Pharmacology
Drug mechanisms, pharmacokinetics, pharmacodynamics, autonomic pharmacology, antimicrobials, cardiovascular drugs, CNS agents, endocrine pharmacology, chemotherapy, and every drug class, receptor, and clinical application across the full scope of pharmacology.
01 Overview & Significance
Pharmacology is the study of how drugs interact with biological systems to produce therapeutic effects, adverse reactions, and toxicities. It is the bridge between basic science and clinical medicine — every prescription, every dose adjustment, every adverse drug reaction, and every drug interaction traces back to pharmacologic principles. Mastery of pharmacology is essential for safe prescribing, rational therapeutics, and success on USMLE Step 1 (where pharmacology accounts for 15–22% of questions).
Why This Matters
Pharmacology integrates biochemistry, physiology, and pathology into the single most clinically actionable discipline. A physician who understands drug mechanisms can predict side effects, anticipate interactions, adjust for special populations, and make evidence-based therapeutic decisions at the bedside.
Branches of Pharmacology
| Branch | Focus |
|---|---|
| Pharmacokinetics | What the body does to the drug (ADME: absorption, distribution, metabolism, excretion) |
| Pharmacodynamics | What the drug does to the body (receptor interactions, dose–response) |
| Pharmacogenomics | Genetic variation affecting drug response (e.g., CYP2D6 polymorphisms) |
| Pharmacovigilance | Post-marketing safety surveillance and adverse event monitoring |
| Toxicology | Adverse effects, poisoning, antidotes, and drug overdose management |
| Clinical Pharmacology | Rational drug therapy in patients, therapeutic drug monitoring |
Drug Development & Regulation
Drug development proceeds through preclinical testing (in vitro and animal studies), then four clinical trial phases: Phase I (safety, pharmacokinetics in healthy volunteers; ~20–80 subjects), Phase II (efficacy and dosing in patients with the target disease; ~100–300 subjects), Phase III (large-scale randomized controlled trials confirming efficacy and monitoring adverse effects; ~1,000–3,000 subjects), and Phase IV (post-marketing surveillance after FDA approval). The entire process typically takes 10–15 years and costs over $1 billion.
Phase I trials determine the maximum tolerated dose and pharmacokinetic profile. Phase III failures are the most costly because of the large sample sizes involved. Phase IV surveillance detects rare adverse effects that Phase III was underpowered to identify.
Drug Nomenclature & Naming Conventions
Drug names follow systematic conventions that encode class information. Understanding common stems (suffixes) allows rapid identification of drug mechanism:
| Stem / Suffix | Drug Class | Examples |
|---|---|---|
| -olol | β-Adrenergic blockers | Metoprolol, atenolol, propranolol |
| -pril | ACE inhibitors | Lisinopril, enalapril, ramipril |
| -sartan | Angiotensin II receptor blockers | Losartan, valsartan, irbesartan |
| -dipine | Dihydropyridine CCBs | Amlodipine, nifedipine |
| -statin | HMG-CoA reductase inhibitors | Atorvastatin, rosuvastatin |
| -azole | Antifungal azoles | Fluconazole, ketoconazole |
| -cillin | Penicillin antibiotics | Amoxicillin, ampicillin |
| -mycin / -micin | Aminoglycosides / macrolides | Gentamicin, azithromycin |
| -mab | Monoclonal antibodies | Rituximab, trastuzumab, infliximab |
| -nib / -tinib | Tyrosine kinase inhibitors | Imatinib, erlotinib, sunitinib |
| -gliptin | DPP-4 inhibitors | Sitagliptin, saxagliptin |
| -gliflozin | SGLT2 inhibitors | Empagliflozin, dapagliflozin |
| -glutide | GLP-1 receptor agonists | Semaglutide, liraglutide |
| -prazole | Proton pump inhibitors | Omeprazole, pantoprazole |
| -tidine | H2 receptor antagonists | Ranitidine, famotidine |
| -setron | 5-HT3 antagonists (antiemetics) | Ondansetron, granisetron |
| -triptan | 5-HT1B/1D agonists (migraines) | Sumatriptan, rizatriptan |
Recognizing drug suffixes is a rapid shortcut on board exams. If you see an unfamiliar drug ending in "-olol," you can immediately reason about β-blocker side effects (bradycardia, bronchospasm, fatigue) and contraindications. This often gives the answer without needing to memorize the specific drug.
02 Core Principles & Drug–Receptor Theory
Drug–Receptor Interactions
Most drugs produce effects by binding to specific receptors — proteins (enzymes, ion channels, G-protein coupled receptors, nuclear receptors, or transporters) that transduce the drug signal into a cellular response. The binding follows the law of mass action: Drug + Receptor ↔ Drug–Receptor Complex → Effect. The affinity of a drug for its receptor determines how tightly it binds (quantified by Kd, the dissociation constant — lower Kd = higher affinity). The intrinsic activity (efficacy) determines the magnitude of response once bound.
Agonists, Antagonists & Partial Agonists
| Type | Affinity | Efficacy | Example |
|---|---|---|---|
| Full agonist | Yes | Maximal (Emax) | Isoproterenol (β-adrenergic), morphine (μ-opioid) |
| Partial agonist | Yes | Submaximal | Buprenorphine (μ-opioid), pindolol (β-blocker with ISA) |
| Competitive antagonist | Yes | Zero (blocks agonist) | Naloxone (μ-opioid), atropine (muscarinic) |
| Non-competitive antagonist | Yes (allosteric or irreversible) | Zero (reduces Emax) | Phenoxybenzamine (α-adrenergic) |
| Inverse agonist | Yes | Negative (reduces basal activity) | Some benzodiazepine analogs, certain antihistamines |
A partial agonist in the presence of a full agonist acts as a net antagonist (it competes for receptors but produces less effect). This is why buprenorphine can precipitate withdrawal in a patient who is on a full μ-agonist such as heroin.
Receptor Types
| Receptor Type | Mechanism | Speed | Examples |
|---|---|---|---|
| Ligand-gated ion channel | Ion flux through pore | Milliseconds | Nicotinic ACh, GABAA, NMDA |
| G-protein coupled (GPCR) | Second messengers (cAMP, IP3, DAG) | Seconds | Muscarinic, adrenergic, opioid, dopamine |
| Enzyme-linked (receptor tyrosine kinase) | Phosphorylation cascades | Minutes–hours | Insulin, EGF, PDGF receptors |
| Intracellular / nuclear | Gene transcription modification | Hours–days | Steroid, thyroid, vitamin D receptors |
G-Protein Signaling Pathways
GPCRs signal through heterotrimeric G proteins with distinct α-subunits:
| G-Protein | Effect | Coupled Receptors |
|---|---|---|
| Gs | Stimulates adenylyl cyclase → ↑cAMP → PKA activation | β1, β2, D1, H2, V2 |
| Gi | Inhibits adenylyl cyclase → ↓cAMP | α2, M2, D2, GABAB, μ/δ-opioid |
| Gq | Activates phospholipase C → ↑IP3 + DAG → Ca2+ release + PKC | α1, M1, M3, H1, V1, AT1 |
High-Yield Mnemonic
Gs = "Stimulatory" → ↑cAMP. Gi = "Inhibitory" → ↓cAMP. Gq = "qPLC" → IP3/DAG/Ca2+. Remember: HAV1 M1AM3 = H1, α1, V1, M1, AT1, M3 couple to Gq.
Therapeutic Index & Safety
The therapeutic index (TI) = TD50 / ED50 (or LD50 / ED50 in animal studies), where TD50 is the dose producing toxicity in 50% and ED50 is the effective dose in 50% of the population. A narrow TI means the toxic dose is close to the therapeutic dose, requiring careful monitoring. Drugs with narrow TI include warfarin, lithium, digoxin, theophylline, aminoglycosides, phenytoin, and cyclosporine.
The therapeutic index is the single most important safety parameter in pharmacology. Drugs with a narrow TI require therapeutic drug monitoring (TDM). Always know which drugs have a narrow TI — this is heavily tested.
03 Key Terminology & Abbreviations
| Term / Abbreviation | Definition |
|---|---|
| ADME | Absorption, Distribution, Metabolism, Excretion |
| Vd | Volume of distribution — theoretical volume needed to contain total drug at plasma concentration |
| t1/2 | Half-life — time for plasma concentration to decrease by 50% |
| Css | Steady-state concentration — reached after ~4–5 half-lives |
| CL | Clearance — volume of plasma cleared of drug per unit time |
| F | Bioavailability — fraction of administered dose reaching systemic circulation |
| EC50 | Concentration producing 50% of maximal effect |
| Emax | Maximal effect achievable by a drug |
| Kd | Dissociation constant — concentration at which 50% of receptors are occupied |
| pKa | pH at which 50% of drug is ionized and 50% is non-ionized |
| TDM | Therapeutic drug monitoring |
| TI | Therapeutic index (TD50 / ED50) |
| AUC | Area under the curve — total drug exposure over time |
| P-gp | P-glycoprotein — efflux transporter limiting drug absorption/distribution |
| CYP | Cytochrome P450 — family of drug-metabolizing enzymes |
| ISA | Intrinsic sympathomimetic activity |
| NNT / NNH | Number needed to treat / Number needed to harm |
| MIC | Minimum inhibitory concentration (antimicrobials) |
04 Absorption & Bioavailability
Absorption is the movement of drug from the site of administration into the systemic circulation. The rate and extent of absorption determine the bioavailability (F) — defined as the fraction of administered drug that reaches the systemic circulation in unchanged form. IV administration has F = 1.0 (100%) by definition.
Factors Affecting Absorption
| Factor | Effect on Absorption | Clinical Example |
|---|---|---|
| Route of administration | IV > IM > SC > PO (general order of speed) | IV morphine onset ~5 min vs PO ~30 min |
| Drug lipophilicity | More lipophilic = better membrane penetration | Diazepam (lipophilic) absorbs rapidly PO |
| Ionization state (pKa) | Non-ionized (uncharged) form crosses membranes | Aspirin (weak acid, pKa 3.5) absorbed in acidic stomach |
| Gastric pH | Affects ionization of weak acids/bases | PPIs reduce ketoconazole absorption (needs acid) |
| Gastric emptying | Faster emptying = faster absorption for most drugs | Metoclopramide accelerates, opioids slow emptying |
| First-pass metabolism | Hepatic extraction reduces bioavailability | Nitroglycerin F <5% PO (use sublingual) |
| P-glycoprotein efflux | Pumps drug back into gut lumen | Digoxin, cyclosporine subject to P-gp efflux |
Ion Trapping
Weak acids are non-ionized in acidic environments (stomach) and ionized in basic environments (blood). Weak bases are the opposite. Non-ionized drug crosses membranes; ionized drug is "trapped." This principle explains why aspirin overdose is treated with urinary alkalinization (traps ionized salicylate in urine) and why weak acid drugs are absorbed well in the stomach.
First-Pass Effect
After oral absorption, drugs enter the portal circulation and pass through the liver before reaching systemic circulation. Drugs with high hepatic extraction ratios undergo extensive first-pass metabolism, dramatically reducing oral bioavailability. Examples: nitroglycerin (F <5%), morphine (F ~25%), propranolol (F ~25%), lidocaine (F ~35%). Routes that bypass first-pass: sublingual, rectal (partially), transdermal, inhalational, IV.
Bioavailability = (AUCoral / AUCIV) × 100%. For the same drug, if the oral dose must be much higher than the IV dose, suspect high first-pass metabolism.
05 Distribution & Protein Binding
Once absorbed, drugs distribute from plasma into tissues. The volume of distribution (Vd) = Amount of drug in body / Plasma drug concentration. Vd is a theoretical volume: a large Vd means the drug distributes extensively into tissues (is not primarily in plasma); a small Vd means it stays in the vascular compartment.
| Vd Range | Interpretation | Examples |
|---|---|---|
| <5 L (~plasma volume) | Confined to plasma, high protein binding | Warfarin (Vd ~8 L), heparin |
| 5–15 L (~ECF) | Distributes into extracellular fluid | Aminoglycosides (Vd ~15 L) |
| 15–40 L (~TBW) | Distributes into total body water | Ethanol, phenytoin |
| >40 L | Extensive tissue binding/sequestration | Chloroquine (Vd ~13,000 L), digoxin (~500 L) |
Protein Binding
Drugs bind to plasma proteins, primarily albumin (acidic drugs: warfarin, phenytoin, salicylates) and α1-acid glycoprotein (basic drugs: lidocaine, propranolol). Only the free (unbound) fraction is pharmacologically active, can cross membranes, and can be metabolized/excreted. Conditions that decrease albumin (hepatic failure, nephrotic syndrome, malnutrition) increase the free fraction of highly protein-bound drugs, potentially causing toxicity.
Phenytoin is ~90% protein-bound. In hypoalbuminemia, the free fraction increases. Use the Sheiner-Tozer correction: Adjusted phenytoin = Measured phenytoin / (0.2 × albumin + 0.1). This is a classic board question.
Blood-Brain Barrier (BBB)
The BBB consists of tight junctions between brain capillary endothelial cells, limiting passage to small, lipophilic, non-ionized molecules. Drugs that cross the BBB well: diazepam, thiopental, fentanyl. Drugs that do not cross well: penicillin G (unless meninges are inflamed), aminoglycosides, first-generation antihistamines cross (causing sedation) while second-generation (e.g., loratadine) are P-gp substrates excluded from the CNS.
