Pharmacology System
Pharmacology
High-yield pharmacology for USMLE Step 2/3 — ANS receptors, cardiovascular drugs, anti-infectives, endocrine pharmacology, toxicology, and drug interactions, extracted from Divine Intervention and organized by clinical cluster for exam performance.
Cardiovascular Pharmacology
Cardiovascular drugs dominate Step 2/3 pharmacology. The mechanistic hierarchy — preload vs afterload reduction, rate vs rhythm control, vasospasm vs thrombosis — organizes every choice. Know when nitrates hurt (hypotension), why beta blockers help in HF but worsen vasospasm, and which QT-prolonging drugs trigger torsades.
EP432
Pharmacology Blitz — Cardiovascular Drugs
- Nitrates — mechanism: Venodilators → ↓ preload → ↓ cardiac workload. Used for MI chest pain, angina, acute decompensated HF. Classic side effect: hypotension + reflex tachycardia. Nitrates + sildenafil = lethal hypotension (both dilate vessels)
- Hydralazine: Direct arteriolar dilator → ↓ afterload. Used in HF (with isosorbide dinitrate for Black patients — BiDil), hypertension in pregnancy. Drug-induced lupus (+ procainamide, isoniazid, quinidine)
- ACE inhibitors vs ARBs: Both improve survival in HF and diabetic nephropathy. ACEi → cough (bradykinin accumulation) and angioedema. ARBs = no cough. Both cause hyperkalemia + rising creatinine (especially with NSAIDs). Contraindicated in pregnancy (fetal renal agenesis)
- Spironolactone / eplerenone: Aldosterone antagonists (K-sparing diuretics). Improve survival in HF. Side effect: gynecomastia (spironolactone, not eplerenone). Hyperkalemia especially with ACEi + ARB
- Loop diuretics (furosemide): ↓ preload, reduce pulmonary edema in acute HF. Cause ototoxicity (especially with aminoglycosides), hypokalemia, metabolic alkalosis. Give with KCl supplementation
- Digoxin: ↑ contractility (inhibits Na/K-ATPase → ↑ intracellular Ca) + slows AV node (vagotonic). Used in HFrEF + AFib rate control. Narrow therapeutic index — toxicity: yellow-green vision, nausea, arrhythmias. Hypokalemia ↑ digoxin toxicity. Treat toxicity with digoxin Fab fragments
Heart Failure Drug Hierarchy
| Drug Class | Mechanism | Key Benefit | Key Toxicity |
|---|---|---|---|
| ACE inhibitors (lisinopril) | ↓ Ang II → ↓ afterload + preload | Improve survival HFrEF | Cough, angioedema, hyperkalemia, teratogen |
| ARBs (losartan) | Block AT1 receptor | Same as ACEi; use if ACEi cough | No cough; same renal/K risks |
| Sacubitril/valsartan (Entresto) | ARB + neprilysin inhibitor → ↑ BNP | Mortality benefit over ACEi alone in HFrEF | Hypotension; never combine with ACEi |
| Beta blockers (carvedilol, metoprolol, bisoprolol) | ↓ catecholamine toxicity | Improve survival in stable HF | Avoid acute decompensation; bradycardia |
| Spironolactone / eplerenone | Aldosterone antagonist | Survival benefit, esp. post-MI HF | Gynecomastia (spirono), hyperkalemia |
| SGLT-2 inhibitors (empagliflozin) | Block renal glucose reabsorption | Improve HF outcomes independent of diabetes | UTI, DKA (euglycemic), genitourinary infections |
| Hydralazine + isosorbide dinitrate | Arteriolar + venous dilation | Alternative to ACEi; preferred in Black patients | Reflex tachycardia, drug-induced lupus (hydralazine) |
Drug-Induced Lupus — The HIQP Mnemonic
Drugs causing SLE-like syndrome (positive ANA, anti-histone antibodies): Hydralazine, Isoniazid, Quinidine, Procainamide. Anti-histone antibodies = drug-induced lupus (contrast with anti-dsDNA = real SLE, anti-Sm = specific for SLE). Syndrome resolves on drug discontinuation.
Digoxin Toxicity — Recognition and Management
- Symptoms: Nausea/vomiting, yellow-green visual halos, bradycardia, AV block, ventricular arrhythmias
- Precipitating factors: Hypokalemia (most important — K competes with digoxin for Na/K-ATPase), hypomagnesemia, renal failure (digoxin renally cleared)
- EKG: Scooped ST depression ("Salvador Dali mustache"), bradycardia, heart block
- Treatment: Stop digoxin; correct hypokalemia; digoxin-specific Fab antibody fragments for severe toxicity. Atropine for bradycardia
Nitrate + PDE-5 Inhibitor — Absolute Contraindication
Sildenafil, tadalafil (PDE-5 inhibitors) prevent cGMP breakdown → sustained vasodilation. Nitrates also work via cGMP. Combined effect: catastrophic hypotension. Never co-administer. If patient took sildenafil and presents with MI, cannot give nitrates — use morphine and other analgesics only.
