PHC 7010 Exam 2: Neuropharmacology
What works in parallel with neuronal synaptic network relying on fast, ionotropic receptor-mediated synaptic transmission?
"modulatory" neuronal/synaptic network relying on metabotropic receptors (NE, serotonin, histamine ACh, adenosine, peptides, dopamine)
What are some key features of focal seizures with altered mental status?
*Altered consciousness* (cessation of activity, loss of contact w/ reality). Symptoms typically result from abnormal activity in the *temporal lobe* (amygdala, hippocampus) or *frontal lobe*. Often associated with involuntary automatisms ranging from simple repetitive movements (lip smacking, hand wringing) to highly skilled activity (driving, playing musical instrument). Impaired memory of ictal phase, classically preceded by an aura
How are analgesics different from local anesthetics?
*Analgesics*: Specific inhibitors of pain pathways. Act at specific receptors that transmit pain information to the CNS. Peripheral nerve conduction is not blocked by analgesics. *LAs*: Block nerve conduction nonspecifically in peripheral sensory, motor and autonomic nerves. (general)
What are some key features of focal seizures without altered mental status?
*Consciousness is preserved*. Symptoms vary depending on location of abnormal activity in brain: involuntary, repetitive movement (motor cortex), paresthesias (sensory cortex), flashing lights (visual cortex). Spread to ipsilateral regions within cortex (jacksonian march).
Etomidate (amidate) disadvantages:
*Transiently depressed adrenocortical function: potent as an inhibitor of steroid synthesis*, does not produce analgesia, high incidence of postoperative nausea and vomiting, pain on injection
What type of drug is topiramate (topamax)?
multiple MOAs, broad spectrum. Used in refractory migraine, bipolar disorder.
When does anesthesia commence before inhalation anesthetics?
must equilibrate with all compartments of the body to equilibrium before anesthesia commences.
How do nerves perpetuate peripheral sensitization?
nerves release substances that bind to receptors and leads to PKC activation and PKA activation. Activates receptors/ Na+ channel. Na+ influx propagates AP.
what is primary drug class used for management of acute, moderate to severe pain?
opioid receptor agonists
Transmission
opioids, antidepressants, NSAIDS, anti-epileptics, alpha2 adrenergic agonists, celecoxib)
Buprenorphine?
partial µ opioid agonist. Long lived. Effective analgesic.
what is Levetiracetam (Keppra) effective against?
partial, primary generalized tonic-clonic, myoclonic seizures
What are APDs more effective in treating?
positive symptoms more than negative symptoms
How does partial agonist, buprenorphine work for opioid addiction?
prevents withdrawal, has lower risk of OD, will blunt high of an abused full agonist. Suboxone formulation also contains naloxone that is released only if diverted (but not if used sublingually). Other Rx may be needed for long term dysphoria/ dysfunctional reward system.
Isoflurane?
pungent odor
What is analgesia?
relief of pain without loss of consciousness
Off target effects of opioid?
respiratory depression (can cause death), GI (constipation)
Where is AMPA-R, NMDA-R, mGluR, NK1 and CGRP located?
secondary relay neuron, postsynaptic membrane
What are other therapeutic effects of opioid receptor agonists?
sedation/relaxation, cough suppression, anti-diarrheal
Mirtazapine has little effect on?
sexual function
conduction
sodium channel blockers
How does third order neuron travel in dorsal column medial lemniscus pathway?
thalamus to primary somatosensory cortex
How does third order travel in anterolateral pathway?
thalamus to primary somatosensory cortex
Where does primary generalized seizure occur?
thalamus, spread throughout brain
What are risk factors for adults to get epilepsy?
trauma, tumors
What inhibitory receptors are present pre-synaptically?
α2 (NE), GABAB, μ (endorphins/enkaphalins). They decrease calcium influx.
What inhibitory receptors are present post-synaptically?
α2 (NE), GABAB, μ (endorphins/enkaphalins). They increase K+ efflux. and GABAA channels (increase Cl-).
What is morphine bind to?
μ receptors
What are the three conformations of sodium channel?
-Closed (resting). Na+ cannot enter -Open (activated). Na+ enters the channel resulting in nerve conduction -Closed (inactive) conformation. Membrane repolarizes and sodium channel reverts to closed form.
What is example of balanced anesthesia?
-premedication (sedatives, opioid analgesics) -IV anesthetic for induction -Muscle relaxants so a lighter level of general anesthesia can be used -Mixture of inhalation anesthetic gases to maintain anesthesia
What is outside mV of cell?
0 and inside is negative
What are some adverse effects of typical APDs (on target) ? (The 3 acute extrapyramidal side effects)
1. Acute dystonic reaction, involuntary muscle contractions (primarily face or back) 2. Akathisia (uncontrollable restlessness) 3. Parkinsonism, looks like idiopathic PD, take enough drug you looks like you have parkinson's disease.
What are two functions of LAs?
1. Inhibit perception of sensations (pain): signals not transmitted to the brain 2. Prevent movement (depending on route of administration
What are determinants of LA blockage sensitivity in nerves?
1. Nerve diameter (smaller diameter, easier to block) 2. Myelination (myelinated nerves, easier to block) 3. Firing rate (faster nerve, easier to block)
How can hydrophobic properties change among LAs?
1. R group on aromatic ring 2. R group on amino nitrogen
What structural feature allow ion channels to sense voltage?
4 transmembrane helices (S1, S2, S3, S4)
Consequences of extremely long half life of fluoxetine and its active metabolite?
5 week washout of fluoxetine is required before starting a MAOI to mitigate the risk of serotonin syndrome
What are the cause of individual differences for drugs of abuse?
50-60% of variance associated with drug abuse is genetic
What receptor does clozapine have higher affinity for?
5HT2A, lesser for D2. Led to development of "clozapine-like" atypical APDs
A drug trial of adequate dosage can be considered unsuccessful if the patient does no respond favorable in how many weeks?
8-12 weeks
Mechanism of action and effect of donepezil?
AChE inhibitor. Increases synaptic acetylcholine.
Where does glutamate bind in fast synaptic transmission?
AMPA-R (Na+ influx) and NMDA-R (Ca2+ and Na+ influx)
What are some ionotropic glutamate receptors?
APMA, Kainate and NMDA
What is seizure?
Abnormal electrical activity in the brain and its clinical manifestations
What are the three types of primary generalized seizures?
Absence seizure (petit mal), myoclonic seizure, tonic clonic
How do antiepileptic drugs work for focal seizures? (general)
Act at four molecular targets to enhance inhibition and prevent spread of synchronous activity
What does Gq/11 do?
Activate PLCbeta
How do metabotropic receptors work?
Activate heterotrimeric G proteins (Galpha subunit bound to GTP) which then signal their effects
What do opioid analgesics activate?
Activate opiate receptors
What does DA pathway activate?
Activated by all drugs of abuse/
What does alcohol bind to?
Activates GABA-A (hyperpolarization) and inhibits NMDA receptors. Causes decreased excitability, anxiolysis/sedation and coma.
What does Gs do?
Activates adenylate cyclase (increases cAMP)
What does D1 family do?
Activates. Increases cAMP (via Gs) and PIP2 hydrolysis (Ca2+ mobilization via IP3), PKC activation (via DAG)
What determines how neurons work within central networks?
Activation of intracellular signaling cascades
What are two classes of general anesthetics?
Administered by inhalation and administered intravenously
When does levodopa reduced its efficacy?
After 2-5 years. Require more drug. Followed by on and off phenomenon and dyskinesia (in 80% of patients, 5-8 yrs) related to dopa-PD interaction.
What role do voltage gated sodium channels play after chemical, mechanical and thermal receptors are bound?
After Na+/Ca2+ influx--> generator potential (membrane depolarization) Na+ channel converts membrane potential into AP.
What is a risk factor for PD?
Age (~5-10% @ age 85)
What are Z drugs?
Agents used in management of insomnia, lacks anti-convulsant or muscle relaxing properties and has minimal effect on sleep architecture.
Prevalent adverse effects of newer antidepressants?
Agitation, insomnia, GI effects and sexual dysfunction
What do clinically effective antipsychotic drugs have in common?
All block DA receptors
Low sensitivity to block?
Alpha, beta and gamma fibers
What does withdrawal of morphine do?
Altered gene transcription, increased excitability, increased neurotransmitter release and withdrawal symptoms (dysphoria, lacrimation and diarrhea)
What is the "new normal"?
