Foundational Pharmacology & Autonomics
Real-time pharmacokinetic and pharmacodynamic equations, autonomic second messenger cascades (HAVe 1 M&M vs MAD 2s), CYP450 metabolic modulators, and an exhaustive 20-antidote toxicology lookup vault.
Interactive Pharmacokinetics Lab
Modify dosing variables to observe real-time recalculation of volume of distribution, clearance, half-life, and maintenance schedules.
t1/2 = (0.693 × Vd) / CL
LD = (Cp × Vd) / F
Depends only on Volume of Distribution (Vd); unaffected by renal/hepatic impairment!
MD = (Cp × CL × τ) / F
Depends directly on Clearance (CL); must be decreased in renal/hepatic failure!
Rate In = Rate Out = CL × Cp
At steady-state equilibrium, the rate of drug administration equals rate of drug elimination.
Zero-Order vs First-Order Elimination (Board Favorite)
Constant AMOUNT eliminated per unit time
Rate is independent of plasma concentration. Metabolic enzymes become saturated. Linear decrease on linear plot. Half-life increases as concentration rises!
Constant FRACTION eliminated per unit time
Rate is directly proportional to plasma concentration. Constant half-life (t1/2). Exponential decay on linear plot; linear on logarithmic plot. Most drugs follow first-order.
Pharmacodynamics & Receptor Theory
Dose-response curves, competitive vs non-competitive antagonist shifts, and the Narrow Therapeutic Index (NTI) vault.
Agonists vs Antagonists
Therapeutic Index (TI) & Safety
Median Toxic Dose divided by Median Effective Dose. Safer drugs have a HIGHER TI (wide margin between therapeutic and lethal doses).
Dose that produces toxicity in 1% of population divided by dose that is effective in 99%. Must be > 1 for safe non-monitored medications.
Narrow Therapeutic Index (NTI) Compendium
"Warning: These Drugs Lethal Guard Carefully Please"
Extremely short-acting reversible acetylcholinesterase inhibitor. Historically used to differentiate Myasthenic crisis (undermedication → symptoms IMPROVE with edrophonium) from Cholinergic crisis (excess AChEi causing depolarization block → symptoms WORSEN or no change; treat with atropine).
Centrally-acting lipid-soluble acetylcholinesterase inhibitors used as first-line symptomatic treatment for Alzheimer disease. Modestly slow cognitive decline by augmenting acetylcholine transmission in the nucleus basalis of Meynert.
Prazosin, Doxazosin, Terazosin: Selective α1-blockers that cause arteriolar and venular dilation; treat both hypertension and BPH (risk of first-dose orthostatic hypotension). Tamsulosin: Selective α1A-blocker targeting prostatic smooth muscle; relieves BPH bladder outlet obstruction with minimal systemic hypotension.
Autonomic Pharmacology Curriculum Module
Master Atlas & Clinical SuitesSynchronized 2K Second Messenger Schema • Cardiovascular Hemodynamics • Ophthalmic Dynamics • Prometric Pan/Zoom
Autonomic Receptors, G-Protein Coupling & Second Messengers
Comprehensive mapping of HAVe 1 M&M (Gq → PLC → IP3/DAG → Ca2+), MAD 2s (Gi → ↓ cAMP → K+ hyperpolarization), and Gs (Adenylyl Cyclase → ↑ cAMP/PKA) receptor distributions and physiologic responses.
H1, α1, V1, M1, M3 Receptors
- α1: Vascular smooth muscle constriction (mydriasis, ↑ SVR/BP, ↑ urinary sphincter tone).
- M1: CNS excitation, gastric acid secretion.
- M3: Bronchoconstriction, miosis (pupillary sphincter), lacrimation, salivation, sweating, bladder detrusor contraction.
- H1: Bronchoconstriction, nasal mucus, pruritus, vascular permeability.
- V1: Vascular smooth muscle contraction (vasopressin pressor effect).
M2, α2, D2 Receptors
- α2: Presynaptic negative feedback autoreceptor (↓ NE release, ↓ insulin release, ↓ aqueous humor production). Target of Clonidine and α-methyldopa.
- M2: Cardiac SA/AV nodal inhibition (↓ heart rate, ↓ conduction velocity, vagal tone).
- D2: CNS inhibition of prolactin secretion (tuberoinfundibular pathway); extrapyramidal movement pathways.
β1, β2, β3, D1, H2, V2 Receptors
- β1: Heart (↑ inotropy, ↑ chronotropy, ↑ dromotropy), Kidney (↑ renin release by juxtaglomerular cells).
- β2: Smooth muscle relaxation: bronchodilation (Albuterol), vasodilation in skeletal muscle, uterine relaxation (tocolysis), ↑ glycogenolysis, ↑ insulin.
- β3: Bladder detrusor relaxation (Mirabegron), adipose lipolysis.
- H2: Gastric parietal cells (↑ H+ secretion into lumen; Famotidine).
- V2: Renal collecting ducts (aquaporin-2 water reabsorption).
End-Organ Autonomic Physiology Matrix
Comparative sympathetic vs. parasympathetic organ actions and high-yield board correlations
| Organ System | Sympathetic Action & Receptor | Parasympathetic Action & Receptor | Clinical High-Yield Pearl |
|---|---|---|---|
| Pupil & Eye | Mydriasis / Dilation (pupillary dilator, α1) | Miosis (sphincter, M3); Ciliary contraction for near vision (M3) | Atropine causes severe cycloplegia (blurred near vision) and mydriasis; precipitates acute angle-closure glaucoma! |
| Heart | ↑ HR and inotropy (β1) | ↓ HR and AV conduction velocity (M2) | Carotid sinus massage stimulates CN IX afferents → ↑ vagal CN X efferents → terminates PSVT. |
| Bronchioles | Bronchodilation (β2) | Bronchoconstriction, ↑ secretions (M3) | Ipratropium/Tiotropium (M3 blockers) treat COPD. Non-selective β-blockers (Propranolol) can trigger fatal bronchospasm. |
| Urinary Bladder | Internal sphincter contraction (α1), Detrusor relaxation (β3) | Detrusor contraction (M3), Internal sphincter relaxation | Bethanechol (muscarinic agonist) treats postoperative urinary retention. Oxybutynin (M3 blocker) treats urge incontinence. |
| Male Genitalia | Ejaculation (α1) | Erection (pelvic splanchnic nerves, NO release) | Mnemonic: "Point and Shoot" • Parasympathetic = Point (erection); Sympathetic = Shoot (ejaculation). |
Hemodynamic Vasopressor Reflexes & Dale's Reversal
Full hemodynamic traces and baroreceptor arc analysis of Norepinephrine reflex bradycardia, Epinephrine differential pressor/depressor states, and Dale's Epinephrine Reversal under α-blockade.
Hemodynamic Reflex Loops & Vasopressor Matrix
Complete comparative hemodynamics, receptor profiles, and carotid sinus baroreceptor reflex responses
| Vasopressor / Inotrope | Primary Receptors | Systolic BP | Diastolic BP | MAP | Heart Rate (HR) | SVR | Physiologic Mechanism & Board Pearl |
|---|---|---|---|---|---|---|---|
| Norepinephrine | α1 > α2 > β1 | ↑↑ | ↑↑ | ↑↑ | ↓ (Reflex) | ↑↑ | Potent α1 vasoconstriction surges MAP → intense carotid sinus baroreceptor firing overrides modest direct β1 stimulation → Reflex Bradycardia. 1st-line for septic shock. |
| Epinephrine (Low Dose) | β1, β2 > α1 | ↑ | ↓ | ↔ / ↑ | ↑↑ | ↓ | β2 skeletal muscle vasodilation decreases DBP and SVR; β1 increases inotropy and HR (direct + mild reflex). Wide pulse pressure. |
| Epinephrine (High Dose) | α1 > β1 > β2 | ↑↑ | ↑ | ↑↑ | ↑ | ↑ | α1 effects dominate → generalized vasoconstriction, high MAP, and tachycardia. Drug of choice for anaphylactic shock (IM) and cardiac arrest (IV). |
| Phenylephrine | α1 pure | ↑↑ | ↑↑ | ↑↑ | ↓↓ (Reflex) | ↑↑ | Pure α1 agonist with zero direct cardiac β activity. Powerful vasoconstriction drives profound vagal baroreceptor reflex bradycardia. Used in neurogenic shock, priapism, and nasal decongestion. |
| Isoproterenol | β1 = β2 pure | ↑ | ↓↓ | ↓ | ↑↑↑ | ↓↓ | Powerful β2 vasodilation plummets SVR and DBP; β1 inotropy elevates SBP. Direct β1 chronotropy PLUS reflex tachycardia produces intense heart rate spike. |
| Dobutamine | β1 > β2, α | ↑ | ↔ / ↓ | ↔ | ↑ (Mild) | ↓ | Selective inotropic agent: increases stroke volume and cardiac output with minimal change in heart rate and decreased afterload. 1st-line for cardiogenic shock and acute decompensated heart failure with low ejection fraction. |
Dale's Epinephrine Reversal Breakdown
In the basal physiological state, intravenous Epinephrine causes a net PRESSOR response (↑ Blood Pressure) because α1-mediated vasoconstriction overpowers β2-mediated vasodilation.
Administer a non-selective α-blocker (such as Phentolamine or Phenoxybenzamine). This completely blocks α1 vascular smooth muscle contraction.
Administer Epinephrine. With α1 blocked, the unaffected β2 receptors are unmasked, resulting in profound vasodilation and a paradoxical DEPRESSOR response (↓ Blood Pressure)!
Glaucoma Pharmacotherapy & Anterior Chamber Outflow
Comprehensive anatomical anterior chamber cross-section mapping trabecular meshwork (Canal of Schlemm), uveoscleral outflow, ciliary epithelium secretion controls, and emergency angle-closure dynamics.
Glaucoma Autonomic Pharmacotherapy Matrix
Aqueous synthesis suppression, outflow pathways, and angle-closure emergencies.
- β-Blockers (Timolol, Betaxolol): Blocks β2 on non-pigmented ciliary epithelium → ↓ cAMP → ↓ aqueous secretion. No change in pupil size or accommodation.
- α2-Agonists (Brimonidine, Apraclonidine): Gi-coupled → ↓ aqueous secretion + minor ↑ uveoscleral outflow. Avoid in infants (risk of CNS depression and apnea).
- Carbonic Anhydrase Inhibitors (Dorzolamide, Acetazolamide): Inhibits carbonic anhydrase in ciliary body → ↓ HCO3- formation → ↓ water transport into posterior chamber.
- Prostaglandin Analogs (Latanoprost, Bimatoprost, Travoprost): 1st-line for Primary Open-Angle Glaucoma. Activates FP receptors → matrix metalloproteinases remodel ciliary body → increases uveoscleral outflow. Adverse: Irreversible brown iris pigmentation, eyelash hypertrichosis.
- Muscarinic Cholinomimetics (Pilocarpine, Carbachol): Contracts ciliary muscle → pulls scleral spur → widens trabecular meshwork pores. Also contracts pupillary sphincter (miosis) → pulls peripheral iris away from angle → relieves Acute Angle-Closure Glaucoma emergency!
Cardiovascular, Renal & Antiarrhythmic Pharmacology
Nephron transport physiology, diuretic electrolyte profiles, Vaughan Williams antiarrhythmic electrophysiology, and characteristic drug-induced ECG toxicities.
Diuretic Mechanisms & Nephron Tubular Transporters
Complete anatomical localization of Carbonic Anhydrase inhibitors (PCT), Osmotic diuretics (thin descending limb), Loop diuretics (NKCC2 in TAL), Thiazides (NCCT in DCT), and K+-sparing diuretics (ENaC and Aldosterone receptor blockers in collecting duct).