EP609
ANS Drugs for Step 2 & 3 — Beta Blockers & Alpha Agents
- Selective beta-1 blockers (A to M): Atenolol, esmolol, acebutolol, metoprolol — heart rate control, HF survival (carvedilol, bisoprolol, metoprolol). Propranolol (non-selective) = migraine prophylaxis, essential tremor, thyroid storm (inhibits 5'-deiodinase), portal hypertension (varices)
- Alpha-1 blockers (prazosin, tamsulosin): BPH (open bladder neck), PTSD nightmares (prazosin), pheochromocytoma pre-op (block alpha before beta — risk of unopposed alpha if reversed). Phenoxybenzamine (irreversible alpha blocker) = pheo pre-op preferred
- Alpha-2 agonists (clonidine, methyldopa): Clonidine = antihypertensive (rebound hypertension if stopped), third-line ADHD. Methyldopa = safe antihypertensive in pregnancy (with hydralazine, labetalol, nifedipine)
- Mirtazapine (alpha-2 blocker): Raises NE (disinhibition); antidepressant without sexual side effects; causes sedation + weight gain → good for anorexic depressed patients
- Beta blockers — glaucoma: Timolol, betaxolol → ↓ aqueous humor production (sympathetics drive humor production). Apraclonidine/brimonidine (alpha-2 agonists) also ↓ aqueous humor
- Carvedilol / labetalol: Alpha + beta blockers. Carvedilol = HF. Labetalol = safe in pregnancy, hypertensive emergencies
Beta Blocker Selection — A to M Rule
| Drug | Selectivity | HY Clinical Use |
|---|---|---|
| Atenolol, metoprolol, bisoprolol | Beta-1 selective | HF survival, MI, rate control AFib |
| Esmolol | Beta-1 selective, ultra-short | Intraoperative HTN, thyroid storm (IV) |
| Propranolol | Non-selective (B1+B2) | Migraine prophylaxis, essential tremor, thyroid storm, varices |
| Timolol / betaxolol | Non-selective / B1 | Open-angle glaucoma (topical) |
| Carvedilol | Alpha-1 + B1 + B2 | Heart failure (mortality benefit) |
| Labetalol | Alpha-1 + B1 + B2 | Pregnancy HTN, hypertensive emergencies |
Pheochromocytoma — Alpha Before Beta (Mandatory)
Always give alpha blockade (phenoxybenzamine or prazosin) BEFORE any beta blocker in pheochromocytoma management. Beta blockers alone → unopposed alpha-1 stimulation → paradoxical hypertensive crisis. Rule: alpha first, then beta, never beta alone.
Antihypertensives Safe in Pregnancy
- Methyldopa — alpha-2 agonist; long safety record
- Hydralazine — arteriolar dilator; first-line for hypertensive emergencies in pregnancy
- Labetalol — alpha+beta blocker; safe, widely used
- Nifedipine — calcium channel blocker (dihydropyridine); safe; also used as tocolytic >32 weeks
- Contraindicated: ACEi, ARBs (fetal renal agenesis), thiazides (teratogenic)
EP398
Pharmacology Scenarios — Coronary Vasospasm, QT Prolongation & TCA Toxicity
- Cocaine / meth → coronary vasospasm: ↑ catecholamines at adrenergic synapses → coronary vasoconstriction → MI with minimal atherosclerosis (30% stenosis on cath). Meth = prominent hallucinations (differentiator from cocaine)
- Sumatriptan / ergotamine: Net vasoconstrictors (used for migraines) → contraindicated in variant angina, Raynaud's, prior MI. Vasospastic coronary disease is the mechanism
- Variant angina (Prinzmetal): Female smoker, chest pain worse at rest (especially at night), normal coronaries on cath. Treat with calcium channel blockers (both classes). Avoid beta blockers (unopposed alpha → vasoconstriction worsens) and sumatriptan
- QT prolongation → Torsades de Pointes: Mechanism = sodium OR potassium channel blockade. Drugs: TCAs, ziprasidone (antipsychotic with strongest QT effect), ondansetron (Zofran), macrolides, fluoroquinolones, azole antifungals. Hypokalemia and hypomagnesemia worsen risk
- TCA toxicity (anti-HAM): Anti-H1 (sedation), Anti-Alpha-1 (orthostatic hypotension), Anti-Muscarinic (anticholinergic syndrome). Also: sodium channel blockade → wide QRS → treat with sodium bicarbonate. Widened QRS is the telltale EKG sign
- Vancomycin — Red Man Syndrome: Histamine release → cutaneous flushing, not allergic reaction. Reduce infusion rate + pretreat with antihistamine. IV antibiotics required for endocarditis/osteomyelitis (not oral)
