Absorption describes the movement of a drug from its site of administration into systemic circulation. Enteral routes (oral, sublingual, rectal) depend on GI physiology, pH, and blood flow. Oral absorption occurs primarily in the small intestine via passive diffusion (non-ionized, lipophilic drugs) and active transport (e.g., levodopa via L-amino acid transporter). Bioavailability (F) is the fraction of an administered dose reaching systemic circulation intact. IV drugs have F = 1.0 by definition. Oral drugs undergo first-pass metabolism in the liver and gut wall, reducing bioavailability. Drugs with high first-pass extraction (e.g., propranolol, verapamil, lidocaine) have oral doses far exceeding IV doses. Sublingual and rectal routes bypass first-pass to varying degrees. Transdermal, inhalation, and intramuscular routes offer alternative absorption profiles. Food can alter absorption: grapefruit juice inhibits intestinal CYP3A4, increasing bioavailability of many drugs (statins, CCBs). Gastric pH (altered by PPIs, antacids) affects dissolution of weak acids/bases. Prodrugs (e.g., enalapril, valacyclovir) are designed to improve absorption and are converted to active metabolites after absorption.

Distribution refers to the reversible transfer of drug between compartments. The volume of distribution (Vd) is a theoretical volume relating the total amount of drug in the body to its plasma concentration: Vd = Dose / Cp₀. Drugs highly bound to plasma proteins (albumin for acids, α-1-acid glycoprotein for bases) have restricted distribution and low Vd (e.g., warfarin Vd ~10 L). Drugs that extensively bind tissues (e.g., digoxin, amiodarone) have massive Vd (>500 L). The blood-brain barrier (BBB) is formed by tight junctions of cerebral capillary endothelial cells; only lipophilic, un-ionized drugs cross readily (e.g., diazepam, fentanyl). P-glycoprotein (P-gp) is an efflux transporter at the BBB actively removing drugs (e.g., loperamide, ivermectin). Protein binding is relevant for displacement interactions: sulfonamides displace bilirubin in neonates → kernicterus. Vd determines loading dose: Loading Dose = (Vd × Target Cp) / F. A large Vd means a large loading dose is needed to achieve steady state quickly.

Drug metabolism occurs primarily in the liver but also in gut wall, kidney, and lung. Phase I reactions (oxidation, reduction, hydrolysis) introduce or unmask functional groups. The cytochrome P450 (CYP450) superfamily is the dominant Phase I enzyme system. Major isoforms: CYP3A4 (metabolizes ~50% of drugs), CYP2D6 (~25%), CYP2C9, CYP2C19, CYP1A2, CYP2E1. Genetic polymorphisms exist for CYP2D6 (poor, intermediate, extensive, ultrarapid metabolizers) and CYP2C19. CYP3A4 is induced by rifampin, carbamazepine, phenytoin, St. John’s Wort → reduces drug levels. CYP3A4 is inhibited by ketoconazole, clarithromycin, ritonavir, grapefruit juice → increases drug levels. Phase II reactions (conjugation: glucuronidation, sulfation, acetylation, methylation, glutathione conjugation) produce water-soluble metabolites for excretion. UGT (UDP-glucuronosyltransferase) conjugates bilirubin, morphine, acetaminophen. Acetylation is polymorphic (NAT2): rapid vs slow acetylators affect isoniazid toxicity. Prodrugs (codeine → morphine via CYP2D6; clopidogrel → active metabolite via CYP2C19) rely on metabolism for activity.

Elimination occurs via renal excretion (glomerular filtration, tubular secretion, reabsorption) and hepatic clearance (biliary excretion, metabolism). Renal clearance = (urine flow rate × urine concentration) / plasma concentration. Drugs that are water-soluble, polar, and low molecular weight are renally excreted unchanged (e.g., gentamicin, lithium, digoxin). Glomerular filtration rate (GFR ~120 mL/min) filters unbound drug. Tubular secretion via OAT (penicillins, NSAIDs) and OCT (cimetidine, metformin) transporters can be saturated and competitively inhibited. Tubular reabsorption of lipophilic drugs is pH-dependent: alkalinizing urine (NaHCO₃) increases excretion of weak acids (salicylate, phenobarbital); acidifying urine (NH₄Cl) increases excretion of weak bases (amphetamine). Clearance (CL) is the volume of plasma cleared of drug per unit time. Total CL = CL_renal + CL_hepatic + CL_other. Elimination rate constant (k_e) = CL / Vd. Half-life (t_½) = 0.693 / k_e = 0.693 × Vd / CL. First-order kinetics (most drugs): constant fraction eliminated per time. Zero-order kinetics (ethanol, phenytoin, high-dose aspirin): constant amount eliminated per time, leading to nonlinear accumulation.

Half-life determines dosing frequency and time to steady state. After 1 half-life: 50% of steady state. After 3.3 half-lives: ~90% of steady state. After 5 half-lives: ~97% (essentially at steady state). Maintenance Dose = CL × Cp_ss × τ / F where τ is the dosing interval. Loading Dose = Vd × Cp / F. Therapeutic drug monitoring (TDM) is essential for drugs with narrow therapeutic index: digoxin, lithium, vancomycin, gentamicin, phenytoin, cyclosporine. Trough levels guide maintenance dosing for aminoglycosides and vancomycin. Peak levels guide efficacy and toxicity for aminoglycosides. Time-dependent killing (beta-lactams): concentration > MIC for 40–50% of dosing interval. Concentration-dependent killing (aminoglycosides, fluoroquinolones): peak/MIC ratio >8–10. AUC/MIC ratio (vancomycin: >400) predicts efficacy. Drug interactions can alter half-life dramatically: rifampin reduces oral contraceptive levels through CYP induction; ketoconazole increases midazolam levels through CYP inhibition.

Renal impairment reduces clearance of renally eliminated drugs: adjust doses using Cockcroft-Gault (Cl_cr = [(140 − age) × weight (kg)] / (72 × S_cr) × 0.85 for females). CKD-EPI is preferred for staging CKD. For drugs like vancomycin, gentamicin, and DOACs, dosing intervals must be extended or doses reduced based on eGFR. Hepatic impairment (Child-Pugh class B or C) reduces CYP metabolism: reduce doses of opioids, benzodiazepines, many statins. Obesity increases Vd for lipophilic drugs (propofol, fentanyl, voriconazole); dose on total body weight for loading, ideal body weight for maintenance. Pregnancy increases GFR and Vd, often requiring higher doses of renally cleared drugs and antiepileptics. Neonates have immature hepatic and renal function: prolonged half-lives for many drugs (e.g., chloramphenicol → gray baby syndrome). Elderly patients have decreased renal function, reduced hepatic mass, and increased body fat: start low, go slow. Pharmacogenomics: HLA-B*5701 screening before abacavir → prevents hypersensitivity. HLA-B*1502 screening before carbamazepine in Asian populations → prevents SJS/TEN. TPMT genotyping before azathioprine/6-MP → prevents severe myelosuppression.

Receptors are macromolecular protein targets (GPCRs, ion channels, enzymes, transporters, nuclear receptors) that mediate drug effects. The binding of a drug to its receptor follows the law of mass action: [D] + [R] ↔ [DR] → Effect. Affinity is the strength of binding (inverse of K_d, the dissociation constant). Intrinsic efficacy is the ability of a drug to activate the receptor once bound. Full agonists have both high affinity and high intrinsic efficacy, producing a maximal response (e.g., morphine at mu-opioid receptors, isoproterenol at beta-adrenergic receptors). Partial agonists (e.g., buprenorphine, aripiprazole) have lower intrinsic efficacy and cannot produce a maximal response even at full receptor occupancy. Inverse agonists (e.g., flumazenil at the benzodiazepine site, some antihistamines) reduce constitutive receptor activity. Antagonists bind receptors without activating them: competitive antagonists (e.g., naloxone at mu-opioid receptors) shift the dose-response curve rightward without affecting maximal response (surmountable). Non-competitive antagonists (e.g., ketamine at NMDA receptors) reduce the maximal response (insurmountable). Allosteric modulators (e.g., benzodiazepines at GABA-A receptors) bind at distinct sites and alter receptor conformation.

The graded dose-response curve plots drug concentration (x-axis, log scale) vs effect magnitude (y-axis). Key parameters: E_max (maximal effect), EC₅₀ (concentration producing 50% of maximal effect). Potency is determined by EC₅₀: a drug with lower EC₅₀ is more potent (e.g., fentanyl is more potent than morphine). Efficacy is determined by E_max: a drug with higher E_max has greater efficacy (e.g., morphine has higher efficacy than buprenorphine for pain). The quantal dose-response curve plots cumulative percentage of population responding vs dose. From this curve we derive: ED₅₀ (dose effective in 50% of population), TD₅₀ (dose toxic in 50%), LD₅₀ (dose lethal in 50%). Therapeutic Index (TI) = TD₅₀ / ED₅₀ (or LD₅₀ / ED₅₀). A narrow TI (e.g., warfarin, digoxin, lithium) means the therapeutic and toxic doses are close, requiring TDM. Clinical utility: TI guides dosing safety; drugs with wide TI (e.g., penicillins) are generally safer with standard dosing. The steepness of the dose-response curve is clinically relevant: steep curves (heparin, propofol) require careful titration.

G protein-coupled receptors (GPCRs) are the largest family: β-adrenergic, muscarinic, opioid, dopamine, serotonin receptors. GPCR signaling involves G_s (stimulatory → ↑cAMP), G_i (inhibitory → ↓cAMP), G_q (→ ↑IP3/DAG → ↑Ca²⁺). Receptor tyrosine kinases (RTKs) include insulin receptor, growth factor receptors. Ligand-gated ion channels (ionotropic receptors): GABA-A (Cl⁻ channel, target of benzodiazepines/barbiturates), NMDA (Ca²⁺/Na⁺ channel, target of ketamine), nAChR (Na⁺/Ca²⁺ channel, target of nicotine/succinylcholine). Voltage-gated ion channels: Na⁺ channels (target of local anesthetics, anticonvulsants), Ca²⁺ channels (target of CCBs), K⁺ channels (target of sulfonylureas). Nuclear receptors (intracellular): steroid receptors, thyroid receptor, PPARs (target of thiazolidinediones), VDR (vitamin D). Enzymes as drug targets: ACE (target of ACE inhibitors), COX (target of NSAIDs), HMG-CoA reductase (target of statins), dihydrofolate reductase (target of methotrexate). Transporters: SGLT2 (target of gliflozins), serotonin transporter (target of SSRIs), Na⁺/K⁺-ATPase (target of digoxin).

Tolerance is a diminished response to a drug with repeated administration, requiring dose escalation for the same effect. Pharmacokinetic tolerance (induction of metabolizing enzymes) occurs with carbamazepine, rifampin, alcohol. Pharmacodynamic tolerance involves receptor adaptations: downregulation (decreased receptor number) with chronic beta-agonist use; desensitization (uncoupling of receptor from effector) with GPCR kinases and β-arrestin recruitment. Tachyphylaxis is rapid tolerance (e.g., nitroglycerin → nitrate-free interval needed; nicotine → rapid desensitization of nAChRs). Dependence is a physiologic state requiring continued drug exposure to prevent withdrawal; physical dependence occurs with opioids, benzodiazepines, alcohol, beta-blockers. Psychological dependence (addiction) involves compulsive drug-seeking behavior mediated by mesolimbic dopamine pathways. Cross-tolerance occurs between drugs in the same class (e.g., alcohol and benzodiazepines at GABA-A receptors). Rebound effects upon abrupt discontinuation: beta-blocker withdrawal → tachycardia, hypertension; SSRI withdrawal → dizziness, paresthesias; opioid withdrawal → diarrhea, mydriasis, autonomic hyperactivity. Desensitization can be homologous (only the occupied receptor desensitizes) or heterologous (other receptors also desensitize, mediated by second messenger changes).

Pharmacodynamic interactions occur at the same or interacting receptor sites. Synergism (additive or supra-additive): alcohol + benzodiazepines → excessive CNS depression; NSAIDs + anticoagulants → increased bleeding risk; ACEi + ARB → hyperkalemia. Antagonism: naloxone reverses opioid effects; flumazenil reverses benzodiazepine effects; protamine reverses heparin. Potentiation: one drug enhances the effect of another (e.g., probenecid + penicillin → increased penicillin levels by inhibiting tubular secretion). Summation: drugs from different classes with similar effects (e.g., beta-blocker + verapamil → bradycardia, heart block). The danger of polypharmacy increases exponentially with the number of drugs: a patient on 5 drugs has a ~50% chance of an interaction; on 8+, risk >90%. The Beers Criteria identify potentially inappropriate medications in older adults. The STOPP/START criteria guide prescribing in elderly. Pharmacodynamic interactions can also be beneficial: trimethoprim + sulfamethoxazole provides sequential blockade of folate synthesis; amoxicillin + clavulanate provides suicide inhibition of β-lactamase.

The two-state model of receptor activation explains constitutive activity (receptors spontaneously in active conformation) and inverse agonism. Spare receptors exist when maximal response is achieved at less than full receptor occupancy (e.g., β-adrenergic receptors in heart: spare receptors explain why low-dose isoproterenol produces max inotropic effect). Receptor reserve explains why competitive antagonists may require high doses to block response. Bias signaling (functional selectivity) describes ligands that preferentially activate one signaling pathway over another (e.g., carvedilol → biased β-arrestin signaling at β-adrenergic receptors; some mu-opioid agonists biased away from β-arrestin may have less tolerance). The therapeutic window is the range of doses producing therapeutic effect without unacceptable toxicity. The Hill coefficient describes cooperativity: >1 indicates positive cooperativity (e.g., O₂ binding to hemoglobin); <1 indicates negative cooperativity. Quantal dose-response curves allow determination of ED₉₅ and ED₉₉ used in anesthetic dosing (e.g., MAC for inhaled anesthetics). Chronopharmacology considers circadian rhythms: corticosteroid dosing in the morning mimics endogenous cortisol rhythm; HMG-CoA reductase inhibitors more effective when taken at night.

The autonomic nervous system (ANS) has two main divisions: sympathetic (thoracolumbar, “fight or flight”) and parasympathetic (craniosacral, “rest and digest”). Preganglionic sympathetic fibers release ACh (nicotinic receptors); postganglionic sympathetic fibers release norepinephrine (NE) except for sweat glands (ACh) and adrenal medulla (ACh → epinephrine). Preganglionic parasympathetic fibers release ACh (nicotinic); postganglionic parasympathetic fibers release ACh (muscarinic). Sympathetic effects: ↑HR, ↑contractility, vasoconstriction, bronchodilation, mydriasis, ↓GI motility, bladder sphincter contraction, ejaculation. Parasympathetic effects: ↓HR, vasodilation, bronchoconstriction, miosis, ↑GI motility & secretion, bladder contraction, erection. The enteric nervous system functions autonomously but is modulated by both divisions. Adrenergic receptors: α₁ (vascular smooth muscle → vasoconstriction, mydriasis, prostate contraction), α₂ (presynaptic inhibition of NE release, platelet aggregation, ↓insulin), β₁ (heart → ↑HR, ↑contractility, ↑renin), β₂ (bronchodilation, vasodilation, ↓GI motility, uterine relaxation, tremor, glycogenolysis), β₃ (bladder detrusor relaxation). Muscarinic receptors: M₁ (CNS, gastric acid), M₂ (heart → bradycardia, ↓contractility), M₃ (smooth muscle contraction, secretion, miosis).