Altered homeostatic set points in the continued presence of drug. CNS and autonomic responses seen in its absence.
Why are there so many apparent receptor subtype from so few genes for opiod receptor subtypes?
Alternative splicing of common gene product, receptor dimerization, interaction of common gene product with signaling proteins (*biased agonism*)
Bupivacaine (Marcaine)
Amide linkage, highly hydrophobic (potent), produces prolonged anesthesia (long duration of action), dilute, more sensory than motor blockade, caution: cardiotoxic properties
Cocaine? (LA)
Amine associated with complex cyclic structure contain a secondary ester linkage, medium duration of action, has dual vasoconstrictor action, high toxicity due to effect on reducing catecholamine uptake in CNS and PNS, adrenergic phenomenon (hypertension, tachycardia, arrhythmia and other serious cardiac effects), heavily regulated because of high abuse potential
What enzyme is more promiscuous and abundant in dopamine synthesis?
Amino Acid decarboxylase (AADC) aka aromatic L-amino acid decarboxylase
What are some early adverse effects related to excess/ dysregulated DA?
Anorexia, nausea and hypotension
Drugs for epilepsy are?
Anti-seizure, not antiepileptogenic (clinical evidence for prevention or reversal of pathological processes is not strong).
What are LAs as unprotonated (non-ionized) amides?
Are weak bases (pka 8-9). Lower pKa= stronger acid.
What is the chemical structure of Local Anesthetics?
Aromatic ring connected to tertiary amine via intermediate linkage (ester or amide bond)
What is difference between typical and atypical APDs?
At clinically effective doses, typical APDs occupy mostly striatal D2 receptors, whereas atypical APDs occupy lower proportion of D2 but more cortical 5HT2A receptors
What are most common adverse effects of Levetiracetam (Keppra)?
Ataxia, headache, diploplia, somnolence (strong desire to sleep)
How do antimuscarnic drugs work for PD?
Attenuate neurochemical imbalance in striatum due to loss of DA
What sensory afferent neurons conduct painful stimuli?
Aδ and C fibers
What happens in pathway with healthy people?
Balanced activity of direct and indirect pathways
How was cannabidiol approved?
Basis of multicenter double blind, placebo controlled study (NEJM '18)
Inhalation Anesthetics?
Behave as gases rather than liquids, require different pharmacokinetics to be used in analyzing their uptake and distribution. IAs are taken through alveolar blood-gas exchange and partition between blood-gas and blood tissue (all organs and tissue).
Rapid onset (pKA 3.5) within 1-min and short acting (15-20 min)
Benzocaine (Americaine)
What is methemoglobinemia?
Benzocaine (Americaine) causes this. Blood disorder in which there are increased quantities of hemoglobin in which the iron of heme is oxidized to Fe+3 and is ineffective in carrying oxygen.
What type of drug is gabapentin (neurontin)?
Binds HVA Ca2+ channel subunit. Used in focal seizures, neuropathic pain, migraine, anxiety and surgical analgesia
MOA of LAs?
Block voltage dependent Na+ channels associated with excitable membranes by reducing influx of Na+ thereby preventing depolarization of the membrane and blocking conduction of the action potential.
What does permeability of drug depend on without carriers?
Blood brain barrier (more lipophilic, more likely it will cross)
Is schizophrenia environmental or genetic?
Both, 17% concordance in dizygotic twins and 50% in monozygotic twins, multifactorial etiology.
What are some clinical features of PD?
Bradykinesia (slowness, poverty of movement, difficulty in initiating movement), muscular (cogwheel) rigidity, resting (pill-rolling) tremor ( as opposed to intention tremor) and impairment of postural stability (festination, retropulsion).
What are key features of myoclonic seizure?
Brief (1 second or less) muscle contraction; symptoms may occur in individual muscle or generalize to all muscle groups of body. Associated with systemic disease states (uremia, hepatic failure, hereditary degenerative conditions, Cruetzfeldt-Jakob disease.
What antidepressants do NOT cause sexual dysfunction?
Bupropion (NDRI), Mitrazapine (NaSSA), Trazodone (SARI), Vilazodone (SPARI)
What causes less sexual dysfunction than SSRIs?
Bupropion, a NDRI
Entacapone, tolcapone?
COMT inhibitor
COX 2 inhibitors have serious
CV risks
What is the Nerst equation used for?
Calculates equilibrium potential for ions. Eion= 2.303 (RT/ZF)log [ion]o/[ion]i Na+= 26.7ln (145/15)= +61mV Cl-= -26.7ln (122/4.2)= -90mV
What can flumazenil not do?
Cannot antagonize the depressant effects of barbiturates or alcohol
What are some drugs for focal and generalized tonic clonic seizures (first generation drugs)?
Carbamazepine (tegretol), levetiracetam (keppra), valproic acid (depakene), Gabapentin (neurontin), topiramate (topamax)
What family of neurotransmitters does dopamine fall into?
Catecholamine
Inhalation anesthetics on liver?
Causes a concentration-dependent decrease in hepatic blood flow
What does withdrawal of cocaine use do?
Causes increase in DA transporter on post synaptic neuron and fatigue/dysphoria due to less DA in synapse
Adverse effects of clozapine?
Causes seizures in 1-4% patients, causes agranulocytosis in 1-2% patients--> potentially fatal, develops between weeks 6-18, need weekly blood counts for first 6 months; then 3 weeks thereafter
What LAs are less able to cross membranes?
Charged
What are some typical first generation APDs?
Chlorpromazine and haloperidol
DRD2 receptor blockade?
Chlorpromazine, haloperidol
In patients with alzheimer's disease, current treatments are used to increase transmission at the what receptors?
Cholinergic and ChE inhibitors result in increased synaptic concentrations of ACh
Guidelines for the treatment of an early stage of Alzheimer's disease recommend the use of what class of drugs?
Cholinesterase (ChE) inhibitors to improve cholinergic transmission
What is epilepsy?
Chronic disorder characterized by recurrent seizures, 1% of population has epilepsy (most common neuro disorder after stroke)
What is area postrema?
Circumventricular organ in medulla oblongata, outside BBB, mediates emesis
What ion travels through GABA ionotropic receptors?
Cl-
What are some atypical (second generation) APDs?
Clozapine and olanzapine
5HT2A receptor blockade?
Clozapine, olanzapine and other atypicals
What is risk of developing drug abuse disorder a function of?
Co-occuring psychiatric and medical disorders, genetic factors, environmental variables (societal attitudes, cost and availability)
All LAs except what produce smooth muscle relaxation (produces some degree of arteriolar vasodilation)?
Cocaine
Current theory of the mechanisms of action in GA?
Combination of lipid and protein theory. Act on membrane proteins in CNS or effect receptor function. Both alter ion flux.
Multimodal analgesia?
Combination therapeutics that intervene at multiple levels (may be required to achieve adequate analgesia)
When is anterior temporal lobectomy done?
Common partial seizure of adults. If seizures refractory and harmful, majority of patients seizure free for 5 years.
How do ions contribute to cell membrane potential?
Concentration gradient across membrane and membrane permeability
When does K+ efflux stop?
Concentration gradient pulling K+ outward is balanced by electrical force pulling K+ in (because cell is negative, it pulls K+ in)
What happens in pharmacological treatment failure for epilepsy?
Consider epilepsy surgery or vagal nerve stimulation. NEJM study (2012) supports surgery ASAP after failure of two first line drugs (rather than waiting more than 10 years after treatment failure as is typically seen at present)
Standard drug therapies for seizures?
Control seizures for 2/3 of epileptic pop. Somewhat better for new onset epilepsy in adults. Leaving hundreds of thousands in US with poor seizure control.
What type of surgery is done for severe, mixed refractory childhood forms of seizure?
Corpus callostomy, hemispherectomy
What causes migraine?
Cortical activation, then inactivation (cortical spreading depression), then release of neuropeptides in dural vasculature, activating trigeminal afferents, leading to central sensitization, tactile allodynia
How does wave of depolarization (AP) travel along axon?
Current flow depolarizes nearby membranes
What are some current pharmocotherapies for PD?
Current therapeutics based are symptomatic; based on restoring DA levels. Ex: DA precursors, DA receptors agonists, inhibitors of DA degradation.
What receptors make up D1 receptor family?
D1 (striatum, neocortex) and D5 (hippocampus, hypothalamus)
What dopamine receptor family predominates by far?