QT-Prolonging Drugs — Master List
| Drug Class | Examples | Key Note |
|---|---|---|
| Antipsychotics | Ziprasidone (strongest), haloperidol, thioridazine | Ziprasidone = highest QT risk of all antipsychotics |
| Tricyclic antidepressants | Amitriptyline, nortriptyline | Also wide QRS via Na+ channel blockade → NaHCO3 tx |
| 5-HT3 antagonists | Ondansetron (Zofran) | High-dose IV; avoid in congenital long QT |
| Macrolide antibiotics | Azithromycin, erythromycin | Azithromycin Z-pack + cardiac history = concern |
| Fluoroquinolones | Ciprofloxacin, levofloxacin, moxifloxacin | Moxifloxacin highest QT risk in class |
| Azole antifungals | Fluconazole, voriconazole | Also CYP3A4 inhibitors → can raise levels of other QT drugs |
| Antiarrhythmics (class Ia, III) | Quinidine, sotalol, amiodarone | Amiodarone = many side effects (thyroid, lung, liver, cornea, skin) |
TCA Toxicity — Anti-HAM Framework
H = antiHistamine → sedation
A = anti-Alpha-1 → orthostatic hypotension (especially combined with CCBs, nitrates)
M = antiMuscarinic → anticholinergic syndrome (hot, dry, flushed, tachycardic, confused)
PLUS sodium channel blockade → wide QRS on EKG → treat with IV sodium bicarbonate (alkalinize + provide Na+)
Flush Reactions — Differentiating Causes
Multiple drugs cause cutaneous flushing: Niacin (prostaglandin-mediated; reduce with aspirin), Vancomycin (Red Man — histamine; slow infusion), Adenosine (used for SVT/stress test), Nitrates, CCBs (especially dihydropyridines), Echinocandins (caspofungin, micafungin). Stable vitals = infusion reaction, not anaphylaxis.
Autonomic & CNS Pharmacology
Autonomic pharmacology on Step 2/3 is applied physiology — understanding alpha vs beta receptors explains everything from anaphylaxis treatment to PTSD management to glaucoma therapy. Anesthetic complications have gained emphasis since the November 2020 USMLE changes: malignant hyperthermia, opioid respiratory depression, and OSA management are now regularly tested.
EP609
ANS Receptors — Full Map for Step 2 & 3
- Alpha-1 (vessels, bladder neck, eye): Stimulate → vasoconstriction (↑ afterload + preload), ↓ urination (bladder neck closes), mydriasis. Reflex bradycardia follows BP rise. Phenylephrine/ephedrine = alpha-1 agonists (nasal congestion, intraoperative hypotension)
- Alpha-2 (presynaptic sympathetic neurons): Stimulate → ↓ NE production. Clonidine (agonist) = antihypertensive, PTSD, ADHD (3rd line). Alpha-2 agonists in eye (apraclonidine, brimonidine) = ↓ aqueous humor
- Beta-1 (heart + JG cells): Stimulate → ↑ HR + ↑ contractility + ↑ renin. Thyroid hormone inserts more beta-1 receptors → hyperthyroid tachycardia + AFib. Dobutamine (beta-1 agonist) = cardiogenic shock, pharmacologic stress test
- Beta-3 (bladder detrusor): Stimulate → detrusor relaxation → prevents urination. Mirabegron (beta-3 agonist) = urge incontinence (overactive bladder). Fight-or-flight: you don't pee → beta-3 stops detrusor
- Muscarinic (DUMBELS locations): Airway = bronchoconstriction; AV node = slow conduction; bladder = detrusor contraction; GI = ↑ motility; eye = miosis. Muscarinic antagonists (oxybutynin, tolterodine) = urge incontinence. Anticholinergics → delirium in elderly
- Nicotinic receptors: Target of autoantibodies in myasthenia gravis. Target of neuromuscular blocking agents (succinylcholine, rocuronium). Pyridostigmine (AChEI) = MG treatment. Physostigmine = atropine overdose reversal
ANS Receptor Master Table
| Receptor | Location | Stimulation Effect | HY Drug |
|---|---|---|---|
| Alpha-1 | Vessels, bladder neck, eye (dilator pupillae) | Vasoconstriction, bladder neck closes, mydriasis | Phenylephrine (agonist); Prazosin (blocker) |
| Alpha-2 | Presynaptic sympathetic nerve terminals | ↓ NE release (inhibitory Gi) | Clonidine (agonist = ↓ BP); Mirtazapine (blocker = ↑ NE) |
| Beta-1 | Heart (SA/AV node, myocardium), JG cells (kidney) | ↑ HR, ↑ contractility, ↑ renin | Dobutamine (agonist); Metoprolol (blocker) |
