Pharm exam 6

Innate vs acquired tolerance

*Innate tolerance* refers to preexisting interindividual variations that are present before administration of the drug - Genetic variations of receptors - Differences in drug pharmacokinetics *Acquired tolerance* results when repeated administration of a drug shifts dose-response curve of the drug to the right - Larger dose required to produce the same effect.

What is the PK and CU of the rapid acting insulin?

*Insulin Lispro, Aspart, Glulisine* *PK*: - Modifications prevent self-aggregation. - Rapid onset: < 20 min. - Early peak - Short duration of action: 2-4 h *CU*: preferred prandial hyperglycemic control - Injected just before (<10 min) a meal.

What are the ultralong-acting insulin? Pharmakinetics and Clinical uses?

*Insulin degludec* *PK* - Conjugated to hexadecanedioic acid at B29 - Form multi-hexamers in subcutaneous tissue - Slow onset 1-9 hours, duration of action > 42 hours. *CU*: basal insulin, subcutaneous, daily.

What are the long acting insulin? Pharmakinetics and clinical uses?

*Insulin glargine* (*L*antus) - Two arginine are attached to the B-chain - Asparagine is substituted for glycine at A21 - Precipitates after subcutaneous injection in body pH. *Insulin detemir* (*L*evemir) - Myristic acid is attached to the B29 lysine - Increases self-aggregation, reversible albumin binding. *PK*: - Slow onset - long duration >12 hours. *CU*: basal insulin.

What is the cause and treatment for type 2 diabetes?

*Insulin resistance*, impaired insulin secretion, increased hepatic glucose production. *amylin* deposit *Treatment*: Oral agents *(metformin)* *Amyloid fibrils: Islet amylod polypeptide (amylin)*

Phencyclidine (PCP) Intoxication and withdrawal

*Intoxication* - Belligerence - Impulsivity - Fever - Psychomotor agitation - Analgesia - Vertical and horizontal nystagmus - Tachycardia - Homicidality - Psychosis - Delirium - Seizures *Withdrawal* - Depression - Anxiety - Irritability - Restlessness - Lack of energy - Disturbance of thought and sleep

Intoxication and overdose (Opioids)

*Intoxication* - Euphoria - Light to moderate CNS depression - Decreased gag reflex - Pupillary constriction (pinpoint pupils) *Overdose* - Altered level of consciousness - Decreased respiratory drive -> Apnea.

Intoxication and withdrawal of cocaine

*Intoxication* - Impaired judgement - Pupillary dilation - Hallucinations (including tactile) - Paranoid ideations - Angina - Sudden cardiac death *Withdrawal* - Hypersomnolence - Bradycardia - Malaise - Severe psychological craving - Depression - Suicidal ideations

Intoxication/overdose and physical exam findings of benzodiazepines

*Intoxication/Overdose* - Ataxia - Minor CNS depression - Dizziness - Confusion - Anxiety - Agitation Effects can be reverse with flumazenil *Physical Exam Findings* - Nystagmus - Hallucinations - Slurred speech - Coma - Hypotonia - Weakness - Altered mental status - Amnesia - Hypotension

What are the physiological effects of thyroid hormones?

1. Growth and development of nervous, skeletal, and reproductive systems. - Severe mental retardation can occur if T3 is absent or low during fetal and early neonatal development. 2. Maintain metabolic homeostasis in adults. - Calorigenesis (temperature regulation). - Cardiovascular effects (increased B receptor sensitivity and contractility) - Respiration, erythropoiesis, cholesterol metabolism.

Anatomical functional blockade of local anesthetics

1. Local anesthetics (LA) are applied outside the peripheral nerve epineurium. 2. Perineurium is the most difficult layer to penetrate. 3. LA then pass through the endoneurium, which envelops the nerves In general, more proximal regions of the body (shoulder, thigh) are innervated by axons traveling relatively superficially, while more distal regions (hands, feet) are innervated by axons traveling closer to the nerve core. - Anatomic progression of functional block: proximal numbness before distal numbness.

What localized toxicity effects can come from local anesthetics?

1. Neural Injury - Most closely associated with inadvertent injection into intrathecal space or excessive exposure to the arachnoid space 2. *Transient Neurological Symptoms (TNS)* - syndrome of transient pain (severe pain that exceeds pain induced by surgery alone) or dysesthesia, or both. Mostly associated with spinal anesthesia using *lidocaine*

Hypothalamic-pituitary-thyroid axis pathway

1. Thyroid-releasing hormone (TRH) from the hypothalamus is released and travels to the pituitary which stimulates thyroid-stimulating hormone (TSH) release. 2. TSH stimulates the growth of thyroid gland and secretion of thyroid hormone. 3. Thyroid hormone exerts negative feedback control of both TRH and TSH.

Thyroid hormone synthesis, storage, and release

1. Tyrosine + I2 -> Monoiodotyrosine (MIT) and Di-iodotyrosine (DIT). 2. DIT + DIT -> Thyroxine (T4) 3. DIT + MIT -> 3, 5, 3'- triiodothyronine (T3) and 3, 3', 5'- triiodothyronine (reverse T3). T4 is converted to T3 in peripheral tissues. T3 is 10x more potent than T4 but T4 stays longer in circulation.

What are the 4 main adverse effects of antiepileptic drugs?

A. Cutaneous effects B. Bone health C. Women of childbearing age D. Suicidality

Non-halogenated anesthetics Nitrous oxide characteristics

"Laughing gas" Very strong analgesic properties - Activates opioid neurons in the periaqueductal gray matter and adrenergic neurons in the locus ceruleus - Used primarily as an adjunct to other anesthetics. Least potent inhalation anesthetic -> fastest induction and recovery - Can only produce anesthesia under hyperbaric conditions (>1 atm) Rapid uptake can improve induction rate of co-administered halogenated anesthetics Rapid diffusion out of the blood can dilute O2 in the lungs -> *Diffusional hypoxia* - 100% O2 to avoid hypoxia. Nitrous oxide will exchange with N2 in any air containing cavity in the body - Nitrous oxide enters the body cavity faster than nitrogen gas can escape -- Increased volume and pressure in the cavity --- Ear drum, bowel, pneumothorax Nitrous oxide can interact with cobalt of vitamin B12 and inactivate methionine synthase - Megaloblastic anemia, peripheral neuropathy -- Especially in patients with malnutrition, B12 deficiency, and alcoholism.

Benzodiazepine metabolic pathways

* means Active metabolite

What is the pharmacokinetics of local anesthetics specifically absorption and metabolism?

*Absorption* - Local anesthetics diffuse away from the site of action -> taken up into tissue and eliminated from systemic circulation - Systemic absorption results in systemic adverse effects - Vasoconstrictors are often used to restrict the blood-flow and limit systemic absorption *Metabolism* - Ester-linked local anesthetics are metabolized by tissue/plasma cholinesterases - Amide-linked local anesthetics are metabolized by CYP P450 enzymes

What is the absorption, distribution, metabolism of GABAergic anxiolytics (benzodiazepine and barbiturates)

*Absorption* - Varies based on lipophilicity of the drug - Many of the anxiolytic drugs are rapidly absorbed following oral administration *Distribution* - GABAergic anxiolytics cross the placental barrier - Also detected in breast milk -- Depressed vital functions in neonate -- Avoided in pregnancy and nursing mothers. *Metabolism* - Most anxiolytics require CYP enzymes for biotransformation -- Out the liver benzodiazepines undergo Phase II metabolism -- A small percentage of barbiturates are excreted unchanged Barbiturates *induce* CYP enzymes Benzodiazepines *inhibit* CYP enzymes

Adverse effects of Donepezil

*Adverse effects (donepezil)*: - Cholinergic adverse effects (diarrhea, nausea, vomiting) - Bradycardia - Syncope -> precipitate fall-related injuries - GI bleeding

Adverse effects of Rivastigmine

*Adverse effects (rivastigmine)*: - Cholinergic adverse effects (same as above) -- More GI adverse effects than donepezil - Risk of bradycardia and AV block

What are the adverse effects of lithium?

*Adverse effects*: - Lithium reduces the kidneys ability to concentrate urine which can precipitate *nephrogenic diabetes insipidus* -- Low specific gravity urine and low osmolality polyuria - *Tremor* - Muscle weakness - *Hypothyroidism* - goiter is common (40-50% patients) - Leukocytosis (WBC count above normal) - Changes in ECG - T-wave flattening or inversion, AV block, and bradycardia Hypothyroidism and goiter - occur within the first two years of treatment. Hypothyroidism occurs more frequently in women age 45 and over. The risk of hypothyroidism increases with age. Late appearing side effects - Alopecia - Rash - Weight gain

What is cause and treatment for type 1 diabetes

*Autoimmune destruction* of pancreatic B-cells and *insulin deficiency* *Leukocyte infiltrate* in islet *Treatment: Insulin* *Insulitis: lymphocytic infiltrate in the islet*

Insulin use: basal vs bolus?

*Basal*: provide a constant "low-level" of insulin. *Bolus*: mimic insulin secretion after a meal

Behavioral tolerance vs conditioned tolerance

*Behavioral tolerance* - Compensatory behavior to mask the effects of intoxication -- Learned behavior? *Conditioned tolerance* - Environmental cues associated with drug use induce a preemptive, reflexive compensatory change -- Seeing drug paraphernalia -> Bradycardia in cocaine user - Unconscious phenomenon which is often the basis for relapse

Buprenorphine in the treatment of opioid addiction

*Buprenorphine* - MOA: 𝜇-opioid partial agonist - Alleviates withdrawal symptoms associated with decreased plasma levels of opioids - Low risk of overdose since it is a partial agonist - Withdrawal from buprenorphine is mild - Likely to replace methadone treatment

Which antidepressants are considered atypical?

*Bupropion* *Mirtazapine* *Trazodone* Atypical antidepressants are newer drugs which do not fit the classical mechanism of the other antidepressants.

Organ effects of opioids

*CNS Effects* (mostly associated with μ receptor) - *Analgesia* - primarily μ receptors - *Euphoria* - μ receptor; κ receptor causes dysphoria - *Sedation* - *Respiratory depression* -- Inhibit respiratory control center in the brain stem -- *Primary cause of death in opioid overdose* - Cough suppression - suppress cough reflex - Miosis - Nausea and vomiting - activation of chemoreceptor trigger zone *Peripheral Effects* - Constipation, bradycardia, hypotension (histamine)

Which drugs *inhibit glucose reabsorption in kidney*, MOA, CU, AE, and CI?

*Canagliflozin, Dapagliflozin, Empagliflozin* *MOA*: *Inhibit Sodium-glucose co-transporter 2 (SGLT2)*. - *Decrease glucose reabsorption* - *Increase urinary glucose excretion* - *Works in the proximal convoluted tubule* *CU: Type 2 DM*: - Combination with metformin - Reduce major adverse cardiovascular events. *AE*: - *Urinary tract infection* - *Genital infection* - Weight loss - Hypotension - Dehydration - Renal dysfunction *CI:*GFR < 30 ml/min/1.73 m2, end-stage renal disease or patients on dialysis.

Clinical indications, mechanism of action, intoxication symptoms, and withdrawal symptoms of amphetamine

*Clinical Indications* - Attention-deficit hyperactivity disorder (ADHD) - Nasal decongestants - Analeptics - Antidepressants - Diet pills *Mechanism of action* - Mixing acting -- Tyramine-like effect: increases DA and other neurotransmitter release by reversing DAT -- Cocaine-like effect: reuptake inhibitor -- Inhibits MAO *Intoxication* - Euphoria - Grandiosity - Pupillary dilation - Prolonged wakefulness and attention - Hypertension - Tachycardia - Anorexia - Paranoia - Fever *Withdrawal* - Anhedonia - Increased appetite - Hypersomnolence - Existential crisis

What is hypothyroidism, symptoms, and treatment strategy?

*Decreased serum T3 and T4* Symptoms include: - cold intolerance, fatigue, dry skin, unexplained weight gain - mental and memory impairment - slowed heart rate *Treatment Strategy*: replaces deficient thyroid hormone

Which drugs are benzodiazepines, clinical indications? Adverse effects? Paradoxical reaction? Metabolism?

*Diazepam, midazolam, alprazolam, oxazepam, temazepam, and lorazepam* *Clinical indications*: - Sedative (anxiolytic), hypnotic (insomnia) - Induction of anesthesia (midazolam) - Status epilepticus (lorazepam, diazepam) - Alcohol withdrawal - Spasticity *Adverse effects*: - CNS depression - Respiratory depression - Sedation -- Overdose can be treated with flumazenil Tolerance and dependence *Paradoxical reaction* - a rare but serious behavioral adverse effect in which the patient exhibits extreme behaviors - Emotional outburst - Delirium - Behavioral disinhibition - Aggression - Violence -- Reversible with *flumazenil* - Most are metabolized by phase I CYP enzymes to active metabolites - Metabolites of chlordiazepoxide, *diazepam*, and flurazepam are long-acting - Metabolites of *midazolam*, *alprazolam*, and *triazolam* are short-acting - *Oxazepam*, *temazepam*, and *lorazepam* do not have metabolites and are directly conjugated for elimination (*Out ThE Liver*) -- Since phase II biotransformation is less likely to be affected by hepatic insufficiency, this group of agents is more useful for elderly individuals or people with reduced liver function

What is hyperthyroidism, symptoms, and treatment strategy?

*Elevated serum T3 and T4* Symptoms include: - heat intolerance, anxiety, sweating, weight loss - increased metabolic rate - increased heart rate *Treatment Strategy*: inhibits thyroid hormone synthesis and action

Etomidate mechanism of action and side effects

*Etomidate* *Mechanism of action* - Potentiation of GABAa receptors -- No analgesic properties Side effects - Nausea and vomiting - Increased EEG activity -> seizures - Cardiovascular stability -- Advantageous over sedative-hypnotics for patients prone to hemodynamic instability - Inhibits adrenal enzymes required for cortisol and other steroid production - Safe for induction, but not recommended for long-term infusion (major limitation).

What can be used in situations of benzodiazepine and ZZZ agent overdose?

*Flumazenil* Flumazenil, benzodiazepine antagonist, can be used in situations of benzodiazepine and ZZZ agent overdose Not effective in barbiturate overdose.

What are the classifications of seizures?

*Focal* - Symptoms vary depending on the location of the focus -- Can involve motor, sensory, emotional manifestations - Ipsilateral, can progress to generalized seizure - Consciousness is a sub-classification *Primary Generalized* - Bilateral seizure activity - Multiple different manifestations

What are the rapid acting insulin?

*Glulisine* *Aspart* *Lispro* Don't have to memorize the positions.

What hormones do incretins target, what is the function of incretins?

*Gut hormones* - Glucagon-like peptide-1 (*GLP-1*) - Glucose-dependent insulinotropic peptide (*GIP*) - GLP-1 and GIP are rapidly degraded by dipeptidyl peptidase-4 (*DDP-4*) -Functions: *Decrease blood glucose levels* 1. *Increase Glucose-dependent* insulin release 2. Decrease glucagon release 3. Decrease gastric emptying 4. Decrease appetite.

What are the adverse events of insulin?

*Hypoglycemia* - *Symptoms*: -- Tachycardia, palpitations, sweating, tremulousness, nausea, convulsion, coma. *Treatment* - *Conscious*: sugar-containing beverage or food. - *Unconscious*: -- IV glucose solution -- Glucagon injection then glucose -- Small amount of honey or syrup can be inserted into the buccal pouch. *Hypokalemia* - Insulin increases ATP amount which increases the ATPase pump, pushing more potassium into cells causing hypokalemia (3Na+ out, 2K+ in). *Hypersensitivity* - Allergy (urticarial (hives), anaphylaxis). *Increased cancer risk*

Summary of hypo/hyperthyroidism treatments

*Hypothyroidism treatment*: levothyroxine, Liothyronine *Hyperthyroidism Treatments*: 1. Anti-thyroid drugs: - Methimazole, propylthiouracil - Potassium iodide 2. Radioactive iodine: 131- I 3. Adjunct for symptomatic control: propranolol, esmolol.

What are the indications and side effects of benzodiazepines?

