaloid -Hydrogenated ketone of Morphine Derivative

HYDROCODONE: Class

*Semisynthetic Opioid Agonist

Aδ Fiber: Location

*Sensory roots and Afferent peripheral nerves

C Dorsal Root Fiber: Location

*Sensory roots and Afferent peripheral nerves

Cationic Cys-loop Receptors (3):

*Serotonin (5-HT) *Nicotinic acetylcholine (nAChR) *Zinc-activated ion channel (ZAC)

What is the mechanism of action of local anesthetics?

*Short answer: Blocks sodium channels *Longer answer: The non-ionized portion which is lipid soluble enters the nerve, reequilibrates and the remaining ionized fraction attaches to the local anesthetic receptor on the inside of the sodium channel.

Patterns of Stimulation

*Single-twitch *Train-of -Four *Tetanic Stimulation *Post-Tetanic Count *Double-burst stimulation

C Fibers: General

*Slow/Chronic Pain *Synapse at Rexed lamina 2 & 3 (Substantia gelatinosa) *First order neurons from C-fibers release the excitatory neurotransmitter substance P (SP) which binds to NK-1 receptors on the postsynaptic membranes of second order neurons in the substantia gelatinosa

pKa best indicates...

*Speed of Onset

What does carbonation do to local anesthetics?

*Speeds the onset and intensity of action of neural blockade - CO2 readily diffuses into the nerve lowering its pH - the lipid form of anesthetic enters the nerve and becomes more ionized, increasing the concentration affecting sodium channels

Events associated with down-regulation of nAChRs:

*Spinal cord injury *CVA *Thermal injury *Prolonged immobility *Prolonged exposure to neuromuscular blocking agents *Multiple Sclerosis *GBS

What is "Tumescent Anesthesia"?

*Subcutaneous injection of dilute local anesthetic with epinephrine with doses of lidocaine from 35 to 55mg/kg which peak in 8 to 12 hours after infusion - used most commonly by plastic surgeons during liposuction. Mostly good outcomes.

Electrodes

*Surface or needle *Small conducting area of 7-8mm *Skin clean & dry *Hand held stimulators do not use electrodes or needles *For HH stimulators clean skin w/ alcohol or skin cleaner, then dry

Tetanic Stimulation

*Sustained burst of pulse at 30,50 or 100Hz *Usually held for around 5 seconds *Used to "kick start" the nerve under deep paralysis *Sustained tetnus >5 sec means <50% of receptors are occupied *Sensititive test

PENTAZOCINE (Talwin): Class

*Synthetic Agonist-Antagonist Opioid (Benzomorphan)

NALBUPHINE (Nubain): Class

*Synthetic Opioid (Morphinan)

METHADONE (Dolophine): Class

*Synthetic Opioid (Phenylheptylamine)

PROPOXYPHENE: Class

*Synthetic Opioid (Phenylheptylamine)

ALFENTANIL (Alfenta): Class

*Synthetic Opioid (Phenylpiperidine)

FENTANYL (Sublimaze): Class

*Synthetic Opioid (Phenylpiperidine)

MEPERIDINE (Demerol): Class

*Synthetic Opioid (Phenylpiperidine)

REMIFENTANIL (Ultiva): Class

*Synthetic Opioid (Phenylpiperidine)

SUFENTANIL (Sufenta): Class

*Synthetic Opioid (Phenylpiperidine)

NALTREXONE: CLASS

*Synthetic Opioid Antagonist (Phenylpiperidine)

NALOXONE (Narcan): Class

*Synthetic Opioid Antagonist (Phenylpiperidine) -Derivative of oxymorphone

Double-burst Stimulation

*TOF on steroids *2 short bursts of 50Hz tetanus 3/4 sec apart *Easier to detect tham with TOF

Aβ Fiber: Function

*Tactile & Proprioception

Is the elimination half-life of amide local anesthetics shorter or longer in a newborn than an adult? Why?

*The elimination half life is longer in the newborn because of a greater volume of distribution

Determinant of LA DOA:

*The greater the protein binding the longer the DOA *Protein bound LA at the site provides a reservoir of LA. As the portion of LA that is not protein bound diffuses away, the protein bound reservoir releases LA to diffuse into the nerve axons. *Lipid solubility also determines DOA. *High lipid solubility = longer DOA d/t more LA bound in reservoir. Local anesthetics that are poorly protein bound have a shorter duration. LA that are highly protein bound have a longer duration. Local blood flow washes the LA from the protein receptor site, so if it clings on stronger (I believe, due to increased lipid solubility), it elicits its effects longer.

Neostigmine should not be used when...

*The intestine or urinary bladder is obstructed *When peritonitis is present *hen the viability of the bowel is doubtful *When bowel dysfunction results from inflammatory bowel disease

What does the pKa of a local anesthetic affect?

*The lower the pKa is the faster the onset *The closer the pKa is to 7.4 the closer it is to being 50% ionized

Determinants of LA potency:

*The more lipid soluble the LA, the greater the potency.

What does the level of protein binding affect?

*The more protein bound a local anesthetic is, the longer the duration of action

Around physiologic pH (7.4), local anesthetics exist in these two forms:

*The positively charged conjugated acid *The unprotonated neutral form ...the ratio described by the Henderson-Hasselbach equation.

Context-Sensitive Half-Time:

*The time required to achieve a 50% decrease in plasma concentration after stopping a continuous, steady-state infusion. *The CSHT is a means of normalizing the pharmacokinetic behavior of drugs so that rational comparisons can be made regarding the predicted offset of drug effect. *The CSHT is thus focused on "Back-End Kinetics"

What is the one sign that a practitioner should look for when assessing for local anesthetic toxicity?

*There isn't one, the initial signs vary considerably and may be CNS or cardiovascular

What happens if you inject local anesthetic into acidotic or infected tissues?

*They are rendered ineffective due to the loss of lipid solubility - that is, they become more ionized and lose their ability to cross nerve membranes

The binding site for local anesthetics is located interior of the ion-selective pore and can be approached via two different pathways:

*Through the pore interior, or hydrophilic pathway *Laterally through the lipid membrane, or hydrophobic pathway When bound, local anesthetics stabilize the inactivated state and prevent further activation. They can also bind in the ion channel pore to prevent ion flux (open-state block).

BENZOCAINE (Anbesol, Cepacol, Lanacane, Hurricaine): Indications

*Topical anesthetic *Procedural Airway anesthesia *Pruritus

EMLA Cream: Indications

*Topically prior to IV starts or blood draws

AMITRIPTYLINE (Elavil): Class

*Tricyclic Antidepressant (TCA)

CARBAMAZEPINE (Tegretol, Equetro): Indications

*Trigeminal neuralgia *Phantom limb syndrome *Complex regional pain syndrome *Paroxysmal extreme pain disorder *Neuromyotonia *Intermittent explosive disorder *Anticonvulsant *Mood-stabilizer *Epilepsy *Bipolar disorder *Borderline personality disorder *ADHD *Schizophrenia *PTSD

Some quick tips on avoiding local anesthetic systemic toxicity

*Use the lowest effective dose *Use incremental injections *Aspirate before injection *Use an intravascular marker such as epinephrine which increases heart rate by about 10 and SBP by about 15 *Ultrasound is recommended but not proven to reduce incidence

PNS- Orbicularis Occuli (Facial Nerve)

*Used for induction *Not quantifiable *Most closely resembles level of blockade at the diaphragm

PNS- Adductor Pollicis (Ulnar Nerve)

*Used for recovery *most common *only look at adduction of the thumb

How does local anesthetics affect uterine tone and blood flow?

*Uterine tone, uterine and umbilical blood flow are unaffected

SUCCINYLCHOLINE (Anectine, Quelicin): VD/PB%

*VD: 0.04 L/kg *PB: Low

IBUPROFEN (Motrin, Advil): VD/PB

*VD: 0.1 L/kg *PB: 99%

CISATRACURIUM BESYLATE (Nimbex): VD/PB

*VD: 0.145 L/kg *PB: Low

KETOROLAC (Toradol): VD/PB

*VD: 0.15 L/kg *PB: 99%

ATRACURIUM BESYLATE (Tracrium): VD/PB

*VD: 0.2 L/kg *PB: Low

VECURONIUM BROMIDE (Norcuron): VD/PB

*VD: 0.25 L/kg *PB: 70%

PANCURONIUM BROMIDE (Pavulon): VD/PB

*VD: 0.25 L/kg *PB: Low

REMIFENTANIL (Ultiva): VD/PB%

*VD: 0.3 L/kg *PB%: 80

ROCURONIUM (Zemuron): VD/PB

*VD: 0.3 L/kg *PB: 30%

ALFENTANIL (Alfenta): VD/PB%

*VD: 0.6 *PB%: 92

GABAPENTIN (Neurontin): VD/PB

*VD: 0.8 L/kg *PB: <3%

ACETAMINOPHEN (Tylenol): VD/PB

*VD: 0.95 L/kg *PB: 20-50%

DIAZAPAM (Valium): VD/PB%

*VD: 1 L/kg *PB%: >95%

LORAZEPAM (Ativan): VD/PB%

*VD: 1 L/kg *PB%: >95%

MIDAZOLAM (Versed): VD/PB%

*VD: 1 L/kg *PB%: >95%

CARBAMAZEPINE (Tegretol, Equetro): VD/PB

*VD: 1 L/kg *PB: 75%

MORPHINE: VD/PB%

*VD: 1-3 L/kg *PB%: 35%

PRECEDEX (Dexmedetomidine): VD/PB%

*VD: 1.5 L/kg *PB%: 95%

AMITRIPTYLINE (Elavil): VD/PB

*VD: 19 L/kg *PB: >95%

CATAPRES (Clonidine): VD/PB%

*VD: 2 L/kg *PB%: 20-40%

NALOXONE (Narcan): VD/PB%

*VD: 2 L/kg *PB%: 50%

PROPOFOL (Diprivan): VD/PB%

*VD: 2-8L/kg *PB%: >95%

OXYCODONE: VD/PB%

*VD: 2.5 L/kg *PB%: 50%

MEPERIDINE (Demerol): VD/PB%

*VD: 2.5 L/kg *PB%: 70%

KETAMINE (Ketalar): VD/PB%

*VD: 2.5-3.5L/kg *PB%: 10%

ETOMIDATE (Amidate): VD/PB%

*VD: 2.5-4.5L/kg *PB%: 75

THIOPENTAL SODIUM (Pentothal): VD/PB%

*VD: 2.5L/kg *PB%: 85%

TRAMADOL (Ultram): VD/PB%

*VD: 2.6 L/kg *PB: 20%

BUPRENORPHINE (Buprenex, Subutex, Suboxone, Butrans): VD/PB%

*VD: 2.8 L/kg *PB: 95%

CODEINE: VD/PB%

*VD: 3 L/Kg *PB: 25%

SUFENTANIL (Sufenta): VD/PB%

*VD: 3 L/kg *PB%: 95

FENTANYL (Sublimaze): VD/PB%

*VD: 4 L/kg *PB%: 85

METHADONE (Dolophine): VD/PB%

*VD: 4 L/kg *PB%: 85%

HYDROCODONE: VD/PB%

*VD: 4 L/kg *PB: 50%

PENTAZOCINE (Talwin): VD/PB%

*VD: 4-8 L/kg *PB: 50%

NALBUPHINE (Nubain): VD/PB%

*VD: 4.8 L/kg *PB: 50%

BUTORPHANOL (Stadol): VD/PB%

*VD: 5 L/kg *PB: 80%

METHOHEXITAL SODIUM (Brevital): VD/PB%

*VD: ~2.5L/kg *PB%: 85%

M3G is inactive, but M6G is an analgesic with a potency rivaling...

morphine. Very high levels of M6G and life-threatening respiratory depression can develop in patients with renal failure.

A metaanalysis found that α2-receptor agonists reduce perioperative cardiac...

mortality and ischemia, a benefit likely attributable to reduced sympathetic outflow and reduced shivering.

GABAA receptors are responsible for...

most inhibitory neurotransmission in the CNS.

The levels of glutamate are 1,000 to 10,000-fold higher than...

most of the other "classical" neurotransmitters, including dopamine, serotonin, norepinephrine, and acetylcholine.

Glutamatergic neurons innervate the gut and influence both...

motility and secretion. Both ionotropic and metabotropic glutamate receptors have been identified in the gut.

Different nerve types show varying susceptibility to nerve block. Clinically, sensory functions are blocked before...

motor function.

An acute porphyria attack results in...

motor, sensory, and autonomic dysfunction by accumulating porphyrinogen. Of particular importance to anesthesia is the potential for many drugs to induce the activity of ALA synthetase.

Butorphanol (a kappa receptor agonist-antagonist) stops shivering more effectively than opioids with a predominant...

mu opioid receptor agonist effect. Evidence for a role of kappa receptors in the antishivering effects of meperidine and butorphanol is the failure of naloxone to completely inhibit this drug-induced effect.

Opioid receptors are classified as...

mu, delta, and kappa receptors (MOR, DOR, and KOR respectively). These opioid receptors belong to a superfamily of guanine (G) protein- coupled receptors that constitute 80% of all known receptors and includes muscarinic, adrenergic, gamma-aminobutyric acid, and somatostatin receptors.

Tetracaine is highly lipid soluble and a significant amount can be absorbed when used in the...

mucous membrane or wounded skin.

Pancuronium has a vagolytic action, presumably from blockade of...

muscarinic receptors, which leads to tachycardia.

Unnecessary administration of anticholinesterases can cause...

muscle weakness. Weakness of the airway dilator muscle genioglossus can lead to upper airway collapse during inspiration. Unnecessary administration of neostigmine (0.03 mg/kg) can also cause diaphragmatic dysfunction.

Meperidine does not cause miosis but rather tends to cause...

mydriasis, reflecting its modest atropine-like actions. A dry mouth and an increase in heart rate are further evidence of the atropine-like effects of meperidine.

Schwann cells produce...

myelin that wraps around the axons to form the myelin sheath.

A and B fibers are...

myelinated

Opioids reduce gastrointestinal motility via receptors in the...

myenteric plexus, and decrease fluid secretion via receptors in the submucosal plexus. Opioids increase sympathetic activity while reducing parasympathetic activity in these regions. Although centrally mediated effects may play a role, gastrointestinal effects are thought to result predominantly from peripheral actions.

Large doses of meperidine result in decreases in...

myocardial contractility, which, among opioids, is unique for this drug.

Nitroglycerin has been used to treat cocaine-induced...

myocardial ischemia.

Nalbuphine is related structurally to...

naloxone and oxymorphone.

Effects such as pruritus and nausea and vomiting are common after epidural and subarachnoid administration of opioids and may also be reversed with...

naloxone if necessary.

It may be necessary to reverse opioid-induced biliary smooth muscle spasm with...

naloxone so as to correctly interpret the cholangiogram.

While tramadol-induced analgesia is not entirely reversible by...

naloxone, tramadol-induced respiratory depression is reversed by naloxone. However, the use of naloxone increases the risk of seizure in patients exposed to tramadol.

Tonic-clonic seizures, occasionally seen as part of the toxic syndrome with meperidine, propoxyphene, and tramadol, are ameliorated by treatment with...

naloxone.

Nausea and vomiting appear to be closely related to the dose and speed of injection of...

naloxone. Administration of naloxone slowly over 2 to 3 minutes rather than as a bolus seems to decrease the incidence of nausea and vomiting. Awakening occurs either before or simultaneously with vomiting, which ensures that the patient's protective upper airway reflexes have returned and the likelihood of pulmonary aspiration is minimized.

Clonidine also is useful in treating and preparing addicted subjects for withdrawal from...

narcotics, alcohol, and tobacco. Clonidine may help ameliorate some of the adverse sympathetic nervous activity associated with withdrawal from these agents, as well as decrease craving for the drug.

Life-threatening bronchospasm may follow the administration of ketorolac to patients with...

nasal polyposis, asthma, and aspirin sensitivity. Cross-tolerance between aspirin and other NSAIDs occurs regularly.

Ibuprofen is relatively contraindicated in individuals with...

nasal polyps, angio-edema, and bronchospastic reactivity to aspirin. Aseptic meningitis (particularly in patients with systemic lupus erythematosus), and fluid retention have been reported.

The sedation produced by dexmedetomidine has been noted to be more akin to...

natural sleep, with patients relatively easy to arouse.

Disadvantages of intrathecal neostigmine to produce analgesia include a high incidence of...

nausea and vomiting, pruritus, and prolongation of sensory and motor block produced by spinal anesthesia.

Despite minimal cardiac and respiratory effects, etomidate does have two major drawbacks. Etomidate has been associated with...

nausea and vomiting. The drug also inhibits adrenal biosynthetic enzymes required for the production of cortisol and some other steroids.

κ-Opioid receptor ligands are also known for their characteristic diuretic effects, due to their ...

negative regulation of antidiuretic hormone (ADH).

After administration of epidural fentanyl or sufentanil to parturients, the concentration of opioid in breast milk is...

negligible.

Edrophonium has approximately one-twelfth the potency of...

neostigmine. Potency increases as spontaneous recovery from neuromuscular block occurs.

Only a very small fraction (1%-2%) of local anesthetic reaches the...

nerve membrane even when placed in close proximity to the nerve.

The common defect of all disorders of the neuromuscular junction is a decrease in the margin of safety for neuromuscular transmission, which can fail at any point from the...

nerve terminal to the muscle endplate or muscle. If the endplate potential fails to reach the threshold for the muscle fiber, an action potential is not generated, the muscle fiber does not contract, and neuromuscular transmission fails.

Naloxone-reversible miosis, nystagmus, and vertigo may occur after...

neuraxial opioids, most commonly morphine.

Favorable pharmacokinetic properties and effects on cerebral blood flow (CBF) and cerebral metabolic requirement for oxygen (CMRO2) have made propofol popular for...

neuroanesthesia. In animal studies, reduction of CBF occurs even when mean arterial blood pressure is held constant, and propofol can reduce ICP even when cerebral perfusion pressure is fixed. Cerebral autoregulation also appears to be preserved in the setting of propofol anesthesia.

High doses of fentanyl can cause...

neuroexcitation and, rarely, seizure-like activity in humans.

The butyrophenone droperidol is used in combination with an opioid, fentanyl, in...

neuroleptanesthesia.

Volatile anesthetics produce dose-dependent enhancement of the magnitude and duration of...

neuromuscular blockade due to nondepolarizing neuromuscular-blocking drugs.

The effects of anticholinesterases are not limited to the motor-endplate. Administration also causes increases in acetylcholine beyond the...

neuromuscular junction. The muscarinic and nicotinic acetylcholine receptors in the parasympathetic system can also be activated, which causes pronounced vagal effects such as bradycardia, prolonged QT-interval, and asystole. Other muscarinic parasympathetic side effects of anticholinesterases include bronchospasm, increased bronchial and pharyngeal secretions, miosis, and increased intestinal tone.

GABA is the primary mediator of...

neuronal inhibition in the brain, as well as being a very important neurotransmitter in the spine and peripheral nervous system.

Botulinum neurotoxin is one of the most potent and lethal substances known and serves as a model for...

neurotoxic action at the NMJ.

A number of naturally occurring toxins act in various ways to inhibit neuromuscular transmission. Botulinum neurotoxin is one of the most potent and lethal substances known and serves as a model for...

neurotoxic action at the NMJ. Botulism is the clinical syndrome caused by the anaerobic gram-positive organism Clostridium botulinum. Seven different serotypes of the organism have been identified, each producing antigenically distinct toxins.

The principal effect of opioid receptor activation is a decrease in...

neurotransmission. This decrease in neurotransmission occurs largely by presynaptic inhibition of neurotransmitter (acetylcholine, dopamine, norepinephrine, substance P) release, although postsynaptic inhibition of evoked activity may also occur.

Although there are several possible routes for glutamate synthesis, it is generally thought that...

neurotransmitter pools of glutamate are generated from glutamine by glutaminase.

The mGluRs are situated on all aspects of the synapse and might be considered sensors of glutamate; they regulate...

neurotransmitter release from the presynaptic nerve terminal, iGluR channel opening, and aspects of astrocytic function.

Alkalinization by sodium bicarbonate addition to local anesthetic solutions increases the pH and shifts the equilibrium in favor of the...

neutral base forms, which facilitates translocation of the local anesthetic into the cellular interior. Once inside the cell, the lower pH shifts the equilibrium toward the positively charged protonated form. The charged form antagonizes Na + channels more potently than the neutral form.

Local anesthetics cross the lipid membrane much faster in their...

neutral lipophilic form than their cationic form.

The use of acetaminophen has been associated anecdotally with...

neutropenia, thrombocytopenia, pancytopenia, hemolytic anemia, and methemoglobinemia.

GABAA receptors are members of the large "Cys-loop" super-family of evolutionarily related and structurally similar ligand-gated ion channels that also includes...

nicotinic acetylcholine receptors, glycine receptors, and the 5HT3 receptor.

Although moderate-dose infusions (> 40 µg/kg/min) can increase triglyceride levels in critically ill patients after just 3 days, low-dose propofol infusions (< 33 µg/kg/min) showed...

no detectable increase in triglycerides after 2 weeks of constant infusion.

Gabapentin is confusingly named because it was originally designed to be a γ-aminobutyric acid (GABA) analogue, but it transpired that it had...

no significant GABA activity; instead, it was involved with voltage gated N-type calcium channels.

Interactions between the κ-receptor and the µ-receptor may be important for modulating...

nociceptive transmission from higher nociceptivecenters, as well as in the spinal cord dorsal horn.

When seen lengthwise, the myelin sheath is punctuated by gaps called...

nodes of Ranvier.

α2-AR trafficking and signaling are tightly regulated by...

non-G protein interacting partners including GPCRs, kinases and scaffolding proteins such as arrestin and spinophilin.

The α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (also known as AMPA receptor, AMPAR, or quisqualate receptor) is a...

non-NMDA-type ionotropic transmembrane receptor for glutamate that mediates fast synaptic transmission in the central nervous system (CNS).

The intravenous NMDA antagonists in current clinical use are primarily channel blockers that bind to the pore only in its open confirmation. They are considered...

non-competitive antagonists and, because their binding requires prior activation by agonist, they are termed use-dependent. Blockers such as ketamine, which remain bound after channel closure, cause prolonged disruption of the associative aspects of neuronal communication. High concentrations of ketamine cause sedation and loss of consciousness with a significant incidence of dysphoric effects.

It is likely that some of the effects from α2-receptor agonists are from actions at...

nonadrenergic imidazoline receptors.

Barbiturate sodium salts require a pH greater than 10 to remain in aqueous solution and precipitate readily when mixed with...

nonbasic solutions such as normal saline. They also precipitate when combined in high concentrations with certain weak bases such as the neuromuscular blockers, forming a "conjugate salt" (e.g., sodium thiopental and rocuronium bromide precipitate to form sodium bromide).

Zn2+ and Cu2+ generally block NMDA current activity in a...

noncompetitive and a voltage-independent manner. However zinc may potentiate or inhibit the current depending on the neural activity.

Inhibition of this presynaptic receptor by NMBAs is primarily competitive, but d-tubocurarine and vecuronium also produce...

noncompetitive inhibition. The effects of blockade on these presynaptic receptors during periods of stress, such as TOF or tetanic stimulation likely accounts for the fade observed in the TOF response with small doses of NMBA, such as those administered before succinylcholine to decrease the incidence and severity of fasciculations of NMBAs.

Disease-induced receptor isoform changes and upregulation of AChRs play a role in the resistance to...

nondepolarizing NMBAs and hyperkalemia in response to SCh.

Prolonged immobility is associated with muscle atrophy due to disuse. Although motor neurons remain intact, immobility results in a relative increase in AChRs. The result is a resistance to...

nondepolarizing NMBAs and increased sensitivity to depolarizing SCh. Resistance to nondepolarizing NMBAs has been reported to emerge as early as 4 days after immobilization and hyperkalemic cardiac arrest after the administration of SCh as early as 5 days after immobilization.

Prolonged block with succinylcholine, based on monitoring of neuromuscular function, appears similar to that of a...

nondepolarizing agent with fade in the TOF response. Administration of an anticholinesterase to facilitate recovery of neuromuscular function is unlikely to be effective because it will also inhibit butyrylcholinesterase, further slowing hydrolysis of the compound.

Patients with LEMS are sensitive to both...

nondepolarizing and depolarizing NMBAs.

Cyclosporine may prolong the duration of neuromuscular blockade produced by...

nondepolarizing neuromuscular-blocking drugs.

The rapid effect-site equilibration characteristic of alfentanil is a result of the low pK of this opioid such that nearly 90% of the drug exists in the...

nonionized form at physiologic pH. It is the nonionized fraction that readily crosses the blood-brain barrier.

Although pancuronium-induced tachycardia is primarily due to a vagolytic action, release of...

norepinephrine from adrenergic nerve endings and blockade of neuronal uptake of norepinephrine may be secondary mechanisms.

Hepatic cytochrome P450 enzymes (especially CYP3A4) metabolize ketamine to...

norketamine by N-methylation in a perfusion-limited manner. Extensive first-pass metabolism leads to less than 20% bioavailability of orally administered ketamine.

Dibucaine, a local anesthetic with an amide linkage, inhibits the activity of...

normal plasma cholinesterase enzyme by approximately 80%, compared with only approximately 20% inhibition of the activity of atypical enzyme. A dibucaine number of 80, which reflects 80% inhibition of enzyme activity, confirms the presence of normal plasma cholinesterase enzyme, whereas approximately 1 in every 3,200 patients is homozygous for an atypical plasma cholinesterase enzyme variant and has a dibucaine number of 20.

When repeated doses of meperidine are given to renal failure patients, the accumulation of...

normeperidine may cause tremor and seizures.

Long-term administration of high doses of thiopental is associated with an increased incidence of...

nosocomial infections and associated mortality. Bone marrow suppression and leukopenia may accompany long-term administration of thiopental to treat increased ICP.

Profound block with a TOF count below 2 should...

not be antagonized by neostigmine because of the risk of inadequate recovery of neuromuscular function.

All patients who receive α2 adrenergic agonist drugs should be warned of the potential danger of discontinuing the drug abruptly, and patients suspected of being noncompliant with medications should...

not be given α2 adrenergic agonists for hypertension.

Whether beta-adrenergic blockade is harmful for coronary vasospasm in the setting of chronic cocaine use is...

not known. Furthermore, administration of beta-blocking drugs in the presence of catecholamine-induced hypertension and tachycardia has been associated with profound cardiovascular collapse and cardiac arrest that is unresponsive to aggressive cardiopulmonary resuscitation. In this situation, administration of a vasodilating drug such as nitroprusside may be the safest intervention.

Anticholinesterases are typically administered in combination with antimuscarinic drugs, such as glycopyrrolate or atropine. These compounds block muscarinic but...

not nicotinic receptors so that neuromuscular block can be antagonized while muscarinic effects are minimized.

The administration of flumazenil to patients being treated with antiepileptic drugs for control of seizure activity is...

not recommended as it could precipitate acute withdrawal seizures

Although toxicity appears to be less than with lidocaine, metabolism of mepivacaine is prolonged in the fetus and newborn and is, therefore...

not used for obstetric anesthesia.

Ketamine's behavioral effects are distinct from those of other anesthetics. The ketamine-induced cataleptic state is accompanied by...

nystagmus with pupillary dilation, salivation, lacrimation, and spontaneous limb movements with increased overall muscle tone.

Urinary excretion of unchanged cocaine (< 1% of the total dose) and metabolites (benzoylecgonine and ecgonine methyl ester representing about 65% of the dose) is similar regardless...

of the route of administration.

Of class A GPCRs, over half of these are predicted to encode...

olfactory receptors while the remaining receptors are liganded by known endogenous compounds or are classified as orphan receptors.

A unique advantage of alfentanil compared with fentanyl and sufentanil is the more rapid...

onset of action (rapid effect-site equilibration) after the IV administration of alfentanil. For example, the effect-site equilibration time for alfentanil is 1.4 minutes compared with 6.8 and 6.2 minutes for fentanyl and sufentanil, respectively

Ketorolac has a rapid...

onset of action and a short duration of action.

Potency is inversely related to onset of neuromuscular block; the more potent a compound, the slower its...

onset of effect. Agents of lower potency are administered at a higher dose providing a higher concentration, and therefore a greater driving force for diffusion down their concentration gradient to the acetylcholine receptors of the neuromuscular junction.

Alkalinization of local anesthetic solutions shortens the...

onset of neural blockade, enhances the depth of sensory and motor blockade, and increases the spread of epidural blockade.

The incidence of opioid-induced skeletal muscle rigidity (generalized hypertonus of skeletal muscles) depends on the...

opioid (most common with fentanyl) and dose used and the rate of administration. Inhibition of striatal release of gamma-aminobutyric acid and increased dopamine production are the likely explanations for opioid-induced increased skeletal muscle tone.

It is assumed that increasing opioid receptor occupancy parallels...

opioid effects.

The triad of coma, pinpoint pupils, and depressed respiration strongly suggests...

opioid poisoning. The finding of needle marks suggestive of addiction further supports the diagnosis. Mixed poisonings, however, are not uncommon.

Many of the autonomic symptoms of opioid withdrawal such as nausea, vomiting, cramps, sweating, tachycardia, and hypertension result from the loss of...

opioid suppression of the locus ceruleus system during the abstinence syndrome. Clonidine, acting upon distinct receptors by cellular mechanisms that mimic opioid effects, can alleviate many of the symptoms of opioid withdrawal, but not the generalized aches and opioid craving.

Postoperative analgesic requirements in patients receiving relatively large doses of remifentanil intraoperatively are often surprisingly high suggesting remifentanil may be associated with acute...

opioid tolerance. In addition, delayed hyperalgesia may be produced by acute exposure to large doses of opioids. Tolerance to opioids is pharmacodynamic and tolerance is dose-dependent. Possible mechanisms for tolerance include alterations of the NDMA receptors and its intracellular second messenger systems.

Clonidine, acting upon distinct receptors by cellular mechanisms that mimic opioid effects, can alleviate many of the symptoms of...

opioid withdrawal, but not the generalized aches and opioid craving.

Morphine does not appear to precipitate serotonergic crisis and is perhaps the drug of choice when...

opioids must be used in patients taking MAOIs.

It is likely that ketorolac potentiates the antinociceptive actions of...

opioids.

The majority of patients with LEMS respond to treatment with...

oral 3,4-diaminopyridine, which blocks voltage-gated K + channels, resulting in prolongation of the action potential and increased quantal release. Treatment of the underlying malignancy can also improve the clinical situation.

Echothiophate is the only...

organophosphate anticholinesterase drug used clinically. Other organophosphate anticholinesterase drugs, such as parathion and malathion, are used as insecticides. *These are "Irreversible" inhibitors of AChE

Propionic acid derivatives are as useful as salicylates in treating various forms of arthritis including...

osteoarthritis, rheumatoid arthritis, and acute gouty arthritis.

The enzyme capacity for red blood cell methemoglobin reductase in children <3 months of age can be overloaded when EMLA cream is administered concurrently with...

other methemoglobin-inducing drugs (sulfonamides, acetaminophen, phenytoin, nitroglycerin, nitroprusside). Likewise, EMLA cream should not be used in those rare patients with congenital or idiopathic methemoglobinemia.

Thebaine has little analgesic action but is a precursor of several important 14-OH compounds, such as...

oxycodone and naloxone.

Naloxone is the N-alkyl derivative of...

oxymorphone

Significant differences in the time course of plasma concentrations of oxycodone metabolites occur depending on the CYP2D6 genotype. Individuals with a CYP2D6 polymorphism that results in CYP2D6 deficiency have lower...

oxymorphone levels compared with individuals with genotypes associated with either normal or ultrarapid metabolism. Individuals with genotype-mediated CYP2D6 deficiency still have low but measurable levels of oxymorphone such that other metabolic pathways must be involved when CYP2D6 is either deficient or nonfunctional.

The metabolites of esters include...

p-aminobenzoic acid (PABA), which can occasionally induce allergic reactions.

Henderson-Hasselbach equation:

pH = pKa + log ([A-]/[HA])

Although equipotent to aspirin in inhibiting central prostaglandin synthesis, acetaminophen has no significant peripheral prostaglandin synthetase inhibition and is therefore less useful than NSAIDs for...

painful inflammatory disorders.

Although ketamine does not produce the classic anesthetic state, patients are amnestic and unresponsive to...

painful stimuli. Ketamine produces profound analgesia, a distinct advantage over other parenteral anesthetics.

Vecuronium is the 2-desmethyl derivative of...

pancuronium. The lack of one methyl group at the quaternary ammonium of the 2 position increases its lipid solubility and significantly alters its degree of metabolism.

Morphine, the principal active compound derived from opium, is a benzylisoquinoline alkaloid; the benzylisoquinoline structural backbone is present in many important naturally occurring drugs, including...

papaverine, tubocurarine, and morphine.

The most likely anatomical location for the opioid induced bradycardia is the nucleus ambiguus. Application of opioids in close proximity of the cardiac parasympathetic neurons of the nucleus ambiguus elicits an increase in...

parasympathetic cardiac activity and subsequent bradycardia. Activation of postsynaptic opioid receptors of these neurons reduces inhibitory Ca2+ currents, which subsequently results in increased activity of cardiac parasympathetic neurons.

Edrophonium has been used for terminating attacks of...

paroxysmal supraventricular tachycardia.

Edrophonium has been administered for the diagnosis and management of cardiac dysrhythmias, especially...

paroxysmal supraventricular tachycardias including those due to Wolff-Parkinson-White syndrome. Administration of edrophonium, 5 to 10 mg IV (25 to 30 mg over 30 minutes), produces principally muscarinic effects manifesting as slowing of the heart rate with no effect on ventricular conduction, contractility, or peripheral vascular tone.

Dexmedetomidine is considered a full agonist at the alpha2 receptor, whereas clonidine is a...

partial agonist (ratio of alpha2 to alpha1 activity for clonidine is 220:1)

Because there is substantial systemic absorption of the fentanyl congeners when injected epidurally, their analgesic effect is...

partially due to a systemic effect.

G protein coupled receptors (GPCRs) are called transmembrane receptors because they...

pass through the cell membrane, and they are called seven-transmembrane receptors because they pass through the cell membrane seven times.

The analgesic properties of ketamine and preservation of respiratory drive are useful for procedures in which it is critical to maintain spontaneous ventilation and preserve airway reflexes. These cases include...

patients with large anterior mediastinal masses who may suffer airway collapse if they become apneic or those patients whose airways must be secured while awake.

Local anesthetics dose-dependently decrease...

peak Na+ current through voltage-gated Na+ channels.

A high tissue affinity is consistent with the lipophilic nature of sufentanil, which permits rapid...

penetration of the blood-brain barrier and onset of CNS effects.

Nicotinic AChRs belong to the cys-loop superfamily of...

pentameric ligand-gated ion channels that share a common architecture, with five subunits surrounding a central ion-conducting pore.

Naloxone reverses the psychotomimetic and dysphoric effects of agonist-antagonist agents such as...

pentazocine, but much higher doses (10-15 mg) are required. The duration of antagonistic effects depends on the dose but usually is 1-4 hours.

Thiopental undergoes some desulfurization to form its parent drug...

pentobarbital. This "metabolite" is likely relevant only to prolonged high-dose administration of thiopental. Both drugs are deactivated by poorly characterized pathways in the liver to form inactive carboxylic acid and alcohol derivatives.

Ketorolac is best avoided in patients with a history of..

peptic ulcer disease or renal impairment.

The μ-receptors exist mostly presynaptically in the...

periaqueductal gray region, and in the superficial dorsal horn of the spinal cord (specifically the substantia gelatinosa of Rolando). *Other areas include the external plexiform layer of the olfactory bulb, the nucleus accumbens, in several layers of the cerebral cortex and in some of the nuclei of the amygdala, as well as the nucleus of the solitary tract.