Diuretics Master Class & Nephron Transport Targets
Tubular sites of action, electrolyte shifts, acid-base alterations, and high-yield board traps.
| Diuretic Class & Prototype | Nephron Site & Target | Electrolyte & Acid-Base Shifts | Clinical Indications | Key Adverse Effects & Board Traps |
|---|---|---|---|---|
| Carbonic Anhydrase Inhibitors Acetazolamide |
Proximal Convoluted Tubule (PCT) Inhibits luminal CA IV and cytoplasmic CA II |
↑ Urine HCO3-, ↑ Na+, ↑ K+ Normal anion gap metabolic acidosis |
Open-angle glaucoma, acute mountain (altitude) sickness, idiopathic intracranial hypertension (pseudotumor cerebri), urine alkalinization (uric acid / cystine stones). | Hyperchloremic metabolic acidosis, calcium phosphate renal stones (insoluble in alkaline urine), sulfa allergy, paresthesias. |
| Osmotic Diuretics Mannitol |
Descending limb of Henle & PCT Non-reabsorbed sugar increases tubular osmolarity |
↑ Water excretion >> ↑ Na+ Increases serum osmolarity acutely |
Elevated intracranial pressure (cerebral edema), acute angle-closure glaucoma (lowers intraocular pressure). | Contraindicated in active CHF and pulmonary edema (rapid extracellular volume expansion worsens heart failure!); severe dehydration. |
| Loop Diuretics Furosemide, Bumetanide, Torsemide, Ethacrynic Acid |
Thick Ascending Limb (TAL) Inhibits Na+/K+/2Cl- cotransporter (NKCC2); abolishes hypertonic medullary gradient |
↑↑ Na+, ↑ K+, ↑ Cl-, ↑ Mg2+, ↑ Ca2+ Hypokalemic hypochloremic metabolic alkalosis |
Acute pulmonary edema, acute decompensated heart failure, cirrhosis with ascites, hypercalcemia. | "Loops Lose Calcium" (hypocalcemia), Ototoxicity (dose-dependent, synergistic with aminoglycosides), sulfa allergy. Ethacrynic acid is NOT a sulfa drug (use in sulfa-allergic patients with severe edema!). |
| Thiazide Diuretics Hydrochlorothiazide, Chlorthalidone |
Early Distal Convoluted Tubule (DCT) Inhibits Na+/Cl- cotransporter (NCCT) |
↑ Na+, ↑ K+, ↑ Cl-, ↓ Ca2+ excretion Hypokalemic metabolic alkalosis, Hyponatremia |
Essential hypertension (1st line), recurrent calcium nephrolithiasis (hypercalciuria), nephrogenic diabetes insipidus. | "Thiazides Save Calcium" (↑ Ca2+ reabsorption via basolateral Na+/Ca2+ exchanger). Mnemonic "hyperGLUC": HyperGlycemia, HyperLipidemia, HyperUricemia (precipitates acute gout!), HyperCalcemia. Sulfa allergy. |
| Aldosterone Antagonists Spironolactone, Eplerenone |
Cortical Collecting Tubule (CCT) Competitively blocks intracellular mineralocorticoid receptors |
↑ Na+, ↓↓ K+, ↓ H+ excretion Hyperkalemic metabolic acidosis |
Heart failure with reduced ejection fraction (HFrEF - proven mortality reduction!), primary hyperaldosteronism (Conn syndrome), hepatic ascites, female hirsutism. | Hyperkalemia (peaked T waves on ECG). Spironolactone causes painful gynecomastia, decreased libido, and erectile dysfunction due to anti-androgenic effects. Eplerenone is a selective aldosterone blocker without anti-androgenic effects. |
| ENaC Inhibitors Amiloride, Triamterene |
Cortical Collecting Tubule (CCT) Directly blocks luminal Epithelial Sodium Channels (ENaC) |
↑ Na+, ↓↓ K+, ↓ H+ excretion Hyperkalemic metabolic acidosis |
Liddle syndrome (gain-of-function ENaC mutation), lithium-induced nephrogenic diabetes insipidus (amiloride blocks lithium entry through ENaC). | Hyperkalemia. Does NOT cause endocrine/gynecomastia side effects. |
Vaughan Williams Antiarrhythmic Classification & Electrophysiology
Action potential modulation across Classes 1A, 1B, 1C, II, III, and IV, highlighting Na+ dissociation kinetics, ERP shifts, and risk profiles for Torsades de Pointes.
Vaughan Williams Antiarrhythmic Electrophysiology
Myocardial and nodal action potential phase targets, QRS and QT interval impacts, and lethal drug toxicities.
| Class & Prototype Drugs | Primary Channel & Mechanism | Action Potential Duration (APD) & ERP | ECG Effect (QRS / QT) | Clinical Utility & Severe Board Toxicities |
|---|---|---|---|---|
| Class IA Quinidine, Procainamide, Disopyramide "Double Quarter Pounder" |
Moderate Na+ channel block (intermediate binding/unbinding kinetics) + some K+ block | ↑ APD • ↑ Effective Refractory Period (ERP) | ↑ QRS, ↑ QT interval | Atrial and ventricular arrhythmias. Torsades de pointes (due to QT prolongation). Procainamide: Drug-induced lupus erythematosus (anti-histone antibodies in slow acetylators). Quinidine: Cinchonism (headache, tinnitus, vertigo) and thrombocytopenia. |
| Class IB Lidocaine, Mexiletine "Lettuce, Mayo" |
Weak Na+ channel block (fast unbinding kinetics). Preferentially binds ischemic / depolarized purkinje fibers. | ↓ APD • ↓ ERP | No change or ↓ QT interval | Acute post-MI ventricular arrhythmias, digitalis-induced arrhythmias. Completely ineffective against supraventricular arrhythmias! Neurologic toxicity: seizures, tremor, confusion, paresthesias. |
| Class IC Flecainide, Propafenone "Fries, Please" |
Strong Na+ channel block (slow dissociation kinetics). Marked use-dependence (stronger effect at higher heart rates). | No change in APD • ERP unchanged | ↑↑ QRS duration markedly (normal QT) | Refractory atrial fibrillation, SVT in normal hearts. STRICTLY CONTRAINDICATED in structural or ischemic heart disease / post-MI (CAST trial demonstrated increased mortality from lethal ventricular proarrhythmias!). |
| Class II Metoprolol, Atenolol, Esmolol, Propranolol |
β-adrenoceptor blockade → ↓ cAMP → ↓ Ca2+ and If pacemaker currents in SA & AV nodes | ↓ SA nodal conduction • ↑ AV nodal ERP | ↑ PR interval (slows AV node) | Ventricular rate control in AFib/AFlutter; SVT; post-MI mortality reduction. Adverse effects: bradycardia, AV block, bronchospasm (non-selective beta blockers in asthma), masking hypoglycemia. Esmolol has ultra-short half-life (~9 min). |
| Class III Amiodarone, Sotalol, Dofetilide, Ibutilide |
K+ channel blockers (inhibits delayed rectifier IKr channels) → delays Phase 3 repolarization | ↑↑ APD • ↑↑ ERP | ↑↑ QT interval markedly | AFib, AFlutter, ventricular tachycardia. Amiodarone Quintet of Toxicities: 1) Pulmonary fibrosis, 2) Thyroid (hypo- or hyperthyroidism due to 40% iodine content), 3) Hepatotoxicity, 4) Corneal microdeposits & optic neuropathy, 5) Blue-gray photodermatitis. Remarkably low Torsades risk despite prolonged QT! Sotalol/Dofetilide have high Torsades risk. |
| Class IV Verapamil, Diltiazem (Non-Dihydropyridines) |
L-type Ca2+ channel blockers → ↓ conduction velocity & prolonged repolarization in AV node | ↓ AV nodal conduction • ↑ ERP in AV node | ↑ PR interval | Rate control in AFib/AFlutter, PSVT. Contraindicated in HFrEF / systolic heart failure (negative inotropic effect worsens decompensation) and AV conduction block. Verapamil causes severe constipation and hyperprolactinemia. |
| Adenosine & Digoxin Miscellaneous Antiarrhythmics |
Adenosine: Activates A1 receptors → Gi → ↑ K+ efflux / hyperpolarization of AV node. Digoxin: Inhibits Na+/K+ ATPase → ↑ intracellular Ca2+ (positive inotrope) + ↑ vagal parasympathetic tone (↓ AV node). |
Transient AV block (Adenosine) Shortened APD • ↑ PR (Digoxin) |
Transient asystole (Adenosine) Scooped ST depression (Digoxin) |
Adenosine: Drug of choice for acute paroxysmal SVT conversion. Blocked by caffeine and theophylline! Causes transient flushing, chest tightness, feeling of doom. Digoxin: HFrEF + AFib. Toxicity exacerbated by hypokalemia (K+ and digoxin compete for binding site). Toxic symptoms: nausea, vomiting, yellow-green halos (xanthopsia), bidirectional VT, and hyperkalemia. Antidote: Digoxin-specific Fab fragments. |
High-Yield Pharmacologic ECG Manifestations
Classic rhythm strip and lead patterns induced by QT-prolonging drugs, electrolyte modulations, and digitalis.
Torsades de Pointes (Polymorphic VT)
Sinusoidal twisting of QRS complexes around the isoelectric baseline. Preceded by prolonged QT interval (QTc > 500 ms) and an "R-on-T" PVC.
Hyperkalemia (Tall, Symmetrical Peaked T Waves)
Narrow-based, tall, symmetric "tented" T waves. As potassium rises (>7.0 mEq/L): PR prolongation, loss of P waves, widening QRS → classic "sine wave" pattern and asystole/VFib.
Digoxin Effect & Lethal Toxicity
Therapeutic Digoxin Effect: Downsloping, concave ST depression resembling "Salvador Dali's mustache", shortened QT interval, flattened/inverted T waves.
Heart Failure GDMT, Antihypertensive Protocols & Anticoagulation
The 4 mortality-reducing pillars of HFrEF, pregnancy/emergency antihypertensives, and the definitive hemostatic pharmacology matrix.
Heart Failure with Reduced Ejection Fraction (HFrEF) • 4 Mortality-Reducing Pillars
Proven Mortality BenefitNeprilysin inhibitor (↑ ANP/BNP, bradykinin) + ARB. Decreases adverse remodeling, promotes natriuresis. Crucial rule: 36-hour washout when switching from ACEi to ARNI to prevent severe angioedema!
ONLY these 3 beta blockers reduce mortality in HFrEF. Prevents catecholamine toxicity and reverse remodels left ventricle. Never Metoprolol Tartrate! Initiate only when euvolemic.
Mineralocorticoid receptor antagonists prevent myocardial fibrosis and sudden cardiac death. Spironolactone causes endocrine gynecomastia; Eplerenone is selective with no gynecomastia risk.
Reduces cardiovascular death and heart failure hospitalizations in all HFrEF patients, with or without diabetes! Promotes osmotic diuresis and shifts myocardial energetics.
Hypertension in Pregnancy
Mnemonic: "He Likes My Neonate"
Hypertensive Emergency Protocols
Severe BP elevation (>180/120 mmHg) with acute target end-organ damage.