D1 and D2 (highly expressed in striatum and in pituitary)
What is direct pathway?
D1 receptors, enables movements
What is indirect pathway?
D2 receptors, inhibits movement
What makes up D2 receptor family?
D2, D3 and D4
What does on-target adverse effects mean?
DA blockade but in wrong site
What is levodopa (L-DOPA) used for?
DA precursor that can cross BBB. Used to treat PD. Absorption via aromatic amino acid systems. Less than 1% reaches brain, but when given with carbidopa (peripheral AADC inhibitor), 10% reaches brain.
What does cocaine block?
DA transporter
Timelines of acute dystonia
Days of taking APD
Inhaled anesthetics on CV system?
Decrease in BP
Antiepileptic drugs in pain conditions?
Decrease in neuronal excitability; use in neuropathic pain. Effects due to use-dependent blockade of voltage gated sodium of calcium channels.
How do local inhibitory and descending projection neurons work?
Decreased Ca+ influx (less transmitter release) or increased Cl- influx or K efflux
What are biological indications of schizophrenia?
Decreased blood flow in frontal lobe, caudate during working memory tasks; reduced hippocampal and medial temporal lobe volume; enlarged ventricles
What is tolerance?
Decreased effect of drug with continued use (D/R curve shift to right)
What does vagus nerve stimulation do?
Decreases frequency of seizures. For partial/ generalized seizures good response (seizure reduction) in 30-75% subjects. Now tested in children long known to work, MOA unclear. Also, tested in depression, anxiety etc). Decreases frequency of seizures.
How does gabapentin work?
Decreases release of excitatory neurotransmitter by inhibiting high voltage (HVA) Ca2+ channel
What is repolarization of AP?
Delayed opening of K+ channels
Inhaled anesthetics on kidney?
Depends on concentration, but decreases glomerular filtration rate and renal blood flow
What do anesthetic absorbed from alveoli to blood and then delivered to various tissues depend on?
Depends on perfusion. Tissues with high blood flow will equilibrate with alveolar partial pressure more rapidly than tissues with medium blood flow (skeletal muscle), low blood flow (adipose). Tissue becomes saturated with anesthetic; venous blood returning= high anesthetic partial pressure and further uptake from alveoli is reduced. When all body compartments in equilibrium, anesthesia commences
How should you target glutamate and neuropeptide receptors?
Depends on their CNS distribution and route of drug administration
What is common in PD?
Depression and dementia, correlated with each other and age of patient
Co-occurence in PD?
Depression, psychosis and dementia: tricky therapeutics in these patients/
General anesthetics act where?
Different anatomic sites that contain a different complement of receptors
How is neuropathic pain different?
Different profile of Na+ channel expression; basis for some efficacy of Na+ channel blockers. Also changes in CNS due to reorganization of synaptic connections in dorsal horn.
What are thermal receptors described as?
Different transient receptor potential (TRP) channels/receptors for different levels of hot, cold etc
What is a first line monotherapy for PD?
Direct acting dopamine receptor agonists, they are no more effective than dopa, induce fewer side effects (dyskinesia).
What happens during parkinson's disease?
Direct pathway inhibited and indirect pathway activated, both leading to reduced movement. Loss of DA leads to decreased excitation of cortex and Parkinson's disease.
What does remission mean in schizophrenia?
Does not mean return to premorbid state
What are COMT inhibitor used as adjunct for?
Dopa/carbidopa
What is second pathway that DA is degraded into HVA (metabolite excreted in urine)?
Dopamine---> 3-methoxytyramine enzyme: COMT 3-methoxytyramine---> HVA enzyme: MAO/ AD
What is first pathway that DA is degraded into HVA (metabolite excreted in urine)?
Dopamine---> DOPAC enzyme: MAO or AD DOPAC-->HVA enzyme: COMT
What is third step in catecholamine synthesis?
Dopamine--> Norepinephrine enzyme: Dopamine β-hydroxylase cofactor: Ascorbic acid, O2, Cu2+
Primary afferents transmit information via synaptic transmission in?
Dorsal horn
What is DA transporter (DAT)?
Driven by Na cotransport gradient. Found on presynaptic neuron cell membrane. Primary means DA inactivation. MAO degrades DA into DOPAC.
Carbidopa?
Drug given to people with Parkinson's disease in order to *inhibit peripheral metabolism of levodopa*. This property is significant in that it allows a greater proportion of peripheral levodopa to cross the blood brain barrier for central nervous system effect
What is nigrostriatal pathway related to in schizophrenia?
Drug induced extrapyramidal (motor) side effects, tardive dyskinesia
What is large factor for DOA to cause addiction?
Drug's ability to cause addiction is related to its ability to activate reward system. More rapid the rise in drug concentration in CNS, greater the reward (IV/smoked greater risk for addiction). Rapid clearance is also a risk factor.
What are some peripheral effects that may contraindicate use of muscarinic drugs in many patients?
Dry mouth, blurred vision, urinary retention and tachycardia
How does central sensitization occur?
Due to alteration in sensory processing in dorsal horn secondary to repetitive synaptic transmission and changes in second messengers
How do changes occur in primary afferents in neuropathic pain?
Due to inflammation, loss of neurotrophic support
Elimination is proportional to?
Duration of anesthesia and magnitude of ventilation
What is cause of Dravet syndrome?
Earlier onset, treatment resistant, linked to loss of function mutation in voltage gated sodium channel SCNA1, *leads to decreased activity of GABA interneurons*
When is levodopa highly effective?
Early on, more so for bradykinesia than tremor.
What are low doses of antimuscarinic drugs used for?
Early onset tremor, rigidity, drooling
What can pain be?
Early warning, protective signal in response to noxious stimuli. Can be incapacitating, pathologic, intractable (tissue/nerve injury, inflammation). Can be dysfunctional (not due to noxious stimuli or lesions, headache, IBS)
What is permeability of ions?
Ease with which ions cross membrane (how many ion channels are open)
What is Levetiracetam (Keppra) not effective in?
Electroshock model; picked up by kindling model
Ketamine (Katalar) disadvantages?
Emergence reactions: psychic sensation can be alteration in mood state and body image, floating sensations, vivid dreams or illusions and occasional delirium.
What is pain?
End perceptual consequence of neural processing of sensory information
What is hypothalamic pathway related to in schizophrenia?
Endocrine effects, eating, temp. regulation
What binds delta receptor?
Enkephalins (can mediate analgesia)
What biological indication is strongly associated with negative symptoms in schizophrenia?
Enlarged ventricles
What other potential causes are there of PD?
Environmental toxins (MPTP), Infection, oxidative stress, mitochondrial defects or damage
Morphine derived full agonist?
Equally effective as morphine. Often used in combination with acetaminophen or NSAIDs. Full agonists also used in formulations that allowed sustained release for more effective control of severe terminal pain.
Benzocaine (Americaine)?
Ester linked lacking terminal amine group, poorly soluble (low hydrophobicity) with low potency, Forms= cream, aerosol or ointment,Rapid onset (pKA 3.5) within 1-min and short acting (15-20 min)
Tetracaine (Pontocaine)?
Ester linked. Highly potent, long duration of action, high hydrophobicity due to butyl group: a. Promotes prolonged interaction with Na+ channel b. Increase time associated with tissue surrounding the nerve. May increase systemic toxicity because more slowly metabolized than other ester LAs (released gradually from tissue into the blood).
Why type of LAs are more likely to induce hypersensitivity (allergic dermatitis or asthmatic attack)?
Esters are more likely to induce allergic reaction (derivatives of p-aminobenzoic acid, PABA) a known allergen. If allergic to esters, give amides.
What is the first line drug for absence seizures only?
Ethosuximide (Zarontin), good absorption, complete metabolism. Good relationship between dose and plasma levels, gastric side effects also dose-related.
What drugs are used against generalized (absence) seizures?
Ethosuzimide (Zarontin), Valproic Acid, Clonazepam (klonopin)
Why is Clozapine good?
Exhibits decreased propensity for inducing EPS and TD. Shown effective in treatment-refractory patients
Olanzapine?
Expensive, atypical APD adverse effects (weight gain, diabetes, other metabolic disturbances), less risk of EPS, no more effective
Clozapine?
Expensive, atypical APD, weight gain/diabetes risk; plus more serious adverse effects, clearly more efficacious (more refractory cases)
What is physiological pain transmittance?