06 Metabolism & CYP450 System
Drug metabolism (biotransformation) converts lipophilic drugs into more hydrophilic metabolites for renal excretion. Metabolism occurs primarily in the liver and is classified into two phases:
Phase I vs Phase II Reactions
| Feature | Phase I | Phase II |
|---|---|---|
| Type | Oxidation, reduction, hydrolysis | Conjugation (glucuronidation, sulfation, acetylation, methylation, glutathione) |
| Primary enzymes | Cytochrome P450 (CYP) family | Transferases (UGT, SULT, NAT, GST) |
| Effect on drug | Adds or exposes a functional group (-OH, -NH2, -SH) | Attaches a polar conjugate to the functional group |
| Metabolite activity | May be active, inactive, or toxic | Usually inactive (more water-soluble) |
| Effect of aging | Decreased significantly in elderly | Relatively preserved in elderly |
Major CYP450 Enzymes
| Enzyme | % Drug Metabolism | Key Substrates | Inducers | Inhibitors |
|---|---|---|---|---|
| CYP3A4 | ~50% | Statins (atorvastatin, simvastatin), cyclosporine, tacrolimus, nifedipine, midazolam, erythromycin | Rifampin, carbamazepine, phenytoin, St. John's wort | Ketoconazole, itraconazole, erythromycin, clarithromycin, ritonavir, grapefruit juice |
| CYP2D6 | ~25% | Codeine, tramadol, tamoxifen, metoprolol, fluoxetine, haloperidol | Not significantly inducible | Fluoxetine, paroxetine, quinidine, bupropion |
| CYP2C19 | ~10% | Omeprazole, clopidogrel, diazepam, phenytoin | Rifampin | Omeprazole, fluconazole, fluvoxamine |
| CYP2C9 | ~10% | Warfarin, phenytoin, NSAIDs, glipizide, losartan | Rifampin | Fluconazole, amiodarone, metronidazole |
| CYP1A2 | ~5% | Theophylline, caffeine, warfarin (minor), clozapine | Smoking, charbroiled meat, omeprazole | Ciprofloxacin, fluvoxamine, cimetidine |
CYP Inducers — Classic Mnemonic
"Queen Barb Takes Phen-Phen and Refuses Grisly Carbs Chronically" — Quinidine (minor), Barbiturates, St. John's wort (take), Phenytoin, Phenobarbital, Rifampin, Griseofulvin, Carbamazepine, Chronic alcohol. Inducers increase CYP activity → faster drug metabolism → decreased drug levels.
Pharmacogenomics & CYP Polymorphisms
CYP2D6 exhibits clinically significant genetic polymorphism: poor metabolizers (~7% Caucasians) cannot convert codeine to morphine (codeine is ineffective) but accumulate parent drugs of other substrates; ultra-rapid metabolizers (~2–10%) convert codeine to morphine excessively, risking respiratory depression. CYP2C19 poor metabolizers (~2–5% Caucasians, ~15–20% Asians) cannot activate clopidogrel (a prodrug), leading to treatment failure. FDA now recommends CYP2C19 genotyping before clopidogrel therapy.
Codeine, tramadol, and clopidogrel are prodrugs requiring CYP activation. Poor metabolizers get no benefit; ultra-rapid metabolizers of codeine may die from respiratory depression (especially neonates via breast milk). This is a board favorite.
07 Excretion & Renal Dosing
Renal excretion is the primary route of drug elimination. It involves three processes: glomerular filtration (free, unbound drug filtered at the glomerulus), tubular secretion (active transport of drug from peritubular capillaries into the tubular lumen — the most efficient mechanism), and tubular reabsorption (passive reabsorption of lipophilic, non-ionized drug from tubular lumen back into blood).
Key Renal Excretion Concepts
| Concept | Detail | Clinical Relevance |
|---|---|---|
| Clearance (CL) | CL = (rate of elimination) / (plasma concentration); CL = Vd × ke | Determines maintenance dose: Dose rate = CL × Css |
| Half-life (t1/2) | t1/2 = 0.693 × Vd / CL | Steady state reached at ~4–5 half-lives; loading dose bypasses wait |
| Loading dose | LD = (Vd × Ctarget) / F | Achieves therapeutic level immediately (independent of clearance) |
| Maintenance dose | MD = (CL × Css) / F | Must be adjusted for renal impairment (reduced CL) |
| Zero-order kinetics | Constant amount eliminated per unit time (enzymes saturated) | Phenytoin, ethanol, aspirin (at toxic doses) |
| First-order kinetics | Constant fraction eliminated per unit time | Most drugs at therapeutic doses |
Zero-Order Drugs
Mnemonic: "PEA" — Phenytoin, Ethanol, Aspirin (at high doses). These drugs exhibit saturation kinetics: small dose increases can cause disproportionate rises in plasma concentration, leading to toxicity. Always titrate carefully.
Renal Dose Adjustment
In renal impairment, drugs primarily excreted by the kidneys accumulate. The Cockcroft-Gault equation estimates CrCl: CrCl = [(140 − age) × weight (kg)] / [72 × serum Cr] (× 0.85 for females). Drugs requiring dose reduction in renal failure include: aminoglycosides, vancomycin, lithium, digoxin, metformin, enoxaparin, gabapentin, and acyclovir.
Other Routes of Excretion
Biliary excretion: Large, polar molecules (molecular weight >300 Da) may be excreted in bile → enterohepatic recirculation can prolong drug half-life (e.g., estrogens, digitoxin, morphine glucuronide). Pulmonary excretion: Volatile anesthetics eliminated via exhalation. Breast milk: Lipophilic, non-ionized drugs cross into breast milk (basic drugs concentrate because milk is slightly acidic, pH ~7.0).
08 Pharmacodynamics & Dose–Response
Dose–Response Relationships
The graded dose–response curve plots drug concentration (x-axis, log scale) vs response magnitude (y-axis) for a single subject. Key parameters: EC50 (concentration at 50% Emax — measure of potency), Emax (maximal achievable effect — measure of efficacy). Potency compares EC50 values between drugs: a lower EC50 means higher potency (left-shifted curve). Efficacy compares Emax values: a higher Emax means greater efficacy.
Quantal Dose–Response
The quantal dose–response curve plots dose vs cumulative % of population responding (all-or-none response, e.g., sleep/no sleep). This yields ED50 (dose effective in 50% of population), TD50 (toxic dose in 50%), and LD50 (lethal dose in 50%). The therapeutic index TI = LD50 / ED50. A safer measure is the therapeutic window = TD1 / ED99.
Competitive vs Non-Competitive Antagonism
| Feature | Competitive Antagonism | Non-Competitive Antagonism |
|---|---|---|
| Binding site | Same site as agonist (orthosteric) | Different site (allosteric) or irreversible |
| Overcome by increasing agonist? | Yes (surmountable) | No (insurmountable) |
| Effect on dose–response curve | Right-shift (increased EC50), Emax unchanged | Decreased Emax, EC50 may be unchanged |
| Example | Naloxone vs morphine, atropine vs ACh | Phenoxybenzamine vs norepinephrine |
On a dose–response curve: potency is position (left = more potent), efficacy is height (taller = more efficacious). A competitive antagonist shifts the curve right without changing the max. A non-competitive antagonist lowers the max. These are fundamental board concepts.
Tachyphylaxis & Tolerance
Tachyphylaxis is rapid loss of drug effect after repeated doses (minutes to hours) — due to receptor desensitization or depletion of mediator stores. Example: indirect sympathomimetics (e.g., ephedrine depletes NE stores). Tolerance is gradual loss of effect over days to weeks. Example: nitrate tolerance (give a nitrate-free interval), opioid tolerance (receptor down-regulation/desensitization).
09 Autonomic Nervous System Overview
The autonomic nervous system (ANS) has two major divisions: sympathetic ("fight or flight") and parasympathetic ("rest and digest"). Both use a two-neuron chain: preganglionic neuron → ganglionic synapse → postganglionic neuron → effector organ.
Neurotransmitters & Receptors
| Component | Sympathetic | Parasympathetic |
|---|---|---|
| Preganglionic NT | ACh (nicotinic NN) | ACh (nicotinic NN) |
| Postganglionic NT | Norepinephrine (NE) [exception: sweat glands use ACh] | ACh (muscarinic M1–5) |
| Adrenal medulla | ACh (NN) → releases epinephrine (80%) and NE (20%) | N/A |
Adrenergic Receptor Subtypes
| Receptor | G-Protein | Location | Effect of Stimulation |
|---|---|---|---|
| α1 | Gq | Vascular smooth muscle, iris dilator, bladder sphincter | Vasoconstriction, mydriasis, urinary retention |
| α2 | Gi | Presynaptic nerve terminals, CNS | ↓NE release (negative feedback), sedation, ↓sympathetic outflow |
| β1 | Gs | Heart (SA node, AV node, myocardium) | ↑HR (chronotropy), ↑contractility (inotropy), ↑conduction velocity |
| β2 | Gs | Bronchial smooth muscle, uterus, vasculature, liver | Bronchodilation, vasodilation, glycogenolysis, tocolysis |
| β3 | Gs | Adipose tissue, bladder detrusor | Lipolysis, bladder relaxation |
Muscarinic Receptor Subtypes
| Receptor | G-Protein | Location | Effect |
|---|---|---|---|
| M1 | Gq | CNS, gastric parietal cells, enteric neurons | CNS excitation, ↑gastric acid secretion |
| M2 | Gi | Heart (SA node, AV node, atrial muscle) | ↓HR, ↓conduction velocity, ↓atrial contractility |
| M3 | Gq | Smooth muscle, glands, endothelium | Bronchoconstriction, ↑secretions, miosis, ↑GI motility, vasodilation (via NO) |
Sympathetic vs Parasympathetic Effects
Heart: Sympathetic ↑HR/contractility (β1); Parasympathetic ↓HR (M2). Lungs: Sympathetic bronchodilation (β2); Parasympathetic bronchoconstriction (M3). Eye: Sympathetic mydriasis (α1); Parasympathetic miosis (M3). GI: Sympathetic ↓motility (α2, β2); Parasympathetic ↑motility (M3). Bladder: Sympathetic retention (α1 sphincter, β2 detrusor relaxation); Parasympathetic voiding (M3 detrusor contraction).
Norepinephrine Synthesis & Metabolism
The catecholamine biosynthetic pathway: Tyrosine ⟶ (tyrosine hydroxylase, rate-limiting) DOPA ⟶ (DOPA decarboxylase) Dopamine ⟶ (dopamine β-hydroxylase, in vesicles) Norepinephrine ⟶ (PNMT, in adrenal medulla) Epinephrine. NE is removed from the synapse by: (1) reuptake-1 (into presynaptic neuron — blocked by TCAs, cocaine), (2) MAO (intraneuronally — inhibited by MAOIs), (3) COMT (extraneuronally — inhibited by entacapone). Metabolites: NE → normetanephrine (COMT) → VMA (vanillylmandelic acid). Urinary VMA and metanephrines are used to diagnose pheochromocytoma.
Acetylcholine Synthesis & Degradation
ACh is synthesized from choline + acetyl-CoA by choline acetyltransferase (ChAT) in the presynaptic terminal. After release, ACh is rapidly hydrolyzed by acetylcholinesterase (AChE) in the synaptic cleft. Choline is then recycled via a high-affinity choline transporter (blocked by hemicholinium). Vesicular ACh transport is blocked by vesamicol. ACh release from vesicles is blocked by botulinum toxin (inhibits SNARE-mediated exocytosis) and enhanced by black widow spider venom (α-latrotoxin).
Botulinum toxin blocks ACh release at the neuromuscular junction, causing flaccid paralysis. Therapeutic uses: dystonia, blepharospasm, hyperhidrosis, chronic migraine, cosmetic wrinkle reduction. Tetanus toxin blocks release of inhibitory neurotransmitters (glycine, GABA) in the spinal cord, causing spastic paralysis.
10 Cholinergic Agonists & Antagonists
Direct Cholinergic Agonists
| Drug | Mechanism | Indications | Key Notes |
|---|---|---|---|
| Bethanechol | Muscarinic agonist (M3) | Postoperative urinary retention, neurogenic bladder | Not hydrolyzed by AChE; avoid in obstruction |
| Carbachol | Muscarinic + nicotinic agonist | Glaucoma (miosis), intraocular surgery | Resistant to AChE |
| Pilocarpine | Muscarinic agonist | Glaucoma (open and closed angle), xerostomia (Sjögren's) | Contracts ciliary muscle → opens trabecular meshwork |
| Methacholine | Muscarinic agonist | Bronchial provocation testing for asthma | Diagnostic use only; causes bronchoconstriction |
Indirect Cholinergic Agonists (Acetylcholinesterase Inhibitors)
| Drug | Type | Indications | Key Notes |
|---|---|---|---|
| Neostigmine | Reversible (carbamate) | Myasthenia gravis, reversal of non-depolarizing NMJ blockade | Does not cross BBB (quaternary amine) |
| Pyridostigmine | Reversible (carbamate) | Myasthenia gravis (chronic treatment) | Longer-acting than neostigmine |
| Edrophonium | Reversible (short-acting) | Tensilon test (diagnosis of MG) — historical | Very short duration (~10 min) |
| Physostigmine | Reversible (carbamate) | Atropine/anticholinergic overdose, glaucoma | Crosses BBB (tertiary amine) — reverses central toxicity |
| Donepezil, rivastigmine, galantamine | Reversible | Alzheimer disease | Improve cholinergic transmission in CNS |
| Organophosphates (sarin, malathion) | Irreversible (phosphorylation) | Pesticides, nerve agents | Treat with atropine + pralidoxime (before "aging") |
Neostigmine does NOT cross the BBB (quaternary amine) — use for peripheral effects. Physostigmine DOES cross the BBB (tertiary amine) — use for anticholinergic toxicity with central symptoms (delirium, seizures). This distinction is a board classic.