Anticoagulants, Antiplatelets & Thrombolytics Master Suite
Hemostasis Matrix| Drug / Class | Molecular Target | Monitoring | Specific Antidote / Reversal | Clinical Board Pearls & Toxicity |
|---|---|---|---|---|
| Unfractionated Heparin (UFH) | Antithrombin III (inactivates Thrombin IIa & Factor Xa 1:1) | PTT (intrinsic pathway) | Protamine Sulfate | Rapid onset, short t1/2. Risk of Heparin-Induced Thrombocytopenia (HIT Type II): antibodies to PF4-heparin complex → platelet activation → thrombosis! Switch immediately to Argatroban or Bivalirudin. |
| LMWH (Enoxaparin, Dalteparin) | Antithrombin III (predominantly Factor Xa > IIa, 3:1) | None routinely (Anti-Xa level if renal failure/obesity) | Protamine (partial reversal ~60%) | Higher subcutaneous bioavailability and longer t1/2 than UFH. Lower risk of HIT. Renally cleared (contraindicated in severe renal failure; use UFH instead). Safe in pregnancy! |
| Warfarin | Inhibits VKORC1 → blocks γ-carboxylation of Factors II, VII, IX, X, Protein C, Protein S | PT / INR (extrinsic pathway) | 4-Factor PCC + IV Vit K (urgent); Oral Vit K (non-urgent) | Shortest t1/2: Factor VII (6h) and Protein C (8h). Early loss of anticoagulant Protein C creates transient hypercoagulable state → Warfarin Skin Necrosis! Must bridge with Heparin. Teratogenic (fetal bone stippling). Target INR: 2.0–3.0 (2.5–3.5 for mechanical mitral valves). |
| DOACs: Factor Xa Inhibitors Apixaban, Rivaroxaban |
Directly bind active site of free and clot-bound Factor Xa | No routine monitoring | Andexanet alfa (recombinant decoy Xa) | 1st-line for non-valvular AFib and DVT/PE treatment. Fixed oral dosing, rapid onset, fewer intracranial hemorrhages than warfarin. Avoid in mechanical prosthetic valves or antiphospholipid syndrome. |
| DOACs: Direct Thrombin Inhibitors Dabigatran (oral), Argatroban (IV) |
Directly bind active site of Thrombin (Factor IIa) | PTT (for Argatroban titration) | Idarucizumab (Fab antibody for Dabigatran) | Argatroban & Bivalirudin: Agents of choice for patients with Heparin-Induced Thrombocytopenia (HIT). Argatroban is hepatically cleared (safe in renal failure). |
| Antiplatelets: P2Y12 Inhibitors Clopidogrel, Ticagrelor, Prasugrel |
Irreversibly block P2Y12 ADP receptors → prevents GPIIb/IIIa activation (Ticagrelor is reversible) | Platelet function assays | Platelet transfusion (if bleeding) | Dual antiplatelet therapy (DAPT = Aspirin + Clopidogrel/Ticagrelor) prevents acute stent thrombosis after PCI. Clopidogrel is a prodrug requiring activation by CYP2C19 (poor metabolizers have higher stent thrombosis risk!). |
| Antiplatelets: GP IIb/IIIa Inhibitors Abciximab, Eptifibatide, Tirofiban |
Block Glycoprotein IIb/IIIa receptors → inhibits fibrinogen cross-linking of platelets | Platelet count (risk of severe acute thrombocytopenia) | Platelet transfusion | Used during percutaneous coronary intervention (PCI) for acute coronary syndromes. Abciximab is a chimeric monoclonal Fab fragment. |
| Thrombolytics (Fibrinolytics) Alteplase (tPA), Tenecteplase |
Convert plasminogen to plasmin → degrades fibrin mesh of pre-formed clots | ↑ PT, ↑ PTT, ↑ D-dimer, ↓ fibrinogen | Aminocaproic Acid • Tranexamic Acid | Used for acute ischemic stroke (<4.5 hrs from onset), massive PE with hemodynamic instability, and STEMI if PCI not available within 120 mins. Strict contraindications: Prior intracranial hemorrhage, active internal bleeding, ischemic stroke within 3 months, aortic dissection. |
Lipid-Lowering Pharmacology Matrix
Dyslipidemia Core| Class / Prototype | Mechanism of Action | Δ LDL | Δ HDL | Δ Triglycerides | High-Yield Toxicities & Board Pearls |
|---|---|---|---|---|---|
| Statins (Atorvastatin, Rosuvastatin) | Inhibit HMG-CoA Reductase → ↓ hepatic cholesterol synthesis → upregulates LDL receptors → clearance of circulating LDL | ↓↓↓ (20–60%) | ↑ | ↓↓ | Proven mortality reduction in CAD. Adverse: Myopathy (check CK if symptomatic; risk surges when combined with Gemfibrozil or CYP3A4 inhibitors), hepatotoxicity (check LFTs). Teratogenic! |
| Ezetimibe | Inhibits NPC1L1 transporter at brush border of enterocytes → blocks intestinal absorption of dietary cholesterol | ↓↓ (15–20%) | ↔ / ↑ | ↓ | First-line add-on therapy to maximally tolerated statin for high-risk patients. Very well tolerated; rare hepatotoxicity when combined with statins. |
| PCSK9 Inhibitors (Evolocumab, Alirocumab) | Monoclonal antibodies bind PCSK9 → prevents degradation of hepatic LDL receptors → massive ↑ recycling of LDL receptors | ↓↓↓↓ (50–70%) | ↑ | ↓ | Subcutaneous injection every 2–4 weeks. Potent LDL lowering in familial hypercholesterolemia. Adverse: Myalgias, injection site reaction, delirium/neurocognitive effects (rare). |
| Fibrates (Gemfibrozil, Fenofibrate) | Activate PPAR-α transcription factor → upregulates Lipoprotein Lipase (LPL) → ↑ clearance of VLDL triglycerides | ↓ | ↑↑ | ↓↓↓↓ (35–50%) | Drug of choice for severe hypertriglyceridemia (>500 mg/dL) to prevent acute pancreatitis. Adverse: Myopathy (severe when combined with statins; Fenofibrate safer than Gemfibrozil), cholesterol gallstones (inhibits 7α-hydroxylase). |
| Niacin (Vitamin B3) | Inhibits hormone-sensitive lipase in adipose tissue → ↓ fatty acid release → ↓ hepatic VLDL and LDL synthesis | ↓↓ | ↑↑↑ (Most potent) | ↓↓ | Most effective agent to raise HDL. Adverse: Prostaglandin-mediated cutaneous facial flushing and pruritus (prevent with Aspirin 30 min before), hyperglycemia (acanthosis nigricans), hyperuricemia (→ triggers gout!). |
| Bile Acid Sequestrants (Cholestyramine, Colestipol) | Positively charged resins bind negatively charged bile acids in terminal ileum → ↓ enterohepatic circulation → liver converts cholesterol to bile acids | ↓↓ | ↑ (Slight) | ↑↑ (Triglyceride surge!) | Adverse: Severe constipation, abdominal bloating, malabsorption of fat-soluble vitamins (A, D, E, K). STRICTLY CONTRAINDICATED in hypertriglyceridemia (>300 mg/dL) as it increases hepatic VLDL output! |
Pulmonary & GI Pharmacology
Asthma and COPD stepwise regimens, leukotriene inhibitors, pulmonary hypertension vasodilators, acid-peptic disease suppressants, antiemetics, and gastrointestinal motility therapeutics.
Pulmonary Bronchodilation & GI Pharmacotherapy Architecture
Complete molecular mapping of β2 and M3 airway tone modulators, 5-LOX and CysLT1 leukotriene inhibitors, parietal cell H+/K+ ATPase acid secretagogues, and chemoreceptor trigger zone (CTZ) antiemetic receptor targets.
Asthma, COPD & Pulmonary Arterial Hypertension
SABAs, LABAs, ICS & Antimuscarinics
Albuterol, Salmeterol, Formoterol, Fluticasone, Budesonide, Ipratropium, Tiotropium.
SABAs (Albuterol, Levalbuterol): β2-agonist → ↑ cAMP → bronchial smooth muscle relaxation. 1st-line for acute bronchospasm / rescue. Adverse: Skeletal muscle tremor, reflex tachycardia, hypokalemia (β2 stimulation shifts K+ intracellularly!).
LABAs (Salmeterol, Formoterol): Lipophilic long-acting β2 agonists for controller maintenance. Black-Box Warning: Never use LABA as monotherapy in asthma (causes downregulation of receptors and increases asthma-related deaths!); MUST always be combined with an Inhaled Corticosteroid (ICS)!
Inhaled Corticosteroids (Fluticasone, Budesonide): 1st-line maintenance anchor for persistent asthma. Inactivates NF-κB → ↓ transcription of inflammatory cytokines (TNF-α, IL-4, IL-5). Board Trap: Causes oral candidiasis (thrush) and dysphonia; patients must use a spacer and rinse mouth and spit after each inhalation!
Muscarinic Antagonists (SAMA Ipratropium, LAMA Tiotropium): Competitively block M3 receptors → prevents vagally mediated bronchoconstriction and reduces mucus secretion. 1st-line bronchodilators for COPD; adjunct in acute asthma exacerbations.
Montelukast, Zileuton & Anti-IgE / Anti-IL-5
Receptor antagonists, 5-LOX inhibitors, Omalizumab, and Mepolizumab.
Montelukast & Zafirlukast: Selectively block CysLT1 (LTD4) receptors → blocks leukotriene-mediated bronchoconstriction, airway edema, and eosinophil migration. 1st-line for Aspirin-Exacerbated Respiratory Disease (AERD / Samter Triad) and exercise-induced bronchoconstriction. Favorable oral adherence in pediatric asthma. Neuropsychiatric adverse warning (abnormal dreams, mood changes).
Zileuton (5-Lipoxygenase Inhibitor): Directly inhibits 5-LOX → blocks conversion of arachidonic acid into ALL leukotrienes (LTB4 neutrophil chemoattractant, LTC4, LTD4, LTE4). Adverse: Significant hepatotoxicity; requires baseline and periodic liver transaminase monitoring!
Omalizumab (Anti-IgE mAb): Binds circulating Fc portion of free IgE, preventing binding to FcεRI on mast cells and basophils → blocks degranulation. Indicated for severe refractory allergic asthma with elevated serum IgE resistant to high-dose ICS + LABA.
Mepolizumab & Benralizumab (Anti-IL-5): Mepolizumab neutralizes free IL-5; Benralizumab blocks IL-5Rα → induces eosinophil apoptosis. Indicated for severe eosinophilic asthma with persistent peripheral eosinophilia.
Theophylline & PAH Targeted Agents
PDE inhibitors, adenosine antagonism, endothelin blockers, and prostacyclins.
Theophylline: Non-selective phosphodiesterase (PDE) inhibitor (↑ cAMP → bronchodilation) and adenosine receptor antagonist. Narrow therapeutic index (10–20 μg/mL). Metabolized by CYP1A2 (induced by cigarette smoking; inhibited by ciprofloxacin, macrolides, cimetidine). Toxicity: Cardiotoxicity (arrhythmias, SVT, VT) and severe refractory seizures!
Bosentan & Ambrisentan: Competitive antagonists at endothelin-1 receptors (ETA & ETB on vascular smooth muscle) → ↓ pulmonary vascular resistance in Pulmonary Arterial Hypertension (PAH). Toxicities: Hepatotoxicity (black-box transaminitis monitoring) and teratogenicity (strict contraception required).
Sildenafil & Tadalafil (PDE-5 Inhibitors): Inhibit PDE-5 in pulmonary vasculature → ↑ cGMP → nitric oxide-mediated vasodilation. Absolute Contraindication: Co-administration with organic nitrates (causes profound, refractory, fatal hypotension!).
Epoprostenol & Iloprost (Prostacyclin / PGI2 Analogs): Direct vasodilators of pulmonary and systemic arterial beds; inhibit platelet aggregation. Continuous IV infusion (epoprostenol) or inhalation (iloprost). Adverse: Jaw pain on chewing, flushing, headache.
Acid-Peptic Disorders, Antiemetics & Bowel Motility
PPIs, H2 Blockers & Cytoprotectants
Omeprazole, Famotidine, Cimetidine, Sucralfate, Misoprostol, Bismuth.
Proton Pump Inhibitors (Omeprazole, Pantoprazole, Esomeprazole): Irreversibly bind and inhibit H+/K+ ATPase in gastric parietal cells. Most potent acid suppressors for GERD, PUD, and Zollinger-Ellison. Board Adverse Effects: ↓ Mg2+ (hypomagnesemia), ↓ Ca2+ absorption (↑ risk of osteoporotic hip fractures), ↑ susceptibility to Clostridioides difficile colitis and community-acquired pneumonia, acute interstitial nephritis, and microscopic colitis.