External stimuli depolarize nerve terminals in primary sensory neurons (high threshold). Action potential in the peripheral nerve synapses on nerve in dorsal root of spinal cord. Projection nerves transfer information to brainstem and thalamus, eventually to cortex.
What does postural instability contribute to in PD?
Falls, immobility, constipation, dependency and depression
Sevoflurane?
Fast recovery. Advantages: outpatient, pleasant odor. Disadvantages: *cause seizure activity in children, nephrotoxic.*
Desflurane?
Fast recovery. advantages: outpatient. disadvantages: very pungent, tachycardia, *airway irritant, expensive*
What are risk factors for children to get epilepsy?
Fever, mental retardation cerebral palsy, genetics
*P*rocaine (Novacaine)?
First synthetic anesthetic, ester linked, slow onset (pKa 8.9), Anesthesia is obtained within 2-5 minutes, Short half life (20 secs); no toxicity, short duration; *p*oor *p*rotein binding and low hydrophobicity= dissociates rapidly from the Na+ channel. Hydrolyzed to *P*ABA, which inhibits effectiveness of sulfonamide (sulfa) drugs.
How many type of dopamine receptors are there?
Five G-protein coupled receptors, divided into D1 and D2 family
What are negative symptoms of schizphrenia?
Flat affects, poverty of speech and lack of motivation
What are Z drugs antagonized by?
Flumazenil
What is the agent used in emergency room for patients who have taken an overdose of benzodiazepines?
Flumazenil, nonselective benzodiazepine antagonist, is used to reverse effects of benzodiazepines in overdose situation.
What is partial seizure also called?
Focal seizure
What is vaplroic acid (depakene) efficacious against?
Focal seizures, generalized tonic-clonic, combination seizures absence seizures, bipolar disorder, migraine
What is neuropathic pain?
Following nerve injury
What is vesicular monoamine transporter (VMAT)?
Found in vesicle membrane in presynaptic neuron. Stores DA, while antiporting protons. Driven by ATPase activity.
What is mean duration of PD?
From diagnosis to death is ~15 years
Where are D4 receptors found?
Frontal cortex, medulla and midbrain
What is primary MOA of clonazepam (Klonopin)?
GABA-A receptor augmentation (secondary effect on thalamic neurons). Use limited by sedation, development of tolerance, withdrawal syndrome.
Protein Theory of GAs?
GAs bind to hydrophobic pockets on all membrane proteins, which undergo conformational changes that alter ion flux across neuronal membrane.
Unitary Theory of GAs?
GAs produce their effects by changing physical properties of cell membranes. 1. Via critical volumes (they expand volume of membranes beyond critical amount, which obstructs ion channels and alters electrical properties of the neuron) 2. Fluidization Theory: increases membrane fluidity= alters ion flow and thus neuronal membrane electrical properties.
What are 1st generation drugs effective in the treatment of?
Generalized tonic-clonic (grand mal) and focal seizures
Are synapses always made from presynaptic neurons to post synaptic neuron?
Generally yes, but not always
Chlorpromazine?
Generic, adverse autonomic effects, some risk of extrapyramidal side effects and tardive dyskinesia
Haloperidol?
Generic, less autonomic effects but strong D2 blockage means higher risk of EPS and tardive dyskinesia
What is general anesthesia?
Global but reversible depression of CNS function resulting in loss of response to and perception to all external stimuli.
What is sensitization?
Greater/new effect for a given dose over time (less common; can see both)
What are the four classes of G proteins?
Gs, Gi/o, Gq/11, G12/13
What GAs are metabolized in liver?
Halothane and sevoflurane
What should you do for treatment failure in epilsepy?
Happens in one half of patients. Try monotherapy with another first line drug. Avoid polypharmacy.
LAs with higher pKa?
Have less rapid onset of action. (fewer molecules are available in their lipid soluble form)
LAs with lower pKa?
Have more rapid onset of action
What does codeine's analgesic activity depend on?
Hepatic demethylation (leads to large individual differences in therapeutic responses)
Where is analgesia mediated?
Higher brain areas, brainstem, spinal cord and primary sensory afferents.
What do ions in solution have?
Hydration shell
LA ester metabolism?
Hydrolysis by pesudocholinesterase enzymes (plasma cholinesterase or buturylcholinesterase). Hydrolysis is rapid, resulting in H2O soluble metabolites, excreted via urinary system.
What is primary factor related to LA potency?
Hydrophobicity
What is current?
I=gV. Straight line on current vs potential graph.
Ketamine (Katalar) advantages?
IV GA. *Profound analgesia*, hypnotic, amnesia (short term), *provides dose-dependent cardiovascular stimulation: increases arterial blood pressure, heart rate and cardiac output*, *bronchodilation*
Ketamine (Katalar) clinical use?
IV GA. *dissociative anesthesia: antagonize NMDA receptor*, cataleptic state: characterized by analgesia, amnesia and altered consciousness, induction in unstable and/or at risk cardiovascular patients, asthmatic patients: low risk of bronchospasm, suitable for pediatric patient
Etomidate (amidate) clinical use?
IV GA. Acts as hypnotic (potentiates GABAa), rapid induction and recovery: single dose or continuous infusion, patients with compromised cardiovascular system, treatment of endogenous hypercortisolemia
Etomidate (amidate) advantages?
IV GA. Hemodynamic stability (no change in BP), *No respiratory depression*, metabolized in liver; metabolite inactive
Propofol (diprivan) properties disadvantages?
IV GA. No analgesic properties, pain on injection, *marked decrease in blood pressure (especially in hypovolemic patients)*, *respiratory depressant: apnea*
Propofol (diprivan) properties advantages?
IV GA. Rapid induction and recovery: no- hangover effect, metabolized in liver and extrahepatic: renal/lungs, *antiemetic (prevents vomitting)*
Propofol (Diprivan) clinical use?
IV GA. Sedative-hypnotic (potentiates GABAa), induction and maintenance: balanced anesthesia, continuous infusion (ambulatory surgery), prolonged sedation of mechanically ventilated patients, antiemetic, controversial if should be used in pediatric patients.
What is leading cause of poor drug tolerability and adherence in seizure?
Iatrogenic overtreatment
What happens when depolarization crosses voltage threshold?
If it crosses -50mV, it elicits AP
When does transmission of signal cease to and from spinal cord?
If sodium channel is *blocked over critical length* of the nerve, propagation across the blocked area is no longer possible
What are some CNS effects that may contraindicate use of muscarinic drugs in many patients?
Impaired memory, drowsiness, confusion, delusions
Where does physiological pain arise?
In periphery, transferred through sensory relays to CNS
How is parkinsonism, EPS, and tardive dyskinesia induced?
In proportion to D2 DA receptor affinity of any given APD
Inhaled anesthetics on CNS?
Increase cerebral blood flow, which increases cerebral blood volume and further increases intracranial pressure
MOA of benzodiazepines?
Increase frequency of opening of chloride ion channels coupled to GABAa receptors. Cannot open chloride ion channel without GABA.
What triggers muscle contraction?
Increase in intracellular calcium concentration
What produces psychotic symptoms?
Increase of DOPA synthesis, stimulation of release of DA at nerve terminal (amphetamine, tyramide), inhibition of breakdown (pargyline), and Inhibition of reuptake (cocaine, amphetamine, benztropine)
Inhaled anesthetics on respiratory system?
Increase respiratory rate (except nitrous oxide)
Opioid usage among pregnant women?
Increased 5X in last decade. Neonatal abstinence syndrome is skyrocketing.
What does alcohol withdrawal do?
Increased excitability, anxiety and seizures. Increased NMDA receptors (depolarization via influx of Ca2+).
What is pharmacokinetic acquired tolerance?
Increased hepatic metabolism
What does increased lipid solubility mean for LAs?
Increased potency= increase duration in action
How do COMT inhibitors work?
Increases L-DOPA in periphery/ blocks its metabolism in periphery. L-DOPA crosses blood brain barrier to be turned into dopamine.
What does out of control drug use do?
Increases glutamate receptors by altered gene transcription (long term synaptic alterations arise)
What does Cl- conductance/ increased K+ conductance do?
Increases postsynaptic hyperpolarization, decreases voltage gated Na+ channels reaching threshold and decreases action potential generation
What are functions of DA pathway?
Increases salience of stimuli, guides motor activity to seek rewarding stimuli and is activated by anticipation of reward
What is innate tolerance?