*Indications* - Sedative (anxiolytic), hypnotic (insomnia) - Induction of anesthesia (midazolam) - Preoperative anesthesia (*amnesia*, muscle relaxation) - Status epilepticus (*Lorazepam, diazepam*) - Alcohol detoxification - Night terrors *Side effects* - CNS depression -- Less than barbiturates -- Overdose can be treated with *Flumazenil* - Tolerance and dependence

How do GABA potentiators work?

- Enhanced GABA mediated inhibition decreases excitatory signaling associated with seizure propagation - Two approaches -- Direct action at GABA receptor -- Enzyme inhibition -> Increase GABA - Receptor variety and tissue distribution leads to varied drug effects

What is the mechanism of action, effects, limitations, and side effects of Ketamine

*Ketamine* "Dissociative anesthetic" *Mechanism of action* - Noncompetitive inhibition of NMDA receptors -- Produces significant analgesia Induces a cataleptic state - Nystagmus with pupillary dilation - Spontaneous limb movement - Analgesia - Amnesia Emergence delirium - Hallucinations - Vivid dreams - Delusions - Characterized by many as out of body experience or complete apathy Limitations - Patient dissatisfaction in adults - *Useful in pediatric patients*- lower incidence and less severe side effects. Side effects: - *Indirect sympathomimetic activity* -- Inhibits central and peripheral catecholamine reuptake; increased BP, HR, and cardiac output. --- Useful in patients at risk of hypotension during anesthesia. - Comparably less respiratory depression than other anesthetics - *Potent bronchodilator* -- Useful in patients at high risk of bronchospasm.

What is the MOA and clinical indications of Lithium?

*MOA* - Inhibits phosphatidylinositol cycle second messenger systems, which evidence suggests dampens excitatory neurotransmission - Inhibits postsynaptic D2 receptor super-sensitivity - Alters cation transport in nerve and muscle cells and influences reuptake of serotonin or norepinephrine *Clinical indications*: - Acute manic episode - Bipolar disorder (drug of choice)

What is the MOA, CU, and AE of Thioamides: Propylthiouracil, Methimazole

*MOA*: - Inhibits thyroid peroxidase - Blocks iodine organification and coupling reactions - Decreases thyroid hormone synthesis - *Propylthiouracil* also inhibits *peripheral deiodination* of *T4 to T3*. Effects seen after 4-6 weeks, after TH stores have depleted. *CU*: - *Methimazole*: generally preferred over propylthiouracil due to less serious adverse effects - *Propylthiouracil* is preferred in two clinical settings: -- *Thyroid crisis/storm*: exacerbation of hyperthyroidism --- Acute, life-threatening, hypermetabolic states --- Fever, tachycardia, cardiovascular shock, nausea, diarrhea, jaundice, extreme restlessness with wide emotional swings, confusion, psychosis, coma. -- *Pregnancy* --- Propylthiouracil is highly bound to protein and less likely to cross the placenta *AE*: well tolerated - *common*: rash, arthralgias (pain in joint). - *Rare*: -- *agranulocytosis*: (lowered white blood cell count) occur within the first 90 days of treatment --- recommend baseline measurement of white blood cell count --- discontinue immediately if develop fever or a sore throat. -- *hepatotoxicity*: hepatitis, liver failure. -- *autoimmune*: drug-induced lupus.

Methadone

*Methadone*: - Taken orally -> less likely to cause sharp "high" like heroin - Long half-life compared to heroin or morphine - Once-daily administration of methadone produces plasma opioid levels that remain relatively constant over time -> prevent craving and withdrawal symptoms

Intravenous anesthetics characteristics

*More commonly used* than inhalation anesthetics for the induction of anesthesia in adults High lipophilicity results in rapid onset and short duration after a single bolus - Redistribution to muscle group decreases drug levels.

What are the intermediate-acting insulin and pharmokinetics?

*N*eutral *p*rotamine *h*agedorn (*NPH, isophane*) insulin *PK* - Protamine is proteolytically degraded - Slower onset: 2-4h - Prolonged duration: 4-16h - Absorption is highly variable - Has to be inverted or rolled prior to injection to ensure uniform dosage.

What drugs are used in the treatment of opioid addiction?

*Naltrexone* is used in the treatment of opioid and alcohol dependence - *MOA*: Opioid antagonist -> competitively blocks the binding of opioids to the opioid receptor *Methadone* is used in opioid detoxification and severe pain - *MOA*: Long-acting opioid agonist - Produces cross-tolerance to other opioids -- Patient who injects heroin while taking methadone experiences a reduced effect of the injected drug Also has significant abuse potential Risk of death by overdose when methadone is combined with other opioid or CNS depressant

Which drugs are barbiturates, what are their clinical indications, adverse effects, contraindication,

*Phenobarbital, pentobarbital, secobarbital, thiopental* *Clinical indications*: - Sedative (anxiolytic), hypnotic, seizure, induction of anesthesia (thiopental) -- Due to long half-life and therapeutic index -> benzodiazepines have mostly replaced use of barbiturates *Adverse effects*: - *Severe CNS depression*, which can be increased by concurrent use of alcohol -- Respiratory depression -- Cardiovascular depression - Tolerance and dependence -- Overdose is treated with supportive care - primarily respiratory assistance and maintenance of blood pressure Contraindicated in patients with *porphyria* - Barbiturates induce α-aminolevulinate synthase (rate-limiting enzyme in porphyrin biosynthesis) - Symptoms: abdominal pain, sun-exposed blistering lesions, red-wine colored urine

What are the barbiturate drugs, their indications, side effects, and contraindications?

*Phenobarbital, pentobarbital, secobarbital, thiopental*. *Indications*: Sedative (anxiolytic), hypnotic, seizure, induction of anesthesia (thiopental) - Due to long half-life and small therapeutic index -> benzodiazepines have mostly replaced use of barbiturates. *Side effects*: Severe CNS depression - Respiratory depression - Cardiovascular depression Tolerance and dependence *Contraindicated* in patients with porphyria - Barbiturates induce a-aminolevulinate synthase (rate-limiting enzyme in porphyrin biosynthesis) - Symptoms: abdominal pain, sun-exposed blistering lesions, *Red-wine colored urine*.

What are the 3 main symptoms of diabetes mellitus? What is the HbA1c percent and fasting plasma glucose to be considered diabetic?

*Polydipsia*: excessive thirst or excess drinking. *Polyuria*: excessive urination *Polyphagia*: excessive eating.

Which drugs are an *Amylin analogue*, their MOA, PK, CU, and AE?

*Pramlintide* (has amlin in its name). *MOA*: 1. Decrease glucagon release 2. Decrease gastric emptying 3. Decrease appetite *PK*: Subcutaneous immediately before meal. *CU*: insulin-treated type 1 and type 2 DM who are unable to achieve their target postprandial blood glucose levels. *AE*: Nausea, weight loss.

What are the steps and characteristics/symptoms of focal seizures?

1. Excitatory initiation at a cellular level 2. Synchronization of surrounding neurons 3. Spread to adjacent brain regions (Jacksonian March) - Preceded by an aura - Paroxysmal depolarizing shift -- sudden depolarization of a group of neurons - Occur with and without altered level of consciousness - Can involve automatisms -- Wringing of hands -- Fidgeting -- Skilled movements (playing an instrument) Can also spread to both hemispheres of the brain -> secondary generalization

What is the mechanism of action, pharmacokinetics, formulation, and side effects of propofol, fospropofol

*Propofol, fospropofol* *Mechanism of action*: Potentiation of GABAa receptors - Sedative hypnotic effects - No analgesic properties - Can cause euphoria on recovery *Pharmacokinetics* - Liver conjugation - Renal excretion *Formulation* Poorly soluble - Formulated with egg yolk phosphatide -- Allergic reactions are possible Associated with painful injection - Preventable with lidocaine Fospropofol is the water-soluble prodrug form of propofol - Not associated with the adverse effects of propofol. *Side effects* - Produces the most pronounced decrease in systolic blood pressure -- Arterial and venous dilation -- Use caution in patients with low blood pressure - Respiratory depression -- Does not produce bronchospasm --- Choice induction agent in asthmatic patients - Antiemetic (anti-vomiting) effects *Propofol infusion syndrome* - Occurs due to prolonged and high-dose infusion in young or head-injured patients Symptoms: - Metabolic acidosis - Hyperlipidemia - Rhabdomyolysis - Enlarged liver

What are the psychiatric symptoms and physical findings of barbiturate intoxication/overdose

*Psychiatric symptoms* - Delirium - Irritability - Combativeness - Paranoia - Lethargy - Coma - Hypothermia - Decreased pupillary light reflex - Nystagmus *Physical findings* - Respiratory depression - Acute respiratory distress syndrome - Hypoxia - Apnea - Tachycardia/Bradycardia - Hypotension - Decreased bowel sounds Barbiturate overdose and withdrawal There is not antidote to reverse barbiturate effects - Barbiturates are weak acids -- Sodium bicarbonate --- Alkalinize the urine - Symptoms of withdrawal -- Delirium -- Life-threatening cardiovascular collapse

What are the short-acting insulin, pharmakinetics, and clinical indications?

*Regular insulin*: identical to human insulin. *PK*: - Insulin hexamers crystallized around a zinc molecule - Dissociation into monomer is the rate-limiting step for absorption - Delayed onset: 30 min- 1 hour. - Prolonged duration: 3-6 hours. *CU*: - *DM:* 30-45 minutes before meal, prandial bolus insulin - *Diabetic ketoacidosis* -- *only type that should be administered intravenously*

What is tetrodotoxin and its mechanism of action?

*Tetrodotoxin* Toxin is produced by marine bacterium and accumulates in the puffer fish - Delicacy in Japan partly due to tingling sensation following eating its flesh Mechanism of Action - Unlike local anesthetics; blocks sodium channels from the extracellular side -- Causes paralysis of the respiratory muscle

What drugs are used in anti-thyroid drug therapy (for hyperthyroidism)?

*Thioamides: Propylthiouracil, Methimazole* - Thionamides in the pharm book. *Potassium Iodide* *B-adrenergic blockers: Propranolol, Esmolol, Metoprolol, Atenolol.* (adjunct for symptomatic control)

What are the 6 methods of administration for local anesthetics?

*Topical*: - Applied to skin, mucous membrane, or cornea before venipuncture or minor surgery *Infiltration*: - Intradermal or subcutaneous injection for minor surgery in conjunction with epinephrine- frequently used in dental procedures *Iontophoresis*: - Use of small electrical current to force the anesthetic into the tissue *Nerve block*: - Injection into or adjacent to a peripheral nerve or nerve plexis to block sensory conduction from that area *Spinal intrathecal anesthesia:* - Injection into the subarachnoid, intrathecal space below the level at which the spinal cord terminates; primarily for surgery on the lower limb or pelvic structures. Can cause *headaches* associated with cerebrospinal fluid leakage from the lumbar puncture, *respiratory depression* if anesthetic ascends too high up the spinal cord. Also may *increase risk of infection* or meningitis *Epidural anesthesia*: - Injection into the lumbar or caudal epidural space to provide anesthesia during labor and delivery

Drug-drug interaction with antiepileptic drugs

*Valproic acid* - Decreases clearance of ethosuximide and lamotrigine - Displaces phenytoin from plasma protein -> increased phenytoin plasma concentration - Inhibits metabolism of: Phenytoin, carbamazepine, and phenobarbital -- Phenobarbital overdose CYP Enzyme inducers/inhibitors - Those AEDs which induce/inhibit CYP enzymes directly affect the metabolism of other drugs

How can you treat nicotine addiction?

*Varenicline* MOA: Partial agonist at a specific subtype of nicotinic acetylcholine receptors Acts as a pharmacologic antagonist at nicotinic receptors in the presence of the full agonist nicotine - Mitigates the dopamine-enhancing effects of nicotine - Similar mechanism of action to buprenorphine treatment of opioid addiction Increases mesolimbic dopaminergic neurotransmission ------------------------------------ *Bupropion* MOA: inhibition of the reuptake of dopamine and norepinephrine Decrease the reward pathway associated with smoking - Buffers withdrawal cravings Adverse effect: - Lowers the seizure threshold

What are the ZZZ agents, what are their indications and mechanisms of action?

*Zolpidem*, *Zaleplon*, *Eszopiclone* Indication: - Insomnia Mechanism of Action: Selective GABAa a1 subunit. - Lack anxiolytic activity - Less effect on sleep architecture - Less potential for tolerance and dependence Overdose can be reversed with *flumazenil* Rapid metabolism -> short duration of action - Reduced daytime sedation and hangover -- Eszopiclone is associated with next-day reduction in alertness - Few amnestic effects The long-term use of treatment is not a recommended practice - Persistent insomnia may indicate psychiatric illness.

Depression statistics

- 8.1% prevalence - persons age 20 and older had depression for a period of 2-weeks or more - Women are 2x more likely than men to have had depression - 16.1 million people aged 18 and older have experienced a major depressive episode in the last year - About 80% of adults with depression reported at least some difficulty with work, home, and social activities because of their depression - 13.42 per 100,000 deaths were suicides (2016) -- Highest suicide rate is in adults aged 45-54 -- Men are 3.53x more likely to die by suicide than women

Severe presentation of Alzheimer's Disease

- All the previous symptoms, including the following: -- Weight loss -- Seizures, skin infections, difficulty swallowing -- Groaning, moaning, or grunting -- Increased sleeping -- Lack of bladder and bowel control

Comorbidities with depression?

- Anxiety/panic disorders - Chronic pain - Coronary artery disease - Chronic physical diseases -- Hypertension -- Diabetes -- Cerebrovascular disease -- End-stage renal disease -- Chronic obstructive pulmonary disease -- Congestive heart failure - Any disease state with a poor prognosis or adverse implications for quality of life

What is epilepsy

- Epilepsy is the 3rd most common neurological disorder in the world - Effects ~2.5 million in the USA - One of the first descriptions of epileptic seizures can be traced back to 2,000 B.C. in Mesopotamia -- Consistent with B.C. Babylonian and Egyptian texts - Epilepsy is a broad diagnosis for seizure disorders of different etiologies characterized by recurrent seizures Any individual can have a seizure - Acute seizures often have known causes -- Injury -- Brain tumor -- Toxicity/Withdrawal - One seizure does not constitute a diagnosis of Epilepsy -- When normal EEG (electroencephalogram) and no family history of epilepsy; only 15% of acute first seizures will result in epilepsy diagnosis (same as risk of adverse drug effect) Pharmacotherapy strategy should begin with monotherapy - Some patients may not be managed well on monotherapy

Caffeine withdrawal

- Fatigue and sleepiness - Depression - Tiredness - Headaches - Anxiety and nervousness - Concentration impairment - Muscle pain and stiffness - Flu-like symptoms - Insomnia - Constipation Caffeine dependence can develop in as little as 1 week of continuous use. Symptom of withdrawal typically begin 12-24 hours after cessation and can last up to 1 week.

How do glutamate receptor inhibitor drugs work?

- Glutamate is the principal excitatory neurotransmitter in the CNS - Over excitement is mediated through glutamate - NMDA and AMPA receptor subtypes - Behavioral side effects make use of glutamate receptor inhibitors a poor clinical option

Rate of opioid related overdose deaths in pennsylvania

- Heroin overdose deaths have increased from 131 to 926 - Synthetic opioid overdose deaths have increased from 98 to 1309 - Prescription opioid overdose deaths have increased from 411 to 729

Moderate presentation of Alzheimer's Disease

- Increasing memory loss and confusion - Shortened attention span - Problems recognizing friends and family members - Difficulty with language; problems with reading, writing, working with numbers - Difficulty organizing thoughts and thinking logically - Inability to learn new things or to cope with new or unexpected situations - Restlessness, agitation, anxiety, tearfulness, wandering, especially in the late afternoon or at night - Repetitive statements or movement; occasional muscle twitches - Hallucinations, delusions, suspiciousness or paranoia, irritability - Loss of impulse control (shown through behavior such as undressing at inappropriate times or places or vulgar language) - Perceptual-motor problems (such as trouble getting out of a chair or setting the table)

Mild presentation of Alzheimer's Disease

- Memory loss - Confusion about the location of familiar places -- Getting lost easily begins to occur - Taking longer to accomplish normal daily tasks - Trouble handling money and paying bills - Compromised judgment often leading to bad decisions - Loss of spontaneity and sense of initiative - Mood and personality changes -- Increased anxiety

What are voltage-gated Na+ channels?