| Beta-2 | Airway smooth muscle, vascular endothelium, uterus | Bronchodilation, vasodilation, uterine relaxation | Albuterol (agonist); Propranolol (non-selective blocker) |
| Beta-3 | Bladder detrusor | Detrusor relaxation → hold urine | Mirabegron (agonist) for urge incontinence |
| Muscarinic (M2) | AV node | ↓ AV conduction speed | Atropine (blocker) for bradycardia |
| Muscarinic (M3) | Bladder, airways, GI, eye (sphincter pupillae) | Detrusor contraction, bronchoconstriction, ↑ motility, miosis | Bethanechol (agonist); Oxybutynin (blocker) |
Epinephrine vs Norepinephrine — HY Receptor Distinction
Norepinephrine: Alpha-1 + Alpha-2 + Beta-1. Primary alpha effect = vasoconstriction = drug of choice in septic shock (Levophed).
Epinephrine: Alpha-1 + Alpha-2 + Beta-1 + Beta-2. Beta-2 = bronchodilation → drug of choice in anaphylaxis. NE lacks beta-2 potency — this is why epi, not NE, is used for anaphylaxis.
Cholinergic Toxidrome vs Anticholinergic Toxidrome
| Cholinergic (DUMBELS) | Anticholinergic (Hot, Mad, Dry, Blind, Tachy) | |
|---|---|---|
| Pupils | Miosis (constriction) | Mydriasis (dilation) |
| Heart | Bradycardia | Tachycardia |
| Secretions | SLUDGE (Salivation, Lacrimation, Urination, Defecation, GI upset, Emesis) | Dry mouth, dry skin, urinary retention |
| Skin | Sweating, diaphoresis | Hot, flushed, dry |
| Cause | Organophosphates, nerve gas, AChEI overdose | Atropine OD, diphenhydramine, TCAs, antipsychotics |
| Treatment | Atropine (blocks muscarinic) + Pralidoxime (regenerates AChE) | Physostigmine (for atropine OD) |
EP475
Beta-2 and Beta-3 Receptors — Clinical Pharmacology
- Albuterol (SABA) — key integrations: Bronchodilation for asthma/COPD. Also stimulates Na/K-ATPase → shifts K+ intracellularly → treats hyperkalemia (after calcium gluconate stabilizes myocardium). Continuous albuterol → hypokalemia (mechanism = K+ redistribution, not renal loss)
- Long-acting beta-2 agonists (LABA): Salmeterol, formoterol → 3rd rung in asthma ladder (add after SABA + inhaled corticosteroid). Never use LABA monotherapy in asthma without ICS (safety concern)
- Asthma management ladder: SABA (albuterol) → add ICS (budesonide, fluticasone) → add LABA → consider biologic (dupilumab for eosinophilic asthma)
- Tocolysis hierarchy: <32 weeks → indomethacin (COX inhibitor; prostaglandins cause uterine contraction); >32 weeks → nifedipine (CCB; Ca needed for contraction). Terbutaline (beta-2 agonist) = historical; avoid on exams if indomethacin or nifedipine are available
- Beta blocker overdose → glucagon antidote: Beta blockers ↓ cyclic AMP intracellularly. Glucagon receptor is stimulatory Gp-coupled receptor (different from adrenergic receptors) → raises cAMP via separate pathway → reverses beta blocker bradycardia and hypotension. Glucagon also relaxes esophagus (food impaction)
- Mirabegron (beta-3 agonist): Relaxes detrusor → treats urge incontinence. Alternative to antimuscarinics (oxybutynin); no anticholinergic side effects; good option in elderly
Hyperkalemia Management — Stepwise
| Step | Drug | Mechanism | Onset |
|---|---|---|---|
| 1 — Stabilize myocardium | Calcium gluconate | Raises threshold potential (membrane stabilization) | Minutes |
| 2a — Shift K+ intracellularly | Albuterol | Beta-2 → stimulates Na/K-ATPase → K+ enters cells | 15-30 min |
| 2b — Shift K+ intracellularly | Insulin + dextrose | Insulin stimulates Na/K-ATPase; glucose prevents hypoglycemia | 15-30 min |
| 3 — Remove K+ from body | Furosemide (if UO intact) | Loop diuretic → renal K+ excretion | Hours |
| 4 — Remove K+ from body | Kayexalate or patiromer | Binds K+ in gut; excreted in stool | Hours to days |
| 5 — Emergency | Dialysis | Directly removes K+ from blood | Fastest definitive removal |
Tocolytic Decision Tree
<32 weeks gestation: Indomethacin (NSAID → ↓ prostaglandins → ↓ uterine contractions). Risk if >32 weeks: closes ductus arteriosus prematurely.