Under normal circumstances, heme tightly controls its own production by feedback inhibition of the first of the seven enzymes in the pathway, aminolevulinic acid (ALA) synthetase. This feedback inhibition can be disrupted in...

periods of bleeding or metabolic stress (infection, dehydration, fasting) resulting in induced ALA synthetase activity. A block in any of the enzymes in the pathway will result in accumulation of porphyrin precursors.

Members of the phenylpiperidine opioids, which include tramadol, fentanyl, alfentanil, sufentanil, and remifentanil, are also serotonin reuptake inhibitors and have been associated with...

perioperative serotonergic toxicity, as has methadone.

Lidocaine was the first widely used local anesthetic, and is available for infiltration as well as...

peripheral (including Bier's block), spinal, and epidural blocks. Its use for spinal anesthesia has declined due to concerns about neurotoxicity and transient neurologic symptoms.

The diaphragm is less susceptible to the effects of NMBAs compared with both...

peripheral muscles and pharyngeal upper airway dilator muscles.

With the introduction of bupivacaine, tetracaine is rarely used in...

peripheral nerve blocks because of the large doses often necessary, its slow onset, and its potential for toxicity.

In the subarachnoid space where the nerves lack a sheath, local anesthetics are able to reach their targets more readily, leading to a more rapid onset of nerve block with a much smaller dose compared to...

peripheral nerves. In peripheral nerve blocks, deposition of local anesthetic is in the vicinity of the nerves and the amount of drug that reaches the nerve depends on the diffusion of the drug and the proximity of the injection to the nerve.

In preanesthetic doses, all benzodiazepines decrease blood pressure and increase heart rate. With midazolam, the effects appear to be secondary to a decrease in...

peripheral resistance, but with diazepam, they are secondary to a decrease in left ventricular work and cardiac output.

Local anesthetics block conduction by decreasing or preventing the large transient increase in the...

permeability of excitable membranes to Na+ that normally is produced by a slight depolarization of the membrane.

The opioid receptors belong to the G protein-coupled receptor family. Activation of the opioid receptors leads to activation of the...

pertussis toxin-sensitive G proteins (Gi and/or Go).

When administered in typical doses in the absence of ongoing opioid therapy (or abuse), naloxone has no discernible...

pharmacodynamic effects. When opioid effects are present, naloxone given in sufficient doses can reverse all effects mediated by opioid receptors.

Numerous anticonvulsants have been used in the treatment of neuropathic pain, including...

phenytoin, topiramate, carbamazepine, and sodium valproate. While some of these agents continue to be used for certain conditions (e.g., carbamazepine for trigeminal neuralgia) the newer anticonvulsants with FDA approval for the management of pain— gabapentin and pregabalin— have largely supplanted their role.

Clonidine has been used in hypertensive patients for the diagnosis of...

pheochromocytoma. The lack of suppression of the plasma concentration of NE to >500 pg/mL 3 hours after an oral dose of 0.3 mg of clonidine suggests the presence of such a tumor. A modification of this test, wherein overnight urinary excretion of NE and epinephrine is measured after administration of a 0.3-mg dose of clonidine at bedtime, may be useful when results based on plasma NE concentrations are equivocal.

Type I receptors include mGluR1 and 5. These receptors primarily activate...

phospholipase C and IP3 production.

The binding of both glutamate and glycine is not sufficient to activate NMDA receptors when the membrane is near −70mV because...

physiologic concentrations of Mg2+ bind to and block channel function. This effect of magnesium is voltage-dependent, such that depolarization removes the Mg2+ from the channel and allows current to pass through the channel.

Most local anesthetics have pKa values relatively close to but higher than...

physiologic pH (with some exceptions such as prilocaine that has a secondary amine and benzocaine that has a primary amine).

Dexmedetomidine may reduce delirium in part because its sedation closely mimics...

physiologic sleep in adults and children.

Reversal of the adverse CNS effects of ketamine by...

physostigmine while analgesia remains intact has been described.

Sedative effects of other drugs, including phenothiazines and tricyclic antidepressants, may also be antagonized by...

physostigmine.

toxic effects of the tricyclic antidepressants and phenothiazines, such as intraventricular conduction deficits and ventricular arrhythmias, are not reversed by...

physostigmine. In addition, physostigmine may precipitate seizures; hence, its usually small potential benefit must be weighed against this risk.

Esters are hydrolyzed and inactivated primarily by a plasma esterase, probably...

plasma cholinesterase. The liver also participates in hydrolysis of local anesthetics.

Halogenation of procaine to chloroprocaine results in a three- to fourfold increase in the hydrolysis rate of chloroprocaine by...

plasma cholinesterase. This rapid hydrolysis rate of chloroprocaine limits the duration of action and systemic toxicity of this local anesthetic.

Neostigmine and pyridostigmine are destroyed by...

plasma esterases, and the quaternary aromatic alcohols and parent compounds are excreted in the urine.

Due to its relatively low potency and extremely low toxicity, relatively high concentrations of chloroprocaine can be used. It also has an extremely short...

plasma half-life because it is metabolized rapidly by plasma cholinesterase.

Compared to other intravenous anesthetics, ketamine has relatively low...

plasma protein binding. This, in conjunction with its lipid solubility, allows rapid accumulation in the CNS. Intravenous bolus administration leads to peak effect site concentration within a minute. Peak effects for other routes of administration are 10-15 minutes for intramuscular injection and 15-30 minutes following oral administration.

Age-related changes in protein binding of local anesthetics also occur. The neonate is relatively deficient in...

plasma proteins that bind local anesthetics and thereby is more susceptible to toxicity.

The amide-linked local anesthetics are extensively (55-95%) bound to...

plasma proteins, particularly α1-acid glycoprotein.

Sugammadex encapsulates and inactivates the NMBA in the...

plasma, rendering it incapable of binding with acetylcholine receptors.

Mepivacaine is slowly metabolized by the fetus, making it a...

poor choice for epidural anesthesia in the parturient.

Procaine and chloroprocaine penetrate mucous membranes...

poorly and are ineffective for topical anesthesia.

Thiopental causes some cytochrome P450 induction but this is generally of no clinical consequence when used as an induction agent. An active...

porphyric crisis could be exacerbated by this mechanism, but triggering an event in a patient with latent porphyria is reported to be unusual. Even so, it is prudent to avoid even potential triggers in patients with porphyria.

The porphyrias are a group of rare inherited or acquired disorders of certain enzymes that normally participate in the production of...

porphyrins and heme. They manifest with either neurological complications or skin problems or occasionally both.

Prejunctional nicotinic receptors are activated by acetylcholine and function in a...

positive feedback control system that serves to maintain the availability of acetylcholine when demand is high. They are involved in mobilization of synaptic vesicles containing acetylcholine toward the release sites in the presynaptic membrane of the motor nerve terminal, but not the actual process of acetylcholine release. These receptors are morphologically different than those at the postjunctional membrane and consist of three α subunits and two β subunits.

Gabapentin is currently FDA approved for...

post-herpetic neuralgia and partial seizures.

ACh released into the cleft binds to nicotinic AChRs on the surface of the...

post-junctional muscle membrane. These heteropentameric ligand-gated ion channels are nonselective cation channels in the postjunctional membrane that allow influx of Na +, resulting in endplate depolarization and muscle contraction.

Neuromuscular transmission in skeletal muscle occurs when a quantum of acetylcholine from the nerve ending is released and binds to nicotinic acetylcholine receptors (AChRs) on the...

postjunctional muscle membrane. These AChRs on the endplate respond by opening channels for the influx of sodium ions and subsequent endplate depolarization leads to muscle contraction. Activation is terminated when acetylcholine immediately dissociates from its receptor and is hydrolyzed by acetylcholinesterase.

Propofol-based TIVA probably confers advantages over volatile agents in anesthetic maintenance for patients at high risk for...

postoperative nausea and vomiting. It is beneficial not only for patients at high risk for malignant hyperthermia or postoperative nausea and vomiting but it also led to improved operating conditions for endoscopic sinus surgery and decreased pain and opioid consumption in gynecologic procedures.

It is speculated that alpha2 agonists act on...

postsynaptic alpha2 receptors in the CNS so as to activate an inhibitory G protein and to increase potassium ion conductance. The inhibitory G protein and hyperpolarization produced by increased potassium conductance results in depression of neuronal excitability characteristic of general anesthesia.

Ligand binding causes the AMPARs to open, and Na+ flows into the...

postsynaptic cell, resulting in a depolarization. NMDARs, on the other hand, do not open directly because their pores are occluded at resting membrane potential by Mg2+ ions. NMDARs can open only when a depolarization from the AMPAR activation leads to repulsion of the Mg2+ cation out into the extracellular space, allowing the pore to pass current.

Opioid receptors may regulate the functions of other ion channels including excitatory...

postsynaptic currents evoked by N-methyl-D-aspartate (NMDA) receptors.

GABAA receptors are primarily...

postsynaptic ligand-gated Cl− ion channels.

Rapid intravenous administration of α2-agonists such as dexmedetomidine can transiently increase BP through vasoconstriction at...

postsynaptic α2b-receptors on arteries and veins. This receptor subtype might also account for their antishivering effect.

GABAB receptor stimulation is mediated by G-proteins that produce a variety of responses, including activation of...

potassium channels, inhibition of presynaptic voltage-gated calcium channels and modulation of intracellular second messenger systems, including adenylate cyclase and phosolipase C.

Lipid solubility is the primary determinant of local anesthetic...

potency and duration of action. The more lipophilic local anesthetics are able to permeate the axonal membranes more readily, and thus are able to bind to the VGSCs with greater affinity.

Hydrophobicity increases both the...

potency and the duration of action of the local anesthetics; association of the drug at hydrophobic sites enhances the partitioning of the drug to its sites of action and decreases the rate of metabolism by plasma esterases and hepatic enzymes.

Sufentanil's distinguishing feature is that it is the most...

potent opioid commonly used in anesthesia practice. Because it is more intrinsically efficacious at the opioid receptor, the absolute doses used are much smaller compared to other less potent drugs (1000-fold less than morphine).

Mg2+ not only blocks the NMDA channel in a voltage-dependent manner but also...

potentiates NMDA-induced responses at positive membrane potentials.

Butorphanol (a kappa receptor agonist-antagonist) stops shivering more effectively than opioids with a...

predominant mu opioid receptor agonist effect.

Patients can become severely hypertensive, particularly during laryngoscopy. Direct acting vasodilators including nitroglycerin and hydralazine or calcium channel blockers are appropriate for treatment and prophylaxis although they worsen...

preexisting tachycardia. Caution should be exercised in the use of beta blockers, in that unopposed α-receptor action can worsen hypertension and lead to myocardial ischemia. The induction agents, ketamine and etomidate, can exacerbate the underlying hemodynamic abnormalities.

Monitoring the facial nerve for determination of onset/intubation may be...

preferable over the ulnar nerve

Clonidine decreases discharges in sympathetic...

preganglionic fibers in the splanchnic nerve and in postganglionic fibers of cardiac nerves.

Aminoglycoside antibiotics produce neuromuscular blockade by inhibiting ACh release from the...

preganglionic terminal (through competition with Ca2 +) and to a lesser extent by noncompetitively blocking the receptor. The blockade is antagonized by Ca2 + salts but only inconsistently by anti-ChE agents.

In addition to opening of the ion channel of postjunctional acetylcholine receptors, neuromuscular transmission is modulated by a population of...

prejunctional cholinergic receptors. These prejunctional nicotinic and muscarinic receptors on the motor nerve endings are involved in the modulation of the release of acetylcholine into the neuromuscular junction.

Antagonism of nondepolarizing neuromuscular block with anticholinesterases requires varying amounts of time that are determined by several factors. Time from administration to peak effect varies with...

presynaptic acetylcholine reserve, as well as the spontaneous rate of recovery from neuromuscular blockade.

All NMBAs tested, including mivacurium, atracurium, cisatracurium, d-tubocurarine, pancuronium, rocuronium, and vecuronium, inhibit...

presynaptic nicotinic acetylcholine receptors in a concentration-dependent fashion. Vecuronium and d-tubocurarine are the most potent inhibitors of this receptor subtype, and mivacurium the least potent.

Botulism is the clinical syndrome caused by the anaerobic gram-positive organism Clostridium botulinum. Seven different serotypes of the organism have been identified, each producing antigenically distinct toxins. The different toxins target different proteins at the...

presynaptic region of the NMJ, resulting in block of release of ACh with ensuing denervation and accompanying muscle paralysis and atrophy.

Some of the anti-hypertensive effects of clonidine may be mediated by activation of...

presynaptic α2 receptors that suppress the release of NE, ATP, and NPY from postganglionic sympathetic nerves.

Neuromuscular junction disorders can be classified as inherited and acquired, or anatomically as...

presynaptic, synaptic, or postsynaptic. The etiology of the dysfunction can also be classified as autoimmune, congenital, pharmacologic, toxic, or traumatic.

In the spinal cord, opioids act at synapses either...

presynaptically or postsynaptically.

The NMBAs compete with ACh at the two binding sites of the AChR. Therefore only one molecule of NMBA is needed to...

prevent activation of the receptor, whereas two ACh molecules are needed for activation. This biases the competition strongly in favor of the antagonist (NMBA) drug.

Amide metabolism: fastest=>slowest

prilocaine (fastest) > lidocaine > mepivacaine > ropivacaine ≈ bupivacaine and levobupivacaine (slowest).

It is well known that opioids decrease the pain-evoked release of tachykinins from...

primary afferent nociceptors. However, at least 80% of tachykinin signaling in response to noxious stimulation remains intact after the intrathecal administration of large doses of opioids. These results suggest that although opioid administration may reduce release of tachykinin from primary afferent nociceptors, this reduction has little functional impact on the actions of tachykinin on postsynaptic pain-transmitting neurons.

The α2A-AR serves as the...

primary presynaptic autoreceptor.

The development of modern organic chemistry enabled the synthesis of the first analogue of cocaine...

procaine (known today by its trade name Novocaine) in 1905.

Tetracaine (PONTOCAINE), is a long-acting amino ester. It is significantly more potent and has a longer duration of action than...

procaine.

Naloxone can easily cross the placenta. For this reason, administration of naloxone to an opioid-dependent parturient may...

produce acute withdrawal in the neonate.

There is a ceiling effect in the reversal of neuromuscular block by anticholinesterases in that...

profound neuromuscular blockade cannot be reversed. Once the maximum dose of neostigmine (0.05-0.07 mg/kg) has been administered, additional anticholinesterase will not produce greater antagonism.

Lidocaine appears to inhibit the release of...

proinflammatory cytokines and prevent leukocyte adhesion.

COX-2 has low baseline expression but is inducible during physiologic stress by agents including...

proinflammatory cytokines, neurotransmitters, and growth factors.

Whenever motor nerves are less active due to trauma or skeletal muscle denervation, extrajunctional cholinergic receptors...

proliferate rapidly. These extrajunctional nAChRs appear over the entire postjunctional membrane rather than being confined to the area of the NMJ.

Excessive plasma concentrations of lidocaine may slow conduction of cardiac impulses through the heart, manifesting as...

prolongation of the P-R interval and QRS complex on the electrocardiogram.

Single doses of fentanyl, alfentanil, and sufentanil all have similar intermediate durations of action (30, 20, and 15 minutes, respectively), but recovery after...

prolonged administration varies considerably.

Advanced age impacts the pharmacokinetics and duration of action of rocuronium. The duration of effect of repeat doses is...

prolonged and the clinical duration of 0.6 mg/kg is almost doubled. Clearance of the compound is significantly decreased in this patient population.

Thiopental and pentobarbital have anticonvulsant effects in the setting of prolonged high-dose administration, whereas...

prolonged use of methohexital leads to epileptiform discharges.

Addition of clonidine, 75 to 150 µg, to a solution containing tetracaine or bupivacaine and placed in the subarachnoid space...

prolongs the duration of sensory and motor blockade produced by the local anesthetic.

The first local anesthetic used in ophthalmology, cocaine, has the severe disadvantages of producing mydriasis and corneal sloughing and has fallen out of favor. The two compounds used most frequently today are...

proparacaine (ALCAINE, OPHTHAINE, others) and tetracaine

When unintentional intravenous injection of local anesthetic is suspected or systemic toxicity is detected, benzodiazepine should be given...

prophylactically as an anticonvulsant. The patient should be monitored closely for any early neurologic signs and symptoms. If the patient seizes, the airway must be protected to prevent aspiration and hypoventilation, and the seizure should be treated promptly with an intravenous anticonvulsant such as diazepam; sodium thiopental or propofol are acceptable alternatives.

Awakening times were similar after 24, 48, 72, and 96-hour constant rate infusions of...

propofol.

Larger doses of naloxone may be needed for patients with overdose involving...

propoxyphene, codeine, and some other opioids.

Diazepam and lorazepam are lipophilic and are traditionally formulated in...

propylene glycol because they are not soluble in water. These formulations are associated with pain on injection and long-term infusions in the intensive care unit (ICU) can lead to glycol toxicity.

The NSAIDs act by inhibiting cyclooxygenase (COX) enzymes that catalyze the conversion of arachidonic acid to...

prostaglandins, thromboxanes, and prostacyclin.

The duration of action of local anesthetics is determined primarily by their...

protein binding. Local anesthetics with a high affinity for protein remain bound to the nerve membrane longer. In other words, binding to Na + channels with higher affinity results in a channel blocking effect of longer duration.

The κ-opioid receptor (KOR) is a...

protein that in humans is encoded by the OPRK1 gene.

The nociceptin receptor or NOP also known as the orphanin FQ receptor or kappa-type 3 opioid receptor is a...

protein that in humans is encoded by the OPRL1 (opioid receptor-like 1) gene.

Rarely, naloxone administration has been complicated by severe adverse hemodynamic effects including...

pulmonary edema and even sudden death in previously healthy individuals (some tachycardia is to be expected).

naloxone administration has been complicated by severe adverse hemodynamic effects including...

pulmonary edema and even sudden death in previously healthy individuals (some tachycardia is to be expected).

Presynaptic defects are associated with abnormalities of...

quantal release of ACh or ACh resynthesis (mutation in choline acetyltransferase).

The neurotransmitter at the NMJ is the...

quaternary ammonium ester acetylcholine.

Alpha-adrenergic blockade may be effective in treatment of coronary vasoconstriction due to cocaine, but in the presence of hypotension this intervention...

questionable. IV administration of a benzodiazepine such as diazepam is effective for control of seizures associated with cocaine toxicity.

function—Because morphine and its congeners are metabolized primarily in the liver, their use in patients in prehepatic coma may be...

questioned. Half-life is prolonged in patients with impaired renal function, and morphine and its active glucuronide metabolite may accumulate; dosage can often be reduced in such patients.

Overall the clinical profile of ropivacaine is similar to...

racemic bupivacaine, taking into account that it is less lipid soluble and less potent than bupivacaine.

Ketamine was originally produced as a...

racemic mixture and most commercial preparations continue to be a racemic mix of the R and S enantiomers. S( +) ketamine, a single enantiomer formulation that is available in some areas of Europe and South America, is more potent in most clinical and experimental settings.

Most of the NSAIDs (eg, ibuprofen, ketoprofen) are...

racemic mixtures, while one, naproxen, is provided as a single enantiomer and a few have no chiral center (eg, diclofenac).

In standard analgesic doses, morphine (a phenanthrene) disrupts normal...

rapid eye movement (REM) and non-REM sleep patterns. This disrupting effect is probably characteristic of all opioids.

Chloroprocaine. Chloroprocaine (NESACAINE, others) is a chlorinated derivative of procaine. Its major assets are its...

rapid onset and short duration of action and its reduced acute toxicity due to its rapid metabolism (plasma t1/ 2 ∼ 25 seconds).

Local anesthetics with pKs nearest to physiologic pH have the most...

rapid onset of action, reflecting the presence of an optimal ratio of ionized to nonionized drug fraction.

Ester local anesthetics undergo hydrolysis by cholinesterase enzyme, principally in the plasma and to a lesser extent in the liver. The rate of hydrolysis varies, with chloroprocaine being most...

rapid, procaine being intermediate, and tetracaine being the slowest. The resulting metabolites are pharmacologically inactive, although paraaminobenzoic acid may be an antigen responsible for subsequent allergic reactions.

Clearance of aminoesters is primarily dependent on hydrolysis of the ester bond by plasma cholinesterases. The rate of enzymatic degradation varies, with chloroprocaine being the most...

rapid, tetracaine being the slowest, and procaine being intermediate.

Opioid agonists elicit typical opioid effects via a reversible...

receptor G-protein coupling. Full opioid agonists (e.g., fentanyl, sufentanil) are highly potent and require only little receptor occupancy for maximal response. Partial opioid agonists (e.g., buprenorphine) require a higher receptor occupancy for maximal efficacy, which is usually lower than that of the full agonists.

Small doses (0.4-0.8 mg) of naloxone given intramuscularly or intravenously prevent or promptly reverse the effects of...

receptor agonists. In patients with respiratory depression, an increase in respiratory rate is seen within 1-2 minutes. Sedative effects are reversed, and blood pressure, if depressed, returns to normal.

Chronic opioid-receptor stimulation can lead to pharmacological tolerance. Opioid tolerance occurs via multiple molecular mechanisms, including...

receptor desensitization, internalization, and degradation. Superactivation of adenylate cyclase and N-methyl-D-aspartate (NMDA) receptor activation may also contribute to tolerance and dependence.

The neuronal response to GABA is mediated through two populations of...

receptors, GABAA and GABAB receptors. While both populations generally produce neuronal inhibition, they do so through wholly different mechanisms.

The speed of onset of neuromuscular block after administration of an NMBA is also related to the speed of...

recovery of neuromuscular function. This appears to be due to the more rapid equilibration between the plasma and effect compartment with drugs that are metabolized or redistributed more quickly.

If the NMBA is not metabolized more quickly than the anticholinesterase, neuromuscular block can...

recur (known as recurarization).

Patients who receive naloxone for the emergency reversal of life threatening ventilatory depression must be monitored for...

recurrence of the opioid effects.

Like most of the intravenous anesthetics, the offset of the hypnotic effect after Propofol bolus administration occurs mainly through...

redistribution from the brain to less well-perfused sites. Plasma concentrations for inducing unconsciousness are 2-2.5 µg/mL and for maintenance of anesthesia are 2-6 µg/mL.

After termination of a sufentanil infusion, the decrease in the plasma drug concentration is accelerated not only by metabolism but by continued...

redistribution of sufentanil into peripheral tissue compartments. Compared with alfentanil, sufentanil may have a more favorable recovery profile when used over a longer period of time.

Kinetic modeling of bolus administration reveals a rapid peak in effect site (CNS) concentration. The subsequent decline in concentration results primarily from...

redistribution to other tissues rather than metabolism and elimination. Repeated bolus dosing or continuous infusions lead to very prolonged recovery times as depicted by plots of the context-sensitive half-time.

An imbalance of excitatory and inhibitory signaling contributes to seizure disorders, and glutamate receptor antagonists...

reduce seizure activity.

Certain analgesics such as codeine and oxycodone are effective orally because they have...

reduced first-pass metabolism.

The dose requirement for propofol is reduced in the elderly because of...

reduced metabolic clearance of drugs and reduced relative volume of the central compartment.

Neostigmine enhances gastric contractions and increases the secretion of gastric acid. After bilateral vagotomy, the effects of neostigmine on gastric motility are greatly...

reduced. The lower portion of the esophagus is stimulated by neostigmine; in patients with marked achalasia and dilation of the esophagus, the drug can cause a salutary increase in tone and peristalsis.

At normal heart rates, diastolic time is sufficiently long for lidocaine dissociation but bupivacaine block intensifies and depresses electrical conduction, causing...

reentrant-type ventricular dysrhythmias, Less lipid-soluble lidocaine dissociates rapidly from cardiac sodium channels and cardiac toxicity is low.

Intravenous administration of lipid emulsion has been used with immediate and successful resuscitation of patients with...

refractory local anesthetic induced cardiac toxicity, and is now a part of standardized treatment algorithms.

If less than the critical length of the axon is blocked, the action potential can be...

regenerated in the proximal membrane segment or node when the decaying depolarization is still above threshold for Na+ channel activation.

The volume of local anesthetic is also important as a sufficient length of axon must be blocked in order to prevent...

regeneration of the impulse in the adjacent node of Ranvier.

Propofol dosing is increased in pediatric populations because...

relative central compartment volume is larger and clearance and metabolism are increased.

Norketamine is roughly one-third as potent as ketamine; its contribution to clinical effects appear...

relatively more significant in settings of long infusions or chronic use.

Fentanyl and sufentanil, are very important drugs in anesthetic practice because of their...

relatively short time to peak analgesic effect, rapid termination of effect after small bolus doses, minimal direct depressant effects on the myocardium, and their ability to significantly reduce the dosing requirement for the volatile agents (" MAC-sparing")

Epidural morphine causes marked detrusor muscle...

relaxation within 15 minutes of injection that persists for up to 16 hours; it is readily reversed with naloxone.

In spite of their close structural resemblance to GABA, gabapentin and pregabalin do not act directly on GABA receptors. They may, however, modify the synaptic or nonsynaptic...

release of GABA. An increase in brain GABA concentration is observed in patients receiving gabapentin.

The sedation produced by dexmedetomidine has been noted to be more akin to natural sleep, with patients relatively easy to arouse. However, dexmedetomidine does not appear to provide...

reliable amnesia and additional agents may need to be employed if lack of recall is desirable.

The relief produced by intravenous morphine in dyspnea from pulmonary edema associated with left ventricular heart failure is...

remarkable. Proposed mechanisms include reduced anxiety (perception of shortness of breath) and reduced cardiac preload (reduced venous tone) and afterload (decreased peripheral resistance).

When a brief pulse of opioid effect followed by a quick offset is desirable (e.g., a brief period of intense analgesia before injection of local anesthetic during a regional block),____________ or ____________ would be rational choices.

remifentanil or alfentanil

Because of the relative lack of renal or hepatic elimination of Atracurium compared to steroidal NMBAs, the pharmacokinetics and duration of action of atracurium are not affected by...

renal disease. Similarly, its elimination half-life is not prolonged in patients with cirrhosis.

About 90% of acetaminophen is hepatically metabolized to sulfate and glucuronide conjugates for...

renal excretion with a small amount secreted unchanged in the urine. Minor metabolites are responsible for the hepatotoxicity seen in overdose. CYP 450 enzyme system induction in the liver by any agent, including ethanol, increases the formation of toxic free radial metabolites and thereby increases hepatotoxicity.

Oxycodone and its metabolites can accumulate under conditions of...

renal failure and have been associated with prolonged action and sedation.

Because of the lack of any known active metabolites, hydromorphone is often recommended for patients with...

renal failure.

The clinical pharmacology of meperidine is significantly altered by...

renal failure. Normeperidine, the main metabolite, has analgesic and excitatory CNS effects that range from anxiety and tremulousness to myoclonus and frank seizures. Because the active metabolites are subject to renal excretion, CNS toxicity secondary to accumulation of normeperidine is especially a concern in patients with renal failure.

Clearance of pancuronium is decreased and elimination half-life prolonged in patients with...

renal failure. Similarly, clearance is decreased and duration of action of pancuronium is prolonged in patients of advanced age.

Fentanyl, remifentanil, sufentanil, alfentanil, and hydromorphone are the opioids of choice for patients with, or at risk for...

renal impairment because these drugs do not depend on renal clearance mechanisms.

Gabapentinoids are excreted almost exclusively by the...

renal system and their clearance is directly related to creatinine clearance.

Because recovery from Atracurium-induced neuromuscular block occurs by nonsaturable chemical degradation rather than metabolism or redistribution, there is little to no cumulative effect with...

repeat doses or continuous infusion. Thus sequential doses administered at the same point in spontaneous recovery have the same recovery characteristics as the preceding dose. With continuous infusion, no dosing revisions are required to maintain a stable depth of neuromuscular block, even with prolonged infusions.

A prolonged latency-to-peak effect means that morphine is less likely to cause acute...

respiratory depression after bolus injection of typical analgesic doses compared to the more rapid acting drugs because the relationship between minute ventilation and the partial pressure of carbon dioxide changes more slowly (thus there is more time for carbon dioxide to rise and sustain ventilatory drive).

Antagonism of opioid effects by naloxone often is accompanied by an "overshoot" phenomenon. For example...

respiratory rate depressed by opioids transiently becomes higher than that before the period of depression. Rebound release of catecholamines may cause hypertension, tachycardia, and ventricular arrhythmias. Pulmonary edema also has been reported after naloxone administration.

Systemic absorption of bupivacaine, such as follows a brachial plexus block, stimulates the ventilatory...

response to carbon dioxide.

The NMDA receptor cation channel is blocked by Mg2+ at...

resting membrane potential. To unblock the channel, the postsynaptic cell must be depolarized.

Treatment of clonidine withdrawal syndrome depends on the urgency of reducing the arterial blood pressure. In the absence of life-threatening target organ damage, patients can be treated by...

restoring the use of clonidine. If a more rapid effect is required, sodium nitroprusside or a combination of an α and β adrenergic blocker is appropriate. β Adrenergic blocking agents should not be used alone in this setting, because they may accentuate the hypertension by allowing unopposed α adrenergic vasoconstriction caused by activation of the sympathetic nervous system and elevated circulating catecholamines.

Ketorolac inhibits platelet thromboxane production and platelet aggregation by...

reversible inhibition of prostaglandin synthetase.

The onset of action of local anesthetic action depends on the...

route of administration and the dose or concentration of drug.

Nonsteroidal antiinflammatory agents are a diverse group of drugs broadly categorized into...

salicylates, acetic acid derivatives, propionic acid derivatives, oxicam derivatives, and the COX-2 selective agents. All act by blocking prostaglandin synthesis, both in the periphery and in the central nervous system (CNS).

The presence of myelin increases conduction velocity via...

saltatory conduction, and the increased nerve diameter increases conduction velocity via improved cable conduction properties.

Acetaminophen, at therapeutic doses, is oxidized only to a small fraction to form traces of the highly reactive metabolite, N-acetyl-p-benzoquinone imine (NAPQI). When overdosed (usually >10 g of acetaminophen), however, the principal metabolic pathways are...

saturated, and hepatotoxic NAPQI concentrations can be formed. Rarely, other NSAIDs also may be complicated by hepatotoxicity.

Activation of the α2A adrenergic receptor by dexmedetomidine produces both...

sedation and analgesia, but does not reliably provide general anesthesia, even at maximal doses.

The α2a-receptor mediates....

sedation and hypnosis, sympatholysis, neuroprotection, diuresis and inhibition of insulin and growth hormone secretion.

Virtually all effects of the benzodiazepines result from their actions on the CNS. The most prominent of these effects are...

sedation, hypnosis, decreased anxiety, muscle relaxation, anterograde amnesia, and anticonvulsant activity. Only two effects of these drugs result from peripheral actions: coronary vasodilation, seen after intravenous administration of therapeutic doses of certain benzodiazepines, and neuromuscular blockade, seen only with very high doses.

Routine administration of flumazenil to patients presenting to the emergency room with the suspicion of overdose can lead to...

seizures via precipitating acute withdrawal in chronic benzodiazepine users. But, there is some evidence that flumazenil has anticonvulsant properties suggesting that this drug may have mixed or partial agonist effects on the GABAA receptor, even in the absence of benzodiazepine administration. In support of this phenomenon is the potential for high doses of flumazenil to potentiate the hypnosis of other positive GABA modulators such as propofol.

Abrupt discontinuation and withdrawal of gabapentinoids may precipitate...

seizures, particularly in a patient with a preexisting seizure disorder. Anxiety, insomnia, nausea, pain, and sweating are the most frequently reported adverse events following abrupt discontinuation.

G protein coupled receptors (GPCRs), also known as seven-transmembrane domain receptors, and G protein-linked receptors (GPLR), constitute a large protein family of receptors that...

sense molecules outside the cell and activate inside signal transduction pathways and, ultimately, cellular responses.

Therefore, it is unlikely that the fiber size per se determines the...

sensitivity to local anesthetic block under steady-state conditions.

Bupivacaine (a racemic mixture of both the R and S enantiomers) provides prolonged and intense...

sensory analgesia, often outlasting the motor block.

Glutamate-dependent signaling is required for essentially all...

sensory and motor processing. It contributes to neuronal migration and synapse formation during development.

Bupivacaine is a potent agent capable of producing prolonged anesthesia. Its long duration of action plus its tendency to provide more...

sensory than motor block has made it a popular drug for providing prolonged analgesia during labor or the postoperative period.

The complexities of normal neuromuscular function are altered by many pathologic states not originally thought to involve the neuromuscular junction such as...

sepsis or acute respiratory distress syndrome, causing substantial morbidity and mortality.

Several drugs used in the perioperative period— notably cocaine, ondansetron, and fentanyl— have the potential to directly or indirectly augment...

serotonergic activity, and this should be considered when assessing patients exhibiting hypermetabolic activity.

Recent reports suggest that acetaminophen acts via the...

serotonergic pathways, COX-3 inhibition, and/or endogenous cannabinoid potentiation to provide analgesia, but its mechanism of action remains poorly understood.

Members of the phenylpiperidine opioids, which include tramadol, fentanyl, alfentanil, sufentanil, and remifentanil, are also...

serotonin reuptake inhibitors and have been associated with perioperative serotonergic toxicity, as has methadone.

Acute porphyric crises are manifested by...

severe abdominal pain, nausea, vomiting, psychiatric disorders, and neurologic abnormalities.

In laboratory animals, the administration of naloxone will reverse or attenuate the hypotension associated with...

shock of diverse origins, including that caused by anaphylaxis, endotoxin, hypovolemia, and injury to the spinal cord.

Compared to the currently marketed fentanyl congeners, remifentanil's context sensitive half-time is...

short, on the order of about 5 minutes. Pharmacodynamically, remifentanil exhibits a short latency-to-peak effect similar to alfentanil.

Naloxone is rapidly metabolized in the liver and has a very high clearance; thus, its duration of action is nearly always...

shorter than that of the opioid whose effects it is intended to reverse.

Concentrations of morphine in colostrums of parturients receiving patient controlled analgesia with morphine are small and it is unlikely that...

significant amounts of drug will be transferred to the breast-fed neonate.

Both types of pain-conducting fibers (myelinated A-delta and nonmyelinated C fibers) are blocked by...

similar concentrations of local anesthetics, despite the differences in the diameters of these fibers.

Ropivacaine is structurally similar to bupivacaine but was developed as a...

single, less toxic enantiomer (as with levo-bupivacaine); it can be administered in larger doses than racemic bupivacaine before early signs of toxicity develop. However, if equipotent concentrations/ dosages are compared, the difference between bupivacaine and ropivacaine becomes less clear.

There is good evidence for an accessory direct action of neostigmine and other quaternary ammonium anti-ChE agents on...

skeletal muscle. Not physostigmine.

Systemic absorption of topical benzocaine is enhanced by defects in the...

skin and mucosa as well as from the gastrointestinal tract should any of the local anesthetic be swallowed.

Both bupivacaine and lidocaine block cardiac sodium ion channels during systole, whereas during diastole, highly lipid soluble bupivacaine dissociates off these channels at a...

slow rate compared with lidocaine, thus accounting for the drug's persistent depressant effect on Vmax and subsequent cardiac toxicity.

Clonidine also stimulates parasympathetic outflow, which may contribute to the...

slowing of heart rate as a consequence of increased vagal tone and diminished sympathetic drive.

The µ agonists are most effective in treating "second pain" sensations carried by...

slowly conducting, unmyelinated C fibers; they are less effective in treating "first pain" sensations (carried by small, myelinated A-δ fibers) and neuropathic pain.

Tetracaine may exhibit increased systemic toxicity because it is more...

slowly metabolized than the other commonly used ester local anesthetics. Currently, it is widely used in spinal anesthesia when a drug of long duration is needed.