Direct-acting cholinergic agonists bind and activate muscarinic receptors. Acetylcholine (ACh) itself is rapidly hydrolyzed by AChE and has no therapeutic use. Bethanechol: selective M₃ agonist used for urinary retention (post-op, neurogenic) and GI atony; contraindicated in asthma, hyperthyroidism, CAD, and GI obstruction. Pilocarpine: non-selective muscarinic agonist used for glaucoma (constricts pupil, opens trabecular meshwork → ↓IOP) and xerostomia (post-radiation). Carbachol: used in glaucoma. Methacholine: used in bronchial challenge testing for asthma diagnosis. Direct agonists cause SLUDGE syndrome (Salivation, Lacrimation, Urination, Defecation, GI upset, Emesis). Indirect-acting cholinergic agonists (AChE inhibitors) increase synaptic ACh by inhibiting acetylcholinesterase. Physostigmine: tertiary amine (crosses BBB), used for anticholinergic toxicity (antidote for atropine overdose). Neostigmine: quaternary amine (does not cross BBB), used for myasthenia gravis, reversal of neuromuscular blockade (given with glycopyrrolate to block muscarinic SE). Pyridostigmine: longer-acting than neostigmine, mainstay of myasthenia gravis therapy. Donepezil, rivastigmine, galantamine: centrally-acting AChE inhibitors for Alzheimer disease. Edrophonium: ultra-short-acting AChE inhibitor used historically for myasthenia diagnosis (Tensilon test). AChE inhibitor poisoning (organophosphates, carbamates): excessive muscarinic, nicotinic, and CNS effects.

Muscarinic receptor antagonists block parasympathetic effects. Atropine: non-selective muscarinic antagonist; uses include bradycardia (0.5 mg IV, may repeat), antisialagogue pre-op, organophosphate poisoning (massive doses), mydriasis/cycloplegia for eye exams. Side effects: dry mouth, blurred vision, photophobia, urinary retention, constipation, tachycardia, heat intolerance (anhidrosis). Central anticholinergic syndrome: confusion, agitation, hallucinations, coma. Scopolamine: crosses BBB well; used for motion sickness (transdermal patch), post-op nausea, and as antisialagogue. Glycopyrrolate: quaternary amine (does not cross CNS); used for GI hypermotility (IBS), antisialagogue, reversal of neuromuscular blockade (given with neostigmine). Ipratropium, tiotropium: inhaled anticholinergics for COPD and asthma; minimal systemic absorption. Tropicamide, cyclopentolate: short-acting mydriatics/cycloplegics for eye exams. Darifenacin, solifenacin, tolterodine, oxybutynin: M₃-selective antagonists for overactive bladder (urinary frequency, urgency). Contraindications to anticholinergics: narrow-angle glaucoma, bladder outlet obstruction, myasthenia gravis, GI obstruction, tachyarrhythmias. In elderly, anticholinergics are Beers-listed: increased risk of falls, delirium, dementia.

Catecholamines (epinephrine, norepinephrine, dopamine, dobutamine, isoproterenol) contain a catechol ring and are rapidly metabolized by COMT and MAO. Non-catecholamines (phenylephrine, albuterol, salmeterol, clonidine, amphetamine) lack the catechol ring and have longer duration. Epinephrine: non-selective α/β agonist. Uses: anaphylaxis (1:1000 IM 0.3 mL, repeat q5–15 min), cardiac arrest (IV push 1 mg q3–5 min), severe asthma, glaucoma, adjunct to local anesthetics (prolongs effect + reduces systemic absorption). Alpha effects dominate at high doses (vasoconstriction → ↑BP); beta effects dominate at low doses (↑HR, bronchodilation). Norepinephrine: potent α₁ and β₁ agonist, minimal β₂. First-line vasopressor for septic shock (titrate to MAP ≥65). Extravasation → phentolamine (alpha blocker) infiltration. Dopamine: dose-dependent effects: 1–5 µg/kg/min (DA₁ → renal/mesenteric vasodilation), 5–10 µg/kg/min (β₁ → ↑contractility, ↑HR), >10 µg/kg/min (α₁ → vasoconstriction). Dobutamine: β₁ > β₂ > α₁; increases CO with less HR increase than isoproterenol; used for cardiogenic shock, stress echo. Isoproterenol: non-selective β agonist (β₁ = β₂); used rarely for bradycardia (if pacing not available) and torsades de pointes (temporary pacing). Phenylephrine: selective α₁ agonist; used for hypotension during spinal anesthesia, nasal decongestant, mydriasis. Alpha-2 agonists: clonidine (antihypertensive, also for ADHD, opioid withdrawal), dexmedetomidine (sedation with minimal respiratory depression, ICU use). Beta-2 agonists: albuterol (SABA short-acting, asthma relief), salmeterol (LABA, maintenance, never as monotherapy in asthma).

Alpha-1 blockers (doxazosin, terazosin, tamsulosin, prazosin): used for BPH (relax prostatic smooth muscle) and HTN. Prazosin also used for PTSD-related nightmares (central α₁ blockade). First-dose syncope: orthostatic hypotension after initial dose → start at bedtime. Tamsulosin is α_1A-selective (fewer BP effects). Non-selective alpha blockers: phentolamine (reversible, used for pheochromocytoma, extravasation of alpha agonists), phenoxybenzamine (irreversible, used for pheochromocytoma pre-op prep). Beta-blockers: cardioselective (β₁ > β₂): metoprolol, atenolol, bisoprolol, esmolol (ultra-short-acting IV). Non-selective (β₁ = β₂): propranolol, nadolol, timolol. Intrinsic sympathomimetic activity (ISA): pindolol, acebutolol (partial agonist activity → less bradycardia, used with caution). With beta-blocker withdrawal: rebound sympathetic activation → taper over 2 weeks. Clinical uses: HTN, angina, HFrEF (carvedilol, bisoprolol, metoprolol succinate), post-MI, atrial fibrillation (rate control), migraine prophylaxis (propranolol), essential tremor (propranolol), stage fright, thyrotoxicosis, glaucoma (timolol eye drops), portal HTN (non-selective BB: propranolol, nadolol → prevent variceal bleeding). Contraindications: asthma (avoid, especially non-selective), severe COPD, heart block (2nd degree or higher), sick sinus syndrome, decompensated HF, severe bradycardia. Beta-blocker overdose: hypotension, bradycardia, hypoglycemia, seizures → glucagon (activates adenylyl cyclase via G_s-coupled receptors bypassing β receptors). Combined alpha-beta blockers: carvedilol, labetalol. Labetalol: IV for hypertensive emergencies (including preeclampsia). Carvedilol: HFrEF and post-MI.

Organophosphate poisoning: irreversible AChE inhibition → cholinergic crisis (SLUDGE, muscle fasciculations, CNS effects, respiratory failure). Treatment: atropine (2–4 mg IV, repeat q3–10 min until pulmonary secretions clear) + pralidoxime (2-PAM, reactivates AChE if given early, before aging occurs). Atropine dosing in OP poisoning is massive (grams, not milligrams). Pralidoxime is useless for carbamate poisoning (aging too fast) and has no effect once aging (phosphorylation dealkylation) has occurred (24–48h for most OPs). Pralidoxime also directly hydrolyzes excess ACh. Glaucoma: pilocarpine (direct muscarinic), latanoprost (prostaglandin analog → ↑uveoscleral outflow), timolol (β-blocker → ↓aqueous production), brimonidine (α₂ agonist), dorzolamide (carbonic anhydrase inhibitor). Asthma step therapy: SABA (albuterol) for rescue; low-dose ICS for mild persistent; LABA (salmeterol) + ICS for moderate; add tiotropium, leukotriene antagonist, or high-dose ICS for severe. LABA as monotherapy in asthma increases mortality (never use without ICS). Pheochromocytoma: pre-op alpha blockade (phenoxybenzamine or doxazosin) first, then beta-blocker (to prevent unopposed alpha-mediated vasoconstriction). Neurogenic shock: loss of sympathetic tone → hypotension, bradycardia → treat with atropine and vasopressors (norepinephrine). Malignant hyperthermia: triggered by volatile anesthetics + succinylcholine → massive Ca²⁺ release from SR → treat with dantrolene.

Class I (Na⁺ channel blockers): Ia (quinidine, procainamide, disopyramide) → moderate Na⁺ block + K⁺ block, prolong QT, used for atrial and ventricular arrhythmias. Quinidine: cinchonism (tinnitus, headache, thrombocytopenia), QTc prolongation, ↑digoxin levels by P-gp inhibition. Procainamide: drug-induced lupus (especially slow acetylators), agranulocytosis. Ib (lidocaine, mexiletine, phenytoin) → fast off-rate, block inactivated Na⁺ channels preferentially in ischemic tissue, used for ventricular arrhythmias. Lidocaine: first-line for ventricular arrhythmias post-MI; CNS toxicity (seizures, perioral numbness, dysarthria) at high levels; significant first-pass metabolism (not given orally). Ic (flecainide, propafenone) → slow off-rate, strong Na⁺ block; used for atrial fibrillation (in structurally normal hearts) and SVT. CAST trial: flecainide increased mortality in post-MI patients with PVCs → contraindicated in CAD. Atrial flutter with Ic drugs: can slow atrial rate causing 1:1 conduction → ventricular rate paradoxically increases → always add AV nodal blocker (BB or CCB). Class II (beta-blockers): metoprolol, bisoprolol, carvedilol, esmolol. Suppress arrhythmias by reducing sympathetic drive, slowing AV conduction, increasing refractoriness. First-line for rate control in Afib, post-MI prevention, and CPVT. Class III (K⁺ channel blockers): amiodarone, sotalol, dofetilide, ibutilide, dronedarone. Prolong repolarization (QT interval) by blocking I_Kr. Amiodarone: most effective but most toxic antiarrhythmic. Contains iodine → thyroid dysfunction (hyper- or hypothyroidism), pulmonary fibrosis (amiodarone lung), liver toxicity, corneal deposits, blue-gray skin, photosensitivity, peripheral neuropathy. Half-life ~40–60 days. Sotalol: also has Class II effect (non-selective BB). Risk of torsades de pointes → monitor QTc, renal adjust. Dofetilide: pure Class III, requires hospital initiation with TDM. Ibutilide: IV only, used for acute Afib/flutter conversion (stop if QTc >500 ms). Class IV (Ca²⁺ channel blockers, non-dihydropyridine): verapamil and diltiazem. Slow AV conduction, used for rate/rhythm control in Afib, SVT prevention, angina. Negative inotropes → avoid in HFrEF and with beta-blockers (heart block risk). Digoxin: inhibits Na⁺/K⁺-ATPase → ↑intracellular Na⁺ → ↑Ca²⁺ via NCX → ↑contractility (↑LVEF). Slows AV node (vagomimetic). Used for rate control in Afib (especially with HF). Narrow TI: toxicity (anorexia, NV, visual halos/xanthopsia, arrhythmias — AV block, bradycardia, atrial tachycardia with block). Toxicity worsened by hypokalemia, hypomagnesemia, hypercalcemia, renal failure. Treatment: digoxin-specific Fab antibodies (Digibind).

First-line for most patients: thiazide diuretics, ACE inhibitors (ACEi), angiotensin receptor blockers (ARB), dihydropyridine CCBs (amlodipine). Thiazides (HCTZ, chlorthalidone, indapamide): inhibit Na⁺/Cl⁻ cotransporter in DCT. Reduce BP initially by ↓volume, chronically by ↓vascular resistance. Side effects: hypokalemia, hyponatremia, hyperglycemia, hyperlipidemia, hyperuricemia, photosensitivity. Chlorthalidone is more potent and longer-acting than HCTZ. ACEi (lisinopril, enalapril, ramipril, captopril): inhibit angiotensin-converting enzyme → ↓Ang II, ↑bradykinin. Side effects: cough (10–20%, due to bradykinin), angioedema (rare but life-threatening), hyperkalemia, acute kidney injury in bilateral RAS, fetal toxicity (contraindicated in pregnancy), metallic taste (captopril). ARB (losartan, valsartan, candesartan, irbesartan): block AT₁ receptor. Similar efficacy to ACEi but no cough (bradykinin not affected). Same renal and fetal risks. CCB: dihydropyridines (amlodipine, nifedipine, felodipine) → vasodilation (edema, reflex tachycardia, flushing); non-dihydropyridines (verapamil, diltiazem) → negative chronotrope/inotrope. Second-line: beta-blockers in specific populations (post-MI, heart failure, angina, migraine). Aldosterone antagonists (spironolactone, eplerenone): MRAs with modest BP effect, mainly used for HFrEF, resistant HTN, primary hyperaldosteronism. Spironolactone: gynecomastia (anti-androgen effect). Eplerenone: less gynecomastia, more expensive. Alpha-1 blockers (doxazosin) are third-line due to ALLHAT trial showing increased HF. Direct vasodilators: hydralazine (reflex tachycardia, drug-induced lupus), minoxidil (hirsutism, pericardial effusion). Central alpha-2 agonists: clonidine (rebound HTN on withdrawal, sedation, dry mouth). Resistant HTN: ≥4 drugs including a diuretic (usually chlorthalidone + MRA). Hypertensive emergencies: labetalol, clevidipine, nicardipine, nitroprusside (risk of cyanide toxicity with prolonged use >48h or renal failure), fenoldopam.

HFrEF (EF ≤40%): quadruple therapy is the standard of care. ARNI (angiotensin receptor-neprilysin inhibitor): sacubitril/valsartan. Neprilysin inhibition increases natriuretic peptides (BNP, ANP), leading to vasodilation, natriuresis, ↓fibrosis. Replaces ACEi/ARB once tolerated. Superior to enalapril in PARADIGM-HF trial. Beta-blocker (bisoprolol, carvedilol, metoprolol succinate): start at low dose, up-titrate to target or max tolerated. Reduces mortality by ~35%. MRA (spironolactone, eplerenone): start when EF ≤35% and eGFR >30. RALES trial showed mortality benefit with spironolactone. Monitor K⁺ and Cr closely. SGLT2i (dapagliflozin, empagliflozin): DAPA-HF and EMPEROR-Reduced trials showed mortality benefit independent of diabetes. Decreases HF hospitalization by ~30%. Loop diuretics (furosemide, torsemide, bumetanide): for volume overload. Torsemide has better absorption (not affected by gut edema) and longer half-life. Digoxin: added when symptomatic despite GDMT; improves symptoms and reduces hospitalization but no mortality benefit (DIG trial). HFpEF (EF ≥50%): SGLT2i is first-line (EMPEROR-Preserved, DELIVER). Manage comorbidities: HTN, CAD, Afib, obesity, DM. Diuretics for volume overload. ARNI may be considered. Nitrates + hydralazine combination is recommended for African American patients with HFrEF. Ivabradine: If current blocker, inhibits I_f current in SA node → ↓HR. Used when HR ≥70 on max BB in sinus rhythm. Vericiguat: soluble guanylate cyclase stimulator for recent HF decompensation. Omecamtiv mecarbil: cardiac myosin activator (increase systolic ejection time) under investigation.

