What is the mechanism of action of Adenosine in terminating paroxysmal supraventricular tachycardia (PSVT), and what antagonizes it?

Activates Gi-coupled A1 adenosine receptors in the SA and AV nodes, opening inward-rectifier K+ channels (IKACh/ADO, causing hyperpolarization) and inhibiting L-type Ca2+ currents, producing transient AV nodal block to terminate AV-nodal-dependent PSVT. Ultra-short half-life (< 10 seconds); administered via rapid IV push followed immediately by a normal saline flush. Antagonized competitively by methylxanthines (caffeine, theophylline); potentiated by dipyridamole and carbamazepine (reduce initial adenosine dose by 50% to 3 mg in patients taking dipyridamole/carbamazepine, in denervated transplanted hearts, or when given via central line). Contraindicated in asthma and pre-excited atrial fibrillation (WPW).

What severe organ toxicities are associated with long-term Amiodarone therapy, and what baseline screening is required?

Contains ~37% iodine by weight and accumulates in tissues. Toxicities: Pulmonary toxicity (fatal chronic interstitial pneumonitis/pulmonary fibrosis), Thyroid dysfunction (hypothyroidism [Wolff-Chaikoff] or hyperthyroidism [Jod-Basedow]), Hepatotoxicity (elevated transaminases, cirrhosis), Corneal microdeposits, Optic neuropathy, and Blue-gray facial skin discoloration. Baseline tests: Chest X-ray, Pulmonary Function Tests (DLCO), Thyroid Function Tests (TSH/free T4), and Liver Function Tests.

What is the mechanism of Serotonin-Norepinephrine Reuptake Inhibitors (SNRIs, e.g., Venlafaxine, Duloxetine), and what unique adverse effect can occur?

Inhibit both the Serotonin Transporter (SERT) and Norepinephrine Transporter (NET), boosting central 5-HT and NE neurotransmission. Indicated for major depressive disorder, generalized anxiety, and chronic neuropathic pain conditions (diabetic neuropathy, fibromyalgia). Due to increased peripheral noradrenergic stimulation, SNRIs can cause dose-dependent sustained elevations in blood pressure and heart rate.

What is the intracellular molecular cascade of Nitroglycerin, and why are PDE-5 inhibitors strictly contraindicated with nitrates?

Nitroglycerin is denitrated by mitochondrial aldehyde dehydrogenase (ALDH2) to release Nitric Oxide (NO) -> activates soluble Guanylyl Cyclase -> increases intracellular cGMP -> activates Protein Kinase G (PKG) -> dephosphorylation of myosin light chains -> profound venodilation and reduced preload. Phosphodiesterase-5 (PDE-5) inhibitors (Sildenafil, Tadalafil) block cGMP degradation; co-administration causes synergistic cGMP accumulation, precipitating profound, refractory, fatal hypotension.

How do Dihydropyridine and Non-Dihydropyridine Calcium Channel Blockers (CCBs) differ in vascular versus myocardial selectivity and clinical use?

Dihydropyridines (e.g., Amlodipine, Nifedipine) selectively block L-type voltage-gated calcium channels in vascular smooth muscle, causing arterial vasodilation and lowering blood pressure; side effects include peripheral dependent edema and reflex tachycardia. Non-dihydropyridines (Verapamil, Diltiazem) act primarily on myocardium and SA/AV nodal tissue, slowing conduction and decreasing contractility; used for rate control in atrial fibrillation and angina, but contraindicated in HFrEF.

What is the therapeutic plasma level of Lithium, and what medications precipitate acute Lithium toxicity by reducing its renal clearance?

Narrow therapeutic window: 0.6 to 1.2 mEq/L (acute toxicity occurs > 1.5 mEq/L: tremor, ataxia, confusion, seizures). Lithium is filtered at the glomerulus and 80% reabsorbed in the proximal convoluted tubule competitively with sodium. Drugs that deplete volume or reduce GFR enhance proximal lithium reabsorption, triggering toxicity: Thiazide diuretics (highest risk), NSAIDs (block renal prostaglandins), and ACE inhibitors / ARBs.

How do Sulfonylureas (Glipizide, Glimepiride) stimulate insulin secretion at the pancreatic beta-cell level?

Bind to and inhibit the SUR1 regulatory subunit of ATP-sensitive Potassium (K_ATP) channels on pancreatic beta-cell membranes. Closure of K_ATP channels prevents potassium efflux, depolarizing the cell membrane. Depolarization opens voltage-gated calcium channels; calcium influx triggers exocytosis of preformed insulin storage granules. Primary adverse risks are severe hypoglycemia and weight gain.

What is the hemodynamic mechanism of ACE inhibitors in the renal glomerulus, and what causes the characteristic dry cough and angioedema?

ACE inhibitors (e.g., Lisinopril, Enalapril) block conversion of Angiotensin I to Angiotensin II, preferentially dilating the EFFERENT glomerular arteriole, which decreases intraglomerular capillary hydrostatic pressure and reduces proteinuria (protecting diabetic kidneys). ACE is identical to Kininase II; its inhibition prevents the degradation of Bradykinin and substance P, leading to dry cough and rare, life-threatening angioedema.