>32 weeks gestation: Nifedipine (calcium channel blocker → ↓ myometrial Ca → relaxation). Safe past 32 weeks, no ductus risk.
Terbutaline (beta-2 agonist): Exam distractor — only pick if indomethacin and nifedipine are NOT available.
EP385
Anesthetic Complications and The USMLEs
- Most common cause of anesthetic complications: Human error (wrong drug, wrong dose). Prevention: color-coded syringes, barcode verification
- Malignant hyperthermia: Autosomal dominant (ryanodine receptor mutation → uncontrolled Ca release from SR). Triggered by depolarizing NMBAs (succinylcholine) or volatile inhaled anesthetics. Presentation: fever (105°F+), rigidity, hyperkalemia, rhabdomyolysis → AKI. Treat with dantrolene (ryanodine receptor antagonist = Ca channel blocker)
- Opioid-induced respiratory depression post-op: Somnolent, RR 5, PCO2 ↑, PaO2 ↓ → respiratory acidosis. Diagnosis: opiate-induced respiratory depression (RASS scale for monitoring). Treat: naloxone (opioid antagonist). NOT reintubation first — give naloxone first
- OSA in anesthesia: Screen with STOP-BANG questionnaire. Use patient's CPAP/BiPAP while hospitalized. Prefer regional over general anesthesia. Limit opioids (additive respiratory depression)
- Beta blockers + surgery: Continue if already on them. Do NOT start de novo in perioperative period (↑ morbidity + mortality). Anemia + beta blockers = dangerous combination (anemia ↑ cardiac demand; beta blockers blunt compensatory HR increase)
- Tension pneumothorax (central line complication): Absent breath sounds unilaterally, hypotension, tracheal deviation. Treat: needle decompression (needle thoracostomy) → then chest tube (tube thoracostomy). If only chest tube available on exam → pick chest tube
Malignant Hyperthermia vs NMS vs Serotonin Syndrome
| Malignant Hyperthermia | Neuroleptic Malignant Syndrome | Serotonin Syndrome | |
|---|---|---|---|
| Trigger | Succinylcholine, volatile anesthetics | Antipsychotics (especially typical) | Serotonergic combinations (SSRI + MAOI, linezolid, methylene blue, meperidine) |
| Setting | Operating room, intraoperative | Hospital, new antipsychotic or dose increase | Any setting after combining serotonergic drugs |
| Rigidity | Severe ("lead pipe") | Severe ("lead pipe") | Hyperreflexia + clonus (not true rigidity) |
| Temperature | Very high (>105°F) | Very high | High but usually less extreme |
| Treatment | Dantrolene (ryanodine antagonist) | Dantrolene + bromocriptine + stop antipsychotic | Cyproheptadine (5-HT2 antagonist) + benzos |
| Genetics | AD — ryanodine receptor mutation | Not genetic | Not genetic |
Malignant Hyperthermia — Electrolyte Consequence
As muscle cells lyse (rhabdomyolysis), intracellular K+ floods into serum → hyperkalemia. Myoglobin release → acute tubular necrosis → AKI → worsens hyperkalemia. Also: metabolic acidosis (anaerobic metabolism). NBME may ask: "most likely electrolyte abnormality in MH?" → Answer: hyperkalemia.
Pre-operative Risk Assessment
- >4 METs: Low cardiac risk; no formal cardiac work-up needed before elective surgery
- High cardiac risk factors: Ischemic heart disease, HF, DM, CKD, age >65
- Post-MI timing: Delay elective surgery ≥60 days after MI
- Quit smoking: Minimum 8 weeks before surgery
- Prone surgery vision loss: Eyes lower than heart → ↑ intraocular pressure → optic ischemia → reverse Trendelenburg (head higher than feet) to prevent
- RA pre-op: Get cervical X-ray to screen for atlanto-axial (C1-C2) instability (also: Down syndrome, ankylosing spondylitis)