Alkalosis increases resistance to Atracurium-induced neuromuscular block, while hypothermia...

slows the temperature-dependent breakdown so that less atracurium is required to maintain a given depth of neuromuscular block.

Differential conduction blockade is illustrated by selective blockade of preganglionic sympathetic nervous system B fibers using low concentrations of local anesthetics. Slightly higher concentrations of local anesthetics interrupt conduction in...

small C fibers and small- and medium-sized A fibers, with loss of sensation for pain and temperature. Nevertheless, touch, proprioception, and motor function are still present such that the patient will sense pressure but not pain with surgical stimulation. In an anxious patient, however, any sensation may be misinterpreted as failure of the local anesthetic.

The ion channel formed by Kainate receptors is permeable to...

sodium and potassium ions.

AMPA receptors are ligand-gated channels permeable to...

sodium and potassium, and under some circumstances calcium.

LA blocks voltage gated NA+ channels. The unionized form of the LA diffuses through the nerve axon into the axolemma. A lower pH inside the neuron/axolemma causes nonionized portion to split into ionized/unionized portions; the ionized portion binds to a receptor on the...

sodium channel when the channel is in the inactivated state. When the sodium channel is inactivated, action potentials cannot be generated.

Meperidine administered intrathecally blocks...

sodium channels to a degree comparable with lidocaine.

The lipid bilayer of the axonal membrane is relatively impermeable to...

sodium ions but selectively permeable to potassium ions.

Local anesthetics prevent transmission of nerve impulses (conduction blockade) by inhibiting passage of...

sodium ions through ion-selective sodium channels in nerve membranes.

If an AMPAR lacks a GluR2 subunit, then it will be permeable to...

sodium, potassium, and calcium.

Stimulation of α2 receptors in the GI tract may increase absorption of sodium chloride and fluid and inhibit secretion of bicarbonate. This may explain why clonidine has been found to be useful in reducing diarrhea in...

some diabetic patients with autonomic neuropathy.

The most commonly available propofol formulations today involve a mixture of...

soy bean oil, glycerol, and purified egg phospholipid to solubilize the drug.

Botulinum toxin targeting the prejunctional SNARE proteins is used therapeutically to treat...

spasticity or spasm in certain neurologic diseases (e.g., torticollis) and cosmetically to treat wrinkles.

pKa generally correlates with...

speed of onset, because penetration by the neutral lipid-soluble form across the lipid bilayer of the axonal membrane is the primary mechanism by which local anesthetics gain access to the local anesthetic binding site.

The µ agonists can produce contraction of the gallbladder smooth muscle and spasm of the...

sphincter of Oddi, potentially causing a falsely positive cholangiogram during gallbladder and bile duct surgery. These untoward effects are completely naloxone reversible and can be partially reversed by glucagon treatment. The mixed agonist-antagonists (e.g., butorphanol) appear to produce less pronounced biliary effects.

Dexmeditomidine has some analgesic qualities and augments the effects of opioids by both...

spinal and supraspinal mechanisms.

Fentanyl (10-25 µg) improves the spread and prolongs the block in...

spinal anesthesia in a dose-dependent manner.

Vasoconstrictors prolong the effect of tetracaine for...

spinal anesthesia. Epinephrine added to a low dose of tetracaine (6 mg) increases the success rate of spinal anesthesia, whereas the success rate is not altered by epinephrine when the subarachnoid dose of tetracaine is 10 mg

Injected intrathecally, tetracaine produces a significant increase in...

spinal cord blood flow, an effect that can be prevented or reversed by epinephrine.

Like propofol, etomidate interacts with GABAA receptors in a...

stereoselective manner. Its enhancement of GABA-mediated current is smaller on receptors containing the β1 subunit. Of all of the clinically used intravenous anesthetics, etomidate exhibits the greatest selectivity for GABAA receptors and has the fewest relevant interactions with other ion channels.

Sugammadex is a cyclodextrin that binds selectively to the...

steroidal neuromuscular blocking agents rocuronium, vecuronium, and pancuronium.

Most opioids produce miosis by...

stimulating the autonomic segment of the nucleus of the oculomotor nerve.

2-3 nodes of Ranvier must be blocked to...

stop nerve conduction

Despite the lack of sequence homology between classes, all GPCRs share a common...

structure and mechanism of signal transduction.

A and C fibers are further divided into...

subclasses by their anatomic location and physiologic functions.

Opioid receptors are abundantly expressed in the substantia gelatinosa, where release of...

substance P from the primary sensory neuron is inhibited by opioids.

Lidocaine in combination with tetracaine (PLIAGLIS) in a formulation that generates a "peel" is approved for topical local analgesia prior to...

superficial dermatological procedures such as filler injections and laser-based treatments.

The cough reflex is independent of the regulation of the respiratory center. The afferent arm of this reflex is represented by myelinated Aδ sensory nerve fibers (also called rapidly adapting receptors) that originate within or slightly beneath the respiratory epithelium. These fibers run first in the...

superior laryngeal nerve and then in the vagal nerve to the nucleus tractus solitarius. The efferent arm of this reflex is represented by the motor fibers of the phrenic nerve innervating the diaphragm.

Benzodiazepine-induced suppression of the hypothalamic-pituitary adrenal axis is..

supported by evidence of suppression of cortisol levels in treated patients.

Investigators reported increased mortality in ICU patients sedated for days with etomidate. The increased mortality was attributed to...

suppression of cortisol synthesis since etomidate is a potent inhibitor of the synthetic enzyme 11β-hydroxylase in the adrenal cortex.

During long-term Methadone administration, there may be excessive....

sweating, lymphocytosis, and increased concentrations of prolactin, albumin, and globulins in the plasma.

Because perioperative hypertension has been described in patients in whom clonidine was withdrawn the night before surgery, surgical patients who are being treated with an α2 adrenergic agonist either should be...

switched to another drug prior to elective surgery or should receive their morning dose and/ or transdermal clonidine prior to the procedure.

Administration of large doses of naloxone to patients addicted to opioids markedly increases efferent...

sympathetic neural outflow and catecholamine plasma concentrations, and evokes cardiovascular stimulation despite general anesthesia, apparently unmasking dampening effects of chronic opioid agonist administration on the sympathetic nervous system.

Clonidine stimulates the α2A subtype of α2 adrenergic receptors in the brainstem, resulting in a reduction in...

sympathetic outflow from the CNS. The decrease in plasma concentrations of NE is correlated directly with the hypotensive effect.

Clonidine decreases discharges in...

sympathetic preganglionic fibers in the splanchnic nerve and in postganglionic fibers of cardiac nerves. These effects are blocked by α2-selective antagonists such as yohimbine.

Cardiac effects related to the sympatholytic action of α2 adrenergic agonist include...

symptomatic bradycardia and sinus arrest in patients with dysfunction of the SA node and AV block in patients with AV nodal disease or in patients taking other drugs that depress AV conduction.

Under normal conditions, acetylcholinesterase rapidly destroys ACh in the...

synaptic cleft thereby improving the competitive advantage of the NMBA to bind to the receptor. If an inhibitor of acetylcholinesterase is added to the mix, the concentration of ACh in the cleft remains high and there is a shift in favor of ACh binding to the receptor.

Acetylcholinesterase is a type-B carboxylesterase enzyme located primarily in the...

synaptic cleft with a smaller concentration in the extrajunctional area.

Calcium flux through NMDARs is thought to be critical in...

synaptic plasticity, a cellular mechanism for learning and memory.

The fentanyl series of opioids are chemically related to meperidine. Meperidine is the first completely...

synthetic opioid and can be regarded as the prototype clinical phenylpiperidine.

Topical treatment with long-acting ChE inhibitors such as echothiophate gives rise to symptoms characteristic of...

systemic ChE inhibition. Echothiophate treatment in advanced glaucoma may be associated with the production of cataracts.

The mechanism of postoperative analgesia produced by epidural administration of highly lipophilic opioids (fentanyl, sufentanil) is primarily a reflection of...

systemic absorption. In fact, it has been proposed that epidural administration of lipophilic opioids may offer no clinical advantages over IV administration.

Although large doses of sufentanil (10 to 30 μg/kg IV) or fentanyl (50 to 150 μg/kg IV) produce minimal hemodynamic effects in patients with good left ventricular function, the...

systemic blood pressure and hormonal (catecholamine) responses to painful stimulation such as median sternotomy are not predictably prevented

Although opioid administration may reduce release of tachykinin from primary afferent nociceptors, this reduction has little functional impact on the actions of...

tachykinin on postsynaptic pain-transmitting neurons.

VGLUT3 is mostly found in presynaptic...

termini of neurons that are not classically considered glutamatergic, including those that utilize serotonin, acetylcholine, and GABA.

The hydrophilic group usually is a...

tertiary amine but also may be a secondary amine; the hydrophobic moiety must be aromatic.

Substituting a butyl group for the amine group on the benzene ring of procaine results in...

tetracaine.

The elimination half-time of morphine in CSF is similar to...

that in plasma.

Many commonly used semisynthetic opioids are created by simple modification of the morphine molecule. Codeine, for example, is...

the 3-methyl derivative of morphine.

Gabapentin is transported into the brain by...

the L-amino acid transporter.

The renal clearance of gabapentin can be slowed by...

the administration of cimetidine.

Etomidate causes less depression of ventilation compared to...

the barbiturates.

Naloxone produces dose-related improvement in myocardial contractility and survival in animals subjected to hypovolemic shock and, to a lesser extent, in those subjected to septic shock. The beneficial effects of naloxone in the treatment of shock occur only with doses >1 mg/kg IV, suggesting that...

the beneficial effects of this drug are not opioid receptor- mediated or, alternatively, are mediated by opioid receptors other than mu receptors— possibly delta and kappa receptors.

Compared with more lipid-soluble opioids such as codeine, heroin, and methadone, morphine crosses...

the blood-brain barrier at a considerably lower rate.

Plasma morphine concentrations after rapid IV injections do not correlate closely with the opioid's pharmacologic activity. Presumably, this discrepancy reflects a delay in penetration of morphine across...

the blood-brain barrier. CSF concentrations of morphine peak 15 to 30 minutes after IV injection and decay more slowly than plasma concentrations.

The ester hydrolysis involved in Atracurium metabolism is catalyzed by a nonspecific esterase distinct from...

the butyrylcholinesterase responsible for hydrolysis of succinylcholine and mivacurium.

Fewer opioid receptors can also be found in cardiac myocytes, which may contribute to...

the cardioprotective effects of opioids in myocardial ischemia.

Mixtures of low-dose ketamine infusions (10-20 µg/kg/min) with propofol infusions (100-200 µg/kg/min) have been used to mitigate...

the cardiovascular effects of both drugs, especially in pediatric anesthesia. However, there is no improvement in respiratory complications compared with using propofol alone.

VGLUT1 and 2 have a complementary distribution in the nervous system with VGLUT1 found in...

the cerebrum and cerebellum and VGLUT2 enriched in brainstem areas.

The S enantiomers of bupivacaine and mepivacaine appear to be less toxic than...

the commercially available racemic mixtures of these local anesthetics.

The indirect-acting cholinesterase inhibitors exert their effect by inhibiting AChE, thereby increasing...

the concentration of endogenous ACh around the cholinoreceptors. They act as alternative substrates for the enzyme.

The biphasic action of SCh from initial excitation to eventual block of transmission results from...

the continuous depolarization of the endplate and inactivation of Na + channels located at the edge of the endplate.

The role of ketamine in patients with neurologic injury is controversial. Its blockade of NMDA receptors could attenuate excitotoxicity, but animal studies have demonstrated neurotoxic effects on...

the developing brain. The tradeoffs are presently unclear but recent German guidelines have outlined a role for ketamine in brain injured patients whose PaCO2 is being controlled with mechanical ventilation. The sympathomimetic properties of ketamine allow sedation with preserved or augmented blood pressure to improve cerebral perfusion. In general, however, ketamine has traditionally been avoided in neuroanesthesia.

There are also other routes for glutamate synthesis from proline or from...

the dipeptide N-acetyl-alpha-L-aspartyl-L-glutamate (NAAG), but these are not thought to be robust sources of neurotransmitter pools of glutamate.

Because cerebrospinal fluid contains little to no cholinesterase enzyme, anesthesia produced by subarachnoid placement of tetracaine will persist until...

the drug has been absorbed into the systemic circulation.

The clinical duration of action (the time required from administration of a dose to recovery of 25% T1 height) defines...

the earliest time that reversal of residual neuromuscular block is recommended.

Impairment of hepatic function and decreases in hepatic perfusion (congestive heart failure) prolong..

the elimination of aminoamide local anesthetics.

GABAB receptors can stimulate the opening of K+ channels which brings the neuron closer to...

the equilibrium potential of K+, hyperpolarizing the neuron. This prevents sodium channels from opening, action potentials from firing, and VDCCs from opening, and so stops neurotransmitter release. Thus GABAB receptors are considered inhibitory receptors. GABAB receptors can also reduce the activity of adenylyl cyclase and decrease the cell's conductance to Ca2+

Gabapentin and pregabalin are branched-chain amino acids and chemical analogues of the neurotransmitter GABA. Despite their name, neither drug has activity in the GABAergic neurotransmission system. They are functionally similar to...

the essential amino acid leucine in that they competitively bind α2δ calcium channel subunits.

Glycine receptors colocalize with GABAA receptors near the cell body. Propofol, etomidate, and thiopental all have some positive modulation of...

the glycine receptors, but ketamine does not.

The amide-linked local anesthetics are, in general, degraded by...

the hepatic CYPs the initial reactions involving N-dealkylation and subsequent hydrolysis.

The Vd and elimination half-time of sufentanil is increased in obese patients, which most likely reflects...

the high lipid solubility of this opioid.

Ketamine has direct negative inotropic and vasodilating activity, but these effects usually are overwhelmed by...

the indirect sympathomimetic action. Thus, ketamine is a useful drug, along with etomidate, for patients at risk for hypotension during anesthesia.

Dexmedetomidine, an α2 agonist, also increases VLPO-mediated inhibition by suppressing...

the inhibitory effect of locus ceruleus neurons on VLPO.

Glutamate is the only precursor for...

the inhibitory neurotransmitter, GABA.

Single doses of meperidine also appear to be effective in the treatment of postanesthetic shivering. Meperidine, 25-50 mg, is used frequently with antihistamines, corticosteroids, acetaminophen, or nonsteroidal anti-Inflammatory drugs (NSAIDs) to prevent or ameliorate infusion-related rigors and shaking chills that accompany...

the intravenous administration of agents such as amphotericin B, aldesleukin (interleukin-2), trastuzumab, and alemtuzumab.

Morphine is principally metabolized by conjugation in the liver; the resulting water-soluble glucuronides (i.e., morphine 3-glucuronide and morphine 6-glucuronide: M3G and M6G) are excreted via...

the kidney. The kidney also plays a role in the conjugation of morphine and may account for as much as half of its conversion to M3G and M6G.

The more potent, lipophilic local anesthetics such as bupivacaine, tetracaine, and etidocaine are more cardiotoxic than...

the less lipophilic agents such as procaine, prilocaine, and lidocaine.

Codeine is actually a prodrug that is metabolized in part by O-demethylation into morphine, a metabolic process mediated by...

the liver P450 isoform CYP2D6.

After oral ingestion, naloxone is destroyed rapidly by...

the liver.

Since spinal fluid contains little or no esterase, anesthesia produced by the intrathecal injection of an anesthetic agent will persist until...

the local anesthetic agent has been absorbed into the circulation.

Prostaglandins are lipid-based compounds derived enzymatically from fatty acids that have important physiologic functions including...

the mediation of the inflammatory response, the transduction of pain signals, and a central pyretic effect.

Alfentanil illustrates how a drug can exhibit different pharmacokinetic profiles depending upon...

the method of administration (i.e., bolus versus continuous infusion).

Succinylcholine, mivacurium, and atracurium also cause histamine release, but to a lesser extent unless administered rapidly. Histamine release typically is a direct action of...

the muscle relaxant on the mast cell rather than IgE-mediated anaphylaxis

Kainate receptors, or KARs, are ionotropic receptors that respond to...

the neurotransmitter glutamate.

Cocaine produces intense euphoria and feelings of increased energy. The drug acts by blocking the reuptake of...

the neurotransmitters dopamine, serotonin, and norepinephrine into nerve terminals, thereby increasing the synaptic concentrations of these neurotransmitters. Effects on dopaminergic neurons are thought to be responsible for the high addictive potential of this drug.

Myasthenia Gravis, the most common and well studied "postsynaptic" neuromuscular transmission disorder, is caused by antibody-mediated reduction in...

the number of functioning postsynaptic AChRs.

Administration of ephedrine, 0.07 mg/ kg IV, prior to injection of rocuronium decreases...

the onset time by 22%, suggesting that increased cardiac output and skeletal muscle blood flow provides more rapid delivery of rocuronium to the neuromuscular junction.

Esmolol, 0.5 mg/ kg IV, administered immediately before the induction of anesthesia, delays...

the onset time of rocuronium by 26%, suggesting that decreased cardiac output and skeletal muscle blood flow slowed delivery of rocuronium to the neuromuscular junction.

Electrophysiologically, the voltage-gated Ca2+ channel is inhibited and the inwardly rectifying K+ channels are activated by...

the opioid receptors. As a result, neuronal excitability is reduced by activation of the opioid receptors.

It thus seems likely that while δ opioid agonists can produce respiratory depression at very high doses, at lower doses they have...

the opposite effect, a fact that may make mixed μ/δ agonists potentially very useful drugs that might be much safer than the μ agonists currently used for pain relief.

NAPQI is referred to as a biologically reactive intermediate, and such intermediates often arise due to drug metabolism. At therapeutic dosing, NAPQI binds to nucleophilic glutathione; but, in overdose, glutathione depletion may lead to...

the pathological finding of hepatic necrosis.

Meperidine crosses the placental barrier and even in reasonable analgesic doses causes a significant increase in...

the percentage of babies who show delayed respiration, decreased respiratory minute volume, or decreased O2 saturation or who require resuscitation.

Administration of naloxone or naltrexone increases the secretion of gonadotropin-releasing hormone and corticotropin-releasing hormone and elevates...

the plasma concentrations of LH, FSH, and ACTH, as well as the steroid hormones produced by their target organs.

Sufentanil metabolites are excreted almost equally in urine and feces, with about 30% appearing as conjugates. The production of a weakly active metabolite and the substantial amount of conjugated metabolite formation imply...

the possible importance of normal renal function for the clearance of sufentanil.

Activation of AMPA receptors causes depolarization of...

the postsynaptic membrane.

Epinephrine should not be used in patients with acute cocaine intoxication due to...

the potential for exacerbation of myocardial ischemia and stroke.

In contrast to the CNS, glutamate is not...

the predominant excitatory neurotransmitter in the periphery.

Methylnaltrexone and alvimopan, permanently charged opioid antagonists that do not easily enter the CNS, were developed for...

the prevention and treatment of opioid induced bowel dysfunction.

Of the three types of glaucoma— primary, secondary, and congenital; anti-AChE agents are of value in the management of...

the primary as well as of certain categories of the secondary type (e.g., aphakic glaucoma, following cataract extraction) *Congenital glaucoma rarely responds to any therapy other than surgery.

Patients with liver disease due to either cholestasis or cirrhosis have an increase in volume of distribution for pancuronium, which might be responsible for...

the relative resistance of these patients to pancuronium-induced block. However, clearance of pancuronium in these patients is decreased, and elimination half-life and duration of action are prolonged.

Neuromuscular-blocking drugs are not highly bound to plasma proteins (up to 50%), and it is unlikely that plasma protein binding, or any changes in protein binding, will have a significant effect on...

the renal excretion of neuromuscular-blocking drugs.

Atipamezole is a specific and selective alpha2 receptor antagonist that rapidly and effectively reverses...

the sedative and cardiovascular effects of IV dexmedetomidine.

There also exist a series of seven transmembrane domain Metabotropic glutamate receptors (mGluR1-8). These receptors are grouped into three families, based on...

the sequence similarity and their signaling properties.

Clonidine also stimulates parasympathetic outflow, which may contribute to...

the slowing of heart rate as a consequence of increased vagal tone and diminished sympathetic drive.

Dexmedetomidine has effects both on...

the spinal cord and in the locus coeruleus. A number of elegant studies in transgenic mice suggest that the α2A subtype receptor mediates the majority of the analgesic and sedative effects on the CNS.

AMPA receptors are tetramers comprised of...

the subunits GluR1-4.

Pyridostigmine, neostigmine, and ambenonium are the standard anti-ChE drugs used in...

the symptomatic treatment of myasthenia gravis.

Monitoring the offest/recovery from NMB is probably better at...

the ulnar nerve

In addition to contributing to myopathy, prolonged immobility results in...

the upregulation of acetylcholine receptors.

While Vecuronium undergoes more hepatic metabolism than pancuronium, it is primarily eliminated unchanged in...

the urine and bile. As much as 40% is cleared through the bile and 20% to 30% is eliminated in the urine. The remainder of the compound is metabolized by the liver to 3-desacetylvecuronium, 17-desacetylvecuronium, and 3,17-desacetylvecuronium.

Risk of TNS is associated with...

the use of lidocaine, lithotomy position, and ambulatory procedures. The risk increases with dose, but does not appear to correlate with the concentration of local anesthetic because there is no difference in the incidence of TNS with 0.5% and 5% lidocaine.

Factors that increase susceptibility to CNS toxicity include...

the use of more potent local anesthetics and the concomitant presence of respiratory or metabolic acidosis (by decreasing the convulsive threshold).

The α2B-AR is involved in...

the vascular hypertensive effect of α2-AR agonists.

NMDA receptors are unique among ligand-gated ion channels in that their probability of opening depends not only on presynaptic release of neurotransmitter but also on...

the voltage across the membrane containing the receptor. Until membrane depolarization occurs, Mg2 + blocks the channel pore whether or not agonist is present.

Although it is possible for the drugs and ligands to interact with this protein in multiple areas, it is generally agreed that the endogenous ligand GABA binds to the receptor in a pocket between...

the α and β subunits. Many of the intravenous anesthetics have their main influence on the activity of this protein in the transmembrane portion of the β subunit, while the benzodiazepines modulate the protein through interactions with transmembrane amino acids between the α and γ subunits near the intracellular side.

Patients severely intoxicated with benzodiazepines only require respiratory assistance when...

they also have ingested another CNS-depressant drug, most commonly ethanol.

Alpha2-adrenergic receptors (α2-ARs) consist of three subtypes, α2A-, α2B-, and α2C-AR, which are encoded by ...

three highly homologous genes. These receptors bind to endogenous ligands, epinephrine and norepinephrine, and are blocked by the antagonist yohimbine.

Although numerous classification schemes have been proposed, the GPCR superfamily is classically divided into...

three main classes (A, B, and C) with no detectable shared sequence homology between classes. The largest class by far is class A, which accounts for nearly 85% of the GPCR genes.

Failure of sodium ion channel permeability to increase slows the rate of depolarization such that...

threshold potential is not reached and thus an action potential is not propagated.

Other adverse effects of ibuprofen have been reported less frequently. They include...

thrombocytopenia, rashes, headache, dizziness, blurred vision, and in a few cases, toxic amblyopia, fluid retention, and edema.

Chloroprocaine is not selected for IV regional anesthesia because of a high incidence of...

thrombophlebitis.

It is important to recognize that the dose of neuromuscular-blocking drug necessary to produce a given degree of neuromuscular blockade at the diaphragm is about twice the dose required...

to produce similar blockade of the adductor pollicis muscle.

Opioid receptors are found throughout the enteric plexus of the bowel; their activation causes...

tonic contraction of gastrointestinal smooth muscle, thereby decreasing coordinated, peristaltic contractions. Clinically, this results in delayed gastric emptying and presumably higher gastric volumes in patients receiving opioid therapy preoperatively.

cocaine. Proparacaine and tetracaine are used topically to perform...

tonometry, to remove foreign bodies on the conjunctiva and cornea, to perform superficial corneal surgery, and to manipulate the nasolacrimal canalicular system. They also are used topically to anesthetize the ocular surface for refractive surgery using either the excimer laser or placement of intrastromal corneal rings.

Benzocaine has a slow onset, short duration of action and is both minimally potent and minimally toxic. Its clinical use is limited to...

topical anesthesia to anesthetize mucous membranes; for example to anesthetize the oral and pharyngeal mucosa before fiberoptic endotracheal intubation.

Benzocaine's pronounced lipophilicity has relegated its application to...

topical anesthesia.

Tetracaine also is incorporated into several...

topical anesthetic preparations.

An overdose of acetaminophen can lead to depletion of cellular glutathione (GSH) levels, thereby increasing the potential for NAPQI to interact with other cellular components resulting in...

toxicity and cell death.

Hydrophobicity also increases...

toxicity, so that the therapeutic index is decreased for more hydrophobic drugs.

TNS is characterized by...

transient hyperalgesia or dysesthesia in the low back, buttocks, and lower extremities following seemingly uneventful spinal anesthesia but without permanent neurologic damage.

In contrast to MG, where there is weakness or fade with repetitive stimulation of nerve, in LEMS with sustained muscle activity there is a...

transient increase in muscle strength from the initial low level. This is likely a consequence of temporary Ca2 + buildup in the nerve terminal and results in increased neuromuscular transmission.

Mepivacaine 4%, placed in the subarachnoid space, has also been associated with...

transient neurologic symptoms.

Ligand-gated ion channels (LGICs) are a group of ...

transmembrane ion channel proteins which open to allow ions such as Na+, K+, Ca2+, or Cl- to pass through the membrane in response to the binding of a chemical messenger (i.e. a ligand), such as a neurotransmitter.

The incidence of Clostridium botulinum infection appears to be increasing, especially in patients with...

traumatic injuries, drug abusers, and tissue allograft recipients.

Meperidine sometimes causes CNS excitation, characterized by...

tremors, muscle twitches, and seizures; these effects are due largely to accumulation of a metabolite, normeperidine.

Carbamazepine is an iminostilbene derivative with a dibenzazepine nucleus, and thus has a...

tricyclic structure similar to imipramine.

A small dose of meperidine (12.5 mg) lowers the shivering...

trigger temperature and effectively stops the activity.

Biologically, cocaine acts as a serotonin-norepinephrine-dopamine reuptake inhibitor, also known as a...

triple reuptake inhibitor (TRI)

Cisatracurium undergoes Hofmann elimination. Clearance, elimination half-life, and volume of distribution are the same when doses of the ED95 or...

twice the ED95 are administered. The duration of action of 0.1 mg/kg Cisatracurium (2 × ED95) is 45 minutes. Doubling the dose to 4 × ED95 increases it to 68 minutes and doubling it again to 8 × ED95 increases it by another 23 minutes, equivalent to the elimination half-life of the compound.

For conduction blockade to occur in an A fiber, it is necessary to expose at least...

two and preferably three successive nodes of Ranvier (approximately 1 cm) to an adequate concentration of local anesthetic.

Gabapentin, and pregabalin are not appreciably metabolized and are excreted...

unchanged in the urine.

The function of spontaneous ZAC activation is...

unknown.

C fibers are...

unmyelinated.

Relative to fentanyl and sufentanil, hepatic metabolism of alfentanil is more...

unpredictable because of the significant interindividual variability of hepatic CYP3A4, the primary enzyme responsible for alfentanil biotransformation. Because alfentanil has a relatively low hepatic extraction ratio compared to fentanyl, it is more vulnerable to variations in CYP3A4 activity.

EMLA should be applied to intact skin surfaces because application to breached skin surfaces can lead to...

unpredictably rapid absorption.

It is important to emphasize that µ agonists, even when given in very high doses, do not reliably produce...

unresponsiveness and amnesia; thus, they cannot be viewed as complete anesthetics when used alone.

At a TOF count of 2 to 3 responses, recovery may take....

up to 10 to 12 minutes following administration of long-acting relaxants and 4 to 5 minutes after intermediate-acting drugs

The use of antacids aluminum hydroxide and magnesium hydroxide may reduce the bioavailability of gabapentin by...

up to 20%.

Administration of NMBAs to critically ill patients contributes to the...

upregulation of acetylcholine receptors. This increase in acetylcholine receptors renders patients increasingly susceptible to hyperkalemia after succinylcholine administration and cardiac arrest. It may also manifest as an increasing requirement for NMBA in order to maintain the same depth of neuromuscular block.

Dysfunction of central motor neurons due to spinal cord trauma or stroke is associated with muscle weakness or paralysis. This causes a reduction in evoked ACh that leads to...

upregulation of immature AChRs. Upregulation of immature AChRs results in susceptibility to SCh-induced hyperkalemia.

Antimuscarinic compounds increase the risk of tachyarrhythmias and other side effects resulting from muscarinic receptor antagonism such as...

urinary retention, blurred vision, photophobia, mydriasis, xerostomia, dry skin, constipation, nausea, urinary retention, insomnia, and dizziness.

The porphyrias are a group of rare conditions caused by excessive accumulation of porphyrinogens, the precursors of heme. In affected individuals these porphyrinogens are excreted in...

urine and on exposure to light change color, resulting in the classic purple urine.

The 3-desacetyl metabolite of Vecuronium has neuromuscular blocking activity. Only 5% is excreted in the...

urine as the 3-desacetyl metabolite. Even so, the prolonged duration of action of vecuronium in critically ill patients with renal failure has been attributed to accumulation of this metabolite.

In the presence of local anesthetics, repeated depolarization results in an incremental decrease in Na + current until it reaches a newer steady level of inhibition, which is termed...

use-dependent or phasic inhibition. With repeated depolarization, a greater number of Na+ channels are in the active or inactivated state and are bound to local anesthetics.

After GABA is synthesized, it is packaged into synaptic vesicles by the vesicular GABA transporter...

vGAT (also known as vesicular inhibitory amino acid transporter, VIAAT). Upon stimulation of the neuron, these vesicles fuse to the presynaptic terminal and release GABA into the synapse via calcium dependent exocytosis.

The fentanyl congeners produce a slowing of heart rate by directly increasing vagal nerve tone in the brainstem...

vagal nerve tone in the brainstem.

Duration of action is also influenced by the rate of...

vascular uptake of local anesthetic from the injection site.

The action of local anesthetics on peripheral vascular smooth muscle is biphasic with...

vasoconstriction at low concentrations and vasodilation at higher concentrations. The exception is cocaine, which produces vasoconstriction at any dose.

The sympathetic effects of cocaine can precipitate...

vasoconstriction or vasospasm in arteries supplying the brain and heart, leading to strokes and myocardial infarction or ischemia. Higher doses lead to ventricular arrhythmias and death.

A unique feature of cocaine is its ability to produce localized...

vasoconstriction, making it useful to shrink the nasal mucosa in rhinolaryngologic procedures and nasotracheal intubation.

Propofol produces a dose-dependent decrease in blood pressure. The fall in blood pressure can be explained by both...

vasodilation and possibly mild depression of myocardial contractility. Propofol appears to blunt the baroreceptor reflex and reduce sympathetic nerve activity.

All the local anesthetics EXCEPT Cocaine and Ropivacaine, possess the ability to cause...

vasodilation in the area injected.

The anesthetic barbiturates produce dose-dependent decreases in blood pressure. The effect is due primarily to...

vasodilation, particularly venodilation, and to a lesser degree to a direct decrease in cardiac contractility. Typically, heart rate increases as a compensatory response to a lower blood pressure, although barbiturates also blunt the baroreceptor reflex.

Activation of opioid receptors on arterial endothelium results in...

vasodilation. The relative contributions of reduced systemic resistance and decreased heart rate to opioid-induced hypotension vary depending on the exogenous opioid administered.

In contrast to lidocaine, mepivacaine lacks...

vasodilator activity.

α2 and imidazoline receptors may cooperatively regulate...

vasomotor tone and may jointly mediate the hypotensive actions of centrally acting drugs with affinity for both receptor types.

Rocuronium has an intermediate duration of action with an ED95 of 0.3 mg/kg, making it about six times less potent than...

vecuronium and faster in onset than either vecuronium or atracurium.

Lidocaine in combination with tetracaine is marketed in a formulation that generates heat upon exposure to air (SYNERA), which is used prior to...

venous access and superficial dermatological procedures such as excision, electrodessication, and shave biopsy of skin lesions. The mild warming is intended to increase skin temperature by up to 5 ° C for the purpose of enhancing delivery of local anesthetic into the skin.

An important benefit of ketorolac-induced analgesia is the absence of...

ventilatory or cardiovascular depression.

Moderate doses of µ agonists produce a decrease in the ventilatory rate (often associated with a slightly increased tidal volume). As the opioid concentration is increased, both...

ventilatory rate and tidal volume progressively decrease, eventually culminating in an irregular ventilatory rhythm and then complete apnea.

Bupivacaine is more cardiotoxic than equi-effective doses of lidocaine. Clinically, this is manifested by severe...

ventricular arrhythmias and myocardial depression after inadvertent intravascular administration.

Lidocaine and other class Ib drugs can be efficacious in the therapy of rapid heart rate conditions including...

ventricular tachycardia and ventricular fibrillation prevention, and also in cases of symptomatic premature ventricular beats.

The fundamental drive to respiration is located in respiratory centers of the brainstem consisting of different groups of neuronal networks in the...

ventrolateral medulla. These centers do not act in isolation but are modulated by influences from different nuclei of the pons such as the nucleus tractus solitarius, the midline medullary raphe, and the locus coeruleus, known as the chemoreactive zone. All areas show a high density of opioid receptors, particularly mu and delta receptors.

Cocaine is usually consumed orally or by snorting. The alkalinized form ("crack cocaine") can be injected, smoked, or snorted and has even greater addictive potential due to...

very rapid absorption with high peak plasma levels. The elimination half-life is 0.5 to 1.5 hours and metabolism is by liver and plasma cholinesterases.

After synthesis, glutamate is actively transported into vesicles by a family of...

vesicular glutamate transporters (VGLUT1-3). These transporters utilize a proton electrochemical gradient to actively accumulate glutamate in synaptic vesicles.

Physostigmine decreases postoperative somnolence after anesthesia with a...

volatile anesthetic. Nevertheless, administration of physostigmine, 2 mg IV, during sevoflurane administration does not change the bispectral index or enhance recovery following discontinuation of the volatile anesthetic.

Lambert-Eaton myasthenic syndrome (LEMS) is an acquired "presynaptic" disorder of neuromuscular transmission caused by autoantibodies directed against...

voltage-gated Ca2 + channels in the motor nerve terminal resulting in down-regulation by endocytosis. This reduces Ca2 + entry into the nerve terminal during an action potential and thus leads to a reduction in the number of quanta (amount of ACh) released.

Local anesthetics block other ion channels besides Na+ channels including...

voltage-gated K+ channels and Ca2+ channels, but with lower potency compared to Na+ channels. Local anesthetics also bind intracellular G protein-coupled receptors and possibly influence the regulation of intracellular Ca2+.

All three Opioid receptors decrease conductance of the...

voltage-gated calcium channels or open the potassium channels, resulting in decreased neuronal activity.

The traditional mechanism of action of local anesthetics is via blockade of axonal action potential generation or propagation by prevention of...

voltage-gated sodium (Na+) channel (VGSC) conductance that mediates these action potentials. Additionally, local anesthetics also interact with calcium (Ca2+) signaling G protein-coupled receptors (GPCRs), and may mediate their anti-inflammatory actions.

Local anesthetics are poorly soluble in water and therefore are marketed most often as...

water-soluble hydrochloride salts. These hydrochloride salt solutions are acidic (pH 6), contributing to the stability of the local anesthetic.

Benzocaine (ethyl aminobenzoate) is unique among clinically useful local anesthetics because it is a...

weak acid (pKa 3.5), so that it exists only in the nonionized form at physiologic pH. As such, benzocaine is ideally suited for topical anesthesia of mucous membranes prior to tracheal intubation, endoscopy, transesophageal echocardiography, and bronchoscopy.