H2 Receptor Antagonists (Famotidine, Cimetidine): Reversible competitive H2 blockers on parietal cells → ↓ cAMP → ↓ basal and nocturnal gastric acid. Cimetidine Board Traps: Potent CYP450 inhibitor (↑ warfarin, theophylline, phenytoin levels) and antiandrogen (blocks androgen receptors → gynecomastia, impotence, galactorrhea).
Sucralfate: Sulfated sucrose aluminum complex that polymerizes in acid to form a thick, protective gel over ulcer craters. Crucial Rule: Requires acidic environment for activation; never administer concurrently with PPIs, H2 blockers, or antacids!
Misoprostol (PGE1 Analog): Stimulates gastric mucosal mucus and bicarbonate secretion; ↓ acid production. Used for prevention of NSAID-induced gastric ulcers. Absolute Contraindication: Women of childbearing potential without reliable contraception (stimulates uterine contractions → spontaneous abortion / abortifacient!).
Bismuth Subsalicylate: Coats ulcers, stimulates prostaglandins, and exerts direct antibacterial action against H. pylori (quadruple therapy). Harmless side effect: black stool and black tongue (bismuth sulfide precipitation; distinguish from melena!).
Ondansetron, Metoclopramide & Aprepitant
5-HT3 antagonists, D2 prokinetics, NK1 antagonists, and vestibulocochlear agents.
5-HT3 Antagonists (Ondansetron, Granisetron): Selectively block 5-HT3 receptors on vagal afferents in gut and centrally in the chemoreceptor trigger zone (CTZ / area postrema). 1st-line for post-operative and chemotherapy-induced vomiting. Adverse: Headache, constipation, QTc prolongation (risk of Torsades de pointes), and Serotonin Syndrome when combined with serotonergic drugs.
D2 Antagonists / Prokinetics (Metoclopramide, Prochlorperazine): Central D2 block in CTZ (antiemetic) and peripheral 5-HT4 agonism → ↑ resting lower esophageal sphincter (LES) tone and accelerates gastric emptying (prokinetic for diabetic gastroparesis). High-Yield Toxicities: Extrapyramidal symptoms (acute dystonia, akathisia, parkinsonism), Tardive Dyskinesia with chronic use, and hyperprolactinemia. Contraindications: Mechanical bowel obstruction (perforation risk!) and Parkinson disease.
NK1 Receptor Antagonists (Aprepitant, Fosaprepitant): Inhibit Substance P at neurokinin-1 (NK1) receptors in brainstem vomiting center. 1st-line for delayed chemotherapy-induced nausea and vomiting (CINV) (24–72 hours post-chemo); synergistic with dexamethasone and 5-HT3 blockers.
Vestibular / Motion Sickness Agents: Scopolamine (transdermal muscarinic M1 antagonist; treats motion sickness, causes dry mouth, blurry vision, mydriasis); Meclizine & Diphenhydramine (1st-gen H1 antihistamines with antimuscarinic activity for vestibular vertigo and motion sickness).
Loperamide, Laxatives & Octreotide
Opioid antidiarrheals, osmotic/stimulant laxatives, chloride channel activators, and somatostatin analogs.
Opioid Antidiarrheals (Loperamide, Diphenoxylate): Peripheral μ-opioid agonists → slows intestinal smooth muscle transit and increases anal sphincter tone. Loperamide has poor CNS penetration at therapeutic doses (minimal addiction potential). Diphenoxylate is combined with subtherapeutic Atropine to discourage recreational abuse (causes anticholinergic symptoms if taken in excess). Trap: Contraindicated in invasive bloody diarrhea or toxic megacolon!
Laxative Classes & Mechanisms:
- Bulk-Forming (Psyllium, Methylcellulose): Soluble fibers draw water into stool → distends colon → peristalsis.
- Osmotic (Polyethylene Glycol / MiraLAX, Magnesium Citrate, Lactulose): Non-absorbable solutes draw water into lumen. Lactulose Board Pearl: Degraded by colonic bacteria into lactic and acetic acid → acidifies lumen → converts diffusible NH3 to non-absorbable NH4+ (ammonia trap for hepatic encephalopathy!).
- Stimulants (Senna, Bisacodyl): Enteric nerve stimulation. Chronic abuse causes Melanosis Coli (dark brown pigment in lamina propria; benign).
- Emollients (Docusate): Anionic surfactant allowing water/lipids to penetrate hard stool.
IBS Therapeutics & Motility: Lubiprostone (type-2 chloride channel opener → ↑ fluid secretion for IBS-C); Linaclotide (guanylate cyclase-C agonist → ↑ cGMP → CFTR activation for IBS-C); Alosetron (5-HT3 blocker for refractory IBS-D in females; risk of ischemic colitis!).
GI Antispasmodics (Dicyclomine / Bentyl, Hyoscyamine): Tertiary amine muscarinic M1/M3 receptor antagonists with secondary direct spasmolytic smooth muscle relaxation for acute colic and IBS crampy abdominal pain. High-Yield Board Traps: Strictly contraindicated in infants < 6 months (apnea, respiratory collapse, seizures, death) and nursing mothers. Beers Criteria high-risk in elderly (delirium, urinary retention, falls). Contraindicated in narrow-angle glaucoma, myasthenia gravis, and obstructive ileus/toxic megacolon. NEVER administer IV (severe thrombophlebitis and systemic toxicity risk).
Octreotide in GI: Somatostatin analog → potent splanchnic vasoconstriction (↓ portal pressures for bleeding esophageal varices); suppresses secretin/VIP/serotonin → stops severe watery diarrhea in VIPoma and Carcinoid Syndrome.
Cytochrome P450 Drug Interactions & Narrow Therapeutic Index Vault
Classic potent inducers (Rifampin, Carbamazepine, Phenytoin, St. John's Wort) vs. inhibitors (Macrolides, Azoles, Cimetidine, Grapefruit juice) and high-stakes monitoring parameters for Warfarin, Lithium, Digoxin, and Theophylline.
Cytochrome P450 Inducers vs Inhibitors
Crucial drug-drug interaction matrix tested heavily on every COMLEX and USMLE exam.
CYP450 Inducers
Inducing CYP450 increases hepatic metabolism of co-administered drugs → decreased serum drug levels and clinical treatment failure (e.g., unplanned pregnancy on OCPs, subtherapeutic INR/thrombus on Warfarin).
- Chronic alcohol
- St. John's Wort (herbal depression remedy)
- Phenytoin
- Phenobarbital
- Nevirapine (NNRTI)
- Rifampin (potent CYP inducer; red/orange tears & urine)
- Griseofulvin (antifungal)
- Carbamazepine (also induces its own metabolism!)
CYP450 Inhibitors
Inhibiting CYP450 halts metabolism → elevated plasma concentrations and dangerous drug toxicity (e.g., supratherapeutic INR > 5 with life-threatening bleeding, myopathy from statins).
- Sodium valproate
- Isoniazid (INH)
- Cimetidine (H2 blocker)
- Ketoconazole & Azole antifungals
- Fluconazole
- Alcohol (acute binge drinking!)
- Chloramphenicol
- Erythromycin / Clarithromycin (Macrolides; Azithromycin does NOT inhibit)
- Sulfonamides (TMP-SMX)
- Ciprofloxacin (Fluoroquinolones)
- Omeprazole (PPI)
- Metronidazole & Grapefruit juice
- Ritonavir: Extremely potent CYP3A4 inhibitor used clinically as a pharmacokinetic "booster" (e.g. Paxlovid = Nirmatrelvir + Ritonavir) → massive potential for lethal drug-drug interactions.
High-Risk Narrow Therapeutic Index Substrates
Autonomic Toxidromes, Poisoning Presentations & Antidote Vault
Direct differential diagnosis for Cholinergic (DUMBBELLS) vs. Anticholinergic (dry/hot/mad/blind) vs. Sympathomimetic vs. Opioid toxidromes with specific antidote pairings (Atropine + 2-PAM, Physostigmine, Naloxone, Fomepizole, N-acetylcysteine, Hydroxocobalamin).
25-Toxin Clinical Antidote Compendium
Searchable clinical antidote registry with molecular reversal mechanisms and emergency board scenarios.
Master Clinical Toxidrome Differential Matrix
Rapid physical exam discriminator for acute toxicologic ingestions and poisonings.
| Toxidrome / Culprits | Pupils | HR & BP | Temp | Skin / Sweating | Bowel Sounds | Neuromuscular Hallmarks | Specific Antidote & Key Clue |
|---|---|---|---|---|---|---|---|
| Anticholinergic Atropine, TCAs, Antihistamines, Scopolamine |
Mydriasis (↑) | Tachycardia • HTN | ↑↑ Fever | ANHIDROTIC (Bone Dry!) | ↓↓ (Absent) | Delirium ("mad as a hatter"), visual hallucinations, urinary retention, flushed skin. | Physostigmine (tertiary amine crosses BBB). Key clue: Axillae and groin are completely dry! |
| Cholinergic Organophosphates, Sarin, Carbamates |
Miosis (↓↓ Pinpoint) | Bradycardia • Hypotension | ↔ | DIAPHORETIC (Drenched!) | ↑↑↑ (Hyperactive) | Fasciculations → flaccid paralysis (nicotinic), copious salivation, lacrimation, bronchorrhea. | Atropine + Pralidoxime (2-PAM). Mnemonic: "DUMBBELLS". Killer is 3 Bs: Bronchorrhea, Bronchospasm, Bradycardia! |
| Sympathomimetic Cocaine, Methamphetamine, MDMA, PCP |
Mydriasis (↑) | Severe Tachycardia • Severe HTN | ↑↑ Hyperthermia | DIAPHORETIC (Profuse Sweating) | ↑ (Active) | Tremor, agitation, paranoia, tactile hallucinations (formication = "cocaine bugs"), seizures. | Benzodiazepines + active cooling. Differentiator: Sweating present (distinguishes from Anticholinergic). Never give pure β-blockers! |
| Opioid Overdose Heroin, Fentanyl, Morphine, Methadone |
Miosis (↓↓ Pinpoint) | Bradycardia • Hypotension | ↓ Hypothermia | Dry / Cool | ↓↓ (Absent) | Depressed mental status / coma, hyporeflexia, flaccidity. Profound Respiratory Depression (RR < 8). | Naloxone (IV/IN). Classic Triad: Pinpoint Pupils + Respiratory Depression + Coma. (Exception: Meperidine causes mydriasis!). |
| Sedative-Hypnotic Benzodiazepines, Barbiturates, Alcohol |
↔ Normal / Sluggish | Mild ↓ HR & BP | ↓ Mild | Normal | ↓ Mild | CNS depression, dysarthria, ataxia, nystagmus. Respiratory depression is mild unless mixed with alcohol or opioids. | Flumazenil (for pure benzo overdose; caution: precipitates acute withdrawal seizures in dependent patients!). |
| Serotonin Syndrome SSRI + MAOI, Linezolid, Tramadol, MDMA |
Mydriasis (↑) | Tachycardia • Labile BP | ↑↑ Hyperthermia | DIAPHORETIC (Sweating) | ↑↑ (Hyperactive) | CLONUS (Spontaneous / Inducible), Hyperreflexia (LE > UE), tremor, akathisia, ocular clonus. Rapid onset (<24 hrs). | Cyproheptadine (5-HT2 antagonist). Differentiator from NMS: Hyperreflexia and CLONUS (NMS has "lead-pipe" rigidity and hyporeflexia!). |
| Toxin / Overdose | Specific Antidote | Reversal Mechanism | Clinical Board Vignette Clues |
|---|
Antimicrobial Classes, Mechanisms & Bacterial Targets
Complete anatomical and molecular layout of 30S vs 50S ribosomal subunit inhibitors, peptidoglycan transpeptidase (PBP) blockers, D-Ala-D-Ala cell wall binders, DNA gyrase inhibitors, and folate synthesis antagonists.
Antimicrobial Molecular Targets
Ribosomal subunits (30S vs 50S), cell wall crosslinking, and mechanisms of resistance.