What is the mechanism of action of Thiazide diuretics (HCTZ, Chlorthalidone), and how does their effect on calcium excretion differ from loop diuretics?

Inhibit the Na+/Cl- cotransporter in the Distal Convoluted Tubule (DCT). In contrast to loop diuretics, thiazides DECREASE urinary calcium excretion (causing hypercalcemia) by enhancing proximal and distal transcellular calcium reabsorption (making them protective in recurrent calcium nephrolithiasis and osteoporosis). Side effects: 'hyperGLUC' (Hyperglycemia, Hyperlipidemia, Hyperuricemia, Hypercalcemia) + Hypokalemia.

What is the classic clinical symptom triad of acute Opioid Overdose, and what is the emergency competitive antagonist?

Triad: 1) Severe Respiratory Depression (decreased respiratory rate and tidal volume); 2) Pinpoint pupils (Miosis; though pupillary dilation can occur with meperidine or severe hypoxia); 3) Central nervous system depression (stupor or coma). The emergency competitive mu-opioid receptor antagonist is Naloxone (Narcan), administered IV, IM, subcutaneous, or intranasally.

What instructions must be given to patients regarding the administration of Levothyroxine (T4) to ensure optimal bioavailability?

Take once daily in the morning on an empty stomach with a full glass of water, at least 30 to 60 minutes before breakfast (or at bedtime at least 3-4 hours after the last meal). Co-administration with Calcium carbonate, Ferrous sulfate (iron), Aluminum hydroxide antacids, Sucralfate, or Proton Pump Inhibitors dramatically impairs gastrointestinal absorption and must be separated by at least 4 hours.

What is the primary mechanism of Second-Generation (Atypical) Antipsychotics, and what life-threatening adverse effect requires mandatory hematologic monitoring with Clozapine?

Combine potent Serotonin 5-HT2A receptor antagonism with Dopamine D2 receptor antagonism (or D2 partial agonism for aripiprazole/brexpiprazole), lowering the incidence of extrapyramidal symptoms compared to first-generation antipsychotics. Clozapine (most effective for treatment-resistant schizophrenia) carries boxed warnings for severe neutropenia/agranulocytosis (ANC < 500/mcL in ~1% of patients), myocarditis, and seizures; baseline and periodic ANC monitoring is clinically indicated (though in February 2025 the FDA removed the centralized Clozapine REMS dispensing program requirement).

What are the primary molecular mechanisms of Phenytoin, Ethosuximide, and Levetiracetam in seizure control?

Phenytoin: use-dependent block of voltage-gated Sodium channels, prolonging the inactivated state and preventing high-frequency repetitive firing (exhibits zero-order kinetics and causes gingival hyperplasia). Ethosuximide: blocks low-threshold T-type Calcium channels in thalamic relay neurons; first-line therapy for Absence (petit mal) seizures. Levetiracetam (Keppra): binds presynaptic Synaptic Vesicle Protein 2A (SV2A), modulating neurotransmitter exocytosis.

What is the mechanism of action of PCSK9 inhibitors (Evolocumab, Alirocumab)?

Fully human monoclonal antibodies directed against Proprotein Convertase Subtilisin/Kexin type 9 (PCSK9). PCSK9 normally binds LDL receptors and targets them for lysosomal degradation. By inhibiting PCSK9, these antibodies prevent receptor degradation, recycling LDL receptors back to the hepatocyte surface and reducing serum LDL cholesterol by 50-60% even in patients already on maximum-dose statin therapy.

What are the four clinical forms of Extrapyramidal Symptoms (EPS) caused by first-generation high-potency antipsychotics (Haloperidol)?

1. Acute Dystonia (hours to days): painful sustained muscle spasms (torticollis, laryngospasm, oculogyric crisis); treated with antimuscarinics (benztropine, diphenhydramine). 2. Akathisia (days to weeks): subjective inner restlessness and inability to sit still; treated with propranolol, benzodiazepines, or dose reduction. 3. Drug-Induced Parkinsonism (weeks to months): bradykinesia, cogwheel rigidity, resting tremor; treated with benztropine or amantadine. 4. Tardive Dyskinesia (months to years): choreoathetoid orofacial and limb movements from postsynaptic D2 receptor supersensitivity; treated with VMAT2 inhibitors (valbenazine, deutetrabenazine).

What is the pathophysiologic mechanism of the hypertensive crisis ('cheese effect') associated with Monoamine Oxidase Inhibitors (MAOIs)?

MAOIs (Phenelzine, Tranylcypromine, Selegiline) irreversibly inhibit MAO-A and MAO-B. Ingestion of tyramine-rich foods (aged cheeses, cured meats, red wine, draft beer) allows unmetabolized tyramine to enter systemic circulation (normally degraded by intestinal MAO-A). Tyramine enters sympathetic terminals via NET and displaces massive amounts of vesicular norepinephrine into the synaptic cleft, triggering severe hypertensive crisis and stroke.

What are the clinical pharmacokinetic profiles of Rapid-Acting, Short-Acting, and Long-Acting basal insulins?