Anticoagulants: Unfractionated heparin (UFH): activates antithrombin III → inactivates thrombin (IIa) and Xa. Monitored by aPTT (goal 1.5–2.5x control). Reversed by protamine (1 mg per 100 U heparin). Side effects: bleeding, HIT (type I/II), osteoporosis with long-term use. Low molecular weight heparin (enoxaparin, dalteparin): more predictable dosing, SC, Xa > IIa inhibition, less HIT, reversed partially by protamine. Fondaparinux: synthetic pentasaccharide (Xa inhibitor), no HIT, once-daily SC, not reversed by protamine. Warfarin: vitamin K antagonist (inhibits II, VII, IX, X, Protein C/S). Monitored by INR (goal 2–3 for most indications; 2.5–3.5 for mechanical mitral valve). Reversed by vitamin K (1–10 mg PO/IV), FFP/PCC for major bleeding. DOACs: direct Xa inhibitors (rivaroxaban, apixaban, edoxaban) and direct thrombin inhibitor (dabigatran). Fixed dosing (no monitoring), fewer drug/food interactions than warfarin. Reversal agents: idarucizumab (dabigatran), andexanet alfa (Xa inhibitors). DOACs preferred for Afib and VTE (lower ICH risk than warfarin). Antiplatelets: Aspirin (ASA): irreversible COX-1 inhibition → ↓TXA₂. P2Y12 inhibitors: clopidogrel (prodrug via CYP2C19), prasugrel (more potent, no CYP2C19 issue), ticagrelor (reversible, not prodrug). DAPT = ASA + P2Y12i for ACS and PCI. GP IIb/IIIa inhibitors (abciximab, eptifibatide, tirofiban): IV for high-risk ACS/PCI. Cilostazol: PDE3 inhibitor, used for PAD (increase walking distance). Thrombolytics/fibrinolytics: alteplase (tPA), tenecteplase (TNK-tPA), streptokinase. Plasminogen activators → ↑plasmin → clot dissolution. Indications: STEMI (<12h if PCI not available), acute ischemic stroke (<3–4.5h), massive PE, severe DVT. Contraindications: active bleeding, recent surgery/stroke/trauma, coagulopathy, severe HTN. Agents differ in half-life, fibrin specificity (TNK-tPA has longest half-life, given as single bolus), and antigenicity (streptokinase is antigenic).

Statins (HMG-CoA reductase inhibitors): atorvastatin, rosuvastatin, simvastatin, pravastatin, lovastatin, pitavastatin, fluvastatin. Reduce LDL by 30–55% (high-intensity: atorvastatin 40–80, rosuvastatin 20–40). Pleiotropic effects (anti-inflammatory, plaque stabilization, ↓CRP, ↓thrombosis). Side effects: myopathy (1–5%), rhabdomyolysis (<0.1%, risk increase with fibrates, CYP3A4 inhibitors), transaminitis (reversible, not true hepatotoxicity), new-onset DM (minor risk). Drug interactions: simvastatin → avoid with CYP3A4 inhibitors; monitor for myopathy. Ezetimibe: inhibits intestinal cholesterol absorption (NPC1L1). Adds 15–20% LDL reduction to statins. IMPROVE-IT trial showed benefit post-ACS. PCSK9 inhibitors (evolocumab, alirocumab): monoclonal antibodies increase LDL receptor recycling → dramatic LDL reduction (50–60%). Reserved for familial hypercholesterolemia, statin intolerance, clinical ASCVD not at goal with maximally tolerated statin. Cost is a barrier. Bempedoic acid: ATP-citrate lyase inhibitor, similar pathway to statins (upstream). For statin-intolerant patients. Fibrates (fenofibrate, gemfibrozil): PPAR-α agonists → ↑HDL, ↓TG. Gemfibrozil increases statin levels (avoid with high-dose statins → rhabdomyolysis risk). Fenofibrate is safer with statins. Omega-3 fatty acids (icosapent ethyl, fish oil): REDUCE-IT trial showed benefit of high-dose icosapent ethyl (4 g/day) for CV risk reduction independent of TG lowering. Niacin: B3 vitamin, ↑HDL, ↓TG, ↓LDL. Flushing (prostaglandin-mediated, mitigated by aspirin taken 30 min prior), hyperglycemia, hepatotoxicity. HPS2-THRIVE trial showed no benefit and increased harm → niacin now rarely used. Bile acid sequestrants (cholestyramine, colesevelam): bind bile acids, interrupt enterohepatic circulation. GI side effects, drug interactions (bind other drugs). AHA/ACC guidelines: high-intensity statin for clinical ASCVD, diabetes age 40–75 with risk factors, primary LDL ≥190, and primary prevention risk ≥7.5% (moderate or high-intensity based on risk).

Stable angina: goal is ↓O₂ demand (↓HR, ↓contractility, ↓wall stress) and/or ↑O₂ supply (vasodilation). Beta-blockers: first-line for stable angina (reduce HR, contractility). Metoprolol, atenolol, bisoprolol. CCBs: non-dihydropyridine (verapamil, diltiazem) → ↓HR, ↓contractility, vasodilation. Dihydropyridine (amlodipine, nifedipine) → vasodilation with reflex tachycardia (often used with BB). Nitrates: venodilators → ↓preload → ↓myocardial O₂ demand. Nitroglycerin (NTG): sublingual for acute attacks; IV for ACS; transdermal for maintenance. Nitrate tolerance: develops within 24h → require nitrate-free interval (10–12h daily). Isosorbide mononitrate/dinitrate: oral for prophylaxis. Side effects: headache, hypotension, reflex tachycardia. Contraindicated with PDE-5 inhibitors (sildenafil, tadalafil, vardenafil) within 24h (risk of severe hypotension). Ranolazine: late Na⁺ current inhibitor → ↓intracellular Ca²⁺ → improves diastolic function, reduces angina. No effect on HR or BP. Used as add-on, especially in patients with inadequate response to BB/CCB. QT prolongation risk (dose adjust for hepatic/renal impairment). Vasospastic (Prinzmetal) angina: CCBs (verapamil, diltiazem, nifedipine) are first-line; nitrates as needed. Microvascular angina: treat with BB, CCB, ranolazine, statin, optimize risk factors. Trimetazidine (not FDA approved in US): metabolic modulator, shifts myocardial metabolism from FFA to glucose → ↑efficiency.

Benzodiazepines (BZDs): positive allosteric modulators of GABA-A receptors, increasing Cl⁻ channel opening frequency. Short-acting: midazolam, triazolam. Intermediate: lorazepam, alprazolam, temazepam. Long-acting: diazepam, chlordiazepoxide, clonazepam. Clinical uses: anxiety, panic disorder, insomnia, seizure (status epilepticus: lorazepam IV first-line), muscle spasm, alcohol withdrawal, pre-op sedation. Metabolism: oxidized by CYP450 (diazepam, alprazolam) vs glucuronidated (lorazepam, oxazepam, temazepam) → safer in liver disease and elderly. Side effects: sedation, tolerance, dependence, withdrawal (anxiety, seizures, insomnia), anterograde amnesia, paradoxical disinhibition (especially in children and elderly), falls. Withdrawal can be life-threatening (seizures, delirium tremens) → taper over weeks to months. Flumazenil: BZD antagonist, reverses sedation. Short half-life (~1h), risk of re-sedation. Contraindicated in mixed overdoses (can provoke seizures in TCA or pro-convulsant co-ingestion) and chronic BZD use (precipitates withdrawal). Z-drugs (zolpidem, zaleplon, eszopiclone): non-BZD hypnotics, selective for α₁ subunit of GABA-A. Faster onset, shorter half-life, but similar tolerance/withdrawal profile. Zolpidem: FDA boxed warning (complex sleep behaviors: sleepwalking, sleep-driving). Avoid in complex job settings (pilots, drivers). Melatonin receptor agonists: ramelteon (MT₁/MT₂ agonist), melatonin. No abuse potential, no tolerance. Buspirone: 5-HT_1A partial agonist, also D₂ antagonist (weak). Non-sedating, no tolerance/withdrawal, no synergy with alcohol. Takes 2–4 weeks for onset. Used for generalized anxiety disorder. Side effects: dizziness, nausea, headache. Do not give with MAOIs (serotonin syndrome risk). Hydroxyzine: antihistamine with anxiolytic effect; sedating, anticholinergic. Beta-blockers (propranolol) for performance anxiety (stage fright).

SSRIs (selective serotonin reuptake inhibitors): fluoxetine, sertraline, paroxetine, citalopram, escitalopram, fluvoxamine. First-line for depression, anxiety, OCD, PTSD, PMDD, bulimia. Mechanism: block SERT → ↑synaptic 5-HT. Side effects: GI upset, sexual dysfunction (delayed ejaculation, anorgasmia), insomnia, agitation, hyponatremia (SIADH, especially elderly), weight gain (paroxetine worst), QTc prolongation (citalopram >40 mg/day contraindicated). Serotonin discontinuation syndrome (dizziness, paresthesias, nausea, flu-like symptoms, electric shock sensations) upon abrupt withdrawal → taper over 4–8 weeks. Fluoxetine: longest half-life (~4–6 days, active metabolite norfluoxetine ~2 weeks), lowest risk of discontinuation syndrome, most activating. Paroxetine: most anticholinergic, most weight gain, most sexual dysfunction, highest withdrawal risk. Sertraline: good first-line, modest CYP interactions. Escitalopram: best tolerability. SNRIs (serotonin-norepinephrine reuptake inhibitors): venlafaxine, duloxetine, desvenlafaxine, levomilnacipran. Venlafaxine: at low doses SSRI-like, at high doses also blocks NET. Used for depression, GAD, panic, social anxiety. Side effects: ↑BP (dose-dependent), nausea, sexual dysfunction. Withdrawal is severe (brain zaps, vertigo, nausea). Duloxetine: approved for diabetic neuropathy, fibromyalgia, chronic MSK pain, GAD, depression. No significant CYP induction/inhibition. Atypical antidepressants: bupropion (NDRI: blocks NET and DAT) → no sexual side effects, activating, weight neutral. Used for depression, smoking cessation, seasonal affective disorder. Contraindicated: seizure disorder, eating disorder (AN/BN → ↑seizure risk). Mirtazapine: α₂ antagonist + 5-HT₂/5-HT₃ antagonist → noradrenergic and specific serotonergic antidepressant (NaSSA). Sedating (H₁ blockade), appetite stimulating (↑weight). No sexual side effects. Useful for insomnia, weight loss, elderly. Trazodone: 5-HT₂ antagonist + weak SERT inhibition. Sedating (higher doses for depression, low dose for insomnia). Priapism (rare but urologic emergency). Vortioxetine: multimodal antidepressant (SERT blocker + 5-HT_1A agonist, 5-HT₃ antagonist, 5-HT_1B partial agonist). Improved cognitive function. Vilazodone: SERT blocker + 5-HT_1A partial agonist. TCAs (tricyclic antidepressants): amitriptyline, nortriptyline, imipramine, desipramine, clomipramine. Block SERT and NET with varying ratios. Also block H₁ (sedation), M₁ (anticholinergic), α₁ (hypotension). Side effects: anticholinergic (dry mouth, constipation, blurred vision, urinary retention), orthostasis, sedation, weight gain, cardiac toxicity (Na⁺ channel blockade → widened QRS, ventricular arrhythmias). Overdose is lethal: treat with NaHCO₃ for QRS >100 ms. Used for depression (second/third line due to side effects), neuropathic pain (nortriptyline, amitriptyline), migraine prophylaxis, OCD (clomipramine). Nortriptyline and desipramine have fewer side effects. MAOIs (monoamine oxidase inhibitors): phenelzine, tranylcypromine, selegiline (MAO-B selective). Irreversible inhibitors of MAO-A and/or MAO-B. MAO-A degrades 5-HT, NE, DA; MAO-B degrades DA. Used for atypical depression, treatment-resistant depression, panic disorder. Dietary restriction: tyramine-rich foods (aged cheese, cured meats, wine, sauerkraut, soy sauce) → hypertensive crisis (“cheese reaction”). Avoid serotonergic drugs (SSRIs, SNRIs, meperidine, dextromethorphan) → serotonin syndrome (hyperthermia, rigidity, autonomic instability, death). Washout period: 2 weeks between MAOIs and other antidepressants (5 weeks for fluoxetine). Selegiline transdermal patch bypasses GI MAO-A, allowing lower dietary restriction at lowest dose.

First-generation (typical) antipsychotics (FGAs): chlorpromazine, haloperidol, fluphenazine, perphenazine, thioridazine. Mechanism: D₂ receptor blockade. Potency: high (haloperidol → few mg, EPS common) vs low (chlorpromazine → hundreds mg, more sedation, more anticholinergic, more orthostasis). Side effects: extrapyramidal symptoms (EPS: dystonia, parkinsonism, akathisia, tardive dyskinesia), hyperprolactinemia, neuroleptic malignant syndrome (NMS). EPS treated with anticholinergics (benztropine, diphenhydramine). NMS: rigidity, fever, autonomic instability, altered mental status, ↑CK → stop antipsychotic, supportive care, dantrolene/bromocriptine. Tardive dyskinesia (TD): late complication (years), orofacial/buccal movements, potentially irreversible. Clozapine has lowest TD risk. Second-generation (atypical) antipsychotics (SGAs): clozapine, risperidone, olanzapine, quetiapine, aripiprazole, ziprasidone, lurasidone, paliperidone, brexpiprazole, cariprazine. Mechanism: D₂ + 5-HT_2A antagonism (or partial agonism for aripiprazole, brexpiprazole). Lower EPS/prolactin risk (except risperidone at higher doses). Side effects: metabolic syndrome (weight gain, diabetes, dyslipidemia) — worst with olanzapine, clozapine; moderate with quetiapine, risperidone; least with aripiprazole, ziprasidone, lurasidone. QTc prolongation (ziprasidone, iloperidone). Clozapine: most effective for treatment-resistant schizophrenia. Mandatory monitoring: absolute neutrophil count (ANC) weekly x 6 months, then q2weeks x 6 months, then monthly → risk of agranulocytosis (~1–2%). Also: myocarditis (first month), orthostasis, sialorrhea, sedation, seizures. LAI (long-acting injectable) antipsychotics: haloperidol decanoate, fluphenazine decanoate, risperidone microspheres, paliperidone palmitate, aripiprazole monohydrate. Improve adherence. Mood stabilizers: Lithium: mechanism unclear (inositol depletion, GSK-3β inhibition, ↑BDNF). First-line for bipolar I and II maintenance, acute mania, suicide risk reduction. Narrow TI (0.6–1.2 mEq/L maintenance, 1.0–1.5 for acute mania). Toxicity >1.5: tremor, ataxia, confusion; >2.5: seizures, coma, death. Side effects: tremor (propranolol responsive), nephrogenic diabetes insipidus (polyuria, polydipsia), hypothyroidism (check TSH q6–12 months), teratogenicity (Ebstein anomaly), weight gain, acne, psoriasis. Check renal function, TSH, serum calcium, and levels q3–6 months. Dehydration, NSAIDs, ACEi, and thiazides ↑lithium levels/toxicity. Valproate (valproic acid, divalproex): broad-spectrum mood stabilizer and antiepileptic. Used for acute mania, mixed episodes, rapid cycling. Side effects: tremor, weight gain, alopecia, PCOS, hepatotoxicity (check LFTs), thrombocytopenia, pancreatitis (rare), teratogenicity (neural tube defects → avoid in pregnancy). TDM: therapeutic level 50–125 µg/mL. Carbamazepine/oxcarbazepine: used for bipolar (especially rapid cycling), trigeminal neuralgia. Autoinduction: induces its own metabolism over 3–5 weeks, may require dose escalation. Potent CYP3A4 inducer → reduces levels of oral contraceptives, warfarin, many others (including other AEDs). Lamotrigine: excellent for bipolar depression maintenance. Slow titration to avoid SJS/TEN (starting 25 mg/day, increase q2weeks). Valproate ↑lamotrigine levels (need slower titration).