Formation of glucuronide conjugates may be impaired by monoamine oxidase inhibitors, which is consistent with exaggerated effects of morphine...

when administered to patients being treated with these drugs.

Clonidine also is beneficial in the treatment of opioid...

withdrawal in an intensive care unit (ICU) setting.

Rifampin and phenytoin accelerate the metabolism of methadone and can precipitate...

withdrawal symptoms.

Even after prolonged administration of high doses of the antagonist alone, discontinuation of naloxone is not followed by any recognizable...

withdrawal syndrome, and the withdrawal of naltrexone, another relatively pure antagonist, produces very few signs and symptoms.

There is evidence that morphine is more potent in...

women than in men (i.e., that a lower concentration is required to produce comparable analgesia) and that it has a slower onset of action in women.

Naloxone stimulates the release of prolactin in...

women.

NMDA receptors are found presynaptically, postsynaptically, and extrasynaptically; they are important targets for...

xenon, nitrous oxide and the dissociative anesthetic ketamine.

Side effects of Gabapentin include...

xerostomia, peripheral edema, angioedema, blurred vision, ataxia, dysarthria, tremor, lethargy, memory impairment, euphoria, constipation, decrease or loss of libido, and weight gain

The benzodiazepines and their active metabolites bind to plasma proteins. The extent of binding correlates strongly with lipid solubility and ranges from...

~ 70% for alprazolam to nearly 99% for diazepam.

In contrast to morphine, methadone and many of its congeners retain a considerable degree of their effectiveness when given orally. In terms of total analgesic effects, methadone given orally is...

~50% as effective as the same dose administered intramuscularly; however, the oral-parenteral potency ratio is considerably lower when peak analgesic effect is considered.

Suppression of the cough reflex is another important therapeutic effect of the...

µ agonists in the practice of anesthesia. This antitussive effect is mediated through the cough centers in the medulla. Attenuation of the cough reflex presumably makes coughing and struggling against an indwelling endotracheal tube less likely.

The pain-modulating effects of κ-receptor agonists in the brainstem appear to oppose those of...

µ-receptor agonists.

In order for GABAA receptors to be sensitive to the action of benzodiazepines they need to contain an...

α and a γ subunit, between which the benzodiazepine binds.

Benzodiazepines are thought to interact with GABAA receptors between the...

α and γ subunits and specific clinical effects have been linked to receptors containing specific α and β subunits.

Benzodiazepines increase the GABA affinity of...

α(1, 2, 3 or 5)βxγx containing GABAA receptors.

The agonist binding sites of the acetylcholine receptor are located at the interface of the...

α-δ and α-ε subunits where the N-terminus of each subunit interacts with that of the other to form the acetylcholine binding site. In order for the central pore of the receptor to open, allowing for influx of Na + and Ca2 + and efflux of K +, two agonist molecules must be bound to the receptor.

The fetal α-γ binding site is generally more sensitive than the mature...

α-ε one. The α-γ binding site has up to a 500-fold greater affinity for d-tubocurarine than does the α-δ binding site. In mature receptors, the α-δ binding site appears to be more important than the α-ε site in determining receptor affinity for pancuronium, vecuronium, and cisatracurium.

Diuretics predictably potentiate the hypotensive effect of...

α2 adrenergic agonists.

Dexmedetomidine also reduces shivering in an additive fashion with meperidine, raising the possibility that effects of both are mediated by...

α2 receptors.

Even more selective is the benzodiazepine-like hypnotic compound, zolpidem. This drug potently enhances α1βxγ2 mediated inhibition, has much weaker effects on...

α2,3βxγ2 mediated currents, and is virtually inactive at all other GABAR subunit combinations.

The locus ceruleus is an important modulator of wakefulness and the major site of the sedative/ hypnotic actions of the...

α2-agonists.

The α2C-AR elicits depressive behaviors, behaving functionally the opposite of the...

α2A-AR subtype.

Central effects of α2-adrenergic ligands, such as the hypotensive, sedative, and antiepileptic effects, are primarily mediated by the ...

α2A-subtype. Conversely, the vascular hypertensive effect of these drugs is achieved through the α2B- subtype.

At doses higher than those required to stimulate central α2A receptors, these drugs can activate α2 receptors of the...

α2B subtype on vascular smooth muscle cells. This effect accounts for the initial vasoconstriction that is seen when overdoses of these drugs are taken, and may be responsible for the loss of therapeutic effect that is observed with high doses.

The mechanism of action for gabapentin and pregabalin is also uncertain, but both drugs have high binding affinities to the...

α2δ-1 subunit of presynaptic voltage-gated calcium channels in the CNS.

The G-protein's α subunit, together with the bound GTP, can then dissociate from the...

β and γ subunits to further affect intracellular signaling proteins or target functional proteins directly depending on the α subunit type (Gαs, Gαi/o, Gαq/11, Gα12/13).

Propofol, etomidate, and barbiturates interact with GABAA receptors within, or proximal to...

β subunits. The β subunits show less specific subcellular localization compared to α subunits, and the distribution of β subunits in mammalian brain does not share the same clear distinctions as α subunits.

The GABAA receptor (GABAAR) is an ionotropic receptor and ligand-gated ion channel. Its endogenous ligand is...

γ-aminobutyric acid (GABA), the major inhibitory neurotransmitter in the central nervous system. Upon activation, the GABAA receptor selectively conducts Cl- through its pore, resulting in hyperpolarization of the neuron. This causes an inhibitory effect on neurotransmission by diminishing the chance of a successful action potential occurring.

The majority of intravenous anesthetics exert their primary clinical anesthetic action by enhancing inhibitory signaling via...

γ-aminobutyric acid type A (GABAA) receptors. Ketamine and dexmedetomidine are notable exceptions.

Thiopental discriminates between synaptic and extrasynaptic GABAA receptors in the hippocampus, suggesting a possible role for the...

δ subunit in barbiturate enhancement of this channel. The β subunit has also been implicated as a molecular site of action of barbiturates at GABAA receptors.

Activation of the κ-opioid receptor appears to antagonize many of the effects of the...

μ-opioid receptor.

SUCCINYLCHOLINE (Anectine, Quelicin): Physiologic Effects

*Variable and unpredictable cardiovascular effects r/t stim of preganglionic autonomic Ach receptors *Bradycardia r/t stimulation of muscarinic receptors at the SA node *Give atropine or glycopyrrolate w/ 1st dose in kids and always before 2nd dose in anyone *HTN or tachycardia related to stimulation of nicotinic Ach receptors at the ganglia of the ANS *Fasciculations occur due to initial release of Ach --> myalgias, myoglobinuria *Hyperkalemia - potassium increases 0.5meq/L *Increased IOP, ICP, and intragastric pressure *Fasiculations prevented with small dose of NDP 3-5 minutes beforehand. Succ dose must be increased to 2-2.5mg/kg due to the antagonistic effect *Can be sustained muscle tension mediated by Ach receptors, usually in the masseter muscle *Blockade is potentiated by inhibitors of acetylcholinesterase, mainly neostigmine and edrophonium. It is reversed by non-depolarizers and their administration increases the ED95 by a factor of 2 *Possible anaphylaxis r/t histamine release *Infants and neonates require about 2x the dose of adults r/t increased body water since Succ is water soluble *Malignant hyperthermia *Pregnancy, uremia, liver disease, malnutrition, burns, plasmapharesis, metoclopramide and oral contraceptives all lower plasma cholinesterase and may result in slightly prolonged blockade *MG pts have antibodies that reduce the number of postsynapytic Ach receptors and are resistant to Succ *↑Mg augments blocks by inhibiting the release of calcium that is necessary to release Ach molecules and reducing the sensitivity of the post junctional membrane to Ach *Succ given after neostigmine (laryngospasm) will last almost 60 min *Anticholinesterases increase Ach release, which augments depolarization and inhibit plasma cholinesterase

C Sympathetic Fiber: Function

*Vasomotor *Visceromotor *Sudomotor *Pilomotor

GABAPENTIN (Neurontin): Considerations

*Withdrawal may occur with abrupt discontinuation

The ionotropic glutamate receptors (iGluR) bind the neurotransmitter glutamate. They form tetramers with each subunit consisting of:

*an extracellular amino terminal domain (ATD, which is involved tetramer assembly) *an extracellular ligand binding domain (LBD, which binds glutamate) *a transmembrane domain (TMD, which forms the ion channel)

G-proteins are made up of three subunits:

*an α subunit that is important for recognition and effector functions *β and γ subunits that are important for membrane localization but also have effector funtions

There are two principal signal transduction pathways involving the G protein-coupled receptors:

*cAMP signal pathway *Phosphatidylinositol signal pathway

Postjunctional membranes possess two types of nAChRs that respond to neuromuscular-blocking drugs:

*nAChRs are present in large numbers on postjunctional membranes *Extrajunctional nAChRs appear throughout skeletal muscles whenever there is deficient stimulation of the skeletal muscle membrane by the nerve

Fentanyl is extensively metabolized by N-demethylation, producing...

*norfentanyl *hydroxyproprionyl-fentanyl *hydroxyproprionyl-norfentanyl ***Norfentanyl is structurally similar to normeperidine and is the principal metabolite of fentanyl in humans. It is excreted by the kidneys and can be detected in the urine for 72 hours after a single IV dose of fentanyl. Less than 10% of fentanyl is excreted unchanged in the urine.

Determinants of LA speed of onset:

*pKa *The amount of LA in unionized form is that determines speed of onset since it is this form that penetrates the axon to gain access to the axolemma. *The closer the drugs pKa is to physiologic pH, the quicker the onset. (except chloroprocaine with a pka of 9.1 which is most likely d/t the higher concentration administration of chloroprocaine=3%)

BENZOCAINE (Anbesol, Cepacol, Lanacane, Hurricaine): pKa

*pKa: 3.5

MEPIVICAINE (Carbocaine, Polocaine): pKa/ % ionized at pH 7.4

*pKa: 7.6 *% Ionized: 60

LIDOCAINE (Xylocaine): pKa/ % ionized at pH 7.4

*pKa: 7.9 *% Ionized: 75

PRILOCAINE (Citanest): pKa/ % ionized at pH 7.4

*pKa: 7.9 *% Ionized: 75

BUPIVICAINE (Marcaine, Sensorcaine): pKa/ % ionized at pH 7.4

*pKa: 8.1 *% Ionized: 85

ROPIVICAINE (Naropin): pKa/ % ionized at pH 7.4

*pKa: 8.1 *% Ionized: 85%

COCAINE: pKa/ % ionized at pH 7.4

*pKa: 8.5 *% Ionized: 95

TETRACAINE (Pontocaine): pKa/ % ionized at pH 7.4

*pKa: 8.5 *% Ionized: 95

CHLOROPROCAINE (Nesacaine): pKa/ % ionized at pH 7.4

*pKa: 8.7 *Ionized: 95%

PROCAINE (Novocaine): pKa/ % ionized at pH 7.4

*pKa: 8.9 *Ionized: 95%

AMITRIPTYLINE (Elavil): MOA

*serotonin-norepinephrine reuptake inhibitor *5-HT2A, 5-HT2C, 5-HT3, 5-HT6, 5-HT7 Antagonist *α1-adrenergic Receptor Antagonist *H1,H2&H4 Antagonist *mAChR Antagonist *σ1 Receptor Agonist *NMDA Receptor Antagonist *Na+ Channel Blocker *Ca2+ Channel Blocker *K+ Channel Blocker *TrkA & TrkB Receptor Agonist

The rate and extent of systemic absorption of local anesthetic depend on multiple factors:

*site of injection *dose *physiochemical properties of the drugs *presence of vasoconstrictive or other adjuvants

Opioid order of potency (relative to morphine) is:

*sufentanil (1000 ×) *remifentanil (300 ×) *fentanyl (100 ×) *alfentanil (15 ×) *morphine (1 ×) *meperidine (0.1 ×)

CATAPRES (Clonidine): Class

*α2 adrenergic receptor agonist -Imidazole derivative

PRECEDEX (Dexmedetomidine): Class

*α2 adrenergic receptor agonist -Imidazole derivative -S-enantiomer of medetomidine

α2-AR Behavioral Effects: Antianxiety

*α2A-AR

α2-AR Behavioral Effects: Antiepileptogenic effect

*α2A-AR

α2-AR Behavioral Effects: Special working memory

*α2A-AR

α2-AR Central Effects: Adrenergic-opioid synergy in spinal antinociception

*α2A-AR

α2-AR Central Effects: Anesthetic-sparing effects of dexmedetomidine

*α2A-AR

α2-AR Central Effects: Antinociceptive effects of α2-adrenergic receptor agonist

*α2A-AR

α2-AR Central Effects: Hypotensive Effect

*α2A-AR

α2-AR Central Effects: Sedative Effect

*α2A-AR

α2-AR Peripheral Effects: Platelet aggregation

*α2A-AR

α2-AR Peripheral Effects: Inhibition of noradrenaline release from nerve terminal invaded into tissues

*α2A-AR *α2B-AR *α2C-AR

α2-AR Central Effects: Antinociceptive effects of moxonidine

*α2A-AR *α2C-AR

α2-AR Central Effects: Hypothermic effects of dexmedetomidine

*α2A-AR *α2C-AR

α2-AR Central Effects: Presynaptic inhibition of norepinephrine, dopamine, serotonin release

*α2A-AR *α2C-AR

α2-AR Central Effects: Analgesic effect of nitrous oxide

*α2B-AR

α2-AR Peripheral Effects: Placenta angiogenesis

*α2B-AR

α2-AR Peripheral Effects: Prevention of respiratory failure

*α2B-AR

α2-AR Peripheral Effects: Salt-induced hypertension

*α2B-AR

α2-AR Peripheral Effects: Vasoconstriction, hypertensive effect

*α2B-AR

α2-AR Behavioral Effects: Inhibition of locomotor stimulation of D-amphetamine

*α2C-AR

α2-AR Behavioral Effects: Inhibition of startle responses

*α2C-AR

α2-AR Behavioral Effects: Latency to attack after isolation

*α2C-AR

α2-AR Peripheral Effects: Inhibition of adrenaline release from adrenal cortex

*α2C-AR

ROCURONIUM (Zemuron): Considerations

*↑potency: Aminoglycoside & polymixin Antibiotics, CCB, inhalation agents, lithium, local anesthetics, neuromuscular disorders,resp acidosis, metabolic alkalosis, hypothermia, hypokalemia, hypocalcemia, MG *Hypermagnesemia augments blocks by inhibiting the release of calcium that is necessary to release Ach molecules and reducing the sensitivity of the post junctional membrane to Ach *Dantrolene directly relaxes smooth muscle & augments block *↓potency: anticonvulsants, cholinesterase inhibitors, muscle trauma, burns, deenervation, immobilization, infection, ↑Ca,K, ↓Mg, demyelinating lesions, peripheral neuropathies, DM, cerebral palsy, severe chronic infections(tetanus, botulism). *Lasix decreases cAMP at the motor nerve terminal, which usually opens calcium channels permitting calcium to enter and cause the release of Ach, so lasix decreases NMB *Slightly vagolytic *Reduce dose in Liver Disease

VECURONIUM BROMIDE (Norcuron): Considerations

*↑potency: Aminoglycoside & polymixin Antibiotics, CCB, inhalation agents, lithium, local anesthetics, neuromuscular disorders,resp acidosis, metabolic alkalosis, hypothermia, hypokalemia, hypocalcemia, MG *Hypermagnesemia augments blocks by inhibiting the release of calcium that is necessary to release Ach molecules and reducing the sensitivity of the post junctional membrane to Ach *Dantrolene directly relaxes smooth muscle & augments block *↓potency: anticonvulsants, cholinesterase inhibitors, muscle trauma, burns, deenervation, immobilization, infection, ↑Ca,K, ↓Mg, demyelinating lesions, peripheral neuropathies, DM, cerebral palsy, severe chronic infections(tetanus, botulism). *Lasix decreases cAMP at the motor nerve terminal, which usually opens calcium channels permitting calcium to enter and cause the release of Ach, so lasix decreases NMB *Slightly vagolytic *Reduce dose in Liver Disease

PANCURONIUM BROMIDE (Pavulon): Considerations

*↑potency: Aminoglycoside & polymixin Antibiotics, CCB, inhalation agents, lithium, local anesthetics, neuromuscular disorders,resp acidosis, metabolic alkalosis, hypothermia, hypokalemia, hypocalcemia, MG *Hypermagnesemia augments blocks by inhibiting the release of calcium that is necessary to release Ach molecules and reducing the sensitivity of the post junctional membrane to Ach *Dantrolene directly relaxes smooth muscle & augments block *↓potency: anticonvulsants, cholinesterase inhibitors, muscle trauma, burns, deenervation, immobilization, infection, ↑Ca,K, ↓Mg, demyelinating lesions, peripheral neuropathies, DM, cerebral palsy, severe chronic infections(tetanus, botulism). *Lasix decreases cAMP at the motor nerve terminal, which usually opens calcium channels permitting calcium to enter and cause the release of Ach, so lasix decreases NMB *Vagolytic *Reduce dose in Renal Disease

The reversal potential the GABAB-mediated IPSP is...

-100 mV, which is much more hyperpolarized than the GABAA IPSP. GABAB receptors are found in the central and peripheral autonomic nervous system.

The reversal potential of the GABAA-mediated IPSP in normal solution is..

-70 mV, contrasting the GABAB IPSP.

The typical dose of neostigmine for antagonism of profound neuromuscular block (a TOF count of 2) is...

0.05 mg/kg and 0.015 to 0.025 mg/kg for antagonism of lesser degrees of neuromuscular block (a TOF count of 4 with no fade).

For epidural analgesia and anesthesia, bupivacaine is usually used at concentrations from...

0.25% to 0.5%, with a 2- to 5-hour duration of action.

The volume of distribution of these anticholinesterases (neostigmine or edrophonium) is...

0.7 to 1.4 L/kg and their elimination half-lives are 60 to 120 minutes. Clearance is 8 to 16 mL/kg/min, which is greater than the glomerular filtration rate because anticholinesterases are actively secreted. Therefore, in patients with renal failure, in whom the duration of action of NMBAs is likely to be increased, clearance of anticholinesterases is also reduced and elimination half-life increased. This makes dose adjustment of anticholinesterases in patients with renal dysfunction unnecessary.

No anticholinesterase is required if TOFR is greater than...

0.9 using a quantitative monitor of neuromuscular function.

Although there is considerable interpatient variation, EMLA cream should be applied under an occlusive dressing for about...

1 hour to provide adequate analgesia for insertion of an intravenous catheter or the drawing of blood at roughly 2.5 g of the cream applied over a 25 cm2 area of skin.

TOF: Tracheal intubation

1 twitch

Cocaine hydrochloride is provided as a...

1%, 4%, or 10% solution for topical application. For most applications, the 1% or 4% preparation is preferred to reduce toxicity.

Dose-dependent systemic effects of lidocaine: Plasma concentration (μg/mL)

1-5:Analgesia 5-10: Lightheadedness, Numbness of tongue, Tinnitus, Muscular twitching 10-15: Seizures, Unconsciousness 15-25: Coma, Respiratory arrest > 25: Cardiovascular depression

Order of Nerve fiber blockade by LA from first to last:

1. B 2. C 3. Aδ 4. Aγ 5. Aβ 6. Aα

The NMDA receptor is distinct in two ways:

1. It is both ligand-gated and voltage-dependent 2. It requires co-activation by two ligands: glutamate and either d-serine or glycine.

What are the signs of local anesthetic toxicity - in order of appearance?

1. Lightheadedness, tinnitus, circumoral and tongue numbness 2. Visual disturbances 3. Muscular twitching 4. Convulsions 5. Unconsciousness 6. Coma 7. Respiratory arrest 8. CVS depression occurs at plasma concentrations of around 25 ng/mL

Order of loss of Blockade: First>>>Last

1.Autonomic regulation 2. Temperature (esp. cold) 3. Dull pain 4. Sharp pain 5. Deep pressure 6. Proprioception 7. Somatic muscle function

Ketorolac, 30 mg IM, produces analgesia that is equivalent to...

10 mg of morphine or 100 mg of meperidine.

Animal models of hemorrhagic shock suggest that the induction dose of Propofol should be reduced to between...

10% and 20% of usual doses if given before fluid resuscitation and decreased 50% if given after resuscitation.

Sufentanil is rapidly metabolized by N-dealkylation at the piperidine nitrogen and by O-demethylation. The products of N-dealkylation are pharmacologically inactive, whereas desmethyl sufentanil has about...

10% of the activity of sufentanil. Less than 1% of an administered dose of sufentanil appears unchanged in urine.

The t1/2 of cocaine in plasma is ∼ 50 minutes, but inhalant (crack) users typically desire more cocaine after...

10-30 minutes. Intranasal and intravenous uses also result in a high of shorter duration than would be predicted by plasma cocaine levels, suggesting that a declining plasma concentration is associated with termination of the high and resumption of cocaine .

Train-of-four: T0

100% blocked

Cetacaine is a combination of...

14% benzocaine, 2% tetracaine, and 2% butamben.

Morphine is well absorbed after IM administration, with onset of effect in...

15 to 30 minutes and a peak effect in 45 to 90 minutes. The duration of action is about 4 hours.

The NMDA receptor forms a heterotetramer between...

2 GluN1 and two GluN2 subunits, 2 obligatory NR1 subunits and 2 regionally localized NR2 subunits.

Acetaminophen is completely and rapidly absorbed following oral administration, and peak serum concentrations are achieved within...

2 hours.

The edrophonium test for evaluation of possible myasthenia gravis is performed by rapid intravenous injection of...

2 mg of edrophonium chloride, followed 45 seconds later by an additional 8 mg if the first dose is without effect; a positive response consists of brief improvement in strength, unaccompanied by lingual fasciculation (which generally occurs in non-myasthenic patients).

At a dose of 2 times the ED95, Rocuronium has an onset of less than...

2 minutes and a clinical duration of less than 40 minutes. Increasing the dose to speed onset of neuromuscular block increases the duration of action.

Many opioids have been used epidurally. Morphine...

2-6 mg, every 6 hours, commonly is used for bolus injections

Following administration of Atracurium at two times the ED95, maximal block occurs in...

2.5 minutes, recovery to 10% of baseline twitch amplitude (approximately 1 twitch in the TOF) occurs in 40 minutes, and complete spontaneous recovery of neuromuscular function occurs in about 60 minutes.

At anesthesia induction, small doses of opioids, such as fentanyl 1 µg/kg, have a small effect on the hypnotic dose of propofol reducing dose requirements by...

20%, but a large effect on propofol dose to suppress movement to pain, reducing dose requirements by 50%.

A brief spray of 20% benzocaine delivers the recommended dose of...

200 to 300 mg.

In the United States, dexmedetomidine is approved for infusions up to...

24 hours, but much longer infusions have been reported in the literature. There are concerns for withdrawal phenomena for prolonged infusions but no clear withdrawal syndrome has been reported.

Elimination half life of carbamazepine is highly variable and is initially...

25 to 65 hours, but reduces to 12 to 17 hours after several weeks of therapy due to autoinduction.

GABAA receptors are heteropentameric protein complexes, generally composed of a combination of...

2α, 2β and either a γ or δ subunit. To date, there are 6α, 3β, 3γ and a single δ isoform subtypes.

Prolonged immobility is associated with muscle atrophy due to disuse. Although motor neurons remain intact, immobility results in a relative increase in...

2α1β1γ and α7 AChRs (immature). The result is a resistance to nondepolarizing NMBAs and increased sensitivity to depolarizing SCh.

Adding sodium bicarbonate will speed the onset of peripheral nerve block and epidural block by...

3 to 5 minutes.

Metabolism of Vecuronium in the liver leads to the primary metabolite...

3-desacetyl vecuronium, which is almost as potent as vecuronium and is cleared more slowly from the plasma.

Methadone is absorbed well from the GI tract and can be detected in plasma within...

30 minutes of oral ingestion; it reaches peak concentrations at ~4 hours. After therapeutic doses, ~ 90% of methadone is bound to plasma proteins. Peak concentrations occur in brain within 1-2 hours of subcutaneous or intramuscular administration, and this correlates well with the intensity and duration of analgesia. Methadone also can be absorbed from the buccal mucosa.

In elderly patients, the clearance of Vecuronium is decreased by...

30% to 55% and elimination half-life is increased by 60%. This results in a three-fold prolongation of the 25% to 75% recovery interval of Vecuronium following either a bolus dose of 0.1 mg/kg or an infusion to maintain 90% suppression of twitch height for 90 minutes.

Like other NSAIDs, aspirin sensitivity is a contraindication to the use of ketorolac. Typical doses are...

30-60 mg (intramuscular), 15-30 mg (intravenous), and 10-20 mg (oral).

Remifentanil is unique among the opioids in undergoing metabolism by nonspecific plasma and tissue esterases to inactive metabolites. The principal metabolite, remifentanil acid, is...

300 to 4,600-fold less potent than remifentanil as a mu agonist and is excreted primarily by the kidneys. This and the other inactive metabolites undergo renal excretion. N-dealkylation of remifentanil is a minor metabolic pathway in humans.

Resistance to nondepolarizing NMBAs has been reported to emerge as early as...

4 days after immobilization and hyperkalemic cardiac arrest after the administration of SCh as early as 5 days after immobilization. After remobilization, these abnormalities should revert to normal but the duration of the restorative process can take months and depends on the severity of the illness. Based on these findings it is prudent to avoid SCh in patients who have been immobilized for more than 48 to 72 hours.

The maximum recommended duration of exposure for EMLA is...

4 hours, although exposures of up to 24 hours have not led to toxic plasma levels of local anesthetics.

Dexmedetomidine is supplied as an aqueous solution of the hydrochloride salt and should be diluted in normal saline to a final concentration of...

4 μg/ mL for intravenous delivery, the only approved route of administration.

Vecuronium is a potent NMBA (ED95 is 0.05 mg/ kg) with a duration of action of...

40 minutes. Typically twice the ED95 is administered to facilitate tracheal intubation. Doses of five to six times the ED95 can be administered for more rapid onset of effect without significant hemodynamic side effects.

When the 4th response to TOF stimulation appears, adequate recovery can be achieved within...

5 minutes of reversal with neostigmine or 2 to 3 minutes after edrophonium

Compared to the currently marketed fentanyl congeners, remifentanil's context sensitive half-time is short, on the order of about...

5 minutes. Pharmacodynamically, remifentanil exhibits a short latency-to-peak effect similar to alfentanil and a potency slightly less than fentanyl.

Bolus doses of either neostigmine or edrophonium result in peak plasma concentrations within...

5 to 10 minutes that decrease rapidly, followed by a slower decline that corresponds to the elimination phase.

After epidural administration, fentanyl blood concentrations peak in...

5 to 10 minutes, whereas blood concentrations of the more lipid-soluble sufentanil peak even sooner. In contrast, blood concentrations of morphine after epidural administration peak after 10 to 15 minutes.

Lidocaine, mepivacaine, and prilocaine demonstrate effects on the CNS at plasma concentrations of...

5 to 10 μg/mL.

NSAIDs are weak acids with pKa values typically lower than...

5, and therefore exist mostly in the ionized form at physiologic pH.

Although pharmacokinetic changes also play a role, pharmacodynamic differences are primarily responsible for the decreased dose requirement in older patients (e.g., older than 65 years of age). These combined pharmacokinetic and pharmacodynamic changes mandate a reduction in remifentanil dosage by at least...

50% or more in seniors. Similar dosage reductions are also prudent for other µ agonists.

Prolonged weakness has been reported following the use of all NMBAs and occurs in 20% of patients receiving NMBAs for more than...

6 days. Administration of corticosteoids increases the incidence to as much as 40%. Minimizing these adverse events requires administering NMBAs only to those patients who require them and allowing intermittent recovery of neuromuscular function (" drug holidays").

Even remote cocaine use can result in myocardial ischemia and hypotension for as long as...

6 weeks after discontinuing cocaine use. Presumably, delayed episodes of myocardial ischemia are due to cocaine-induced coronary artery vasospasm.

There are three known mammalian tachykinin receptors termed NK1, NK2 and NK3. All are members of the...

7 transmembrane G-protein coupled receptor family and induce the activation of phospholipase C, producing inositol triphosphate (so called Gq-coupled).

Train-of-four: T4

70-75% blocked

For post-operative analgesia, spinally administered morphine, 0.2-0.5 mg, usually will provide...

8-16 hours of analgesia.

Dibucaine inhibits normal butyrylcholinesterase more than it does the abnormal enzyme. It inhibits normal butyrylcholinesterase activity by about...

80%; in individuals who are homozygous for the atypical variant, dibucaine inhibits the activity by only 20%. The enzyme activity of individuals who are heterozygous for atypical butyrylcholinesterase is inhibited by approximately 50%.

Train-of-four: T3

85% blocked

Train-of-four: T2

85-90% blocked

Pancuronium doses of 0.08 and 0.1 mg/kg used for tracheal intubation have durations of action of...

86 and 100 minutes, respectively. Its long duration of action is due to its primary elimination through the kidney, while it undergoes some deacetylation in the liver.

Train-of-four: T1

90-95% blocked

Methadone, 20 mg IV, produces postoperative analgesia lasting...

>24 hours, reflecting its prolonged (35 hours) elimination half-time.

Nerves are typically characterized by their degree of myelination, axonal diameter, and speed of impulse conduction. They are classified as...

A, B, and C fibers, which roughly corresponds to their decreasing cross-sectional diameters.

It is worth mentioning that physostigmine causes nonspecific central arousal via increasing...

ACh and cyclic adenosine monophosphate (cAMP) levels in the CNS, which makes identification of drug-induced postoperative somnolence caused by the central anticholinergic action as opposed to a residual anesthetic effect controversial.

The concomitant presence of disease-induced immobilization can contribute to increased...

AChR expression and altered sensitivity to muscle relaxants.

Thermal injury, direct muscle trauma, and infection are all associated with increased...

AChR expression, especially at sites proximate to the injury. The concomitant presence of disease-induced immobilization can contribute to increased AChR expression and altered sensitivity to muscle relaxants.

Postsynaptic defects, which comprise 75% of CMS, are due to mutations in...

AChR subunits that alter the kinetics of AChR ion channels or reduce channel density at the endplate.

Muscle relaxants produce a state of complete immobilization leading to disuse atrophy and even a denervation-like state, evidenced by the upregulation of...

AChRs throughout the muscle membrane. Thus immobilization (disuse) produced by muscle relaxants can aggravate systemic disease-induced muscle wasting in critically ill patients.

Chronic treatment with NMBAs commonly used in the intensive care unit to facilitate mechanical ventilation upregulate...

AChRs, not only because of immobilization but also as a result of antagonism of the receptor itself.

α2A-AR polymorphisms have been linked to increased risk of...

ADHD, hypertension and type 2 diabetes. Additionally, genetic variants in all three subtypes have been associated with various forms of cardiovascular dysfunction.

In addition to GABAA receptors, barbiturates modulate a variety of ligand-gated ion channels in vitro. They block the action of the excitatory neurotransmitter glutamate at...

AMPA and kainate receptor subtypes, but not at NMDA receptors. They also inhibit neuronal nicotinic acetylcholine receptors.

Sub-anesthetic concentrations of barbiturates also can reduce glutamate-induced depolarizations; only the....

AMPA subtypes of glutamate receptors sensitive to kainic acid or quisqualic acid appear to be affected.

PROCAINE (Novocaine): Considerations

About 1 in 3000 people have an atypical form of pseudocholinesterase, which does not hydrolyze ester anesthetics such as procaine, resulting in a prolonged period of high levels of the anesthetic in the blood and increased toxicity.

Amides: Allergies

Allergy to amides is extremely rare, there is no cross allergy among amide class or between the ester and amide agents

Cholinesterase inhibitors are recommended for treatment of patients with mild to moderate...

Alzheimer disease. Four centrally active cholinesterase inhibitors (tacrine, donepezil, rivastigmine, galantamine) are available to treat Alzheimer disease.

Observational studies have suggested that NSAID use, in particular ibuprofen, is associated with lower risk of developing...

Alzheimer's disease.

Amides: Duration of action

Amides are longer acting because they are more lipophilic and protein bound and require transport to the liver for metabolism

TRAMADOL (Ultram): Class

Analgesic

Cisatracurium is the 1 R-cis 1′ R-cis stereoisomer of the 10 stereoisomers that comprise...

Atracurium. Its innovative development involved isolation and testing of individual stereoisomers from the parent mixture, with selection and further development of the one with reduced side effects.

Chloroprocaine is thought to have the lowest...

CNS and cardiovascular toxicity of all agents in current use.

GABA is the most abundant inhibitory neurotransmitter in the brain. GABAA receptors represent the most abundant receptor type for this ubiquitous inhibitory signaling molecule. GABAA receptors are broadly distributed in the...

CNS and regulate neuronal excitability. They appear to mediate unconsciousness, arguably the most recognizable phenotype associated with general anesthesia. There is also strong evidence that GABAA receptors are involved in mediating some of the other classic components of general anesthesia including depression of spinal reflexes and amnesia. The contribution of GABAA receptors in mediating immobility and analgesia is less clear.

Clinically significant cardiovascular depression usually occurs at serum lidocaine levels that produce marked...

CNS effects. The metabolites monoethylglycine xylidide and glycine xylidide may contribute to some of these side effects.

Like morphine, hydromorphone is metabolized by conjugation, yielding hydromorphone-3-glucuronide (H3G), which has...

CNS excitatory properties. However, hydromorphone has not been shown to form significant amounts of a 6-glucuronide metabolite.

Alkalinization of the blood, as produced by hyperventilation of the patient's lungs, will increase the nonionized fraction of morphine and thus enhance its passage into the...

CNS. Nevertheless, respiratory acidosis, which decreases the nonionized fraction of morphine, results in higher plasma and brain concentrations of morphine than are present during normocarbia.

Nebulized morphine may also reduce breathlessness in...

COPD and could act in part on opioid receptors in the lung.

The NSAIDs (eg, indomethacin, ibuprofen) block both prostaglandin and thromboxane formation by reversibly inhibiting...

COX activity. The traditional NSAIDs are not selective for COX-1 or COX-2.

Ibuprofen is approximately equipotent on...

COX-1 and COX-2.

The COX enzymes are now known to exist as three isoforms:

COX-1, COX-2, and COX-3.

COX-3 is a splice variant of...

COX-1, and is now recognized as the once elusive enzyme inhibited by acetaminophen. However, controversy still exists about the existence of COX-3 inhibition in humans and the mechanism by which acetaminophen-mediated analgesia occurs.

Carbamazepine has strong induction effects on...

CYP 1A2, 2B6, 2C8, 2C9, 2C19, 3A4, and P-glycoprotein, and thus has the potential for significant drug interactions.

Metabolism of acetaminophen and the fluorinated volatile anesthetics is predominantly by the...

CYP 2E1 enzyme.

An important enzyme for the metabolism of midazolam, lidocaine, fentanyl, and alfentanil is...

CYP 3A4-5, which is responsible for 50% of drug oxidation reactions and has reduced activity in 6% of Caucasians.

In adults, hepatotoxicity may occur after ingestion of a single dose of 10-15 g (150-250 mg/kg) of acetaminophen; doses of 20-25 g or more are potentially fatal. Conditions of...

CYP induction (e.g., heavy alcohol consumption) or GSH depletion (e.g., fasting or malnutrition) increase the susceptibility to hepatic injury, which has been documented, albeit uncommonly, with doses in the therapeutic range.

Oxycodone is a potent semisynthetic opioid prodrug that is oxidized to oxymorphone by...

CYP2D6 and N-demethylated by CYP3A.

Both midazolam and diazepam are metabolized by...