- Na+ channels adopt the inactivated state in response to depolarization, action potentials are intrinsically self-limiting - Na+ channels will not recover from the inactivated state until the membrane is sufficiently repolarized. - K+ channel opening repolarizes the cell, but the high K+ efflux transiently hyperpolarizes the membrane beyond its resting potential, further increasing the time before a new action potential can be generated.

Alzheimer's disease

- Range of conditions that are characterized by progressive degeneration of the structure and function of the central nervous system or peripheral nervous system - Incurable, debilitating conditions -- Little to no way to cure or slow disease progress - Dementias are responsible for the greatest disease burden -- AD represents ~60-70% of dementia cases - 6th leading cause of death in the US - 5.7 million Americans in 2018 -- Projected to be 14 million by 2050 - 1/10 people over the age of 65 -- 2/3 are women - 16.1 million Americans provide unpaid care for people with AD or dementia - From 2000-2015, deaths from heart disease have decreased by 11%, while deaths from AD have increased 123% - AD is a type of progressive memory impairment, dementia, and cognitive dysfunction -- Loss of hippocampal and cortical neurons that leads to impairment of memory and cognitive ability - Associated with more than 100,000 deaths per year - Tremendous negative impact on patients and family due to devastating effects on cognitive, emotional, and physical function - Annual cost of dementia in the United States is estimated at $150-$223 billion annually - Early onset AD is associated with several gene defects - No known cause and no known cure

Other considerations for anxiety

- Social Emotional -- Support system -- Structure -- Employment status CHANGE! - Upcoming/Recent Events -- Job interview or promotion -- Public speaking -- Board examinations

What is the distinguishing feature between major depression and bipolar disorder? What are the common comorbidies of bipolar disorder, how many of these patients commit suicide?

- The distinguishing feature between major depression and bipolar disorder is mania -- Mania is a period of elevated mood, during which the patient may present as irritable. Common comorbidities include: - Anxiety disorder - Attention deficit disorder - Eating disorders Research reports that approximately 10-15% of patients will commit suicide

Treatment for Alzheimer's Disease

- The goal of pharmacological therapy is to treat the symptoms - The standard medical treatment includes cholinesterase inhibitors and a partial NMDA antagonist - Secondary symptoms can be treated with: -- Antidepressants -- Anxiolytics -- Antiparkinsonian agents -- β-blockers -- Antiepileptic drugs Treatment of mild to moderate AD: - Maintain highest levels of cognitive and functional ability possible - Cholinesterase inhibitors and mental exercises are used to prevent deterioration of cognition - Cholinesterase inhibitors - improve cholinergic neurotransmission in affected areas of the brain -- *Donepezil* - reversible inhibition of AChE -- *Rivastigmine* - newer, centrally acting, reversible cholinesterase inhibitor --- Significantly delays global cognitive impairment associated with AD for 6 months -- *Galantamine* - Mentally challenging activities may slow rate of disease -- Crossword puzzles -- Brainteasers

What are the 3 ways to treat hyperthyroidism?

1. *Anti-thyroid drug therapy* - Most useful for young patients with small glands and mild disease. - Only therapy that leaves intact thyroid gland - Require long period of treatment (12-18 months) 2. *Destruction of gland with radioactive iodine* - Preferred for most patients > 21 years old. 3. *Thyroidectomy* - Treatment of choice for very large glands.

What are the 6 types of antidiabetic agents?

1. *Insulin sensitizer* a) Metformin b) Glitazones (aka thiazolidinediones) 2. *Insulin secretagogues* a) Sulfonylureas b) Glinides 3. *Incretins* a) Glucagon-like peptide-1 [GLP-1] receptor agonists b) Dipeptidyl peptidase-4 [DPP-4] inhibitors 4. *Inhibit intestinal absorption of glucose* a) α-glucosidase inhibitors 5. *Amylin analogue* 6. *Inhibit reabsorption of glucose in the kidney* a) sodium-glucose co-transporter 2 [SGLT2] inhibitors

What are the 3 delivery systems of insulin?

1. *Subcutaneously injected*: - Insulin syringe - Portable pen - Insulin pumps 2. *Intravenously infusion:* - Hyperglycemic emergencies 3. *Inhaled*: - A dry powder of regular insulin (Afrezza). - *CI: Asthma, COPD, smoker*.

What are the symptoms of systemic toxicity associated with local anesthetic use?

1. CNS Toxicity - Early symptoms: circumoral (surrounding mouth) and tongue numbness, and a metallic taste - High concentration causes CNS stimulation -- Restlessness, tremor, seizures -> Respiratory depression 2. Cardiotoxicity - closely associated with lipophilic and potent anesthetics (bupivacaine) - Reduces electric excitability, conduction rate, and force of contraction

What causes a seizure?

A seizure results when a sudden imbalance occurs between the excitatory and inhibitory forces within the network of cortical neurons in favor of a sudden-onset net excitation. Rapid synchronized excitatory signaling Spreads uncontrollably Two major elements involved in neuronal function/dysfunction - Receptor(s) - Neuronal network Any defect or insult to either can lead to seizure propagation.

Addiction

A condition in which a person engages in use of a substance or in a behavior for which the rewarding effects provide a compelling incentive to repeatedly pursue the behavior despite detrimental consequences - Change to brain structure and function - Can be long-lasting and lead to the harmful behaviors seen in people who abuse drugs Association of dopamine transporter reduction with psychomotor impairment in methamphetamine abusers

What is the criteria for manic episode

A distinct period of abnormally and persistently elevated, expansive, or irritable mood. Characteristics (3 or more per DMS-IV): - Inflated self-esteem - Decreased need for sleep - More talkative or pressure to continue talking - Flight of ideas, or subjective experience that thoughts are racing - Distractibility - Increase in goal-directed activity - Excessive involvement in pleasurable activities that have a high potential for painful consequences -- Foolish impulsive investments, unrestrained buying sprees, sexual indiscretions

Alzheimer's Disease Summary

AD is a progressive loss of cholinergic neurons resulting in progressive memory impairment, dementia, and cognitive dysfunction Symptoms are largely a loss of cognition Treatment is aimed at increasing cholinergic transmission and preventing neuronal damage - Cholinesterase inhibitors - NMDA antagonist

What is the absorption, distribution, metabolism, and excretion of the sedative-hypnotic drugs?

Absorption - Varies based on lipophilicity of the drug - Many of the sedative-hypnotic drugs are rapidly absorbed following oral administration Distribution - Sedative-hypnotics cross the placental barrier. - Also detected in breast milk -- Depressed vital functions in neonate -- Avoided in pregnancy and nursing mothers. Metabolism - All sedative-hypnotics (anxiolytics) require CYP enzymes for biotransformation -> clearance. -- A small percentage of barbiturates are excreted unchanged. - Barbiturates *induce* CYP enzymes - Benzodiazepines *inhibit* CYP enzymes Excretion - Phase II conjugates of phase I metabolites are excreted by the kidneys. The elderly and those with severe liver disease have increased drug half-life -> increased sedative effects and CNS depression.

What are the factors that alter drug movement of local anesthetics?

Acidic pH medium will convert local anesthetics (weak bases) to more protonated form (charged form) Protonated (charged) form is less likely to permeate through the cell membrane to reach its site of action in the cytoplasmic pore - In infected tissue (acidic medium), local anesthetics become charged and cannot permeate - Require more anesthetic!!

Discontinuing pharmacotherapy: Antiepileptics

After a two to four-year seizure free interval, it is reasonable to consider discontinuing antiseizure drugs This decision must weigh the risk of seizure recurrence against the possible benefits of drug withdrawal - Quality of life Risk of seizure recurrence - Identifiable brain disease - Multiple seizure types - Poor initial response to pharmacotherapy - Polytherapy - EEG or MRI findings - Family history of epilepsy Drugs must be tapered off slowly to minimize the risk of seizure - Benzodiazepines and phenobarbital must be tapered slowly If patient is being treated with polytherapy taper one drug at a time Withdrawal seizures and alcoholic hallucinations (hallucinations that develop within 12 - 24 h and resolve within 24 - 48 h) Delirium Tremens (DTs): hallucinations, disorientation, tachycardia, hypertension, fever, agitation, and diaphoresis. Symptoms can persist for up to 7d

Acute treatment of depression

Acute treatment results in an increased concentration of serotonin in the synaptic cleft. However, negative feedback inhibition will decrease the amount of neurotransmitter released in response to the elevated serotonin levels.

Alcohol

Alcohol abuse stands as the most prevalent drug problem in the United States - Early intoxication, CNS stimulation and euphoria result from inhibitory control - Aspects of discrimination, memory, and insight - Increases in blood alcohol level result in impairment in judgment, emotional control, and motor coordination - Respiratory depression and death can result from overdose -- Aspiration risk Alcohol modulated GABA activity at GABAA and inhibits specific subtypes of NMDA receptors - GABA effect mediates anxiolytic and sedative effects - NMDA effect plays a role in tolerance and dependence - Rewarding effects of alcohol may be mediated by indirect activation of cannabinoid receptors -- Act as a feedback mechanism to enhance dopaminergic activity in the reward pathway -- Endocannabinoid signaling has been implicated in reward learning, appetite regulation, mood regulation, pain modulation, and cognition

Alcohol summary

Alcohol withdrawal can be fatal! - Liver function must be assessed in treatment of withdrawal - MOA: GABAA modulator, NMDA antagonist, and cannabinoid activity - Treat withdrawal with benzodiazepines

Bupivicaine characteristics

Amide-type *Bupivicaine*- lipophilic, potent, long duration of action (prolonged binding). - *Associated with cardiotoxicity* -- Lead to the development of levobupivicaine and ropivacaine (less potent) - Sensory block > motor block -- Useful for prolonged analgesia during labor

Lidocaine characteristics

Amide-type *Lidocaine* - Prototypical amide local anesthetic - High incidence of *transient neurological symptoms* when used as spinal anesthetic - Lowest incidence of adverse effects of local anesthetics - Used as an *antiarrhythmic*

Mepivacaine characteristics

Amide-type *Mepivacaine* - Due to its pKa (7.6), more likely to be ion-trapped in the neonate due to lower pH in neonatal blood -- Not used in obstetrical anesthesia.

Analgesia vs anesthesia

Analgesics are specific for the *inhibition of pain* Anesthesia is inhibition of pain, paralysis, amnesia, and unconsciousness Local anesthetics are a set of locally applied agents which *inhibit the perception of pain* and prevent movement (voluntary and involuntary) - Inhibit action potentials in all afferent and efferent nerve fibers.

What is the MOA and CU of B-adrenergic blockers: propranolo, esmolol, metoprolol, and atenolol?

Anti-thyroid drug therapy *B-adrenergic blockers: Propranolol, Esmolol, Metoprolol, Atenolol* *MOA*: treat symptoms of hyperthyroidism. - Severe hyperthyroidism resembles nonspecific B-adrenergic stimulation: tremor, tachycardia. - B-adrenergic blockers control heart rate -- *Propranolol* also inhibit peripheral conversion from *T4 to T3*. *CU*: thyroid storm.

What is the MOA, CU, and AE of potassium iodide.

Anti-thyroid drug therapy (for treatment of hyperthyroidism). *Potassium Iodide* *MOA: Wolff-Chaikoff effect* - Excess iodine transiently inhibits thyroid hormone synthesis and release. - Reduces the size and vascularity of the thyroid gland *CU*: used before thyroid gland surgery - Leads to easier excision of the gland *AE*: uncommon, reversible - Acneiform rash, swollen salivary glands.

Anxiety symptoms

Anxiety is a normal and necessary response for good functioning. - Homeostasis - amygdala - Disorder - symptoms interfere with daily life Symptoms: - Subjective -- Worry, apprehension, edginess, tension - Behavioral -- Distractibility, hypervigilance, insomnia, self-consciousness, social withdrawal - Motor -- Shakiness, trembling, fatigability, fidgeting, elevated tonus - Autonomic -- Increased BP and HR, sweating, upset stomach, diarrhea, dry mouth

What is anxiety

Anxiety is an unpleasant state of mind, characterized by a sense of dread and fear - May be based on actual anticipated experiences or past experiences - May be exaggerated responses to imaginary negative situations 19.1% of U.S. adults had any anxiety disorder in the past year An estimated 31.1% of U.S. adults experience any anxiety disorder at some time in their lives

What drugs are anxiolytic drugs

Anxiolytic drugs reduce anxiety and exert a calming effect. - The mechanism of action of these drugs make some compounds more selective for the treatment of anxiety

Anxiolytic classification

Anxiolytics can be chemically classified: - Barbiturates (GABAergic drug) - Benzodiazepines (GABAergic drug) - Pure anxiolytic (Buspirone) -- Does not produce sedation or hypnosis Selective serotonin reuptake inhibitors (SSRIs) are also indicated in the treatment of anxiety - Use is limited to long term treatment as they are not effective for acute anxiety relief

Structure and function of local anesthetics

Aromatic groups confers hydrophobicity (lipophilicity) - Drug movement to the cytoplasmic side of the voltage-gated Na+ channels Amine group determines ionization state - Weak bases- BH+ ⇄ B

What is the MOA, clinical indications, black box warning, adverse effects of Trazodone

Atypical antidepressant *Trazodone* *MOA*: selective 5- HT2A/2C antagonist - Antagonist of histamine and α1 receptors *Clinical indications*: - Depression - high doses are required to attain the antidepressant effects of trazodone -- Onset of action is approximately 6-weeks for antidepressant effects - Off-label uses include: -- Insomnia (primary use) -- Aggressive behavior -- Cocaine and alcohol withdrawal -- Migraine prophylaxis *Black box warning* - Increased risk of suicidal thinking and behavior in children, adolescents, and young adults (<24 years) taking antidepressants for major depressive disorders -- Effects were not observed in patients >24 year old -- A slight decrease in suicidal thinking was seen in adults >65 years *Adverse effects*: - *Priapism* - Sedation - antihistamine effects - Postural hypotension - α1 antagonism - Dizziness - Dry mouth

What is the MOA, clinical indications, black box warning, and adverse effects of Mirtazapine?

Atypical antidepressants *Mirtazapine* *MOA*: - potent 5-HT2A/2C, 5-HT3, and histamine receptor antagonist - α2 auto-receptor antagonist, which results in increased release of norepinephrine *Clinical indications*: - Depression - Off label uses include: -- Insomnia -- PTSD -- Hot flashes *Black box warning* - Increased risk of suicidal thinking and behavior in children, adolescents, and young adults (<24 years) taking antidepressants for major depressive disorders -- Effects were not observed in patients >24 year old -- A slight decrease in suicidal thinking was seen in adults >65 years *Adverse effects*: - Sedation - antihistamine effects - Dry mouth - antagonism of α1 - Anti-muscarinic effects - Weight gain and increased appetite - which make it useful in the treatment of the elderly and anorexic patients

What is the mechanism of action, clinical indications, black box warning, and adverse effects of Bupropion

Atypical antidepressants *Bupropion* *MOA* - Mechanism of action is not well understood. -- Described as a norepinephrine (NET) and dopamine (DAT) reuptake inhibitor - Nicotinic acetylcholine receptor agonist. *Clinical indications* - Depression - Smoking cessation. *Black box warning* - Increased risk of suicidal thinking and behavior in children, adolescents, and young adults (<24 years) taking antidepressants for major depressive disorders -- Effects were not observed in patients >24 year old - Serious neuropsychiatric events, including, but not limited to; depression, suicidal ideation, suicide attempt, and completed suicide, have been reported in patients taking bupropion for smoking cessation *Adverse effects*: - Decreased seizure threshold -:> contraindicated in patients with a seizure disorder - Electrolyte imbalances -> contraindicated in patients with a history of an eating disorder, or those discontinuing ethanol, sedatives, or antiepileptic drugs as these patients are already predisposed to electrolyte imbalances - Stimulant like effects -- Insomnia -- Tachycardia - Headache - Bupropion lacks the sexual side effects noted in the other antidepressants.

What is the mechanism of action, indications, pharmacokinetics, and adverse effects of Ethosuximide

Calcium channel inhibitors *Ethosuximide* *Mechanism of action*: - Reduces low threshold T-type Calcium channels in voltage dependent manner -- Does not effect voltage dependence or recovery of Na+ channels *Indications* - Absence seizures (*1st line*) - Not effective for treatment of focal or secondary-generalized seizures *Pharmacokinetics*: - Hepatic metabolism - Renal clearance -- Monitor patient liver and kidney function - Reduced clearance when administered with Valproic acid (CYP inhibition) *Adverse Effects* - GI effects - Fatigue - Headache - Urticaria - Stevens-Johnson syndrome - Suicidal thoughts and intentions - Hematologic effects

Mechanism of action of GABAergic anxiolytics?