AED mechanisms: Na⁺ channel blockade (phenytoin, carbamazepine, lamotrigine, oxcarbazepine, lacosamide), Ca²⁺ channel blockade (ethosuximide → T-type; gabapentin, pregabalin → α₂δ subunit), GABA enhancement (benzodiazepines, barbiturates, tiagabine, vigabatrin), glutamate inhibition (topiramate, perampanel → AMPA antagonist), SV2A modulation (levetiracetam, brivaracetam). Phenytoin: zero-order kinetics at therapeutic range, narrow TI. Side effects: nystagmus (early), ataxia (moderate), sedation, lethargy (high). Chronic: gingival hyperplasia, hirsutism, coarse facial features, folate deficiency, peripheral neuropathy, osteoporosis, lymphadenopathy, megaloblastic anemia. Teratogenic (fetal hydantoin syndrome). CYP inducer. Carbamazepine: SVT (Na⁺ channel blocker). Side effects: diplopia, dizziness, SIADH (hyponatremia), blood dyscrasias (aplastic anemia, agranulocytosis), Stevens-Johnson syndrome. Autoinduction. Strong CYP inducer. Valproate: broad-spectrum (multiple mechanisms). Good for generalized epilepsies (absence, myoclonic, tonic-clonic). Side effects: tremor, weight gain, alopecia, PCOS, hepatotoxicity, thrombocytopenia, pancreatitis, neural tube defects. Lamotrigine: broad-spectrum, well tolerated. Titrate slowly due to SJS risk. Levetiracetam: broad-spectrum, minimal drug interactions, rapid titration. Side effects: somnolence, dizziness, behavioral/psychiatric effects (irritability, agitation, psychosis). Topiramate: broad-spectrum. Side effects: weight loss, paresthesias, nephrolithiasis (carbonic anhydrase inhibition), cognitive slowing (“dopamax”), acute angle-closure glaucoma, metabolic acidosis. Zonisamide: similar to topiramate (weight loss, nephrolithiasis, paresthesias). Gabapentin/pregabalin: for focal seizures, neuropathic pain, fibromyalgia, anxiety. No significant drug interactions. Side effects: sedation, dizziness, peripheral edema, weight gain. Ethosuximide: T-type Ca²⁺ channel blocker, only for absence seizures. Side effects: NV, headache, lethargy, blood dyscrasias. Perampanel: AMPA glutamate receptor antagonist. Side effects: dizziness, somnolence, aggression/anger, falls. Status epilepticus treatment: lorazepam (0.1 mg/kg IV, max 4 mg/dose, repeat x1) → levetiracetam (60 mg/kg IV), fosphenytoin, valproate → if refractory, anesthetic doses of propofol, midazolam, or pentobarbital with EEG monitoring.

Opioid receptors: μ (mu) → analgesia, euphoria, respiratory depression, constipation, miosis, physical dependence. Kappa (κ) → analgesia, dysphoria, diuresis (antidiuretic hormone inhibition). Delta (δ) → analgesia, antidepressant-like effects. Full mu agonists: morphine (prototype), hydromorphone, oxycodone, hydrocodone, fentanyl (100x morphine), methadone, meperidine, codeine (prodrug → morphine via CYP2D6), tramadol (weak mu + SNRI), tapentadol (mu + NRI). Clinical uses: acute pain, chronic cancer pain, anesthesia, cough suppression, diarrhea. Equianalgesic dosing: morphine 10 mg IV = hydromorphone 1.5 mg IV = fentanyl 100 µg IV = oxycodone 20 mg PO (varies by reference). Side effects: constipation (prophylactic bowel regimen, methylnaltrexone/naloxegol for refractory), nausea/vomiting, sedation, respiratory depression (dose-limiting), tolerance (especially analgesic tolerance), physical dependence, hyperalgesia (opioid-induced, especially with high doses). Miosis (pinpoint pupils) → exception: meperidine may cause mydriasis. Meperidine: active metabolite normeperidine (accumulates in renal failure → seizures). Not recommended for chronic pain. Tramadol: lowers seizure threshold, serotonin syndrome risk with SSRIs/SNRIs. Methadone: long half-life (~24–36h but analgesic duration 4–8h), NMDA antagonist, QTc prolongation, used for opioid use disorder (OUD) and chronic pain. Risk of accumulation and respiratory depression days after start → requires expert initiation. Naloxone: pure mu antagonist, half-life ~30–90 min. IV/IM/IN for opioid overdose (0.04–2 mg, repeat q2–3 min). Duration < most opioids → may require infusion for long-acting opioids (methadone sustained-release formulations). Buprenorphine: partial mu agonist + kappa antagonist. Ceiling effect on respiratory depression. Used for OUD (sublingual tablets/film, monthly injection). Microinduction/low-dose induction for patients on full agonists. Suboxone: buprenorphine + naloxone (to deter IV abuse). Naltrexone: long-acting mu antagonist, used for alcohol and OUD (oral daily or IM monthly). No abuse potential, no withdrawal. Opioid withdrawal: managed with buprenorphine, methadone, symptomatic meds (clonidine for autonomic symptoms, loperamide for diarrhea, antiemetics). COWS (Clinical Opiate Withdrawal Scale) guides buprenorphine initiation timing.

General anesthetics: GABA positive modulators (propofol, etomidate, barbiturates, volatile agents), NMDA antagonists (ketamine), α₂ agonists (dexmedetomidine). Propofol: IV induction/maintenance, rapid onset/offset. Sedative, amnestic, antiemetic. ↓BP, ↓HR, respiratory depression. Green urine (metabolite). Pain on injection. Etomidate: hemodynamically stable induction (for hypotensive patients). Adrenal suppression (even single dose → blunts cortisol response). Ketamine: dissociative anesthetic (NMDA antagonist). Analgesia, amnesia, bronchodilation, hemodynamic stability. Psychotomimetic effects. Used in RSI (rapid sequence intubation), procedural sedation, treatment-resistant depression (low-dose IV). Emergence delirium (midazolam to prevent). Volatile anesthetics: sevoflurane, isoflurane, desflurane. Malignant hyperthermia trigger (with succinylcholine). Succinylcholine: depolarizing NMJ blocker, fasciculations, hyperkalemia risk (burns, denervation, crush injury, muscular dystrophy, prolonged immobility). Apnea with pseudocholinesterase deficiency. Reversal: no agent (spontaneously hydrolyzed). Non-depolarizing NMJ blockers: rocuronium, vecuronium, atracurium, cisatracurium, pancuronium. Reversed by neostigmine (with glycopyrrolate) or sugammadex (selective binder for rocuronium/vecuronium). Anesthetic MAC: minimum alveolar concentration to prevent movement in 50% of patients. MAC decreases with age, hypothermia, other sedatives. Serotonin syndrome: triad of mental status changes, autonomic hyperactivity, neuromuscular abnormalities (hyperreflexia, clonus, tremor). Caused by serotonergic drug combinations (SSRI + MAOI, SSRI + linezolid, SSRI + triptan). Treatment: stop offending agents, supportive care, cyproheptadine (5-HT_2A antagonist) severe cases. Neuroleptic malignant syndrome (NMS): similar to serotonin syndrome but with rigidity (lead pipe), bradyreflexia, hyporeflexia, ↑CK. Treatment: dantrolene, bromocriptine, supportive care.

Type 1 diabetes: absolute insulin deficiency → requires lifelong insulin therapy. Type 2 diabetes: progressive insulin resistance + β-cell dysfunction → multiple oral and injectable options. First-line for T2DM: metformin (unless contraindicated or not tolerated). Mechanism: inhibits hepatic gluconeogenesis (AMPK activation), ↓hepatic glucose output, ↑GLUT4 translocation. Benefits: weight neutral (modest weight loss), no hypoglycemia, ↓CV events (UKPDS), ↓microvascular complications. Side effects: GI intolerance (diarrhea, nausea, metallic taste), lactic acidosis (rare, <1/100,000, risk with eGFR <30, severe liver disease, acute illness with hypoxia, alcohol abuse). Hold for 48h after IV contrast (risk of acute kidney injury + lactic acidosis). Start low, titrate slowly. Sulfonylureas (glipizide, glimepiride, glyburide): stimulate insulin secretion from β-cells (K-ATP channel blocker). Effective for glycemic control but risk of hypoglycemia (especially glyburide) and weight gain. Glyburide contraindicated in elderly (hypoglycemia risk). Glinides (repaglinide, nateglinide): similar mechanism, rapid onset/short duration, taken with meals. Hypoglycemia risk lower than sulfonylureas. TZDs (pioglitazone, rosiglitazone): PPAR-γ agonists → ↑insulin sensitivity in adipose, muscle, liver. Pioglitazone: ↓CV events in PROactive (but heart failure risk, fluid retention, weight gain, fractures, bladder cancer controversy). Rosiglitazone: restricted due to MI risk (RECORD trial was equivocal). DPP-4 inhibitors (sitagliptin, saxagliptin, linagliptin, alogliptin): ↑incretins (GLP-1, GIP) by preventing degradation. Modest A1c reduction (~0.5–0.8%), weight neutral, no hypoglycemia. Possible pancreatitis risk. Saxagliptin: slight ↑HF hospitalization. Linagliptin: no renal adjustment needed. GLP-1 receptor agonists (exenatide, liraglutide, semaglutide, dulaglutide, tirzepatide [GIP/GLP-1 dual agonist]): ↑insulin secretion (glucose-dependent), ↓glucagon, delayed gastric emptying, ↑satiety. Significant weight loss, ↓CV events (liraglutide, semaglutide LEADER, REWIND), renal benefit. Side effects: nausea/vomiting (common, start low, titrate slowly), pancreatitis (rare), medullary thyroid carcinoma risk (rodent data, caution with MEN2), gallbladder disease. Injectable (subQ). Oral semaglutide available. SGLT2 inhibitors (canagliflozin, dapagliflozin, empagliflozin, ertugliflozin): block glucose reabsorption in proximal tubule → glycosuria. ↓A1c, weight loss, ↓BP, ↓CV events (EMPA-REG, CANVAS), ↓HF hospitalization, ↓CKD progression (CREDENCE, DAPA-CKD). Side effects: UTI, genital mycotic infections (especially females), volume depletion, euglycemic DKA (check ketones in sick patients even if glucose normal), acute kidney injury (rare), bone fractures (canagliflozin risk), Fournier gangrene (very rare). Amylin analogs (pramlintide): ↓glucagon, delayed gastric emptying, suppresses appetite. Use in T1DM and T2DM. Insulin: rapid-acting (lispro, aspart, glulisine, onset 5–15 min, peak 1–2h, duration 3–5h), short-acting (regular insulin, onset 30 min, peak 2–4h, duration 5–8h), intermediate-acting (NPH, onset 1–2h, peak 4–12h, duration 12–24h), long-acting (glargine, detemir, degludec, relatively flat, duration ≥24h), ultra-long (degludec >42h). Basal-bolus regimen: long-acting once-daily + rapid-acting with meals. Correction scale: sliding scale regular insulin (ineffective alone in hospitalized patients, prefer basal-bolus).

Hypothyroidism: Levothyroxine (T₄) is drug of choice. Synthetic T₄, half-life ~7 days, once-daily dosing. Start 1.6 µg/kg/day (adults). In elderly or CAD, start low (12.5–25 µg/day) and titrate slowly q4–6 weeks. Take on empty stomach (30–60 min before breakfast, separate from Ca²⁺, Fe²⁺, PPIs, estrogens by 4h). Monitoring: TSH measured 6–8 weeks after dose change, goal 0.5–2.5 mIU/L (non-pregnant). Pregnancy: increase dose by 30–50% immediately upon confirmation → check TSH q4 weeks. Liothyronine (T₃): faster onset, shorter half-life, not routinely used. Desiccated thyroid (Armour): contains T₃ + T₄, not recommended (variable potency). Subclinical hypothyroidism: treat if TSH >10 or with symptoms, pregnancy, positive TPO antibodies. Myxedema coma: IV levothyroxine 200–500 µg load, then 50–100 µg/day + IV T₃ if needed + stress-dose steroids (risk of adrenal insufficiency) + supportive care. Hyperthyroidism: Methimazole (MMI): first-line for Graves disease. Blocks thyroid peroxidase → inhibits thyroid hormone synthesis. Onset delayed until existing stores depleted (3–8 weeks). Side effects: agranulocytosis (0.3–0.5%, highest risk first 3 months, check WBC for fever/sore throat), hepatotoxicity (cholestatic), rash, arthralgias. Propylthiouracil (PTU): second-line (hepatotoxicity black box warning, including liver failure requiring transplant). Preferred in first trimester (though MMI increasingly used) and thyroid storm (inhibits peripheral T₄→T₃ conversion). Side effects: agranulocytosis, hepatotoxicity (more severe than MMI), ANCA-associated vasculitis. Radioactive iodine (I-131): ablation of thyroid tissue for Graves, toxic nodule, toxic MNG. Contraindicated in pregnancy, breastfeeding. Beta-blockers (propranolol) for symptom control (↓HR, tremor, anxiety; propranolol also inhibits T₄→T₃ conversion). Iodine (SSKI, Lugol’s solution): inhibits thyroid hormone release (Wolff-Chaikoff effect). Given pre-op for thyroidectomy (reduces vascularity). Thyroid storm: propranolol + MMI or PTU (high dose, loading) + iodine (1h after MMI) + corticosteroids (inhibit T₄→T₃) + supportive care (cooling, fluids, manage precipitating event).