Muscarinic Antagonists (Anticholinergics)
| Drug | Indications | Key Notes |
|---|---|---|
| Atropine | Bradycardia, organophosphate poisoning, mydriasis | Blocks M1–5; also used pre-operatively to reduce secretions |
| Ipratropium / Tiotropium | COPD, asthma (adjunct) | Inhaled — minimal systemic absorption; tiotropium is long-acting |
| Scopolamine | Motion sickness, preoperative antisecretory | Crosses BBB — can cause sedation, amnesia |
| Oxybutynin / Tolterodine | Overactive bladder, urge incontinence | Block M3 on detrusor; anticholinergic side effects |
| Benztropine / Trihexyphenidyl | Parkinson disease (tremor), EPS from antipsychotics | Central muscarinic blockade; caution in elderly (delirium) |
| Glycopyrrolate | Reduce secretions (preanesthetic), drooling | Quaternary amine; does not cross BBB |
Anticholinergic Toxidrome
"Hot as a hare (hyperthermia, no sweating), Dry as a bone (dry mucous membranes, anhidrosis), Red as a beet (flushing), Blind as a bat (mydriasis, cycloplegia), Mad as a hatter (delirium, hallucinations), Full as a flask (urinary retention), Stuffed as a sausage (decreased bowel sounds)." Treatment: physostigmine for severe central symptoms; supportive care otherwise.
11 Adrenergic Agonists & Antagonists
Direct Sympathomimetics
| Drug | Receptor Activity | Indications | Key Effects / Notes |
|---|---|---|---|
| Epinephrine | α1, α2, β1, β2 | Anaphylaxis, cardiac arrest, asthma (acute) | Low dose: β2 vasodilation; high dose: α1 vasoconstriction |
| Norepinephrine | α1 > α2 > β1; minimal β2 | Septic shock (first-line vasopressor) | ↑SVR, ↑MAP; reflex bradycardia possible |
| Phenylephrine | α1 selective | Nasal decongestion, hypotension, mydriasis | Pure vasoconstriction; reflex bradycardia |
| Isoproterenol | β1 = β2 (non-selective β) | Refractory bradycardia, AV block | ↑HR, ↑contractility, vasodilation; rarely used now |
| Dobutamine | β1 > β2 | Acute HF (cardiogenic shock), cardiac stress testing | ↑Contractility with less ↑HR; does NOT significantly increase SVR |
| Dopamine | D1, β1, α1 (dose-dependent) | Shock, renal perfusion (low dose — debated) | Low: D1 (renal vasodilation); medium: β1 (cardiac); high: α1 (vasoconstriction) |
| Clonidine | α2 agonist (central) | Hypertension, ADHD, opioid withdrawal, Tourette syndrome | ↓Sympathetic outflow from CNS; rebound HTN if stopped abruptly |
| Albuterol | β2 selective | Asthma, COPD (acute bronchospasm) | Bronchodilation; tremor, tachycardia at high doses; ↓K+ |
| Terbutaline | β2 selective | Tocolysis (preterm labor), asthma | Relaxes uterine smooth muscle |
Indirect Sympathomimetics
| Drug | Mechanism | Indications | Notes |
|---|---|---|---|
| Amphetamine | ↑NE/DA release from vesicles | ADHD, narcolepsy | Also blocks reuptake; subject to tachyphylaxis |
| Ephedrine | ↑NE release + direct α/β agonism | Nasal decongestion, hypotension | Tachyphylaxis with repeated use (NE depletion) |
| Cocaine | Blocks NE/DA/5-HT reuptake | Local anesthetic (topical nasal), drug of abuse | Only local anesthetic that causes vasoconstriction; risk: MI, arrhythmia |
Alpha-Blockers
| Drug | Selectivity | Indications | Key Notes |
|---|---|---|---|
| Prazosin, terazosin, doxazosin | α1 selective | HTN, BPH | First-dose orthostatic hypotension; give at bedtime |
| Tamsulosin | α1A selective | BPH | Minimal hypotension (prostate selectivity); floppy iris syndrome |
| Phenoxybenzamine | Non-selective α (irreversible) | Pheochromocytoma (preoperative) | Must give before β-blocker to avoid unopposed α stimulation |
| Phentolamine | Non-selective α (reversible) | Pheochromocytoma crisis, NE extravasation | Short-acting; can cause reflex tachycardia |
Beta-Blockers
| Drug | Selectivity | Key Features | Indications |
|---|---|---|---|
| Metoprolol, atenolol | β1 selective | Cardioselective (still can block β2 at high doses) | HTN, HF, post-MI, rate control |
| Propranolol | Non-selective (β1 + β2) | Lipophilic — crosses BBB (migraine, tremor, stage fright) | HTN, migraine prophylaxis, essential tremor, thyrotoxicosis |
| Carvedilol, labetalol | α1 + β blockade | Combined α/β blockade | HF (carvedilol), HTN in pregnancy (labetalol) |
| Esmolol | β1 selective | Ultra-short-acting (t1/2 ~9 min) | Intraoperative tachycardia, aortic dissection, thyroid storm |
| Timolol | Non-selective | Topical ophthalmic | Open-angle glaucoma (reduces aqueous humor production) |
In pheochromocytoma: ALWAYS give α-blocker (phenoxybenzamine) BEFORE β-blocker. If a β-blocker is given first, unopposed α-stimulation causes hypertensive crisis. This is one of the most commonly tested pharmacology principles.
12 Antihypertensives
ACE Inhibitors & ARBs
| Class | Mechanism | Examples | Side Effects | Contraindications |
|---|---|---|---|---|
| ACE Inhibitors (-pril) | Block ACE → ↓angiotensin II, ↓aldosterone, ↑bradykinin | Lisinopril, enalapril, ramipril, captopril | Dry cough (bradykinin), hyperkalemia, angioedema (rare), teratogenic | Bilateral renal artery stenosis, pregnancy, angioedema history |
| ARBs (-sartan) | Block AT1 receptor → same RAAS suppression, no bradykinin effect | Losartan, valsartan, irbesartan | Hyperkalemia, teratogenic; NO dry cough | Pregnancy, bilateral RAS |
Calcium Channel Blockers
| Subclass | Examples | Primary Effect | Indications | Side Effects |
|---|---|---|---|---|
| Dihydropyridines (-dipine) | Amlodipine, nifedipine | Vascular smooth muscle relaxation → vasodilation | HTN, Raynaud's, angina | Peripheral edema, reflex tachycardia (nifedipine > amlodipine), flushing |
| Non-dihydropyridines | Verapamil, diltiazem | Cardiac effects: ↓HR, ↓conduction, ↓contractility | HTN, SVT, rate control in AFib, angina | Constipation (verapamil), bradycardia, HF exacerbation; avoid with β-blockers |
Diuretics
| Class | Site of Action | Mechanism | Examples | Key Side Effects |
|---|---|---|---|---|
| Thiazides | Distal convoluted tubule | Block Na+/Cl− cotransporter | Hydrochlorothiazide, chlorthalidone | Hypokalemia, hyperuricemia, hypercalcemia, hyperglycemia, hyponatremia |
| Loop diuretics | Thick ascending limb of Henle | Block Na+/K+/2Cl− cotransporter | Furosemide, bumetanide, torsemide | Hypokalemia, hypocalcemia, ototoxicity, hypomagnesemia |
| K+-sparing | Collecting duct | Block ENaC (amiloride, triamterene) or aldosterone receptor (spironolactone, eplerenone) | Spironolactone, eplerenone, amiloride | Hyperkalemia; gynecomastia (spironolactone) |
| Carbonic anhydrase inhibitors | Proximal tubule | Block CA → ↓HCO3− reabsorption | Acetazolamide | Metabolic acidosis, paresthesias, altitude sickness prophylaxis |
| Osmotic diuretics | Proximal tubule, descending limb | Osmotically retain water in tubule | Mannitol | ↑ICP treatment, rhabdomyolysis; contraindicated in anuria, HF |
Diuretic Electrolyte Effects
Thiazides: hypokalemia + hypercalcemia (paradoxically increase Ca2+ reabsorption — useful in osteoporosis and calcium stone prevention). Loop diuretics: hypokalemia + hypocalcemia (wash out the medullary concentration gradient, lose Ca2+ — used for acute hypercalcemia). K+-sparing: hyperkalemia. Mnemonic for thiazide side effects: "HyperGLUC" — Glucose, Lipids, Uric acid, Calcium all go up.
13 Antiarrhythmics
Vaughan-Williams Classification
| Class | Mechanism | Subclass | Examples | Key Uses / Notes |
|---|---|---|---|---|
| I (Na+ channel blockers) | Block fast Na+ channels → ↓phase 0 depolarization | IA: moderate block, ↑APD | Quinidine, procainamide, disopyramide | Procainamide: SLE-like syndrome; quinidine: cinchonism, ↓digoxin CL |
| IB: weak block, ↓APD | Lidocaine, mexiletine | Post-MI ventricular arrhythmias; lidocaine also a local anesthetic | ||
| IC: strong block, no APD change | Flecainide, propafenone | SVT, AFib in structurally normal hearts; contraindicated post-MI (proarrhythmic) | ||
| II (β-blockers) | ↓cAMP → ↓Ca2+ influx → ↓SA/AV node activity | — | Metoprolol, esmolol, propranolol | Rate control, post-MI mortality reduction |
| III (K+ channel blockers) | Block K+ channels → ↑APD → ↑refractory period | — | Amiodarone, sotalol, ibutilide, dofetilide | Amiodarone: broad-spectrum but pulmonary fibrosis, thyroid dysfunction, hepatotoxicity, corneal deposits; sotalol: also β-blocker |
| IV (Ca2+ channel blockers) | Block L-type Ca2+ channels → ↓SA/AV conduction | — | Verapamil, diltiazem | SVT termination, rate control in AFib |
| Other | Various mechanisms | — | Adenosine, digoxin, Mg2+ | Adenosine: first-line for SVT (6 mg rapid push); digoxin: rate control; Mg2+: torsades |
Amiodarone has class I, II, III, and IV activity — it is the most broad-spectrum antiarrhythmic but also the most toxic. Remember its side effects with the mnemonic: "Amiodarone is TOO TOXIC" — Thyroid (hypo/hyper), Ocular (corneal microdeposits, optic neuropathy), Organ (pulmonary fibrosis, hepatotoxicity), Skin (blue-gray discoloration, photosensitivity), plus QT prolongation and peripheral neuropathy.
QT Prolongation
Drugs that prolong the QT interval risk torsades de pointes (polymorphic VT). Common culprits: Class IA (quinidine, procainamide), Class III (sotalol, dofetilide), macrolides, fluoroquinolones, antipsychotics (haloperidol, ziprasidone), methadone, ondansetron. Treatment of torsades: IV magnesium (first-line), overdrive pacing, isoproterenol.
14 Heart Failure & Antianginal Drugs
Heart Failure Pharmacotherapy
| Drug Class | Mechanism | Mortality Benefit in HFrEF | Key Drugs |
|---|---|---|---|
| ACEi / ARB / ARNI | RAAS blockade; ARNI (sacubitril/valsartan) also ↑natriuretic peptides | Yes (all three) | Enalapril, losartan, sacubitril/valsartan |
| β-Blockers (select) | ↓HR, reverse remodeling, ↓sympathetic activation | Yes | Carvedilol, metoprolol succinate, bisoprolol |
| MRAs (aldosterone antagonists) | Block aldosterone → ↓fibrosis, ↓K+ wasting | Yes | Spironolactone, eplerenone |
| SGLT2 inhibitors | Block glucose reabsorption; cardioprotective mechanisms beyond glucose | Yes | Dapagliflozin, empagliflozin |
| Hydralazine + Isosorbide dinitrate | Arterial vasodilation + venous vasodilation | Yes (esp. African Americans) | Fixed-dose combination (BiDil) |
| Digoxin | Inhibits Na+/K+-ATPase → ↑intracellular Ca2+ → ↑contractility | No (reduces hospitalizations) | Digoxin |
| Loop diuretics | Volume management — symptom relief | No | Furosemide, bumetanide |
The "four pillars" of guideline-directed medical therapy for HFrEF: ACEi/ARB/ARNI + β-blocker + MRA + SGLT2 inhibitor. All four reduce mortality. Initiate and titrate to target doses. Digoxin and diuretics improve symptoms but do not reduce mortality.