Barbiturates and benzodiazepines are GABAA modulators - *MOA*: enhance the action of endogenous GABA (inhibitory neurotransmitter) on GABAA receptor - Barbiturates can directly activate the GABAA channel at high concentrations The anxiolytic effects are achieved by dose-dependent inhibition of CNS - Dose-dependent increased depression of the CNS can shift a drug from an anxiolytic sedative to hypnotic (sleep inducer) Barbiturates and benzodiazepines GABAA receptor - Cl- channel activated by γ-aminobutyric acid (GABA) - GABAA is pentameric -- Contains 2α, 2β, γ subunits - Benzodiazepines bind to α subunit - Barbiturates have a distinct binding site Barbiturate *MOA*: increase *duration* of GABAA channel opening in response to GABA increased Cl- conductance - At higher concentrations barbiturates can directly activate Cl- channels Benzodiazepine *MOA*: increase *frequency* of GABAA channel opening in response to GABA increased Cl- conductance - *Flumazenil*, benzodiazepine antagonist, can be used in situations of benzodiazepine overdose - characterized by severe sedation and respiratory depression -- Not effective in barbiturate overdose

Pharmacodynamics of GABAergic anxiolytics benzodiazepine and barbiturates?

Barbiturates have a much narrower therapeutic index than benzodiazepines. Barbiturates cause cardio and respiratory depression which can lead to coma and death. For this reason their use as an anxiolytic is limited.

What are the actions of barbiturates vs benzodiazepines on GABAa channel?

Barbiturates increase *duration* of GABAa channel opening -> increase Cl- conductance. - At higher concentrations barbiturates can directly activate Cl- channels. Benzodiazepines increase *frequency* of GABAa channel opening -> increased Cl- conductance

What are the pharmacodynamics of sedative-hypnotics

Barbiturates, benzodiazepines, and ZZZ agents all bind to the GABAa receptor. - Cl- channel activated by y-aminobutyric acid (GABA) - GABAa is pentameric -- Contains 2a, 2b,y subunits. Benzodiazepines bind to α subunit ZZZ agents are α1-selective Barbiturates have a distinct binding site.

Which sedative-hypnotics are GABAa modulators?

Barbiturates, benzodiazepines, and ZZZ agents are GABAa modulators. - Enhance the action of endogenous GABA (inhibitory neurotransmitter) on GABAa receptor. -- Barbiturates can directly activate GABAa channel at high concentrations --- Linear dose response -> coma. (GABAa receptors are ligand-gated ion channels (also known as ionotropic receptors) and triggers opening of chloride-ion sensitive pore)

Mechanism of action, pharmacokinetics, and side effects of Thiopental

Barbiturates: *Thiopental* *Mechanism of action* - Potentiation of GABAa receptors- duration -- No analgesic properties *Pharmacokinetics* - Highly lipophilic, accumulates in fat -- Very high context-sensitive half-time -- Good for induction, not preferred for maintenance of anesthesia. *Side effects* - Nausea and vomiting - Suppresses EEG activity - Dose-dependent decrease in BP - Respiratory depression -- Also cause release of histamine from mast cells ---- Use caution in asthmatics.

Mechanism of action, indications, pharmacokinetics, and side effects of midazolam

Benzodiazepine: *Midazolam* *Mechanism of action* - Potentiation of GABAa receptors- frequency -- No analgesic properties *Indications* - Preoperative; amnestic, anxiolytic, and sedative *Pharmacokinetics* - High lipid solubility -> rapid induction - Midazolam is the only benzodiazepine suitable for continuous infusion -- Shortest context-sensitive half-time of benzodiazepines. *Side effects* - Decreased blood pressure - Minimal respiratory depression -- Severe respiratory depression when used in combination with opioids --- Overdose -> Flumazenil

What drugs are used in the treatment of alcohol addiction

Benzodiazepines (Lorazepam) - Control psychomotor agitation - Prevent progression of severe withdrawal symptoms Acamprosate - MOA: antagonist of NMDA glutamate receptors - Used to maintain abstinence Topiramate - MOA: inhibits AMPA/kainate glutamate receptors *Disulfiram* inhibits aldehyde dehydrogenase, a critical enzyme in the alcohol metabolism pathway - If an individual ingests ethanol while taking disulfiram, acetaldehyde accumulates (toxic metabolite) - Acetaldehyde causes facial flushing, headache, nausea, vomiting, weakness, orthostatic hypotension, and respiratory difficulty

Theraputic index of benzodiazepines vs barbiturates?

Benzodiazepines have a better therapeutic index.

3 factors for addiction

Biological - Drugs alter the chemistry of the brain and body functioning Continued use can cause damage or injury to vital organs Psychological - Altered brain chemistry affects the brain's ability to think, alters feeling states, and impacts the personality of the user Sociological - Behavioral interactions with family and social contacts are altered and/or misinterpreted by the user and those observing the behavior Psychiatric comoridities are common - Genetic determinants - Environmental determinants "Genetics load the gun, environment pulls the trigger"

Mechanism of action of cocaine

Blocks the dopamine transporter (DAT) - Increases DA in the NAc which leads to euphoria - Higher concentrations inhibit the serotonin transporter (SERT) and the norepinephrine transporter (NET) In PNS, cocaine inhibits voltage-gated Na+ channels can cause fatal cardiac arrhythmias

What are the side effects of inhaled anesthetics in the Cardiovascular system?

Cardiovascular system *Depressed cardiac contractility* Decreased cardiac output - Decreased mean arterial pressure - Trigger baroreceptor reflex -> increased heart rate -- Enflurane and sevoflurane attenuate baroreceptor input -> *No increase in heart rate* Nitrous oxide activates the sympathetic nervous system -> *maintaining cardiac output* - Use in combination with halogenated anesthetics to decrease cardiac depression Halothane sensitizes the heart to catecholamines -> Increased risk of *cardiac dysrhythmias*.

Adverse effects: bone health in antiepileptic drugs, which ones most responsible, etc? Recommendations?

Both epilepsy and AEDs are associated with adverse effects on bone health. Persons with epilepsy treated with AEDs have increased rates of bone loss and abnormalities in bone and mineral metabolism - Contribute to increased risk of bone fracture -- osteomalacia/rickets -- osteoporosis or low bone mass *Phenytoin, carbamazepine, phenobarbital, and valproic acid* Multiple hypotheses - CYP induction -> increased catabolism of vitamin D - Changes to bone and mineral metabolism -- *Valproic acid* - CYP inhibitor --- Dose and duration of therapy are directly associated --- Consistent reports bone loss, abnormal biochemical indices of bone and mineral metabolism, and higher fracture rates --- Cell culture studies; suppressed cartilage formation (longitudinal bone growth) and accelerated ossification of growth plate. *Topiramate* - carbonic anhydrase inhibitor - May expect; Metabolic acidosis-> foster dissolution of calcium and decreased bone formation - Potent inhibitor of osteoclastic bone resorption -- Improved bone mineral density *Recommendations* - Lifestyle changes -- Regular weight bearing exercise -- Smoking cessation -- Limited alcohol intake -- Fall prevention measures - Calcium - Vitamin D - Pharmacological interventions have not been well established

Benzodiazepines and Barbiturates

CNS depressant effects of barbiturates is more severe and dangerous than benzodiazepines - Benzodiazepines are GABAA specific Co-occurring dependence on benzodiazepines/barbiturates and alcohol is prevalent - Combination can be fatal due to synergistic depression of cardiorespiratory centers - Benzodiazepines are used in the treatment of alcohol withdrawal -- Alleviate withdrawal symptoms when alcoholics cannot drink

What is the mechanism of action, indications, pharmacokinetics, and adverse effects of gabapentin and pregabalin

Calcium channel inhibitors *Gabapentin and Pregabalin* Gabapentin - one of the first rationally designed antiepileptic drug *Mechanism of action*: - Inhibition of High-voltage-activated Calcium channels - Increased GABA concentration has been reported *Indications* - Used as adjunct - partial and tonic-clonic seizures -- Not as effective as other antiepileptic drugs - *Neuropathic pain* - Fibromyalgia (Pregabalin) *Pharmacokinetics*: - Not metabolized by hepatic enzymes - Cleared by kidney - Drug-drug interactions are limited *Adverse Effects:* - Edema - Viral disease - Ataxia - Nystagmus - Psychiatric (pediatrics) - disordered thoughts, hostile behavior, hyperactive behavior - Suicidal thoughts

What is the mechanism of action, indications, pharmacokinetics, black box warning, and adverse effects of Valproic Acid?

Calcium channel inhibitors *Valproic acid* *Mechanism of action*: - Reduces low threshold T-type Calcium channels in voltage dependent manner - Acts directly on Na+ channels to increase recovery time from inactive state to closed state - Increased GABA concentration has been reported *Indications* - Idiopathic generalized seizures - Absence seizures - Focal or secondary-generalized seizures (alternate to phenytoin or carbamazepine) - Bipolar disorder *Pharmacokinetics*: - Displaces phenytoin from plasma protein - *Inhibits metabolism of phenobarbital, carbamazepine and phenytoin* (Displaces phenytoin so it spikes the plasma concentration- follows zero kinetics so once spiked takes a long time to fix it.) -- Barbiturate induced stupor or coma - Decreases the clearance of lamotrigine *Black Box Warnings* - Idiosyncratic hepatotoxicity - *Teratogen*- Spina bifida - Pancreatitis *Adverse Effects*: - Thrombocytopenia (dose related) (low blood platelet count) - *Tinnitus* -> ototoxicity (deafness) - Alopecia - Asthenia (physical weakness, lack of energy) - Tremor - Weight gain

Cannabinoids

Cannabinoids are compounds derived from Cannabis sativa (marijuana) - Primary psychoactive component of marijuana is Δ9-tetrahydrocannabinol (THC) -- Partial agonist at cannabinoid receptor type 1 (CB1; GPCR) - CB1 receptor is widely distributed within the prefrontal cortex, hippocampus, amygdala, basal ganglia, and cerebellum - Cannabinoid use causes a prompt, generalized "high" characterized by euphoria, laughter, giddiness, and depersonalization -- After 1-2 hours, cognitive functions such as memory, reaction time, coordination, and alertness are compromised Causes a "mellowing" effect

Caffeine symptoms

Coffee, tea, energy drinks, headache relief, powder Symptoms - Agitation, tremor, tachypnea, tachycardia, palpitations, GI upset, cardiac arrhythmia, and seizure - Hypokalemia can occur

Symptoms of Alzheimer's Disease result from?

Symptoms result from the destruction of cholinergic and other neurons in the cortex, limbic structures of brain (amygdala, basal forebrain, and hippocampus) - Cortical atrophy - Neurofibrillary tangles - Neuritic plaques -- Amyloid-β protein

Cocaine

Cocaine is a psychostimulant - Use is consistent over time because it is inexpensive and widely available -- Crack - alkaloid "free base" for smoking -- HCL powder - IV and nasal route of administration - Profound sense of well-being, energy, and optimism when used -- Reinforces use, but can progress to psychomotor agitation, severe paranoia, and even psychosis. Cocaine blocks the direction of neurotransmitter transporters - Dopamine - Norepinephrine - Serotonin Potentiate dopaminergic, adrenergic, and serotonergic neurotransmission Most potent at blocking the dopamine transporter (DAT) - Potency lends to the rapid high-amplitude mood cycling associated with use/abuse -- Elevated mood is followed by listlessness, drowsiness, and depressed mood.

Drug Dependence

Condition where an individual feels compelled to repeatedly administer a psychoactive drug - Physical dependence - avoid physical discomfort or withdrawal - Psychological dependence - need for stimulation, pleasure, or to escape reality Results from mechanisms related to those that produce pharmacodynamic and learned tolerance *Dependence syndrome* results from the need for the drug in the brain to maintain "near-normal" functioning

Nicotine withdrawal

Decreases in plasma levels of nicotine results in a strong and spontaneous withdrawal syndrome *Major symptoms* - Irritability - Anxiety - Autonomic arousal - Intense craving Symptoms are readily relieved by smoking- high rate of relapse

Define status epilepticus, what is the first line treatment for it? What is the 1st line prophylaxis?

Defined as: ≥5 minutes of continuous seizure activity, or more than one seizure without recovery in between - ~20% mortality rate - Few controlled studies regarding treatment -- Empirically developed Benzodiazepines (diazepam, midazolam, lorazepam) are *1st line for status epilepticus* -> Titrate until the seizure subsides - Diazepam is common - stable liquid dosage form, high lipid solubility, limited by time of action due to redistribution - Route of administration -- IV/IO is preferred -- IM -- Buccal/nasal -- Rectal Phenytoin (*1st line prophylaxis*) or valproic acid is added if seizure activity does not subside If unresolved barbiturates and general anesthesia may be used - phenobarbital and propofol

What is the monoamine hypothesis?

Depression is a result of deficiency in cortical and limbic serotonin, norepinephrine, and dopamine - Some studies suggest changes in serotonin and norepinephrine receptor expression -- These finding have been inconsistent All current pharmacotherapies appear to have an effect on the monoamine system

What are the stages of anesthesia?

Diethyl ether was the prototype for induction of anesthesia - Modern anesthesia provides faster induction -> avoiding stage II excitement - Surgical window is between stage III and IV. -- Stage IV risks patient injury or death.

Different states of Na+ channel

Different conformational states of the sodium channel (resting, various closed, open, and inactivated) bind local anesthetics with different affinities Local anesthetics have higher affinity for the *open*, *closed*, and *inactivated* states (use-dependent) Binding prolongs the refractory period, especially in the area of injury, where channels are more active

Long term treatment of depression

Drug efficacy is attained when the auto-receptors on the presynaptic terminal are downregulated, allowing serotonin to be released. Coupled with the reuptake inhibiting drugs, the amount of serotonin in the synapse is drastically increased and the drug effects can be observed.

What do calcium channel inhibitors drugs do in regards to epilepsy?

Drugs target either T-type Calcium channels or High-voltage-gated Calcium channels (HVA) T-type Calcium channel is depolarized and inactive during awake state. - Absence seizures - paroxysmal hyperpolarization activates channel producing characteristic Spike and Wave discharge pattern HVA calcium channels control calcium flux in presynaptic terminal -> regulate neurotransmitter release

Differential functional blockade

During onset, different fiber types are also blocked at different times due to intrinsic susceptibility to blockade Susceptibility of nerve blockade: - Small myelinated > small unmyelinated > large myelinated > large unmyelinated General order for functional deficits are: 1. 1st pain > 2nd pain 2. Temperature 3. Touch 4. Proprioception (pressure, position, or stretch) 5. Skeletal muscle tone and voluntary tension

Benzocaine characteristics

Ester-Type *Benzocaine* - Mostly used topically to prevent systemic adverse effects - *methemoglobinemia* (prevents rbc from carrying oxygen)

Cocaine Characteristics

Ester-type *Cocaine* - Naturally occurring, 1st discovered - Sympathomimetic properties, only anesthetic with vasoconstrictive effects - Due to cardiotoxic (arrhythmia) and abuse (euphoria-producing) potential, primary use is restricted to both topical anesthesia and control bleeding (nose surgery)

Procaine characteristics

Ester-type *Procaine*- 1st synthetic - Use limited by low potency and short duration of action

Tetracaine characteristics

Ester-type *Tetracaine* - Highly lipophilic, long duration of action and potent - Butyl group - allows it to remain in the tissue longer, slow metabolism due to slow release from tissue to blood - Used for peripheral nerve blocks - mostly replaced by bupivacaine

Where does control begin when dealing with epilepsy?