CYP3A family members in the liver and are subject to interactions with erythromycin and antifungal medications. Diazepam is also metabolized by CYP1A2 and CYP2C19.

The benzodiazepines are metabolized extensively by hepatic CYPs, particularly...

CYPs 3A4 and 2C19.

The NMDA receptor is a non-specific cation channel that can allow the passage of...

Ca2+ and Na+ into the cell and K+ out of the cell.

A higher than expected incidence of muscular back pain following epidural anesthesia with 2-chloroprocaine has also been reported. This back pain is thought to be due to tetany in the paraspinus muscles, which may be a consequence of...

Ca2+ binding by the EDTA included as a preservative; the incidence of back pain appears to be related to the volume of drug injected and its use for skin infiltration.

Gabapentin and pregabalin bind avidly to the α2δ subunit of voltage-gated Ca2+ channels. This appears to underlie the main mechanism of action, which is decreasing...

Ca2+ entry, with a predominant effect on presynaptic N-type channels. A decrease in the synaptic release of glutamate provides the antiepileptic effect.

The excitatory postsynaptic potential (EPSP) produced by activation of an NMDA receptor increases the concentration of...

Ca2+ in the cell. The Ca2+ can in turn function as a second messenger in various signaling pathways.

Functional studies show that intrathecal opioids inhibit the ...

Ca2+ influx of incoming peripheral sensory neurons and the subsequent spinal release of glutamate and neuropeptides such as substance P. In addition, postsynaptic opioid receptors open G-protein-coupled inwardly rectifying K+ (GIRK) channels and hyperpolarize the membrane. These two mechanisms may underlie the potent analgesic effects of intrathecally or epidurally applied opioids.

The metabolism of midazolam, alfentanil, fentanyl, methadone, tramadol, and most nondepolarizing muscle relaxants is increased with...

Carbamazepine use, but the effect of reduced plasma concentration is countered by generalized enhancement of the CNS depressant effects of anesthetic drugs.

Hofmann elimination accounts for 77% of total clearance of...

Cisatracurium and renal elimination 16%. The slight dependence on renal elimination likely contributes to the increase in elimination half-life of 14% and decrease in clearance of 13% observed in patients with renal failure. Despite these pharmacokinetic changes in patients with renal dysfunction, no prolongation of the duration of action is found following a bolus dose.

In all, GPCRs can be grouped into 6 classes based on sequence homology and functional similarity:

Class A (or 1) (Rhodopsin-like) Class B (or 2) (Secretin receptor family) Class C (or 3) (Metabotropic glutamate/pheromone) Class D (or 4) (Fungal mating pheromone receptors) Class E (or 5) (Cyclic AMP receptors) Class F (or 6) (Frizzled/Smoothened)

Activation of GABAA receptors produces...

Cl− ion fluxes that directly alter membrane potential.

The reinforcing effects of cocaine and cocaine analogs correlate best with their effectiveness in blocking the transporter that recovers DA from the synapse. This leads to increased...

DA concentrations at critical brain sites. However, cocaine also blocks both NE and 5-HT reuptake, and chronic use of cocaine leads to reductions in the neurotransmitter metabolites 3-methoxy-4 hydroxyphenethyleneglycol (MOPEG or MHPG) and 5-hydroxyindoleacetic acid (5-HIAA).

Opioid Receptor: Inhibits Dopamine release

Delta (δ)

Local skin reactions, such as pallor, erythema, and alterations in temperature sensation, edema, pruritus, and rash are common after...

EMLA cream application.

Esters: Duration of action

Ester drugs tend to be shorter acting due to ready metabolism - tetracaine is the longest acting ester

The nociceptin receptor is a...

G protein-coupled receptor whose natural ligand is known as nociceptin or orphanin FQ, a 17 amino acid neuropeptide. This receptor is involved in the regulation of numerous brain activities, particularly instinctive and emotional behaviors.

GABAB receptors are...

G-protein coupled receptors found on both pre- and postsynaptic terminals.

All opioid receptors appear to be coupled to...

G-proteins and inhibit the activity of adenylate cyclase. G-protein interactions affect ion channels.

GABAB receptors via...

G-proteins to potassium channels. The changing potassium concentrations hyperpolarize the cell at the end of an action potential.

Gabapentinoids are structural analogues of...

GABA but have no GABA receptor effects.

Gabapentin and pregabalin are both cyclic analogs of...

GABA, although pregabalin is around three times more potent.

Maturing neurons express very little KCC2, and anion homeostasis is largely determined by a different Cl− transporter (NKCC1) that preferentially transports Cl− into the cell. This produces high levels of intracellular Cl− that allow...

GABAA receptor activation to produce a depolarizing efflux of anions that can generate action potentials, intracellular calcium waves, and relieve Mg++ block of NMDA receptors.

Of all of the clinically used intravenous anesthetics, etomidate exhibits the greatest selectivity for...

GABAA receptors and has the fewest relevant interactions with other ion channels.

In normal adult neurons, robust activity of the Cl− transporter KCC2 results in low intracellular Cl− levels compared to the extracellular fluid, thereby producing a hyperpolarizing influx of negative Cl− ions when...

GABAA receptors are activated. In contrast, maturing neurons express very little KCC2, and anion homeostasis is largely determined by a different Cl− transporter (NKCC1) that preferentially transports Cl− into the cell.

Ibuprofen is thought to be better tolerated than aspirin and indomethacin and has been used in patients with a history of...

GI intolerance to other NSAIDs. Nevertheless, 5-15% of patients experience GI side effects.

The black box warning for ketorolac stresses the possibility of serious adverse...

GI, renal, bleeding, and hypersensitivity reactions from the use of this potent NSAID analgesic. Patients receiving greater than recommended doses or concomitant NSAID therapy and those at the extremes of age appear to be particularly at risk.

Following binding of a ligand to the opioid receptor a conformational change in the three-dimensional structure of the receptor will occur so that the ligand-receptor complex reaches a state of high affinity for intracellular...

Ga/Gbγ heterotrimeric G proteins. This promotes a GDP/GTP exchange, resulting in receptor binding of the Ga subunit and liberation of the Gbγ subunit.

The AMPAR's permeability to calcium and other cations, such as sodium and potassium, is governed by the...

GluR2 subunit.

Kainate receptors are comprised of...

GluR5-7 and KA1-KA2.

The activity of NMDA receptors is also strikingly sensitive to the changes in...

H+ concentration, and partially inhibited by the ambient concentration of H+ under physiological conditions.

Numerous studies show the efficacy of gabapentin in...

HIV-related neuropathic pain, pain associated with Guillain-Barré syndrome, neuropathic cancer pain, complex regional pain syndrome, phantom limb pain, and neuropathic pain in spinal cord injury patients.

Atracurium was the first NMBA introduced into clinical practice that does not require elimination by enzyme-catalyzed hydrolysis or excretion by the kidneys or liver. Chemical degradation to inactive products by...

Hofmann elimination is primarily responsible for its inactivation; enzymatic ester hydrolysis and renal elimination have lesser roles. Other studies have found that ester hydrolysis can be responsible for metabolism of as much as 66% of an atracurium dose and that renal elimination can have a larger role in the pharmacokinetics of atracurium than initially appreciated.

Systemic absorption of tetracaine, and to a lesser extent lidocaine, after placement on the tracheobronchial mucosa produces plasma concentrations similar to those present after...

IV injection of the local anesthetic. For example, plasma lidocaine concentrations 15 minutes after laryngotracheal spray of the local anesthetic are similar to those concentrations present at the same time after an IV injection of lidocaine.

Ropivacaine, although less likely to produce cardiotoxicity than bupivacaine, is not recommended for...

IV regional anesthesia.

PRILOCAINE (Citanest): Considerations

In some patients, a metabolite of prilocaine may cause the unusual side effect of methemoglobinemia, which may be treated with methylene blue.

Upon ligand binding, opioid receptors transduce the information by activating intracellular guanine nucleotide binding proteins (G proteins) that in turn alter membrane conductance for...

K+ and Ca2+ and levels of second messengers such as cyclic adenosine monophosphate (cAMP).

Opioid Receptor: Diuresis

Kappa (κ)

Opioid Receptor: Dysphoria

Kappa (κ)

The analgesic activity of methadone, a racemate, is almost entirely the result of its content of...

L-methadone, which is 8-50 times more potent than the D isomer. D-methadone also lacks significant respiratory depressant action and addiction liability but possesses antitussive activity.

Esters: Allergies

LA allergy is uncommon, esters have a higher allergy potential - if there is a reaction to one, all other esters should be avoided

Because of morphine's high hepatic extraction ratio, the bioavailability of orally administered morphine is significantly lower than after parenteral injection. The hepatic first pass effect on orally administered morphine results in high...

M6G levels; in fact, it appears that M6G may be the primary active compound when morphine is administered orally.

NMDA receptors are activated by the agonist glutamate and co-agonist glycine only when voltage changes displace...

Mg2 + from the ion channel pore. Ketamine also acts primarily by a pore-blocking mechanism.

A positive change in transmembrane potential will make it more likely that the ion channel in the NMDA receptor will open by expelling the...

Mg2+ ion that blocks the channel from the outside. This property is fundamental to the role of the NMDA receptor in memory and learning.

Opioid Receptor: Inhibits Acetylcholine release

Mu (μ)

Opioid Receptor: Bradycardia

Mu (μ1)

Opioid Receptor: Euphoria

Mu (μ1)

Opioid Receptor: Hypothermia

Mu (μ1)

Opioid Receptor: Low Abuse Portential

Mu (μ1) Kappa (κ)

Opioid Receptor: Miosis

Mu (μ1) Kappa (κ)

Opioid Receptor: Sedation

Mu (μ1) Kappa (κ)

Opioid Receptor: Analgesia (Supraspinal)

Mu (μ1) Kappa (κ3) Delta (δ)

Opioid Receptor: Urinary retention

Mu (μ1), Delta (δ)

Opioid Receptor: Nausea & Vomiting

Mu (μ2)

Opioid Receptor: Physical Dependence

Mu (μ2) Delta (δ)

Opioid Receptor: Pruritus

Mu (μ2) Delta (δ)

Opioid Receptor: Analgesia (Spinal)

Mu (μ2) Kappa (κ1) Delta (δ)

Opioid Receptor: Respiratory Depression

Mu (μ2), Delta (δ)

Opioid Receptor: Constipation

Mu (μ2), Delta (δ)

Some patients experience a rapid and dramatic rise in the INR following standard doses of acetaminophen. Recent evidence suggests that this interaction is caused by...

N-acetyl (p)-benzoquinoneimine, the highly reactive acetaminophen metabolite that is responsible for hepatic injury following overdose that also inhibits vitamin K- dependent carboxylase activity.

Acetaminophen is metabolized to nontoxic glucuronide and sulfate conjugates, and to a highly reactive metabolite...

N-acetyl-p-benzoquinoneimine (NAPQI) via CYP isoforms.

iGluRs are named for exogenous agonists that selectively activate subtypes of glutamate receptors, including...

N-methyl-aspartate (NMDA), α-amino-3-hydroxyl-5-methyl-4-isoxazole-propionate (AMPA), and kainate.

Acetaminophen toxicity is associated with increased levels of...

NAPQI and hepatic necrosis.

Acetaminophen is partially transformed by CYP2E1 to the toxic metabolite...

NAPQI. Intake of ethanol, a potent inducer of the 2E1 isoenzyme, may lead to increased susceptibility to acetaminophen poisoning after overdose.

Clonidine decreases the plasma concentration of...

NE and reduces its excretion in the urine.

Methadone is not only a potent μ-receptor agonist but its racemic mixture of D- and L-methadone isomers can also block both...

NMDA receptors and monoaminergic reuptake transporters. These nonopioid receptor properties may help explain its ability to relieve difficult-to-treat pain (neuropathic, cancer pain), especially when a previous trial of morphine has failed.

There are two broad categories of excitatory synaptic receptors that use the amino acid L-glutamate as their chemical messenger:

NMDA receptors and non-NMDA receptors. The latter group can be subdivided into AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid) receptors and kainate receptors.

NMDA (N-methyl-D-aspartate) is the name of a selective agonist that binds to...

NMDA receptors but not to other 'glutamate' receptors.

In the nociceptive circuitry of the spinal cord, repeated peripheral nerve stimulation results in an increase in response to subsequent stimuli through activation of...

NMDA receptors. This "wind up" phenomenon is associated with hyperalgesia, and both knockout and knockdown of NR1 blocks inflammatory pain in animals. This, combined with their ability to modify opioid tolerance, makes NMDA receptor antagonists promising treatments for chronic pain.

Opioid receptors are also present on endothelial cells of arterial vessels, and their activation evokes...

NO mediated vasodilation. While fentanyl- and sufentanil induced hypotension is mainly due to a decrease in heart rate, remifentanil-induced hypotension is caused by both a decrease in heart rate and systemic resistance.

In nonspine orthopedic surgery, there is good evidence of...

NSAID analgesic efficacy and no significant association with compromised bone healing.

Although acetaminophen is used to treat similar conditions, it is not considered a true...

NSAID as it lacks significant antiinflammatory effects.

Drug-induced meningitis has been observed following administration of...

NSAIDs (especially ibuprofen) and H2 receptor antagonists

COX-1 and COX-2 are the isoforms targeted by the traditional...

NSAIDs, while the more selective COX-2 inhibitors preferentially block COX-2.

Ketamine has some local anesthetic properties on...

Na + channels and binds µ- and κ-opioid receptors. Although blunted responses to ketamine have been noted in µ-opioid receptor knockout mice, the limited effect of naloxone on ketamine actions in humans suggests a limited role for these receptors.

Because it activates acetylcholine receptors, which causes opening of the perijunctional voltage-gated Na + channels, allowing generation of a muscle response to neural stimulation, succinylcholine causes influx of...

Na + into muscle cells and the efflux of K +. In normal patients, this typically results in an increase of 0.5 mEq/ L of plasma K +.

Local anesthetics must penetrate through the lipid-rich nerve sheaths and cell membrane in order to reach their targets, voltage-gated...

Na+ channels (Nav). The binding site of local anesthetics is located inside the channel pore and is not readily reachable from the extracellular side as inferred from pharmacologic studies.

NMDA receptors are ligand-gated channels permeable to...

Na+, K+, and Ca2+.

Lidocaine selectively targets the open and inactivated states of...

Nav1.5, with low affinity for the deactivated (closed or resting) state.

Preferred Ligand: NK2

Neurokinin A

Preferred Ligand: NK3

Neurokinin B

Local spinal mechanisms, in addition to descending inhibition, underlie the analgesic action of...

Opioids.

Opioids reduce the responsiveness to CO2 by elevating the end-tidal...

PCO2 threshold, and attenuate the hypoxic ventilator response to a decreased PO2. With a gradual increase in the dose of opioids, slowly developing hypercapnia maintains respiration. However, when this occurs rapidly, from an intravenous bolus, apnea occurs immediately until PCO2 reaches a steady state which permits respiration return.

Methadone is also increasingly used in the treatment of chronic pain patients, particularly cancer-related pain. Methadone's propensity to prolong the...

QT interval of the electrocardiogram by blocking the delayed rectifier potassium ion channel (IKr) may contribute to increased mortality in this patient population.

Unlike other opioids, methadone is associated with the prolonged...

QT syndrome and is additive with agents known to prolong the QT interval.

sought. Bupivacaine is a racemic mixture of the (+) and (−) enantiomers, with lesser toxicity associated with the...

S-( −) form compared to the R-( +) form.

Myelinated nerve axons are surrounded by...

Schwann cells.

Preferred Ligand: NK1

Substance P

Opioid peptides share the common amino-terminal sequence of...

Try-Gly-Gly-Phe-(Met or Leu).

CHLOROPROCAINE (Nesacaine): VD/PB%

VD: 0.5L/kg PB%:

ROPIVICAINE (Naropin): VD/PB%

VD: 0.85L/kg PB%: 95

PROCAINE (Novocaine): VD/PB%

VD: 0.95 L/kg PB: 6%

BUPIVICAINE (Marcaine, Sensorcaine): VD/PB%

VD: 1 L/kg PB: 95%

MEPIVICAINE (Carbocaine, Polocaine): VD/PB%

VD: 1.2L/kg PB: 75%

LIDOCAINE (Xylocaine): VD/PB%

VD: 1.3L/kg PB: 65%

COCAINE: VD/PB%

VD: 2 L/kg PB: >95%

PRILOCAINE (Citanest): VD/PB%

VD: 2.7L/kg PB: 55%

HYDROMORPHONE (Dilaudid): VD/PB%

VD: 4 L/kg PB%: 10-20%

TETRACAINE (Pontocaine): VD/PB%

VD: n/a PB%: 94

Local anesthetics inhibit neuronal conduction by directly binding to and inhibiting the ability of...

VGSCs to conduct the inward Na+ current that mediates the rapid depolarizing phase of the action potential. The inhibition results from local anesthetic binding at a receptor site in the channel's inner pore, accessible from the axoplasmic opening.

Despite the clinical impression that fentanyl has a short duration of action, its elimination half-time is longer than that for morphine. This longer elimination half-time reflects a larger...

Vd of fentanyl because clearance of both opioids is similar. The larger Vd of fentanyl is due to its greater lipid solubility and thus more rapid passage into tissues compared with the less lipid-soluble morphine.

The context-sensitive half-time of sufentanil is actually less than that for alfentanil for continuous infusions of up to 8 hours in duration. This shorter context-sensitive half-time can be explained in part by the large...

Vd of sufentanil compared to alfentanil. After termination of a sufentanil infusion, the decrease in the plasma drug concentration is accelerated not only by metabolism but by continued redistribution of sufentanil into peripheral tissue compartments.

The extensive protein binding of sufentanil (92.5%) compared with that of fentanyl (79% to 87%) contributes to a smaller...

Vd, which is characteristic of sufentanil.

The term benzodiazepine refers to the portion of the structure composed of...

a benzene ring (A) fused to a seven-membered diazepine ring (B).

In contrast to dose-dependent analgesic effects of opioids, ketorolac and other NSAIDs appear to exhibit...

a ceiling effect with respect to postoperative analgesia.

Adjustment of the pH of the chloroprocaine solution with the addition of 1 mL of 8.4% sodium bicarbonate added to 30 mL of chloroprocaine solution just before placement into the epidural space may improve the efficacy of...

a chloroprocaine-bupivacaine combination.

An excessive dose of an anti-ChE drug results in...

a cholinergic crisis (SLUDGE). The condition is characterized by weakness resulting from generalized depolarization of the motor end plate; other features result from overstimulation of muscarinic receptors.

Opioid receptor-mediated inhibition of adenylate cyclase is not responsible for an immediate effect but may have...

a delayed effect, possibly via a reduction in cyclic adenosine monophosphate (cAMP)- responsive neuropeptide genes and reduction in neuropeptide messenger RNA concentrations.

Neostigmine blocks acetylcholine receptors, and excessive acetylcholine can cause both...

a depolarizing block and an open-channel block.

Induction doses of Etomidate are associated with a high incidence of myoclonus, possibly via...

a loss of cortical inhibition during the transition from consciousness to unconsciousness. Although this myoclonic activity could be mistaken for generalized tonic-clonic seizures, etomidate has anticonvulsant activity in several experimental models.

While the majority of GABAA receptors (those containing α1-, α2-, α3-, or α5-subunits) are benzodiazepine sensitive there exists...

a minority of GABAA receptors (α4- or α6-subunit containing) which are insensitive to classical 1,4-benzodiazepines, but instead are sensitive to other classes of GABAergic drugs such as the neurosteroids and alcohol.

Axons such as postganglionic autonomic efferent and some of the nociceptive afferent fibers lack...

a myelin sheath.

Despite Etomidates favorable hemodynamic profile it should be noted that patients with high sympathetic tone such as those suffering from shock, intoxication or drug withdrawal can have...

a precipitous drop in blood pressure even when etomidate is used to induce anesthesia.

The availability of controlled-release dosage forms of some drugs can lead to abuse, as in the case of controlled-release oxycodone marketed as OXYCONTIN. Crushing and snorting the delayed-release tablets results in...

a rapid release of the drug, increased absorption, and high peak serum concentrations.

Adenylate cyclase is inhibited by activation of the opioid receptor, thereby resulting in...

a reduction in cellular cyclic adenosine monophosphate (AMP) content.

Oral clonidine, 150 to 200 µg, administered 1.0 to 1.5 hours before institution of spinal anesthesia with tetracaine or lidocaine results in...

a significant prolongation of sensory anesthesia. In another report, oral clonidine, 200 µg, shortened the onset time of tetracaine's sensory block and prolonged the duration of sensory and motor block.

Voltage-gated Na+ channels consist of...

a single α-subunit and varying auxiliary β-subunits. The α subunit forms the ion-conducting pore of the channel and consists of four homologous domains, each with six α-helical transmembrane segments.

Meperidine shares several structural features that are present in local anesthetics including...

a tertiary amine, an ester group and a lipophilic phenyl group.

Cardiovascular stimulation after administration of naloxone manifests as increased sympathetic nervous system activity, presumably reflecting the...

abrupt reversal of analgesia and the sudden perception of pain. This increased sympathetic nervous system activity may manifest as tachycardia, hypertension, pulmonary edema, and cardiac dysrhythmias. Even ventricular fibrillation has occurred after the IV administration of naloxone and the associated sudden increase in sympathetic nervous system activity.

Lidocaine causes vasodilation at most concentrations; the addition of epinephrine can significantly reduce...

absorption of lidocaine by nearby vessels, allowing more of the initially administered dose to enter the neural compartment, thereby prolonging the duration of action by as much as 50%.

For a given route of administration, increasing the concentration can...

accelerate onset. For instance, chloroprocaine is much slower in onset than lidocaine at equal concentrations because its pKa of 9.1 favors the positively charged form at physiologic pH. However, a 3% solution is the typical concentration of chloroprocaine used clinically, which provides a much faster onset than other agents at their clinically used concentrations (e.g., 0.25% bupivacaine, 0.5% ropivacaine, or 1.5% mepivacaine) simply because there are more molecules present to diffuse into the nerve.

β Adrenergic blocking agents should not be used alone in α2 adrenergic agonist withdrawal syndrome because they may...

accentuate the hypertension by allowing unopposed α adrenergic vasoconstriction caused by activation of the sympathetic nervous system and elevated circulating catecholamines.

Controversy exists regarding the use of chloroprocaine related to reports of persistent, serious neurologic deficits associated with...

accidental massive subarachnoid injection (i.e., adhesive arachnoiditis). Initially, the agent itself was implicated, but subsequent evaluation suggested that the preservative antioxidant bisulfite is responsible. However, after elimination of bisulfite a number of reports of back pain have appeared.

Although midazolam is often considered a short-acting benzodiazepine, prolonged infusions in critically ill patients leads to markedly delayed awakening in part due to...

accumulation of its active metabolite 1-hydroxymidazolam. For longer periods of sedation, the benzodiazepine of choice is lorazepam, but some formulations of lorazepam are formulated in a glycol-based vehicle and prolonged infusions lead to glycol toxicity.

Acetylcysteine is also used orally as an antidote for...

acetaminophen overdose.

The effects of anticholinesterases are not limited to the motor-endplate. Administration also causes increases in...

acetylcholine beyond the neuromuscular junction. The muscarinic and nicotinic acetylcholine receptors in the parasympathetic system can also be activated, which causes pronounced vagal effects such as bradycardia, prolonged QT-interval, and asystole.

Physostigmine, 15 to 60 μg/ kg IV, is effective in antagonizing restlessness and confusion (central anticholinergic syndrome) due to atropine or scopolamine. Presumably, physostigmine increases concentrations of...

acetylcholine in the brain, making more neurotransmitters available for interaction with cholinergic receptors. The duration of action of physostigmine is shorter than that of anticholinergic drugs. For this reason, it may be necessary to repeat the dose of physostigmine used in the treatment of central anticholinergic syndrome.

Depression of cholinergic transmission in the CNS as a result of opioid-induced inhibition of...

acetylcholine release from nerve endings may play a prominent role in the analgesic and other side effects of opioid agonists.

Neostigmine probably produces analgesia by inhibiting the breakdown of spinally released...

acetylcholine which is increased in the presence of pain.

Anticholinesterases used for reversal of neuromuscular blockade inhibit...

acetylcholinesterase at the neuromuscular junction, which increases the concentration of acetylcholine at the motor endplate to overcome the NMBA-induced competitive block.

In contrast to ACh, which has a brief duration of action (~ 1 ms or less) as a result of its rapid degradation by acetylcholinesterase, SCh is not susceptible to hydrolysis by...

acetylcholinesterase. Therefore, SCh remains in the synaptic cleft until the plasma concentration of SCh decreases or disappears due to breakdown by plasma pseudocholinesterase (butyrylcholinesterase) or elimination by the kidney.

The imidazole ring of midazolam allows the preparation of...

acidic aqueous solutions, which cause minimal pain on injection. Once at physiologic pH, midazolam assumes a more lipophilic ring conformation and can gain rapid access to the CNS

Amount of methadone excreted in the urine is increased when the urine is...

acidified.

The κ-opioid receptor may provide a natural addiction control mechanism, and therefore, drugs that..

act as agonists and increase activation of this receptor may have therapeutic potential in the treatment of addiction.

Sodium ion channels tend to recover from local anesthetic-induced conduction blockade between...

action potentials and to develop additional conduction blockade each time sodium channels open during an action potential (frequency-dependent blockade). Therefore, local anesthetic molecules can gain access to receptors only when sodium channels are in activated-open states. For this reason, selective conduction blockade of nerve fibers by local anesthetics may be related to the nerve's characteristic frequencies of activity as well as to its anatomic properties, such as diameter. Indeed, a resting nerve is less sensitive to local anesthetic-induced conduction blockade than is a nerve that has been repetitively stimulated.

Local anesthetics have a higher affinity for Na+ channels in the...

activated (open) and inactivated (channel pore in open conformation but intracellularly closed by inactivation gate) state than those in the resting closed state.

Local anesthetic molecules can gain access to receptors only when sodium channels are in...

activated-open states. For this reason, selective conduction blockade of nerve fibers by local anesthetics may be related to the nerve's characteristic frequencies of activity as well as to its anatomic properties, such as diameter. Indeed, a resting nerve is less sensitive to local anesthetic-induced conduction blockade than is a nerve that has been repetitively stimulated.

A property of the NMDA receptor is its voltage-dependent...

activation, a result of ion channel block by extracellular Mg2+ ions. This allows the flow of Na+ and small amounts of Ca2+ ions into the cell and K+ out of the cell to be voltage-dependent.

Barbiturates can induce fatal attacks of porphyria in patients with...

acute intermittent or variegate porphyria and are contraindicated in such patients.

There are mixed results regarding the efficacy of gabapentinoids in treating...

acute postoperative pain.

Chronic exposure of the opioid receptors to agonists induces cellular...

adaptation mechanisms that may be involved in opioid tolerance, dependence, and withdrawal symptoms. Short-term desensitization probably involves phosphorylation of the opioid receptors via protein kinase C. A number of other kinases have also been implicated, including protein kinase A and β-adrenergic receptor kinase (βARK).

Patients being treated with certain antidysrhythmic drugs (mexiletine) may experience...

additive and potentially synergistic effects when exposed to EMLA cream.

Diazepam increases coronary flow, possibly by an action to increase interstitial concentrations of...

adenosine, and the accumulation of this cardiodepressant metabolite also may explain the negative inotropic effects of the drug.

Long-term tolerance to opioids has been thought to be associated with superactivation of...

adenylyl cyclase activity—a counter-regulatory response to the decrease in cyclic AMP levels seen after acute opioid administration. This effect is prevented by pretreatment of cells with pertussis toxin, thus demonstrating the involvement of G proteins (Gi and/or Go).

GABAB receptors can also reduce the activity of ...

adenylyl cyclase and decrease the cell's conductance to Ca2+.

Ketorolac appears to have little potential for producing renal toxicity when...

adequate fluid balance is maintained and renal function does not depend on renal prostaglandins.

All opioids show a decrease in plasma concentration with initiation of cardiopulmonary bypass. The degree of this decrease is greater with fentanyl because a significant proportion of the drug...

adheres to the surface of the cardiopulmonary bypass circuit. The decrease is least with opioids that have a large Vd such that the addition of prime volume is less important. In this respect, sufentanil and alfentanil may provide more stable plasma concentrations during cardiopulmonary bypass.

The elimination half-life of propofol is prolonged because of the slow mobilization from...

adipose tissue. Regardless, obesity should not be considered a contraindication to its use for induction or maintenance. Obesity does not drastically prolong recovery and dose adjustments based on lean body weight have been suggested.

Clonidine is an α2 adrenergic agonist that decreases...

adrenergic neurotransmission from the locus ceruleus.

Opioids do not alter responsiveness of ...

afferent nerve endings to noxious stimulation, nor do they impair conduction of nerve impulses along peripheral nerves.

Sufentanil is a thienyl analogue of fentanyl. The analgesic potency of sufentanil is five to ten times that of fentanyl, which parallels the greater...

affinity of sufentanil for opioid receptors compared with that of fentanyl.

Flumazenil antagonizes both the electrophysiological and behavioral effects of ....

agonist and inverse-agonist benzodiazepines and β-carbolines.

Flumazenil antagonizes both the electrophysiological and behavioral effects of...

agonist and inverse-agonist benzodiazepines and β-carbolines.

Extrajunctional nAChRs are highly responsive to...

agonists such as acetylcholine or SCh.

Depolarizing NMBAs act, at least initially, by mimicking the effect of ACh and therefore can be considered...

agonists, although they block neurotransmission after initial stimulation. SCh, the only clinically used depolarizing NMBA, binds to the receptor, thereby opening AChR and allowing ion flow that results in endplate depolarization.

In humans, administration of even a moderate dose of anticholinesterase (neostigmine 0.03 mg/kg IV with glycopyrrolate 0.0075 mg/kg) given to healthy volunteers after complete spontaneous recovery from neuromuscular block increased...

airway collapsibility to a degree found with a TOF ratio = 0.5, and reduced compensatory genioglossus activity in response to negative airway pressure.

Propofol has a number of advantages over other intravenous agents for induction and maintenance of anesthesia. It depresses...

airway reflexes, reduces nausea, does not induce adrenocortical suppression, and has a short context-sensitive half-time even after prolonged infusion. Simulations of bolus kinetics indicate that it is second only to ketamine in speed of onset and offset.

Thiopental is highly protein bound (75%-90%) in the plasma, primarily to...

albumin. Decreased albumin levels such as those seen in chronic renal or hepatic disease can markedly increase free drug levels and may warrant decreased dosing.

Following intravenous injection, etomidate is tightly bound to plasma proteins such as...

albumin. The uncharged drug is highly lipophilic so etomidate rapidly penetrates the blood-brain barrier.

Edrophonium is a simple...

alcohol that contains a quaternary ammonium group.

Naloxone, a derivative of oxymorphone, is a competitive antagonist of...

all opioid receptor types, but its greatest affinity is for the µ receptor.

Ketamine binds uncompetitively within the ion channel pore in a use-dependent fashion, but there is some evidence for...

allosteric binding as well. Experimental data support a role for NMDA receptors in mediating analgesia, but their role in ketamine anesthesia is unclear.

Ropivacaine is highly bound to...

alpha1-acid glycoprotein.

In patients with renal failure, in whom the duration of action of NMBAs is likely to be increased, clearance of anticholinesterases is...

also reduced and elimination half-life increased. This makes dose adjustment of anticholinesterases in patients with renal dysfunction unnecessary.

Because formation of glucuronide metabolites of lorazepam is not entirely dependent on hepatic microsomal enzymes, the metabolism of lorazepam is less likely than that of diazepam to be influenced by...

alterations in hepatic function, increasing age, or drugs that inhibit P-450 enzymes such as cimetidine. Indeed, the elimination half-time of lorazepam is not prolonged in elderly patients or in those treated with cimetidine.

Uptake by the lung also may play an important role in the distribution of...

amide-linked local anesthetics in the body.

The initial step of amide metabolism is conversion of the amide base to...

aminocarboxylic acid and a cyclic aniline derivative. Complete metabolism usually involves additional steps, such as hydroxylation of the aniline moiety and N-dealkylation of the aminocarboxylic acid.

True allergic reactions to local anesthetics are rare, but may be associated with the metabolites of the...

aminoester local anesthetics or preservatives in the local anesthetic solutions

The abnormal synthesis of protoporphyrin (important in hemoglobin production) results in excess porphobilinogen. Barbiturates induce...

aminolevulinic acid synthase, an enzyme responsible for phophobilinogen synthesis. This leads to excessive porphobilinogen levels and can precipitate acute porphyric crises that are manifested by severe abdominal pain, nausea, vomiting, psychiatric disorders, and neurologic abnormalities.

In contrast to other agents, dexmedetomidine has limited...

amnestic effect and so should be avoided as a sole agent in patients with neuromuscular blockade.

A minimal length of myelinated nerve fiber must be exposed to...

an adequate concentration of local anesthetic for conduction blockade of nerve impulses to occur. For example, if only one node of Ranvier is blocked (site of change in sodium permeability), the nerve impulse can jump (skip) across this node and conduction blockade does not occur.

The G protein-coupled receptor is activated by ...

an external signal in the form of a ligand or other signal mediator. This creates a conformational change in the receptor, causing activation of a G protein. Further effect depends on the type of G protein.

While not arrhythmogenic, ketamine increases myocardial O2 consumption and is not...

an ideal drug for patients at risk for myocardial ischemia.

SCh remains available for sustained AChR stimulation causing prolonged channel opening and depolarization of the endplate. SCh exerts a biphasic action on muscle:

an initial contraction, observed as fasciculation, followed by relaxation lasting minutes to hours. The time required to hydrolyze or eliminate the drug from the body is the principal determinant of the duration of block (paralysis).

The typical local anesthetics contain hydrophilic and hydrophobic moieties that are separated by...

an intermediate ester or amide linkage.

Benzodiazepines produce decreases in cerebral metabolic oxygen requirements (CMRO2) and cerebral blood flow analogous to barbiturates and propofol. In contrast to these drugs, however, midazolam is unable to produce...

an isoelectric EEG, emphasizing that there is a ceiling effect with respect to the decrease in CMRO2 produced by increasing doses of midazolam.

Ketamine also inhibits nicotinic acetylcholine receptors at clinically relevant concentrations, which could contribute to...

analgesia but does not appear to influence its sedative properties.

Intrathecal (50-100 μg) or epidural (1-4 μg/kg) injection of neostigmine produces...

analgesia in the postoperative period and in patients with chronic pain.

Activation of δ receptors produces some...

analgesia, although less than that of mu-opioid agonists. Many δ agonists may also cause seizures at high doses, although not all δ agonists produce this effect.

Hydromorphone is metabolized to hydromorphone-3-glucoronide which has no...

analgesic effects. Like the morphine metabolite, morphine-3-glucoronide, if levels of hydromorphone-3-glucuronide build up in ones system, it can produce excitatory neurotoxic effects such as restlessness, myoclonus and hyperalgesia. Metabolite build up can occur in patients with compromised kidney function, or sometimes in older patients

Ibuprofen, naproxen, and diclofenac are nonsteroidal propionic acid derivatives with prominent...

analgesic, antipyretic, and antiinflammatory effects, reflecting inhibition of prostaglandin synthesis.

The actions of µ-receptor agonists are invariably...

analgesic, whereas those of κ-receptor agonists can be either analgesic or antianalgesic.

In a prospective randomized study, dexmedetomidine initiated at the end of coronary artery bypass surgery and continued into the ICU resulted in reduced use of...

analgesics, β-blockers, diuretics, antiemetics, and epinephrine, and achieved adequate sedation compared to propofol sedation.

The lipophilic portion is essential for...

anesthetic activity, and therapeutically useful local anesthetics require a delicate balance between lipid solubility and water solubility.