Glucocorticoids (cortisol, prednisone, prednisolone, methylprednisolone, dexamethasone, hydrocortisone). Anti-inflammatory & immunosuppressive effects: inhibit PLA₂ → ↓arachidonic acid → ↓prostaglandins, leukotrienes; suppress pro-inflammatory cytokines (IL-1, IL-6, TNF); ↓NF-κB. Mineralocorticoid effects: hydrocortisone (high), prednisone (moderate), dexamethasone (none). Uses: asthma, COPD, allergic reactions, autoimmune diseases (SLE, RA, IBD), inflammatory conditions, adrenal insufficiency, cerebral edema (dexamethasone), COVID-19 (dexamethasone), pre-term labor (betamethasone). Side effects: osteoporosis, weight gain, hyperglycemia, diabetes, hypertension, fluid retention, cataracts, glaucoma, thin skin, easy bruising, impaired wound healing, immune suppression, increased infection risk, avascular necrosis of femoral head, myopathy, adrenal insufficiency upon withdrawal (suppression of HPA axis). Withdrawal: taper over weeks to months depending on duration and dose. Stress dose steroids: for patients on ≥5 mg prednisone/day >3 weeks undergoing surgery or acute illness. Addisonian crisis: IV hydrocortisone 100 mg, then 100 mg q8h + IVF + treat precipitating cause. Mineralocorticoids: Fludrocortisone for primary adrenal insufficiency (Addison disease). Sex hormones: Estrogen therapy (estradiol, conjugated estrogens, ethinyl estradiol) for menopause symptoms, hormone replacement therapy (HRT), contraception. Side effects: VTE risk (dose-dependent), breast cancer risk (prolonged use), gallbladder disease. Contraindications: h/o VTE, breast cancer, liver disease, pregnancy, migraine with aura (with combined OCP). Progesterone/progestins: for contraception, luteal phase support, endometriosis. Medroxyprogesterone acetate (DMPA, Depo-Provera): injection q3 months, weight gain, bone density loss. Testosterone replacement: for male hypogonadism. Side effects: ↑hematocrit (polycythemia), sleep apnea, ↓HDL, acne, gynecomastia (aromatization to estradiol), prostate stimulation (controversial). Contraindicated in breast/prostate cancer. Androgen deprivation therapy (GnRH agonists: leuprolide, goserelin): for prostate cancer. SERMs (tamoxifen, raloxifene): estrogen receptor modulators. Tamoxifen is partial agonist in bone, endometrium (increases endometrial cancer risk) and antagonist in breast. Raloxifene is agonist in bone but antagonist in endometrium (less cancer risk). Used for breast cancer prevention and osteoporosis. Aromatase inhibitors (anastrozole, letrozole, exemestane): ↓estrogen production in postmenopausal women; used for breast cancer. Side effects: arthralgias, myalgias, bone loss, hot flashes.

Bisphosphonates (alendronate, risedronate, ibandronate, zoledronic acid): inhibit osteoclast-mediated bone resorption by blocking farnesyl pyrophosphate synthase. First-line for postmenopausal osteoporosis, glucocorticoid-induced osteoporosis, Paget disease, hypercalcemia of malignancy, multiple myeloma bone disease. Oral bisphosphonates: taken on empty stomach with plain water, remain upright 30–60 min to minimize GI side effects (esophagitis, esophageal ulcers). Long-term concerns: atypical femoral fractures (risk ↑with >5 years use), osteonecrosis of jaw (ONJ, especially IV zoledronic acid, risk with dental procedures, poor oral hygiene). Drug holiday after 3–5 years for low-risk patients. Denosumab: RANKL inhibitor (monoclonal antibody), inhibits osteoclast maturation/activity. Used for osteoporosis, bone metastases (breast, prostate). No renal adjustment needed (but hypocalcemia risk with CKD). No drug holiday: rebound bone loss and ↑fracture risk upon discontinuation (give one dose of bisphosphonate if stopping). Onset/offset more rapid than bisphosphonates. Teriparatide: recombinant PTH (1-34), anabolic for bone (↑bone formation if given intermittently). Used for severe osteoporosis (high fracture risk), especially in men and glucocorticoid-induced. Black box: osteosarcoma risk (rodent data) → limit to 2 years lifetime use. Abaloparatide: similar to teriparatide, slightly different profile. Romosozumab: sclerostin inhibitor (monoclonal antibody), ↑bone formation + ↓bone resorption. Monthly SC injection, limit to 1 year. Black box: increased CV events → avoid in patients with recent MI/stroke. Calcitonin: salmon calcitonin, ↓bone resorption, modest effect. Used for Paget disease, hypercalcemia, vertebral fracture pain. Not first-line. Vitamin D (cholecalciferol D₃, ergocalciferol D₂): ↑intestinal Ca²⁺ absorption. Calcitriol (active 1,25-dihydroxyvitamin D): used for CKD-MBD (renal failure), hypoparathyroidism, severe deficiency. Calcipotriene: topical vitamin D analog for psoriasis. Cinacalcet: calcimimetic, activates CaSR → ↓PTH. Used for secondary hyperparathyroidism in CKD, parathyroid carcinoma. Side effects: hypocalcemia, NV. Calcium supplements: calcium carbonate (40% elemental Ca, requires acid) vs calcium citrate (21% elemental Ca, better absorption with PPIs and achlorhydria).

Hypoglycemia management: conscious patient → 15 g fast-acting glucose (3–4 glucose tabs, 4 oz juice). Unconscious or unable to take PO → IM glucagon (1 mg, family members trained) or IV D₅₀ (25 g). Inpatient: dextrose infusion, octreotide for refractory sulfonylurea-induced hypoglycemia. Cushing syndrome treatment: surgical resection of pituitary adenoma (transsphenoidal) or adrenal tumor. Medical: ketoconazole, metyrapone, mitotane, mifepristone (RU-486, GR antagonist). Post-transsphenoidal: hydrocortisone taper. Hypercalcemia: aggressive IVF (NS), calcitonin (rapid onset but tachyphylaxis), bisphosphonates (zoledronic acid IV, onset 2–4 days), denosumab, steroids (for granulomatous disease or myeloma), cinacalet (if elevated PTH), dialysis if severe. Osteoporosis treatment algorithm: fracture risk assessment (FRAX), treat if prior fragility fracture, T-score −2.5 or worse, or FRAX 10-year major fracture ≥20% or hip ≥3%. First-line: bisphosphonate (alendronate, risedronate, zoledronic acid). If intolerant or very high risk: teriparatide, romosozumab, or denosumab. Hirsutism: spironolactone, eflornithine cream, OCPs (anti-androgen effects). Acromegaly: octreotide, lanreotide (somatostatin analogs), pegvisomant (GH receptor antagonist), surgery (transsphenoidal). Prolactinoma: bromocriptine, cabergoline (D₂ agonists). Cabergoline is more effective, better tolerated (once or twice weekly).

Cell wall synthesis inhibitors: Penicillins → bind PBPs → inhibit transpeptidase, activate autolysins. Narrow-spectrum: penicillin G (gram+ cocci, spirochetes, anaerobes except Bacteroides). Anti-staphylococcal: nafcillin, oxacillin, dicloxacillin (penicillinase-resistant). Aminopenicillins: ampicillin, amoxicillin (broader gram+ and some gram−). Anti-pseudomonal: piperacillin, ticarcillin (with beta-lactamase inhibitors: piperacillin-tazobactam, ticarcillin-clavulanate). Allergic reactions: maculopapular rash, urticaria, anaphylaxis (risk ~0.01%). Cephalosporins: 1st gen (cefazolin, cephalexin) → gram+ cocci; 2nd gen (cefoxitin, cefuroxime, cefotetan) → gram+ and gram− + anaerobes (cefoxitin/cefotetan); 3rd gen (ceftriaxone, cefotaxime, ceftazidime, cefpodoxime) → gram− (ceftazidime anti-pseudomonal); 4th gen (cefepime) → gram+ and gram− + anti-pseudomonal; 5th gen (ceftaroline) → MRSA + gram+ and gram−. Ceftriaxone: crosses BBB, avoid in neonates if jaundiced (displaces bilirubin). Cefoxitin/cefotetan: anti-anaerobic. Cefepime: safe in febrile neutropenia. Ceftazidime-avibactam, ceftolozane-tazobactam: ESBL and CRE activity. Carbapenems (imipenem, meropenem, ertapenem, doripenem): broadest spectrum gram+, gram−, anaerobes. Imipenem: renal metabolism by DHP-1 (given with cilastatin). Meropenem: less seizure risk. Ertapenem: not active against Pseudomonas, Acinetobacter. Carbapenemase producers (KPC, NDM, OXA) → require ceftazidime-avibactam, meropenem-vaborbactam, imipenem-relebactam, or cefiderocol. Monobactams: aztreonam (safe in penicillin allergy, only gram−). Glycopeptides: vancomycin, teicoplanin. Vancomycin: inhibits cell wall synthesis (D-Ala-D-Ala binding). MRSA, gram+ cocci. TDM: trough 15–20 mg/L (serious infections), AUC/MIC ≥400. Nephrotoxicity, ototoxicity, red man syndrome (histamine release, slow infusion rate, pre-treat with antihistamines). Daptomycin: Ca²⁺-dependent membrane depolarization → gram+. Used for MRSA, VRE. Does not work in lung (inactivated by surfactant) → not for pneumonia. CK elevation (monitor weekly). Protein synthesis inhibitors: Aminoglycosides (gentamicin, tobramycin, amikacin, plazomicin): 30S ribosome binding. Concentration-dependent killing, post-antibiotic effect. Oto/nephrotoxicity. Once-daily dosing (7 mg/kg gentamicin), TDM. Plazomicin: active against CRE. Macrolides (erythromycin, azithromycin, clarithromycin): 50S binding. Atypical coverage (Mycoplasma, Chlamydia, Legionella, H. pylori, MAC). Azithromycin: QTc prolongation. Erythromycin: motilin agonist (GI prokinetic), CYP3A4 inhibitor. Clarithromycin: potent CYP3A4 inhibitor. Tetracyclines (doxycycline, minocycline, tigecycline): 30S binding. Doxycycline: Lyme, RMSF, malaria prophylaxis, acne. Tigecycline: broad-spectrum (ESBL, CRE, MRSA, VRE, anaerobes). FDA black box: all-cause mortality increase (not first-line). Oxazolidinones (linezolid, tedizolid): 50S binding. Linezolid: MRSA, VRE. Myelosuppression (↓platelets) beyond 2 weeks. MAOI activity: avoid tyramine, serotonergic drugs. Tedizolid: once-daily, less myelosuppression. Fluoroquinolones (ciprofloxacin, levofloxacin, moxifloxacin): topoisomerase II/IV inhibition (DNA synthesis). Ciprofloxacin: Pseudomonas, gram− rods. Levofloxacin: respiratory (including TB). Moxifloxacin: anaerobic activity (but no UTI levels). FDA black box: tendonitis/tendon rupture, QT prolongation, peripheral neuropathy, CNS effects, aortic dissection risk. Metronidazole: inhibits DNA synthesis via reduced metabolites. Anaerobes, C. difficile (oral), protozoa. Metallic taste, peripheral neuropathy (long-term), disulfiram-like reaction with alcohol. Polymyxins (colistin, polymyxin B): disrupt cell membrane, last-resort for MDR gram− (Pseudomonas, Acinetobacter, CRE). Nephrotoxicity, neurotoxicity.

Anti-HSV/VZV: Acyclovir, valacyclovir, famciclovir. Acyclovir: thymidine kinase (viral) activated → acyclovir triphosphate → inhibits viral DNA polymerase. Topical, oral, IV. Valacyclovir is prodrug (better oral bioavailability). Side effects: renal crystals (IV acyclovir → hydrate, slow infusion), neurotoxicity (elderly, renal failure). Foscarnet: directly inhibits viral DNA polymerase (no TK activation), used for acyclovir-resistant HSV/VZV (CMV retinitis in HIV). Nephrotoxicity, electrolyte disturbances (hypoCa²⁺, hypoMg²⁺, hypoPO₄). Cidofovir: CMV retinitis, nephrotoxic. Anti-CMV: Ganciclovir, valganciclovir (oral prodrug). Myelosuppression (neutropenia, thrombocytopenia). Anti-influenza: Oseltamivir (neuraminidase inhibitor), zanamivir (inhaled), baloxavir (cap-dependent endonuclease inhibitor). Oseltamivir effective within 48h of symptom onset for influenza A/B. Side effects: NV, neuropsychiatric effects (especially children). Peramivir: IV neuraminidase inhibitor. Amantadine/rimantadine: M₂ ion channel blocker (influenza A only, no longer circulating in seasonal flu). Anti-HBV: Entecavir, tenofovir (TDF, TAF), lamivudine, adefovir, interferon. Entecavir: first-line, low resistance. Tenofovir: also active against HIV. Anti-HCV: Direct-acting antivirals (DAAs): NS3/4A protease inhibitors (glecaprevir, grazoprevir, voxilaprevir), NS5A inhibitors (ledipasvir, velpatasvir, daclatasvir, pibrentasvir), NS5B polymerase inhibitors (sofosbuvir, dasabuvir). Combinations cure >95% of HCV genotypes over 8–12 weeks. Side effects: headache, fatigue, no major toxicity. Drug interactions: many with statins, PPIs, amiodarone, anticonvulsants. Anti-retrovirals (HIV): NRTIs (tenofovir, abacavir, emtricitabine, lamivudine, zidovudine) → nucleoside analogs. Abacavir: HLA-B*5701 screening required (hypersensitivity). Tenofovir (TDF): renal toxicity, bone loss. TAF: less renal/bone toxicity. Zidovudine: myelosuppression, nausea, headache. NNRTIs (efavirenz, nevirapine, doravirine, rilpivirine): non-nucleoside RT inhibitors. Efavirenz: CNS side effects (vivid dreams, dizziness), teratogenic (avoid in first trimester). Nevirapine: severe rash including SJS, hepatotoxicity. PIs (darunavir, atazanavir, lopinavir/ritonavir): HIV protease inhibitors. Boosted with ritonavir or cobicistat (CYP3A4 inhibitor). Atazanavir: bilirubin elevation (unconjugated, benign jaundice). PIs increase insulin resistance, lipodystrophy, CV risk. Integrase strand transfer inhibitors (INSTIs): raltegravir, dolutegravir, bictegravir, cabotegravir. Well tolerated, low drug interactions. Dolutegravir: small ↑neural tube defect risk (folate supplementation). Cabotegravir + rilpivirine: monthly IM long-acting regimen. Entry inhibitors: Maraviroc (CCR5 antagonist, need tropism assay), enfuvirtide (fusion inhibitor, SC injection).