Antianginal Drugs
| Drug | Mechanism | Effect | Notes |
|---|---|---|---|
| Nitroglycerin (sublingual, IV, patch) | Releases NO → venodilation > arterial dilation | ↓Preload → ↓myocardial O2 demand | Headache, hypotension; contraindicated with PDE5 inhibitors; tolerance with continuous use |
| β-Blockers | ↓HR, ↓contractility | ↓Myocardial O2 demand | First-line chronic stable angina; avoid in Prinzmetal (variant) angina |
| CCBs (dihydropyridines) | Coronary vasodilation | ↑O2 supply, ↓afterload | First-line for Prinzmetal angina (coronary vasospasm) |
| Ranolazine | Inhibits late Na+ current | ↓Intracellular Ca2+ overload | Add-on for refractory angina; prolongs QT |
15 Anticoagulants, Antiplatelets & Thrombolytics
Anticoagulants
| Drug | Mechanism | Monitoring | Reversal | Key Notes |
|---|---|---|---|---|
| Heparin (UFH) | Activates antithrombin III → inhibits IIa (thrombin) and Xa | aPTT | Protamine sulfate | HIT (heparin-induced thrombocytopenia) — type II is immune-mediated, causes paradoxical thrombosis |
| LMWH (enoxaparin) | Activates ATIII → primarily anti-Xa | Anti-Xa levels (if needed) | Protamine (partial) | More predictable PK; renal dosing needed |
| Warfarin | Inhibits vitamin K epoxide reductase → ↓factors II, VII, IX, X, protein C and S | PT / INR | Vitamin K, FFP, 4-factor PCC | Narrow TI; many drug/food interactions; teratogenic; initial hypercoagulable state (protein C/S t1/2 shorter) |
| DOACs: rivaroxaban, apixaban | Direct Xa inhibitors | Not routinely monitored | Andexanet alfa | Fewer interactions than warfarin; renal dosing for apixaban |
| Dabigatran | Direct thrombin (IIa) inhibitor | Not routinely monitored | Idarucizumab | Renally cleared; risk of GI bleeding |
Antiplatelets
| Drug | Mechanism | Indications | Key Notes |
|---|---|---|---|
| Aspirin | Irreversibly inhibits COX-1 → ↓TXA2 (platelet aggregator) | ACS, stroke prevention, post-PCI | Low dose (81 mg) for antiplatelet; Reye syndrome in children with viral illness |
| Clopidogrel | Irreversibly blocks P2Y12 ADP receptor on platelets | ACS, post-PCI (DAPT), stroke prevention | Prodrug — requires CYP2C19 activation; omeprazole may reduce efficacy |
| Prasugrel, ticagrelor | P2Y12 inhibitors (prasugrel irreversible; ticagrelor reversible) | ACS, post-PCI | More potent than clopidogrel; ticagrelor: dyspnea side effect; prasugrel: more bleeding |
| GP IIb/IIIa inhibitors (abciximab, eptifibatide, tirofiban) | Block fibrinogen binding to GP IIb/IIIa on platelets | ACS, PCI | IV only; risk of thrombocytopenia |
Thrombolytics
Alteplase (tPA), reteplase, tenecteplase — activate plasminogen → plasmin → fibrin clot dissolution. Used in acute STEMI (if PCI unavailable within 120 min), acute ischemic stroke (within 4.5 hours), massive PE. Major risk: hemorrhage (including intracranial). Absolute contraindications include active internal bleeding, recent (3 months) intracranial surgery/stroke/head trauma, intracranial neoplasm, and suspected aortic dissection.
Warfarin initially creates a transient hypercoagulable state because protein C (anticoagulant, short t1/2 ~8 hrs) drops before factors II, IX, X (longer t1/2). This is why warfarin is bridged with heparin for the first 5–7 days. It also explains warfarin-induced skin necrosis (microvascular thrombosis in protein C-deficient patients).
16 Lipid-Lowering Agents
| Class | Mechanism | Primary Effect | Examples | Side Effects |
|---|---|---|---|---|
| Statins (-statin) | HMG-CoA reductase inhibitor → ↓cholesterol synthesis → ↑LDL receptor expression | ↓↓LDL (25–55%) | Atorvastatin, rosuvastatin, simvastatin, pravastatin | Myopathy/rhabdomyolysis (check CK), hepatotoxicity, ↑diabetes risk |
| Ezetimibe | Blocks NPC1L1 transporter → ↓intestinal cholesterol absorption | ↓LDL (15–20%) | Ezetimibe | Generally well tolerated; diarrhea |
| PCSK9 inhibitors | Monoclonal antibodies → ↓PCSK9 → ↑LDL receptor recycling | ↓↓↓LDL (50–70%) | Evolocumab, alirocumab | Injection site reactions; expensive |
| Fibrates | PPAR-α agonists → ↑lipoprotein lipase → ↑TG clearance | ↓↓TG, ↑HDL | Gemfibrozil, fenofibrate | Myopathy (esp. with statins), gallstones, hepatotoxicity |
| Niacin (vitamin B3) | Inhibits lipolysis in adipose → ↓VLDL synthesis | ↓TG, ↓LDL, ↑↑HDL (best HDL raiser) | Niacin | Flushing (prostaglandin-mediated — pretreat with aspirin), hyperuricemia, hyperglycemia |
| Bile acid resins | Bind bile acids in gut → ↓enterohepatic recycling → ↑LDL receptor | ↓LDL | Cholestyramine, colesevelam | GI upset, ↑TG, impair absorption of other drugs |
Statins are the only lipid-lowering agents with proven mortality benefit in primary and secondary prevention of cardiovascular disease. Simvastatin and atorvastatin are CYP3A4 substrates — watch for interactions with CYP3A4 inhibitors (rhabdomyolysis risk). Pravastatin and rosuvastatin are NOT significantly CYP-metabolized and have fewer drug interactions.
Vasodilators & Other Cardiovascular Agents
| Drug | Mechanism | Indication | Key Side Effects |
|---|---|---|---|
| Hydralazine | Direct arteriolar vasodilator (increases cGMP in vascular smooth muscle) | HTN, HF (with isosorbide dinitrate) | Reflex tachycardia, drug-induced lupus (slow acetylators), fluid retention |
| Nitroprusside | Releases NO → vasodilation (arterial + venous) | Hypertensive emergency (IV drip) | Cyanide toxicity (monitor with thiosulfate); thiocyanate toxicity in renal failure |
| Fenoldopam | D1 receptor agonist → renal vasodilation | Hypertensive emergency | Tachycardia, hypotension; increases renal perfusion (useful in renal impairment) |
| Milrinone | PDE3 inhibitor → ↑cAMP in cardiac and vascular smooth muscle | Acute decompensated HF (IV) | Arrhythmias, hypotension; inodilator (positive inotropy + vasodilation) |
| Ivabradine | Blocks funny current (If) in SA node → ↓HR | HFrEF (HR ≥70 bpm on max β-blocker), chronic stable angina (Europe) | Bradycardia, luminous phenomena (phosphenes), atrial fibrillation |
| Nesiritide | Recombinant BNP → vasodilation, natriuresis | Acute decompensated HF | Hypotension; no mortality benefit demonstrated; rarely used now |
Vasopressors for Shock
| Agent | Receptor Activity | Primary Use | Key Effect |
|---|---|---|---|
| Norepinephrine | α1 > β1 | Septic shock (first-line) | ↑SVR, ↑MAP; some ↑CO via β1 |
| Vasopressin | V1 receptors on vascular smooth muscle | Septic shock (adjunct to NE) | Catecholamine-independent vasoconstriction; useful in refractory septic shock |
| Epinephrine | α1, β1, β2 | Anaphylaxis, cardiac arrest, refractory shock | ↑SVR + ↑CO; may worsen splanchnic perfusion |
| Phenylephrine | Pure α1 | Neurogenic shock, drug-induced hypotension | Pure vasoconstriction; reflex bradycardia; avoid in cardiogenic shock |
| Dobutamine | β1 > β2 | Cardiogenic shock | ↑Contractility, may ↓SVR slightly; inodilator |
| Dopamine | Dose-dependent: D1 → β1 → α1 | Shock (second-line), symptomatic bradycardia | Low (<5): renal vasodilation; medium (5–10): cardiac; high (>10): vasoconstriction; more arrhythmogenic than NE |
In septic shock, norepinephrine is the first-line vasopressor (Surviving Sepsis Campaign 2021). Vasopressin is added as a second agent if target MAP is not achieved. Epinephrine is an alternative. Dopamine is no longer recommended as first-line due to increased arrhythmia risk compared to norepinephrine. Dobutamine may be added if there is evidence of cardiac dysfunction (low CO despite adequate volume resuscitation).
17 Sedative-Hypnotics & Anxiolytics
Benzodiazepines
Mechanism: Bind GABAA receptor → increase frequency of Cl− channel opening → enhanced inhibitory neurotransmission. Effects: anxiolysis, sedation, muscle relaxation, anticonvulsant, amnesia.
| Drug | Onset / Duration | Active Metabolite | Primary Use |
|---|---|---|---|
| Diazepam | Rapid / Long-acting | Desmethyldiazepam (long t1/2) | Anxiety, alcohol withdrawal seizures, muscle spasm, status epilepticus |
| Lorazepam | Intermediate / Intermediate | None (glucuronidation only) | Status epilepticus (first-line), anxiety, alcohol withdrawal |
| Midazolam | Rapid / Short | Minimal | Procedural sedation, preoperative, ICU sedation |
| Alprazolam | Intermediate / Short-intermediate | Minimal | Panic disorder, generalized anxiety |
| Chlordiazepoxide | Intermediate / Long | Yes | Alcohol withdrawal (classic choice) |
| Triazolam | Rapid / Ultra-short | None | Insomnia |
BZD vs Barbiturate GABA Pharmacology
Benzodiazepines increase the frequency of Cl− channel opening. Barbiturates increase the duration of Cl− channel opening and at high doses can directly open the channel (without GABA). This explains why barbiturate overdose is more lethal — there is no ceiling effect. BZD reversal: flumazenil (competitive antagonist at BZD site; risk of seizures in chronic BZD users or mixed overdose).
Non-Benzodiazepine Hypnotics
Zolpidem, zaleplon, eszopiclone ("Z-drugs") — act at the α1 subunit of GABAA receptor (selective for sedation over anxiolysis/muscle relaxation). Short-acting; used for insomnia. Side effects: sleepwalking, sleep-driving, complex sleep behaviors. Suvorexant — orexin receptor antagonist for insomnia. Ramelteon — melatonin MT1/MT2 receptor agonist; no abuse potential.
18 Antidepressants & Mood Stabilizers
Antidepressant Classes
| Class | Mechanism | Examples | Key Side Effects |
|---|---|---|---|
| SSRIs | Selectively block serotonin (5-HT) reuptake | Fluoxetine, sertraline, paroxetine, citalopram, escitalopram | Sexual dysfunction, GI upset, serotonin syndrome (with MAOIs); citalopram → QT prolongation |
| SNRIs | Block 5-HT + NE reuptake | Venlafaxine, duloxetine, desvenlafaxine | HTN (venlafaxine dose-dependent), sexual dysfunction, nausea |
| TCAs | Block 5-HT + NE reuptake; also block muscarinic, H1, α1 | Amitriptyline, nortriptyline, imipramine, desipramine, clomipramine | Anticholinergic effects, sedation, weight gain, orthostatic hypotension; cardiotoxic in overdose (Na+ channel block → wide QRS) |
| MAOIs | Inhibit MAO-A/B → ↑5-HT, NE, DA | Phenelzine, tranylcypromine, selegiline | Hypertensive crisis with tyramine-containing foods; serotonin syndrome with SSRIs; wait 2 weeks between MAOI and SSRI switch |
| Atypical | Various mechanisms | Bupropion (NE/DA reuptake inhibitor), mirtazapine (α2 antagonist, 5-HT2/H1 antagonist), trazodone (5-HT2A antagonist) | Bupropion: lowers seizure threshold, no sexual dysfunction, used for smoking cessation; mirtazapine: weight gain, sedation; trazodone: priapism |
TCA overdose is a medical emergency: wide QRS on ECG (Na+ channel blockade), seizures, arrhythmias, and anticholinergic toxicity. Treatment: sodium bicarbonate (alkalinizes serum, increases protein binding, overcomes Na+ channel blockade) for QRS >100 ms. This is a must-know for boards and clinical practice.
Mood Stabilizers
| Drug | Mechanism | Indications | Key Toxicity / Monitoring |
|---|---|---|---|
| Lithium | Not fully elucidated; inhibits IMPase, GSK-3β; modulates second messengers | Bipolar disorder (acute mania and maintenance) | Narrow TI (0.6–1.2 mEq/L); nephrotoxicity (diabetes insipidus — nephrogenic), hypothyroidism, Ebstein anomaly (teratogenic), tremor; toxicity enhanced by thiazides, NSAIDs, ACEi (all reduce renal Li clearance) |
| Valproate | ↑GABA, blocks Na+/Ca2+ channels | Bipolar disorder, seizures, migraine | Hepatotoxicity, pancreatitis, thrombocytopenia, neural tube defects (teratogenic), weight gain |
| Carbamazepine | Na+ channel blockade | Bipolar disorder, trigeminal neuralgia, seizures | Agranulocytosis/aplastic anemia, SIADH, SJS (HLA-B*1502 in Asians), CYP inducer (auto-induction) |
| Lamotrigine | Na+ channel blockade, ↓glutamate | Bipolar depression (maintenance), seizures | SJS/TEN (slow titration required); relatively well tolerated |
Serotonin Syndrome
Caused by excess serotonergic activity (e.g., MAOI + SSRI, meperidine + MAOI, linezolid + SSRI). Classic triad: (1) Altered mental status (agitation, confusion), (2) Autonomic instability (hyperthermia, tachycardia, diaphoresis, diarrhea), (3) Neuromuscular hyperactivity (myoclonus, hyperreflexia, clonus — especially lower extremity). Treatment: stop offending drug, cyproheptadine (5-HT2A antagonist), supportive care. Distinguish from NMS (lead-pipe rigidity, no clonus, caused by dopamine antagonists).
19 Antipsychotics
First-Generation (Typical) Antipsychotics
Mechanism: Block D2 receptors in the mesolimbic pathway (therapeutic effect on positive symptoms) but also block D2 in other pathways (causing side effects).
| Potency | Examples | Characteristic Side Effects |
|---|---|---|
| High potency | Haloperidol, fluphenazine, pimozide | More EPS (dystonia, akathisia, parkinsonism, tardive dyskinesia), less sedation/anticholinergic effects |
| Low potency | Chlorpromazine, thioridazine | More sedation, anticholinergic effects, orthostatic hypotension; less EPS. Thioridazine: retinal deposits, QT prolongation |
Second-Generation (Atypical) Antipsychotics
| Drug | Key Features | Unique Side Effects |
|---|---|---|
| Clozapine | Most effective for treatment-resistant schizophrenia; low EPS risk | Agranulocytosis (requires weekly-biweekly CBC); seizures, myocarditis, metabolic syndrome, drooling (sialorrhea) |
| Risperidone | Highest D2 affinity among atypicals | Hyperprolactinemia (most common among atypicals), EPS at higher doses |
| Olanzapine | Effective for both positive and negative symptoms | Significant weight gain and metabolic syndrome (worst among atypicals); sedation |
| Quetiapine | Used for schizophrenia, bipolar, adjunct depression, insomnia (off-label) | Sedation, weight gain, cataracts (rare) |
| Aripiprazole | D2 partial agonist (unique mechanism) | Minimal weight gain, less sedation; akathisia; low metabolic risk |
| Ziprasidone | Least weight gain among atypicals | QT prolongation (take with food for absorption) |
Neuroleptic Malignant Syndrome (NMS)
Life-threatening reaction to dopamine antagonists (especially high-potency typical antipsychotics). Features: FALTER — Fever, Autonomic instability (diaphoresis, labile BP), Leukocytosis, Tremor/rigidity (lead-pipe), Elevated CK (rhabdomyolysis), Renal failure (myoglobinuria). Treatment: stop the offending drug, dantrolene (muscle relaxant), bromocriptine (D2 agonist), supportive care with cooling and IV fluids.