Individual differences in drug sensitivity because of genetic variations in ADME. This can be a risk factor for drug adverse effects or drug abuse.
What can continued inflammatory mediators induce?
Induce lowered activation threshold in primary sensory afferents. This results in allodynia (normal stimuli is painful) and hyperalgesia (painful stimuli is more painful)
Nitrous oxide?
Induction/Recovery: Fast Advantages: *Analgesic* minimal respiratory depression and odorless disadvantages: low potency (balanced anesthesia), *risk of anemia (inactivates vitamin B12)*
How do NSAIDs work?
Inhibit COX-1 and COX-2 by reducing activation of primary afferents, decrease prostaglandin production. Decrease inflammatory hyperalgesia and allodynia.
How do MAO B inhibitors work?
Inhibit DA metabolism. Can be used in combo with dopa.
What produces antispychosis?
Inhibition of DOPA synthesis (α-methyltyrosine), interference with vesicular storage (reserpine, tetrabenazine), and blocking of DA receptors and autoreceptors (perphenazine and haloperidol).
What does Gi/o do?
Inhibits adenylate cyclase (decreases cAMP), activates K channels
What does D2 receptor family do?
Inhibits, decreases cAMP (via Gi), increases K+ currents and decreases voltage gated Ca2+ currents
High systemic LA levels in CNS?
Initial stimulation followed by depression
What are some key features of focal seizures with secondary generalization?
Initially manifests with symptoms of focal seizure with or without altered mental status. Evolves into a tonic-clonic seizure with sustained contraction (tonic) followed by rhythmic movements (clonic) of all limbs. *Loss of consciousness*. Preceded by aura.
How does IV anesthetic travel through body?
Initially transported through vascular system, then redistributed to the brain and highly vascular tissues (peaks within 1 minute), loss of consciousness.
What is the current view of management of PD patients?
Initiate DA therapy with newer, direct acting agonist (has less side effects). If necessary, then add low dose L-DOPA/Carbidopa. If long term complications of L-DOPA, add COMT inhibitor ( prevents peripheral metabolism of dopamine). MAO-B inhibitor could be used as an adjunct (or initial trial). Can use anticholinergics for tremor or drooling. For treatment failures with intact cognition, consider DBS.
How do lower motor neurons work?
Innervate muscle fibers and release acetylcholine
What is resistor in cell membrane?
Ion Channel.
What channels are highly diverse, and structurally related?
Ion Channels (can open or close)
What functional group of an LA confers the blocking action of the LA in the Na+ channel?
Ionizable terminal amine
What does ganglionic synaptic transmission rely on?
Ionotropic and metabotropic receptors
What were some early treatments for schizophrenia?
Isolation, sedation, hydrotherapy, electric shock treatment and lobotomy
Why is clinical pain difficult to treat?
It involves a combination of mechanisms (inflammation, changes in peripheral or central nerve function)
Which ion contributes most to the resting membrane potential?
K+ moves down its concentration gradient (efflux)
NMDA antagonist for pain condition?
Ketamine, dissociative anesthetic for severe acute pain w/o respiratory depression
What causes long term sensitization?
Kinase activation (PKC, CAMK II, ERK)--> phosphorylation of gene regulatory proteins--> altered gene expression--> long term sensitization
What causes short term sensitization?
Kinase activation-->Phosphorylation of postsynaptic proteins (AMPA-R and NMDA-R)--> short term sensitization
What is second step in catecholamine synthesis?
L-DOPA--> Dopamine enzyme: aromatic L-amino acid decarboxylase (AADC) cofactors: pyridoxal phosphate
LA lipid soluble form?
LA + H+ (uncharged)
What form of LA binds Na+ channel?
LAH+ (charged, pharmacologically active. Only binds when Na+ channel is open)
What formation are LAs at physiological pH?
LAs are in their charged cationic form (ionized), does not cross neural membrane as easily
Why is faster nerve firing easier to block by LAs?
LAs gain access to inner sodium channel by traveling through the channel when it is open in addition to passing through the neural membrane.
What is most effect LA?
LAs with moderate to high hydrophobicity (Low Hydro cannot cross membrane, extremely hydro gets stuck in lipid bilayer)
What is Levetiracetam (Keppra) pharmackinetic profile?
Largely secreted unchanged, not an inhibitor or substrate of CYP450 enzymes
What is function of Nigrostriatal DA?
Learning and execution of purposeful movement
What are primary molecular targets of GAs?
Ligand gated ion channels (GABA, nicotinic Ach, 5-hydroxytryptamine, glycine, glutamate)
What do most snyapses in the brain use?
Ligand gated ion channels and either glutamate (ex) or GABA (inhib)
How do nicotinic receptors work?
Ligand gated ion channels that allow flux of sodium and potassium ions into cell. They open in response to binding of two molecules of Ach.
Where are D3 receptors found?
Limibic. Olfactory tubercle, nucleus accumbens and hypothalamus.
Where does secondary generalized seizure occur?
Localized to one area of brain and thalamus
Where does partial seizure occur?
Localized to one part of brain
What are LAs?
Locally applied chemicals with similar molecular structure that inhibit peripheral nerve transmission without loss of consciousness or vital functions
What are areas of brain interconnected through?
Long tract projections
What benzodiazepines are of choice in patients with liver dysfunction or who is elderly?
Lorazepam or oxazepam (they are directly conjugated and have no active metabolites)
What are some features of substance dependence (addiction)?
Loss of control over drug seeking and use; salience to behavioral repertoire. Neuroadaptations.
What is PD primarily a disease of?
Loss of nigrostriatal DA neurons. 80% loss of DA required to see symptoms.
What is therapeutic index of most antiseizure drugs?
Low and toxicity not uncommon
What is ketogenic diet?
Low cal diet, 4 gm fat/gm protein or carb. Creates ketones by fat metabolism, mimic fasting, *ketones replace glucose as brain fuel*. Treatment refractory seizures in children (Lennon-Gastuat syndrome).
Smaller the dissociation constant at D2 receptor
Lower antipsychotic drug dose needed (Spiroperidol)
What are adverse effects of second generation (Atypical) APDs?
Lower risk of inducing acute extrapyramidal side effects, lessened risk of tardive dyskinesia, *weight gain common, accompanied by insulin resistance, type II diabetes, hyperlipidemia*
What does slow EPSP act on?
M1 receptor
How are MAO B and MAO A inhibitors different?
MAO B have less interaction with tyramine in diet.
Selegine?
MAO-B inhibitor
Second line treatment for patients with MDD unresponsive to other antidepressants?
MAOIs
What increases elimination of general anesthesia?
Magnitude of ventilation, increased accelerates recovery
What does removing hydration shell do to ions?
Makes it energetically unfavorable and separates ions across lipid bilayer
Antidepressants in pain conditions?
May cause reductions in central sensitization (neuronal plasticity), used in neuropathic pain, effects could be due to increased activity of descending monoamine pathways. Least selective ADPs work best.
Newer drugs in epilepsy?
May have lesser side effects, but have not yet changed prevalence of drug resistant seizures
Halothane?
Medium recovery. Advantages: *pediatric only* potent, pleasant odor, bronchodilator, used worldwide. Disadvantages: *hepatoxicity, sensitization to catecholamine induced dysrhythmias*
Why do we need to use Goldman- Hodgkin Katz equation?
Membrane potential is calculated by contributions from multiple ions, not just one (or else we would use nerst equation)
LA amide metabolism?
Metabolized primarily by microsomal P-450 enzymes in the liver (N-alkylation and hydroxylation). Rate of metabolism varies. Excretion occurs via urinary system.
What type of receptor are muscarinic receptors?
Metabotropic (GPCR) 1. NT binds 2. G protein is activated 3. G protein subunits or intracellular messengers modulate ion channels 4. Ion Channel opens 5. Ions flow across membranes
Low penetration into brain
Methotrexate, mannitol, sodium, penicillin, morphine, dopamine
What is the top condition topiramate (topamax) is prescribed for?
Migraine/headache, epilepsy/seizure, bipolar disorder, anxiety, weightloss
What is function of mesolimbic DA?
Modulates motivation, goal directed thinking, affect and reward
What is helpful in instances of suspected non-adherence or to evaluate unexplained toxicity or uncontrolled seizures?
Monitoring plasma levels
What treatment had modest benefits as initial monotherapy/ dopa co-therapy?
Monoamine oxidase-B inhibitors.
What is associated with poorer prognosis of schizophrenia?