Rapid-acting (Lispro, Aspart, Glulisine): amino acid substitutions prevent hexamer dimerization; onset 10-20 min, peak 1-2 hours, duration 3-5 hours (administered immediately before meals). Short-acting (Regular insulin): hexamers dissociate slowly; onset 30-60 min, peak 2-4 hours, duration 6-8 hours (only form used for IV DKA infusion). Long-acting basal (Glargine, Degludec): precipitates in subcutaneous tissue or forms multi-hexamers; onset 1-2 hours, essentially PEAKLESS, duration >= 24 hours.

How do Benzodiazepines and Barbiturates differ in their molecular modulation of the GABA-A receptor, and what is the reversal agent for benzodiazepines?

GABA-A receptors are pentameric ligand-gated chloride channels. Benzodiazepines (lorazepam, diazepam, midazolam) bind between alpha and gamma subunits to increase the FREQUENCY of Cl- channel opening in the presence of endogenous GABA. Barbiturates (phenobarbital) increase the DURATION of Cl- channel opening and at high doses directly open the channel (narrower safety margin). The competitive benzodiazepine antagonist is Flumazenil, which must be used with caution as it can precipitate refractory withdrawal seizures in chronic benzodiazepine users or patients with tricyclic antidepressant co-ingestion.

How do Spironolactone and Eplerenone differ from Amiloride and Triamterene in potassium-sparing diuretic mechanisms and side effects?

Spironolactone and Eplerenone are competitive mineralocorticoid (aldosterone) receptor antagonists in the cortical collecting tubule, preventing expression of ENaC and basolateral Na+/K+-ATPase. Spironolactone also non-selectively blocks androgen receptors, causing gynecomastia and erectile dysfunction; Eplerenone is highly selective with no antiandrogenic effects. Amiloride and Triamterene are direct epithelial sodium channel (ENaC) blockers.

What is the pharmacological mechanism of GLP-1 receptor agonists (Semaglutide, Liraglutide), and what is their Black Box Warning?

Incretin mimetics that bind and activate the Glucagon-Like Peptide-1 (GLP-1) receptor, stimulating glucose-dependent insulin secretion from pancreatic beta cells, suppressing inappropriate glucagon secretion, slowing gastric emptying, and centrally increasing satiety. Black Box Warning: contraindicated in patients with a personal or family history of Medullary Thyroid Carcinoma (MTC) or Multiple Endocrine Neoplasia syndrome type 2 (MEN 2) due to thyroid C-cell tumor risk.

What is the cellular mechanism of action of Digoxin, and what electrolyte disturbances potentiate its toxicity?

Inhibits the cardiac sarcolemmal Na+/K+-ATPase pump -> increases intracellular Na+ -> decreases Na+/Ca2+ exchanger activity -> increases intracellular Ca2+ storage in sarcoplasmic reticulum -> positive inotropy. Also stimulates central vagal tone (slowing AV conduction). Hypokalemia, Hypomagnesemia, and Hypercalcemia strongly potentiate digoxin toxicity because K+ normally competes with digoxin for binding to the Na+/K+-ATPase.

What is the primary mechanism of action of SSRIs, and how long does it take for clinical antidepressant efficacy to manifest?

Selectively inhibit the presynaptic Serotonin Transporter (SERT), blocking 5-HT reuptake and increasing synaptic serotonin. Full antidepressant efficacy requires 4 to 6 weeks due to downstream neuroplastic adaptations, including presynaptic 5-HT1A autoreceptor desensitization and increased BDNF expression. Combining SSRIs with MAOIs, linezolid, or tramadol risks Serotonin Syndrome (clonus, hyperreflexia, hyperthermia, agitation; treated with cyproheptadine), requiring a 2-week washout when switching to/from MAOIs (5 weeks when stopping fluoxetine due to norfluoxetine's long half-life).

What is the enzymatic target and acid-base consequence of Acetazolamide?

Inhibits Carbonic Anhydrase (primarily CA-II and CA-IV) in the brush border and cytoplasm of the Proximal Convoluted Tubule, blocking reabsorption of sodium bicarbonate (NaHCO3). Promotes urinary bicarbonate excretion (alkaline urine), producing a mild Normal Anion Gap (hyperchloremic) Metabolic Acidosis. Used for Acute Mountain Sickness prophylaxis, glaucoma, and metabolic alkalosis.

What is the enzymatic target of Statin drugs (Atorvastatin, Rosuvastatin), and how do they reduce circulating LDL cholesterol?

Competitively inhibit HMG-CoA Reductase, the rate-limiting enzyme converting HMG-CoA to Mevalonate in cholesterol biosynthesis. Decreased intracellular hepatocyte cholesterol triggers SREBP-2 transcription factor upregulation, dramatically increasing cell-surface LDL Receptor expression, which clears ApoB-100 containing LDL and VLDL remnants from circulation. Adverse effects: myopathy, rhabdomyolysis, and transaminitis.

What is the mechanism of Mannitol, and what are its primary clinical indications and contraindications?