Glycine receptors have an inhibitory role, particularly in the lower brainstem and spinal cord. They are likely major contributors to...

anesthetic immobility, especially that produced by the volatiles:

Both AMPA and kainate receptors mediate fast excitatory postsynaptic currents (EPSCs) and show relatively little...

anesthetic sensitivity. NMDA receptors, by contrast, mediate EPSCs of relatively prolonged duration.

GABA is removed from the synapse by...

another class of GABA transporter, GATs. It is important to note that while the function of vGAT and GAT are similar, their structure and mechanisms of transport are very different.

The NMDA receptor is considered a "coincidence detector", it is activated when...

another receptor causes sufficient membrane depolarization, as would be expected to occur with high frequency stimulation. This unique property of the NMDA receptor is linked to synaptic plasticity that may underlie memory formation.

Nondepolarizing NMBAs block neuromuscular transmission predominantly by competitive...

antagonism of ACh at the post-junctional receptor. The effect of this competitive antagonism depends on the relative concentrations of NMBA and ACh and the comparative affinities of each for the AChR.

Pb2+ lead is a potent NMDAR...

antagonist.

Ketorolac, a heteroaryl acetic acid derivative, is a potent analgesic but only a moderately effective...

anti-Inflammatory drug.

A subset of NSAIDs, including indomethacin, ibuprofen, piroxicam, and cyclooxygenase (COX)-2 inhibitors, can antagonize...

anti-hypertensive therapy, especially with regimens employing angiotensin-converting enzyme inhibitors, angiotensin receptor antagonists, and β adrenergic receptor antagonists.

Increased salivation that attends ketamine administration can be effectively prevented by...

anticholinergic agents such as glycopyrrolate.

Serotonin syndrome (autonomic instability with hypertension, tachycardia, diaphoresis, hyperthermia, behavioral changes including confusion and agitation, and neuromuscular changes manifesting as hyperreflexia) occurs when drugs capable of increasing serotonin administration are administered. In severe cases, coma, seizures, coagulopathy, and metabolic acidosis may develop. Administration of meperidine to patients receiving...

antidepressant drugs (monoamine oxidase inhibitors, fluoxetine) may elicit this syndrome.

Propofol inhibits some subtypes of voltage-gated Na + channels, which could contribute to its...

antiepileptic activity. In high doses, ketamine can also block Na + channel activity.

Ketorolac is a NSAID that exhibits potent analgesic effects but only moderate...

antiinflammatory activity when administered IM or IV.

Lidocaine, one of the most studied local anesthetics, has been shown to possess an...

antiinflammatory effect. Lidocaine appears to inhibit the release of proinflammatory cytokines and prevent leukocyte adhesion.

In 2007, the Food and Drug Administration (FDA) mandated that all propofol emulsions in the United States contain an...

antimicrobial agent (EDTA or sodium metabisulfite). The FDA also recommended that, to minimize the potential for bacterial contamination, both the vial and prefilled syringe formulations must be used on only one patient, administration must commence immediately after the vial or syringe has been opened, and administration from a single vial or syringe must be completed within 6 hours of opening.

Acetaminophen has not been implicated in Reye's syndrome and is the drug of choice for...

antipyresis in children, teens and young adults.

Central nervous system toxicity manifests initially as...

anxiety, dizziness, circumoral numbness, lightheadedness, and tinnitus. Objective symptoms include shivering, muscle twitching, tremors, and eventually generalized tonic-clonic seizure.

Among the many desirable properties of α2-agonists that promote their use in the perioperative period are...

anxiolysis, sedation, reductions in minimal alveolar concentration (MAC) of volatile anesthetics, reduced chest wall rigidity from opioids, reduction in intraoperative BP variability from intubation, extubation and surgical stress response, and reductions in postanesthetic shivering.

Preganglionic B fibers are more readily blocked by local anesthetics than...

any fiber, even though these fibers are myelinated.

Because gabapentin undergoes minimal metabolism, it is unlikely to have...

any interactions with other medications.

The primary source of prostaglandins in humans is...

arachidonic acid, a 20-carbon polyunsaturated essential fatty acid that is, in turn, derived from cell membrane phospholipids.

Cocaine produces a dose-dependent increase in heart rate and blood pressure accompanied by increased...

arousal, improved performance on tasks of vigilance and alertness, and a sense of self-confidence and well-being. Higher doses produce euphoria, which has a brief duration and often is followed by a desire for more drug. Repeated doses may lead to involuntary motor activity, stereotyped behavior, and paranoia.

Lidocaine at clinically useful plasma concentrations depresses the ventilatory responses to...

arterial hypoxemia). In this regard, patients with carbon dioxide retention whose resting ventilation depends on hypoxic drive may be at risk of ventilatory failure when lidocaine is administered for treatment of cardiac dysrhythmias.

Most NSAIDs are distributed widely throughout the body and readily penetrate...

arthritic joints, yielding synovial fluid concentrations in the range of half the plasma concentration.

When there is only 1 response to TOF stimulation, successful reversal may take....

as long as 30 minutes

Ibuprofen should not be taken within 30 minutes of the ingestion of low-dose...

aspirin and low-dose aspirin should not be ingested within 8 hours of a dose of ibuprofen. Patients at high risk for cardiovascular events should preferentially use analgesics that do not interfere with platelet action.

Aspirin-induced asthma usually occurs within an hour of ingesting...

aspirin or other NSAIDs (Ketorolac) and can be accompanied by life-threatening bronchospasm and hypotension.

The concomitant administration of ibuprofen and aspirin antagonizes the irreversible platelet inhibition induced by...

aspirin. Thus, treatment with ibuprofen in patients with increased cardiovascular risk may limit the cardioprotective effects of aspirin. Furthermore, the use of ibuprofen concomitantly with aspirin may decrease the total anti-inflammatory effect.

Users who smoke crack cocaine can induce...

asthma or develop pulmonary hemorrhages.

Inhalation of nebulized lidocaine can cause bronchoconstriction in some patients with...

asthma, which may become an important consideration when bronchoscopy is planned in these patients.

Cross-sensitivity between aspirin and other NSAIDs must be considered in any patient with...

asthma.

Compared to propofol, barbiturates produce a higher incidence of wheezing in...

asthmatics, attributed to histamine release from mast cells, during induction of anesthesia.

Mepivacaine, bupivacaine, and ropivacaine are chiral drugs because the molecules possess an...

asymmetric carbon atom.

Physostigmine, with its shorter duration of action, is useful in the treatment of intoxication by...

atropine and several drugs with anticholinergic side effects, it also is indicated for the treatment of Friedreich's or other inherited ataxias.

Structurally, meperidine is similar to...

atropine, and it possesses a mild atropine-like antispasmodic effect.

Patients become tolerant to the sedating effects of methadone and can...

attend school or function in a job. Opioids also have a persistent, mild, stimulating effect noticeable after tolerance to the sedating effect, such that reaction time is quicker and vigilance is increased while on a stable dose of methadone.

Acting at spinal and brain µ receptors, opioids are thought to provide analgesia both by...

attenuating the nociceptive traffic from the periphery and by altering the affective response to painful stimulation centrally.

Among the occasional patients who exhibit prolonged apnea following the administration of succinylcholine or mivacurium, most have an...

atypical plasma cholinesterase or a deficiency of the enzyme owing to allelic variations, hepatic or renal disease, or a nutritional disturbance; however, in some, the enzymatic activity in plasma is normal

The miotic effect of opioids occurs through a direct action on the...

autonomic (Edinger-Westphal) nucleus of the oculomotor nerve. The result is an increase in parasympathetic tone.

The pattern of withdrawal symptoms after abrupt discontinuation of meperidine differs from that of morphine in that there are few...

autonomic nervous system effects. In addition, symptoms of withdrawal develop more rapidly and are of a shorter duration compared with those of morphine.

Clonidine has been found to have efficacy in the treatment of diarrhea in diabetics with...

autonomic neuropathy, perhaps because of its ability to enhance salt and water absorption from the intestine.

Nonselective GABAA receptor-active drugs, like...

barbiturates, and inhaled anesthetics, propofol and etomidate, are commonly used for surgery. At low concentrations, these agents enhance the effects of endogenous GABA, but at higher concentrations they directly and indiscriminately activate GABAA receptors throughout the brain.

Porphyria attacks have been implicated after administration of drugs such as...

barbiturates, etomidate, ketamine, benzodiazepines, metoclopramide, mepivacaine, atracurium, vecuronium, diclofenac, and ranitidine all have been implicated in precipitating an acute attack in susceptible individuals.

Because active metabolites of some benzodiazepines are biotransformed more slowly than are the parent compounds, the duration of action of many benzodiazepines...

bears little relationship to the t1/2 of elimination of the parent drug that was administered.

In general, autonomic fibers, small unmyelinated C fibers (mediating pain sensations), and small myelinated Aδ fibers (mediating pain and temperature sensations) are blocked...

before the larger myelinated Aγ, Aβ, and Aα fibers (mediating postural, touch, pressure, and motor information).

Methemoglobinemia is a rare but potentially life-threatening complication following topical application of...

benzocaine, especially when the dose exceeds 200 to 300 mg.

Unlike barbiturates, benzodiazepines do not activate GABAA receptors directly; rather...

benzodiazepines act allosterically by modulating the effects of GABA.

GABAA receptors are critical targets for...

benzodiazepines, barbiturates, etomidate, and propofol.

Cimetidine and oral contraceptives inhibit N-dealkylation and 3-hydroxylation of...

benzodiazepines.

Erythromycin, clarithromycin, ritonavir, itraconazole, ketoconazole, nefazodone, and grapefruit juice are inhibitors of CYP3A4 and can affect the metabolism of...

benzodiazepines.

Receptors composed solely of α and β subunits produce functional GABAA receptors that also respond to barbiturates, but they neither bind nor are affected by...

benzodiazepines. Benzodiazepines are believed to bind at the interface between α and γ subunits, and both subunits determine the pharmacology of the benzodiazepine binding site.

The α subunit of the GABAA receptor appears to differentially mediate the CNS effects ofThe α subunit of the GABAA receptor appears to differentially mediate the CNS effects of...

benzodiazepines. For example, α2-containing receptors play an important role in anxiolysis, anti-hyperalgesia, and centrally mediated muscle relaxation, while α1-containing subunits are important mediators of the sedative, amnestic, and anticonvulsive effects of benzodiazepines.

A total of 1 mg flumazenil given over 1-3 minutes usually is sufficient to abolish the effects of therapeutic doses of...

benzodiazepines; patients with suspected benzodiazepine overdose should respond adequately to a cumulative dose of 1-5 mg given over 2-10 minutes; a lack of response to 5 mg flumazenil strongly suggests that a benzodiazepine is not the major cause of sedation. Additional courses of treatment with flumazenil may be needed within 20-30 minutes should sedation reappear.

Although esmolol has been recommended to treat tachycardia due to cocaine overdose, there is also evidence that...

beta-adrenergic blockade accentuates coronary artery vasospasm in the setting of acute cocaine overdose.

Incidence of residual neuromuscular bock in the recovery room?

between 30-40%

Unlike opioids, ketorolac has little or no effect on...

biliary tract dynamics, making this drug a useful analgesic when spasm of the biliary tract is undesirable

The different Botulinum toxins target different proteins at the "presynaptic" region of the NMJ, resulting in...

block of release of ACh with ensuing denervation and accompanying muscle paralysis and atrophy.

Pancuronium has a vagolytic action, presumably from...

blockade of muscarinic receptors, which leads to tachycardia.

Methadone prolongs the QT interval of the electrocardiogram by...

blocking the delayed rectifier potassium ion channel (IKr).

Carbamazepine carries two FDA black box warnings for ...

blood dyscrasias and dermatologic reactions. *A spectrum of hematologic abnormalities, including agranulocytosis, aplastic anemia, neutropenia, leukopenia, and thrombocytopenia have been reported, and monitoring standards similar to those for clozapine are recommended. Severe dermatologic reactions include fatal toxic epidermal necrolysis and Stevens-Johnson syndrome.

The α2A-AR appears to be critical for agonist-mediated lowering of...

blood pressure, sedation, "anesthetic sparing", and working memory. The α2A-AR also appears to respond to endogenous catecholamines to suppress epileptogenesis (kindling) and depressive symptoms.

Physostigmine, a tertiary amine, crosses the...

blood-brain barrier, in contrast to the quaternary anti-AChE drugs.

Methylnaltrexone and alvimopan are µ receptor antagonists whose physicochemical properties prevent them from crossing the...

blood-brain-barrier in appreciable amounts. These drugs thus block the µ receptors in the gut without antagonizing the therapeutic µ agonist effects that are mediated in the CNS. Controlled, randomized trials have demonstrated their efficacy in the prevention and treatment of postoperative ileus and the constipation associated with chronic opioid use.

The rapid peak effect of alfentanil at the brain is useful when an opioid is required to...

blunt the response to a single, brief stimulus such as tracheal intubation or performance of a retrobulbar block.

Opioids can sometimes be associated with a paradoxical increase in coughing, typically after a...

bolus dose is administered. This poorly understood phenomenon is often briefly observed during induction of anesthesia when opioids are used as part of the induction regimen.

The cardiovascular actions of anti-ChE agents are complex, since they reflect both ganglionic and postganglionic effects of accumulated ACh on the heart and blood vessels and actions in the CNS. The predominant effect on the heart from the peripheral action of accumulated ACh is...

bradycardia, resulting in a fall in cardiac output. Higher doses usually cause a fall in blood pressure, often as a consequence of effects of anti-ChE agents on the medullary vasomotor centers of the CNS.

κ-Opioid receptors are widely distributed in the...

brain (hypothalamus, periaqueductal gray, and claustrum), spinal cord (substantia gelatinosa), and in pain neurons.

Opioids also produce vasodilation by depressing vasomotor centers in the ...

brainstem (i.e., by decreasing central vasomotor tone) and to a lesser extent by a direct effect on vessels. This action affects both the venous and arterial vasculature, thereby reducing both preload and afterload. At typical clinical doses, opioids do not appreciably alter myocardial contractility.

The µ agonists also depress the hypoxic drive to...

breathe, although this effect is less important clinically than the effect on carbon dioxide controlled ventilatory drive.

GABA is a multifunctional neurotransmitter capable of producing...

brief, phasic responses or tonic currents that may be either excitatory or inhibitory, depending on the age, brain region, and cell-type being studied.

Morphine and methadone are effective for cough, but indicated only for intractable cough associated with...

bronchial carcinoma.

Respiratory effects of ketamine include...

bronchodilation, preservation of respiratory drive, and maintenance of respiratory muscle tone. It produces direct relaxation of airway smooth muscle ex vivo but may also cause bronchodilation indirectly through the modulation of vagal tone.

Muscarinic parasympathetic side effects of anticholinesterases include...

bronchospasm, increased bronchial and pharyngeal secretions, miosis, and increased intestinal tone. Therefore anticholinesterases are typically administered in combination with antimuscarinic drugs, such as glycopyrrolate or atropine. These compounds block "Muscarinic" but not "Nicotinic" receptors so that neuromuscular block can be antagonized while muscarinic effects are minimized.

Propranolol impairs...

bupivacaine extraction by the lungs, perhaps reflecting a common receptor site for the two drugs).

Addition of a butyl group to the piperidine nitrogen of mepivacaine results in...

bupivacaine, which is 35 times more lipid soluble and has a potency and duration of action three to four times that of mepivacaine.

Placement of chloroprocaine in the epidural space may decrease the efficacy of subsequent epidural...

bupivacaine-induced analgesia during labor. It is speculated that the low pH of the chloroprocaine solution could decrease the nonionized pharmacologically active fraction of bupivacaine. Tachyphylaxis to the local anesthetic mixture could also reflect local acidosis due to the low pH of the bathing solution.

Ropivacaine appears to be suitable for both epidural and regional anesthesia, with a duration of action similar to that of bupivacaine. Interestingly, it seems to be even more motor-sparing than...

bupivacaine.

Ventricular tachycardia and fibrillation are relatively uncommon consequences of local anesthetics other than...

bupivacaine.

Higher doses of naloxone are required to antagonize the respiratory-depressant effects of...

buprenorphine; 1 mg naloxone intravenously completely blocks the effects of 25 mg heroin.

The binding site for benzodiazepines is distinct from the binding site for barbiturates and GABA on the GABAA receptor, and also produces different effects on binding, with the benzodiazepines causing...

bursts of chloride channel opening to occur more often, while the barbiturates cause the duration of bursts of chloride channel opening to become longer.

Recovery of neuromuscular function after administration of succinylcholine is prolonged by a decreased concentration of...

butyrylcholinesterase or decreased butyrylcholinesterase activity. Reduced butyrylcholinesterase, whether because of malnutrition, chronic disease, pregnancy, or medications, prolongs the duration of action of succinylcholine.

The dibucaine number is used to identify individuals who have an atypical genotype for...

butyrylcholinesterase. Dibucaine inhibits normal butyrylcholinesterase more than it does the abnormal enzyme.

Furosemide, 1 mg/kg IV, enhances neuromuscular blockade produced by nondepolarizing neuromuscular-blocking drugs. This effect most likely reflects furosemide-induced inhibition of...

cAMP production, leading to decreased prejunctional output of acetylcholine. Conversely, large doses of furosemide may inhibit phosphodiesterase, making more cAMP available and leading to antagonism of nondepolarizing neuromuscular-blocking drugs.

Release of acetylcholine is a...

calcium-dependent process and is triggered by increases in the concentrations of free calcium ions in nerve terminals. It is speculated that a nerve action potential activates adenylate cyclase in membranes of nerve terminals leading to the formation of cyclic adenosine monophosphate (cAMP). cAMP subsequently opens calcium ion channels, causing synaptic vesicles to fuse with the nerve membrane and release acetylcholine.

The presence of a GluR2 subunit will almost always render the channel impermeable to...

calcium.

Epidural clonidine is indicated for treatment of severe...

cancer pain (0.5 µg/kg/hr). When given in this manner, bradycardia and sedation can occur but respiratory drive is maintained.

Neostigmine, Pyridostigmine & Physostigmine are carbamic acid esters of alcohols and contain a quaternary or tertiary ammonium group. These agents form a...

carbamyl-ester complex at the esteratic site of cholinesterase. This drug-enzyme complex then degrades in the same manner as the ACh-cholinesterase complex. The carbamate group is transferred to AChE, leaving it unable to hydrolyze ACh.

Physostigmine abolishes the somnolent effects of opioids and may reverse the depression of the ventilatory response to...

carbon dioxide, but not analgesia produced by prior administration of morphine. It is speculated that opioids diminish the ventilatory response to carbon dioxide by decreasing the amount of acetylcholine in the area of the respiratory center that would normally be released in response to hypercarbia. Other data, however, do not support an antagonist effect of physostigmine on opioid-induced depression of ventilation.

Levobupivacaine demonstrates comparable potency and efficacy as bupivacaine but has significantly less...

cardiac and central nervous system toxicity likely related to reduced affinity for subtypes of Na+ channels expressed in brain and cardiac tissues.

Risks of cocaine, beyond the potential for addiction, include...

cardiac arrhythmias, myocardial ischemia, myocarditis, aortic dissection, cerebral vasoconstriction, and seizures. Death from trauma also is associated with cocaine use.

Meperidine is not used in high doses because of significant negative...

cardiac inotropic effects plus histamine release in a substantial number of patients.

Local anesthetics affect the cardiovascular system both directly by affecting...

cardiac myocytes and peripheral vascular smooth muscle cells, and indirectly by actions on the autonomic nervous system.

The α2 adrenergic agonists lower arterial pressure by an effect on both...

cardiac output and peripheral resistance. In the supine position, when the sympathetic tone to the vasculature is low, the major effect is to reduce both heart rate and stroke volume; however, in the upright position, when sympathetic outflow to the vasculature is normally increased, these drugs reduce vascular resistance. This action may lead to postural hypotension. The decrease in cardiac sympathetic tone leads to a reduction in myocardial contractility and heart rate that could promote congestive heart failure in susceptible patients.

The more potent, more lipid-soluble drugs (bupivacaine, etidocaine, and ropivacaine) appear to have an inherently greater...

cardiotoxicity than the less potent drugs.

Bupivacaine is not recommended for IV regional anesthesia considering its greater likelihood than other local anesthetics for producing...

cardiotoxicity when the tourniquet is deflated at the conclusion of the anesthetic.

The nucleus tractus solitarii (NTS) of the medulla, often considered the command center of the autonomic nervous system, controls...

cardiovascular and digestive tract reflexes and contains both glutamatergic afferents and efferents.

Etomidate when compared with other induction agents, it has minimal effects on the...

cardiovascular system. Because of its association with nausea and prolonged suppression of adrenocortical synthesis of steroids, its main clinical use is for inductions in which hemodynamic stability is essential. The R( +) isomer has much greater hypnotic effects and it is formulated as a single enantiomer.

Opioid receptors, particularly m and d, are densely expressed in respiratory centers of the brainstem and the nuclei of the pons that influence the respiratory drive, as well as in the periphery within the...

carotid body, which detects blood levels of O2 and CO2.

Both the α2A- and α2C-ARs are involved in suppression of...

catecholamine release from neuronal terminals.

Zinc-activated ion channel (ZAC), is a human protein encoded by the ZACN gene. ZAC forms a...

cation-permeable ligand-gated ion channel of the "Cys-loop" superfamily.

In the sympathoinhibitory pathway, second order glutamatergic neurons in the NTS excite GABAergic interneurons in the...

caudal ventrolateral medulla (CVL). These CVL interneurons project to and inhibit glutamatergic neurons in the rostral ventrolateral medulla (RVLM), which in turn innervate preganglionic sympathetic neurons in the spinal cord. These spinal cord neurons release acetylcholine at the sympathetic ganglion.

In general, compounds containing a quaternary ammonium group do not penetrate...

cell membranes readily; hence, anti-ChE agents in this category are absorbed poorly from the GI tract or across the skin and are excluded from the CNS by the blood-brain barrier after moderate doses.

Serious cases of methemoglobinemia present with...

central cyanosis that is refractory to oxygen therapy, which may be fatal if unrecognized. Diagnosis requires a high index of suspicion, which is confirmed by qualitative measurements of methemoglobinemia by co-oximetry. Treatment consists of intravenous methylene blue (1-2mg/kg), which accelerates the reduction of methemoglobinemia via an alternative pathway for hemoglobin reduction.

Acute dystonia has been described after administration of alfentanil to a patient with untreated Parkinson's disease. This may reflect an ability of opioids to decrease...

central dopaminergic transmission and suggests caution in administration of this opioid to patients with untreated Parkinson's disease.

Opioids act as agonists at stereospecific opioid receptors at presynaptic and postsynaptic sites in the...

central nervous system (CNS) (principally the brainstem and spinal cord) and outside the CNS in peripheral tissues .

Opioid-induced pruritus seems to be mainly a central mechanism, since pruritus elicited by intravenous fentanyl, remifentanil, and morphine could be reversed by naltrexone, which enters the...

central nervous system, but not by methylnaltrexone, which does not penetrate the blood-brain barrier

There is evidence that opioid-induced pruritus is a...

centrally mediated mechanism. Treatment with naloxone and naltrexone attenuates analgesia; an alternative option is the use of agents which stimulate kappa opioid receptors to suppress itching while antagonizing mu opioid receptors.

Opioid suppression of the coughing reflex is predominantly...

centrally regulated, although this is independent of opioid effects on the respiratory center

Cephalad movement of opioids in the CSF principally depends on lipid solubility. For example, lipid-soluble opioids such as fentanyl and sufentanil are limited in their...

cephalad migration by uptake into the spinal cord, whereas less lipid-soluble morphine remains in the CSF for transfer to more cephalad locations.

Other receptors, such as glycine receptors, voltage-gated Na + channels, and two-pore domain potassium channels deserve attention in that they probably contribute to...

certain components of the balanced anesthetic state with intravenous anesthetics.

In obstetrics, epidural chloroprocaine, with or without bicarbonate, is used to attain rapidly surgical levels of anesthesia in preparation for...

cesarean section. Another theoretical advantage in obstetrics is that there is virtually no transmission of chloroprocaine to the fetus.

Pretreatment of patients with H1 and H2 receptor antagonists does not alter release of histamine evoked by morphine but does prevent...

changes in systemic blood pressure and systemic vascular resistance.

The cys-loop receptors are named after a...

characteristic loop formed by a disulfide bond between two cysteine residues in the N terminal extracellular domain. They are subdivided with respect to the type of ion that they conduct (anionic or cationic) and further into families defined by the endogenous ligand.

The tetracyclines also can produce neuromuscular blockade, possibly by...

chelation of Ca2 +. Additional antibiotics that have neuromuscular blocking action, through both presynaptic and postsynaptic actions, include polymyxin B, colistin, clindamycin, and lincomycin.

Hypnotic doses of benzodiazepines are without effect on respiration in normal subjects, but special care must be taken in the treatment of...

children and individuals with impaired hepatic function, such as alcoholics.

Benzodiazepines act on a subset of GABAA receptors containing γ subunits to potentiate...

chloride conductance upon GABA binding. This modulatory mode of action is postulated to create a "ceiling effect" that limits CNS depression, although when combined with other drugs, benzodiazepines can lead to dangerous respiratory depression.

Approximately 50% of the released ACh is hydrolyzed into...

choline and acetate before reaching the receptor. Choline is taken up by the nerve terminal and reused for synthesis of ACh.

There is increasing evidence of opioid receptors expressed in the heart. High abundance of delta-opioid receptors in the canine sinoatrial node and somewhat lower abundance in the atria are predominantly associated with presynaptic...

cholinergic nerve terminals, supporting the hypothesis that prejunctional d-opioid receptors regulate vagal transmission within the heart. Fewer opioid receptors can also be found in cardiac myocytes, which may contribute to the cardioprotective effects of opioids in myocardial ischemia.

Remifentanil does not appear to be a substrate for butyrylcholinesterases (pseudocholinesterase), and thus its clearance should not be affected by...

cholinesterase deficiency or anticholinergics.

Hematopoietic suppression characterized by agranulocytosis and bone marrow granulocytic aplasia has been associated with...

chronic administration of ibuprofen

Methadone is also increasingly used in the treatment of...

chronic pain patients, particularly cancer-related pain. Methadone's propensity to prolong the QT interval of the electrocardiogram by blocking the delayed rectifier potassium ion channel (IKr) may contribute to increased mortality in this patient population.

Local anesthetics such as bupivacaine, which are highly lipid soluble, are distributed less into the...

circulation than are less lipid-soluble agents such as lidocaine.

A single IV dose of sufentanil has a similar elimination half-time in patients with or without...

cirrhosis of the liver.

Methohexital differs from the two intravenous barbiturates in its much more rapid...

clearance; thus, it accumulates less during prolonged infusions.

Meperidine is the first completely synthetic opioid and can be regarded as the prototype...

clinical phenylpiperidine. Fentanyl is a simple modification of the basic phenylpiperidine structure found within meperidine; the other commonly used fentanyl congeners like alfentanil and sufentanil are somewhat more complex versions of the same phenylpiperidine skeleton.

About 15-20% of patients develop contact dermatitis when using...

clonidine in the transdermal system.

In the CNS, stimulation of postsynaptic alpha2 receptors by drugs such as...

clonidine or dexmedetomidine results in enhanced potassium ion conductance and membrane hyperpolarization manifesting as decreased anesthetic requirements.

Tricyclic antidepressants may inhibit the anti-hypertensive effect of...

clonidine, but the mechanism of this interaction is not known.

Patients who have had a spinal cord transection above the level of the sympathetic outflow tracts do not display a hypotensive response to...

clonidine.

PGs have long been implicated in the maintenance of patency of the ductus arteriosus, and indomethacin, ibuprofen, and other NSAIDs have been used in neonates to...

close the inappropriately patent ductus.

D-serine has also been found to...

co-agonize the NMDA receptor with even greater potency than glycine

Absorption of local anesthetics from the mucous membrane is significant and therefore can result in systemic toxicity. Tetracaine has the most rapid rate of absorption, followed by...

cocaine and lidocaine, respectively. Peak plasma levels occur 5 minutes after the application of tetracaine or cocaine to the pyriform fossae of the laryngopharynx.

The exception to hydrolysis of ester local anesthetics in the plasma is...

cocaine, which undergoes significant metabolism in the liver.

patients who lack CYP2D6 because of deletion, frame shift, or splice mutations (approximately 10% of the Caucasian population) or whose CYP2D6 is inhibited (e.g., patients taking quinidine) do not respond normally to...

codeine even though they exhibit a normal response to morphine.

Interestingly, Asians have less CYP2D6 activity and thus may be an ethnic group that are particularly resistant to...

codeine therapy. Conversely, certain ethnic groups (e.g., Ethiopians) carry frequently duplicated, functional CYP2D6 genes, resulting in the ultra rapid conversion of codeine to morphine, and are thought to be particularly susceptible to the effects of codeine.

CYP2D6 ultrarapid metabolizers are at greater risk for...

codeine toxicity.

Hydrocodone is a semi-synthetic opioid derived from...

codeine.

Bupivacaine-induced cardiac toxicity can be very difficult to treat, and its severity is enhanced by...

coexisting acidosis, hypercarbia, and hypoxemia.

Acetylcholinesterase is secreted by the muscle and remains attached to it by...

collagen fastened to the basal lamina. ACh molecules that do not bind immediately with a receptor or those released after reacting with a receptor are hydrolyzed almost instantly (in less than 1ms) by acetylcholinesterase.

Ca2 + channel blockers enhance neuromuscular blockade produced by both...

competitive and depolarizing antagonists. When neuromuscular blocking agents are administered to patients receiving these agents, dose adjustments should be considered; if recovery of spontaneous respiration is delayed, Ca2 + salts may facilitate recovery.

Since the nondepolarizing NMBAs block neuromuscular transmission primarily by...

competitive antagonism of ACh at the post-junctional receptor, the most straightforward way to overcome the effects of the blockade is to increase the competitive position of ACh by increasing the number of molecules available at the junctional cleft.

NMDA antagonists are classified by their mechanism of action. Volatile anesthetics may exert some of their effects as...

competitive antagonists by displacing the coagonist glycine from NMDA receptors. The intravenous NMDA antagonists in current clinical use are primarily channel blockers that bind to the pore only in its open confirmation. They are considered uncompetitive antagonists and, because their binding requires prior activation by agonist, they are termed use-dependent.

Flumazenil binds with high affinity to specific sites on the GABAA receptor, where it...

competitively antagonizes the binding and allosteric effects of benzodiazepines and other ligands.

The quality of nerve blockade is determined not only by the potency of the individual local anesthetic, but also by the...

concentration and volume of the local anesthetic.

When a ligand binds to the GPCR it causes a...

conformational change in the GPCR, which allows it to act as a guanine nucleotide exchange factor (GEF). The GPCR can then activate an associated G-protein by exchanging its bound GDP for a GTP.

Binding of the local anesthetic is a dynamic process characterized by differing affinities for the receptor site based on...

conformational changes of the VGSC, induced by temporal changes in the membrane potential.

Propofol is metabolized via...

conjugation into inactive metabolites, however its clearance (total body clearance estimated at 25 mL/kg/min) exceeds that of hepatic blood flow and continues even during the anhepatic phase of liver transplantation; this argues for some extrahepatic metabolism of the drug.

Propofol is metabolized in the liver by...

conjugation to sulfate and glucunoride to less active metabolites that are renally excreted; however, its clearance exceeds hepatic blood flow, and anhepatic metabolism, particularly in the lungs and kidneys, has been demonstrated.

When applied locally to the conjunctiva, anti-ChE agents cause...

conjunctival hyperemia and constriction of the pupillary sphincter muscle around the pupillary margin of the iris (miosis) and the ciliary muscle (block of accommodation reflex with resultant focusing to near vision).

In the brain, ketamine has a unique profile combining depressed...

consciousness with increased sympathetic tone. This sympathetic activation leads to increases in cardiac output in patients with normal catecholamine stores, which can make ketamine a useful induction agent in patients with hypovolemia.

Cisatracurium is approximately threefold more potent than Atracurium (ED95 of 0.05 mg/kg) and, like Atracurium, has an intermediate duration of action. Because of its greater potency, however, its onset of effect is...

considerably slower. For this reason, doses of 3 to 5 times the ED95 are recommended for endotracheal intubation. In contrast to Atracurium, administration of such large doses is not associated with histamine release, and resultant hypotension or tachycardia.

μ receptors are also found in the intestinal tract. This causes...

constipation, a major side effect of μ agonists, due to inhibition of peristaltic action.

Fentanyl has minimal effects on intracranial pressure when ventilation is...

controlled and the arterial CO2 concentration is not allowed to rise.

While classically thought of as an inhibitory neurotransmitter, GABAA receptors also have the unusual capacity to...

convey excitatory responses, depending on the Cl− reversal potential across the neuronal membrane.

Acute cocaine administration is known to cause...

coronary vasospasm, myocardial ischemia, myocardial infarction, and ventricular cardiac dysrhythmias, including ventricular fibrillation. Associated hypertension and tachycardia further increase myocardial oxygen requirements at a time when coronary oxygen delivery is decreased by the effects of cocaine on coronary blood flow.

Unlike morphine and its congeners, meperidine is not used for the treatment of...

cough or diarrhea.

Methohexital and to a lesser degree other barbiturates can produce excitatory symptoms on induction such as...

cough, hiccup, muscle tremors, twitching, and hypertonus.

Small amounts of NMBA do cross the blood-brain barrier, but larger amounts most likely cross in...

critical illness where the blood-brain barrier is more permeable. The long-term effects of NMBAs on AChRs in the central nervous system are unclear, although inadvertent acute direct administration is known to cause seizures.

The primary mode of NSAID elimination is by hepatic biotransformation by...

cytochrome P450 (CYP 450) mediated oxidation or glucuronide conjugation. Renal excretion of unmetabolized drug is much less important, accounting for less than 10% of the administered dose.

Aminoamides are metabolized in the liver by the...

cytochrome P450 enzymes CYP1A2 and CYP3A4 via N-dealkylation, amide bond hydrolysis, and hydroxylation.

After bolus injection, remifentanil and alfentanil predicted effect site concentrations reach a peak quickly and then...

decline significantly before any of the other opioids have even begun to peak. This rapid achievement of peak effect site concentrations for these two highly lipid soluble fentanyl congeners is likely a function of their high "diffusible fractions"

The most common side effects of dexmedetomidine include hypotension and bradycardia, both of which are attributed to...

decreased catecholamine release by activation peripherally and in the CNS of the α2A receptor.

The sympatholytic effects of dexmedetomidine lead to...

decreased heart rate and blood pressure, which can be helpful, harmful, or of no clinical consequence. In many scenarios these effects are minimal and well tolerated. In patients with cardiac disease there is a potential benefit of decreased myocardial demand in response to painful stimuli. A recent meta-analysis found decreased mortality in vascular surgery patients, but with increased bradycardia and hypotension.

In patients with renal failure, the clearance of rocuronium is marginally...

decreased or unchanged, volume of distribution is increased, and elimination half-life is prolonged.

Cirrhosis of the liver is accompanied by up to fivefold increases in the elimination half-time of diazepam. Prolongation of the elimination half-time of diazepam in the presence of cirrhosis of the liver is due to...

decreased protein binding of the drug, leading to an increased Vd. In addition, hepatic clearance of diazepam is likely to be decreased, reflecting decreased hepatic blood flow characteristic of cirrhosis of the liver.

Noradrenergic neurons in the sympathetic ganglion activate vasoconstriction. However, because excitation of GABAergic interneurons in the CVL causes downstream inhibition of the pathway, the net result is ...

decreased vasoconstriction. Thus, activation of baroreceptors activates two homeostatic pathways collectively known as the baroreceptor reflex, causing heart rate and blood pressure to decrease.