Buy AT 30, CCEL at 50
Aminoglycosides: Inhibit initiation complex → mRNA misreading. Ototoxicity & nephrotoxicity. Requires O2 for uptake (ineffective against anaerobes!).
Tetracyclines: Block aminoacyl-tRNA binding to A-site. Teeth discoloration in kids <8; photosensitivity.
Chloramphenicol (peptidyltransferase → gray baby syndrome, aplastic anemia).
Clindamycin (peptide bond formation → C. diff pseudomembranous colitis).
Erythromycin / Macrolides (translocation → motilin receptor agonist, QT prolongation).
Linezolid (initiation complex → thrombocytopenia, serotonin syndrome with SSRIs).
Cell Wall Crosslinking
Enzymatic Blockade
Tuberculosis RIPE Regimen
Rifampin: Inhibits DNA-dependent RNA polymerase. Potent CYP450 inducer (speeds drug breakdown). Harmless orange-red urine, tears, sweat.
Isoniazid (INH): Activated by KatG catalase-peroxidase; inhibits mycolic acid cell wall synthesis. Causes peripheral neuropathy (must co-administer Vitamin B6 / Pyridoxine!), drug-induced lupus (anti-histone antibodies), hepatotoxicity.
Pyrazinamide: Converted to pyrazinoic acid in acidic phagolysosomes. Adverse: hyperuricemia triggering acute gout flares; hepatotoxicity.
Ethambutol: Inhibits arabinosyltransferase (blocks arabinogalactan wall). Adverse: retrobulbar optic neuritis with loss of visual acuity and red-green color blindness.
Ergosterol & Glucan Blockers
Azoles (Fluconazole, Voriconazole): Inhibit 14α-demethylase (blocks lanosterol → ergosterol). Voriconazole causes visual color disturbances. Potent CYP450 inhibitors.
Echinocandins (Caspofungin): Inhibit β-1,3-D-glucan synthase (cell wall synthesis).
Terbinafine: Inhibits squalene epoxidase (dermatophytes / onychomycosis).
HIV ART & Direct-Acting Antivirals
NRTIs (Tenofovir, Emtricitabine, Abacavir): Chain terminators lacking 3'-OH. Abacavir requires HLA-B*5701 testing to prevent fatal hypersensitivity.
NNRTIs (Efavirenz): Allosteric RT blockers (vivid nightmares, CNS symptoms).
Protease Inhibitors (-navir): Block pol aspartyl protease (hyperglycemia, lipodystrophy).
INSTIs (-tegravir: Dolutegravir, Bictegravir): Block viral DNA integration into host genome (1st-line anchor!).
HCV DAAs: Sofosbuvir (NS5B RNA-dependent RNA polymerase inhibitor) + Ledipasvir / Velpatasvir (NS5A replication complex inhibitor) cures >95% of HCV.
Acyclovir: Monophosphorylated by HSV/VZV thymidine kinase; chain terminator. Ganciclovir (CMV UL97 kinase; causes neutropenia).
Antimalarials, Nematode & Trematode Agents
Chloroquine: Blocks biocrystallization of toxic heme to hemozoin → accumulation of free heme lyses Plasmodium. Resistance via pfcrt efflux pump. Adverse: Retinopathy, QT prolongation.
Primaquine: Destroys dormant hypnozoites in liver (P. vivax, P. ovale) to prevent disease relapse. Absolute Board Rule: MUST screen for G6PD deficiency prior to administration (causes fatal oxidative hemolytic anemia)!
Atovaquone-Proguanil (Malarone): 1st-line daily prophylaxis for chloroquine-resistant P. falciparum (inhibits mitochondrial electron transport and folate synthesis). Mefloquine used for prophylaxis; contraindicated in patients with neuropsychiatric or seizure disorders (causes vivid nightmares, psychosis).
Albendazole & Mebendazole: Inhibit β-tubulin polymerization → halts microtubule synthesis and glucose uptake in nematodes (pinworm, Ascaris, hookworm) and cestodes (Taenia solium neurocysticercosis, hydatid cysts).
Praziquantel: ↑ membrane permeability to Calcium (Ca2+) → persistent tetanic muscular contraction and tegument disintegration. 1st-line for all Schistosoma species (blood flukes), Clonorchis (liver fluke), and adult tapeworms.
Ivermectin: Opens glutamate-gated chloride channels → hyperpolarization and flaccid paralysis. 1st-line for Strongyloides and Onchocerca volvulus (River Blindness), and refractory crusted scabies.
Metronidazole: Forms toxic nitro free radical intermediates in anaerobes/protozoa → DNA fractures. Treats Giardia, Trichomonas, and Entamoeba histolytica. Board Trap: Causes severe Disulfiram-like reaction when consumed with alcohol (flushing, tachycardia, severe vomiting)!
CMV, Kinase-Independent Polymerase & Influenza Inhibitors
Foscarnet: Direct pyrophosphate analog that binds and inhibits viral DNA polymerase WITHOUT requiring phosphorylation by viral thymidine kinase (TK) or UL97 kinase! Indicated for acyclovir-resistant HSV/VZV and ganciclovir-resistant CMV retinitis. High-Yield Toxicities: Direct nephrotoxicity and chelation of divalent cations → profound hypocalcemia, hypomagnesemia, and hypokalemia (triggers seizures and fatal arrhythmias)!
Cidofovir: Cytidine nucleotide analog; phosphorylated exclusively by host cellular enzymes. Treats resistant CMV retinitis and acyclovir-resistant HSV. Co-administered with oral Probenecid and aggressive IV saline hydration to block active renal tubular secretion and prevent acute tubular necrosis!
Oseltamivir (Tamiflu) & Zanamivir: Potent neuraminidase inhibitors → block cleavage of terminal sialic acid residues → newly synthesized virions remain clumped to host cell surface and cannot bud/disseminate. Clinical Rule: Must be initiated within 48 hours of symptom onset to significantly reduce duration of illness!
Baloxavir Marboxil: Inhibits viral cap-dependent endonuclease → halts viral mRNA synthesis and transcription. Single-dose oral therapy with efficacy equivalent to a full 5-day course of oseltamivir.
Neuro & Psychiatric Pharmacology
Antidepressant mechanisms, antipsychotic extrapyramidal symptoms, antiepileptic drug toxicity matrices, and Parkinson disease therapeutics.
Neuropsychopharmacology, Antiepileptics & Receptor Binding Profiles
Complete receptor profiles of monoamine reuptake blockers, 1st vs 2nd-generation antipsychotic dopamine pathways, antiepileptic ion channel modulators, and opioid mu-receptor signaling.
Antidepressants & Serotonin Syndromes
Reuptake inhibitors, receptor modulators, enzyme blockers, and hyperadrenergic toxicity distinctions.
SSRIs & SNRIs
Fluoxetine, Sertraline, Escitalopram, Citalopram; Venlafaxine, Duloxetine.
Mechanism: SSRIs inhibit 5-HT reuptake transporter (SERT). SNRIs inhibit both SERT and NET (norepinephrine transporter). Takes 4-6 weeks for clinical response.
Adverse: Sexual dysfunction (anorgasmia, decreased libido), GI upset, SIADH (hyponatremia in elderly). Venlafaxine causes dose-dependent hypertension. Duloxetine also treats diabetic neuropathy & fibromyalgia.
Amitriptyline & Nortriptyline
Imipramine, Clomipramine (1st-line for severe OCD), Doxepin.
Mechanism: Inhibit 5-HT and NE reuptake; also block α1, H1, mACh, and cardiac fast Na+ channels.
- Convulsions (GABA antagonism)
- Coma (antihistaminic / anticholinergic)
- Cardiotoxicity (wide QRS arrhythmia & hypotension via fast Na+ channel blockade)
Phenelzine, Tranylcypromine, Selegiline
MAO-A (serotonin/NE) and MAO-B (dopamine) irreversible inhibition.
Atypical Depression: Mood reactivity, leaden paralysis, interpersonal rejection sensitivity, hypersomnia.
Bupropion, Mirtazapine, Trazodone
Distinct receptor targets tailored to patient comorbidities.
Bupropion (NDRI): Inhibits NE/dopamine reuptake. Zero sexual side effects, weight neutral/loss, smoking cessation. Absolute contraindication: Bulimia, anorexia nervosa, and epilepsy (significantly lowers seizure threshold!).
Mirtazapine: α2-adrenergic antagonist → ↑ NE and 5-HT release; blocks 5-HT2/3 and H1. Promotes sedation and marked appetite stimulation with weight gain (ideal for frail, underweight depressed geriatric patients!).
Trazodone: 5-HT2 and α1 blocker. Primarily used for insomnia. Adverse: Priapism ("trazo-BONE").
Antipsychotics & Extrapyramidal Symptom (EPS) Staging
First generation (typical) vs Second generation (atypical), receptor affinities, and acute vs late extrapyramidal sequelae.
| Class & Specific Drugs | Receptor Binding Profile | Hallmark Adverse Effects & Clinical Pearls | Antidote / Management Strategy |
|---|---|---|---|
|
1st Gen High Potency Haloperidol, Fluphenazine, Trifluoperazine |
Potent D2 receptor blockade in mesolimbic pathway |
Very high risk of Extrapyramidal Symptoms (EPS) and Hyperprolactinemia (galactorrhea, amenorrhea, gynecomastia). Low anticholinergic/sedative effect. EPS Chronological Timeline: • 4 hours: Acute Dystonia (painful torticollis, oculogyric crisis, trismus). • 4 days to 4 weeks: Akathisia (intense subjective motor restlessness, pacing). • 4 weeks to 4 months: Parkinsonism (cogwheel rigidity, bradykinesia, mask facies, pill-rolling tremor). • 4 months to years: Tardive Dyskinesia (involuntary choreoathetoid movements of face/tongue; often irreversible!). |
Acute dystonia: IV Benztropine or Diphenhydramine (anticholinergics). Akathisia: Propranolol (Beta-blocker) or Benzodiazepine. Tardive Dyskinesia: Discontinue drug, switch to Clozapine; VMAT2 inhibitor (Valbenazine). |
|
1st Gen Low Potency Chlorpromazine, Thioridazine |
Weak D2 blockade; potent α1, H1, mACh antagonism |
Low EPS risk, but prominent anticholinergic dry mouth, orthostatic hypotension (α1), and heavy sedation (H1). • Chlorpromazine: Corneal epithelial deposits ("corneal deposits = Chlorpromazine"). • Thioridazine: Retinal pigmentation ("retinal deposits = Thioridazine"), QT prolongation / Torsades risk. |
Dose reduction; switch to atypical antipsychotic; monitor annual ophthalmologic exams. |
|
2nd Gen Atypicals Clozapine, Olanzapine, Risperidone, Quetiapine, Aripiprazole, Ziprasidone |
5-HT2A antagonist + D2 antagonist (Aripiprazole is partial D2 agonist) |
Treats both positive and negative symptoms of schizophrenia; lower risk of EPS. • Metabolic Syndrome: Massive weight gain, dyslipidemia, diabetes (highest risk: Olanzapine & Clozapine). • Clozapine: Reserved for treatment-resistant schizophrenia and suicidality. Causes fatal Agranulocytosis (mandatory regular absolute neutrophil count [ANC] monitoring!), myocarditis, and lowers seizure threshold. • Risperidone: Highest prolactin elevation among 2nd gen. • Ziprasidone: Black box warning for QT prolongation. |
Monitor fasting glucose, lipid panel, and BMI. Clozapine requires strict REMS ANC registry (>1500/µL to continue therapy). |
|
Neuroleptic Malignant Syndrome (NMS) Idiosyncratic reaction to all antipsychotics |
Acute profound central dopamine D2 receptor hypofunction |
Classic Tetrad: "Lead-pipe" generalized muscle rigidity, extreme hyperthermia (>40°C), autonomic instability (tachycardia, labile BP, diaphoresis), and altered mental status. Laboratory: massive creatine kinase (CK) elevation and rhabdomyolysis with acute tubular necrosis. Distinction from Serotonin Syndrome: NMS has lead-pipe rigidity and hyporeflexia; Serotonin Syndrome has hyperreflexia, clonus, and tremor! |
Immediate discontinuation of antipsychotic; ICU aggressive cooling; Dantrolene (blocks Ryanodine receptor Ca2+ release from SR) and/or Bromocriptine (dopamine agonist). |
Antiepileptics, Mood Stabilizers & Parkinson Therapeutics
Channel blockers, vesicular SV2A modulators, dopamine replenishment, and dopa-decarboxylase synergy.