Estimated 10 billion neurons & 1014 synapses - Proper function depends on isolation and regulation Control begins at the level of ion channel and subsequent effect on organized neuronal networks Abnormal ion channel and network function result in rapid, synchronous and uncontrolled spread of electrical activity (seizure)

Neutrotrophic hypothesis and depression

Evidence suggests that depression is associated with a loss of neurotrophic support - Brain-derived neurotrophic factor (BDNF) -- Studies have associated stress and pain with decreased BDNF levels in animals and humans --- Depression has high comorbidity with pain disorders -- Some animal studies have shown stressors to increase BDNF resulting in increased depressive behaviors

Phenylethylamines summary

Example: "club drugs" - MDMA (ecstasy, molly) - MDA MOA: serotonin, dopamine, adrenergic reuptake inhibitors; multiple actions. Clinical signs- euphoria, alertness, hypertension, and hallucinations Structurally related to amphetamines

What is the mechanism of action, indications, pharmacokinetics, back box warning, and adverse effects of Vigabatrin

GABA Potentiator *Vigabatrin* *Mechanism of action*: - Irreversibly inhibits GABA transaminase (degrades neurotransmitter GABA) -- Increases GABA in the brain *Indications* - Refractory focal epilepsy - Infantile spasms *Pharmacokinetics*: - Not extensively metabolized - Excreted by the kidneys -- Renal dose adjustments are necessary - CYP 2C *inducer* -- Co-administration with phenytoin results in decreased phenytoin plasma concentrations *Black Box Warning*:Causes permanent vision loss in infants, children, and adults and includes progressive and permanent bilateral concentric visual field constriction in >30% of patients and ranges in severity from mild to severe, including tunnel vision to within 10 degrees of visual fixation, and can result in disability *Adverse Effects*: - Weight gain - Delayed puberty - Malignant hyperthermia -- Treated with Dantrolene - Stevens-Johnson syndrome - Psychiatric disorders -- Apathy -- Delirium

Rate of elimination of inhaled anesthetics

For agents that are very soluble in blood and tissue, the accumulated amount of inhalation anesthetics prevent blood partial pressures from falling rapidly -> slower rate of elimination For agents that are not very soluble in blood, elimination is rapid.

What is the rate of induction for inhaled anesthetics?

For agents with low solubility in the blood (nitrous oxide) equilibrium is achieved quickly - ↑ rate of induction For agents with higher solubility in the blood; the apparent space which must be filled is larger for the blood compartment Since Pcns is dependent on Pblood, onset of anesthesia is slower for very soluble agents. Rate of induction is dependent on the lipid solubility, or partition coefficient. At equilibrium, partial pressures are equal in all tissues but concentration of anesthetic in each tissue is different.

Thyroid gland characteristics

Functional unit: follicle. Thyroid follicular cells: - Contain TSH receptors - Concentrate iodide - Produce the thyroid hormones -- Thyroxine (T4) -- Triiodo-thyronin (T3) -- Reverse triiodothyronin (rT3 inactive).

What is the mechanism of action, indications, pharmacokinetics, adverse effects, and discontinuation of benzodiazepines?

GABA Potentiators *Benzodiazepines* *Mechanism of action*: • Bind to allosteric (benzodiazepine) site on GABAA receptor - in reticular nucleus - Increases GABAA affinity for the GABA receptor and increases *frequency* of channel opening increased Cl- conductance. *Indications* • *Acute seizure activity* • Generalized convulsive status epilepticus - IV - lorazepam (1st line) or diazepam - IM/nasal/buccal - midazolam • Focal seizures • Tonic-clonic seizures Spasticity *Pharmacokinetics*: •Hepatic metabolism (CYP 3A4) - Rate and metabolic pathway is drug specific - Many active metabolites •Clearance of parent drug may not correlate to clinical effects -> excessive sedation •Tolerance develops *Adverse Effects*: - *Teratogen* - facial cleft and cardiac malformations -- FDA: risk of discontinuing drug therapy in pregnant woman may out weigh teratogenic risk -- Avoid use in first trimester - Respiratory depression(overdose) - CNS effects - paradoxical reaction -- Behavioral disinhibition, aggression, delirium, and violence *Flumazenil* - antidote - Competitive antagonist at benzodiazepine binding site of GABAA *Discontinuation*: - Abrupt discontinuation or large decreases in dose of benzodiazepines can cause withdrawal -- Increase seizure risk -- Anxiety -- Sleep disturbances -- Palpitations -- irritability

What is the mechanism of action, indications, pharmacokinetics, and adverse effects of Tiagabine

GABA Potentiators *Tiagabine* *Mechanism of action*: - Inhibits GAT1 GABA transporter (removes GABA from synaptic cleft) -- GAT1 specifically expressed in forebrain and hippocampus - Rationally designed *Indications* - Adjunct for focal seizures *Pharmacokinetics*: - Metabolized by CYP 3A4 - Hepatic insufficiency requires dosing adjustment - Excreted primarily in feces -- Biliary excretion - Dose adjustments necessary if administered with an enzyme inducer *Adverse Effects*: - Asthenia (abnormal physical weakness or lack of energy.) - Difficulty concentrating - Anxiety - Tremor - Insomnia - Psychosis (rare) - Idiosyncratic rash - Suicidal intentions - Do not discontinue abruptly

What is the mechanism of action, indications, pharmacokinetics, contraindications, adverse effects, discontinuation, drug-drug interactions, and pregnancy of Barbiturates

GABA potentiator *Barbiturates* *Mechanism of action*: - Bind to allosteric (barbiturate) site on GABAA receptor -- Increases GABAA affinity for the GABA receptor and increases *duration* of Cl- channel opening. - Weak agonist activity *Indications*: Phenobarbital (1st line in neonates) - Focal seizures - Tonic-clonic seizures -- May exacerbate absence seizures --- Act on GABAA receptors in both reticular nucleus and thalamic relay cells (enhancing T-type Ca2+ channel activity) - Status epilepticus (2nd line) - Sedation - Hypnotic *Pharmacokinetics*: - Metabolized by hepatic oxidative hydroxylation - Metabolites: Inactive - *Enzymes induced*: CYP1A2, CYP2B6, CYP2C19, CYP2C9/10, CYP3A4 - Long half-life -- Consider night time dosing - limit hypnotic effects on quality of life *Contraindications*: - Patients with porphyria -- induce α-aminolevulinate synthase (rate-limiting enzyme in porphyrin biosynthesis) - Concomitant use of rilpivirine - non-nucleoside reverse transcriptase inhibitor (anti-viral) - Respiratory disease *Adverse Effects*: - Cardiorespiratory depression - Megaloblastic anemia - Hepatic injury - Hallucinations - Excitement (pediatrics) *Discontinuation*: - Withdrawal - Delirium - Convulsions *Drug-drug interactions*: - Drugs metabolized by induced enzymes -> decreased plasma concentration -- Oral contraceptives -- Anti-virals - Sedatives - additive respiratory depression -- Benzodiazepines *Pregnancy*: - Barbiturates decrease uterine contraction - Barbiturates cross the placental barrier -- Respiratory depression -- Neonatal withdrawal --- Seizures --- Hyper-irritability -- Neonatal coagulation defects --- Intracranial bleeding ---- Vitamin K prophylaxis recommended

GABAergic Treatment Cessation

GABAergic treatment cessation has a high rate of symptomatic relapse. A small subset of patients will experience symptoms which are more severe than those experienced prior to initial treatment.

Neurodegeneration & Pharmacology -- Pharmacokinetics and Pharmadynamics.

Goal of drug therapy is to prevent, cure, or alleviate the symptoms of neurodegenerative disease *Pharmacokinetics* - *CNS complications* -- Complexity of the brain -- Adverse effects in the CNS -- Blood-brain barrier *Pharmacodynamics* - *Examines the influence of drug concentrations and the response in the body* -- Interaction with receptors -- Molecular consequences of interactions -- Effect in the patient

GABAergic anxiolytics

Generally classified into older and newer generations - Older: Barbiturates and alcohol Newer: Benzodiazepines Older generations (A) - Linear dose-response - Higher doses can lead to anesthesia and eventually depress respiratory and vasomotor centers, leading to death Newer generations (B) - Deviate from the linear dose-response

What is the difference between older and newer generations of sedative-hypnotics?

Generally classified into older and newer generations- Older: Barbiturates and alcohol Newer: Benzodiazepines. Older generations (A) - Linear dose-response - Higher doses can lead to anesthesia and eventually depress respiratory and vasomotor centers, leading to death Newer generations (B) - Deviate from the linear dose-response. - "suicide proof" in a sense because it takes alot more to enter coma due to the plateau effect.

What are the side effects of inhaled anesthetics in the Liver and kidneys?

Halothane hepatitis (Hepatic necrosis) - CYP mediated biotransformation produces a reactive metabolite which causes hypersensitivity reaction and acetylation of liver proteins (hepatitis) - More common in second exposures - Fatal in 50% of patients - Pharmacokinetics and adverse effects -> no longer used in the US. Nephrotoxicity (methoxyflurane- withdrawn from market) - Metabolite causes proximal tubular necrosis - Other effects; polyuria, hyponatremia, dehydration

What is the mechanism of action, indication, pharmacokinetics, and adverse effects of Rufinamide?

Glutamate Receptor Inhibitor *Rufinamide* *Mechanism of action* - Prolongs Na+ channel inactivation - High doses inhibit mGluR5 subtype of glutamate receptor *Indication* - *Lennox-Gastaut Syndrome* (is a complex, rare, and severe childhood-onset epilepsy. It is characterized by multiple and concurrent seizure types, cognitive dysfunction, and slow spike waves on electroencephalogram (EEG). Typically, it presents in children aged 3-5 years and can persist into adulthood.) *Pharmacokinetics* - *Induces* CYP 3A4 - *Inhibits* CYP 2E1 *Adverse Effects* - Diplopia - Somnolence

What is the mechanism of action and adverse effects of Felbamate

Glutamate Receptor Inhibitor *Felbamate* *Mechanism of action* - Inhibition of NR2B subunit of NMDA receptor -- Specificity alleviates behavioral effects seen in other NMDA ligands *Adverse Effects* - Aplastic anemia - fatal - Liver failure Primarily reserved for use in patients with refractory epilepsy (drug resistant epilepsy)

Characteristics of Desflurane

Halogenated anesthetic *Desflurane* - Volatile liquid at room temperature with *pungent* odor -- Typically used for maintenance - More than 99% is exhaled unchanged by the lungs - Widely used -> outpatient surgery -- Rapid onset and recovery

Characteristics of Enflurane

Halogenated anesthetic *Enflurane* - Clear, colorless liquid at room temperature with mild, sweet odor. - Fluoride ions are by-products of metabolism, may cause fluoride-induced nephrotoxicity. - Increased incidence of *seizures*

Characteristics of Sevoflurane

Halogenated anesthetic *Sevoflurane* - Volatile liquid at room temperature - 3% is metabolized by CYP2E1 to release fluoride -- Potential for nephrotoxicity (not evident) - Exothermic reaction with desiccated CO2 absorbent -> may produce airway burns; also produce CO -- Improved machinery overcame the disadvantage - Rapid onset and recovery, *close to ideal anesthetic*

Characteristics of Isoflurane

Halogenated anesthetic *Isoflurane* - Volatile liquid at room temperature with *pungent* odor -- Typically used for maintenance - More than 99% is exhaled unchanged by the lungs - Good safety profile -> commonly used - Relatively slow onset and delivery.

Cannabinoids adverse effects, tolerance, and withdrawal

High doses of marijuana can cause anxiety, overt panic reactions, perceptual disorders, impairments in reality testing, and rarely, overt psychosis in susceptible individuals - Overt panic reactions are the most common reason for discontinuation of marijuana use Tolerance occurs via a down-regulation of CB1 receptor expression and post-translational modifications that reduce signal transduction efficiency Withdrawal is generally mild due to its high volume of distribution and long elimination half-life - Symptoms may include insomnia, loss of appetite, irritability, and anxiety

What is the MOA, PK (pharmakinetics), AE, and Contraindications of radioactive iodine?

Hyperthyroidism therapy *Radioactive iodine (131 I)* *MOA*: - absorbed, concentrated by the thyroid, incorporated into storage follicles. - Emits B (beta) rays that destroy thyroid parenchyma. *PK*: easy administration (oral), effective, low expense, absence of pain. *AE*: hypothyroidism *Contraindicated*: in pregnant women or nursing mothers because it crosses the placenta and is excreted in breast milk - Destroys the fetal and infant thyroid gland.

What are the DPP-4 inhibitors (dipeptidyl peptidase-4), MOA, CU, and AE?

Incretins: DPP-4 inhibitors *Sitagliptin, Saxagliptin, Linagliptin* *MOA*: Inhibit DPP-4 and Increase endogenous GLP-1. 1. Increase glucose-dependent insulin release 2. Decrease glucagon release *CU*: Type 2 DM - In combination with metformin. - *Oral*, once daily (compared to GLP-1 which are subcutaneous) - Adjust the dose in renal dysfunction. *AE*: - Hypersensitivity: urticaria, facial edema. - *Pancreatitis*: contraindicated in pancreatic disease. - *Increase risk of upper respiratory infection*.

What is the MOA, CU, AE, and CI of GLP-1 (glucagon-like peptide 1) receptor agonists?

Incretins: GLP-1 receptor agonists *Exenatide*: Subcutaneous, twice a day/weekly. *Liraglutide*: long-acting, half life > 12 hours, once daily *Albiglutide*: a GLP-1 dimer fused to human albumin, half life 4-7 days, once weekly. *MOA*: 1. *Increase glucose-dependent* insulin release - Insulin secretagogues - *does not cause hypoglycemia* 2. Decrease glucagon release 3. Decrease gastric emptying 4. Decrease appetite. *CU*: Type 2 DM, combination therapy with metformin. *AE/CI*: - Nausea, vomiting, diarrhea. - *Weight loss*: -- Liraglutide was approved for treatment of obesity in 2014 - *Medullary thyroid cancer*: "black box" warning -- *Contraindicated* in medullary thyroid carcinoma, multiple endocrine neoplasm. - *Pancreatitis*: rare, contraindicated in pancreatic disease. -- Acute or asymptomatic chronic pancreatitis. (Can cause medullary thyroid cancer and pancreatitis)

What is the uptake and distribution of inhaled anesthetics?

Inhalation anesthetics behave like gases in the body rather than liquids. - Anesthesia is achieved when the partial pressure of gas in the brain (Pcns) ≥ MAC (minimal alveolar concentration). Equilibrium is reached when the partial pressures of the anesthetic gas are equal in all tissues Clinically; equilibrium is achieved when partial pressure in inspired gas (Pi) is equal to the partial pressure in end-tidal (alveolar) gas (Palv).

Which drugs *inhibit intestinal glucose absorption*, their MOA, CU, AE, and CI?

Inhibit intestinal glucose absorption *Acarbose, Miglitol* *MOA*: competitively inhibit the *intestinal brush-border a-glucosidase* (Alpha-glucosidase breaks down starch and disaccharides to glucose) - Decrease sugar hydrolysis, Decrease glucose absorption. - *Decrease post-prandial blood glucose rise* *CU*: Type 2 DM - Taken just before each meal - Combination therapy with metformin, sulfonylureas. *AE*: Flatulence, diarrhea, abdominal pain. *CI*: inflammatory bowel disease, intestinal obstruction.

What is the MOA, PK, CU, and AE of Sulfonylureas?

Insulin secretagogues (promotes insulin secretion)- Sulfonylureas. - 1st generation: *Tolbutamide, Chlorpropamide* -- No longer used: a greater incidence of hypoglycemia, more frequent drug interactions (disulfiram-like effects). - 2nd generation: *Glyburide, Glipizide, Glimepiride* -- Rapid onset of action, better coverage of the postprandial glucose rise. -- Caution: significant hepatic or renal dysfunction. *Sulfonylureas* *MOA*: - Binds to sulfonylurea receptors on B-cell - Inhibits Katp channel - Block K+ efflux -> depolarization (potassium is positive, since it can't get out it can't balance out the Na+ coming in so the membrane becomes more positive/depolarizes) - Opens a voltage-gated calcium channel - Calcium influx - Release of pre-formed insulin. *PK*: oral, metabolized by liver, cleared by kidney *CU*: type 2 DM of relatively recent onset (<5 years). *AE*: - *Weight gain* - *Hypoglycemia*: Elderly individuals -- Delayed meals, increased physical activity, renal insufficiency. - "Sulfa" allergy.

What is the MOA, PK, CU, AE, and CI of Glinides?