Administration of fentanyl and sufentanil to head injury patients has been associated with modest increases (6 to 9 mm Hg) in ICP despite maintenance of an unchanged PaCO2. These increases in ICP are typically accompanied by...

decreases in mean arterial pressure and cerebral perfusion pressure.

Opioids can cause urinary retention by ...

decreasing bladder detrusor tone and by increasing the tone of the urinary sphincter. Although the urinary retention associated with opioid therapy is not typically pronounced, it can be troublesome in males, particularly when the opioid is administered intrathecally or epidurally.

Numerous studies have shown that serum levels of gabapentin and pregabalin increased with...

decreasing renal function, and that both drugs are readily dialyzable.

Local anesthetics act directly on the cardiovascular system by...

decreasing the conduction in Purkinje fibers and cardiomyocytes by prolonging the recovery time. Local anesthetics are also direct myocardial depressants via a mechanism related to reduced Ca2+ influx and release from the sarcoplasmic reticulum.

Elevated PaCO2 leads to cerebral vasodilation and increased...

delivery of drug to the CNS. However, acidosis promotes amine protonation leading to less diffusion into nerve cells.

Thiopental maintains the ratio of myocardial O2 supply to...

demand in patients with coronary artery disease within a normal blood pressure range.

The combination of an opioid agonist such as morphine or fentanyl with nitrous oxide results in cardiovascular...

depression (decreased cardiac output and systemic blood pressure plus increased cardiac filling pressures), which does not occur when either drug is administered alone.

Gabapentin and pregabalin are associated with an increased risk of...

depression and suicide. Sudden withdrawal of these agents can precipitate seizures, even in patients who have not seized previously.

The primary disadvantage of propofol is its...

depressive effect on the cardiovascular system. Patients who are hypovolemic, debilitated, or reliant on high sympathetic tone to maintain blood pressure require careful titration of propofol to avoid severe hypotension.

Bronchoconstriction associated with ingestion of aspirin in sensitive patients is likely caused by...

derangement of arachidonic acid metabolism with increased production of leukotrienes.

The µ-receptor produces analgesia within...

descending pain control circuits, at least in part by the removal of GABAergic (transmitting or secreting γ-aminobutyric acid) inhibition of RVM-projecting neurons in the PAG and spinally projecting neurons in the RVM.

Although lidocaine and bupivacaine both rapidly block cardiac Na + channels during systole, bupivacaine dissociates much more slowly than does lidocaine during...

diastole, so a significant fraction of Na+ channels at physiological heart rates remains blocked with bupivacaine at the end of diastole. Thus, the block by bupivacaine is cumulative and substantially more than would be predicted by its local anesthetic potency.

While metabolism of alfentanil, fentanyl, and sufentanil can be affected by CYP3A4 activity, CYP3A4 gene polymorphisms have not been associated with...

differences in clinical effects for these opioids.

Different neuromuscular units have different sensitivities to NMBAs and different time courses of onset of and recovery from neuromuscular block. This has been attributed to...

different blood flow to these different muscles. These differences must be considered when dosing is based on monitoring at different sites. The mimetic muscles recover more quickly than those of the periphery, and the depth of block in response to a dose of NMBA is less profound than that in the arm or the leg. While different sites can be monitored, dosing recommendations for NMBAs are based on the response of the adductor pollicis to stimulation of the ulnar nerve.

Succinylcholine is comprised of two molecules of acetylcholine bound at their acetate methyl groups. This structural similarity to acetylcholine allows it to stimulate acetylcholine receptors as an agonist, causing muscle depolarization. Its neuromuscular blocking activity is terminated by...

diffusion out of the neuromuscular junction into plasma where it is hydrolyzed by butyrylcholinesterase (also known as plasma cholinesterase) to succinylmonocholine and choline. The hydrolysis of succinylcholine by butyrylcholinesterase accounts for its short elimination half-life, which is estimated to be less than 1 minute.

The respiratory depression produced by opioids is the result of...

direct depression of the respiratory centers and activation of the mu-2 receptors in the brainstem. Respiratory rate, minute volume, and tidal volume are decreased.

True allergies to barbiturates are rare; however...

direct drug-induced histamine release is occasionally seen.

The analgesic properties of morphine, hydromorphone, oxymorphone, propoxyphene, and fentanyl are largely due to their...

direct influence on opioid receptors and do not require additional metabolism.

The fentanyl congeners produce a slowing of heart rate by...

directly increasing vagal nerve tone in the brainstem. If the bradycardia is considered undesirable in patients, it can be readily treated with antimuscarinic drugs.

Benzodiazepines act at GABAA receptors by binding...

directly to a specific site that is distinct from that of GABA binding.

The diagnosis of Myasthenia Gravis depends on clinical features, the presence of autoantibodies, and electrophysiologic evidence of...

disordered neuromuscular transmission. Fade can be observed during repetitive nerve stimulation, even in the absence of NMBA, confirming the decreased margin of safety.

Compared with lorazepam, diazepam has a longer elimination half-time but shorter duration of action because it...

dissociates more rapidly than lorazepam from GABAA receptors, permitting more rapid redistribution to inactive tissue sites.

It is now widely accepted that κ-opioid receptor (partial) agonists have...

dissociative and delirium-inducing effects, as exemplified by salvinorin A

Benzodiazepines do not bind to the same receptor site on the protein complex as the endogenous ligand GABA (whose binding site is located between α- and β-subunits), but bind to...

distinct benzodiazepine binding sites situated at the interface between the α- and γ-subunits of α- and γ-subunit containing GABAA receptors.

Protein binding of local anesthetics will influence their...

distribution and excretion. In this regard, protein binding parallels lipid solubility of the local anesthetic and is inversely related to the plasma concentration of drug.

Becuse only a very small fraction of ropivacaine is excreted unchanged in the urine (about 1%) when the liver is functioning normally, dosage adjustments based on renal function...

do not seem necessary. However, in uremic patients, 2,6-pipecoloxylidide may accumulate and produce toxic effects.

Transdermal fentanyl patches are approved for use in sustained pain. The opioid permeates the skin, and a "depot" is established in the stratum corneum layer. Unlike other transdermal systems (i.e., transdermal scopolamine), anatomic position of the patch...

does not affect absorption. However, fever and external heat sources (heating pads, hot baths) can increase absorption of fentanyl and potentially lead to an overdose.

Cirrhosis of the liver, but not cholestatic disease, prolongs the elimination half-time of alfentanil. Renal failure...

does not alter the clearance or elimination half-time of alfentanil.

Nociceptin is thought to be an endogenous antagonist of dopamine transport that may act either directly on...

dopamine or by inhibiting GABA to affect dopamine levels. Within the central nervous system its action can be either similar or opposite to those of opioids depending on their location

Gabapentin and pregabalin bind the α2δ-1 subunit of presynaptic voltage-gated calcium channels in the...

dorsal horn of the spinal cord and brain thereby preventing calcium influx and the release of excitatory neurotransmitters.

In the PAG area administered exogenous opioids bind to opioid receptors and activate descending inhibitory pathways that project to the...

dorsal horn of the spinal cord to inhibit nociceptive processing. These descending inhibitory pathways are also stimulated by a release of endogenous opioid peptides following certain stressful stimuli.

At the level of the spinal cord a high density of opioid-receptor binding sites has been demonstrated within the...

dorsal horn. Consistently, mu, delta, and kappa-opioid receptor- specific immunohistochemistry showed distribution in laminae I and II of the spinal cord. These opioid receptors are located both presynaptically on central nerve terminals of peripheral sensory neurons and postsynaptically on second-order spinal cord neurons.

There is significant opioid receptor-ligand binding and little detectable receptor mRNA expression in the spinal cord dorsal horn but high levels of opioid receptor mRNA in the...

dorsal root ganglia. This distribution might suggest that the actions of opioid receptor agonists relevant to analgesia at the spinal level are predominantly presynaptic.

For bupivacaine, first-pass pulmonary extraction is...

dose dependent, suggesting that the uptake process becomes saturated rapidly.

To some extent, cardiac dysrhythmias following succinylcholine administration are...

dose related. Large doses can cause tachycardia, and in adults second doses administered within a few minutes of the first can cause bradycardia or a nodal rhythm. Succinylcholine also lowers the threshold for arrhythmias induced by circulating catecholamines and increases circulating catecholamine levels.

In neuraxial anesthesia, the first indication a block is working is usually a...

drop in blood pressure.

The side effects of lidocaine seen with increasing dose include...

drowsiness, tinnitus, dysgeusia, dizziness, and twitching. As the dose increases, seizures, coma, and respiratory depression and arrest will occur.

The rate of vascular uptake significantly affects local anesthetic...

duration of action as local anesthetics provide their effect as long as they remain at the site of deposition. Therefore deposition of local anesthetics at a highly vascular site such as the intercostal space has a higher rate of vascular uptake. Vasoconstriction slows the rate of vascular absorption and thus prolongs the duration of action. For this purpose, vasoconstrictive agents such as epinephrine and phenylephrine are frequently added to local anesthetics as adjuvants to increase duration.

Hydromorphone is a derivative of morphine that is about 5-8 times as potent as morphine but has a slightly shorter...

duration of action. This opioid produces somewhat more sedation and evokes less euphoria than morphine.

It is likely that highly protein-bound local anesthetics are removed from the nerve at a decreased rate, resulting in slower uptake and absorption, which accounts for the increased...

duration of action. Thus, increased protein binding correlates with increased lipid solubility, which leads to increased potency and duration of action of the local anesthetic as a result of increased local anesthetic content within nerves.

Moderate hepatic or renal impairment has little effect on Propofol's...

duration of clinical effect.

The κ-opioid receptor is a type of opioid receptor that binds the opioid peptide...

dynorphin as the primary endogenous ligand (substrate naturally occurring in the body). In addition to dynorphin, a variety of natural alkaloids and synthetic ligands bind to the receptor.

κ-Opioid agonists have recently been investigated for their therapeutic potential in the treatment of addiction and evidence points towards...

dynorphin, the endogenous κ-opioid agonist, to be the body's natural addiction control mechanism.

enkephalins and beta-endorphin but low affinity for...

dynorphins.

The sedation produced by dexmedetomidine is different in that patients tend to be...

easily arousable. This feature, in combination with its minimal effects on respiratory drive, allows continuation of infusions during weaning from mechanical ventilation and after extubation without the need for dose titration.

In contrast to neostigmine and pyridostigmine, acetylcholinesterase does not break down...

edrophonium but rather edrophonium forms a reversible electrostatic attachment to the enzyme.

Dexmedetomidine reduces shivering in an additive fashion with meperidine, raising the possibility that...

effects of both are mediated by α2 receptors.

Despite initial concerns that the egg-derived lecithin might precipitate anaphylaxis in egg allergic individuals, it appears that propofol can be safely used in...

egg allergic patients. Most egg allergies are related to egg albumin (in egg whites) as opposed to lecithin (primarily in the egg yolk), and a small study revealed no hypersensitivity to propofol in egg allergic patients undergoing skin prick testing.

Edrophonium produces reversible inhibition of acetylcholinesterase by...

electrostatic attachment to the anionic site and hydrogen bonding at the esteratic site of the enzyme.

Edrophonium is considered a reversible inhibitor of cholinesterase because it...

electrostatically attaches to the anionic site of AChE and is stabilized by hydrogen binding at the esteratic site of the enzyme. Because a true chemical bond is not formed, ACh competes with edrophonium for the binding site of AChE, and therefore it has a shorter duration of action than those of compounds that form a bond.

The similarities between natural sleep and the anesthetized state suggest that anesthetics might also modulate...

endogenous sleep regulating pathways, which include ventrolateral preoptic (VLPO) and tuberomammillary nuclei.

Nerve fibers are encased in...

endoneurium, loose connective tissue that consists of glial cells and fibroblasts along with blood capillaries. These fibers are grouped together by dense collagenous perineurium to form a unit called a fascicle. The fascicles are surrounded by a thicker layer of epineurium. The nerves are further encased in fascia. These are the structures that local anesthetics must penetrate in order to block effectively nerve conduction.

Synaptic defects can be due to mutations in the...

endplate acetylcholinesterases and result in a deficiency of neurotransmission at the NMJ due to AChR downregulation as a result of sustained excess in synaptic ACh concentration.

The μ-opioid receptors (MOR) are a class of opioid receptors with high affinity for...

enkephalins and beta-endorphin but low affinity for dynorphins.

The δ-opioid receptor, also known as delta opioid receptor or simply delta receptor, abbreviated DOR, is an opioid receptor that has...

enkephalins as its endogenous ligands.

The kinetics of redistribution of diazepam and other lipophilic benzodiazepines are complicated by...

enterohepatic circulation. The volumes of distribution of the benzodiazepines are large and in many cases are increased in elderly patients. These drugs cross the placental barrier and are secreted into breast milk.

Chronic cocaine users can develop intraoperative hypotension that is unresponsive to...

ephedrine that will usually respond to direct acting vasoconstrictors such as phenylephrine.

Because of its lipid solubility, it is sometimes used instead of morphine for...

epidural or spinal administration when a wide area of analgesia is needed.

Sufentanil, being even more lipophilic than fentanyl, provides similar plasma levels regardless of whether it is administered by an intravenous or...

epidural route. Nevertheless, some authors suggest that sufentanil (0.75-1 µg/mL) is a valuable adjuvant for epidural analgesia with improved analgesia and decreased intravenous opioid requirement.

There are no plasma cholinesterases in either the...

epidural space or the CSF.

The α2C-AR is critical for suppression of...

epinephrine release from the adrenal chromaffin cells.

It has been postulated that clonidine might prolong the duration of action of local anesthetics by a mechanism similar to that observed with...

epinephrine. Studies show that clonidine reduces local blood flow, and the decrease in blood flow correlates with the injected dose.

Both midazolam and diazepam are metabolized by CYP3A family members in the liver and are subject to interactions with...

erythromycin and antifungal medications.

Unlike the neuromuscular junction, where acetylcholine mediates rapid excitatory signaling, glutamate mediates...

essentially all rapid excitatory signaling in the mammalian CNS. This excitatory signaling is counter-balanced by GABA- or glycine-mediated inhibition.

The major route for cocaine metabolism involves hydrolysis of each of its two...

ester groups. Benzoylecgonine, produced on loss of the methyl group, represents the major urinary metabolite and can be found in the urine for 2-5 days after a binge.

Etomidate is metabolized in the liver by...

ester hydrolysis to a pharmacologically inactive metabolite.

True allergy to local anesthetics is rare but occurs more commonly with...

ester local anesthetics than with amide local anesthetics. The accepted explanation is that amino-esters are metabolized to PABA, which is immunogenic. Some preparations of amino-amides contain methylparaben, which has a similar chemical structure as PABA and is a possible allergen in cases of allergic reaction with the use of amide local anesthetics.

Cocaine and procaine are both...

ester local anesthetics.

Tetracaine is a slow onset, potent and intermediate to long acting...

ester-type local anesthetic. Even longer duration of action can be achieved when administered along with a vasoconstrictor such as epinephrine. However it is quite toxic, and has been suggested to cause neurotoxicity at high doses in animal studies resulting in cauda equina syndrome with repeated spinal dosing. It is used mainly topically or sometimes for spinal anesthesia.

Dysfunction of central motor neurons due to spinal cord trauma or stroke is associated with muscle weakness or paralysis. This causes a reduction in...

evoked ACh that leads to upregulation of immature AChRs. Upregulation of immature AChRs results in susceptibility to SCh-induced hyperkalemia.

The most common clinical use of naloxone perioperatively is the reversal of...

excessive opioid induced ventilatory depression. Other uses include the emergency reversal of ventilatory depression in neonates whose mothers received opioids for labor analgesia and in cases of accidental or intended opioid overdose (e.g., heroin) in the emergency department.

Administration of meperidine to a patient treated with MAO inhibitors may result in an...

excitatory (type I) response (agitation, headache, skeletal muscle rigidity, hyperpyrexia) or a depressive (type II) response characterized by hypotension, depression of ventilation, and coma.

Postsynaptic Kainate receptors are involved in...

excitatory neurotransmission.

In addition to its accepted role as an inhibitory neurotransmitter in brainstem and spinal cord, glycine also contributes to...

excitatory signaling.

Lorazepam is conjugated with glucuronic acid in the liver to form pharmacologically inactive metabolites that are...

excreted by the kidneys.

Ultrarapid metabolizers of codeine have as much as 50% higher plasma morphine concentrations compared with..

extensive codeine metabolizers.

AMPARs open and close quickly, and are thus responsible for most of the...

fast excitatory synaptic transmission in the central nervous system.

EMLA cream is not recommended for use on mucous membranes because of the...

faster absorption of lidocaine and prilocaine than through intact skin. Similarly, EMLA cream is not recommended for skin wounds, and the risk of wound infection may be increased .

Clinically, botulism generally presents with symptoms of...

fatigability of the bulbar and ocular muscles and in severe cases weakness of neck, extremities, and trunk, producing a generalized paralysis.

Opioid-induced muscle rigidity is another potentially serious adverse effect of this drug class. Typically observed during the rapid administration of high bolus doses of the...

fentanyl congeners, opioid-induced muscle rigidity can make bag-and-mask ventilation during anesthesia induction impossible; the difficulty with bag-and-mask ventilation appears to be in large part a function of vocal cord rigidity and closure.

Cocaine produces dose-dependent decreases in uterine blood flow that result in...

fetal hypoxemia . Cocaine may produce hyperpyrexia, which could contribute to seizures.

Nebulized lidocaine is used to produce surface anesthesia of the upper and lower respiratory tract before...

fiberoptic laryngoscopy and/ or bronchoscopy and as a treatment for patients experiencing intractable coughing.

The lungs also serve as a large, inactive storage site, with an estimated 75% of the initial fentanyl dose undergoing...

first-pass pulmonary uptake. This nonrespiratory function of the lungs limits the initial amount of drug that reaches the systemic circulation and may play an important role in determining the pharmacokinetic profile of fentanyl.

Morphine, unlike fentanyl, does not undergo significant...

first-pass uptake into the lungs.

The GABAA receptor is a pentameric transmembrane receptor that consists of...

five subunits arranged around a central pore. Each subunit comprises four transmembrane domains with both the N- and C-terminus located extracellularly. The receptor sits in the membrane of its neuron, usually localized at a synapse, postsynaptically. However, some isoforms may be found extrasynaptically.

The ionotropic GABAA receptors consist of...

five subunits that co-assemble to form an integral chloride channel.

Opioids stimulate the chemoreceptor trigger zone in the area postrema on the...

floor of the fourth ventricle (opioid receptors are expressed here) in the brain. This can lead to nausea and vomiting, an effect that is exacerbated by movement (this is perhaps why ambulatory surgery patients are more likely to be troubled by postoperative nausea and vomiting [PONV]). The use of postoperative opioids is a clear risk factor for the occurrence of PONV.

Both clonidine and dexmedetomidine are useful in the intensive care unit to prevent drug withdrawal symptoms..

following long-term sedation with benzodiazepines.

Consistently, a central and peripheral component of the hypercapneic response to opioids can be observed, though the...

former contributes to it much more strongly than the latter.

Drugs such as physostigmine, neostigmine, and pyridostigmine produce reversible inhibition of acetylcholinesterase by...

forming a carbamyl ester complex at the esteratic site of the enzyme.

NMDA receptors are tetramers consisting of...

four subunits arranged circumferentially around a central ion channel pore.

NMDA receptors are comprised of four...

four subunits, two of which must be NR1 subunits, and the other two can be comprised of either NR2 or NR3 subunits.

The neuroexcitatory effects of M3G do not appear to be mediated by μ receptors but rather by the GABA/glycinergic system. In contrast, approximately 10% of morphine is metabolized to morphine-6-glucuronide (M6G), an active metabolite with analgesic potency...

four to six times that of its parent compound. However, these relatively polar metabolites have limited ability to cross the blood-brain barrier and probably do not contribute significantly to the usual CNS effects of morphine given acutely. Nevertheless, accumulation of these metabolites may produce unexpected adverse effects in patients with renal failure or when exceptionally large doses of morphine are administered or high doses are administered over long periods.

Intramuscular administration of meperidine does not affect heart rate significantly, but intravenous administration...

frequently produces a marked increase in heart rate.

Rarely, hepatotoxicity is linked to...

gabapentin use.

Symptoms that occur during the first 2 days of acute poisoning by acetaminophen reflect...

gastric distress (e.g., nausea, abdominal pain, anorexia) and belie the potential seriousness of the intoxication. Plasma transaminases become elevated, sometimes markedly so, beginning 12-36 hours after ingestion. Clinical indications of hepatic damage manifest within 2-4 days of ingestion of toxic doses, with right subcostal pain, tender hepatomegaly, jaundice, and coagulopathy. Renal impairment or frank renal failure may occur. Liver enzyme abnormalities typically peak 72-96 hours after ingestion.

COX-1 is considered to be the constitutive enzyme (often called the housekeeping enzyme), generating prostanoids involved in normal physiologic functioning such as...

gastrointestinal mucosal protection and hemostasis.

Acetaminophen has few side effects in the usual dosage range; unlike NSAIDs, no significant...

gastrointestinal toxicity or platelet function inhibition occur. Acetaminophen has, however, been associated with the development of hypertension but has not yet been associated with increased cardiovascular risk.

It has been widely used to treat pediatric emergence delirium associated with...

general anesthesia. A prophylactic dose of 1 mcg/kg approximately 30 minutes prior to emergence is usually effective. Existing emergence delirium can be treated with a 0.125 mcg/kg bolus and repeated as needed to avoid oversedation.

In patients with a history of ethanol abuse or liver disease, acetaminophen should...

generally be avoided.

There is evidence that preoperative administration of NSAIDs (ketorolac) to well-hydrated patients anesthetized with sevoflurane does not produce...

glomerular or tubular dysfunction.

Ketorolac is metabolized principally by...

glucuronic acid conjugation.

Naloxone is metabolized primarily in the liver by conjugation with...

glucuronic acid to form naloxone-3-glucuronide.

Dexmedetomidine is metabolized in the liver primarily by...

glucuronidation with a small portion undergoing hydroxylation by CYP2A6. The distribution half-life is 6 to 8 minutes and its lipophilicity leads to a high volume of distribution. The context-sensitive half-times range from 25 to 120 minutes for a 1-hour infusion to 87 to 250 minutes for infusions greater than 6 hours.

Activation of these receptors requires the two compounds...

glutamate and glycine (or possibly D-serine).

Functional studies show that intrathecal opioids inhibit the Ca2+ influx of incoming peripheral sensory neurons and the subsequent spinal release of...

glutamate and neuropeptides such as substance P. In addition, postsynaptic opioid receptors open G-protein-coupled inwardly rectifying K+ (GIRK) channels and hyperpolarize the membrane.

Nearly all GABA found in the mammalian brain is synthesized by decarboxlyation of...

glutamate by two forms of glutamic acid decarboxylase, GAD65 and GAD67.

Activation of NMDA receptors requires binding of...

glutamate or aspartate (aspartate does not stimulate the receptors as strongly). In addition, NMDARs also require the binding of the co-agonist glycine for the efficient opening of the ion channel, which is a part of this receptor.

AMPA receptors (AMPAR) are both...

glutamate receptors and cation channels that are integral to plasticity and synaptic transmission at many postsynaptic membranes.

The AMPA receptor (AMPAR, or quisqualate receptor) is a non-NMDA-type ionotropic transmembrane receptor for...

glutamate that mediates fast synaptic transmission in the central nervous system (CNS).

Stroke and head trauma cause an increase in extracellular...

glutamate, excessive activation of glutamate receptors, and cell death. This form of cell death is referred to as "excitotoxicity".

Remifentanil is not used intraspinally because of its formulation with...

glycine, an inhibitory transmitter in the spinal dorsal horn.

The GlyR receptor can be activated by a range of simple amino acids including...

glycine, β-alanine and taurine, and can be selectively blocked by the high-affinity competitive antagonist strychnine. Caffeine has recently been found to also be a competitive antagonist.

Lidocaine is commonly used for epidural anesthesia because of its...

good diffusion capabilities through tissues.

The receptor site for opioids administered in the intrathecal or epidural space is within the...

gray matter of substantia gelatinosa located in the dorsal horn of the spinal cord. Opioids bind to presynaptic and postsynaptic receptor sites, which selectively blocks transmission of afferent nociceptive stimuli from Aδ and C fibers.

Epileptic attacks occur less frequently during etomidate anesthesia but it is likely that propofol and thiopental possess...

greater anticonvulsant effects; etomidate is therefore a viable option for electroconvulsive therapy.

The resistance of the diaphragm to neuromuscular blockade can be explained by a...

greater number of both acetylcholine-containing vesicles being released from presynaptic terminals with neural stimulation and postjunctional nicotinic acetylcholine receptors than in peripheral muscles.

Upon ligand binding, opioid receptors transduce the information by activating intracellular...

guanine nucleotide binding proteins (G proteins) that in turn alter membrane conductance for K+ and Ca2+ and levels of second messengers such as cyclic adenosine monophosphate (cAMP)

The principal metabolite of midazolam, 1-hydroxymidazolam, has approximately...

half the activity of the parent compound. This active metabolite is rapidly conjugated to 1-hydroxymidazolam glucuronide and is subsequently cleared by the kidneys.

In patients or addicts who are tolerant to the depressant effects of meperidine, large doses repeated at short intervals may produce an excitatory syndrome including...

hallucinations, tremors, muscle twitches, dilated pupils, hyperactive reflexes, and convulsions. These excitatory symptoms are due to the accumulation of normeperidine, which has a t1/ 2 of 15-20 hours, compared to 3 hours for meperidine.

Sudden discontinuation of clonidine and related α2 adrenergic agonists may cause a withdrawal syndrome consisting of...

headache, apprehension, tremors, abdominal pain, sweating, and tachycardia. The arterial blood pressure may rise to levels above those that were present prior to treatment, but the syndrome may occur in the absence of an overshoot in pressure.

Use of propofol in patients with cardiac tamponade or critical aortic stenosis can result in...

hemodynamic collapse.

High doses of MOR agonists, such as fentanyl and sufentanil, used as anesthetic induction agents, have only modest effects upon...

hemodynamic stability, in part because they do not cause release of histamine.

The high lipid solubility of sufentanil results in maximal renal tubular reabsorption of free drug as well as its enhanced access to hepatic microsomal enzymes. Extensive hepatic extraction means that clearance of sufentanil will be sensitive to changes in...

hepatic blood flow but not to alterations in the drug-metabolizing capacity of the liver.

A prolonged elimination half-time for fentanyl in elderly patients is due to decreased clearance of the opioid because Vd is not changed in comparison with younger adults. This change may reflect age-related decreases in...

hepatic blood flow, microsomal enzyme activity, or albumin production, as fentanyl is highly bound (79% to 87%) to protein. For these reasons, it is likely that a given dose of fentanyl will be effective for a longer period of time in elderly patients than in younger patients.

The extensive use of amide-linked local anesthetics in patients with severe...

hepatic disease requires caution.

As with Atracurium, both volume of distribution and clearance of Cisatracurium are increased in patients with...

hepatic failure. Elimination half-life is unchanged, and thus the clinical duration of action and 25% to 75% recovery interval (the time required to recover from 25% to 75% of baseline twitch height) is unchanged in patients with liver failure.

The duration of action of single and repeat doses of rocuronium can be prolonged in patients with...

hepatic failure. This is due to a decrease in its clearance and an increase in its volume of distribution.

The elimination of amide local anesthetics is highly dependent on...

hepatic function. Thus hepatic perfusion, extraction, enzyme function, as well as protein binding determine the rate of clearance of aminoamides.

On intravenous administration, flumazenil is eliminated almost entirely by...

hepatic metabolism to inactive products with a t1/ 2 of ~ 1 hour; the duration of clinical effects usually is only 30-60 minutes.

Clearance values and elimination half-times for amide local anesthetics probably represent mainly...

hepatic metabolism, because renal excretion of unchanged drug is minimal.

Short-term administration of barbiturates has no clinically significant effect on the...

hepatic, renal, or endocrine systems.

Modification of the morphine molecule with retention of the five-ring structure results in the semisynthetic drugs...

heroin and hydromorphone.

All three subtypes of α2-ARs share the same signaling pathways through the Gi/o subfamily of...

heterotrimeric G proteins, but display distinct trafficking profiles.

Bradycardia can be dangerous in the setting of heart block and dexmedetomidine should be used with caution in this setting. Significant hypotension is more likely in patients with...

high sympathetic tone such as diabetics, the elderly, and those with hypovolemia.

Toxicity owing to overdose of pentazocine and other opioids with mixed actions may require...

higher doses of naloxone.

NSAIDs, except aspirin, which is 50% to 80% bound, are...

highly bound to plasma proteins, primarily albumin.

Administration of codeine IV is not recommended, because...

histamine-induced hypotension is likely.

There are some differences among the opioids in their acute effects, with morphine producing more of a...

histamine-releasing effect and meperidine producing more excitation or confusion.

In almost all instances, an ester (-CO-) or an amide (-NHC-) bond links the...

hydrocarbon chain to the lipophilic aromatic ring. The nature of this bond is the basis for classifying drugs that produce conduction blockade of nerve impulses as ester local anesthetics or amide local anesthetics

Local anesthetics consist of a lipophilic and a hydrophilic portion separated by a connecting...

hydrocarbon chain. The hydrophilic group is usually a tertiary amine, such as diethylamine, whereas the lipophilic portion is usually an unsaturated aromatic ring, such as paraaminobenzoic acid.

Methadone is thought to be involved in about one-third of all prescription opioid-related deaths, exceeding...

hydrocodone and oxycodone, despite being prescribed one-tenth as often.

Parenterally administered physostigmine is largely destroyed within 2-3 hours, mainly by...

hydrolytic cleavage by plasma esterases; renal excretion plays only a minor role in its elimination.

The amide-linked local anesthetics are, in general, degraded by the hepatic CYPs the initial reactions involving N-dealkylation and subsequent hydrolysis. However, with prilocaine, the initial step is...

hydrolytic, forming o-toluidine metabolites that can cause methemoglobinemia.

Amide compounds undergo enzymatic degradation in the liver, whereas ester compounds are...

hydrolyzed in plasma by esterase enzymes. Cocaine, an ester, is an exception, as it is metabolized predominantly by the liver.

The receptor site for these drugs on Na+ channels is thought to be...

hydrophobic, so that receptor affinity for anesthetic agents is greater for more hydrophobic drugs.

Ibuprofen is primarily eliminated by metabolism to...

hydroxyl or carboxyl conjugates with < 1% of the drug appearing unchanged in the urine.

Midazolam is metabolized rapidly, primarily by...

hydroxylation of the methyl group on the fused imidazo ring; only small amounts of 3-hydroxyl compounds are formed. The α-hydroxylated compound, which has appreciable biological activity, is eliminated with a t1/2 of 1 hour after conjugation with glucuronic acid.

In patients with significant burns, hemiparesis, or any other pathologic process that causes proliferation of extrajunctional receptors, the response to succinylcholine can be exaggerated, potentially resulting in...

hyperkalemic dysrhythmias and cardiac arrest. The exaggerated efflux of K + is due to α7 receptors as well as extrajunctional nicotinic receptors.

When GABAA receptors are activated, transmembrane chloride conductance increases, resulting in...

hyperpolarization of the postsynaptic cell membrane and functional inhibition of the postsynaptic neuron.

At higher dexmedetomidine drug concentrations, the α2B subtype is activated, resulting in...

hypertension and a further decrease in heart rate and cardiac output.

Cocaine should be used with caution, if at all, in patients with...

hypertension or coronary artery disease and in patients receiving drugs that potentiate the effects of catecholamines, such as monoamine oxidase inhibitors.

Use of meperidine with an MAOI can lead to...

hypertension, convulsions, and coma.

Cocaine inhibits the neuronal reuptake of catecholamines and can therefore cause...

hypertension, tachycardia, dysrhythmias, and other serious cardiac effects.

Sketetal Muscle Rigidity: This phenomenon, often incorrectly called truncal or chest wall rigidity, is actually a generalized...

hypertonus of striated muscle throughout the body. The condition is usually seen when potent opioids are administered rapidly and is most commonly produced by fentanyl and its congeners. The mechanism appears to be an inhibition of striatal g-aminobutyric acid (GABA) release and an increase in dopamine production.

Prolonged, high-dose Propofol infusions can lead to...

hypertriglyceridemia or a constellation of metabolic acidosis, rhabdomyolysis,renal failure, and hemodynamic instability, known as propofol infusion syndrome. These complications are not common but patients should be monitored closely for propofol infusions greater than 48 hours.

Basic studies using isobolographic analysis have shown midazolam and fentanyl or alfentanil to act synergistically to produce...

hypnosis. Midazolam also potently suppresses opioid requirements to reduce movement to a noxious stimulus.

The most common side effects of dexmedetomidine include...

hypotension and bradycardia, both of which are attributed to decreased catecholamine release by activation peripherally and in the CNS of the α2A receptor. Nausea and dry mouth also are common untoward reactions.

Plasma lidocaine concentrations of 5 to 10 μg/ mL, and equivalent plasma concentrations of other local anesthetics, may produce profound...

hypotension due to relaxation of arteriolar vascular smooth muscle and direct myocardial depression.

Indirect cardiovascular effects of local anesthetics are related to the use of neuraxial techniques and include...

hypotension, bradycardia, and cardiopulmonary collapse if not treated promptly. Mild to moderate symptoms are usually responsive to intravenous fluids and indirect or direct acting adrenergic agents such as ephedrine and phenylephrine.

The very useful antipyretic effect of acetaminophen is thought to be a direct effect on the...

hypothalamic heat-regulating centers via inhibiting action of endogenous pyrogens.

Another major output of the NTS where glutamate plays a role is the...

hypothalamus. Glutamatergic activity in the hypothalamus also influences the baroreceptor reflex.

Hypotension can be severe in Barbiturate treated patients with an impaired ability to compensate for venodilation such as those with...

hypovolemia, cardiomyopathy, valvular heart disease, coronary artery disease, cardiac tamponade, or β adrenergic blockade. None of the barbiturates has been shown to be arrhythmogenic.

Enkephalin and opioid receptors are also identified in the glomus region of the carotid body, the main sensor for...

hypoxia and hypercapnia. Consistently, a central and peripheral component of the hypercapneic response to opioids can be observed, though the former contributes to it much more strongly than the latter

κ-Opioid agonism is neuroprotective against...

hypoxia/ischemia.

At higher doses, such as those used for preanesthetic medication or for endoscopy, benzodiazepines slightly depress alveolar ventilation and cause respiratory acidosis as the result of a decrease in...

hypoxic rather than hypercapnic drive; these effects are exaggerated in patients with chronic obstructive pulmonary disease (COPD), and alveolar hypoxia and CO2 narcosis may result. These drugs can cause apnea during anesthesia or when given with opioids.

Questions remain about whether the sympatho-inhibitory action of clonidine results solely from its α2 receptor agonism or whether part or all of its actions are mediated by...

imidazoline receptors. Imidazoline receptors include three subtypes (I1, I2, and I3) and are widely distributed in the body, including the CNS. Clonidine, as an imidazoline, binds to these imidazoline receptors, in addition to its well-described binding to α2 receptors.

In some pathologic states such as denervation, burns, immobilization, inflammation, and sepsis, there is upregulation of...

immature AChRs, resulting in susceptibility to succinylcholine-induced hyperkalemia.

Acetaminophen clearance is reduced in preterm neonates probably due to their...

immature glucuronide conjugation system (sulphatation is the principal route of biotransformation at this age). Therefore, acetaminophen dosing intervals need to be extended (8-12 hours) or daily doses reduced to avoid accumulation and liver toxicity.

Patients with LEMS not associated with malignancy often respond to...

immunosuppressive treatment.