Polyenes (amphotericin B, nystatin): bind ergosterol → pore formation → fungal cell death. Amphotericin B deoxycholate: broadest spectrum (Candida, Aspergillus, Mucor, Cryptococcus, Histoplasma, Blastomyces, Coccidioides). Side effects: infusion reactions (fever, chills, rigors, hypotension → pre-medications), nephrotoxicity (azotemia, K⁺ wasting, Mg²⁺ wasting, RTA), hypokalemia, hypomagnesemia, anemia (suppresses erythropoietin). Liposomal amphotericin B: less nephrotoxic but expensive. Nystatin: topical only, oral suspension for oral thrush (not absorbed). Azoles (fluconazole, itraconazole, voriconazole, posaconazole, isavuconazole): inhibit 14α-demethylase → ↓ergosterol synthesis. Fluconazole: good CNS penetration, Candida (albicans, parapsilosis, tropicalis), Cryptococcus. Not effective against Aspergillus, Candida glabrata/krusei. Fluconazole in pregnancy: high doses associated with miscarriage/teratogenicity. Itraconazole: Aspergillus, histoplasmosis, dermatophytes. Variable oral absorption (take with food for capsules, empty stomach for solution). CYP3A4 inhibition. Voriconazole: Aspergillus first-line, Candida, Scedosporium, Fusarium. Visual disturbances (photopsia, photophobia), CYP interactions, CYP2C19 polymorphism (poor metabolizers → high levels). TDM recommended. Hepatotoxicity. Posaconazole: prophylaxis in neutropenia/AML, Mucor. Prophylaxis is superior to fluconazole/itraconazole in high-risk patients. Isavuconazole: broad-spectrum (including Mucor), fewer drug interactions, no visual disturbance, linear PK. Echinocandins (caspofungin, micafungin, anidulafungin, rezafungin): inhibit β-glucan synthase → ↓cell wall integrity. Fungicidal for Candida (including azole-resistant), fungistatic for Aspergillus. No activity against Cryptococcus, Mucor. Well tolerated (few drug interactions, minimal toxicity). First-line for invasive candidiasis (especially non-albicans, azole-resistant). Flucytosine (5-FC): converted to 5-FU → inhibits DNA/RNA synthesis. Used in combination with amphotericin B for cryptococcal meningitis. Bone marrow suppression. Terbinafine: inhibits squalene epoxidase → ↓ergosterol. Dermatophytes (tinea, onychomycosis). Hepatotoxicity. Griseofulvin: inhibits fungal mitosis. Dermatophytes. Better for tinea capitis in children (course 4–8 weeks). Headache, photosensitivity, ↑warfarin metabolism (CYP induction).

Malaria: Chloroquine (blood schizontocide, for P. falciparum in sensitive areas, also for P. vivax/ovale/malariae). Resistance widespread. Hydroxychloroquine: used for autoimmune diseases (SLE, RA), retinal toxicity → baseline + annual eye exam (cumulative dose >5 g/kg). Quinine: used with doxycycline or clindamycin for chloroquine-resistant falciparum. Cinchonism (tinnitus, nausea, headache, visual disturbances), hypoglycemia (insulin secretion), QTc prolongation. Artemisinin-based combination therapies (ACT): artemether/lumefantrine, artesunate (IV for severe malaria). Artemisinins: most rapidly acting antimalarials, active against all Plasmodium species. Side effects: mild, neutropenia with prolonged use. IV artesunate: WHO recommended for severe malaria (loading dose then daily). Primaquine: radical cure of P. vivax/ovale hypnozoites (liver stage). Also gametocytocidal. G6PD screening required → hemolytic anemia in G6PD deficiency. Atovaquone/proguanil (Malarone): prophylaxis and treatment. Well tolerated. Doxycycline: prophylaxis (not for treatment alone). Mefloquine: prophylaxis (once weekly). Neuropsychiatric side effects (anxiety, hallucinations, psychosis, seizures). Helminths: Albendazole, mebendazole (microtubule polymerization inhibition). Broad-spectrum for intestinal nematodes (Ascaris, hookworm, Trichuris, Enterobius). Albendazole also for neurocysticercosis, hydatid disease. Mebendazole: poor absorption, mainly GI. Ivermectin: macrocyclic lactone, glutamate-gated Cl⁻ channel activator. Strongyloides, onchocerciasis, scabies (including crusted scabies). Side effects: Mazzotti reaction (fever, pruritus, lymphadenopathy in onchocerciasis). Praziquantel: increases Ca²⁺ influx → spastic paralysis. Schistosomiasis, taeniasis (tapeworm), neurocysticercosis (with steroids). Nitazoxanide: Cryptosporidium, Giardia. Amebiasis: Tinidazole, metronidazole, paromomycin (luminal agent). Leishmaniasis: sodium stibogluconate, amphotericin B, miltefosine. Trypanosomiasis: suramin, pentamidine, eflornithine. Scabies/pediculosis: permethrin 5% cream (scabies), 1% rinse (lice), ivermectin PO for severe scabies. Lindane: second-line due to neurotoxicity.

Alkylating agents (cyclophosphamide, ifosfamide, cisplatin, busulfan, temozolomide): cross-link DNA → ↓replication. Cyclophosphamide: hemorrhagic cystitis (mesna protection), SIADH. Ifosfamide: hemorrhagic cystitis, CNS toxicity. Cisplatin: nephrotoxicity (hydration, Mg²⁺ supplementation), ototoxicity, peripheral neuropathy. Temozolomide: crosses BBB (glioblastoma). Antimetabolites (methotrexate, 5-FU, capecitabine, gemcitabine, cytarabine, fludarabine, pemetrexed): disrupt DNA/RNA synthesis. Methotrexate: DHFR inhibitor, leucovorin rescue, nephrotoxicity (MTX crystals, alkalinize urine), hepatotoxicity, mucositis, myelosuppression. Can cause renal failure, pneumonitis. 5-FU/Capecitabine: DPD deficiency → severe toxicity (check DPYD genotype). Hand-foot syndrome (palmar-plantar erythrodysesthesia). Gemcitabine: myelosuppression, flu-like symptoms. Microtubule agents: Vinca alkaloids (vincristine, vinblastine) → inhibit tubulin polymerization. Vincristine: peripheral neuropathy (dose-limiting), constipation, SIADH. No significant myelosuppression. Vinblastine: myelosuppression. Taxanes (paclitaxel, docetaxel) → inhibit microtubule disassembly. Hypersensitivity reactions (pre-medicate with steroids, H1/H2 blockers), peripheral neuropathy, myelosuppression, alopecia. Nab-paclitaxel: albumin-bound, fewer hypersensitivity reactions. Anthracyclines (doxorubicin, daunorubicin, epirubicin, idarubicin): topoisomerase II inhibition + free radical generation. Cardiotoxicity: acute and chronic (dilated cardiomyopathy, dose-dependent >450–550 mg/m²). Dexrazoxane (cardioprotectant). Emetogenic potential. Topoisomerase inhibitors (irinotecan, topotecan, etoposide): Irinotecan: conversion by CES2 → SN-38. GI toxicity (diarrhea), UGT1A1*28 → increased toxicity. Etoposide: hypersensitivity, myelosuppression. Targeted therapy: TKIs (imatinib, dasatinib, nilotinib for CML → BCR-ABL); erlotinib, gefitinib, osimertinib (EGFR mutant lung cancer); crizotinib, alectinib (ALK+ lung); sorafenib, sunitinib, lenvatinib (VEGFR/multikinase). Side effects: fatigue, diarrhea, rash, hand-foot syndrome, hypertension (VEGF inhibitors), QT prolongation (some), bleeding. Monoclonal antibodies: trastuzumab (HER2+ breast), rituximab (CD20+ lymphoma), cetuximab (EGFR), bevacizumab (VEGF). Trastuzumab: cardiotoxicity (reversible cardiomyopathy, monitor LVEF). Rituximab: infusion reactions, PML (progressive multifocal leukoencephalopathy). Immune checkpoint inhibitors (pembrolizumab, nivolumab, ipilimumab, atezolizumab, avelumab, durvalumab): anti-PD-1/PD-L1 and anti-CTLA-4. Immune-related adverse events (irAEs): pneumonitis, colitis, hepatitis, myocarditis, thyroiditis, dermatitis, hypophysitis. Hormonal therapies: breast cancer: tamoxifen (SERM), aromatase inhibitors (anastrozole, letrozole, exemestane), fulvestrant (SERD), CDK4/6 inhibitors (palbociclib, ribociclib, abemaciclib). Prostate cancer: GnRH agonists (leuprolide, goserelin), anti-androgens (enzalutamide, bicalutamide, apalutamide), abiraterone (CYP17 inhibitor).

Resistance mechanisms: β-lactamase production (ESBLs, KPC, NDM, OXA), target modification (PBPs in MRSA, DNA gyrase in FQ resistance), efflux pumps (tetracyclines, FQs, macrolides), target site alteration (vancomycin resistance → D-Ala-D-Lac in VRE), ribosomal methylation (linezolid resistance). ESBL: Enterobacteriaceae resistant to 3rd-gen cephalosporins; treat with carbapenem. AmpC: inducible β-lactamase in Enterobacter, Serratia, Citrobacter → avoid 3rd-gen cephalosporins. MRSA: treat with vancomycin, daptomycin, ceftaroline, linezolid. VRE: linezolid, daptomycin, tigecycline. CRE (carbapenem-resistant Enterobacteriaceae): ceftazidime-avibactam, meropenem-vaborbactam, imipenem-relebactam, cefiderocol, tigecycline, polymyxins. MDR Pseudomonas: double coverage (anti-pseudomonal beta-lactam + aminoglycoside or FQ). Empiric antibiotic guidelines: CAP: ceftriaxone + azithromycin (or respiratory FQ monotherapy). HAP/VAP: anti-pseudomonal beta-lactam (cefepime, piperacillin-tazobactam, meropenem) +/- vancomycin/linezolid (if MRSA risk). Complicated UTI: ceftriaxone, FQ, or carbapenem; if ESBL risk → carbapenem, ceftolozane-tazobactam, ceftazidime-avibactam. Intra-abdominal infection: ceftriaxone + metronidazole, piperacillin-tazobactam, carbapenem. Febrile neutropenia: cefepime, piperacillin-tazobactam, or carbapenem; add vancomycin if catheter infection or hemodynamic instability. Meningitis: ceftriaxone + vancomycin + ampicillin (elderly, immunocompromised for Listeria). De-escalation based on culture results is critical for antimicrobial stewardship. Procalcitonin guidance can shorten duration of therapy in respiratory infections.

Non-steroidal anti-inflammatory drugs (NSAIDs) inhibit cyclooxygenase (COX-1 and/or COX-2), converting arachidonic acid to prostaglandins and thromboxanes. COX-1 is constitutively expressed in most tissues: GI mucosa (cytoprotective prostaglandins), platelets (TXA₂ → aggregation), kidney (renal blood flow regulation), and vascular endothelium (prostacyclin, PGI₂). COX-2 is induced by inflammation (cytokines, growth factors) but also constitutive in kidney, brain, and endothelium (PGI₂). Non-selective NSAIDs: ibuprofen, naproxen, indomethacin, diclofenac, ketorolac, piroxicam, sulindac, ketoprofen, flurbiprofen, meloxicam (preferential COX-2 at low dose). COX-2 selective: celecoxib, etoricoxib, rofecoxib (rofecoxib withdrawn for CV toxicity, Vioxx). Celecoxib: sulfonamide structure, contraindicated in sulfa allergy. NSAID potencies: 400 mg ibuprofen ≈ 500 mg naproxen ≈ 50 mg diclofenac ≈ 10 mg ketorolac IM ≈ 25 mg indomethacin. Ketorolac: only NSAID approved for moderate-to-severe acute pain (IM/IV, maximum 5 days due to GI/renal toxicity). Indomethacin: preferred for gout flare, closure of PDA in neonates, ankylosing spondylitis, pericarditis. Diclofenac: topical and oral, for osteoarthritis and musculoskeletal pain. Aspirin (acetylsalicylic acid): irreversible COX-1 and COX-2 inhibitor (acetylation). Low-dose (≤100 mg/day) selectively inhibits COX-1 in platelets → antiplatelet (cardioprotective). High-dose (≥650 mg) for anti-inflammatory/analgesic/antipyretic. Reye syndrome (aspirin + viral illness in children: acute encephalopathy + liver failure). Hypersensitivity: aspirin-exacerbated respiratory disease (AERD, Samter triad: asthma, nasal polyps, aspirin sensitivity). Desensitization available.

GI toxicity: dyspepsia, gastritis, peptic ulcer disease (gastric > duodenal), upper GI bleeding/perforation. Risk factors: age >65, h/o PUD/GI bleed, high dose, multiple NSAIDs, concurrent steroids/anticoagulants/antiplatelets, H. pylori infection. Prevention: use lowest effective dose/shortest duration; COX-2 selective or NSAID + PPI (misoprostol if PPI intolerance). H. pylori eradication before starting NSAIDs. Enteric coating does NOT reduce GI risk (systemic effect via COX-1). Renal effects: ↓renal blood flow → acute kidney injury (especially in CKD, CHF, cirrhosis, volume depletion, elderly), Na⁺ and water retention (→ edema, ↑BP), hyperkalemia (hyporeninemic hypoaldosteronism), papillary necrosis (chronic high-dose, especially phenacetin → withdrawn). NSAIDs blunt efficacy of ACEi, ARB, diuretics. CV risk: all NSAIDs (except low-dose aspirin) increase CV events (MI, stroke, HF exacerbation) → COX-2 selective > non-selective at high doses. Naproxen may have lowest CV risk. NSAIDs are contraindicated in CABG surgery. Other: hepatotoxicity (diclofenac highest risk), bronchospasm (aspirin-sensitive asthma), photosensitivity (piroxicam), aseptic meningitis (ibuprofen in SLE), reversible platelet dysfunction (avoid NSAIDs before surgery except aspirin). Toxicity management: activated charcoal if early; supportive care; no specific antidote. NSAID overdose rarely lethal alone (but can augment bleeding).

Mechanism: weak COX inhibition in periphery, but centrally inhibits COX-3 variant and activates descending serotonergic pathways (inhibits reuptake of endogenous cannabinoids). Analgesic and antipyretic, minimal anti-inflammatory effect. Preferred for mild-to-moderate pain when anti-inflammatory effect not needed. Safe at therapeutic doses (max 4 g/day in adults; 3 g/day in elderly, hepatically impaired, chronic alcohol use). Overdose: hepatic necrosis potentially fatal. Metabolism: 90% glucuronidation/sulfation (non-toxic), 5% CYP2E1/3A4 to NAPQI (toxic metabolite), which is detoxified by glutathione conjugation. In overdose, glutathione stores depleted → NAPQI causes hepatotoxicity. Toxic dose: >7.5–10 g (150 mg/kg) in adults; as low as 4–6 g/day with chronic alcohol, malnutrition, CYP induction. Phase I: N/V, malaise (0–24h). Phase II: RUQ pain, LFT elevations (24–48h). Phase III: hepatic necrosis, jaundice, coagulopathy, encephalopathy, renal failure (72–96h). Treatment: NAC (N-acetylcysteine) as early as possible, ideally <8h. PO NAC: 140 mg/kg loading, then 70 mg/kg q4h x 17 doses. IV NAC: 21-hour protocol (150 mg/kg in 200 mL D5W over 60 min, then 50 mg/kg in 500 mL over 4h, then 100 mg/kg in 1000 mL over 16h). NAC restores glutathione, conjugates NAPQI, provides substrate for sulfate conjugation. NAC side effects: NV, anaphylactoid reaction (IV, histamine-mediated, slow infusion). Rumack-Matthew nomogram: plots acetaminophen level vs time post-ingestion; treatment line starts at 150 µg/mL at 4h, down to 4.7 µg/mL at 24h. Only reliable for single acute ingestion. Liver transplant criteria: King’s College criteria (pH <7.3 after resuscitation, PT >100s, Cr >3.4 mg/dL, grade III/IV encephalopathy). Chronic therapeutic excess is harder to manage (no nomogram).