Insulin secretagogues- Glinides *Repaglinide, Nateglinide* *MOA*: - Bind Katp channel - Block K+ efflux -> depolarization - Open a voltage-gated calcium channel - Calcium influx - Release of preformed insulin - Compared with sulfonylureas -- Rapid onset -- Short duration of action *PK*: metabolized by liver *CU*: Type 2 DM - Patients with irregular meal schedule - Sulfur allergy *AE*: Hypoglycemia, weight gain *CI*: - Hypersensitivity - Concurrent use of sulfonylureas and Repaglinide.

What is the MOA, PK, CU, AE, and CI of Metformin?

Insulin sensitizer Biguanide: *Metformin* *MOA*: - *Decrease* hepatic glucose production - *Increase* peripheral glucose uptake (insulin sensitivity) - Activates *AMP-dependent protein kinase* (Enzyme that plays a role in cellular energy homeostasis, largely to activate glucose and fatty acid uptake and oxidation when cellular energy is low) *PK* - Oral, 500-850 mg once or twice daily. - Excreted by kidney *CU*: *First-line therapy for type 2 diabetes* - Monotherapy - Combination with other oral agents or with insulin. *AE*: - GI discomfort: diarrhea, anorexia, nausea, metallic taste. - *Vitamin B12 deficiency*: megaloblastic anemia (without vitamin B12, DNA synthesis is impaired so the RBC will go through cell cycle to G2 but can't undergo mitosis, so they are big but can't divide), paresthesias. - *Lactic acidosis*: rare but most severe -- Buildup of lactic acid, metabolic acidosis. -- Symptoms: myalgia, abdominal discomfort, malaise, daytime somnolence. - *Predisposing conditions (CI)*: hepatic disease, alcohol abuse, moderate renal insufficiency, congestive heart failure, sepsis. (Would get lactic acidosis because of impaired renal excretion of lactic acid or impaired uptake of the lactic acid by the liver)

What is the MOA, PK, CU, AE, and CI of the Thiazolidinediones (aka Glitazones)

Insulin sensitizer Thiazolidinediones: *Pioglitazone, Rosiglitazone*. *MOA*: activates peroxisome proliferator-activated receptor-gamma (*PPAR-γ)* - Redistributes lipid stores among adipose, muscle, and liver: -- Promote fatty acids uptake and storage in adipose tissue. -- Muscle and liver become more sensitive to insulin. - *Decreases* hepatic glucose production. - Anti-inflammatory: ↓CRP, IL-6 *PK*: oral, no dosage adjustment is required in renal impairment. *CU*: Type 2 DM - Monotherapy - Combination with other oral agents or with insulin. *AE*: - *Weight gain*: fluid retention and increase total fat mass. - *Anemia:* Dilutional effect. - *Exacerbate heart failure* - *Macular edema*: rare - *Osteoporosis:* Decrease osteoblast formation. -- Increase risk of fracture in postmenopausal women. - *Liver toxicity* -- *FDA: Liver function test prior to initiating therapy*. - *Pioglitazone: Increase risk of bladder cancer*. *CI*: *Congestive heart failure*, Active liver disease.

Intoxication symptoms of alcohol

Intoxication symptoms: - Emotional lability - Slurred speech - Ataxia - Coma - Blackouts

What are the symptoms/characteristics of generalized seizures?

Involve the entire brain - Originates in the central brain regions -> spreading rapidly to both hemispheres - Not commonly preceded by an aura - Loss of consciousness Generalized Seizures - Tonic-clonic - Absence

Depression drug onset?

It normally takes 4-8 weeks for antidepressants which affect neurotransmitter reuptake to take effect. This creates issues surrounding patient compliance -> "if there is no beneficial effect why should I keep taking this drug?"

What 2 drugs are used to treat hypothyroidism?

Levothyroxine and Liothyronine

Clinical considerations of lithium

Patient monitoring is essential for effective treatment of bipolar disorder and prevention of toxicity - Maintenance of diet and hydration are essential -- Caffeine and alcohol use is discouraged Patient serum drug concentrations should be monitored closely and regularly Lithium is excreted almost exclusively by the kidneys

Lithium characteristics

Lithium is a univalent cation of the white metal series, closely related to both sodium and potassium, but having no known role in human physiology. Lithium can substitute for sodium in several sodium channels which directly correlate to the adverse effects - Particularly in the kidneys: the sodium-hydrogen exchanger in the proximal tubule (NHE3), the sodium/potassium/2chloride exchanger in the thick ascending limb of the loop of Henle (NKCC2), and the epithelial channel of the cortical collecting tubule (ENaC)

Clinical use of lithium

Lithium is an effective treatment for acute mania, and after 6-8 weeks of use is effective for management of symptoms of depression - Research suggests that lithium alone may not be sufficient to treat mania with psychotic features -- The addition of an antidepressant or anticonvulsant --- Risks associated with the addition of these medications include: sedation, weight gain, GI upset, and tremors The therapeutic window of lithium is very small - Toxicity can occur at doses very close to therapeutic levels -- The elderly, those on a sodium restricted diet, and those suffering from dehydration can present with symptoms of lithium toxicity at therapeutic plasma concentrations Symptoms of lithium toxicity include: diarrhea, incontinence, incoordination, impaired cognition, arrhythmias, and seizures - Lithium toxicity can be treated by dialysis - Drug-drug interactions -- Diuretics -- Tetracycline antibiotics -- NSAIDs (with the exception of aspirin) The use of diuretics in patients being treated with lithium has been shown to increase the risk of lithium toxicity. Thiazide use has been reported to increase lithium toxicity by up to 40% The use of tetracycline antibiotics with lithium is reported to enhance lithium toxicity by increasing lithium absorption and impairing excretion. The use of NSAIDs (with the exception of aspirin) in patients being treated with lithium is not recommended. NSAID inhibition of the synthesis of prostaglandin PGE2 results in decreased renal blood flow and in turn decreased clearance of lithium.

Lithium and pregnancy

Lithium use is *contraindicated in pregnancy.* - The use of lithium during pregnancy has been linked to congenital cardiac malformations, fetal and neonatal cardiac arrhythmias, hypoglycemia, and premature delivery. The fetal cardiac malformation associated with lithium administration during pregnancy is Ebstein's anomaly. Ebstein's anomaly is a rare heart defect in which the tricuspid valve — the valve between the upper right chamber (right atrium) and the lower right chamber (right ventricle) of the heart — isn't formed properly. As a result, blood leaks back through the valve and into the right atrium. Atrial septal defect, the most common defect associated with Ebstein's anomaly, is a hole between the two upper chambers of the heart. A normal heart is shown on the left.

What are the long term effects of barbiturate and benzodiazepine use? What do barbiturates, benzodiazepines, ZZZ agents, and remelteon do to sleep?

Long term barbiturate and benzodiazepine use causes *receptor desensitization/downregulation* - Tolerance and physical dependence Barbiturates and benzodiazepines (and alcohol) alter sleep architecture - Stage 3 and REM sleep suppression ZZZ agents and remelteon have little effect on sleep architecture - Used for restoration of sleep patterns.

Effects of GABAa Activation

Long term barbiturate and benzodiazepine use causes receptor *desensitization/downregulation* - Tolerance and physical dependence Barbiturates and benzodiazepines alter sleep architecture - Stage 3 and REM sleep suppression -- Similar to insomnia

What is the minimal alveolar concentration?

MAC (minimal alveolar concentration): alveolar partial pressure that abolishes movement response to a surgical incision in 50% of patients - Intubation is more noxious (harmful) MAC is inversely proportional to potency.

Phenylethylamines complication

MDMA causes the release of biogenic amines by reversing the action of the respective transporters - Specifically SERT -- Can lead to serotonin syndrome --- Agitation or restlessness --- Confusion --- Rapid heart rate and high blood pressure --- Dilated pupils --- Loss of muscle coordination or twitching muscles --- Muscle rigidity --- Heavy sweating --- Diarrhea Release is so profound that there is marked intracellular depletion for 24 hours after a single dose

Cocaine and amphetamine summary

MOA: Dopamine, adrenergic, and serotonin reuptake inhibitors Clinical signs- euphoria, alertness, hypertension, and paranoia Withdrawal- Hypersomnolence

MOA, clinical signs, and symptoms of PCP (phencyclidine)

MOA: NMDA antagonist Clinical signs- hallucinations and hostile behavior Symptoms- people feel detached from their bodies and environment around them, observe themselves from up above.

Cannabinoids summary

MOA: cannabinoid receptor 1 & 2 agonist Clinical signs - hunger, giddiness, and changes in mood Therapeutically used for: Amyotrophic lateral sclerosis • Autism • Cancer • Crohn's disease • Damage to the nervous tissue of the spinal cord with objective neurological indication of intractable spasticity • Epilepsy • Glaucoma • Human Immunodeficiency Virus (HIV)/ Acquired Immune Deficiency Syndrome (AIDS) • Huntington's disease • Inflammatory bowel disease • Intractable seizures • Multiple sclerosis • Neuropathies • Parkinson's disease • Post-traumatic stress disorder • Severe chronic or intractable pain of neuropathic origin or severe chronic or intractable pain in which conventional therapeutic intervention and opiate therapy is contraindicated or ineffective • Sickle cell anemia

Opioids summary

MOA: 𝜇-opioid agonist Euphoria, followed by sedation and respiratory depression Used therapeutically as analgesics

Symptoms of depression

Major Depressive Disorder - Depressed mood (pediatrics: irritable mood) - Feeling of worthlessness - Anhedonia - Significant weight change or appetite disturbances - Fatigue, sleep disturbances - Indecisiveness - Recurrent thoughts of death, recurrent suicidal ideation with or without a specific plan for committing suicide

What are the cutaneous effects of antiepileptic drugs and which drugs are most responsible?

Many antiepileptic drugs have been shown to produce cutaneous adverse effects - The most serious of which is Stevens-Johnson syndrome -- Usually develops within the first week of taking the drug -- Serious and potentially fatal skin reaction with sheet-like skin and mucosal loss -- Rare immune-complex-mediated hypersensitivity *Most closely associated with*: - Phenytoin - Carbamazepine - Ethosuximide - Lamotrigine

CDC on Marijuana- negative effects, fast facts

Marijuana and the teen brain - Unlike adults, the teen brain is actively developing and often will not be fully developed until the mid 20s. Marijuana use during this period may harm the developing teen brain. Negative effects include: - Difficulty thinking and problem solving. - Problems with memory and learning. - Impaired coordination. - Difficulty maintaining attention. Fast Facts - 38% of high school students report having used marijuana in their life. - Research shows that marijuana use can have permanent effects on the developing brain when use begins in adolescence, especially with regular or heavy use. - Frequent or long-term marijuana use is linked to school dropout and lower educational achievement.

What medical disorders associated with high anxiety

Medical disorders associated with high anxiety - Hyperthyroidism - Cardiac disease (arrhythmias, tachycardia) - Mitral valve prolapse - Hypoglycemia - Depression - Alcohol/Drug withdrawal - Caffeine/Tobacco use - Epilepsy

What are the indications, mechanism of action, and side effects of melatonin receptor agonists?

Melatonin Receptor Agonists *Ramelteon* Indication: - Insomnia Mechanism of action MT1 and MT2 agonist - MT1 and MT2 are located in the suprachiasmatic nucleus and both activate *Gi*- coupled receptors (adenylyl cyclase inhibitor). - MT1 activation causes sleepiness; MT2 is involved with dark-light synchronization of circadian rhythm. Efficacy less than benzodiazepine but more than melatonin (melatonin not regulated by the FDA). Side effects: - Dizziness - Fatigue - Endocrine abnormalities -- Increase testosterone -- Decrease prolactin Use caution - Moderate hepatic impairment - Concomitant CYP1A2 inhibitors

Which drugs are esters, which are amides?

Metabolites of *ester-type* contain para-aminobenzoic acid - *Decreases the effectiveness of sulfonamides* - Can cause *allergic reactions* -- Switch to amide-type.

Phenylethylamines effects and adverse effects

Methylenedioxymethamphetamine (MDMA) is one class of phenylethylamine hallucinogenics - Known as ecstasy or molly Chemically related to methamphetamine Primary effect is on serotonergic transmission - MDMA causes serotonin relapse into the extracellular space, inhibition of serotonin synthesis, and blocks serotonin reuptake - "Selective serotonergic neurotoxin" Central stimulant effect similar to cocaine and amphetamine, also has hallucinogenic effects Effects are a perceived increase in energy, euphoria, higher pleasure from and desire for physical touch, increased levels of sexuality and sexual arousal, elevated alertness and focus - Effects last from 30 min - 6 hours *Adverse effects*: nausea, muscle cramping, fever, sweating and chills, shaking and tremors, hallucinations, blurred vision, increased heart rate and blood pressure, and feeling faint Loss of consciousness, extreme increase in body temperature (can lead to organ damage) may occur

Which drugs are monoamine oxidase inhibitors, what is their MOA, clinical indications, adverse effects, interactions, and diet

Monoamine oxidase inhibitors *Tranylcypromine, phenelzine, isocarboxazid, and selegiline (selective for MAO-B)* *MOA*: Inhibition of monoamine oxidase resulting in increased levels of amine neurotransmitter in the brain (serotonin, norepinephrine, and dopamine). - There are two forms of monoamine oxidase -- MAO-A- found in adrenergic and dopaminergic neurons in the brain as well as; gut and liver -> major substrates: norepinephrine, epinephrine, and serotonin. -- MAO-B- found primarily in serotonergic and histaminergic neurons in the brain, as well as; liver and platelets -> major substrates: dopamine, tyramine, phenylethylamine, and benzylamine. *Clinical indications* - Atypical depression and anxiety disorders. *Adverse effects* - Hypertensive crisis -- Tyramine displaces NE from adrenergic neurons and vesicles -- Tyramine is found in wine, cheese, and fermented sausage - normally metabolized by MAO - Sexual dysfucntion- highest rate of the antidepressants -- Decreased libido and/or failure to become aroused or orgasm. - CNS stimulation - agitation, confusion, restlessness. *Interactions* - The concurrent use of SSRIs, SNRIs, or TCAs can result in *serotonin syndrome* *Diet* - A low tyramine diet is recommended in patients taking TCAs.

Clinical pharmacology of epilepsy drugs

Monotherapy will limit adverse effects and drug-drug interaction - CYP inducers and inhibitors Adjunct therapy is often reserved for patients with hard to control seizures - Have not responded to monotherapies - Plasma drug concentrations is useful for older antiepileptics -- Newer drugs do not correlate plasma concentration and seizure control well

Adverse effects: Suicidality

Mood disorders, particularly anxiety and depression, are common in patients with epilepsy - Reports as high as 35% comorbidity Suicidal thoughts or intentions may increase with use of AEDs (antiepileptic drugs)(FDA labeling) - Some studies refute this claim - Cannot link suicidality to pharmacotherapy

What are the 3 main types of medications used to treat bipolar disorder?

Mood stabilizers- lithium Anticonvulsants Antipsychotics

How are benzodiazepines metabolized?

Most are metabolized by phase I CYP enzymes to active metabolites Metabolites of *Chlordiazepoxide*, *diazepam*, and flurazepam are long-acting Metabolites of *midazolam*, *alprazolam*, and *triazolam* are short-acting *Oxazepam*, *Temazepam*, and *Lorazepam* do not have metabolites and are directly conjugated for elimination (*O*ut *T*h*E* *L*iver) - Since phase II biotransformation is less likely to be affected by hepatic insufficiency, this group of agents is more useful for elderly individuals or people with reduced liver function.

Pharmacokinetics of opioids

Most opioids have low bioavailability - First pass metabolism Renal excetion Use caution in patients with hepatic and renal insufficiency

What are the side effects of inhaled anesthetics in the nervous system?

Nervous system Increased intracranial pressure - Dilate cerebral vasculature, increased cerebral blood flow. Seizures - Enflurane causes excitation of the CNS.

Drug movement of local anesthetics

Neutral base crosses the membrane easier than charged form Charged form binds with higher affinity to the target binding site - Located in the pore of the voltage gated Na+ channels, accessible from intracellular entrance.

Nicotine

Nicotine activates nicotinic acetylcholine receptors located centrally, peripherally, and at the neuromuscular junction - Cholinergic neurons activate nicotinic and muscarinic acetylcholine receptors on dopaminergic neurons in VTA Activation of presynaptic nicotinic receptors on dopaminergic neurons facilitates the release of dopamine (Positive feedback loop- heteroreceptors) Strong effects on reward pathway, inhalation route, and the short half-life of nicotine explain the high addiction potential of nicotine Activation of central nicotinic receptors produces anxiolytic effects, increases arousal, and suppresses appetite Activation of peripheral nicotinic receptors increases blood pressure and stimulates smooth muscle contraction.