Valproate, Lamotrigine, Levetiracetam
First-line for both generalized tonic-clonic and focal seizures.
Valproic Acid: Prolongs Na+ inactivation and increases GABA synthesis. Adverse: Fatal fulminant hepatotoxicity (monitor LFTs), acute pancreatitis, weight gain, alopecia, and severe neural tube defects (spina bifida) in utero!
Lamotrigine: Blocks voltage-gated Na+ channels and inhibits glutamate release. Bipolar depression. Adverse: Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) → must titrate very slowly!
Levetiracetam (Keppra): Modulates synaptic vesicle protein SV2A. Minimal drug interactions. Adverse: neuropsychiatric agitation and mood changes.
Phenytoin, Carbamazepine, Ethosuximide
Sodium channel blockers & absence seizure specific therapy.
Phenytoin: Blocks Na+ channels; exhibits zero-order elimination kinetics at therapeutic levels! Adverse: Gingival hyperplasia (PDGF release), hirsutism, peripheral neuropathy, megaloblastic anemia (folate), drug-induced lupus, fetal hydantoin syndrome (cleft lip/palate).
Carbamazepine: 1st line for trigeminal neuralgia & focal seizures. Potent CYP450 inducer. Adverse: Agranulocytosis / aplastic anemia, SIADH (hyponatremia), DRESS syndrome, SJS (HLA-B*1502 in Asian ancestry).
Ethosuximide: 1st line for Absence Seizures (3-Hz spike-and-wave on EEG). Blocks thalamic T-type Ca2+ channels. Mnemonic: "EFGHIJ: Ethosuximide, Fatigue, GI distress, Headache, Itching, Stevens-Johnson".
Levodopa/Carbidopa & Adjuncts
Rebalance dopamine vs acetylcholine in nigrostriatal pathway.
Levodopa / Carbidopa: L-DOPA crosses blood-brain barrier (converted to dopamine by DOPA decarboxylase). Carbidopa inhibits peripheral DOPA decarboxylase → increases CNS bioavailability from 1% to 10% and dramatically reduces peripheral side effects (nausea, arrhythmias, postural hypotension). Long-term: "on-off" motor fluctuations.
COMT Inhibitors: Entacapone (peripheral), Tolcapone (central + peripheral, hepatotoxic). Prevent peripheral degradation of L-DOPA to 3-OMD.
Dopamine Agonists: Pramipexole, Ropinirole (non-ergot, restless legs syndrome). Side effect: impulse control disorders (gambling, hypersexuality).
Amantadine: Increases dopamine release; causes livedo reticularis (purplish mottled lace rash on legs).
Anticholinergics (Benztropine, Trihexyphenidyl): M1 antagonists; improves resting tremor and rigidity.
General Anesthetics, NMJ Blockade & Local Anesthesia
Inhaled MAC kinetics, Malignant Hyperthermia, Succinylcholine Phase I/II block, and Local Anesthetic amides vs esters.
Inhaled & IV Anesthetics
MAC (Minimum Alveolar Concentration): Inverse of potency (↓ MAC = ↑ potency). 1 MAC prevents movement in 50% of patients. Halothane: Low MAC (0.75%), high potency.
Blood/Gas Partition Coefficient: Solubility in blood. Inverse of induction rate (↓ solubility = ↑ rapid induction/recovery). Nitrous Oxide & Desflurane: Low solubility = rapid onset!
- Propofol: Potentiates GABA-A. Rapid onset/recovery; causes vasodilation and hypotension.
- Etomidate: GABA-A agonist. Cardiovascularly neutral (ideal for shock/unstable intubations). Inhibits 11β-hydroxylase → risk of acute adrenal insufficiency!
- Ketamine: NMDA receptor antagonist. Dissociative anesthesia; bronchodilation; maintains BP. Adverse: Vivid emergence delirium.
Neuromuscular Blockers
Nicotinic ACh receptor agonist. Hydrolyzed by plasma pseudocholinesterase (atypical pseudocholinesterase causes prolonged paralysis!).
Phase I Block: Constant depolarization; transient fasciculations then flaccid paralysis. No fade on Train-of-Four (TOF). Neostigmine augments Phase I!
Phase II Block: Continuous exposure desensitizes receptor; shows fade on TOF. Reversed by neostigmine.
Board Hazard: Severe hyperkalemia in patients with burns, crush injuries, denervation (upregulated extrajunctional nAChRs)!
Competitive antagonists at nAChR (Rocuronium, Vecuronium, Cisatracurium). Display progressive fade on TOF.
Cisatracurium: Spontaneous non-enzymatic Hofmann elimination in plasma → drug of choice in renal and hepatic failure!
Reversal: Neostigmine + Glycopyrrolate/Atropine (must co-administer anticholinergic to prevent muscarinic bradycardia/bronchospasm!) OR Sugammadex (cyclodextrin encapsulator).
Local Anesthetics: Esters vs Amides
- Amides (Two "i"s): Lidocaine, Bupivacaine, Ropivacaine, Mepivacaine. Metabolized hepatically by CYP450.
- Esters (One "i"): Procane, Tetracaine, Benzonataine, Cocaine. Metabolized by plasma pseudocholinesterase to PABA (higher allergic risk!).
- Benzocaine: Oxidizes Fe2+ → Fe3+ causing Methemoglobinemia (cyanosis, chocolate-brown blood, oxygen saturation ~85%). Treat with IV Methylene Blue!
- Bupivacaine: Severe cardiotoxicity (refractory ventricular arrhythmias, arrest). Rescue with IV 20% Lipid Emulsion ("lipid sink").
Opioids, Sedative-Hypnotics & Mood Stabilizers
Mu-receptor agonists/antagonists, harm reduction, GABA-A channel frequency vs duration, and the Lithium master matrix.
Full Agonists, Partial Agonists & Antagonists
Morphine, Fentanyl, Methadone, Buprenorphine, Naloxone, Naltrexone.
Mechanism: Bind μ-opioid GPCRs → open K+ channels (hyperpolarization) and close voltage-gated Ca2+ channels → ↓ release of Substance P, glutamate, and acetylcholine.
Morphine & Fentanyl: Morphine causes mast cell degranulation (histamine release → non-allergic pruritus and vasodilation); its active metabolite M6G accumulates in renal failure. Fentanyl is 100x more potent than morphine, highly lipophilic (transdermal patch for chronic pain), with zero histamine release.
Meperidine (Demerol): Anticholinergic opioid (causes mydriasis, not miosis). Toxic metabolite normeperidine lowers seizure threshold (tremors/seizures); serotonergic (triggers Serotonin Syndrome with MAOIs/SSRIs!). Avoid in renal failure and elderly.
Methadone (Maintenance): Long-acting oral full μ-agonist (t1/2 > 24–36h); suppresses cravings without euphoria. Board Trap: Causes QTc prolongation and Torsades de pointes (mandatory ECG monitoring!).
Buprenorphine (Partial Agonist): High receptor affinity with submaximal efficacy. Precipitated Withdrawal: If given to a patient with full agonists on their receptors, buprenorphine displaces them and precipitates acute severe withdrawal! Suboxone (Buprenorphine + Naloxone): Sublingual Naloxone has ~0% oral bioavailability; if crushed and injected IV, Naloxone blocks μ-receptors, aborting abuse.
Naloxone vs Naltrexone: Naloxone (Narcan) is a rapid-acting IV/intranasal antagonist (short t1/2 ~30–90 min; watch for re-narcotization as opioid outlasts it!). Naltrexone is long-acting oral/IM used for relapse prevention and reducing alcohol cravings.
Benzodiazepines, Barbiturates, Z-Drugs & Buspirone
Chloride channel mechanics, LOT liver-safe rule, and non-addictive GAD relief.
Benzos vs Barbiturates Mnemonic:
• Benzodiazepines: Increase FREQUENCY of GABA-A chloride channel opening ("Fren-Z-odiazepines"). High therapeutic index.
• Barbiturates (Phenobarbital, Thiopental): Increase DURATION of GABA-A chloride channel opening ("Barbi-DURAT-es"). Directly open Cl- channels at high doses. Low therapeutic index (fatal respiratory depression; alkalinize urine with IV NaHCO3 to accelerate clearance!).
The "LOT" Rule for Hepatic Impairment: Lorazepam, Oxazepam, and Temazepam undergo direct Phase II glucuronidation without Phase I CYP450 oxidation → safest in cirrhosis and elderly patients!
Antidote Flumazenil: Competitive antagonist at BZ receptor. Black-Box Warning: Can precipitate acute, refractory withdrawal seizures in chronic benzodiazepine-tolerant patients or TCA co-ingestion!
Z-Drugs (Zolpidem, Zaleplon, Eszopiclone): Selectively bind the BZ1 receptor (α1 subunit) of GABA-A. Rapid onset, short duration, preserve normal sleep architecture with minimal REM rebound, lower addiction risk. Reversed by Flumazenil.
Buspirone (Non-Benzodiazepine Anxiolytic): Partial agonist at 5-HT1A receptors. 2nd-line for Generalized Anxiety Disorder (GAD). Unique Profile: Non-sedating, does NOT cause muscle relaxation, zero cross-tolerance with alcohol, and zero addiction/abuse potential! Takes 1–2 weeks for clinical onset.
Lithium Carbonate & Toxicity Triggers
Inositol monophosphatase inhibition, renal handling, and drug-drug interactions.
Mechanism of Action: Inhibits inositol monophosphatase (IMPase) → depletes cellular inositol and halts phosphoinositide (PIP2) signaling cascade; inhibits glycogen synthase kinase-3 (GSK-3). 1st-line for acute mania and maintenance in Bipolar Disorder; proven to reduce suicide mortality.
Narrow Therapeutic Index: Target trough serum level: 0.6 – 1.2 mEq/L. Toxic at >1.5 mEq/L; life-threatening at >2.5 mEq/L. Cleared entirely by the kidneys (80% reabsorbed in proximal tubule with Na+).
Toxicity Triggers (Board Favorites): Any drug reducing GFR or causing sodium depletion triggers compensatory proximal tubule Na+ and Lithium reabsorption → toxic surge:
• Thiazide Diuretics: Massive lithium retention!
• NSAIDs: Afferent arteriolar constriction → ↓ GFR → ↑ lithium.
• ACE Inhibitors & ARBs: Efferent vasodilation → ↓ GFR.
• Dehydration / Diaphoresis / Salt restriction.
Adverse Effects & Teratogenicity:
• Tremor: Fine postural hand tremor (treat with Propranolol).
• Renal: Nephrogenic Diabetes Insipidus (NDI) via ENaC entry in collecting ducts → blocks ADH action. Treat with Amiloride.
• Endocrine: Hypothyroidism, goiter, hyperparathyroidism.
• Teratogen: Ebstein Anomaly (atrialized right ventricle with severe tricuspid regurgitation).
Endocrine, Rheumatology & Antineoplastics
Diabetes insulin kinetics, thyroid and adrenal modulators, NSAIDs/APAP/DMARD cascades, and the comprehensive Chemotherapy & Targeted Monoclonal Antibody Matrix.
Chemotherapy Cell-Cycle Kinetics & Endocrine-Rheumatology Targets
Complete molecular mapping of S-phase vs M-phase antineoplastics, classic organ toxicities and rescue antidotes, oral antidiabetic mechanisms, and gout immunopharmacology.