Morphine is used to alleviate the dyspnea of acute left ventricular failure and pulmonary edema, and the response to intravenous morphine may be dramatic. The mechanism underlying this relief is not clear. It may involve an alteration of the patient's reaction to...

impaired respiratory function and an indirect reduction of the work of the heart owing to reduced fear and apprehension. However, it is more probable that the major benefit is due to cardiovascular effects, such as decreased peripheral resistance and an increased capacity of the peripheral and splanchnic vascular compartments.

Although the sympathetic and parasympathetic nervous systems innervate the organs using norepinephrine and acetylcholine, respectively, glutamate is...

important for central control of these systems.

Local anesthetics, once bound to the inside of the voltage-gated sodium channel, stabilize and prolong the duration of the...

inactivated state, thus inhibiting VGSC opening during further depolarization. This inhibits neuronal conduction.

Conduction block is frequency dependent=>the greater the frequency of action potentials, the faster the nerve is blocked by LA and LA must attach to sodium channel when it is in the...

inactivated/closed (yet open)/absolute refractory state, thus the faster the nerve fires, the more opportunities for LA to catch the sodium channel in inactivated state and sensory fibers fire at greater frequency than motor fibers thus more likely to be blocked; both unionized and ionized forms of the LA are required for conduction block.

Meperidine, in contrast to morphine, rarely causes bradycardia but instead may...

increase heart rate, reflecting its modest atropine-like qualities.

Thermal injury, direct muscle trauma, and infection are all associated with...

increased AChR expression, especially at sites proximate to the injury.

Experimentally, intravenous lidocaine profoundly suppresses both...

increased peripheral neuronal "firing" induced by injury and inflammation as well as central sensitization of wide dynamic range neurons in the spinal cord dorsal horn.

The intracellular biochemical events initiated by occupation of opioid receptors with an opioid agonist are characterized by...

increased potassium conductance (leading to hyperpolarization), calcium channel inactivation, or both, which produce an immediate decrease in neurotransmitter release.

Symptoms of α2 adrenergic agonist withdrawal syndrome typically occur 18-36 hours after the drug is stopped and are associated with...

increased sympathetic discharge, as evidenced by elevated plasma and urine concentrations of catecholamines. The exact incidence of the withdrawal syndrome is not known, but it is likely dose related and more dangerous in patients with poorly controlled hypertension. Rebound hypertension also has been seen after discontinuation of transdermal administration of clonidine.

The impact of hepatic failure on the dose requirement of Vecuronium is more predictable due to its dependence on the liver for its elimination. Volume of distribution is...

increased, clearance is decreased, and elimination half-life prolonged in patients with hepatic failure due to either cholestasis or cirrhosis. Accordingly, the duration of action of vecuronium in increased in this patient population.

κ-Opioid receptor activation by agonists is coupled to the G protein Gi/G0, which subsequently...

increases phosphodiesterase activity. Phosphodiesterases break down cAMP, producing an inhibitory effect in neurons.

As the anesthetic action progressively develops in a nerve, the threshold for electrical excitability gradually...

increases, the rate of rise of the action potential declines, impulse conduction slows, and the safety factor for conduction decreases. These factors decrease the probability of propagation of the action potential, and nerve conduction eventually fails.

There are several possible means of enhancing recovery of neuromuscular function. These include...

increasing acetylcholine concentration at the neuromuscular junction or decreasing plasma concentrations of the NMBA through either encapsulation of the NMBA or increased metabolism.

There is functional and anatomical evidence of both pre- and postsynaptic opioid receptors, mainly mu and kappa opioid receptors, within the nucleus tractus solitarius. While the main antitussive effect of opioids is centrally regulated, there is...

increasing evidence for peripheral opioid receptors on C and Aδ nerve fibers within the tracheal and bronchial wall.

Ketamine is a potent bronchodilator due to its...

indirect sympathomimetic activity and perhaps some direct bronchodilating activity. Thus, ketamine is particularly well-suited for anesthetizing patients at high risk for bronchospasm.

Gabapentin does not induce or inhibit hepatic enzymes and therefore it does not appear to be affected by drugs that are....

inducers or inhibitors of cytochrome P450 enzymes.

CYP2D6 activity is genetically diminished in 7% of whites, 3% of blacks, and 1% of Asians (Eichelbaum and Gross, 1990); rendering oxycodone, hydrocodone, and codeine relatively...

ineffective analgesics in these "poor metabolizers" and potentially toxic for "ultra-rapid" metabolizers.

CYP2D6 activity is genetically diminished in 7% of whites, 3% of blacks, and 1% of Asians; rendering oxycodone, hydrocodone, and codeine relatively...

ineffective analgesics in these "poor metabolizers" and potentially toxic for "ultra-rapid" metabolizers.

Inadvertent intra-arterial injection of thiobarbiturates can induce a severe...

inflammatory and potentially necrotic reaction that can threaten limb survival.

Fentanyl's duration of action lengthens the most with...

infusion, sufentanil's much less so, and alfentanil's the least.

All three opioid receptor classes couple to G proteins and subsequently...

inhibit adenyl cyclase, decrease the conductance of voltage-gated calcium channels, or open inward flowing potassium channels. Any of these effects ultimately results in decreased neuronal activity.

Aminoglycoside antibiotics produce neuromuscular blockade by...

inhibiting ACh release from the preganglionic terminal (through competition with Ca2 +) and to a lesser extent by noncompetitively blocking the receptor. The blockade is antagonized by Ca2 + salts but only inconsistently by anti-ChE agents.

Gabapentinoids bind to the α2δ-1 subunit of presynaptic voltage-gated Ca2+ channels in the CNS; their analgesic effects might be related to...

inhibition of Ca2+ influx and the release of excitatory neurotransmitters in spinal and supraspinal pathways.

Type II receptors include mGluR2 and 3. These receptors primarily signal through...

inhibition of adenylate cyclase and a reduction in cAMP levels.

Type III receptors include mGluR4, 6, 7 and 8. These receptors primarily signal through...

inhibition of adenylate cyclase and a reduction in cAMP levels.

Unlike other anesthetics, induction doses of ketamine typically increase blood pressure, heart rate, and cardiac output. The cardiovascular effects are indirect and are most likely mediated by...

inhibition of both central and peripheral catecholamine reuptake.

Binding of opioid agonists with the receptors leads to activation of the G-protein (actually three distinct G-protein subunits), producing effects that are primarily...

inhibitory (decreased cAMP production, decreased Ca2 + influx, increased K + efflux); these effects ultimately culminate in membrane hyperpolarization of the cell and reduction of neuronal excitability.

Presynaptic kainate receptors have been implicated in...

inhibitory neurotransmission by modulating release of the inhibitory neurotransmitter GABA through a presynaptic mechanism.

Benzodiazepines appear to exert most of their effects by interacting with...

inhibitory neurotransmitter receptors directly activated by GABA.

Dexmedetomidine leads to hyperpolarization via K + influx with a subsequent decrease in neuronal firing as well as reduced norepinephrine release mediated by...

inhibitory presynaptic autoreceptors. It also decreases cAMP concentration by inhibiting adenylyl cyclase. Many of its effects stem from this decreased sympathetic outflow, but in some cases direct effects on peripheral α2B and α2A receptors predominate and blood pressure increases. This hypertensive response is sometimes seen during loading doses and is the reason that dexmedetomidine should not be administered as a bolus.

Cocaine-abusing parturients are at higher risk for...

interim peripartum events such as hypertension, hypotension, and wheezing episodes.

Amide local anesthetics undergo varying rates of metabolism by microsomal enzymes located primarily in the liver. Prilocaine undergoes the most rapid metabolism; lidocaine and mepivacaine are...

intermediate; and etidocaine, bupivacaine, and ropivacaine undergo the slowest metabolism among the amide local anesthetics.

In general, areas with greater tissue perfusion will have more rapid and complete uptake than those with more fat, regardless of type of local anesthetic. Thus, rates of absorption generally decrease in the following order:

interpleural > intercostal > caudal > epidural > brachial plexus > sciatic/femoral > subcutaneous tissue

In particular, inhibitory Gai/o subunits show a preference for opioid receptors, resulting in reduced...

intracellular cAMP levels, inhibition of Ca2+ current, and increase in extracellular K+ current. This will finally lead to a decrease in the neuronal excitation and to an inhibition of neurotransmitter and/or neuropetide release.

Inhibitory Gai/o subunits show a preference for opioid receptors, resulting in reduced...

intracellular cAMP levels, inhibition of Ca2+ current, and increase in extracellular K+ current. This will finally lead to a decrease in the neuronal excitation and to an inhibition of neurotransmitter and/or neuropetide release.

Meperidine is absorbed by all routes of administration, but the rate of absorption may be erratic after...

intramuscular injection. The peak plasma concentration usually occurs at ~ 45 minutes, but the range is wide.

The use of ketorolac is limited to ≤ 5 days for acute pain requiring opioid-level analgesia and can be administered...

intramuscularly, intravenously, or orally.

Meperidine is the only opioid considered adequate for surgery when administered...

intrathecally.

Lipid solubility of the local anesthetic is important in this redistribution, as well as being a primary determinant of...

intrinsic local anesthetic potency. After distribution to highly perfused tissues, the local anesthetic is redistributed to less well perfused tissues, including skeletal muscles and fat. Consideration of cardiac output is important for describing the overall tissue distribution of local anesthetics and presumably their intercompartmental clearance.

Most local anesthetics, with the exception of ropivacaine, possess...

intrinsic vasodilator properties.

G protein-coupled receptors are...

involved in many diseases, and are also the target of approximately 40% of all modern medicinal drugs.

Activation of NMDA receptors results in the opening of an...

ion channel that is nonselective to cations with an equilibrium potential near 0 mV.

Ion channels are multi-subunit transmembrane proteins that fold in a complex manner to form...

ion selective pores gated by voltage or ligands.

Mepivacaine, however, is more toxic to the neonate and thus is not used in obstetrical anesthesia. The increased toxicity of mepivacaine in the neonate is related to...

ion trapping of this agent because of the lower pH of neonatal blood and the pKa of mepivacaine rather than to its slower metabolism in the neonate.

Neuromuscular-blocking drugs, because of their quaternary ammonium groups, are highly...

ionized water-soluble compounds at physiologic pH and possess limited lipid solubility. As a result of these two characteristics, the volume of distribution of these drugs is limited, and is similar to the extracellular fluid volume (about 0.2 L/kg).

Once released into the synapse, glutamate activates...

ionotropic (ligand-gated ion channel) or metabotropic (G-protein-coupled) glutamate receptors, called iGluRs or mGluRs.

The NMDAR is a specific type of ...

ionotropic glutamate receptor.

The glycine receptor, or GlyR, is the receptor for the amino acid neurotransmitter glycine. GlyR is an...

ionotropic receptor that produces its effects through chloride current. It is one of the most widely distributed inhibitory receptors in the central nervous system and has important roles in a variety of physiological processes, especially in mediating inhibitory neurotransmission in the spinal cord and brain stem.

The control of GABAergic signaling involves multiple proteins, many of which have multiple isoforms. The regulation of GABAergic signaling...

is a critical determinant of nervous system function, and disruption of this system is thought to play a crucial role in many neurological disorders.

A resting nerve is less sensitive to local anesthetic-induced conduction blockade than...

is a nerve that has been repetitively stimulated.

Lidocaine and bupivacaine are marketed in both...

isobaric and hyperbaric preparations, and if desired, can be diluted with sterile, preservative-free water to make them hypobaric.

Meperidine does not cause as much constipation as does morphine, even when given over prolonged periods of time; this may be related to...

its greater ability to enter the CNS, thereby producing analgesia at lower systemic concentrations.

Local anesthetics must cross the nerve membrane into the cell interior by diffusing through the lipid bilayer in order to reach their binding site. Consequently, the potency of each local anesthetic is closely related to...

its lipid solubility and its dependence on pH.

Prilocaine is an amide local anesthetic that is metabolized to orthotoluidine. Orthotoluidine is an oxidizing compound capable of converting hemoglobin to...

its oxidized form, methemoglobin, resulting in a potentially life-threatening complication, methemoglobinemia (see the section, Methemoglobinemia).

Meperidine may be effective in suppressing postoperative shivering that may result in detrimental increases in metabolic oxygen consumption. The antishivering effects of meperidine may reflect stimulation of...

kappa receptors (estimated to represent 10% of its activity) and a drug-induced decrease in the shivering threshold (not present with alfentanil, clonidine, propofol, or volatile anesthetics).

Finally, knockout of the HCN1 receptor in mice abolishes the hypnotic effect of...

ketamine and propofol but not of etomidate.

The antisialagogue effect of dexmedetomidine represents an advantage over...

ketamine for awake fiberoptic intubations.

Emergence delirium, characterized by hallucinations, vivid dreams, and delusions, is a frequent complication of...

ketamine that can result in serious patient dissatisfaction and can complicate postoperative management. Delirium symptoms are most frequent in the first hour after emergence and appear to occur less frequently in children. Benzodiazepines reduce the incidence of emergence delirium.

In patients with shock and depleted catecholamine reserves, the inability to mount a sympathetic surge unmasks a direct myocardial depressant effect of...

ketamine.

A retrospective analysis of 288 patients who underwent instrumented spinal fusion from L4 to the sacrum demonstrated a 5 times higher nonunion rate when...

ketorolac was used in the immediate postoperative period.

Modest increases in plasma concentrations of liver transaminase enzymes may occur in some patients treated with...

ketorolac. Gastrointestinal irritation and perforation, nausea, sedation, and peripheral edema may accompany the administration of this NSAID.

Remifentanil's metabolism is not impacted by...

kidney disease (although the inactive acid metabolite does accumulate in such patients).

The renal clearance of gabapentin does decrease in patients with...

kidney disease, and the drug is dialyzable.

Prilocaine can be metabolized in the...

kidney.

Cocaine may induce premature...

labor and abruptio placentae.

It is well documented that adductor pollicis monitoring is a poor indicator of...

laryngeal relaxation (cricothyroid muscle), whereas facial nerve stimulation and monitoring the response of the orbicularis oculi muscle more closely reflects the onset of neuromuscular blockade at the diaphragm.

Opioid physicochemical properties are thought to have important implications on their clinical behavior. For example, highly lipid-soluble, relatively unbound, un-ionized molecules like alfentanil and remifentanil have a shorter...

latency-to-peak effect after bolus injection, presumably due to their more rapid transfer across cellular membranes.

Morphine's pKa renders it almost completely ionized at physiologic pH. This property, combined with its low lipid solubility, presumably accounts for morphine's prolonged...

latency-to-peak effect; morphine penetrates the CNS slowly.

An important detail relating to morphine's clinical pharmacology is its slow onset time. Morphine's pKa renders it almost completely ionized at physiologic pH. This property, combined with its low lipid solubility, presumably accounts for morphine's prolonged...

latency-to-peak effect; morphine penetrates the CNS slowly. This feature has both advantages and disadvantages.

The pipecoloxylidide local anesthetics (mepivacaine, bupivacaine, ropivacaine, levobupivacaine) are chiral drugs because their molecules possess an asymmetric carbon atom. As such, these drugs may have a...

left- (S) or right- (R) handed configuration. Mepivacaine and bupivacaine are available for clinical use as racemic mixtures (50: 50 mixture) of the enantiomers.

Nephrotoxicity can occur with acetaminophen but...

less frequently than it occurs with NSAIDs.

Bupivacaine and ropivacaine at similar concentrations (0.5% to 0.75%) produce similar prolonged sensory anesthesia (ropivacaine has a greater tendency to block A-delta and C fibers) when used for epidural anesthesia, but the motor anesthesia produced by ropivacaine is...

less intense and of shorter duration.

Propranolol decreases plasma clearance of...

lidocaine and bupivacaine, presumably reflecting propranolol-induced decreases in hepatic blood flow or inhibition of hepatic metabolism

Direct neuronal tissue toxicity (e.g., transient neurologic symptoms [TNS] and cauda equina syndrome) has been described with multiple local anesthetics, but the incidence appears to be significantly higher with...

lidocaine and mepivacaine than bupivacaine, prilocaine, and procaine.

EMLA cream is a eutectic mixture of the local anesthetics...

lidocaine and prilocaine, each at a concentration of 2.5%.

Grand mal seizures have been suppressed by IV administration of low doses of...

lidocaine or mepivacaine. Presumably, these and perhaps other local anesthetics, when present at low plasma concentrations, are effective in suppressing seizures through initial depression of hyperexcitable cortical neurons.

Vasoconstrictors appear to be most effective in prolonging tetracaine-induced spinal anesthesia (up to 100%) and less effective at prolonging...

lidocaine spinal anesthesia, whereas the effect on bupivacaine spinal anesthesia remains controversial and is, at best, minimal.

Mepivacaine has pharmacologic properties similar to those of...

lidocaine, although the duration of action of mepivacaine is somewhat longer.

The lungs are capable of extracting local anesthetics such as...

lidocaine, bupivacaine, and prilocaine from the circulation. After rapid entry of local anesthetics into the venous circulation, this pulmonary extraction will limit the concentration of drug that reaches the systemic circulation for distribution to the coronary and cerebral circulations.

Risk of TNS is associated with the use of...

lidocaine, lithotomy position, and ambulatory procedures.

There is no difference between the intranasal anesthetic or vasoconstrictive effects of cocaine and those of a...

lidocaine-oxymetazoline or tetracaine-oxymetazoline mixture, emphasizing the usefulness of these combinations as substitutes for cocaine.

When used for spinal anesthesia, mepivacaine has a slightly lower incidence of TNS than..

lidocaine.

Like AMPA receptors, kainate receptors are also...

ligand-gated channels permeable to sodium and potassium.

Although, ropivacaine-induced cardiac arrest has been described following peripheral nerve block anesthesia, in contrast to bupivacaine, cardiac resuscitation is more...

likely to be successful.

Like lithium and valproate, carbamazepine increases...

limbic GABAB receptors and has effects on inositol cycling. It has unique effects at peripheral-type benzodiazepine receptors, increases stimulatory G protein alpha subunits (Gsα), and decreases inhibitory G protein subunits (Giα). It appears to lack the effects on GSK-3 and protein kinase C possessed by lithium and valproate. It has anticholinergic, antidiuretic, and muscle relaxant properties.

When an appropriate dose of a competitive blocking agent is injected intravenously in human beings, motor weakness progresses to a total flaccid paralysis. Small, rapidly moving muscles such as those of the eyes, jaw, and larynx relax before those of the...

limbs and trunk. Ultimately, the intercostal muscles and finally the diaphragm are paralyzed, and respiration then ceases. Recovery of muscles usually occurs in the reverse order to that of their paralysis, and thus the diaphragm ordinarily is the first muscle to regain function.

The lungs are capable of extracting local anesthetics such as lidocaine, bupivacaine, and prilocaine from the circulation. After rapid entry of local anesthetics into the venous circulation, this pulmonary extraction will...

limit the concentration of drug that reaches the systemic circulation for distribution to the coronary and cerebral circulations.

The surface of the nerve axon is formed by the...

lipid bilayer membrane that is embedded with various proteins including ion channels.

Structurally, gabapentin resembles the inhibitory neurotransmitter GABA but the inclusion of a carbon ring greatly enhances its...

lipid solubility and ability to cross the blood-brain barrier.

The potency of local anesthetics correlates with increasing molecular weight, which confers increased...

lipid solubility and protein binding, both of which increase the duration of action, but slow the onset of conduction block.

with increasing length of the carbon backbone, local anesthetics exhibit greater...

lipid solubility, protein binding, potency, and duration of action. However, these relationships are not linear and are often influenced by multiple other factors.

Cephalad movement of opioids in the CSF principally depends on...

lipid solubility. For example, lipid-soluble opioids such as fentanyl and sufentanil are limited in their cephalad migration by uptake into the spinal cord, whereas less lipid-soluble morphine remains in the CSF for transfer to more cephalad locations.

Compared with procaine, tetracaine is more...

lipid soluble, is ten times more potent, and has a longer duration of action corresponding to a four- to fivefold decrease in the rate of metabolism.

Alkalinization increases the percentage of local anesthetic existing in the...

lipid-soluble form that is available to diffuse across lipid cellular barriers.

The pKa of local anesthetics used clinically is near 8, so that only a small fraction (about 3%) of the local anesthetic exists in the...

lipid-soluble form.

Local anesthetics are weak bases that have pK values somewhat above physiologic pH. As a result, < 50% of the local anesthetic exists in a...

lipid-soluble nonionized form at physiologic pH. For example, at pH 7.4, only 5% of tetracaine exists in a nonionized form. Acidosis in the environment into which the local anesthetic is injected (as is present with tissue infection) further increases the ionized fraction of drug. This is consistent with the poor quality of local anesthesia that often results when a local anesthetic is injected into an acidic infected area.

Truncal rigidity reduces thoracic compliance and thus interferes with ventilation. The effect is most apparent when high doses of the highly...

lipid-soluble opioids (eg, fentanyl, sufentanil, alfentanil, remifentanil) are rapidly administered intravenously. Truncal rigidity may be overcome by administration of an opioid antagonist, which of course will also antagonize the analgesic action of the opioid. Preventing truncal rigidity while preserving analgesia requires the concomitant use of neuromuscular blocking agents.

Clinically used local anesthetics are often classified as amino-amides or amino-esters. This classification is based on the type of chemical bond, amide or ester, linking the...

lipophilic phenyl ring with the hydrophobic tertiary amine.

In the plasma, barbiturates are readily protonated and become quite...

lipophilic, which leads to profound anesthesia 30 to 60 seconds after bolus injection.

In order to exert its effect, an NMBA must get into the neuromuscular junction, which is facilitated by its...

lipophilicity.

Naloxone is rapidly metabolized in the...

liver and has a very high clearance; thus, its duration of action is nearly always shorter than that of the opioid whose effects it is intended to reverse.

Reduced cardiac output slows delivery of the amide compounds to the....

liver, reducing their metabolism and prolonging their plasma half-lives.

Rocuronium, like vecuronium, is eliminated primarily through the...

liver. Because only 10% is eliminated through the kidneys, it is even less dependent on renal elimination than vecuronium.

Respiratory acidosis also reduces protein binding of local anesthetics, increasing...

local anesthetic availability for further toxic effects.

Meperidine has well known...

local anesthetic properties, particularly noted after epidural administration.

Tetracaine, with a slow onset of anesthesia and a high potential to cause systemic toxicity, is not recommended for...

local infiltration or peripheral nerve block anesthesia.

Opioid actions within the CNS are well characterized at the...

locus coeruleus, the periaquaeductal gray (PAG), and the ventral tegmental area, in which a high density and overlap of both opioid receptors and opioid peptides can be identified.

Available in both intravenous and oral forms, racemic methadone has long been a mainstay in the treatment of opioid addicts because its...

long acting pharmacokinetic profile makes the development of an acute withdrawal syndrome less likely (i.e., methadone maintenance therapy). The N-methyl-D-aspartate (NMDA) receptor antagonism action of the dextrorotatory isomer of methadone may also serve to attenuate the effects of opioid tolerance and withdrawal syndrome.

Chloroprocaine is used commonly for epidural anesthesia. It is also used for peripheral blocks in combination with other...

long-acting, slow-onset local anesthetics for the combined effect of rapid onset and prolonged duration.

One of the most widely and thoroughly investigated forms of plasticity in the nervous system is known as...

long-term potentiation, or LTP.

The anesthetic profile of mepivacaine is also similar to lidocaine but with a slightly...

longer duration of action. However, it is not as effective when applied topically.

Lidocaine is the archetypal class Ib antiarrhythmic. Like all class Ib drugs, its rapid binding and unbinding rates (endowing it with use-dependency or frequency-dependency) greatly diminish its effects at...

low heart rates, and exaggerate its effects at high heart rates.

Some NSAIDs (ibuprofen, naproxen) have been shown to interfere with the antiplatelet activity of...

low-dose aspirin, and aspirin's cardioprotective effect may be diminished in patients who take low-dose aspirin and a NSAID concomitantly.

Lorazepam has a slower onset of action than midazolam or diazepam because of its...

lower lipid solubility and slower entrance into the CNS.

Bupivacaine used for spinal anesthesia is more effective than tetracaine in preventing...

lower-extremity tourniquet pain during orthopedic surgery. This effectiveness may reflect the ability of bupivacaine to produce greater frequency-dependent conduction blockade of fibers than does tetracaine.

Appropriate monitoring should be applied to assess cardiovascular and pulmonary function. Hypoventilation and respiratory acidosis should be supported with supplemental oxygen or artificial airway and mechanical ventilation. Hypotension and bradycardia should be treated with intravenous fluids and chronotropes, inotropes, and vasoactive agents. Epinephrine is still considered the...

mainstay of immediate treatment and the use of vasopressin has also been suggested.

Although midazolam is often considered a short-acting benzodiazepine, prolonged infusions in critically ill patients leads to...

markedly delayed awakening in part due to accumulation of its active metabolite 1-hydroxymidazolam.

Acute administration of clonidine has been used in the differential diagnosis of patients with hypertension and suspected pheochromocytoma. In patients with primary hypertension, plasma concentrations of NE are...

markedly suppressed after a single dose of clonidine; this response is not observed in many patients with pheochromocytoma.

An investigation of spinal neurons estimated that propofol's effects on immobility were mediated almost entirely via GABA receptors, whereas the immobility caused by sevoflurane was predominantly...

mediated by glycine receptors.

At least a portion of the cardiac toxicity of bupivacaine may be mediated centrally, as direct injection of small quantities of bupivacaine into the...

medulla can produce malignant ventricular arrhythmias.

The main anatomic substrate for depression of ventilation by the µ agonists is the ventilatory control center in the...

medulla. The µ agonists alter the ventilatory response to arterial carbon dioxide.

Within the CNS, a large density of α2-receptors is located in the...

medullary dorsal motor complex and in the locus ceruleus.

Administration of physostigmine, 40 μg/kg IV, at the conclusion of anesthesia decreases the incidence of postoperative shivering similar to...

meperidine and clonidine. It is postulated that physostigmine enhances secretion of neurotransmitters that are involved in the control of body temperature, especially at the hypothalamic thermoregulatory centers.

Several psychopharmacologic agents are associated with effects on cardiac conduction, seizure threshold, CNS depression, autonomic and serotonergic responsivity, the neuroendocrine response to stress, bleeding tendency, and other parameters relevant to anesthetic care. Interaction between some drugs, such as...

meperidine with monoamine oxidase inhibitors, can be severe or fatal.

Physostigmine, 2 mg produces analgesia comparable to that produced by...

meperidine, 50 mg.

Enhanced serotonin activity in the brain is presumed to be responsible for excitatory reactions evoked by...

meperidine. Meperidine is capable of inhibiting neuronal serotonin uptake.

Patients receiving monoamine oxidase inhibitors may experience exaggerated CNS depression and hyperpyrexia after administration of an opioid agonist, especially...

meperidine. This exaggerated response may reflect alterations in the rate or pathway of metabolism of the opioid.

Indeed, ibuprofen, a cox inhibitor, prevents facial flushing and cardiovascular changes associated with...

mesenteric traction.

Gabapentin and pregabalin are absorbed after oral administration and are not...

metabolized in humans.

Gabapentin is well absorbed after oral administration, is not...

metabolized or bound to plasma proteins, but is excreted unchanged by the kidneys.

Dexmedetomidine is highly protein bound and is primarily hepatically...

metabolized; the glucuronide and methyl conjugates are excreted in the urine.

GABABRs are similar in structure to and in the same receptor family with...

metabotropic glutamate receptors.

Serious cardiac arrhythmias, including torsades de pointes, have been observed during treatment with...

methadone.

Whereas diminished activity of the CYP2D6 isoenzyme will lead to less efficacy of prodrug opioids, the opposite occurs with...

methadone. Although methadone is primarily metabolized through the CYP3A4 isoenzyme, genetic polymorphisms involving deficiencies in the CYP2C9, CYP2CI9, and CYP2D6 isoenzymes may lead to surprisingly high methadone plasma concentrations resulting in overdose.

The duration of action of the available antagonists is shorter than that of many opioids; hence patients can slip back into coma. This is particularly important when the overdosage is due to...

methadone. The depressant effects of these drugs may persist for 24-72 hours, and fatalities have occurred as a result of premature discontinuation of naloxone. In cases of overdoses of these drugs, a continuous infusion of naloxone should be considered....

When the dose of prilocaine is >600 mg, there may be sufficient...

methemoglobin present (3 to 5 g/dL) to cause the patient to appear cyanotic, and oxygen-carrying capacity is decreased.

Prilocaine shows the least systemic toxicity of all amide local anesthetics and is therefore useful for intravenous regional anesthesia. However, it causes...

methemoglobinemia (>500 mg dose) due to its metabolite o-toluidine, which has significantly limited its use.

The potential systemic toxic effects of local anesthetics include...

methemoglobinemia (primarily due to benzocaine and the metabolite of prilocaine, o-toluidine), seizures, and malignant ventricular dysrhythmias with cardiovascular collapse.

Benzocaine and a metabolite of prilocaine (o-toluidine) may cause clinically significant...

methemoglobinemia, a condition in which the ferrous form (Fe2+) of hemoglobin is oxidized to the ferric form (Fe3+). While in this oxidized state, hemoglobin cannot bind or transport oxygen.

Excessive use of benzocaine is associated with...

methemoglobinemia.

With prilocaine, the initial of metabolism step is hydrolytic, forming o-toluidine metabolites that can cause...

methemoglobinemia.

Methemoglobinemia is readily reversed by the administration of...

methylene blue, 1 to 2 mg/ kg intravenously (IV), over 5 minutes (total dose should not exceed 7 to 8 mg/kg).

Amide local anesthetics undergo varying rates of metabolism by...

microsomal enzymes located primarily in the liver. Prilocaine undergoes the most rapid metabolism; lidocaine and mepivacaine are intermediate; and etidocaine, bupivacaine, and ropivacaine undergo the slowest metabolism among the amide local anesthetics.

Phenytoin and oxcarbazepine induce CYP enzymes, increasing the metabolism of commonly used anesthetic agents including...

midazolam, fentanyl, alfentanil, and aminosteroidal muscle relaxants.

Anti-inflammatory analgesics such as aspirin and ibuprofen are often helpful in controlling the pain of...

migraine.

A single induction dose of thiopental does not alter tone of the gravid uterus, but may produce...

mild transient depression of newborn activity.

The potency of a local anesthetic can be expressed as the...

minimum effective concentration (MEC) at which complete nerve block is established.

Opioids stimulate the Edinger-Westphal nucleus of the oculomotor nerve to produce...

miosis. Even small doses of opioid elicit the response and very little tolerance to the effect develops.

Local anesthetics are available either as single enantiomers or racemic mixtures. Enantiomers consist of two stereoisomers (left/sinister or right/dexter) that are...

mirror images of each other with respect to a specific chiral center. A racemic mixture contains equal amounts of the two enantiomers.

While the precise mechanisms by which PRIS occurs are not clear, alterations in...

mitochondrial metabolism and electron transport chain function have been described.

The effects of ketamine on seizure activity appear...

mixed, without either strong pro- or anticonvulsant activity.

Na+, K+ and Ca2+ not only pass through the NMDA receptor channel but also...

modulate the activity of NMDA receptors.

The N-methyl-D-aspartate receptor (also known as the NMDA receptor or NMDAR), a glutamate receptor, is the predominant...

molecular device for controlling synaptic plasticity and memory function.

Benzodiazepines also have some immunomodulatory effects on..

monocytes and T cells in vitro, but the clinical significance of these effects is not clear.

Lidocaine is dealkylated in the liver by CYPs to...

monoethylglycine xylidide and glycine xylidide, which can be metabolized further to monoethylglycine and xylidide. Both monoethylglycine xylidide and glycine xylidide retain local anesthetic activity. In humans, ∼75% of the xylidide is excreted in the urine as the further metabolite 4-hydroxy-2, 6-dimethylaniline

In contrast to non-NMDA glutamate receptors, which are selective for sodium ions (Na +), the pore of NMDA receptors permit entry of both...

monovalent and divalent cations (Na + and Ca2 +) into the cell upon activation. The Ca2 + flux is important for activating Ca2 +-dependent processes in the postsynaptic cell such as long-term potentiation (LTP), a form of synaptic plasticity thought to play an important role in memory.

Following administration of an intubating dose of a competitive NMBA, recovery of diaphragmatic function occurs...

more rapidly than recovery in muscles of the extremity, such as the adductor pollicis, which is the muscle commonly used in clinical practice for monitoring depth of neuromuscular block.

The time to peak analgesic effect after intravenous administration of fentanyl and sufentanil (~ 5 minutes) is notably less than that for...

morphine and meperidine (~15 minutes).

Histamine release probably accounts for the urticaria commonly seen at the site of injection. Though controversial, it is not blocked by naloxone and thought not to be mediated by opioid receptors. Itching is readily seen with...

morphine and meperidine but to a much lesser extent with oxymorphone, methadone, fentanyl, or sufentanil.

Renal failure has implications of major clinical importance with respect to...

morphine and meperidine.

The incidence of sphincter of Oddi spasm is increased with all opioids, although...

morphine appears to be more potent in this regard.

Hydromorphone, oxymorphone, hydrocodone, and oxycodone also are made by modifying the...

morphine molecule.

Codeine is actually a prodrug that is metabolized in part by O-demethylation into...

morphine, a metabolic process mediated by the liver P450 isoform CYP2D6.

Although perhaps not typically thought of as an acute effect that would be relevant to perioperative practice, opioids are known to depress cellular immunity. This effect is particularly well documented for...

morphine, although data exist for other µ agonists as well. Morphine and the endogenous opioid β-endorphin, for example, inhibit the transcription of interleukin-2 in activated T cells, among other immunologic effects. It appears that individual opioids (and perhaps classes of opioids) differ in terms of the exact nature and extent of their immunomodulatory effects.

Codeine, hydrocodone, and oxycodone are weak analgesic prodrugs that are metabolized into the much more effective analgesic drugs...

morphine, hydromorphone, and oxymorphone, respectively, by CYP2D6.

Noncardiogenic pulmonary edema is seen commonly with opioid poisoning. It probably is not due to contaminants or to anaphylactic reactions, and it has been observed after toxic doses of...

morphine, methadone, propoxyphene, and pure heroin.

Naloxone (0.25 μg/kg/hour IV) is effective in attenuating the side effects (nausea and vomiting, pruritus) associated with...

morphine-induced analgesia delivered by a patient-controlled IV delivery system.

Antidepressants may enhance...

morphine-induced analgesia.

Fentanyl and sufentanil are, respectively, approximately 800 and 1,600 times as lipid soluble as...

morphine. After epidural administration, CSF concentrations of fentanyl peak in about 20 minutes and sufentanil in about 6 minutes. In contrast, CSF concentrations of morphine, after epidural administration, peak in 1 to 4 hours. Furthermore, only about 3% of the dose of morphine administered epidurally crosses the dura to enter the CSF.

Heroin (diacetylmorphine) is rapidly hydrolyzed to 6-monoacetylmorphine (6-MAM), which in turn is hydrolyzed to...

morphine. Heroin and 6-MAM are more lipid soluble than morphine and enter the brain more readily. Evidence suggests that morphine and 6-MAM are responsible for the pharmacological actions of heroin. Heroin is excreted mainly in the urine largely as free and conjugated morphine.

Codeine has an exceptionally low affinity for opioid receptors, and the analgesic effect of codeine is due to its conversion to...

morphine. However, codeine's antitussive actions may involve distinct receptors that bind codeine itself, and codeine is commonly employed for the management of cough.

Naloxone-reversible miosis, nystagmus, and vertigo may occur after neuraxial opioids, most commonly...

morphine. Neuraxial opioids may delay gastric emptying, most likely reflecting an interaction of the opioid with a spinal cord opioid receptor.

Hypotension after meperidine injection is more frequent and more profound than after comparable doses of...

morphine. Orthostatic hypotension suggests that meperidine, like morphine, interferes with compensatory sympathetic nervous system reflexes.