What are the non-halogenated and halogenated inhalation anesthetics?

Non-halogenated: - Nitrous oxide Halogenated: - Halothane - Methoxyflurane - Enflurane - Isoflurane - Desflurane - Sevoflurane

What are absence seizures

Often occur in children - Misdiagnosed as inattentive ADHD Less dramatic, but may be more frequent Seizures appear to arise from reciprocal firing between the thalamus and cerebral cortex Characteristic spike-and-wave discharge pattern on EEG Vacant stare, eyes roll upward, eyelid flutter, lip smacking Involves low threshold T-type calcium channels - Drug target specific for absence seizures

GABAergic Treatment cessation

Only 55% of patients without rebound symptoms. Some patients may require long term gabaergic treatment to get rid of their anxiety but with long term use tolerance builds up and the therapeutic index becomes narrower.

Cure for opioid overdose MOA

Opioid Overdose *Naloxone* - *MOA*: opioid antagonist -> competitively block the binding of opioids to the opioid receptor - Rapidly reverses opioid activity - Available as IV, intranasal spray, and auto-injector

What drugs are CNS depressants

Opioids Alcohol Barbiturates Benzodiazepines

Mechanism of action, indication, and overdose cure for morphine, fentanyl

Opioids: *Morphine, Fentanyl* *Mechanism of action* - μ - opioid receptor agonist -- Does not produce amnesia -- Does not produce loss of consciousness -- Combined with other anesthetics --- Droperinol - antidopaminergic agent- used in combination produces neuroleptanesthesia (twilight sleep) ---- Provides adequate analgesia and sedation during surgery while maintaining consciousness to permit the patient to respond to questions during surgery. *Indications* (fentanyl) - Epidural during labor - Post-operative analgesia Overdose can be reversed with opioid antagonist - *naloxone*

What is Brivaracetam used for? Adverse effects?

Other Mechanism of Action *Brivaracetam* Approved for use February 19, 2016 Treatment of focal seizures in patients 16 years and older. - Levetiracetam derivative -- Metabolized by CYP 2C19 -> renal excretion *Adverse Effects*: - Dizziness -> cerebellar ataxia - Suicidal behavior or intentions - Mood and behavioral changes - bronchospasm

What is the mechanism of action, indications, pharmacokinetics, and adverse effects of Levitiracetam

Other Mechanism of Action *Levitiracetam* *Mechanism of Action* - Selectively binds to synaptic vesicular protein SV2A -- Modulates release of glutamate and GABA - Inhibition of N-type calcium channels and inhibition of calcium release from intracellular stores *Indications* - Adjunct for focal seizures Tonic-clonic seizure (pediatric) *Pharmacokinetics*: - No known metabolites - Excreted by kidneys -- Half-life increases with renal insufficiency *Adverse Effects* - Stevens-Johnson syndrome - Suicidal behavior or intention - Pancytopenia (deficiency of all three cellular components of the blood (red cells, white cells, and platelets) - Somnolence - Asthenia - Ataxia - Weight loss - Alopecia - Abnormal liver tests - Decrease in bone mineral density (not well established)

What is the mechanism of action, indications, pharmacokinetics, and adverse effects of Topiramate?

Other Mechanism of Action *Topiramate* *Mechanism of Action:* - Not well understood -- Sodium channel inhibition -- GABAA potentiation -- AMPA receptor antagonism -- Weak carbonic anhydrase inhibitor *Indications* - Adjunct therapy for focal and tonic-clonic seizures - Migraine *Pharmacokinetics*: - *Induces* CYP 3A4 - *Inhibits* CYP 2C19 - Excreted by the kidneys -- Dialyzable - Hepatic metabolism -- 70% of the drug is excreted unchanged *Adverse Effects*: - Paresthesia - Weight loss - loss of appetite - Reduced serum bicarbonate - metabolic acidosis - Liver failure - Glaucoma - Suicidal thoughts or intentions - Kidney stones - Mental dulling

What is the paradoxical reaction with benzodiazepines?

Paradoxical reaction - Behavioral disinhibition - Aggression - Delirium - Violence -- Reversible with flumazenil

What is hemoglobin A1c (HbA1c) and when should you check up on it?

Percentage of glycated hemoglobin A1c. Clinical: an important marker for long-term management of diabetes - American diabetes association recommends: -- 3-4 times/y for type 1 DM and poorly controlled type 2 DM -- 2 times/y for well controlled type 2DM

Management of addiction, pharmacological vs psychological

Pharmacological - Focused on detoxification to relieve withdrawal symptoms -- Has no affect on long-term addiction or outcomes Psychological - Counseling techniques such as cognitive behavioral therapy -- Addiction is often a comorbid condition

Antiepileptic drugs fun facts and which drugs are antiepileptic?

Pharmacological intervention is only palliative - There is not curative treatment ~30% of those diagnosed with epilepsy are not well controlled with current pharmacotherapies - No improvement in patient outcomes from 1st generation of antiepileptics - Improved tolerability, not efficacy A. Sodium channel inhibitors B. Calcium channel inhibitors C. GABAa channel potentiators D. Glutamate receptor inhibitors E. Other mechanisms

Phencyclidine (PCP)

Phencyclidine was initially developed as a dissociative anesthetic - Discontinued due to behavioral toxicity PCP blocks NMDA glutamate receptors - NMDA glutamate receptors mediate excitatory synaptic transmission - Involved in synaptic plasticity and memory - PCP produces complex effects such as anesthesia, delirium, hallucinations, intense paranoia, agitation, and amnesia

What is the mechanism of action, indications, pharmacokinetics, and adverse effects of Lacosamide?

Sodium channel inhibitors *Lacosamide* *Mechanism of action*: - Enhances slow inactivation of voltage-gated sodium channels, without blocking the channel directly - Binds to collapsin response mediator protein-2 (CRMP-2), a phosphoprotein that is expressed mainly in the nervous system and is involved in neuronal differentiation and control of axonal outgrowth *Indications* - Focal seizures - Adjunct - focal seizures *Pharmacokinetics* - Metabolized by CYP 3A4, 2C9, 2C19 - Excreted in urine - Dialyzable - *Does not induce or inhibit CYP enzymes* *Adverse Effects*: - Diplopia - Prolonged PR interval - use caution in patients with conduction issues (dose dependent) - Suicidal thoughts or behaviors - Bradycardia (IV infusion) - Phenylketonuria (oral suspension)

What is the mechanism of action of inhaled anesthetics?

Potentiate inhibitory synaptic activity - Enhance GABAa and glycine receptors, increase Cl- influx, activate K+ channels (increase K+ efflux) -> hyperpolarizes cell. Diminish excitatory synaptic activity - Inhibit nACh (nicotinic acetylcholine) and NMDA (N-methyl-D-aspartate) receptors and decrease Ca2+ and Na+ influx.

What are the 9 intravenous anesthetics?

Propofol, fospropofol Ketamine Etomidate Barbiturates - Thiopental - Methohexital Benzodiazepine - Midazolam Opioids - Morphine - Fentanyl

Patient management in depression

Psychotherapy - American Psychiatric Association guidelines recommend psychotherapy as 1st line treatment for mild cases -- Interpersonal psychotherapy -- Cognitive-behavioral therapy Pharmacotherapy - APA recommends combining psychotherapy with antidepressant medication for patients with moderate to severe major depressive disorder -- Selective serotonin reuptake inhibitors (SSRIs) -- Serotonin/norepinephrine reuptake inhibitors (SNRIs) -- Tricyclic antidepressants (TCAs) - also a reuptake inhibitor -- Monoamine oxidase inhibitors (MAOIs) -- Atypical antidepressants

What is the MOA, clinical indication, pharmacokinetics, cautions, adverse effects, and benefits of Buspirone

Pure Anxiolytic *Buspirone* *MOA*: High affinity agonist for serotonin 5-HT1A and 5-HT2 - No sedating, anticonvulsant, or muscle relaxing effects, and no abuse potential Moderate affinity for D2 dopamine receptor *Clinical indication*: general anxiety disorder (Super short half-life, have to take it like 3x daily) *Pharmacokinetics*: - 2-4 weeks for onset of action -- Patient compliance -- Not useful for the treatment of acute symptoms - Metabolized by CYP 3A4 *Cautions*: - Use in severe renal/hepatic impairment not recommended - Use with MAO inhibitors may result in hypertensive reaction due to increased serotonergic effect *Adverse effects*: - Drowsiness - Dizziness - May cause cognitive motor impairment - Tinnitus *Benefits*: - Selective for anxiety -- No sedative-hypnotic effects - No tolerance observed in studies lasting 6 months - Better post cessation outcomes than GABAergic anxiolytics

What is the indication, mechanism of action, pharmacokinetics, cautions, and adverse effects for Buspirone use?

Pure Anxiolytic: *Buspirone* Indication: - General anxiety - Smoking cessation (off label) Mechanism of Action - Partial agonist of the 5HT1A and 5HT2 receptor. - Moderate affinity for D2 dopamine receptor -- Relieves anxiety without sedative-hypnotic effects -- No abuse potential Pharmacokinetics - 2-4 weeks for onset of action -- Patient compliance -- Not useful for as needed pharmacotherapy - Metabolized by CYP3A4 Cautions - Use in severe renal/hepatic impairment not recommended - Use with MAO inhibitor may result in hypertensive reaction. Adverse effects: - Drowsiness - Dizziness - May cause cognitive motor impairment - Restlessness syndrome associated with therapy

Pharmacokinetic tolerance

Repeated exposure to a drug results in upregulation of CYP enzymes and transporters responsible for drug clearance - Typically the result of CYP induction -> increased drug metabolism -- Resulting in lower [drug] at the site of action Neuronal adaptation resulting in decreased cellular response to the same concentration of drug at the site of action *Acute* - Changes in neurotransmitter release and clearance - Decrease in number of neurotransmitter receptors - Altered conductance of ion channels - Modified signal transduction *Chronic* - Changes to gene expression related to the pharmacologic actions of the drug

Tolerance

Repeated or continuous drug use can result in decreased effect over time when the dose remains constant - Dose must be increased to experience the desired effects - Sensitization inverse tolerance

What are the side effects of inhaled anesthetics in the respiratory system?

Respiratory system Respiratory depression - Increased PaCO2 -> apnea (cessation of breathing) - Increased dose -> decreased uptake Bronchodilation - Sevoflurane and nitrous oxide are not pungent -- Useful in patients with bronchospasm - Isoflurane and desflurane are pungent and can provoke airway irritation and coughing -- Use caution in patients with bronchospasm.

Cannabinoids pharmacokinetics, intoxication and withdrawal

Route of administration alters kinetics Large Vd 65% excreted in feces *Intoxication* - Euphoria - Increased appetite - Dry mouth - Anxiety - Paranoid delusions - Perception of slowed time - Impaired judgement - Social withdrawal - Conjunctival injection - Hallucinations *Withdrawal* - Irritability - Depression - Insomnia - Nausea - Anorexia

How do you treat secondary symptoms of Alzheimer's Disease?

Secondary symptoms: - Anxiety, agitation, depression, and psychotic behavior - Antidepressants -- Depression is observed in 30% of patients with AD -- SSRIs: --- *Citalopram* --- *Fluoxetine* -- 5HT-2 antagonist --- *Trazodone* - Anxiolytics -- *Lorazepam* -- *Oxazepam*

What do sedative-hypnotics do?

Sedative-hypnotic drugs are able to cause sedation or encourage sleep (hypnosis) - Sedatives reduce anxiety and exert a calming effect- anxiolytic. - Hypnotic agents produce drowsiness and encourage onset and/or maintenance of sleep. -- Dose-dependent increased depression of the CNS can shift a drug from sedative to hypnotic.

What are the 4 classifications of sedative-hypnotics?

Sedative-hypnotics can be chemically classified: 1. Barbiturates 2. Benzodiazepines 3. Non-benzodiazepine hypnotics - Benzodiazepine-like (ZZZ) - Melatonin receptor agonist (Ramelteon) 4. Pure Anxiolytic (Buspirone) - Does not produce sedation or hypnosis.

What are the main antidepressants?

Selective Serotonin Reuptake Inhibitors (SSRIs) Serotonin Norepinephrine Reuptake Inhibitors (SNRIs) Tricyclic Antidepressants (TCAs) Monoamine Oxidase Inhibitors (MAOis)

Which drugs are selective serotonin repuptake inhibitors and what is their MOA, clinical indications, pharmacokinetics, pharmacodynamics, adverse effects, and ssri-discontinuation syndrome?

Selective serotonin Reuptake inhibitors *Citalopram* *Fluoxitine* *Sertraline* *Paroxetine* *Fluvoxamine* *MOA*: inhibition of serotonin specific transporter (SERT) resulting in increased serotonin in the synaptic cleft *Clinical indications*: - Depression - Generalized anxiety disorder - Panic disorder - Obsessive compulsive disorder - Social phobias - Bulimia - PTSD *Pharmacokinetics* - Fluoxetine, fluvoxamine, and paroxetine are CYP inhibitors *Pharmacodynamics* - At high doses SSRIs can lose their selectivity and bind to norepinephrine transporter (NET) - Despite common mechanism of action, due to patient variability and functional polymorphisms, failure of one drug does not discount the use of others drugs within the class - At therapeutic doses ~80% of SERT activity is inhibited - Higher therapeutic index than tricyclic antidepressants -- Do not act on muscarinic (cholinergic), histamine, adrenergic, or dopamine receptors --- Better tolerability *Adverse Effects* - Sexual dysfunction -- Decreased libido and/or failure to orgasm --- Reports as high as 40% incidence, typically do not diminish over time - GI distress (early, improve over time) - QTc prolongation (high dose - citalopram) - Bleeding complications - rare - Hyponatremia - rare - Serotonin syndrome - Treatment-emergent mania -- The use of SSRIs in patients with bipolar disorder can result in a shift to manic state -- There are reports of treatment-emergent mania in patients diagnosed with unipolar depression (rare) *SSRI-discontinuation syndrome* - Abrupt withdrawal of SSRI can result in withdrawal symptoms which include: -- Anxiety -- Dysphoria -- Gastrointestinal flu-like symptoms -- Insomnia -- Depersonalization -- Suicidality (all symptoms of depression) Symptoms typically appear 1-2 days after discontinuation and can persist for a week or more.

Diagnosis of depression?

Self reporting is the primary diagnostic method for depression - Patient Health Questionnaire - 9 (PHQ-9) - Beck Depression Inventory (BDI) Hamilton Depression Rating Scale - Screening completed by trained professional not the patient There are no diagnostic laboratory tests available to diagnose major depressive disorder

What drugs are serotonin-norepinephrine reuptake inhibitors? What is the MOA, clinical indications, and adverse effects.

Serotonine-Norepinephrine reuptake inhibitors *Venlafaxine* *Duloxetine* *MOA* Inhibition of serotonin transporter (SERT) and norepinephrine transporter (NET) resulting in increased serotonin and norepinephrine in the synapse. *Clinical indications* - Depression - Venlafaxine: generalized anxiety disorder, panic disorder, PTSD - Duloxetine: diabetic peripheral neuropathy. *Adverse effects* - SNRIs have many of the same serotonergic adverse effects as SSRIs. - SNRIs have marked noradrenergic adverse effects -> *Increased blood pressure*, and heart rate, as well, CNS effects: agitation and anxiety.

What are some anxiety disorders?

Six month prevalence for all anxiety disorders 8-10% - 2/3 are Generalized Anxiety Disorder (GAD) Other anxiety disorders: - PTSD - OCD - Panic disorders - Social anxiety disorder Treatment, drug choice, and patient outcomes vary based on the anxiety disorder being treated

What is the mechanism of action, indication, pharmacokinetics, and IV incompatability, adverse effects, and teratogen of Phenytoin?