20 Opioids & Analgesics
Opioid Receptor Pharmacology
| Receptor | G-Protein | Effects of Activation | Key Agonists |
|---|---|---|---|
| μ (mu) | Gi | Analgesia (supraspinal), euphoria, respiratory depression, miosis, constipation, physical dependence | Morphine, fentanyl, methadone, heroin |
| κ (kappa) | Gi | Analgesia (spinal), sedation, dysphoria, miosis | Butorphanol, nalbuphine, pentazocine |
| δ (delta) | Gi | Analgesia, anxiolysis, antidepressant effects | Enkephalins (endogenous) |
Opioid Agents
| Drug | Receptor Activity | Key Features |
|---|---|---|
| Morphine | Full μ agonist | Gold standard opioid; histamine release (pruritus, hypotension); active metabolite (M6G) accumulates in renal failure |
| Fentanyl | Full μ agonist | 100× more potent than morphine; rapid onset; no histamine release; transdermal patch for chronic pain |
| Methadone | Full μ agonist + NMDA antagonist | Long t1/2 (15–60 hr); opioid use disorder maintenance; QT prolongation risk |
| Codeine | Weak μ agonist (prodrug → morphine via CYP2D6) | Antitussive; ineffective in CYP2D6 poor metabolizers; dangerous in ultra-rapid metabolizers |
| Tramadol | Weak μ agonist + NE/5-HT reuptake inhibitor | Serotonin syndrome risk; seizure risk; dual mechanism |
| Meperidine | μ agonist | Neurotoxic metabolite (normeperidine) → seizures; avoid in renal failure and with MAOIs (serotonin syndrome) |
| Buprenorphine | Partial μ agonist, κ antagonist | Ceiling effect for respiratory depression; used in opioid use disorder (with naloxone = Suboxone) |
| Naloxone | μ, κ, δ antagonist | Opioid overdose reversal; short t1/2 (30–90 min) — may need repeat doses; precipitates withdrawal |
| Naltrexone | μ, κ, δ antagonist (long-acting) | Maintenance therapy for opioid and alcohol use disorders; oral or monthly IM injection |
Naloxone has a shorter half-life than most opioids. After reversing an overdose, the patient must be monitored for re-sedation and respiratory depression as the naloxone wears off. Fentanyl overdose may require higher or repeated doses of naloxone due to fentanyl's high receptor affinity.
Non-Opioid Analgesics
NSAIDs (ibuprofen, naproxen, ketorolac, indomethacin): Inhibit COX-1/COX-2 → ↓prostaglandin synthesis. Side effects: GI ulceration/bleeding (COX-1), renal vasoconstriction (AKI), platelet dysfunction, cardiovascular risk (especially COX-2 selective). Acetaminophen: centrally acting analgesic/antipyretic; no anti-inflammatory effect. Hepatotoxic in overdose (NAPQI metabolite depletes glutathione) — antidote is N-acetylcysteine (NAC). Celecoxib: selective COX-2 inhibitor; less GI toxicity but increased cardiovascular risk.
NSAID Pharmacology in Detail
| Drug | COX Selectivity | Key Features |
|---|---|---|
| Aspirin | Irreversible COX-1 > COX-2 | Antiplatelet at low dose (81 mg); analgesic/anti-inflammatory at higher doses; Reye syndrome in children |
| Ibuprofen | Non-selective COX-1/COX-2 | Most common OTC NSAID; GI, renal, CV risk; can interfere with aspirin's antiplatelet effect |
| Naproxen | Non-selective COX-1/COX-2 | Longer t1/2 (BID dosing); possibly lower CV risk than other NSAIDs |
| Indomethacin | Non-selective | Potent; used for gout flares, PDA closure (neonates); highest GI risk |
| Ketorolac | Non-selective | IV/IM NSAID for acute pain; limit to 5 days (GI/renal toxicity) |
| Celecoxib | Selective COX-2 | Less GI bleeding; increased CV risk (thrombotic events); sulfonamide allergy caution |
COX-1 vs COX-2
COX-1 is constitutive (housekeeping): maintains gastric mucosal protection (PGE2), renal perfusion (PGI2), and platelet aggregation (TXA2). Inhibiting COX-1 causes GI ulcers, renal vasoconstriction, and antiplatelet effects. COX-2 is inducible (inflammation): mediates pain, fever, and inflammation. Selective COX-2 inhibitors spare the stomach but increase thrombotic risk (PGI2 is COX-2 dependent in endothelium; loss of PGI2 tips the balance toward TXA2-mediated platelet aggregation).
Anesthetics
| Category | Drug | Mechanism | Key Notes |
|---|---|---|---|
| Local anesthetics (amides) | Lidocaine, bupivacaine, ropivacaine | Block voltage-gated Na+ channels → prevent nerve depolarization | Amides metabolized by liver (CYP); bupivacaine: cardiotoxic in overdose (use lipid emulsion rescue); lidocaine also an antiarrhythmic |
| Local anesthetics (esters) | Procaine, tetracaine, cocaine | Same Na+ channel blockade | Esters metabolized by plasma cholinesterases; higher allergy risk (PABA metabolite); cocaine: only LA causing vasoconstriction |
| General (IV induction) | Propofol, etomidate, ketamine, thiopental | Various: GABAA (propofol, thiopental), NMDA antagonist (ketamine) | Propofol: hypotension, propofol infusion syndrome; etomidate: adrenal suppression; ketamine: dissociative, ↑ICP, emergence reactions |
| General (inhaled) | Sevoflurane, isoflurane, desflurane, N2O | Unclear; likely enhance GABAA, inhibit NMDA | MAC = minimum alveolar concentration for 50% immobility; malignant hyperthermia risk (treat with dantrolene); N2O: megaloblastic anemia (B12 inactivation) |
| Neuromuscular blockers (depolarizing) | Succinylcholine | Depolarizes NMJ (phase I → phase II block) | Rapid onset/offset; contraindicated in burns, crush injury, hyperkalemia (massive K+ release); malignant hyperthermia trigger; metabolized by pseudocholinesterase |
| Neuromuscular blockers (non-depolarizing) | Rocuronium, vecuronium, cisatracurium | Competitive antagonists at nicotinic NM receptor | Reversed with neostigmine + glycopyrrolate (or sugammadex for rocuronium) |
Malignant hyperthermia is triggered by succinylcholine or volatile anesthetics (halothane, sevoflurane, etc.) in patients with RYR1 mutations. Presents with rapidly rising temperature, rigidity, hyperkalemia, rhabdomyolysis, and metabolic acidosis. Treatment: immediate dantrolene (blocks ryanodine receptor Ca2+ release), stop triggering agent, cool the patient.
21 Antiepileptics & Parkinson Drugs
Antiepileptic Drugs (AEDs)
| Drug | Mechanism | Primary Indications | Key Side Effects |
|---|---|---|---|
| Phenytoin | Na+ channel blockade (use-dependent) | Focal seizures, generalized tonic-clonic, status epilepticus | Zero-order kinetics, gingival hyperplasia, hirsutism, SJS, fetal hydantoin syndrome, cerebellar atrophy, CYP inducer |
| Carbamazepine | Na+ channel blockade | Focal seizures, trigeminal neuralgia, bipolar | Agranulocytosis, aplastic anemia, SIADH, SJS (HLA-B*1502), auto-induction |
| Valproic acid | ↑GABA, Na+ channel block, T-type Ca2+ block | Broad-spectrum: absence, tonic-clonic, myoclonic, bipolar | Hepatotoxicity, pancreatitis, neural tube defects, thrombocytopenia, weight gain; inhibits CYP |
| Ethosuximide | Blocks T-type Ca2+ channels in thalamus | Absence seizures (first-line) | GI distress, Stevens-Johnson, fatigue |
| Levetiracetam | Binds SV2A (synaptic vesicle protein) | Broad-spectrum; adjunct/monotherapy | Behavioral changes (irritability, depression); minimal drug interactions |
| Lamotrigine | Na+ channel blockade | Focal, generalized, Lennox-Gastaut, bipolar | SJS/TEN (slow titration); valproate inhibits its metabolism |
| Gabapentin / Pregabalin | Bind α2δ subunit of voltage-gated Ca2+ channels | Neuropathic pain, focal seizures (adjunct), fibromyalgia (pregabalin) | Sedation, ataxia, peripheral edema; renally cleared |
| Benzodiazepines (lorazepam, diazepam) | ↑GABAA Cl− channel frequency | Status epilepticus (first-line), acute seizure clusters | Sedation, respiratory depression, tolerance |
For status epilepticus: first-line is IV lorazepam (or IM midazolam if no IV access). If seizures persist, give IV fosphenytoin (or phenytoin, valproate, levetiracetam). If refractory, proceed to continuous infusion (midazolam, propofol, or pentobarbital) with EEG monitoring.
Parkinson Disease Drugs
| Drug | Mechanism | Key Notes |
|---|---|---|
| Levodopa/carbidopa | Levodopa is a DA precursor; carbidopa inhibits peripheral DOPA decarboxylase (prevents peripheral conversion) | Most effective for motor symptoms; long-term: on-off phenomenon, dyskinesias, wearing off |
| Dopamine agonists (pramipexole, ropinirole) | Direct D2/D3 agonists | Monotherapy in early PD or adjunct; impulse control disorders, orthostatic hypotension |
| Selegiline, rasagiline | MAO-B inhibitors → ↓DA breakdown | Early PD monotherapy or adjunct; selegiline metabolized to amphetamine |
| Entacapone, tolcapone | COMT inhibitors → ↓levodopa peripheral metabolism | Extend levodopa effect; tolcapone: hepatotoxicity (monitor LFTs) |
| Amantadine | Increases DA release, NMDA antagonist | Mild symptomatic benefit; reduces levodopa-induced dyskinesias; livedo reticularis |
| Benztropine, trihexyphenidyl | Central muscarinic antagonists | Tremor-predominant PD; also treats drug-induced EPS; avoid in elderly (delirium) |
22 Antibacterials
Cell Wall Synthesis Inhibitors
| Class | Mechanism | Spectrum / Examples | Key Side Effects / Resistance |
|---|---|---|---|
| Penicillins | Bind PBPs → inhibit transpeptidation (cross-linking of peptidoglycan) | Penicillin G/V (strep, syphilis); ampicillin/amoxicillin (broader gram+, some gram−); piperacillin/tazobactam (Pseudomonas) | Hypersensitivity (anaphylaxis ~0.05%); resistance via β-lactamase (overcome with clavulanate, sulbactam, tazobactam) |
| Cephalosporins | Same as penicillins (bind PBPs) | 1st gen (cefazolin): gram+; 3rd gen (ceftriaxone): gram−, meningitis; 4th gen (cefepime): Pseudomonas; 5th gen (ceftaroline): MRSA | Cross-reactivity with penicillin allergy ~2%; ceftriaxone: biliary sludge |
| Carbapenems | Bind PBPs; very broad-spectrum | Imipenem/cilastatin, meropenem, ertapenem | Imipenem: seizures (use meropenem for CNS infections); ertapenem: no Pseudomonas coverage |
| Vancomycin | Binds D-Ala-D-Ala terminus → inhibits transglycosylation | MRSA, C. difficile (oral only for C. diff) | Red man syndrome (histamine release — slow infusion), nephrotoxicity, ototoxicity; VRE resistance: D-Ala-D-Lac substitution |
Protein Synthesis Inhibitors
| Target | Class | Examples | Key Notes |
|---|---|---|---|
| 30S ribosome | Aminoglycosides | Gentamicin, tobramycin, amikacin | Bactericidal; nephrotoxicity, ototoxicity (vestibular & cochlear); concentration-dependent killing; avoid in pregnancy |
| 30S ribosome | Tetracyclines | Doxycycline, minocycline, tetracycline | Bacteriostatic; photosensitivity, teeth discoloration (children <8), esophageal ulceration; cover: Rickettsia, Lyme, Chlamydia, acne |
| 50S ribosome | Macrolides | Azithromycin, clarithromycin, erythromycin | Bacteriostatic; GI upset, QT prolongation; erythromycin: prokinetic (motilin agonist), CYP3A4 inhibitor; cover: atypicals, Mycobacterium avium |
| 50S ribosome | Chloramphenicol | Chloramphenicol | Aplastic anemia (idiosyncratic), gray baby syndrome (neonates); broad-spectrum; rarely used in US |
| 50S ribosome | Clindamycin | Clindamycin | Anaerobes, streptococci, MRSA (some); C. difficile colitis risk; used for aspiration pneumonia |
| 50S ribosome | Linezolid | Linezolid | VRE, MRSA; serotonin syndrome risk (weak MAOI); thrombocytopenia with prolonged use |
DNA/RNA Synthesis Inhibitors & Others
| Class | Mechanism | Examples | Key Notes |
|---|---|---|---|
| Fluoroquinolones | Inhibit DNA gyrase (topoisomerase II) and topoisomerase IV | Ciprofloxacin, levofloxacin, moxifloxacin | Tendon rupture (Achilles), QT prolongation, CNS effects, aortic aneurysm risk; cipro: CYP1A2 inhibitor; moxi: anaerobe coverage |
| Sulfonamides / TMP | Inhibit folate synthesis: sulfa blocks dihydropteroate synthase; TMP blocks dihydrofolate reductase | TMP-SMX (Bactrim) | UTIs, PJP prophylaxis/treatment, MRSA (CA-MRSA); hyperkalemia, bone marrow suppression, SJS, kernicterus in neonates |
| Metronidazole | Forms toxic free radicals damaging DNA | Metronidazole | Anaerobes (Bacteroides, C. difficile), protozoa (Giardia, Entamoeba, Trichomonas); disulfiram-like reaction with alcohol, metallic taste, peripheral neuropathy |
| Rifamycins | Inhibit DNA-dependent RNA polymerase | Rifampin, rifabutin | TB treatment (combination therapy); potent CYP inducer (turns body fluids orange); rifabutin: less CYP induction (used with antiretrovirals) |
| Daptomycin | Depolarizes cell membrane (gram+ only) | Daptomycin | MRSA bacteremia, endocarditis; inactivated by surfactant — cannot use for pneumonia; monitor CPK (myopathy) |
Daptomycin is inactivated by pulmonary surfactant and must NOT be used for pneumonia. For MRSA pneumonia, use vancomycin or linezolid instead. This is a frequently tested distinction.