More prominent negative symptoms
How many classes of G proteins do neurotransmitters target? How?
More than one. They have different receptor isoforms (each have the potential to selectively couple to specific G protein class). Serotonin has multiple GPCR isoforms and one ligand gated ionophore.
What is gold standard for analgesia?
Morphine
What binds mu receptor?
Morphine, other opioid agonists and antagonists (endogenous peptides less active here)
What are the potential causes of PD?
Most cases are "idiopathic" (environmental, multigenic). Poor concordance in twins.
What makes up peripheral NS?
Motor and Sensory neurons
Fetanyl?
Much more potent, short acting, lipophilic. Used after surgery, severe, or breakthrough pain.
How does LA cross nerve membrane?
Must be uncharged (nonionized)
What can carbamazepine exacerbate?
Myoclonic and absence (petit mal) seizures
In addition to absence seizures, what is clonzepam (Klonopin) also efficacious in?
Myoclonic and atonic seizures, infantile spasms
What is glutamate and neuropeptide (CGRP and substance P) controlled by?
N-type voltage gated calcium channels
Where do neuropeptides bind (CGRP and substance P) bind?
NK1 and CGRP1
What receptor is blocked to prevent induction and maintenance of central sensitization?
NMDA (how ketamine works)
MOA and effect of memantine?
NMDA receptor antagonist
How do phenytoin and carbamazepine, lamotrigine work?
Na+ channel inhibitors, prevent rapid neuronal firing by selectively prolonging Na+ channel inactivation in rapidly firing neurons.
What creates the negative membrane potential of cell?
Na+/K+ ATPase. 3Na+ leave for every 2k+ entering.
Opioid antagonist?
Naloxone, naltrexone (uses restricted to drug abuse). Methylnaltrexone.
Future therapeutics for schizophrenia?
Need to be based on better understanding of molecular pathophysiology
What is mesocortical pathway related to in schizophrenia?
Negative symptoms
What kind of membrane potential do cells have? Why?
Negative. More negative ions on inside than outside. Vm= Vin-Vout.
How is membrane potential determined?
Nernst potential and their relative permeability, goldman-hodgkin Katz equation. -61.5mv log [(Pk*Kout)+(PNa*Naout)+(Pcl*Clin)]/[(Pk*Kin)+(PNa*Nain)+(PCl*Pout)]
What are the overall mechanisms underlying addiction?
Neuroadaptations arise, change in abundance, composition or distribution of receptors or of intracellular signaling molecules.
What is pharmacodynamic acquired tolerance?
Neuroadaptations at synaptic or genomic levels (explains long lasting changes likely to explain cravings and relapse).
Describe synaptic organization of cerebellar cortex?
Neurons form local circuits (positive synapse to negative synapse)
What is long term goal for PD treatment?
Neuroprotection (neurorestoration), want dopamine making cells.
What happens after vesicle fusion?
Neurotransmitter diffuses across synaptic cleft and binds ionotropic and metabotropic receptors to elicit post synaptic reponse.
Ropivacaine (Naropin)
Newer amide LA, low cardiotoxcity; less lipid soluble, preferentially blocks sensory neurons, also has intrinsic vasoconstrictor properties.
How are newer seizure drugs being identified?
Newer phenotypical models (gene mutant mice, models of kindling or neuropathic pain), better targeting of defined biochemical mechanisms (GABA uptake, metabolism, receptor effects). Novel AED (antiepileptic drug) targets-- glutamate receptors, K or Ca channels.
What receptor does Ach bind to in NMJ?
Nicotinic cholingeric receptors. These then depolarize and excite muscle fiber.
Where is 80% of CNS DA found?
Nigrostriatal DA
Primary inhalation anesthetics?
Nitrous oxide, halothane, enflurane, methoxyflurane, isoflurane, desflurane, sevoflurane
Primary inhalation anesthetics examples ?
Nitrous oxide, halothane, isoflurane, desflurane and sevoflurane.
Do tolerance and dependence imply pathologic drug use?
No
What is benefit of specific D2 blockers?
No added benefit in terms of efficacy, but different profile of adverse effects
Premedication with benzodiazepines on LA cardiovascular toxicity?
No effect on cardiovascular toxicity.
Are side effects common in valrpoic acid (depakene)?
No, but may result in severe idiosyncratric hepatotoxicity (requires monitoring of liver function)
How does first order travel in anterolateral pathway?
Nociceptors or thermoreceptor to lissauer's tract
What is fourth step in catecholamine synthesis?
Norepinephrine--> Epinephrine enzyme: phenylethanolamine N-methyltransferase cofactor: S-adenosylmethionine
What do drugs hijack?
Normal evolutionary functions of reward
APD mechanism of action?
Not really understood, D2 DA receptor is still commonality
OD from opioids?
OD from painkillers has increased >4X in last decade. Ironically, some new restrictions on painkillers and their high cost have contributed to increased heroin abuse
What distinguishes morphine, codeine and heroin?
OH modification
When does cardiovascular toxicity of LAs occur?
Occurs after high systemic LA doses are obtained and effects on CNS are produced.
Primary effect of LA cardiovascular toxicity?
On myocardium, resulting in depression= decreased conduction rate, force of contraction, overall cardiac output.
How do ROS species contribute to PD?
Ongoing generation of ROS may make DA cells more susceptible to a variety of insults
Why are myelinated nerves easier to block?
Only nodes of Ranvier need to blocked for successful prevention of further nerve depolarization. (significantly smaller portion needs to exposed to anesthetic to achieve anesthesia)
How do Na+ channels open?
Open then inactivate
What happens when AP reaches presynaptic terminal?
Open voltage dependent calcium channels, this triggers vesicle of neurotransmitter to fuse with plasma membrane and release neurotransmitter into synaptic cleft (specialized form of exocytosis)
Why is AP transient, all or none depolarization?
Opening of Na+ channels triggers further depolarization, by opening more Na+ channels.
What is dependence?
Operationally defined by tolerance, withdrawals when discontinued, drug craving, drug-seeking behavior in response to conditioned stimuli
Where do postganglionic neurons travel to?
Originate in paravertebral chain ganglion and go to smooth muscle, prevertebral ganglion or adrenal medulla
What is order of sensory loss?
Pain, temp, touch and pressure
Tramadol?
Parent compound blocks monoamine uptake. Metabolite is a weak opioid agonist. Use should be restricted to more chronic (neuropathic) pain.
What binds kappa?
Partial agonists strong here. Can mediate analgesia, and psychotomimetic effects. Dynorphin.
What pathways interact with VTA dopamine pathway?
Pathways signaling arousal, novelty stress, anxiety and decision making
What are surgical procedures (deep brain stimulation) reserved for special patients?
Patients refractory to med treatment, with significant dyskinesia or with significant clinical fluctuations on dopa, but with intact cognition.
What do late, slow EPSP act on?
Peptidgergic (neurotransmitters that are short chain peptide chains)
What is the AP ion permeability like?
Permeable to Na+ then DELAYED K+ permeability (conductance over time graph)
What was one of the first antipsychotic drugs used?
Phenothiazine chlorpromazine (had antihistaminic and sedative effects). Shown to have antipsychotic effects by blocking DA receptors. Made patients calmer.
What is backbone of catechol nucleus?
Phenyl group, with two hydroxyl groups and R group
What is the capacitor in a cell?
Plasma membrane, it stores electrical energy.
What does complication of immobility lead to in PD?
Pneumonia
Change for opioid epidemic?
Prescribing habits of physicians, restriction on length of opioid use/ conditions for which they are dispensed, formulations that cannot be crushed/cooked for injection (or release opioid antagonists when this is done), destigamatize addiction, promote fund/treatments (cognitive behavioral therapy, self-help programs etc)
Opioid epidemic includes both
Prescription opioids and heroin
How do barbiturates work/ benzodiazepenes work?
Prevent seizure spread by acting on GABAa receptor (chloride ion channel) to potentiate GABA-mediated inhibition. GABA binds, chloride enters
How do antiepileptic drugs work on absence seizure (petit mal)?
Prevent synchronous thalamocortical cycle by acting on at two molecular targets.
Lidocaine drugs in pain conditions?
Primarily local anesthetic, used topically for subcutaneous pain. Also a use-dependent sodium channel blocker.
What are the multiple MOA of valproic acid (depakene)?