Sodium channel inhibitor *Phenytoin* *Mechanism of action* - Acts directly on Na+ channels to increase recovery time from inactive state to closed state. *Indications* - Focal seizures - Tonic-clonic seizures (*1st line*) - Status epilepticus (*1st line prophylaxis*) -- *NOT used for the treatment of absence seizures (makes it worse)* *Pharmacokinetics* - Metabolized by the liver -- Modulation of CYP enzymes directly effects Phenytoin metabolism. - Metabolism shows evidence of saturation kinetics (*Zero order kinetics!!*) -- Unpredictable increase in plasma drug concentration *IV incompatability* - Benzodiazepines, glucose, dextrose -> precipitate. (Really important that it is zero order kinetics- alcohol, aspirin, and phenytoin all follow zero order- certain amount of drug being metabolized per unit time independently of the drug concentration in the body.) *Adverse effects*: - Ataxia (Impaired balance or coordination) - Nystagmus (involuntary eye movement) - *Hirsutism* (male pattern growth in women) - *Gingival hyperplasia* - *Megaloblastic anemia* (folate deficiency) - Systemic lupus-like erythematosus - Stevens-Johnson syndrome (HLA-B 1502) -- Asian descent - Bone health - osteopenia (weaker than normal bones) *Teratogen* (an agent or factor which causes malformation of an embryo.) - *Fetal hydantoin syndrome* -- Flat, broad bridge of the nose -- A short nose -- Eyes that are farther apart -- Crossed eyes (strabismus) -- Eyelids that droop (ptosis) -- A large, wide mouth -- Malformed ears - Maternal epoxide (EPHX1) genotypes 113 H and 139 R- higher risk -- Cleft lip -- Cleft palate -- Congenital heart disease -- Intellectual disability (Don't give to anyone of childbearing age unless on implantable)

What is the mechanism of action, indications, pharmacokinetics, contraindications, adverse effects, and teratogen of Carbamazepine?

Sodium channel inhibitors *Carbamazepine* *Mechanism of action*: - Acts directly on Na+ channels to increase recovery time from inactive state to closed state *Indications* - Focal seizures (*1st Line*) - Tonic-clonic seizures (*1st line*) -- Not used for the treatment of absence seizures - Trigeminal neuralgia (1st line) (chronic pain condition that affects the trigeminal nerve) *Pharmacokinetics*: - Metabolized by CYP 3A4 - Active metabolite - *Induces*: CYP1A2, CYP2C9, CYP3A4 -- Induces its own metabolism (constantly have to increase patient's dose to attain effective plasma concentrations. Increasing dose leads to increased toxicity). *Contraindications*: - HLA-B*1502 gene variant (Chinese and Asian descent) Stevens-Johnson Syndrome - History of bone marrow suppression - MAOi administration within 14 days *Adverse Effects*: - *Blood dyscrasias* - Agranulocytosis (lowered WBC count) and aplastic anemia (body stops producing new RBCs) - Diplopia (double vision) - Ataxia - *Liver toxicity* - Stevens-Johnson syndrome - *SIADH* - syndrome of inappropriate antidiuretic hormone (ADH) secretion -> Hyponatremia -- (excess water not lack of Na+) *Teratogen*: One of the lowest risk antiepileptics. *Open spina bifida* *Lower risk than Valproic acid*

What is the mechanism of action, indications, pharmacokinetics, adverse effects, and teratogen of Lamotrigine?

Sodium channel inhibitors *Lamotrigine* *Mechanism of action*: - Acts directly on Na+ channels to increase recovery time from inactive state to closed state - Not well defined - inhibition of high-voltage-activated calcium channel (useful in absence seizures) -> inhibits glutamate release *Indications* - Focal seizures - Tonic-clonic seizures - Absence seizures (3rd choice) (Works really well in patients with Asian descent for absence seizure) *Pharmacokinetics* - Hepatic and renal metabolism through glucuronidation - Half-life -- Approximately halved if taking enzyme-inducing drugs -- Approximately doubled if also taking valproic acid *False-positive drug test assays*, particularly for phencyclidine (PCP) *Adverse Effects*: - Stevens-Johnson syndrome -- *Must be titrated slowly* - Potential suicidal thoughts or behavior (FDA warning) - Hematologic effects *Teratogen:* - Oral cleft - early exposure

What is Fosphenytoin, what does it treat, advantages over phenytoin, and black box warning?

Sodium channel inhibitors *Fosphenytoin* Prodrug - Converted to phenytoin after injection IV and IM use - More soluble than phenytoin Commonly used to treat convulsive status epilepticus IV *Black Box Warning* - Risk of hypotension and arrhythmias with high infusion rates -- Cardiac monitoring required.

What do sodium channel inhibitors do? Which drugs are sodium channel inhibitors?

Sodium channels are the key player in neuronal membrane depolarization and action potential propagation. Na+ channel inactivation provides a mechanism by which rapid firing can be prevented Antiepileptics acting on Na+ channels increase receptor inactivation enhancing inhibition at the single-cell level Drugs: *Phenytoin, carbamazepine, lamotrigine, lacosamide, and valproic acid* - Drugs in this class show a strong specificity for focal and secondary-generalized seizures

Detoxification

Step one in the treatment of dependence Goals of detox - Withdraw the offending agent - Allow the body to adapt to the absence of the offending agent -> homeostasis - Diagnose/treat comorbid conditions - Prepare the patient for long-term rehabilitation

What are the classes and structures of local anesthetics?

Structurally classified 1. Ester-linked 2. Amide-linked All local anesthetics have three structural domains 1. Aromatic group 2. Amine group 3. Ester or Amide bridge

Alternative therapies to antiepileptic drugs?

Surgery - Vagal nerve stimulation -- Decreased frequency in resistant epilepsies - Focal ablation Ketogenic Diet - High fat, adequate protein, low carbohydrate diet -- Ketosis - long and medium-chain fatty acids, are directly anticonvulsant Herbal - Cannabinoids (not THC) -- Anecdotal evidence, no controlled studies -- Law limits research and application -- Some studies report proconvulsant effects

What are the symptoms of serotonin syndrome and what causes it?

Symptoms of serotonin syndrome include: - Hyperthermia - Muscle rigidity - Myoclonus (quick, involuntary muscle jerk) - Rapid fluctuations in mental status and vital signs -- Can range from mild to lethal Serotonin syndrome is thought to be caused by overstimulation of 5-HT receptors in the central gray nuclei and the medulla (withdrawal of causative agents and supportive measures such as hemodynamic stabilization, sedation, temperature control, hydration, and monitoring for complications)

Detoxification strategies

Taper - Gradually decrease the dose of the drug to ease the symptoms of withdrawal -- Nicotine -- Opioids -- Alcohol Long-acting drugs of the same class which demonstrate cross-tolerance can be used

Opioids and examples

Use was described in Egyptian, Sumerian, and Persian texts Medically used to treat *diarrhea* - Nausea and vomiting - Feeling of pleasantness (high dose) 1805: German pharmacist, Wilhelm Sertürner, isolated Morphium (morphine) Examples: Morphine, heroin codeine, oxycodone, fentanyl.

What is the partition coefficient of the various gasses?

VERY IMPORTANT The MAC (minimal alveolar concentration) of a volatile substance is inversely proportional to its lipid solubility (oil:gas coefficient) MAC is inversely proportional to potency. - The higher the MAC the lower the potency.

Addiction continued

The interplay of learning, dopaminergic reward mechanism, and individual factors determine addiction - The drug becomes the only means to experiencing positive emotion -- Cessation of drug use results in anhedonia --- Cravings, sleep disturbances, increased reactivity.

What is dependence syndrome?

The need for the drug to be present in the brain to maintain "near-normal" functioning.

GABAergic Abuse liability

The withdrawal of GABAergic anxiolytics must be tapered slowly to eliminate withdrawal. Abrupt discontinuation of GABAergic treatment can result in rebound anxiety (less intense with benzodiazepines), restlessness, seizures, and insomnia. The intensity and duration of these symptoms depends on tolerance, which has been shown to be dose and treatment duration dependent. Short acting barbiturates display intense withdrawal symptoms, which persist for a shorter period of time than many of the other GABAergic anxiolytics.

Adverse effects: women of childbearing age contraception, fertility, and teratogens with antiepileptic drugs.

There are a number of considerations in treating women of child bearing age for epilepsy - Contraception - Fertility - Teratogens *Contraception* - Decrease in estrogen and progesterone in patients taking many antiepileptic drugs -- *Phenytoin, carbamazepine, phenobarbital, felbamate, topiramate, and vigabatrin* -- Intrauterine devices and depot injections do not appear to have increased failure rate - *Lamotrigine* metabolism is increased in patients taking oral contraceptives -> decreased seizure control *Fertility* - Some studies have asserted that there is an increased rate of infertility in women with epilepsy - 33-38% -- Refuted - Links to polytherapy and older age -- *Valproic* acid was also linked to increased risk of polycystic ovary disease - leading cause of infertility in women *Teratogens* - Increased risk of both major and minor malformations -- *valproic acid, phenytoin, carbamazepine, phenobarbital, and topiramate* - Drug, polytherapy, and gestational timing all play a role - *Valproic acid and carbamazepine* have been linked to increased risk of spina bifida - *Valproic acid* - 10- to 20- fold increase in risk - Other malformations include: orofacial clefts, cardiac malformations, limb malformations, and genitourinary defects

Positive and negative reinforcement

There is a learned component to addiction Positive reinforcement - Perceived reward -- Euphoria -- Anxiolytic Negative reinforcement - Relief factor -- Acute withdrawal -- Reduced stress -- Reduced dysphoria

Cocaine and Amphetamine treatment

There is no FDA approved treatment for the treatment of cocaine and amphetamine addiction - Desipramine is a tricyclic antidepressant -- Blocks monoamine uptake (especially norepinephrine) - Fluoxetine is a selective serotonin reuptake inhibitor Both agents reduce cravings but do not stop future use.

What are Lithium effects on IP3

This is the mechanism by which lithium is reported to promote mood stabilization. - IP3 cascade is reported to underlie manic episodes. Activation of PKC and mobilization of Ca+ results in changes in neurotransmitter release and gene expression which may play a role in mania. - Intracellular IP3 is recycled via two enzymes, polyphosphate-1-phosphatase (IPP) and inositol monophosphatase (IMPase). Lithium is thought to suppress inositol signaling by inhibiting these enzymes and reducing free inositol

Hormonal abnormalities and depression

Thyroid dysregulation has been reported in up to 25% of patients - Blunted response of thyrotropin to thyrotropin-releasing hormone Clinically, hypothyroidism often presents with symptoms of depression - Symptoms resolve with thyroid hormone replacement -- Can be used in combination with antidepressants to increase efficacy Sex hormone deficiencies have also been associated with depressive symptoms - Symptoms resolve with hormone therapy

Nociceptor activation

Tissue damage generates action potentials which are conducted to the spinal cord to the somatosensory cortex of the brain

Challenges in pain management

Tolerance begins with the first dose- Differential tolerance Partial cross-tolerance can develop - Opioid rotation - Minimize tolerance - Lowest possible dose with longest interval

What is the MOA, CU, and AE of Liothyronine?

Treatment of hypothyroidism *Liothyronine* *MOA*: L-isomer of T3 - Shorter half life (24 h), multiple daily dosing, higher costs. - 3-4 times more potent than levothyroxine. *CU*: not recommended for routine replacement therapy. - Used in life-threatening hypothyroidism -- Unconsciousness, coma, dry skin, low heart rate, low body temperature -- History of thyroidectomy or radioactive iodine therapy. Shorter half life than Levothyroxine, therapeutic levels are reached faster.

What is the MOA, CU, and AE of Levothyroxine?

Treatment of hypothyroidism. *Levothyroxine* *MOA*: L-isomer of T4 - Thyroid hormone replacement - Stable, low cost, long half-life (7 days). *CU*: drug of choice for hypothyroidism - Oral, once daily to weekly administration - Monitor TSH levels every 6 months to a year *AE*: tachycardia, heat intolerance, tremors.

Treatment of moderate to severe Alzheimer's Disease, drug used, MOA of drug, and adverse effects

Treatment of moderate to severe disease: - Excitotoxic activation of glutamate transmission via NMDA receptors is hypothesized to contribute to the pathophysiology of AD *Memantine* *MOA*: low potency, noncompetitive antagonist of NMDA receptor - Attenuates the excitotoxic effects of glutamate - May be used in combination with cholinesterase inhibitors *Adverse effects*: dizziness, headache, and confusion

What are the tricyclic antidepressants, their MOA, clinical indications, and adverse effects?

Tricyclic Antidepressants *Amitriptyline, Nortriptyline, Imipramine, Desipramine, Clomipramine, Doxepin, Amoxapine* *MOA* - Inhibition of SERT and NET resulting in increased serotonin and norepinephrine in the synapse *Clinical indications* - Major depression - Obsessive compulsive disorder (clomipramine) - Peripheral neuropathy - Chronic pain - Migraine - Doses needed to relieve pain are lower than those needed for the treatment of depression. *Adverse effects* - TCAs are nonspecific -- Inhibition of voltage-gated sodium channels and potassium efflux -> decreased conduction leading to prolonged QT interval -- Anticholinergic effects (muscarinic receptors): nausea, vomiting, anorexia, dry mouth, blurred vision, confusion, constipation, tachycardia, and urinary retention. - Antihistamine effects: sedation and weight gain - Antiadrenergic effects: postural hypotension (a1) and reflex tachycardia. - TCA overdose can be treated with sodium bicarbonate - TCAs may precipitate manic state in patients with bipolar disorder. (Use of tricyclic antidepressants has decreased significantly with the development of the SSRI and SNRI agents which are more well tolerated)

What are the 2 main types of general anesthetics and what are the 5 desired effects?

Two main types of general anesthetics A. Inhalation B. Intravenous Five desired effects of general anesthetics: 1. Analgesia 2. Amnesia 3. Immobility 4. Inhibition of autonomic reflexes 5. Unconsciousness None of the currently available general anesthetics are capable of achieving all desired effects - Modern anesthesia uses a combination of inhalation and intravenous general anesthetics to achieve all desired effects -- Balanced anesthesia.

What are the 2 types of insulin regimens for type 1 diabetes

Type 1 DM: 0.4 - 1 units/kg/day of insulin - 50% as basal insulin - 50% as bolus insulin 1. *Long-acting insulin + insulin analogue* - Long-acting insulin: supply *basal* insulin, before bedtime. - Rapid/short-acting insulin: provide *prandial insulin*, before meal. 2. *NPH + insulin analogue* - *Morning*: -- Give two thirds of daily insulin subcutaneously -- Ratio of regular/rapid insulin to NPH insulin 1:2. - *Evening*: -- Give one third of daily insulin subcutaneously -- Ratio of regular insulin to NPH insulin 1:1. - Forces a rigid schedule on the patient NPH is Neutral protamine Hagedorn, an intermediate acting insulin.

What is the use of intravenous anesthetic based on? Which anesthetics is the preferred intravenous anesthetic?

Use of intravenous anesthetic is based on the *context-sensitive half-time* - Defined as elimination half-life after a continuous infusion as a function of the duration of the infusion. After a prolonged infusion, the half-time of propofol is relatively short, making it the *preferred intravenous anesthetic*, ketamine and etomidate have similar characteristic, but their use is limited by other effects.

Opioid addiction

Ventral tegmental area (VTA) - GABAergic neurons inhibit the dopaminergic neurons which project to award centers of the brain - Endogenous opioids inhibit the GABAergic terminals -- Resulting in increased dopaminergic signaling. - Exogenous opioids bind and activate the µ-opioid receptors -> disinhibition of dopaminergic neurons - This positive reinforcement lends to the addictive potential of opioids

How is insulin made?

Via recombinant DNA technology

What receptors are involved in seizure activity?

Voltage-gated Sodium Channels - Voltage gated - Propagates action potential GABAa Channels - Cl- channel - Inhibitory signal Voltage-gated calcium channels - Upregulated in absence epilepsy Glutamate channels - Primary excitatory neurotransmitter - AMPA (non-NMDA receptor) and NMDA -- Glycine binding site (NMDA)

Withdrawal

When the drug is eliminated from the body, the adaptations that produce dependence become apparent and *acute withdrawal syndrome* is observed - Withdrawal persists until the system restores homeostasis in the absence of the drug -- Symptoms and duration vary based on the drug and duration of use/abuse

Alcohol withdrawal symptoms, severe withdrawal

Withdrawal symptoms: - Anxiety - Tremor - Seizures - Insomnia Severe withdrawal: - Autonomic hyperactivity - Delirium tremens