Antimicrobial Resistance Mechanisms
| Resistance Mechanism | Examples |
|---|---|
| Enzymatic drug inactivation | β-Lactamases (penicillin resistance), aminoglycoside-modifying enzymes, chloramphenicol acetyltransferase |
| Altered drug target | PBP modification (MRSA: mecA gene → PBP2a), ribosomal methylation (macrolide resistance), DNA gyrase mutations (quinolone resistance) |
| Decreased permeability | Porin mutations in gram-negative bacteria (carbapenem resistance in Pseudomonas) |
| Efflux pumps | Tetracycline resistance, multidrug-resistant Pseudomonas, P-glycoprotein in fungi |
| Target bypass | VRE: D-Ala-D-Lac substitution (vancomycin cannot bind); MRSA: alternative PBP2a |
Bactericidal vs Bacteriostatic
Classification
Bactericidal (kill bacteria): Penicillins, cephalosporins, carbapenems, vancomycin, aminoglycosides, fluoroquinolones, metronidazole, daptomycin, isoniazid. Bacteriostatic (inhibit growth): Tetracyclines, macrolides (usually), chloramphenicol, clindamycin, TMP-SMX, linezolid. Note: bacteriostatic drugs can be bactericidal at high concentrations or against certain organisms. In immunocompromised patients and endocarditis/meningitis, bactericidal agents are generally preferred.
Antimicrobial Prophylaxis — Key Scenarios
| Scenario | Prophylactic Agent |
|---|---|
| Surgical prophylaxis (clean/clean-contaminated) | Cefazolin (1st-gen cephalosporin) within 60 min of incision |
| Dental procedures in high-risk cardiac patients | Amoxicillin (or clindamycin if penicillin allergic) |
| PJP prophylaxis (HIV with CD4 <200) | TMP-SMX (first-line); alternatives: dapsone, atovaquone, aerosolized pentamidine |
| MAC prophylaxis (HIV with CD4 <50) | Azithromycin |
| TB prophylaxis (latent TB) | Isoniazid × 9 months (+ pyridoxine/B6) or rifampin × 4 months |
| Meningococcal exposure prophylaxis | Rifampin, ciprofloxacin, or ceftriaxone |
| Recurrent UTI prophylaxis | Nitrofurantoin or TMP-SMX |
| Group B Strep (GBS) in labor | IV penicillin G (or ampicillin) |
23 Antifungals, Antivirals & Antiparasitics
Antifungals
| Drug | Mechanism | Spectrum | Key Toxicity |
|---|---|---|---|
| Amphotericin B | Binds ergosterol → forms pores in fungal membrane | Broad-spectrum (Aspergillus, Candida, Crypto, Mucor, Histo, Coccidio) | Nephrotoxicity (dose-limiting), infusion-related fever/chills ("shake and bake"), hypokalemia, hypomagnesemia; liposomal form less toxic |
| Azoles (fluconazole, itraconazole, voriconazole, posaconazole) | Inhibit 14-α-demethylase (CYP51) → ↓ergosterol synthesis | Fluconazole: Candida, Crypto; voriconazole: Aspergillus (first-line); itraconazole: Histo, Blasto, Sporo | Hepatotoxicity, CYP inhibitors (drug interactions); voriconazole: visual disturbances, photosensitivity |
| Echinocandins (caspofungin, micafungin, anidulafungin) | Inhibit β-(1,3)-D-glucan synthase → disrupt cell wall | Candida (including azole-resistant), Aspergillus | Generally well tolerated; hepatotoxicity (rare); NO activity against Cryptococcus or Mucor |
| Terbinafine | Inhibits squalene epoxidase → ↓ergosterol | Dermatophytes (onychomycosis) | Hepatotoxicity, taste disturbance |
| Flucytosine (5-FC) | Converted to 5-FU → inhibits DNA/RNA synthesis | Used with ampho B for Cryptococcal meningitis | Bone marrow suppression, hepatotoxicity |
Antivirals
| Drug | Mechanism | Indications | Key Notes |
|---|---|---|---|
| Acyclovir / Valacyclovir | Guanosine analog; requires viral thymidine kinase for activation → inhibits viral DNA polymerase | HSV, VZV | Nephrotoxicity (crystalluria — hydrate), neurotoxicity; valacyclovir is oral prodrug with better bioavailability |
| Ganciclovir / Valganciclovir | Similar to acyclovir; activated by viral UL97 kinase | CMV | Myelosuppression (neutropenia, thrombocytopenia), teratogenic |
| Oseltamivir / Zanamivir | Neuraminidase inhibitors → prevent viral release from host cells | Influenza A and B | Must start within 48 hours of symptoms; zanamivir: inhaled (bronchospasm risk) |
| Ribavirin | Inhibits IMP dehydrogenase → ↓guanine nucleotides | Hepatitis C (with DAAs), RSV | Hemolytic anemia, teratogenic (pregnancy category X) |
| Tenofovir, emtricitabine | NRTIs (nucleotide/nucleoside reverse transcriptase inhibitors) | HIV, Hepatitis B, PrEP | Tenofovir disoproxil: nephrotoxicity, Fanconi syndrome; tenofovir alafenamide: less renal/bone toxicity |
| Sofosbuvir + ledipasvir/velpatasvir | NS5B polymerase inhibitor + NS5A inhibitor (direct-acting antivirals) | Hepatitis C (cure rates >95%) | Well tolerated; check for drug interactions |
Antiparasitics (Selected)
| Drug | Target Organism | Key Notes |
|---|---|---|
| Chloroquine / Hydroxychloroquine | Plasmodium (malaria), SLE, RA | Retinal toxicity (require ophthalmologic screening), QT prolongation; resistance in P. falciparum widespread |
| Artemisinin-based combinations (ACTs) | P. falciparum (first-line globally) | Rapid parasite clearance; artemisinin resistance emerging in SE Asia |
| Ivermectin | Strongyloides, Onchocerca, ectoparasites (scabies, lice) | Strengthens GABA-gated Cl− channels in parasites; generally well tolerated |
| Mebendazole / Albendazole | Helminths (hookworm, pinworm, roundworm, whipworm) | Inhibit microtubule polymerization; albendazole: neurocysticercosis, echinococcosis |
| Metronidazole | Giardia, Entamoeba histolytica, Trichomonas | Also covers anaerobic bacteria; disulfiram-like reaction |
24 Endocrine Pharmacology
Diabetes Medications
| Class | Mechanism | Examples | Key Side Effects |
|---|---|---|---|
| Metformin | Activates AMPK → ↓hepatic gluconeogenesis, ↑insulin sensitivity | Metformin | Lactic acidosis (rare, contraindicated in eGFR <30), GI upset, B12 deficiency; no hypoglycemia, weight neutral/loss |
| Sulfonylureas | Block KATP channels on β-cells → ↑insulin secretion | Glipizide, glyburide, glimepiride | Hypoglycemia, weight gain; glyburide: avoid in elderly/CKD |
| SGLT2 inhibitors (-gliflozin) | Block SGLT2 in proximal tubule → ↓glucose reabsorption | Empagliflozin, dapagliflozin, canagliflozin | UTIs, genital mycotic infections, euglycemic DKA, Fournier gangrene (rare); CV and renal benefits |
| GLP-1 receptor agonists | Incretin mimetic → ↑glucose-dependent insulin, ↓glucagon, ↓gastric emptying | Semaglutide, liraglutide, dulaglutide, exenatide | Nausea, pancreatitis (rare), medullary thyroid carcinoma (animal data — avoid in MEN 2); significant weight loss; CV benefit |
| DPP-4 inhibitors (-gliptin) | Inhibit DPP-4 → ↑endogenous GLP-1 and GIP | Sitagliptin, saxagliptin, linagliptin | Well tolerated; minimal hypoglycemia; weight neutral |
| Thiazolidinediones (TZDs) | PPAR-γ agonists → ↑insulin sensitivity in adipose/muscle | Pioglitazone, rosiglitazone | Fluid retention → HF exacerbation, weight gain, bone fractures, bladder cancer risk (pioglitazone) |
| Insulin | Exogenous insulin replacement | Rapid (lispro, aspart), short (regular), intermediate (NPH), long-acting (glargine, detemir) | Hypoglycemia, weight gain, lipodystrophy |
Thyroid Drugs
| Drug | Mechanism | Indication | Key Notes |
|---|---|---|---|
| Levothyroxine (T4) | Synthetic T4 replacement | Hypothyroidism | Take on empty stomach; monitor TSH (target: normalize TSH) |
| Methimazole | Inhibits TPO → blocks thyroid hormone synthesis | Hyperthyroidism (Graves disease) | Agranulocytosis (rare), teratogenic in first trimester; preferred antithyroid drug outside of pregnancy 1st trimester |
| PTU (propylthiouracil) | Inhibits TPO + blocks peripheral T4→T3 conversion | Hyperthyroidism (preferred in first trimester, thyroid storm) | Hepatotoxicity (fulminant), agranulocytosis, ANCA-positive vasculitis |
Corticosteroids
Glucocorticoids (prednisone, prednisolone, dexamethasone, hydrocortisone) — bind intracellular receptors → modulate gene transcription → anti-inflammatory and immunosuppressive effects. Side effects (chronic use): Cushing syndrome, osteoporosis, adrenal suppression, hyperglycemia, immunosuppression, cataracts, avascular necrosis, myopathy, psychiatric effects, poor wound healing. Dexamethasone has the longest duration and highest potency (no mineralocorticoid activity). Fludrocortisone is a synthetic mineralocorticoid used for adrenal insufficiency (salt retention).
Never abruptly stop chronic glucocorticoids — the hypothalamic-pituitary-adrenal axis is suppressed and abrupt withdrawal causes adrenal crisis (hypotension, shock). Taper gradually. Patients on chronic steroids need stress-dose steroids during surgery or acute illness.
GI Pharmacology
| Drug Class | Mechanism | Examples | Indications / Notes |
|---|---|---|---|
| Proton pump inhibitors (PPIs) | Irreversibly inhibit H+/K+-ATPase (proton pump) on parietal cells | Omeprazole, pantoprazole, esomeprazole | GERD, PUD, Zollinger-Ellison; long-term risks: C. diff, osteoporosis, hypomagnesemia, B12 deficiency, CKD |
| H2 blockers | Block histamine H2 receptors on parietal cells → ↓acid | Famotidine, cimetidine | GERD (mild), PUD; cimetidine: CYP inhibitor, antiandrogen effects (gynecomastia) |
| Antacids | Neutralize gastric acid directly | Al(OH)3, Mg(OH)2, CaCO3 | Rapid symptom relief; aluminum causes constipation, magnesium causes diarrhea |
| Sucralfate | Binds to ulcer base, forming protective barrier (requires acidic pH) | Sucralfate | Duodenal ulcers; do not give with PPIs (needs acid to activate) |
| Misoprostol | PGE1 analog → ↑mucosal protection, ↓acid | Misoprostol | NSAID-induced ulcer prevention; contraindicated in pregnancy (abortifacient) |
| Ondansetron | 5-HT3 receptor antagonist | Ondansetron | Antiemetic (chemotherapy, post-op nausea); QT prolongation; constipation |
| Metoclopramide | D2 antagonist, 5-HT4 agonist → prokinetic | Metoclopramide | Gastroparesis, antiemetic; EPS (tardive dyskinesia), hyperprolactinemia |
| Bismuth subsalicylate | Antimicrobial + mucosal protection | Pepto-Bismol | Part of H. pylori triple/quadruple therapy; black tongue/stool |
H. pylori eradication typically uses triple therapy: PPI + clarithromycin + amoxicillin (or metronidazole) for 14 days. Quadruple therapy (PPI + bismuth + metronidazole + tetracycline) is used in penicillin allergy or clarithromycin-resistant areas. Confirm eradication with urea breath test or stool antigen at least 4 weeks after treatment completion.