Full mu agonists: morphine (gold standard), hydromorphone (more potent, less pruritus), oxycodone (oral), hydrocodone, fentanyl (IV, transdermal), methadone (also NMDA antagonist). Partial mu agonists: buprenorphine (ceiling on respiratory depression, used for OUD and pain). Mixed agonist-antagonists: nalbuphine (κ agonist/μ antagonist), butorphanol, pentazocine → may precipitate withdrawal in opioid-dependent patients. Tramadol: weak mu agonist + SNRI (serotonin and norepinephrine reuptake inhibition). Ceiling on respiratory depression. Side effects: seizures (especially with SSRIs/SNRIs), serotonin syndrome. CYP2D6 metabolizes to O-desmethyltramadol (active). Tapentadol: mu agonist + NRI (norepinephrine reuptake inhibition). Less nausea/vomiting than tramadol. Opioid-induced hyperalgesia (OIH): increased pain sensitivity with chronic high-dose opioid use, especially with morphine and high doses. Management: rotate opioid (methadone or buprenorphine), taper, add non-opioid adjuvants. Opioid withdrawal: COWS score guides treatment. Buprenorphine induction: start when COWS ≥8 (objective signs of withdrawal). Symptomatic treatment: clonidine (autonomic), loperamide (diarrhea), dicyclomine (cramps), hydroxyzine (anxiety, nausea). Adjuvant analgesics: Gabapentinoids (gabapentin, pregabalin) for neuropathic pain: diabetic neuropathy, postherpetic neuralgia, fibromyalgia. Start low, titrate for effect. Side effects: sedation, dizziness, peripheral edema, weight gain, cognitive impairment. Pregabalin is more potent, linear PK (vs gabapentin non-linear absorption → limited at high doses). SNRI antidepressants (duloxetine, venlafaxine) for neuropathic pain, fibromyalgia, chronic MSK pain. TCAs (nortriptyline, amitriptyline, desipramine) for neuropathic pain, headache prophylaxis. Start at low doses (10–25 mg at bedtime). Anticholinergic side effects limit use (secondary amines less anticholinergic). Lidocaine 5% patch: for postherpetic neuralgia, localized neuropathic pain. Capsaicin 8% patch: high-concentration for postherpetic neuralgia; painful application (pre-treatment with lidocaine). NMDA antagonists (ketamine, methadone, dextromethorphan) for refractory pain, opioid-induced hyperalgesia. Ziconotide: N-type Ca²⁺ channel blocker, intrathecal only. Severe side effects (psychiatric, neurologic). Skeletal muscle relaxants: cyclobenzaprine (TCA-like, sedation), methocarbamol (CNS depression), baclofen (GABA-B agonist), tizanidine (α₂ agonist, _{monitor LFTs}).

Local anesthetics reversibly block voltage-gated Na⁺ channels, preventing depolarization and impulse conduction in sensory, motor, and autonomic fibers. Structure: lipophilic aromatic ring + intermediate chain + amine group. Esters (procaine, benzocaine, tetracaine, cocaine) → metabolized by plasma pseudocholinesterase, shorter duration, higher allergy risk (PABA metabolites). Amides (lidocaine, bupivacaine, ropivacaine, mepivacaine, prilocaine, articaine) → metabolized by hepatic CYP450, lower allergy risk. Lidocaine: most versatile, rapid onset, moderate duration. Uses: infiltration, peripheral nerve blocks, IV regional anesthesia (Bier block), epidural. Max dose: 4.5 mg/kg (7 mg/kg with epinephrine). Bupivacaine: long duration, more cardiotoxic (ventricular arrhythmias, cardiac arrest → difficult to resuscitate). Ropivacaine: less cardiotoxic, used for epidural labor analgesia. Prilocaine: methemoglobinemia risk (doses >600 mg). Cocaine: only local anesthetic with vasoconstrictor effects (blocks NE reuptake). Used in ENT procedures. Addictive potential. Toxicity: CNS first (perioral numbness, metallic taste, tinnitus, seizures, coma), then CVS (hypotension, arrhythmias, cardiac arrest). Treatment: stop injection, airway management, benzodiazepines for seizures, IV lipid emulsion (Intralipid) for cardiotoxicity (bupivacaine). Lipid emulsion acts as a lipid sink and reverses Na⁺ channel blockade. Epinephrine added to local anesthetics: vasoconstriction → prolongs effect, reduces systemic absorption, and acts as a marker for intravascular injection. Contraindicated in end-artery areas (digits, penis, tip of nose, ear).

Multimodal analgesia combines agents with different mechanisms to improve pain control and reduce opioid requirements (opioid-sparing effect). Components: acetaminophen (scheduled, not PRN), NSAIDs (COX-2 preferred if GI risk), gabapentinoids (pre-op load, post-op maintenance), local anesthetics (regional blocks, wound infiltration, lidocaine infusion), NMDA antagonists (low-dose ketamine infusion for refractory pain), alpha-2 agonists (dexmedetomidine, clonidine), and corticosteroids (dexamethasone as antiemetic and analgesic adjunct). ERAS (Enhanced Recovery After Surgery) protocols emphasize multimodal analgesia with regional anesthesia. Neuraxial analgesia (epidural) provides superior pain control for thoracic and major abdominal surgeries. Patient-controlled analgesia (PCA): IV opioids with demand-only or continuous + demand modes. PCA monitoring: respiratory rate, sedation level, pain scores. Acute pain service manages complex patients. Chronic pain management: multidisciplinary approach (medication management, physical therapy, cognitive behavioral therapy, interventional procedures). Opioid taper: reduce 10% of original dose per week, slower if withdrawal symptoms. Adjuvant medication optimization is key for successful taper. CDC guidelines for opioid prescribing: avoid >90 MME/day; avoid concurrent opioids + benzodiazepines; prescribe lowest effective dose for shortest duration (3–7 days for acute pain).

Beta-2 agonists: Short-acting (SABA: albuterol, levalbuterol) → rescue therapy, onset 5–15 min, duration 4–6h. Long-acting (LABA: salmeterol, formoterol, indacaterol, vilanterol) → maintenance. Formoterol: rapid onset + long duration (can be used for acute relief). LABA monotherapy in asthma: black box warning for increased asthma-related death (SMART trial). Always use with ICS. Indacaterol: once-daily ultra-LABA for COPD. Anticholinergics: Short-acting (SAMA: ipratropium bromide) → onset 15–30 min, duration 4–6h. Long-acting (LAMA: tiotropium, umeclidinium, glycopyrronium, aclidinium) → once-daily for COPD and moderate-severe asthma. Tiotropium: reduces COPD exacerbations, improves lung function. Side effects: dry mouth, bitter taste, glaucoma risk (avoid eye contact). Inhaled corticosteroids (ICS): fluticasone, budesonide, beclomethasone, mometasone, ciclesonide, flunisolide. First-line controller for persistent asthma. Side effects: oral candidiasis (rinse mouth), dysphonia, cough. High-dose ICS: growth suppression in children (lowest effective dose), adrenal suppression (rare), decreased bone density (long-term high-dose). Triple therapy (ICS/LAMA/LABA): fluticasone/umeclidinium/vilanterol, budesonide/glycopyrrolate/formoterol, for COPD with exacerbations despite dual therapy. Leukotriene receptor antagonists (montelukast, zafirlukast): block LTD₄ receptors. Montelukast: oral, once-daily, for mild persistent asthma, especially with allergic rhinitis or exercise-induced bronchoconstriction. FDA black box: neuropsychiatric events (suicidal thoughts, agitation, depression). Zileuton: 5-lipoxygenase inhibitor, inhibits leukotriene synthesis. Multiple daily dosing, CYP induction, hepatotoxicity (monitor LFTs). Mast cell stabilizers (cromolyn sodium, nedocromil): inhibit mast cell degranulation. No bronchodilator effect, require qid dosing. Rarely used. Methylxanthines (theophylline): non-selective PDE inhibitor, weak bronchodilator, anti-inflammatory. Narrow TI (10–20 µg/mL). Metabolism by CYP1A2 and CYP3A4. Side effects: NV, HA, insomnia, tremor, tachycardia, seizures (at toxic levels). Drug interactions: cimetidine, FQ, macrolides ↑levels; smoking, rifampin ↓levels. Rarely used now. Biologics for severe asthma: omalizumab (anti-IgE), mepolizumab, benralizumab (anti-IL-5), dupilumab (anti-IL-4Rα), tezepelumab (anti-TSLP). Reserved for severe eosinophilic or allergic asthma not controlled on ICS/LABA. Anti-IL-5 agents: reduce exacerbations, allow steroid tapering. Dupilumab: also for nasal polyps, atopic dermatitis, eosinophilic esophagitis. Tezepelumab: first biologic effective in non-eosinophilic severe asthma.

H1 antihistamines: First-generation (diphenhydramine, chlorpheniramine, hydroxyzine, promethazine, cyproheptadine) → cross BBB, sedating, anticholinergic (dry mouth, urinary retention, blurred vision). Second-generation (cetirizine, loratadine, fexofenadine, desloratadine, levocetirizine) → less sedating, fewer anticholinergic effects, qd dosing. Fexofenadine: most peripheral, least CNS penetration. Cetirizine: slightly more sedating. Uses: allergic rhinitis, urticaria, pruritus, motion sickness (1st gen). Cyproheptadine: appetite stimulant, serotonin antagonist (carcinoid syndrome, serotonin syndrome). Diphenhydramine: also used for EPS, sleep aid (tolerance develops). H2 antagonists (cimetidine, famotidine, nizatidine, ranitidine [withdrawn due to NDMA impurity]): block gastric H₂ receptors → ↓gastric acid secretion. Used for GERD, PUD, dyspepsia (less effective than PPIs). Cimetidine: potent CYP3A4, CYP2D6, CYP1A2 inhibitor → increases levels of warfarin, theophylline, phenytoin, many others. Famotidine: no significant CYP interactions. Nasal decongestants: oral (pseudoephedrine: α₁ agonist, ↓mucosal edema, risk of ↑BP, tachycardia, anxiety). Topical (oxymetazoline, phenylephrine): rapid relief, but rhinitis medicamentosa with >3 days of continuous use. Cromolyn nasal spray: mast cell stabilizer for allergic rhinitis prophylaxis. Intranasal corticosteroids (fluticasone, mometasone, budesonide, beclomethasone, triamcinolone): first-line for moderate-severe allergic rhinitis. Well tolerated; epistaxis and septal perforation with improper technique.

Proton pump inhibitors (PPIs: omeprazole, esomeprazole, lansoprazole, pantoprazole, rabeprazole, dexlansoprazole): irreversibly inhibit H⁺/K⁺-ATPase in gastric parietal cells. Prodrugs activated in acidic canaliculi. Most potent acid suppression (intragastric pH >4 for 15–18h). Uses: GERD, erosive esophagitis, PUD, H. pylori eradication (with abx), stress ulcer prophylaxis, Zollinger-Ellison syndrome, eosinophilic esophagitis (swallowed fluticasone or budesonide), upper GI bleeding (high-dose IV PPI after endoscopic hemostasis). Side effects: C. difficile infection (↑risk with long-term PPI), pneumonia risk (controversial), hypomagnesemia (with prolonged use), vitamin B12 deficiency (long-term), acute interstitial nephritis (rare), osteoporosis/fractures (controversial, weak association), gastric fundic gland polyps, drug interactions (omeprazole and clopidogrel → CYP2C19 inhibition, though clinical significance debated). Withdrawal: acid rebound hyper-secretion → taper if long-term. H2 receptor antagonists (famotidine, cimetidine): less potent than PPIs, faster onset (useful for on-demand therapy). Nocturnal acid breakthrough: PPI BID + H2RA at bedtime. Antacids (aluminum hydroxide, magnesium hydroxide, calcium carbonate): rapid symptom relief. Aluminum: constipation; Magnesium: diarrhea (combined in products like Mylanta, Maalox). Calcium carbonate: acid-neutralizing, but may cause acid rebound. Sucralfate: forms protective barrier over ulcer; requires acidic pH for activation. Constipation, drug binding (administer 2h apart from other drugs). Misoprostol: PGE₁ analog, ↑mucosal protection. Used for NSAID ulcer prevention. Diarrhea, cramps, and abortifacient (contraindicated in pregnancy). Bismuth subsalicylate: for H. pylori (quadruple therapy), traveler’s diarrhea. Black stools, tinnitus (salicylate).

Prokinetics: Metoclopramide: D₂ antagonist + 5-HT₄ agonist + 5-HT₃ antagonist (at high doses). ↑LES tone, accelerates gastric emptying. Uses: gastroparesis (diabetic), GERD, post-op dysmotility, antiemetic. Side effects: EPS (dystonia, akathisia, parkinsonism), tardive dyskinesia (FDA black box, risk with long-term use especially in elderly), hyperprolactinemia (galactorrhea). Limit use to <12 weeks. Domperidone: D₂ antagonist (does not cross BBB well → less EPS). QT prolongation, hyperprolactinemia. Not FDA approved in US. Erythromycin: motilin agonist → stimulates gastric emptying (used briefly for gastroparesis). Tolerance develops. Prucalopride: 5-HT₄ agonist for chronic idiopathic constipation. No EPS, no cardiac effects. Antiemetics: 5-HT₃ antagonists (ondansetron, granisetron, dolasetron, palonosetron): first-line for chemo-induced and post-op N/V. Ondansetron: QTc prolongation (>16 mg single dose). Constipation (especially with palonosetron). Neurokinin-1 (NK₁) antagonists (aprepitant, fosaprepitant, netupitant): block substance P. Used for delayed chemo-induced N/V (especially cisplatin). CYP3A4 inhibitor → reduce doses of dexamethasone and other CYP3A4 substrates. D₂ antagonists: prochlorperazine, promethazine, haloperidol, droperidol (black box QTc). Anticholinergics: scopolamine (transdermal) for motion sickness, post-op N/V. Cannabinoids: dronabinol, nabilone for refractory chemo-induced N/V. Adjuvant antiemetics: dexamethasone (potent antiemetic, especially in combination), benzodiazepines (for anticipatory N/V). Aprepitant: 125 mg PO day 1, 80 mg day 2–3. Antiemetic regimens by emetic risk: high (cisplatin, AC) → 4-drug (NK₁RA + 5-HT₃RA + dexamethasone + olanzapine); moderate → 3-drug; low → dexamethasone +/- 5-HT₃RA.