An osmotic diuretic that is freely filtered at the glomerulus but poorly reabsorbed; increases tubular fluid osmolarity, drawing water into the lumen to promote osmotic diuresis in proximal tubule and descending loop of Henle. Clinical indications: acute reduction of intracranial pressure (ICP) in cerebral edema and intraocular pressure in acute glaucoma. Contraindications: active intracranial bleeding, anuria, and severe pulmonary edema / congestive heart failure.

What are the '3 Cs' of Tricyclic Antidepressant (TCA) overdose toxicity, and what is the specific antidote for TCA-induced cardiac conduction widening?

The 3 Cs: 1) Cardiotoxicity (QRS widening, VT/VF due to fast cardiac sodium channel blockade); 2) Convulsions / Seizures (GABA-A antagonism); 3) Coma (antihistaminic and antimuscarinic CNS effects). Antidote: Intravenous Sodium Bicarbonate (NaHCO3 1-2 mEq/kg bolus), which increases extracellular sodium to overcome competitive Na+ channel block and raises blood pH to decrease active drug binding.

How do Angiotensin Receptor Blockers (ARBs) differ pharmacologically from ACE inhibitors, and what is their clinical niche?

ARBs such as losartan and valsartan block angiotensin II AT1 receptors without inhibiting ACE (kininase II). They therefore do not inhibit bradykinin breakdown and cause less cough than ACE inhibitors. Angioedema is less common but can still occur, including in people with previous ACE-inhibitor-associated angioedema; it is not a zero-risk alternative.

What is the mechanism of action of Metformin, and why is it temporarily held before intravenous iodinated radiocontrast procedures?

A biguanide that inhibits hepatic mitochondrial complex I and activates AMP-activated protein kinase (AMPK), suppressing hepatic gluconeogenesis and increasing peripheral insulin sensitivity without stimulating insulin secretion (minimal hypoglycemia risk; chronic use can cause vitamin B12 deficiency). Metformin is contraindicated if eGFR < 30 mL/min/1.73 m2 and is temporarily held at the time of or prior to iodinated IV contrast procedures in patients with eGFR 30–60 mL/min/1.73 m2 (or intra-arterial contrast/hepatic/heart failure), with eGFR rechecked at 48 hours before restarting, to prevent Metformin-Associated Lactic Acidosis (MALA).

What are the four classes of the Vaughan Williams antiarrhythmic classification system and their primary electrophysiologic mechanisms?

Class I: Voltage-gated Sodium channel blockers (Ia: Procainamide, Quinidine [prolong APD]; Ib: Lidocaine, Mexiletine [shorten APD]; Ic: Flecainide, Propafenone [no change on APD, profound phase 0 slowing]). Class II: Beta-adrenergic receptor antagonists (Metoprolol, Esmolol; decrease SA/AV nodal automaticity). Class III: Potassium channel blockers (Amiodarone, Sotalol, Dofetilide; prolong repolarization and APD/QT). Class IV: Calcium channel blockers (Verapamil, Diltiazem; slow AV nodal conduction).

How do Propylthiouracil (PTU) and Methimazole differ in mechanisms, trimester preference during pregnancy, and organ toxicities?

Both inhibit thyroid peroxidase (TPO), blocking iodine organification and coupling. PTU ALSO inhibits peripheral 5'-deiodinase, blocking conversion of T4 to active T3 (making PTU first-line in Thyroid Storm). In pregnancy: PTU is preferred in the FIRST trimester (methimazole causes embryopathy: aplasia cutis, choanal atresia); Methimazole is preferred in 2nd and 3rd trimesters due to PTU black box warning for fulminant hepatic necrosis. Both cause agranulocytosis.

What is the molecular target of Loop Diuretics (Furosemide, Bumetanide) in the nephron, and what electrolyte abnormalities do they produce?

Inhibit the Na+/K+/2Cl- cotransporter in the Thick Ascending Limb of the Loop of Henle, dissipating the corticomedullary osmotic gradient and impairing urine concentrating ability. Electrolyte losses: Hypokalemia, Hypomagnesemia, Hypocalcemia (loop diuretics lose calcium by abolishing the positive lumen potential), and Hypochloremic Metabolic Alkalosis; also cause Hyperuricemia and Ototoxicity.

What is the mechanism of SGLT2 inhibitors (Empagliflozin, Dapagliflozin), and what rare metabolic complication can occur?

Selectively inhibit the Sodium-Glucose Cotransporter 2 (SGLT2) in the S1 segment of the proximal convoluted tubule, blocking ~90% of renal glucose and sodium reabsorption, producing glucosuria, natriuresis, weight loss, and reduced cardiovascular mortality and HF hospitalizations. Rare severe complication: Euglycemic Diabetic Ketoacidosis (euDKA, ketoacidosis with blood glucose < 250 mg/dL), alongside mycotic genital infections and Fournier gangrene.

Cardiovascular, Renal, Endocrine & Central Nervous System Pharmacology

Therapeutic pharmacology of the cardiovascular and renal systems (RAAS inhibitors, CCBs, diuretics, antiarrhythmics, lipid-lowering agents), endocrine disorders (diabetes, thyroid), and central nervous system drugs.