Other Endocrine Agents
| Drug | Mechanism | Indication |
|---|---|---|
| Tamoxifen | SERM (estrogen receptor antagonist in breast, agonist in bone/endometrium) | ER+ breast cancer (adjuvant); increases risk of endometrial cancer and DVT |
| Raloxifene | SERM (agonist in bone, antagonist in breast/endometrium) | Osteoporosis prevention; DVT risk but no endometrial cancer risk |
| Aromatase inhibitors (letrozole, anastrozole, exemestane) | Block peripheral estrogen synthesis | ER+ breast cancer in postmenopausal women; arthralgia, osteoporosis |
| Bisphosphonates (alendronate, zoledronic acid) | Inhibit osteoclast activity | Osteoporosis, Paget disease, hypercalcemia of malignancy |
| Denosumab | RANKL monoclonal antibody → ↓osteoclastogenesis | Osteoporosis, bone metastases |
| Cinacalcet | Calcimimetic → activates CaSR → ↓PTH secretion | Secondary hyperparathyroidism (CKD), parathyroid carcinoma |
25 Chemotherapy & Immunosuppressants
Antineoplastic Agents
| Class | Mechanism | Examples | Key Toxicities |
|---|---|---|---|
| Alkylating agents | Cross-link DNA → prevent replication | Cyclophosphamide, cisplatin, busulfan | Cyclophosphamide: hemorrhagic cystitis (prevent with mesna), SIADH; cisplatin: nephrotoxicity (hydrate), ototoxicity, peripheral neuropathy; busulfan: pulmonary fibrosis |
| Antimetabolites | Structural analogs that inhibit DNA/RNA synthesis | Methotrexate (anti-folate), 5-FU (pyrimidine analog), 6-MP (purine analog), cytarabine | Methotrexate: myelosuppression, hepatotoxicity, pneumonitis (rescue with leucovorin); 5-FU: myelosuppression, hand-foot syndrome; 6-MP: metabolized by XO (reduce dose with allopurinol) |
| Topoisomerase inhibitors | Inhibit topoisomerase I or II → DNA strand breaks | Etoposide (topo II), irinotecan (topo I), doxorubicin (topo II + intercalation) | Doxorubicin: dilated cardiomyopathy (dose-dependent, irreversible — lifetime max ~550 mg/m2; dexrazoxane cardioprotectant); etoposide: secondary leukemia |
| Microtubule inhibitors | Vinca alkaloids: prevent polymerization; taxanes: prevent depolymerization | Vincristine, vinblastine; paclitaxel, docetaxel | Vincristine: peripheral neuropathy (dose-limiting), paralytic ileus; vinblastine: myelosuppression; taxanes: peripheral neuropathy, myelosuppression |
| Targeted therapies | Tyrosine kinase inhibitors, monoclonal antibodies | Imatinib (BCR-ABL), trastuzumab (HER2), rituximab (CD20), bevacizumab (VEGF) | Imatinib: CML first-line; trastuzumab: cardiotoxicity; rituximab: infusion reactions, HBV reactivation; bevacizumab: hemorrhage, impaired wound healing, HTN |
| Immune checkpoint inhibitors | Block PD-1, PD-L1, or CTLA-4 → enhance T-cell anti-tumor activity | Nivolumab, pembrolizumab (anti-PD-1); ipilimumab (anti-CTLA-4); atezolizumab (anti-PD-L1) | Immune-related adverse events: colitis, hepatitis, pneumonitis, thyroiditis, hypophysitis, dermatitis |
Doxorubicin cardiotoxicity is irreversible and dose-dependent (dilated cardiomyopathy). Monitor LVEF serially. Dexrazoxane (iron chelator) reduces free radical damage and is cardioprotective. Bleomycin causes pulmonary fibrosis. Vincristine causes neuropathy but spares the bone marrow. These associations are board staples.
Immunosuppressants
| Drug | Mechanism | Indications | Key Toxicity |
|---|---|---|---|
| Cyclosporine | Calcineurin inhibitor (binds cyclophilin) → ↓IL-2 → ↓T-cell activation | Transplant rejection prophylaxis, autoimmune diseases | Nephrotoxicity, HTN, gingival hyperplasia, hirsutism, tremor; narrow TI; CYP3A4 substrate |
| Tacrolimus | Calcineurin inhibitor (binds FKBP) → ↓IL-2 | Transplant rejection (more potent than cyclosporine) | Nephrotoxicity, diabetes, neurotoxicity, hyperkalemia; narrow TI |
| Mycophenolate mofetil | Inhibits IMP dehydrogenase → ↓purine synthesis in lymphocytes | Transplant rejection, lupus nephritis | GI upset, myelosuppression, teratogenic |
| Azathioprine | Purine analog → ↓DNA synthesis in lymphocytes (metabolized to 6-MP) | Transplant rejection, autoimmune diseases | Myelosuppression; metabolized by XO — reduce dose with allopurinol (avoid toxicity) |
| Sirolimus (rapamycin) | mTOR inhibitor (binds FKBP but targets mTOR, not calcineurin) | Transplant rejection, drug-eluting coronary stents | Hyperlipidemia, myelosuppression, impaired wound healing; NOT nephrotoxic (unlike calcineurin inhibitors) |
Calcineurin Inhibitor vs mTOR Inhibitor
Cyclosporine and tacrolimus are calcineurin inhibitors — both cause nephrotoxicity. Sirolimus is an mTOR inhibitor that does NOT cause nephrotoxicity but causes hyperlipidemia and impairs wound healing. All three are used in transplant medicine. In drug-eluting stents, sirolimus/everolimus prevent restenosis via antiproliferative effects on smooth muscle cells.
Respiratory Pharmacology
| Drug Class | Mechanism | Examples | Key Notes |
|---|---|---|---|
| Short-acting β2 agonists (SABAs) | Bronchial smooth muscle relaxation via β2 → Gs → ↑cAMP | Albuterol, levalbuterol | Rescue inhaler; tremor, tachycardia, hypokalemia |
| Long-acting β2 agonists (LABAs) | Same as SABA, sustained duration (12 hr) | Salmeterol, formoterol | Never use as monotherapy (black box — use with ICS); maintenance |
| Inhaled corticosteroids (ICS) | Anti-inflammatory → ↓cytokines, eosinophils, mast cell mediators | Fluticasone, budesonide, beclomethasone | First-line controller in persistent asthma; oral candidiasis (rinse mouth); no significant systemic effects at standard doses |
| Leukotriene receptor antagonists | Block CysLT1 receptor → ↓bronchoconstriction, inflammation | Montelukast, zafirlukast | Asthma controller (add-on); exercise-induced and aspirin-sensitive asthma; neuropsychiatric effects (FDA warning) |
| Muscarinic antagonists (inhaled) | Block M3 on bronchial smooth muscle → bronchodilation | Ipratropium (SAMA), tiotropium (LAMA) | COPD maintenance (tiotropium); ipratropium in acute COPD exacerbation + SABA |
| Methylxanthines | PDE inhibitor → ↑cAMP; adenosine receptor antagonist | Theophylline, aminophylline | Narrow TI; toxicity: seizures, arrhythmias; metabolized by CYP1A2; levels increase with erythromycin, ciprofloxacin |
| Anti-IgE monoclonal antibody | Binds free IgE → ↓mast cell activation | Omalizumab | Severe persistent allergic asthma; SC injection; anaphylaxis risk (monitor) |
| Anti-IL-5 antibodies | Target IL-5 → ↓eosinophil maturation/survival | Mepolizumab, benralizumab | Severe eosinophilic asthma |
Allergy & Histamine Pharmacology
| Drug Class | Mechanism | Examples | Key Notes |
|---|---|---|---|
| 1st-generation H1 antihistamines | Block H1 receptors; cross BBB | Diphenhydramine, chlorpheniramine, hydroxyzine | Sedation, anticholinergic effects; diphenhydramine used as sleep aid, motion sickness |
| 2nd-generation H1 antihistamines | Block H1 receptors; do NOT cross BBB | Loratadine, cetirizine, fexofenadine | Non-sedating (P-gp substrates excluded from CNS); preferred for allergic rhinitis |
| Epinephrine (IM) | α1 (vasoconstriction) + β2 (bronchodilation) + β1 (cardiac support) | EpiPen | First-line for anaphylaxis; IM into anterolateral thigh; repeat every 5–15 min if needed |
| Cromolyn sodium | Mast cell stabilizer → prevents degranulation | Cromolyn | Prophylaxis only (exercise-induced asthma, allergic conjunctivitis); not for acute symptoms |
In anaphylaxis, epinephrine is the ONLY first-line treatment. Do not delay epinephrine for antihistamines or steroids. Antihistamines (H1 + H2 blocker) and corticosteroids are adjunctive and help prevent biphasic reactions but do not reverse the immediate life-threatening airway/hemodynamic compromise.
26 Toxicology & Antidotes
Toxidromes
| Toxidrome | Features | Common Agents |
|---|---|---|
| Anticholinergic | Hyperthermia, dry skin, mydriasis, tachycardia, delirium, urinary retention, ileus | Antihistamines, TCAs, atropine, jimsonweed |
| Cholinergic | DUMBBELSS: Diarrhea, Urination, Miosis, Bronchospasm/Bradycardia, Emesis, Lacrimation, Salivation, Sweating | Organophosphates, carbamates, nerve agents |
| Sympathomimetic | Hyperthermia, mydriasis, tachycardia, HTN, diaphoresis, agitation | Cocaine, amphetamines, MDMA |
| Opioid | Miosis, respiratory depression, CNS depression, bradycardia, hypothermia | Heroin, fentanyl, morphine, oxycodone |
| Sedative-hypnotic | CNS depression, respiratory depression, hypotension, hypothermia, normal pupils | Benzodiazepines, barbiturates, ethanol |
| Serotonin syndrome | Hyperthermia, agitation, clonus/hyperreflexia, diaphoresis, diarrhea | SSRIs + MAOIs, meperidine + MAOIs, linezolid + SSRI |
Specific Antidotes
| Poison / Drug | Antidote | Mechanism / Notes |
|---|---|---|
| Acetaminophen | N-acetylcysteine (NAC) | Replenishes glutathione; use Rumack-Matthew nomogram; most effective within 8 hours |
| Benzodiazepines | Flumazenil | Competitive antagonist at BZD receptor; risk of seizures (chronic BZD users, mixed ingestion) |
| Opioids | Naloxone | μ-receptor antagonist; short t1/2 — may need repeat dosing |
| Organophosphates | Atropine + pralidoxime (2-PAM) | Atropine: blocks muscarinic excess; 2-PAM: reactivates AChE (before aging) |
| Warfarin | Vitamin K + FFP or 4-factor PCC | Vitamin K for non-emergent reversal (takes 12–24 hr); PCC/FFP for acute hemorrhage |
| Heparin | Protamine sulfate | Positively charged protein binds negatively charged heparin; 1 mg per 100 units UFH |
| Digoxin | Digoxin-specific Fab antibodies (Digibind) | Bind free digoxin; indicated for life-threatening arrhythmias, hyperkalemia |
| TCA overdose | Sodium bicarbonate | Alkalinization overcomes Na+ channel blockade (QRS widening); also for seizures, hypotension |
| Methanol / Ethylene glycol | Fomepizole (or ethanol) + dialysis | Inhibits alcohol dehydrogenase → prevents toxic metabolite formation (formic acid / oxalic acid) |
| β-Blocker overdose | Glucagon | Activates adenylyl cyclase via non-adrenergic pathway → ↑cAMP → ↑HR, contractility |
| CCB overdose | Calcium gluconate/chloride, high-dose insulin/dextrose | Ca2+ partially overcomes channel blockade; insulin improves cardiac contractility |
| Iron | Deferoxamine | Iron chelator; indicated when serum iron >500 μg/dL or symptomatic |
| Lead | Succimer (DMSA, oral) or EDTA + dimercaprol (severe) | Chelation therapy; dimercaprol for encephalopathy |
| Cyanide | Hydroxocobalamin or nitrite/thiosulfate kit | Hydroxocobalamin binds CN directly; nitrites generate methemoglobin (binds CN) |
| Carbon monoxide | 100% O2 (hyperbaric if severe) | Displaces CO from hemoglobin; t1/2 of COHb: 5 hr room air, 1.5 hr 100% O2, 20 min hyperbaric |
| Methotrexate | Leucovorin (folinic acid) | Bypasses DHF reductase block; "leucovorin rescue" |
For methanol or ethylene glycol poisoning, fomepizole is preferred over ethanol as an alcohol dehydrogenase inhibitor (easier to dose, fewer side effects). Dialysis is indicated for severe cases (renal failure, severe acidosis, very high levels, visual symptoms with methanol).
Acetaminophen Toxicity in Detail
Acetaminophen (APAP) is the most common cause of acute liver failure in the US. At therapeutic doses, ~90% is conjugated (glucuronidation/sulfation) and 5–10% is oxidized by CYP2E1 to the toxic metabolite NAPQI, which is normally detoxified by glutathione conjugation. In overdose (>150 mg/kg or >7.5 g in adults), glutathione stores are depleted → NAPQI accumulates → hepatocellular necrosis (zone 3 / centrilobular, where CYP2E1 is most concentrated).
| Phase | Timing | Features |
|---|---|---|
| Phase I | 0–24 hours | Nausea, vomiting, malaise, normal labs (or mildly elevated transaminases) |
| Phase II | 24–72 hours | Abdominal pain (RUQ), rising AST/ALT, ↑INR/PT; patients may feel "better" |
| Phase III | 72–96 hours | Peak hepatotoxicity: massive AST/ALT (>10,000), coagulopathy, hepatic encephalopathy, renal failure; may progress to death |
| Phase IV | 4 days–2 weeks | Recovery (if survived); liver regeneration |
N-Acetylcysteine (NAC) is the antidote: replenishes glutathione stores, acts as a glutathione substitute, and enhances sulfation. Most effective when given within 8 hours of ingestion but still beneficial up to 24+ hours. Use the Rumack-Matthew nomogram (plot 4-hour level) to determine need for NAC. Risk factors for toxicity at lower doses: chronic alcohol use (CYP2E1 induction + glutathione depletion), malnutrition, fasting, and CYP-inducing drugs.