Prolong Na channels inactivation, GABA effects, T type Ca2+ channels, histone deacetylase inhibition (increases gene expression), potentiation of Sp family of transcription factors
How do 1st generation drugs work?
Prolong inactivation of voltage-sensitive Na+ channels. Other potentiate GABA by any of several mechanisms.
How does first order neuron travel (afferent) in dorsal column medial lemniscus pathway?
Proprioceptors or mechanoreceptors to grey matter of spinal cord or dorsal column nuclei
What are the chemical properties that determine LA activity?
Protonation (charge), Lipid Solubility and pH
Why is hydrophobicity critical to protonation mechanism?
Protonation occurs after LA has crossed neural membrane (hydrophobicity controls if LA can cross cell membrane)
Lidocaine (Xylocaine)
Protype amide linked drugs, most widely used, forms= ointment, jelly, patch, aerosol or solution. Fast onset (low pKA), hypoallergenic. Moderate hydrophobicity; moderately potent; intermediated duration (1-2 hours). Metabolites retain weak anesthetic activity.
Later symptoms of LA toxicity in CNS?
Pt experiences tremor that progresses into seizure. CNS depression that follows may lead to death from respiratory failure. (benzodiazepines can be given before anesthetic treatment to prevent initial CNS overstimulation)
What does maintenance treatment of APD significantly reduce?
Rates of relapse
What is long tract neuronal organization used for?
Receives and processes sensory information from entire body
How does basal ganglia work?
Receives input from cortex, processes it and sends it back to cortex via thalamus
What is conductance?
Reciprocal of resistance. R=1/g g= conductance
How is action terminated for I.V. GA?
Redistribution between tissues and metabolism in liver.
How is general anesthesia terminated?
Redistribution of the drug from the brain to the blood and elimination of the drug through the lung. Recovery occurs in reverse sequence from those stages of induction; redistributes down partial pressure gradient.
What is peripheral sensitization?
Reduced threshold and augmented response of sensory nerve fibers. Responsive to nonsteroidal anti-inflammatory drugs.
How do you manage 3 acute extrapyramidal side effects (EPS)?
Reducing dose of APD or concurrent temporary treatment with antimuscarinics/antihistaminics
What is function of hypothalamic DA?
Regulates hormones
What does basal ganglia do?
Regulates purposeful movement including learning and execution of complex motor patterns
Why does valproic acid (depakene) treat a broad spectrum of disorders?
Related to multiple MOA
How do benzodiazepines (clonazepam) work on absence seizures?
Remember absence seizures involve thalamocortical cycle. Potentiates GABAa channels in reticular thalamic neurons. This decreases activation of inhibitory reticular neurons and decreases hyperpolarization of thalamic relay neurons.
How does focal seizure occur?
Results from rapid, uncontrolled neuronal firing and loss of surround inhibition
What does G12/13 do?
RhoGEFs
What is the structure of voltage gated ion channel?
S1-S4: Voltage sensor S5-S6: Ion flow
Where do LAs mainly bind?
S6 in domain IV of the alpha subunit (sites have also been identified at S6 in domains I and III) on the intracellular side of the channel (LAs pass through neural membrane or through open channel of rapidly firing nerves).
What does Levetiracetam (Keppra) bind?
SV2A (synapatic vesicle glycoprotein to modify transmitter release)
What are most common side effects of mirtazapine?
Sedation and weight gain
Prevalent adverse effects of TCAs?
Sedation, anticholinergic effects, orthostatic hypotension, and weight gain
What are some off-target adverse effects of APDs?
Sedation, postural hypotension, anticholinergic effects
What is status epilepticus?
Seizures that last longer than 5 minutes or more followed by seizure within five minute period without person returning to normal between them.
What is ramelteon?
Selective agonist at melatonin receptors MT1 and MT2
What is absence seizure (petit mal) caused by?
Self-sustaining cycle of activity generated between thalamic and cortical cells
What is an aura?
Sensations one feels before an seizure happens
What does bupropion not cause?
Sexual dysfunction or weight gain
What often leads to noncompliance with SSRIs?
Sexual dysfunction, common and challenging
What predominates of LA block, myelination or size?
Size. Small myelinated> small unmyelianted> large myelinated> large unmyelinated
What are the effects of mGLuR, NK1 and CGRP-R?
Slow modulatory effects, postsynaptic depolarization, reach voltage gated Na+ channel threshold, and AP!
Summary order of blockade?
Small diameter fibers> large diameter fibers. Myelinated Fibers> non-myelinated.
Fibers transmitting peripheral pain sensations?
Small diameter unmyelinated or small dimater myelinated fibers (more readily blocks by LAs compared to larger diameter myelinated fibers transmitting sensory proprioceptive signals or motor commands for muscle contraction).
What is balanced anesthesia?
Small doses of two or more GA (safer than large dose of single agent). This produces all component changes.
I.V. GA?
Small, hydrophobic, substituted aromatic or heterocyclic compounds. Hydrophobicity plays a key role in their pharmacokinetics. Faster onset of anesthetic action than most rapid inhaled agents. Rapid recovery, good for outpatient procedures.
What does vesicle fusion involve?
Snare proteins (Vsnare on synaptic vesicle joins with Tsnare on pre-synaptic plasma membrane). Synaptotagmin acts as calcium sensor.
Why is AP depolarization transient?
Sodium Channels inactivate
What is a likely primary effect of carbamazepine?
Sodium channel blockade
Nonselective way for pain management?
Sodium channel drugs used for pain (LAs and antiepileptics)
How do Na+ Channels contribute to refractory period?
Sodium channel inactivation make areas unexcitable immediately after an AP. This makes AP travel unidirectionally.
What makes up motor neurons?
Somatic and Autonomic NS
Where does preganglionic neuron reside in autonomic nervous system?
Spinal cord gray matter to paravertebral chain ganglion in sympathetic nerve trunk
Where does sensory neuron travel through?
Spinal cord grey matter to Dorsal root ganglion to skin
What is rare but serious dermatologic side effect when using carbamazepine?
Stevens-Johnson syndrome (predicted largely by presence of HLA-B*1502 allele, almost exclusively present in Asians). Gotta test for allele
What can cause relapse for drugs of abuse?
Stress, cues and drug
Where are D2 receptors (not family) found?
Striatum, substantia nigra, pituitary gland
What are the key features of *absence* seizure (petit mal)?
Sudden, *brief interruption of consciousness*, blank stare, occasional motor symptoms (lip smacking, rapid blinking), not preceded by an aura
How does felbamate work?
Suppresses seizure activity by inhibiting the NMDA receptor and decreasing glutamate mediated excitation.
What are key features of tonic-clonic seizure?
Symptoms like myoclonic seizure, onset is abrupt and not preceded by symptoms of focal seizure.
What is presynaptic terminal highly enriched in?
Synaptic vesicle (containing neurotransmitter)
What is Ethosuximide (Zarontin) MOA?
T-type Channel
Can be lethal when taken at overdose levels?
TCAs
How does long-acting, full agonist, methadone work for opioid addiction?
Taken orally, blunts the peaks and troughs seen with opioid self-injection. Less likely to produce a "high", but prevents withdrawal, mitigates cravings.
Why is use of lowest dose possible of APDs and early recognition (AIMS test) important?
Tardive dyskinesia occurs (late occurring adverse effect)
What is a late occurring adverse effect for APD?
Tardive dyskinesia. Seen in 20-40% of patients chronically treated with typical APDs. Even seen in non-psychiatric use of DA antagonists (metoclopramide, promethazine). Has driven search for atypical APDs.
Where does protonation occur in LA?
Tertiary amine
What happens to membrane potential whenever ion selective channel opens?
The membrane potential shifts towards nernst potential for that ion
What makes it possible for selectivity filter to select between sodium and potassium?
The precise spatial coordination of residues that replaces hydration shell (this is for potassium or sodium channels, not Na+/K+ pump). Makes it specific for one ion.
Describe neurons in somatic NS
There are upper motor neurons in primary motor cortex brain that snyapse to lower motor neurons in spinal cord. LMN synapse onto skeletal muscle.
What did NIMH-sponsored clinical antipsychotic trials of intervention efficacy (CATIE) study discover?
There was equivalent therapeutic efficacy of typical and atypical APDs, aside from clozapine (which works when others don't). Study assessed efficacy and tolerability of APDs, but not their most serious long term neurological side effect (tardive dyskinesia).
What do peripheral terminals of primary afferents respond to?
