Pharmacology — Mechanisms — USMLE Step 2 CK Notes

Autonomic pharmacology is the backbone

• Know receptor → G-protein → second messenger for every autonomic receptor
• Alpha-1 (Gq, IP3/Ca), alpha-2 (Gi, ↓cAMP), beta-1/2 (Gs, ↑cAMP), M1/M3 (Gq), M2 (Gi)

Enzyme-cofactor and toxin pairings the exam loves

• ACE inhibitor → bradykinin accumulation → cough and angioedema; ARBs spare it
• Isoniazid → depletes vitamin B6 → neuropathy; give pyridoxine
• Cholera toxin activates Gs; pertussis toxin inactivates Gi — both raise cAMP
• Diphtheria and Pseudomonas exotoxin A both inactivate elongation factor 2

Pharmacokinetics essentials

• Loading dose = target concentration × volume of distribution; independent of clearance
• Maintenance dose depends on clearance
• Zero-order (constant amount): alcohol, phenytoin, aspirin at high dose
• First-order (constant fraction): most drugs

Classic drug-adverse-effect flags

• Anti-histone antibodies → drug-induced lupus (hydralazine, isoniazid, procainamide)
• Amiodarone → pulmonary fibrosis, thyroid dysfunction, corneal deposits
• Aminoglycosides → nephrotoxic and ototoxic

Autonomic pharmacology

• Cholinergic: muscarinic agonists (bethanechol) and anticholinesterases (neostigmine); antagonists (atropine — antimuscarinic toxidrome). Organophosphates = irreversible AChE inhibition → treat with atropine + pralidoxime.
• Adrenergic: alpha-1 (vasoconstriction), alpha-2 (central sympatholysis — clonidine), beta-1 (heart), beta-2 (bronchodilation). Non-selective beta-blockers avoided in asthma.

Pharmacokinetics & dynamics

• Zero-order (constant amount) elimination: phenytoin, ethanol, aspirin (high dose). First-order = constant fraction.
• Loading dose = target concentration × volume of distribution; maintenance dose depends on clearance.
• Competitive antagonist → right-shifts the curve (surmountable, lowers potency); non-competitive → lowers efficacy (Vmax).

Cytochrome P450 — the exam trap

• Inducers (rifampin, phenytoin, carbamazepine, phenobarbital, chronic alcohol, St John's wort) speed metabolism → lower warfarin/OCP levels.
• Inhibitors (azoles, macrolides, cimetidine, isoniazid, grapefruit, acute alcohol) raise levels → warfarin bleeding.

Key drug classes & signature toxicities

• Aminoglycosides — nephro/ototoxic; vancomycin — 'red man' infusion reaction; tetracyclines — teeth/bones (avoid in children/pregnancy).
• ACE inhibitors — cough/angioedema, hyperkalaemia, teratogen; statins — myopathy; amiodarone — thyroid, lung, liver, skin.
• Antipsychotics — extrapyramidal, NMS, tardive dyskinesia; SSRIs — serotonin syndrome; lithium — tremor, thyroid, nephrogenic DI (narrow window).

Antidotes to know cold

• Paracetamol → N-acetylcysteine; opioids → naloxone; benzodiazepines → flumazenil; warfarin → vitamin K/PCC; heparin → protamine.
• Digoxin → digoxin-specific antibodies; methanol/ethylene glycol → fomepizole; iron → deferoxamine; cyanide → hydroxocobalamin; methaemoglobinaemia → methylene blue.

Pharmacokinetics (ADME)

• Volume of distribution (PET): Plasma (large/charged/protein-bound, low Vd), Extracellular fluid (small hydrophilic), Tissues (small lipophilic, high Vd). Cirrhosis lowers albumin → higher Vd of protein-bound drugs.
• Zero-order elimination (PEA): a constant AMOUNT cleared per unit time (saturated enzymes) — phenytoin, ethanol, aspirin at toxic doses; level falls linearly.
• First-order elimination: a constant FRACTION cleared per unit time; level falls exponentially (most drugs).
• Half-life = 0.693 × Vd / clearance; renal or hepatic failure prolongs it.

Metabolism

• Phase I (Old Rats Hide): Oxidation, Reduction, Hydrolysis via CYP450 — declines first with age ("Old People Fade First").
• Phase II (Mother Goose Ate Soup): Methylation, Glucuronidation, Acetylation, Sulfation — conjugation; intact in the elderly, so lorazepam/oxazepam are safer.
• Slow acetylators + SHIP (Sulfasalazine, Hydralazine, Isoniazid, Procainamide) → drug-induced lupus (anti-histone antibodies, no anti-dsDNA).
• Paracetamol: Phase I generates toxic NAPQI; glutathione normally neutralises it — overdose depletes glutathione → hepatotoxicity (give N-acetylcysteine).

CYP450 interactions

• Inducers (CRAP GPS): Carbamazepine, Rifampin, Alcohol (chronic), Phenytoin, Griseofulvin, Phenobarbital, St John's Wort → subtherapeutic substrate levels.
• Inhibitors (SICKFACES.COM): valproate, isoniazid, cimetidine, azoles, acute alcohol, chloramphenicol, macrolides, sulfonamides, ciprofloxacin, omeprazole, metronidazole → toxicity (e.g. rising INR). Also amiodarone, verapamil, grapefruit juice.
• P-glycoprotein inhibitors (VACINE): verapamil, amiodarone, cyclosporine, itraconazole, nifedipine, erythromycin → higher intracellular drug (e.g. digoxin).

Pharmacodynamics

• Potency = dose needed (EC50); efficacy = maximum achievable effect (Vmax).
• Competitive inhibitor: raises Km, Vmax unchanged (surmountable). Non-competitive: lowers Vmax (insurmountable).
• Therapeutic index = LD50/ED50 — higher is safer.
• G-proteins: Gq (Cutie HAVe 1 M&M: H1, alpha-1, V1, M1, M3) → IP3/DAG/Ca; Gs (beta-1/2, D1, H2, V2) → cAMP up; Gi (M2, alpha-2, D2) → cAMP down.

Toxidromes & class effects

• Anticholinergic (Mad Hatter): hot, dry, red, blind (mydriasis), mad (delirium), full (urinary retention) — "can't pee/see/spit/shit".
• Opioids (SCARED): sedation, constipation, analgesia, respiratory depression, euphoria, dependence; overdose triad = pinpoint pupils + low respiratory rate + coma → naloxone.
• SSRIs (3 S's): stomach upset, sexual dysfunction, serotonin syndrome (SHIVERS: shivering, hyperreflexia, high temp, vitals instability, encephalopathy, restlessness, sweating).

Monoclonal antibody naming (-mab)

• Source substem before -mab: -o- murine (most immunogenic), -xi- chimeric, -zu- humanised, -u- fully human (least immunogenic). More non-human protein → more allergy and faster clearance.

Drugs in pregnancy

• Antihypertensives (safe): labetalol, methyldopa, clonidine, nifedipine, hydralazine, prazosin; avoid ACE inhibitors/ARBs.
• Antimicrobials to avoid (SAFE Moms Take Really Good Care): sulfonamides, aminoglycosides, fluoroquinolones, erythromycin, metronidazole, tetracyclines, ribavirin, griseofulvin, chloramphenicol. Statins also contraindicated.
• Tocolytics (It's Not My Time): indomethacin, nifedipine, magnesium sulfate, terbutaline. Thalidomide → phocomelia; misoprostol is an abortifacient.

High-yield notes contributed by a StepSherpa clinician reviewer.