Level: intermediate
Languages: en → en
Cards: 32
Markdown: Cardiovascular, Renal, Endocrine & Central Nervous System Pharmacology (.md)

Flashcards (32)

#	Front (Term / Question)	Back (Definition / Answer)
1	What is the mechanism of action of Adenosine in terminating paroxysmal supraventricular tachycardia (PSVT), and what antagonizes it?	Activates Gi-coupled A1 adenosine receptors in the SA and AV nodes, opening inward-rectifier K+ channels (IKACh/ADO, causing hyperpolarization) and inhibiting L-type Ca2+ currents, producing transient AV nodal block to terminate AV-nodal-dependent PSVT. Ultra-short half-life (< 10 seconds); administered via rapid IV push followed immediately by a normal saline flush. Antagonized competitively by methylxanthines (caffeine, theophylline); potentiated by dipyridamole and carbamazepine (reduce initial adenosine dose by 50% to 3 mg in patients taking dipyridamole/carbamazepine, in denervated transplanted hearts, or when given via central line). Contraindicated in asthma and pre-excited atrial fibrillation (WPW).
2	What severe organ toxicities are associated with long-term Amiodarone therapy, and what baseline screening is required?	Contains ~37% iodine by weight and accumulates in tissues. Toxicities: Pulmonary toxicity (fatal chronic interstitial pneumonitis/pulmonary fibrosis), Thyroid dysfunction (hypothyroidism [Wolff-Chaikoff] or hyperthyroidism [Jod-Basedow]), Hepatotoxicity (elevated transaminases, cirrhosis), Corneal microdeposits, Optic neuropathy, and Blue-gray facial skin discoloration. Baseline tests: Chest X-ray, Pulmonary Function Tests (DLCO), Thyroid Function Tests (TSH/free T4), and Liver Function Tests.
3	What is the mechanism of Serotonin-Norepinephrine Reuptake Inhibitors (SNRIs, e.g., Venlafaxine, Duloxetine), and what unique adverse effect can occur?	Inhibit both the Serotonin Transporter (SERT) and Norepinephrine Transporter (NET), boosting central 5-HT and NE neurotransmission. Indicated for major depressive disorder, generalized anxiety, and chronic neuropathic pain conditions (diabetic neuropathy, fibromyalgia). Due to increased peripheral noradrenergic stimulation, SNRIs can cause dose-dependent sustained elevations in blood pressure and heart rate.
4	What is the intracellular molecular cascade of Nitroglycerin, and why are PDE-5 inhibitors strictly contraindicated with nitrates?	Nitroglycerin is denitrated by mitochondrial aldehyde dehydrogenase (ALDH2) to release Nitric Oxide (NO) -> activates soluble Guanylyl Cyclase -> increases intracellular cGMP -> activates Protein Kinase G (PKG) -> dephosphorylation of myosin light chains -> profound venodilation and reduced preload. Phosphodiesterase-5 (PDE-5) inhibitors (Sildenafil, Tadalafil) block cGMP degradation; co-administration causes synergistic cGMP accumulation, precipitating profound, refractory, fatal hypotension.
5	How do Dihydropyridine and Non-Dihydropyridine Calcium Channel Blockers (CCBs) differ in vascular versus myocardial selectivity and clinical use?	Dihydropyridines (e.g., Amlodipine, Nifedipine) selectively block L-type voltage-gated calcium channels in vascular smooth muscle, causing arterial vasodilation and lowering blood pressure; side effects include peripheral dependent edema and reflex tachycardia. Non-dihydropyridines (Verapamil, Diltiazem) act primarily on myocardium and SA/AV nodal tissue, slowing conduction and decreasing contractility; used for rate control in atrial fibrillation and angina, but contraindicated in HFrEF.
6	What is the therapeutic plasma level of Lithium, and what medications precipitate acute Lithium toxicity by reducing its renal clearance?	Narrow therapeutic window: 0.6 to 1.2 mEq/L (acute toxicity occurs > 1.5 mEq/L: tremor, ataxia, confusion, seizures). Lithium is filtered at the glomerulus and 80% reabsorbed in the proximal convoluted tubule competitively with sodium. Drugs that deplete volume or reduce GFR enhance proximal lithium reabsorption, triggering toxicity: Thiazide diuretics (highest risk), NSAIDs (block renal prostaglandins), and ACE inhibitors / ARBs.
7	How do Sulfonylureas (Glipizide, Glimepiride) stimulate insulin secretion at the pancreatic beta-cell level?	Bind to and inhibit the SUR1 regulatory subunit of ATP-sensitive Potassium (K_ATP) channels on pancreatic beta-cell membranes. Closure of K_ATP channels prevents potassium efflux, depolarizing the cell membrane. Depolarization opens voltage-gated calcium channels; calcium influx triggers exocytosis of preformed insulin storage granules. Primary adverse risks are severe hypoglycemia and weight gain.
8	What is the hemodynamic mechanism of ACE inhibitors in the renal glomerulus, and what causes the characteristic dry cough and angioedema?	ACE inhibitors (e.g., Lisinopril, Enalapril) block conversion of Angiotensin I to Angiotensin II, preferentially dilating the EFFERENT glomerular arteriole, which decreases intraglomerular capillary hydrostatic pressure and reduces proteinuria (protecting diabetic kidneys). ACE is identical to Kininase II; its inhibition prevents the degradation of Bradykinin and substance P, leading to dry cough and rare, life-threatening angioedema.