Thermal, Mechanical and chemical stimuli
How do ethosuximide and valproic acid work on absence seizures?
They are T-type calcium channel inhibitors. Prevents burst activity of thalamic relay neurons that is required for synchronous activation of cortical cells.
How are different kinds of pain targeted?
They have different mechanisms
How do ion channels catalyze translocation of ions across membrane?
They lower the energy barrier to remove hydration shell. They makes this energetically viable by replacing hydration shell surrounding ion with charged residues within channel lumen.
What is mesolimbic pathway related to in schizophrenia?
Thought to be overactive, related to positive symptoms
What is MOA for 1st generation drugs effective against other generalized seizures (for example absence seizure)?
Thought to block T-type Ca2+ channel-mediated current in thalamic neurons, or otherwise affect activity of these cells
What is the structure of the voltage gated (Na+) channel that LAs bind?
Three subunits: one alpha and two beta isoforms. Alpha subunit contains I-IV domains, each with 6 alpha-helical membrane spans (S1-S6).
What is the DA hypothesis of schizophrenia?
Too much dopamine--> schizophrenia. DA agonists (amphetamine, L-DOPA can induce psychosis. Why? Any drug that increases/ stimulates dopamine.
What does synapse transform?
Transforms electrical signal (AP) into chemical signal (release of neurotransmitter)
How does paddle work in ion channels?
Transmembrane helices (S3, S4) translocate in response to changes in membrane potential. Channel open is probabilistic and depends on voltage.
What was cannabidiol (epidiolex) approved adjunctive treatment?
Treatment for Lennox-Gastaut syndrome and Dravet syndrome
What is carbamazepine?
Tricyclic compound related to certain antidepressants. Also effective in bipolar disorder, trigeminal neuralgia.
What happens when depolarization reaches muscle fiber?
Triggers AP in muscle fiber which triggers release of calcium from sarcoplasmic reticulum
Drugs used for migraine?
Triptans, 5HT1B antagonists; effects on vascular endothelium and its nerve afferents
Most sensitive to LA block?
Type B fiber: preganglionic autonomic: <3 micrometer: light myelination: 3-15 m/s Type C fiber: dorsal root: pain: .4-1.2 micrometer: no myelination: .5-2.3 m/s Type C fiber: sympathetic: postganglionic: .3-1.3: no myelination: .7-2.3 m/s
What is the rate limiting step of dopamine synthesis?
Tyrosine hydroxylase (TH)
What is first step in catecholamine synthesis?
Tyrosine--> L-DOPA enzyme: Tyrosine hydroxylase cofactors: tetrahydrobiopterin, O2, Fe2+
What does LA hydrophobicity determine?
Uncharged (nonionized) drug must first cross nerve membrane to reach the cytoplasm where it is re-protonated (ionized).
What are some early on sign of PD?
Unilateral weakness or fatigue, weak voice, micrographia, olfactory losses
What is Ohm's Law?
V = IR. Relationship between voltage, current and resistance.
Where does pregnaglionic neuron/ somatic motor neuron travel through?
Ventral root
What is increase in sodium conductance a directly result of?
Voltage dependence of sodium channels
What is macroscopic current dependent upon in channel?
Voltage dependent
What is the pharmacological target of LAs?
Voltage-gated sodium channel (expressed by all peripheral nerves). Bind reversibly, block this channel and inhibits AP. Extends refractory period in which the inactivated sodium channel returns to closed (resting) conformation. Prevent transition from #3 to #1.
How is an electrical circuit the same as hydraulic system?
Voltage= pressure Current= Water flow Resistance= Tap
How does LSD work?
Weak 5HT2A agonist, causes some psychotic symptoms. Although 5HT2A antagonists block LSD subjective effects, they are not APDs.
Timeline of akathesia and parkinsonism
Weeks of taking APD
TImeline of true antipsychotic effect
Weeks to month of taking APD
How long does chronic schizophrenia take to treat?
Weeks, acute psychosis may improve rapidly with treatment. Full benefits may take months.
What is dependence evident upon?
Withdrawal
What are the three types of focal seizures?
Without altered mental status, with altered mental status and focal seizure with secondary generalization
Are genetic forms of PD rare?
Yes, but they provide clues regarding PD pathophysiology
What are three Z drugs?
Zolpidem Zaleplon Eszopiclone
What is learned or behavioral acquired tolerance?
accommodation to drug effects
NSAIDS list
acetylalicylic acid, ibuprofen, naproxen, ketorolac, celecoxib, acetaminophen
What are risk factors for elderly to get epilepsy?
alzheimers, stroke
What do you see with out of control drug use for drugs of abuse?
anhedonia, dysphoria and predominance of negative reinforcement
NSAID
blocks signal transduction
What are low doses of antimuscarinic drugs not used for?
bradykinesia (remember L-DOPA mainly reduces bradykinesia)
What is COMT?
catechol-O-methyltransferase. Degrades dopamine into 3- methoxytyramine.
What is dual process model of anesthesia?
cause 1. Potentiation of inhibitory neurotransmitters (GABA and glycine receptor) 2. Inhibition of excitatory neurotransmitters (block release of glutamate, binds presynaptically and postsynaptically)
What are the overall effects of opioid receptor agonists?
closing voltage gated Ca2+ channels on presynaptic terminals and opening K+ channels on post-synaptic neurons (causes decrease action potential generation)
When are neuropeptides released?
co-released with glutamate at higher frequencies, produces slower effects
What does acute use of morphine do?
decreased excitability, decreased neurotransmitter release and then euphoria
How does LA extend channel's refractory period?
delays return to the close conformation. Stabilizes the inactive state of the channel and blocks Na+ influx.
What are the positive symptoms of schizophrenia?
delusions, hallucinations, disorganized speech
How does second order neuron travel (afferent) in dorsal column medial lemniscus pathway?
dorsal column nuclei to decussation of medial lemniscus to dorsal column nuclei to thalamus
What is EPSP?
excitatory post synaptic potential. Caused by influx of Na+. AP spike. Nicotinic receptor.
What does halothane metabolism in liver do?
forms TFA proteins in liver, could be formed during biotransformation: cause direct liver damage or initiate immune mediated responses
What are some chronic adverse effects related to excess/ dysregulated DA?
hallucinations, delusions, agitation, insomnia, pathological gambling, hypersexuality. Maybe related to changes in plasma dopa levels, decreased ability to buffer DA levels with time, post synaptic adaptations that alter cellular responses to DA.
High penetration into brain
heroin, ethanol, nicotine and diazepam (oil/water partition .5-100)
% body fat in inhalation anesthetics?
high lipid soluble drug+ high body fat= slow induction/recovery
When should opioid antagonist, naltrexone be used?
i.m. monthly for abstinent, highly motivated addicts to reduce relapse rate (harm reduction strategy, little evidence of efficacy)
What is IPSP?
inhibitory post synaptic potential hyperpolarization. Muscarinic receptor, M2.
What type of receptor are nicotinic receptors?
ionotropic 1. NT binds 2. Channel opens 3. Ions flow across membrane
Glutamate/GABA synapses rely on....
ionotropic receptors
What is treatment for status epilepticus?
iv benzodiazepene (diazepam or lorazepam) followed by iv drug for tonic clonic (fosphenytoin or phenobarbital)
when does schizophrenia emerge?
late teens to early 20s
What does acute use of cocaine do?
leads to arousal/pleasure (more DA in synapse)
Initial symptoms of LA toxicity in CNS?
lightheadedness, dizziness, followed by visual and auditory disturbances. Patient may feel drowsy and disoriented.
Lipid Theory of GAs?
lipid solubility= anesthetic property. Chemical structure is of minor importance.
How does second order travel in anterolateral pathway?
lissauer's tract, to anterolateral quadrant to lissauer's tract to thalamus
What happens after GAs are administered (component changes)?
loss of consciousness, amnesia, immobility in response to noxious stimuli (skeletal muscle relaxation), analgesia and attenuation of autonomic response to noxious stimulation.
What does sevo*flu*rane do in liver?
metabolism leads to formation of *flu*oride ions (nephrotoxic)
Postganglionic sympathetic neurons release NE that act on?
metabotropic adrenergic (alpha and beta) receptors
Postganglionic parasympathetic neurons release ACh that act on?
metabotropic cholingergic (muscarinic) receptors
What is function of meso*c*ortical DA?
modulates *c*ognition
Timeline of tardive dyskinesia
months to years of taking APD