Diabetes Mellitus Pharmacotherapy
Insulin PK profiles, Biguanides, SGLT2 inhibitors, GLP-1 receptor agonists, and Sulfonylureas.
Rapid vs Basal Kinetics
Rapid-acting (Lispro, Aspart, Glulisine): "No LAG". 15-min onset, 1-hr peak. Taken immediately before meals for postprandial glycemic spikes.
Short-acting (Regular): 30-min onset, 2-3 hr peak. IV drug of choice for Diabetic Ketoacidosis (DKA), Hyperosmolar Hyperglycemic State (HHS), and severe hyperkalemia (+ D50).
Intermediate (NPH): 1-2 hr onset, 4-10 hr peak.
Long-acting (Glargine, Detemir, Degludec): Peakless flat 24-hr basal release.
Metformin & SGLT2 Inhibitors
Metformin (Biguanide): First-line type 2 DM. Inhibits mitochondrial complex I → activates AMPK → suppresses hepatic gluconeogenesis and increases peripheral insulin sensitivity. Weight neutral/loss, zero hypoglycemia risk. Adverse: GI distress, B12 deficiency, lactic acidosis (contraindicated in eGFR < 30 mL/min or before iodinated contrast!).
SGLT2 Inhibitors (-flozins: Empagliflozin, Dapagliflozin): Block Na+/glucose cotransporter 2 in proximal convoluted tubule → glucosuria. Proven mortality reduction in Heart Failure (HFrEF/HFpEF) and diabetic nephropathy! Adverse: Vulvovaginal candidiasis, UTIs, euglycemic DKA.
GLP-1 Agonists & DPP-4i
GLP-1 Receptor Agonists (-tides: Semaglutide, Liraglutide): Incretin mimetics → glucose-dependent insulin secretion, decreased glucagon, delayed gastric emptying, and significant central weight loss. Reduces cardiovascular events. Adverse: Nausea, gastroparesis, pancreatitis. Contraindicated in MEN2 / medullary thyroid cancer.
DPP-4 Inhibitors (-gliptins: Sitagliptin, Linagliptin): Inhibit dipeptidyl peptidase-4 → prolong endogenous GLP-1 half-life. Weight neutral, zero hypoglycemia risk.
Sulfonylureas & Glitazones
Sulfonylureas (Glipizide, Glyburide, Glimepiride): Close ATP-sensitive K+ channels on pancreatic β-cells → depolarization → Ca2+ influx → endogenous insulin exocytosis. High risk of hypoglycemia and weight gain (Glipizide preferred in renal insufficiency due to shorter half-life).
TZDs / Glitazones (Pioglitazone, Rosiglitazone): Bind PPAR-γ nuclear transcription factor → upregulate GLUT4 and adiponectin. Adverse: Fluid retention / peripheral edema (strictly contraindicated in Heart Failure NYHA III/IV!), bone fractures in postmenopausal women.
Antineoplastic & Targeted Monoclonal Master Matrix
Antimetabolites, DNA cross-linkers, microtubule poisons, tyrosine kinase inhibitors, and toxic rescue antidotes.
| Drug Class & Agents | Molecular Mechanism & Cell Cycle Phase | Hallmark Toxicity & Adverse Profile | Specific Rescue Agent / Clinical Antidote |
|---|---|---|---|
|
Methotrexate (MTX) Antimetabolite • S Phase |
Competitively inhibits Dihydrofolate Reductase (DHFR) → blocks dTMP synthesis and de novo purine synthesis | Severe myelosuppression, mucositis/stomatitis, pulmonary fibrosis, and hepatotoxicity. Teratogen. | Leucovorin (Folinic Acid): bypasses DHFR to rescue non-cancerous bone marrow cells. Glucarpidase for acute renal failure. |
|
5-Fluorouracil (5-FU) & 6-MP Pyrimidine & Purine Analogs |
5-FU: Covalently complexes with folic acid to inhibit Thymidylate Synthase → dTMP starvation. 6-MP / Azathioprine: Activated by HGPRT; inhibits de novo purine synthesis. |
5-FU: Myelosuppression, coronary vasospasm, hand-foot syndrome. 6-MP: Bone marrow suppression. CRITICAL DRUG INTERACTION: 6-MP is metabolized by Xanthine Oxidase → concurrent Allopurinol or Febuxostat causes lethal 6-MP accumulation! |
Uridine triacetate for 5-FU overdose. Reduce 6-MP dose by 75% if patient is taking Allopurinol! |
|
Cyclophosphamide & Ifosfamide Alkylating Agent • Cell Cycle Non-Specific |
Cross-links DNA at guanine N-7 position, halting replication and transcription. Activated by hepatic CYP450. | Myelosuppression, SIADH, and Hemorrhagic Cystitis (gross hematuria, dysuria, transitional cell bladder carcinoma) caused by toxic metabolite Acrolein! | Mesna (2-mercaptoethane sulfonate) binds acrolein in urine + aggressive IV hydration. |
|
Cisplatin & Carboplatin Platinum Compounds • Cross-linkers |
Cross-link DNA intra- and interstrand strands, inducing apoptosis in solid tumors (testicular, ovarian, lung). | Severe Nephrotoxicity (acute tubular necrosis, magnesium wasting), Ototoxicity (sensorineural hearing loss / tinnitus), and peripheral neuropathy. Highly emetogenic. | Amifostine (free radical scavenger preventing nephrotoxicity) + vigorous IV saline hydration diuresis. |
|
Doxorubicin & Bleomycin Antitumor Antibiotics |
Doxorubicin: Intercalates DNA, inhibits Topoisomerase II, generates iron-dependent free radicals. Bleomycin: Binds iron and oxygen to generate free radicals → breaks DNA strands in G2 phase. |
Doxorubicin: Dilated Cardiomyopathy with congestive heart failure. Bleomycin: Pulmonary Fibrosis (cough, dyspnea, bilateral basilar crackles) and hyperpigmentation (minimal myelosuppression!). |
Dexrazoxane: iron-chelating agent administered to prevent Doxorubicin cardiotoxicity. |
|
Vincristine vs Vinblastine & Taxanes Microtubule Inhibitors • M Phase |
Vincristine & Vinblastine: Bind β-tubulin and inhibit microtubule polymerization (prevents mitotic spindle formation). Paclitaxel / Docetaxel: Hyperstabilize polymerized microtubules, preventing depolymerization. |
• Vincristine: Peripheral Neuropathy (distal paresthesias, foot drop, paralytic ileus / severe constipation). Mnemonic: "Vincristine crisps nerves". • Vinblastine: Severe bone marrow suppression. Mnemonic: "Vinblastine blasts bone marrow". • Paclitaxel: Myelosuppression and hypersensitivity infusion reactions. |
Premedicate Taxanes with corticosteroids and antihistamines. Dose adjust Vincristine for neurotoxicity. |
|
Targeted Monoclonals & TKIs Imatinib, Trastuzumab, Rituximab, Bevacizumab |
• Imatinib: Inhibits Bcr-Abl tyrosine kinase (CML t(9;22)) & c-kit (GIST). • Trastuzumab: Monoclonal antibody against HER2/neu (erbB2) receptor tyrosine kinase. • Rituximab: Monoclonal against CD20 on B-cell lymphocytes. • Bevacizumab: Monoclonal against VEGF-A (inhibits angiogenesis). |
• Trastuzumab: Cardiotoxicity (decreased ejection fraction; reversible, not dose-dependent!). • Rituximab: Risk of JC virus reactivation → Progressive Multifocal Leukoencephalopathy (PML). • Bevacizumab: Severe bleeding, GI perforation, hypertension, impaired wound healing. |
Echocardiogram monitoring before and during Trastuzumab. Hold Bevacizumab ≥ 4 weeks before and after major surgery. |
Immunosuppressants, Gout Therapeutics & Reproductive/Bone Pharmacology
Organ transplant calcineurin/mTOR inhibitors, acute vs chronic gout algorithms, and SERM/osteoporosis pharmacodynamics.
Transplant & Autoimmune Immunosuppressive Agents
Immunology Core| Drug | Immunologic Mechanism of Action | Clinical Use | Characteristic Toxicities & Board Pearls |
|---|---|---|---|
| Cyclosporine | Binds Cyclophilin → inhibits Calcineurin → prevents dephosphorylation of NFAT → blocks transcription of IL-2 | Solid organ transplant rejection prophylaxis; psoriasis, rheumatoid arthritis | Nephrotoxicity (afferent arteriolar vasoconstriction; monitor serum creatinine), hypertension, Gingival Hyperplasia, Hirsutism, tremor. |
| Tacrolimus (FK506) | Binds FKBP-12 → inhibits Calcineurin → blocks NFAT activation → halts IL-2 transcription (100x more potent than cyclosporine) | Solid organ transplant rejection prophylaxis (kidney, liver, heart) | Nephrotoxicity, neurotoxicity (headache, peripheral neuropathy, seizures), ↑ risk of Post-Transplant Diabetes Mellitus. Crucial distinction: NO gingival hyperplasia or hirsutism! |
| Sirolimus (Rapamycin) | Binds FKBP-12 → inhibits mTOR (mammalian target of rapamycin) → blocks cell cycle response to IL-2 (blocks G1 → S transition) | Kidney transplant rejection prophylaxis; drug-eluting coronary stents (prevents restenosis) | Mnemonic: "Sir-Runs-on-mTOR". Pancytopenia (anemia, leukopenia, thrombocytopenia), hyperlipidemia, insulin resistance. KIDNEY-SPARING (NOT nephrotoxic!). |
| Mycophenolate Mofetil | Reversibly inhibits Inosine Monophosphate Dehydrogenase (IMPDH) → halts de novo purine synthesis in B and T lymphocytes | Transplant prophylaxis, Lupus nephritis | GI distress (nausea, cramping, diarrhea), myelosuppression. Associated with opportunistic CMV viremia/infection. |
| Azathioprine | Antimetabolite prodrug converted to 6-Mercaptopurine (6-MP) → purine analog that halts nucleic acid synthesis | Kidney transplant rejection, Crohn's disease, Ulcerative colitis, autoimmune hepatitis | Metabolized by Xanthine Oxidase. FATAL INTERACTION: Co-administration with Allopurinol or Febuxostat inhibits xanthine oxidase → massive 6-MP toxic accumulation → severe pancytopenia and bone marrow failure! Reduce dose by 75%. |
Acute Flare: Terminate Inflammation
Goals: Inhibit neutrophil activation and suppress cytokine cascade. Never initiate allopurinol during an acute attack!
Reversible COX-1/COX-2 inhibition → ↓ prostaglandins. Avoid in renal failure, peptic ulcer disease, or heart failure.
Binds β-tubulin → inhibits microtubule polymerization → halts neutrophil chemotaxis, phagocytosis, and degranulation. Adverse: Severe secretory diarrhea, nausea, myelosuppression.
Oral Prednisone or intra-articular Triamcinolone injection. Ideal when NSAIDs and colchicine are contraindicated by chronic kidney disease.
Chronic Prevention: Lower Serum Urate
Initiate ≥ 2–4 weeks after acute flare has completely subsided. Co-prescribe NSAID or colchicine prophylaxis during initiation.
Inhibit xanthine oxidase → blocks conversion of hypoxanthine → xanthine → uric acid. Allopurinol toxicity: SJS/TEN and DRESS syndrome, especially in patients with HLA-B*5801 allele!
Inhibits URAT-1 anion transporter in proximal convoluted tubule → ↓ uric acid reabsorption → ↑ urinary excretion. Contraindication: History of uric acid renal stones or GFR < 30 mL/min.
Recombinant urate oxidase enzyme converts insoluble uric acid into highly soluble Allantoin. Pegloticase treats refractory tophaceous gout; Rasburicase prevents Tumor Lysis Syndrome.