9	What is the mechanism of action of Thiazide diuretics (HCTZ, Chlorthalidone), and how does their effect on calcium excretion differ from loop diuretics?	Inhibit the Na+/Cl- cotransporter in the Distal Convoluted Tubule (DCT). In contrast to loop diuretics, thiazides DECREASE urinary calcium excretion (causing hypercalcemia) by enhancing proximal and distal transcellular calcium reabsorption (making them protective in recurrent calcium nephrolithiasis and osteoporosis). Side effects: 'hyperGLUC' (Hyperglycemia, Hyperlipidemia, Hyperuricemia, Hypercalcemia) + Hypokalemia.
10	What is the classic clinical symptom triad of acute Opioid Overdose, and what is the emergency competitive antagonist?	Triad: 1) Severe Respiratory Depression (decreased respiratory rate and tidal volume); 2) Pinpoint pupils (Miosis; though pupillary dilation can occur with meperidine or severe hypoxia); 3) Central nervous system depression (stupor or coma). The emergency competitive mu-opioid receptor antagonist is Naloxone (Narcan), administered IV, IM, subcutaneous, or intranasally.
11	What instructions must be given to patients regarding the administration of Levothyroxine (T4) to ensure optimal bioavailability?	Take once daily in the morning on an empty stomach with a full glass of water, at least 30 to 60 minutes before breakfast (or at bedtime at least 3-4 hours after the last meal). Co-administration with Calcium carbonate, Ferrous sulfate (iron), Aluminum hydroxide antacids, Sucralfate, or Proton Pump Inhibitors dramatically impairs gastrointestinal absorption and must be separated by at least 4 hours.
12	What is the primary mechanism of Second-Generation (Atypical) Antipsychotics, and what life-threatening adverse effect requires mandatory hematologic monitoring with Clozapine?	Combine potent Serotonin 5-HT2A receptor antagonism with Dopamine D2 receptor antagonism (or D2 partial agonism for aripiprazole/brexpiprazole), lowering the incidence of extrapyramidal symptoms compared to first-generation antipsychotics. Clozapine (most effective for treatment-resistant schizophrenia) carries boxed warnings for severe neutropenia/agranulocytosis (ANC < 500/mcL in ~1% of patients), myocarditis, and seizures; baseline and periodic ANC monitoring is clinically indicated (though in February 2025 the FDA removed the centralized Clozapine REMS dispensing program requirement).
13	What are the primary molecular mechanisms of Phenytoin, Ethosuximide, and Levetiracetam in seizure control?	Phenytoin: use-dependent block of voltage-gated Sodium channels, prolonging the inactivated state and preventing high-frequency repetitive firing (exhibits zero-order kinetics and causes gingival hyperplasia). Ethosuximide: blocks low-threshold T-type Calcium channels in thalamic relay neurons; first-line therapy for Absence (petit mal) seizures. Levetiracetam (Keppra): binds presynaptic Synaptic Vesicle Protein 2A (SV2A), modulating neurotransmitter exocytosis.
14	What is the mechanism of action of PCSK9 inhibitors (Evolocumab, Alirocumab)?	Fully human monoclonal antibodies directed against Proprotein Convertase Subtilisin/Kexin type 9 (PCSK9). PCSK9 normally binds LDL receptors and targets them for lysosomal degradation. By inhibiting PCSK9, these antibodies prevent receptor degradation, recycling LDL receptors back to the hepatocyte surface and reducing serum LDL cholesterol by 50-60% even in patients already on maximum-dose statin therapy.
15	What are the four clinical forms of Extrapyramidal Symptoms (EPS) caused by first-generation high-potency antipsychotics (Haloperidol)?	1. Acute Dystonia (hours to days): painful sustained muscle spasms (torticollis, laryngospasm, oculogyric crisis); treated with antimuscarinics (benztropine, diphenhydramine). 2. Akathisia (days to weeks): subjective inner restlessness and inability to sit still; treated with propranolol, benzodiazepines, or dose reduction. 3. Drug-Induced Parkinsonism (weeks to months): bradykinesia, cogwheel rigidity, resting tremor; treated with benztropine or amantadine. 4. Tardive Dyskinesia (months to years): choreoathetoid orofacial and limb movements from postsynaptic D2 receptor supersensitivity; treated with VMAT2 inhibitors (valbenazine, deutetrabenazine).
16	What is the pathophysiologic mechanism of the hypertensive crisis ('cheese effect') associated with Monoamine Oxidase Inhibitors (MAOIs)?	MAOIs (Phenelzine, Tranylcypromine, Selegiline) irreversibly inhibit MAO-A and MAO-B. Ingestion of tyramine-rich foods (aged cheeses, cured meats, red wine, draft beer) allows unmetabolized tyramine to enter systemic circulation (normally degraded by intestinal MAO-A). Tyramine enters sympathetic terminals via NET and displaces massive amounts of vesicular norepinephrine into the synaptic cleft, triggering severe hypertensive crisis and stroke.