Laxatives: Bulk-forming (psyllium, methylcellulose, polycarbophil): slow-acting, natural, minimal side effects. First-line for chronic constipation. Osmotic: Polyethylene glycol (PEG 3350, MiraLax): gentle, non-absorbed, draws water into colon. Good for chronic constipation and colonoscopy prep. Lactulose: synthetic disaccharide, also lowers ammonia (hepatic encephalopathy). Gas, bloating. Magnesium citrate/hydroxide: rapid acting, hypermagnesemia risk with renal failure. Stimulant (bisacodyl, senna): stimulate colonic peristalsis. Cramping, melanosis coli (senna, reversible). Short-term use only. Surfactant (docusate): stool softener, minimal efficacy (weak evidence). Chloride channel activators (lubiprostone), guanylate cyclase-C agonists (linaclotide, plecanatide): ↑intestinal fluid secretion. For chronic idiopathic constipation and IBS-C. Nausea, diarrhea (linaclotide). Opioid-induced constipation: peripherally acting mu opioid antagonists (PAMORAs) — methylnaltrexone, naloxegol, naldemedine. Do not cross BBB → reverse GI opioid effects without affecting CNS analgesia. Antidiarrheals: Loperamide: peripheral mu agonist, slows GI transit. Does not cross BBB significantly. Safe at standard doses (2–8 mg/day). High doses: QTc prolongation, cardiac toxicity (abuse potential). Bismuth subsalicylate: for traveler’s diarrhea. Octreotide: somatostatin analog, for severe secretory diarrhea (carcinoid, VIPoma, dumping syndrome). IBD therapy: 5-ASA compounds (mesalamine, balsalazide, olsalazine, sulfasalazine): first-line for mild-moderate UC. Sulfasalazine: sulfapyridine moiety → side effects (NV, hemolysis in G6PD deficiency, male infertility, folate deficiency). Mesalamine: better tolerated. Immunomodulators: azathioprine, 6-MP, methotrexate for steroid-sparing, maintenance. TPMT testing before azathioprine. Biologics: anti-TNF (infliximab, adalimumab, certolizumab, golimumab) for moderate-severe CD and UC. Anti-integrin (vedolizumab: gut-selective), anti-IL-12/23 (ustekinumab), JAK inhibitors (tofacitinib, upadacitinib). Anti-TNF: risk of reactivation TB, HBV, fungal infections, infusion reactions. Tofacitinib: JAK inhibitor, oral, for UC. Black box: thrombosis, malignancy, MACE.

GERD management: algorithm → lifestyle modification (elevate head of bed, avoid trigger foods, weight loss, avoid late meals). Mild/intermittent: antacids, H2RA on demand. Moderate/severe or erosive: PPI once daily (prefer dexlansoprazole, esomeprazole, or rabeprazole for faster onset). Non-erosive GERD: 4–8 week PPI trial, then step down regimen. Refractory GERD: double PPI, check compliance/timing (30 min before breakfast), add H2RA at bedtime for nocturnal acid breakthrough, consider pH impedance testing and fundoplication. PPI therapy is safe in pregnancy if needed (omeprazole, lansoprazole preferred). Functional dyspepsia: PPI trial, prokinetic, low-dose antidepressant. IBS treatment: IBS-C: linaclotide, lubiprostone, plecanatide, psyllium, PEG. IBS-D: loperamide, rifaximin (non-absorbed antibiotic), eluxadoline (mixed mu/kappa agonist), alosetron (5-HT₃ antagonist, restricted for severe IBS-D in women). IBS with mixed stool pattern: low-FODMAP diet, gut-directed hypnotherapy, tricyclic antidepressants (low dose). Tricyclics for IBS: reduce visceral hypersensitivity, slow transit (IBS-D) or accelerate transit (nortriptyline at low doses?). SSRIs for IBS with comorbid anxiety/depression. Cascara sagrada and aloe vera are not recommended. H. pylori eradication: triple therapy (PPI + amoxicillin + clarithromycin) for 14 days (in areas with <15% clarithromycin resistance). Quadruple therapy (PPI + bismuth + metronidazole + tetracycline) for 14 days if resistance high or previous failure. Test of cure: stool antigen or urea breath test at least 4 weeks after completion.

Initial assessment: stabilize ABCs (airway, breathing, circulation), check glucose, treat seizures and hypotension. Decontamination: activated charcoal (1 g/kg PO) if within 1–2h of ingestion and protected airway (no risk of aspiration). Gastric lavage: only if life-threatening ingestion and within 1h (rarely indicated). Whole bowel irrigation: for sustained-release, iron, lithium, or body packers. Enhanced elimination: multiple-dose activated charcoal (MDAC) for carbamazepine, dapsone, phenobarbital, quinine, theophylline → interrupts enteroenteric recirculation. Urine alkalinization: NaHCO₃ infusion (target urine pH 7.5–8) for salicylates, phenobarbital, MTX (weak acids). Hemodialysis: for severe methanol, ethylene glycol, lithium, metformin, salicylate, valproate, phenobarbital, theophylline toxicity. Poison center consultation recommended for all significant exposures. Specific antidotes (summary): NAC (acetaminophen), naloxone (opioids), flumazenil (BZDs), atropine + pralidoxime (organophosphates), NaHCO₃ (TCA, wide QRS), digoxin-specific Fab (digoxin), deferoxamine (iron), octreotide (sulfonylurea overdose), glucagon (beta-blocker, CCB overdose), high-dose insulin + glucose (CCB overdose), methylene blue (methemoglobinemia), ethanol or fomepizole (methanol, ethylene glycol), vitamin K + FFP/PCC (warfarin), protamine (heparin), idarucizumab (dabigatran), andexanet alfa (Xa inhibitors), pyridoxine (isoniazid overdose), physostigmine (anticholinergic syndrome), dimercaprol/BAL and EDTA (heavy metals).

Most common pharmaceutical overdose in the US and UK. Toxic dose: >7.5–10 g or 150 mg/kg in adults; lower thresholds in chronic alcoholics, malnutrition, liver disease, CYP inducers (phenytoin, rifampin, carbamazepine, isoniazid). Phases: Phase I (0–24h): anorexia, nausea, vomiting, malaise, pallor, diaphoresis. LFTs typically normal. Phase II (24–72h): RUQ pain, hepatomegaly, bilirubin and transaminase elevations, increased INR, oliguria. Phase III (72–96h): hepatic necrosis, jaundice, coagulopathy, encephalopathy, renal failure, hypoglycemia, metabolic acidosis, cerebral edema. Phase IV (4–14 days): recovery (if survived) over days to weeks; liver regeneration possible. Laboratory: serum acetaminophen level (Rumack-Matthew nomogram): plot level vs time post-ingestion. Treatment line connects 150 µg/mL at 4h to 4.7 µg/mL at 24h (semi-log graph). Megadoses >30 g can exceed the nomogram line (level-dependent). NAC protocol: PO (140 mg/kg load, then 70 mg/kg q4h x 17 doses) or IV (21-hour: 150 mg/kg over 1h, 50 mg/kg over 4h, 100 mg/kg over 16h). NAC is most effective when started <8h; efficacy declines after 8h but still beneficial up to 24–48h. NAC for chronic overdose: 3-bag IV protocol, base treatment on LFTs and level, not nomogram (unreliable). Liver transplantation criteria (King’s College): pH <7.30 after resuscitation, or PT >100 sec (INR >6.5) + Cr >3.4 mg/dL + grade III/IV encephalopathy. Prognostic markers: arterial lactate >3 mmol/L post-resuscitation and >2.5h after overdose is predictive of poor outcome.

Clinical triad: miosis (pinpoint pupils), respiratory depression (≤8–10 breaths/min), CNS depression (coma). Exceptions: meperidine (may cause mydriasis), mixed overdoses (e.g., opioid + sympathomimetic). Naloxone (Narcan): competitive mu-opioid receptor antagonist. Onset IV: 1–2 min; IM/SC: 2–5 min; IN: 3–5 min. Half-life ~30–90 min (shorter than most opioids). Dosing: initial 0.04–0.4 mg IV, titrate to respiratory rate >12/min. For opioid-naive patients with respiratory arrest: 2 mg IV/IM/IN. Repeat q2–3 min PRN. Reversal of full mu agonists requires repeated doses; consider infusion (2/3 of dose that worked as hourly infusion). Naloxone infusion: 0.25–2 mg/h titrated. Caution: abrupt reversal can precipitate acute opioid withdrawal (agitation, NV, pulmonary edema, autonomic instability). Pulmonary edema (naloxone-induced): non-cardiogenic, treat with supportive care, PEEP. Supervised observation period: 4–6h for heroin/short-acting opioids; 12–24h for methadone/buprenorphine/long-acting formulations. Overdose prevention: prescribe naloxone to all patients on ≥50 MME/day or with respiratory risk factors (COPD, OSA). Buprenorphine overdose: respiratory depression is partial (ceiling effect) but prolonged; high doses of naloxone may be needed. Buprenorphine has high receptor affinity → displaces naloxone slowly. Methadone overdose: accumulation over days, QTc prolongation risk.

BZD overdose: CNS depression, respiratory depression (less than opioids), ataxia, dizziness, slurred speech. Typically benign in BZD-only overdose. Flumazenil: competitive BZD antagonist. Indications: reversal of excessive sedation from BZDs during procedures (diagnostic), GABA reversal in anesthesia. Contraindications: chronic BZD use (precipitates withdrawal, seizures), mixed overdose with TCA or pro-convulsants (risk of PVCs, VT, status epilepticus), seizure disorder. Dose: 0.2 mg IV over 30 sec, repeat 0.3–0.5 mg q1min, max 3 mg. Half-life ~1h, re-sedation common (especially with long-acting BZDs) → repeat dosing or infusion. Risk of seizures: higher with flumazenil than previously thought; use restricted to diagnostic reversals and pediatric unintentional ingestion. Supportive care: airway management, mechanical ventilation if needed, IV fluids. Activated charcoal within 1–2h if protected airway. Flumazenil does NOT reverse effects of non-BZD hypnotics (zolpidem, zaleplon), alcohol, barbiturates, or general anesthetics. Physostigmine: can reverse anticholinergic delirium but not recommended for BZD reversal (increases seizure risk). Z-drug overdose: similar to BZD overdose, flumazenil may be partially effective. Barbiturate overdose: more dangerous than BZD overdose — severe respiratory depression, hypotension, hypothermia, skin bullae. Supportive care is mainstay; hemodialysis for phenobarbital. Urine alkalinization enhances phenobarbital elimination.

Anticholinergic toxidrome: hyperthermia, flushed dry skin, dilated pupils (mydriasis), blurred vision, dry mucous membranes, urinary retention, ileus, seizures, delirium, hallucinations, tachycardia, hypertension. “Red as a beet, dry as a bone, blind as a bat, mad as a hatter, hot as a hare, full as a flask.” Causes: antihistamines (diphenhydramine), TCAs, atropine, scopolamine, benztropine, jimsonweed (Datura). Treatment: physostigmine (0.5–2 mg IV slowly). Cholinergic toxidrome: SLUDGE (salivation, lacrimation, urination, defecation, GI upset, emesis), bronchial secretions, wheezing, muscle fasciculations, weakness, bradycardia, miosis. Causes: organophosphates, carbamate insecticides, nerve agents (sarin, VX), pilocarpine, donepezil, neostigmine, nicotine (mushroom toxins). Treatment: atropine (to dry secretions) + pralidoxime (organophosphates only). Sympathomimetic toxidrome: mydriasis, diaphoresis, hypertension, tachycardia, hyperthermia, agitation, seizures, psychosis. “Mydriasis, sweating, psychosis, hypertension, tachycardia, hyperthermia.” Causes: cocaine, amphetamines, methamphetamine, MDMA (ecstasy), theophylline, caffeine, pseudoephedrine, phencyclidine (PCP). Treatment: benzodiazepines (sedation, control BP/HR), cooling for hyperthermia, avoid beta-blockers (unopposed α stimulation). Opioid/sedative toxidrome: miosis, respiratory depression, CNS depression, bradycardia, hypotension, hypothermia. Causes: opioids, BZDs, barbiturates, clonidine, alcohol, GHB. Treatment: naloxone, flumazenil (with caution), supportive care, mechanical ventilation. Serotonin syndrome: clonus, hyperreflexia, tremor, agitation, hyperthermia, autonomic instability. Causes: SSRI + MAOI, SSRI + linezolid, MDMA, dextromethorphan, tramadol + SSRI. Treatment: cyproheptadine, supportive care, cooling. Neuroleptic malignant syndrome (NMS): rigidity, bradyreflexia, hyperthermia, autonomic instability, ↑CK. Treatment: dantrolene, bromocriptine, supportive care.

Carbon monoxide (CO) poisoning: CO binds hemoglobin with 200–250x affinity of O₂ → carboxyhemoglobin → tissue hypoxia. Non-cardiac pulmonary edema, metabolic acidosis, cherry-red skin (unreliable), headache, confusion, syncope, seizures, coma. Treatment: 100% O₂ via non-rebreather mask (half-life COHb ~90 min vs 4–6h on room air). Hyperbaric oxygen (HBO): ↓half-life to ~20 min, ↓risk of delayed neurologic sequelae (cognitive deficits, choreoathetosis, Parkinsonism). Indications: COHb >25%, loss of consciousness, neurologic symptoms, metabolic acidosis, pregnancy (fetal COHb >15%). Cyanide poisoning: from smoke inhalation (closed-space fire), nitroprusside, amygdalin. Prevents cytochrome oxidase → cellular asphyxia. Lactic acidosis, bright red venous blood. Treatment: hydroxocobalamin (5 g IV, turns urine/ skin red) or amyl nitrite + sodium nitrite + sodium thiosulfate (Lilly kit). Methemoglobinemia: can be acquired (prilocaine, dapsone, nitrites, aniline dyes). Dyspnea, chocolate-brown blood, pulse oximetry reads ~85% despite adequate PO₂. Treatment: methylene blue 1–2 mg/kg IV (contraindicated in G6PD deficiency → use exchange transfusion). Iron toxicity: children and pregnant women. Phases: GI (N/V/D, GI bleed), latent (apparent improvement, 6–24h), shock/metabolic acidosis (24–48h), hepatic necrosis (2–5 days), late gut strictures (weeks). Abdominal X-ray: radiopaque tablets. TIBC > serum iron excludes toxicity. Treatment: deferoxamine (IV infusion, chelates iron, urine turns “vin rosé”). Poison control: 1-800-222-1222. Alcohol withdrawal: CIWA-Ar protocol, benzodiazepines (diazepam, chlordiazepoxide, lorazepam IV for severe), thiamine (prevent Wernicke encephalopathy), folate, multivitamin. For refractory withdrawal: phenobarbital, propofol, dexmedetomidine.