Reproductive, Bone Metabolism & Prostate Pharmacology
Endocrine Core| Class / Drug | Mechanism of Action | Clinical Indication | Crucial Board Pearls & Toxicities |
|---|---|---|---|
| Tamoxifen (SERM) | Competitive estrogen receptor antagonist in breast; partial agonist in endometrium and bone | ER+ breast cancer treatment and chemoprevention | Agonist effect on endometrium increases risk of Endometrial Hyperplasia & Adenocarcinoma! Also increases risk of thromboembolism (DVT/PE). Prevents bone loss. |
| Raloxifene (SERM) | Estrogen receptor antagonist in breast AND endometrium; agonist in bone | Postmenopausal osteoporosis treatment and breast cancer prophylaxis | NO increased risk of endometrial cancer! Still carries increased thromboembolism risk (DVT/PE) and hot flashes. |
| Aromatase Inhibitors Anastrozole, Letrozole, Exemestane |
Inhibit peripheral aromatase enzyme → blocks conversion of androstenedione to estrone | 1st-line for ER+ breast cancer in postmenopausal women | No endometrial cancer risk. Causes severe bone mineral density loss (osteoporosis) and arthralgias due to profound systemic estrogen depletion. |
| Finasteride • Dutasteride | Inhibits 5α-Reductase → blocks conversion of Testosterone → Dihydrotestosterone (DHT) | Benign Prostatic Hyperplasia (BPH) • Male-pattern androgenic alopecia | Takes 6–12 months to reduce prostate volume. Decreases serum PSA by ~50% (must double measured PSA for screening!). Adverse: Gynecomastia, erectile dysfunction. Teratogenic! |
| Tocolytics "It's Not My Time" |
Indomethacin (COX inhibitor → ↓ prostaglandins) Nifedipine (CCB → myometrial relaxation) Magnesium Sulfate (membrane stabilization) Terbutaline (β2 agonist → ↑ cAMP) |
Arrest preterm labor contractions (<34 weeks) to allow antenatal corticosteroid lung maturation | Indomethacin causes premature closure of fetal ductus arteriosus and oligohydramnios. MgSO4 provides fetal neuroprotection (<32 weeks); toxicity causes loss of deep tendon reflexes and respiratory arrest (antidote: IV Calcium Gluconate!). |
| Bisphosphonates Alendronate, Zoledronic Acid |
Pyrophosphate analogs bind hydroxyapatite in bone → taken up by osteoclasts → inhibit farnesyl pyrophosphate synthase → osteoclast apoptosis | Osteoporosis, Paget disease of bone, Hypercalcemia of malignancy | Pill-induced corrosive esophagitis (must take with full glass of water and remain upright for 30 mins!), Osteonecrosis of the Jaw (ONJ) following invasive dental procedures, and Atypical subtrochanteric femur fractures with prolonged use. |
| Teriparatide • Denosumab |
Teriparatide: Recombinant human PTH 1-34 administered in pulsatile daily SQ doses → stimulates osteoblasts > osteoclasts. Denosumab: Monoclonal antibody binds RANKL → prevents RANK activation on osteoclasts. |
Severe osteoporosis with high fracture risk | Teriparatide carries Black Box Warning for Osteosarcoma (avoid in Paget disease, prior radiation, or elevated alkaline phosphatase!). Denosumab causes hypocalcemia and rebound vertebral fractures upon sudden discontinuation. |
Thyroid, Adrenal & Pituitary Pharmacotherapy
Thionamides (PTU vs Methimazole), somatostatin analogs, dopamine agonists, vasopressin modulators, and steroidogenesis blockers.
Thionamides & Wolff-Chaikoff Effect
PTU, Methimazole, Levothyroxine, Potassium Iodide.
Thionamides (PTU vs Methimazole):
• Both: Inhibit Thyroid Peroxidase (TPO) → block iodine organification and coupling of iodotyrosines.
• PTU Extra Action: Also inhibits peripheral 5'-deiodinase (blocks conversion of T4 → T3).
• Trimester Rules: PTU preferred in 1st trimester of pregnancy (less teratogenic) and in Thyroid Storm (rapid peripheral T3 cutoff). Methimazole preferred in 2nd & 3rd trimesters due to black-box warning for PTU fulminant hepatic failure!
• Methimazole Teratogen: Causes Aplasia Cutis Congenita (scalp defects) and choanal atresia.
• Universal Toxicity: Agranulocytosis (sudden fever & sore throat → discontinue drug and obtain CBC immediately!).
Potassium Iodide (Lugol's Solution): High doses acutely suppress thyroid hormone synthesis and release via the Wolff-Chaikoff effect; reduces gland vascularity pre-thyroidectomy.
Levothyroxine (T4): Synthetic T4 prodrug converted peripherally to active T3. Take on an empty stomach (calcium/iron bind and block absorption).
Octreotide, Cabergoline & DDAVP
Somatostatin analogs, prolactin suppressors, and vasopressin agonists/antagonists.
Octreotide (Somatostatin Analog): Suppresses GH, IGF-1, gastrin, VIP, and glucagon. Treats Acromegaly, Carcinoid Syndrome, VIPoma, and acute bleeding esophageal varices (splanchnic vasoconstriction). Adverse: Cholelithiasis (biliary sludging via CCK inhibition) and steatorrhea.
Cabergoline & Bromocriptine: D2 dopamine receptor agonists → inhibit prolactin release from anterior pituitary. 1st-line for Prolactinomas (restores fertility, reverses galactorrhea/amenorrhea). Cabergoline is preferred due to higher efficacy and fewer GI side effects.
Desmopressin (DDAVP): Selective V2 receptor agonist. 1st-line for Central Diabetes Insipidus (distinguishes from nephrogenic DI which has no response). Stimulates endothelial release of Factor VIII and vWF from Weibel-Palade bodies (used in mild Hemophilia A and type 1 vWD).
Vaptans (Conivaptan, Tolvaptan): Vasopressin V2 receptor antagonists → promote aquaresis (free water excretion) without sodium wasting. 1st-line for euvolemic and hypervolemic hyponatremia in SIADH and CHF.
Fludrocortisone, Metyrapone & Ketoconazole
Mineralocorticoids, 11β-hydroxylase inhibitors, and steroidogenesis arrest.
Fludrocortisone: Synthetic corticosteroid with high mineralocorticoid-to-glucocorticoid potency ratio. 1st-line aldosterone replacement in Primary Adrenal Insufficiency (Addison Disease) and neurogenic orthostatic hypotension. Restores distal tubular Na+ reabsorption and K+/H+ excretion.
Metyrapone: Inhibits 11β-hydroxylase → blocks conversion of 11-deoxycortisol to cortisol. Diagnostic challenge for intact hypothalamic-pituitary-adrenal (HPA) axis: normal response is a surge in ACTH and 11-deoxycortisol; failure to surge indicates secondary/tertiary adrenal insufficiency. Also treats severe Cushing disease.
Ketoconazole (High-Dose): Non-selectively inhibits 17,20-lyase and cholesterol desmolase (CYP11A1) → shuts down all adrenal steroidogenesis and gonadal androgen synthesis. Used for refractory Cushing syndrome. Adverse: Severe gynecomastia, hypogonadism, transaminitis, and QT prolongation.
Spironolactone & Eplerenone: Aldosterone receptor antagonists; treat primary hyperaldosteronism (Conn syndrome) and secondary hyperaldosteronism (CHF, cirrhosis).
NSAIDs, Acetaminophen & Rheumatoid DMARDs
COX-1/2 inhibition, Reye syndrome, salicylate acid-base cascades, NAPQI hepatotoxicity, and mandatory latent tuberculosis biologic screening.
Aspirin, Reye Syndrome & Overdose
Acetylsalicylic acid, platelet lifespan inhibition, and biphasic acid-base toxicity.
Mechanism: Irreversibly acetylates and inhibits both COX-1 and COX-2. Antiplatelet effect persists for the entire lifespan of the platelet (~7–10 days; anucleate platelets cannot synthesize new COX!).
Reye Syndrome: Microvesicular fatty liver change and acute encephalopathy in children administered aspirin during viral infections (influenza, varicella). Board Rule: Strictly contraindicated under age 19 (use Acetaminophen or Ibuprofen instead!), except in Kawasaki disease.
AERD (Samter Triad): Asthma, chronic rhinosinusitis with nasal polyps, and acute bronchospasm upon taking NSAIDs (due to COX-1 inhibition shunting arachidonate into 5-LOX → leukotriene surge!).
Salicylate Poisoning (Biphasic Acid-Base Disorder):
1. Early: Direct medullary respiratory stimulation → hyperventilation → Primary Respiratory Alkalosis (low PaCO2).
2. Late: Uncoupling of oxidative phosphorylation → lactic acidosis & ketoacidosis → Primary High Anion Gap Metabolic Acidosis.
3. Treatment: IV Sodium Bicarbonate → alkalinizes urine (pH ≥ 7.5) → traps ionized salicylate in renal tubules → rapid excretion!
NSAIDs, Celecoxib & Acetaminophen
Renal afferent arteriole hemodynamics, sulfa precautions, and NAPQI hepatotoxicity.
Non-Selective NSAIDs (Ibuprofen, Naproxen, Indomethacin, Ketorolac): Reversible competitive inhibition of COX-1 and COX-2. Indomethacin is used to close a Patent Ductus Arteriosus (PDA). Renal Hemodynamic Trap: Renal prostaglandins (PGE2, PGI2) keep the afferent arteriole dilated. NSAIDs block prostaglandins → afferent constriction → acute prerenal azotemia / acute kidney injury, fluid retention, and renal papillary necrosis!
Celecoxib (COX-2 Selective): Spares constitutive COX-1 (gastric mucosa, platelet TXA2) while selectively inhibiting inducible COX-2 (inflammatory pain). Benefit: Lower GI ulcer/bleeding rate. Drawbacks: Contains a sulfonamide moiety (sulfa allergy alert!) and increases risk of arterial thrombosis, MI, and stroke (due to unopposed platelet TXA2 aggregation without endothelial PGI2 prostacyclin!).
Acetaminophen (APAP): Centrally acting reversible COX inhibitor with antipyretic/analgesic efficacy but NO peripheral anti-inflammatory action. Safe in children and peptic ulcer disease.
NAPQI Hepatotoxicity: ~5% of APAP is metabolized by CYP2E1 into toxic NAPQI, neutralized by hepatic glutathione. Overdose exhausts glutathione → free NAPQI causes centrilobular hepatic necrosis. Antidote: N-Acetylcysteine (NAC) replenishes glutathione stores!
Methotrexate, HCQ & Anti-TNF Biologics
DHFR inhibition, retinal screening, and mandatory latent tuberculosis precautions.
Methotrexate (1st-Line Anchor DMARD): Irreversibly inhibits Dihydrofolate Reductase (DHFR) → blocks dTMP synthesis → halts lymphocyte proliferation. High-Yield Toxicities: Myelosuppression (prevented/rescued with Leucovorin / Folinic acid), hepatotoxicity, pulmonary fibrosis, stomatitis, and severe teratogenicity (neural tube defects!).
Hydroxychloroquine: Mild DMARD for RA and SLE; impairs lysosomal antigen processing. Board Mandate: Causes irreversible retinal toxicity / bull's-eye maculopathy; requires baseline and annual dilated ophthalmologic slit-lamp exams!
Sulfasalazine: Cleaved by colonic bacteria into sulfapyridine (active for RA) and 5-ASA (active for ulcerative colitis). Causes reversible male oligospermia and sulfa hypersensitivity.
Leflunomide: Inhibits dihydroorotate dehydrogenase → halts pyrimidine synthesis. Hepatotoxic, severe teratogen.
Biologic TNF-α Inhibitors (Infliximab, Adalimumab, Etanercept): Etanercept is a soluble TNF receptor fusion protein (TNFR2 + Fc). Infliximab/Adalimumab are monoclonal antibodies. Critical Board Rule: TNF-α is mandatory for granuloma maintenance. MUST screen for Latent Tuberculosis with PPD or IGRA (QuantiFERON) prior to therapy to prevent fatal disseminated TB reactivation! Contraindicated in NYHA Class III/IV severe heart failure.