17	What are the clinical pharmacokinetic profiles of Rapid-Acting, Short-Acting, and Long-Acting basal insulins?	Rapid-acting (Lispro, Aspart, Glulisine): amino acid substitutions prevent hexamer dimerization; onset 10-20 min, peak 1-2 hours, duration 3-5 hours (administered immediately before meals). Short-acting (Regular insulin): hexamers dissociate slowly; onset 30-60 min, peak 2-4 hours, duration 6-8 hours (only form used for IV DKA infusion). Long-acting basal (Glargine, Degludec): precipitates in subcutaneous tissue or forms multi-hexamers; onset 1-2 hours, essentially PEAKLESS, duration >= 24 hours.
18	How do Benzodiazepines and Barbiturates differ in their molecular modulation of the GABA-A receptor, and what is the reversal agent for benzodiazepines?	GABA-A receptors are pentameric ligand-gated chloride channels. Benzodiazepines (lorazepam, diazepam, midazolam) bind between alpha and gamma subunits to increase the FREQUENCY of Cl- channel opening in the presence of endogenous GABA. Barbiturates (phenobarbital) increase the DURATION of Cl- channel opening and at high doses directly open the channel (narrower safety margin). The competitive benzodiazepine antagonist is Flumazenil, which must be used with caution as it can precipitate refractory withdrawal seizures in chronic benzodiazepine users or patients with tricyclic antidepressant co-ingestion.
19	How do Spironolactone and Eplerenone differ from Amiloride and Triamterene in potassium-sparing diuretic mechanisms and side effects?	Spironolactone and Eplerenone are competitive mineralocorticoid (aldosterone) receptor antagonists in the cortical collecting tubule, preventing expression of ENaC and basolateral Na+/K+-ATPase. Spironolactone also non-selectively blocks androgen receptors, causing gynecomastia and erectile dysfunction; Eplerenone is highly selective with no antiandrogenic effects. Amiloride and Triamterene are direct epithelial sodium channel (ENaC) blockers.
20	What is the pharmacological mechanism of GLP-1 receptor agonists (Semaglutide, Liraglutide), and what is their Black Box Warning?	Incretin mimetics that bind and activate the Glucagon-Like Peptide-1 (GLP-1) receptor, stimulating glucose-dependent insulin secretion from pancreatic beta cells, suppressing inappropriate glucagon secretion, slowing gastric emptying, and centrally increasing satiety. Black Box Warning: contraindicated in patients with a personal or family history of Medullary Thyroid Carcinoma (MTC) or Multiple Endocrine Neoplasia syndrome type 2 (MEN 2) due to thyroid C-cell tumor risk.
21	What is the cellular mechanism of action of Digoxin, and what electrolyte disturbances potentiate its toxicity?	Inhibits the cardiac sarcolemmal Na+/K+-ATPase pump -> increases intracellular Na+ -> decreases Na+/Ca2+ exchanger activity -> increases intracellular Ca2+ storage in sarcoplasmic reticulum -> positive inotropy. Also stimulates central vagal tone (slowing AV conduction). Hypokalemia, Hypomagnesemia, and Hypercalcemia strongly potentiate digoxin toxicity because K+ normally competes with digoxin for binding to the Na+/K+-ATPase.
22	What is the primary mechanism of action of SSRIs, and how long does it take for clinical antidepressant efficacy to manifest?	Selectively inhibit the presynaptic Serotonin Transporter (SERT), blocking 5-HT reuptake and increasing synaptic serotonin. Full antidepressant efficacy requires 4 to 6 weeks due to downstream neuroplastic adaptations, including presynaptic 5-HT1A autoreceptor desensitization and increased BDNF expression. Combining SSRIs with MAOIs, linezolid, or tramadol risks Serotonin Syndrome (clonus, hyperreflexia, hyperthermia, agitation; treated with cyproheptadine), requiring a 2-week washout when switching to/from MAOIs (5 weeks when stopping fluoxetine due to norfluoxetine's long half-life).
23	What is the enzymatic target and acid-base consequence of Acetazolamide?	Inhibits Carbonic Anhydrase (primarily CA-II and CA-IV) in the brush border and cytoplasm of the Proximal Convoluted Tubule, blocking reabsorption of sodium bicarbonate (NaHCO3). Promotes urinary bicarbonate excretion (alkaline urine), producing a mild Normal Anion Gap (hyperchloremic) Metabolic Acidosis. Used for Acute Mountain Sickness prophylaxis, glaucoma, and metabolic alkalosis.
24	What is the enzymatic target of Statin drugs (Atorvastatin, Rosuvastatin), and how do they reduce circulating LDL cholesterol?	Competitively inhibit HMG-CoA Reductase, the rate-limiting enzyme converting HMG-CoA to Mevalonate in cholesterol biosynthesis. Decreased intracellular hepatocyte cholesterol triggers SREBP-2 transcription factor upregulation, dramatically increasing cell-surface LDL Receptor expression, which clears ApoB-100 containing LDL and VLDL remnants from circulation. Adverse effects: myopathy, rhabdomyolysis, and transaminitis.
25	What is the mechanism of Mannitol, and what are its primary clinical indications and contraindications?	An osmotic diuretic that is freely filtered at the glomerulus but poorly reabsorbed; increases tubular fluid osmolarity, drawing water into the lumen to promote osmotic diuresis in proximal tubule and descending loop of Henle. Clinical indications: acute reduction of intracranial pressure (ICP) in cerebral edema and intraocular pressure in acute glaucoma. Contraindications: active intracranial bleeding, anuria, and severe pulmonary edema / congestive heart failure.
26	What are the '3 Cs' of Tricyclic Antidepressant (TCA) overdose toxicity, and what is the specific antidote for TCA-induced cardiac conduction widening?	The 3 Cs: 1) Cardiotoxicity (QRS widening, VT/VF due to fast cardiac sodium channel blockade); 2) Convulsions / Seizures (GABA-A antagonism); 3) Coma (antihistaminic and antimuscarinic CNS effects). Antidote: Intravenous Sodium Bicarbonate (NaHCO3 1-2 mEq/kg bolus), which increases extracellular sodium to overcome competitive Na+ channel block and raises blood pH to decrease active drug binding.
27	How do Angiotensin Receptor Blockers (ARBs) differ pharmacologically from ACE inhibitors, and what is their clinical niche?	ARBs such as losartan and valsartan block angiotensin II AT1 receptors without inhibiting ACE (kininase II). They therefore do not inhibit bradykinin breakdown and cause less cough than ACE inhibitors. Angioedema is less common but can still occur, including in people with previous ACE-inhibitor-associated angioedema; it is not a zero-risk alternative.
28	What is the mechanism of action of Metformin, and why is it temporarily held before intravenous iodinated radiocontrast procedures?	A biguanide that inhibits hepatic mitochondrial complex I and activates AMP-activated protein kinase (AMPK), suppressing hepatic gluconeogenesis and increasing peripheral insulin sensitivity without stimulating insulin secretion (minimal hypoglycemia risk; chronic use can cause vitamin B12 deficiency). Metformin is contraindicated if eGFR < 30 mL/min/1.73 m2 and is temporarily held at the time of or prior to iodinated IV contrast procedures in patients with eGFR 30–60 mL/min/1.73 m2 (or intra-arterial contrast/hepatic/heart failure), with eGFR rechecked at 48 hours before restarting, to prevent Metformin-Associated Lactic Acidosis (MALA).
29	What are the four classes of the Vaughan Williams antiarrhythmic classification system and their primary electrophysiologic mechanisms?	Class I: Voltage-gated Sodium channel blockers (Ia: Procainamide, Quinidine [prolong APD]; Ib: Lidocaine, Mexiletine [shorten APD]; Ic: Flecainide, Propafenone [no change on APD, profound phase 0 slowing]). Class II: Beta-adrenergic receptor antagonists (Metoprolol, Esmolol; decrease SA/AV nodal automaticity). Class III: Potassium channel blockers (Amiodarone, Sotalol, Dofetilide; prolong repolarization and APD/QT). Class IV: Calcium channel blockers (Verapamil, Diltiazem; slow AV nodal conduction).
30	How do Propylthiouracil (PTU) and Methimazole differ in mechanisms, trimester preference during pregnancy, and organ toxicities?	Both inhibit thyroid peroxidase (TPO), blocking iodine organification and coupling. PTU ALSO inhibits peripheral 5'-deiodinase, blocking conversion of T4 to active T3 (making PTU first-line in Thyroid Storm). In pregnancy: PTU is preferred in the FIRST trimester (methimazole causes embryopathy: aplasia cutis, choanal atresia); Methimazole is preferred in 2nd and 3rd trimesters due to PTU black box warning for fulminant hepatic necrosis. Both cause agranulocytosis.
31	What is the molecular target of Loop Diuretics (Furosemide, Bumetanide) in the nephron, and what electrolyte abnormalities do they produce?	Inhibit the Na+/K+/2Cl- cotransporter in the Thick Ascending Limb of the Loop of Henle, dissipating the corticomedullary osmotic gradient and impairing urine concentrating ability. Electrolyte losses: Hypokalemia, Hypomagnesemia, Hypocalcemia (loop diuretics lose calcium by abolishing the positive lumen potential), and Hypochloremic Metabolic Alkalosis; also cause Hyperuricemia and Ototoxicity.
32	What is the mechanism of SGLT2 inhibitors (Empagliflozin, Dapagliflozin), and what rare metabolic complication can occur?	Selectively inhibit the Sodium-Glucose Cotransporter 2 (SGLT2) in the S1 segment of the proximal convoluted tubule, blocking ~90% of renal glucose and sodium reabsorption, producing glucosuria, natriuresis, weight loss, and reduced cardiovascular mortality and HF hospitalizations. Rare severe complication: Euglycemic Diabetic Ketoacidosis (euDKA, ketoacidosis with blood glucose < 250 mg/dL), alongside mycotic genital infections and Fournier gangrene.