Chronic alcoholics are at increased risk for acetaminophen toxicity at lower doses because alcohol induces CYP2E1 (more NAPQI production) AND depletes glutathione (less detoxification). The recommended maximum daily dose should be reduced to 2 g/day in chronic alcohol users.
27 Special Populations & Drug Interactions
Pregnancy Drug Safety
The FDA replaced the old letter categories (A, B, C, D, X) with the Pregnancy and Lactation Labeling Rule (PLLR) in 2015, but letter categories remain commonly referenced. Key teratogenic drugs to know:
| Drug | Teratogenic Effect | Timing of Risk |
|---|---|---|
| Warfarin | Nasal hypoplasia, stippled epiphyses, CNS abnormalities | First trimester (6–9 weeks) |
| ACE inhibitors / ARBs | Renal agenesis, oligohydramnios, pulmonary hypoplasia | Second/third trimester |
| Valproic acid | Neural tube defects (spina bifida), craniofacial anomalies | First trimester |
| Isotretinoin | Multiple congenital anomalies (cardiac, craniofacial, thymic, CNS) | First trimester |
| Thalidomide | Limb defects (phocomelia) | First trimester |
| Methotrexate | Craniofacial, limb, CNS defects; spontaneous abortion | First trimester |
| Lithium | Ebstein anomaly (tricuspid valve malformation) | First trimester |
| Phenytoin | Fetal hydantoin syndrome (cleft lip/palate, digital hypoplasia, nail hypoplasia) | First trimester |
| Tetracyclines | Teeth discoloration, bone growth inhibition | Second/third trimester |
| Fluoroquinolones | Cartilage damage | All trimesters |
| Statins | Multiple congenital anomalies (contraindicated) | All trimesters |
Geriatric Pharmacology
Age-related changes affecting drug handling: ↓hepatic blood flow and ↓phase I metabolism (phase II relatively preserved) → slower drug clearance. ↓GFR (~1 mL/min/year after age 40) → reduced renal clearance. ↓Total body water and ↑body fat → increased Vd for lipophilic drugs (longer t1/2), decreased Vd for hydrophilic drugs (higher peak levels). ↓Albumin → increased free fraction of protein-bound drugs. The Beers Criteria lists potentially inappropriate medications in the elderly (e.g., long-acting BZDs, anticholinergics, NSAIDs, TCAs).
Pediatric Pharmacology
Neonates have immature hepatic enzymes (especially glucuronidation — risk of chloramphenicol "gray baby syndrome" and unconjugated bilirubin toxicity), ↑total body water (larger Vd for water-soluble drugs), ↓plasma protein binding, and immature renal function. Drug dosing is typically weight-based (mg/kg) or BSA-based. Avoid certain drugs: aspirin (Reye syndrome), tetracycline (teeth/bone), fluoroquinolones (cartilage), codeine (respiratory depression in ultra-rapid metabolizers).
Major Drug Interactions
| Interaction | Mechanism | Clinical Consequence |
|---|---|---|
| Warfarin + rifampin | CYP induction → ↑warfarin metabolism | ↓INR, loss of anticoagulation |
| Warfarin + azole antifungals | CYP inhibition → ↓warfarin metabolism | ↑INR, bleeding risk |
| Statins + CYP3A4 inhibitors | ↓Statin metabolism → ↑statin levels | Rhabdomyolysis risk |
| MAOI + tyramine-rich foods | ↓Tyramine breakdown → massive NE release | Hypertensive crisis |
| MAOI + SSRI/meperidine | Excess serotonergic activity | Serotonin syndrome |
| Methotrexate + NSAIDs | ↓Renal MTX clearance | MTX toxicity (myelosuppression) |
| Lithium + thiazides/NSAIDs/ACEi | ↓Renal lithium clearance | Lithium toxicity |
| Digoxin + amiodarone/verapamil | ↓Digoxin clearance (P-gp inhibition) | Digoxin toxicity (halve the digoxin dose) |
| Clopidogrel + omeprazole | CYP2C19 inhibition → ↓clopidogrel activation | Reduced antiplatelet effect |
| Sildenafil + nitrates | Both cause cGMP-mediated vasodilation | Severe hypotension — contraindicated |
Always think of drug interactions in terms of the mechanism: CYP induction (faster metabolism, lower drug levels), CYP inhibition (slower metabolism, higher drug levels), protein binding displacement, or pharmacodynamic synergy/antagonism. The most dangerous interactions involve drugs with narrow therapeutic indices.
Renal & Hepatic Impairment
| Condition | Pharmacokinetic Change | Clinical Implications |
|---|---|---|
| Renal impairment | ↓GFR → ↓renal clearance of drugs and active metabolites | Dose reduce: aminoglycosides, vancomycin, lithium, digoxin, metformin, enoxaparin, gabapentin, acyclovir, allopurinol; loading doses usually unchanged |
| Hepatic impairment | ↓Phase I metabolism, ↓protein synthesis (albumin), portosystemic shunting | ↑Bioavailability of high-extraction drugs (propranolol, morphine); ↑free fraction of protein-bound drugs; avoid hepatotoxic drugs; use Child-Pugh score for dose adjustment |
| Combined renal + hepatic | Both clearance pathways impaired | Extreme caution; use drugs with extrarenal/extrahepatic clearance when possible |
Therapeutic Drug Monitoring (TDM)
TDM is indicated for drugs with a narrow TI, significant interpatient PK variability, and a defined relationship between concentration and effect/toxicity. Key drugs requiring TDM:
| Drug | Therapeutic Range | Timing of Levels |
|---|---|---|
| Vancomycin | Trough 15–20 mg/L (serious infections); AUC/MIC-guided dosing preferred | Trough before 4th or 5th dose |
| Aminoglycosides (gentamicin) | Peak 5–10 mg/L; trough <2 mg/L (conventional dosing) | Peak 30 min after infusion; trough before next dose |
| Lithium | 0.6–1.2 mEq/L (maintenance); 0.8–1.2 (acute mania) | 12 hours after last dose (trough) |
| Phenytoin | 10–20 μg/mL (total); adjust for albumin | Trough; free level if low albumin |
| Digoxin | 0.5–2.0 ng/mL (target <1.0 in HF) | At least 6 hours after dose (distribution phase) |
| Theophylline | 10–20 μg/mL | Trough for sustained-release formulations |
| Cyclosporine / Tacrolimus | Variable by organ/time post-transplant | Trough (C0) before morning dose |
| Carbamazepine | 4–12 μg/mL | Trough; recheck after auto-induction (2–4 weeks) |
28 High-Yield Review
Board-Critical Concepts
The following topics are the most heavily tested pharmacology concepts across USMLE Step 1, Step 2, and shelf exams. Master these and you will be well prepared.
Top 30 High-Yield Facts
| # | Fact |
|---|---|
| 1 | Competitive antagonists shift dose–response curve right (same Emax); non-competitive antagonists reduce Emax |
| 2 | Potency = EC50 (left on curve = more potent); Efficacy = Emax (height of curve) |
| 3 | Therapeutic index = TD50/ED50; narrow TI drugs: warfarin, lithium, digoxin, theophylline, aminoglycosides, phenytoin |
| 4 | Zero-order kinetics: PEA (Phenytoin, Ethanol, Aspirin at high doses) — constant amount eliminated per time |
| 5 | Steady state is reached at 4–5 half-lives; loading dose achieves target concentration immediately |
| 6 | Phase I metabolism (CYP450, oxidation) is decreased in elderly; Phase II (conjugation) is preserved |
| 7 | CYP3A4 metabolizes ~50% of drugs; rifampin is the most potent CYP inducer; ketoconazole/ritonavir are potent CYP3A4 inhibitors |
| 8 | Gs → ↑cAMP (β1, β2, D1, H2, V2); Gi → ↓cAMP (α2, M2, D2, opioid); Gq → PLC/IP3/DAG (α1, M1, M3, H1, V1) |
| 9 | Benzodiazepines increase frequency of GABAA Cl− channel opening; barbiturates increase duration |
| 10 | Neostigmine (quaternary, no BBB crossing) vs physostigmine (tertiary, crosses BBB) |
| 11 | Pheochromocytoma: α-blocker BEFORE β-blocker (phenoxybenzamine → then propranolol) |
| 12 | Thiazides cause hypercalcemia; loops cause hypocalcemia. Both cause hypokalemia |
| 13 | Amiodarone has all four Vaughan-Williams class actions; toxicities: pulmonary fibrosis, thyroid, liver, cornea, skin |
| 14 | Torsades de pointes treatment: IV magnesium (first-line) |
| 15 | Warfarin: initial hypercoagulable state (protein C/S drop first) — bridge with heparin |
| 16 | HIT type II: immune-mediated (anti-PF4/heparin antibodies) → paradoxical thrombosis; switch to argatroban or bivalirudin |
| 17 | TCA overdose: wide QRS → treat with sodium bicarbonate |
| 18 | Serotonin syndrome (clonus, agitation, diaphoresis) vs NMS (lead-pipe rigidity, ↑CK, caused by D2 antagonists) |
| 19 | Acetaminophen overdose: NAC (replenishes glutathione); use Rumack-Matthew nomogram |
| 20 | Methanol/ethylene glycol poisoning: fomepizole (preferred) or ethanol + dialysis |
| 21 | Organophosphate poisoning: atropine (muscarinic blockade) + pralidoxime (reactivates AChE) |
| 22 | Doxorubicin: dose-dependent dilated cardiomyopathy (dexrazoxane for prevention); bleomycin: pulmonary fibrosis |
| 23 | Vincristine: neurotoxicity; cyclophosphamide: hemorrhagic cystitis (mesna); cisplatin: nephro/ototoxicity |
| 24 | Cyclosporine/tacrolimus: nephrotoxic (calcineurin inhibitors); sirolimus: NOT nephrotoxic (mTOR inhibitor) |
| 25 | Metformin: first-line T2DM; contraindicated eGFR <30 (lactic acidosis); no hypoglycemia |
| 26 | SGLT2 inhibitors and GLP-1 agonists have cardiovascular mortality benefit in T2DM |
| 27 | HFrEF mortality benefit: ACEi/ARB/ARNI + β-blocker + MRA + SGLT2 inhibitor |
| 28 | Clozapine: most effective antipsychotic for treatment-resistant schizophrenia; requires CBC monitoring (agranulocytosis) |
| 29 | Daptomycin is inactivated by surfactant — cannot use for pneumonia; use vancomycin or linezolid for MRSA pneumonia |
| 30 | CYP2D6 poor metabolizers: codeine/tramadol ineffective, clopidogrel (CYP2C19) ineffective; ultra-rapid CYP2D6: codeine toxicity |
Key Drug–Side Effect Associations
| Side Effect | Classic Drug(s) |
|---|---|
| Gray baby syndrome | Chloramphenicol |
| Red man syndrome | Vancomycin (histamine release from rapid infusion) |
| Fanconi syndrome | Tenofovir disoproxil, expired tetracyclines |
| Drug-induced lupus | Hydralazine, procainamide, isoniazid, minocycline (anti-histone antibodies) |
| Disulfiram-like reaction | Metronidazole, certain cephalosporins, sulfonylureas |
| Gingival hyperplasia | Phenytoin, cyclosporine, nifedipine |
| Gynecomastia | Spironolactone, ketoconazole, cimetidine, digoxin |
| Pulmonary fibrosis | Bleomycin, amiodarone, busulfan, methotrexate, nitrofurantoin |
| Tendon rupture | Fluoroquinolones (especially with corticosteroids) |
| Photosensitivity | Tetracyclines, sulfonamides, amiodarone, voriconazole |
| Aplastic anemia | Chloramphenicol, carbamazepine, benzene, NSAIDs (rare) |
| Nephrogenic diabetes insipidus | Lithium, demeclocycline |
| SIADH | Carbamazepine, cyclophosphamide, SSRIs |
| Hepatic veno-occlusive disease | Cyclophosphamide (SCT conditioning), pyrrolizidine alkaloids |
| QT prolongation | Sotalol, dofetilide, quinidine, haloperidol, macrolides, fluoroquinolones, methadone, ondansetron |
| Drug-induced pancreatitis | Valproic acid, didanosine, azathioprine, thiazides, GLP-1 agonists (rare) |
| Hemolytic anemia (G6PD deficiency) | Primaquine, dapsone, sulfonamides, nitrofurantoin, rasburicase |
| Drug-induced parkinsonism / EPS | Haloperidol, fluphenazine, metoclopramide, prochlorperazine |
| Megaloblastic anemia | Methotrexate, phenytoin, TMP-SMX (folate antagonism); N2O (B12 inactivation) |
| Interstitial nephritis (acute) | NSAIDs, penicillins, cephalosporins, sulfonamides, PPIs, rifampin |
| Pseudomembranous colitis | Clindamycin (classic), fluoroquinolones, broad-spectrum antibiotics → C. difficile overgrowth |
Drug Class Quick-Reference Tables
Drugs That Cause Hyponatremia
| Mechanism | Drugs |
|---|---|
| SIADH (inappropriate ADH secretion) | Carbamazepine, SSRIs, cyclophosphamide, oxytocin, vincristine, chlorpropamide |
| Water retention / dilutional | Thiazide diuretics, desmopressin |
Drugs That Cause Hyperkalemia
| Mechanism | Drugs |
|---|---|
| ↓Renal K+ excretion | ACE inhibitors, ARBs, K+-sparing diuretics (spironolactone, amiloride, triamterene), TMP, heparin, NSAIDs |
| K+ shift out of cells | Succinylcholine, β-blockers (non-selective), digoxin (Na+/K+-ATPase inhibition) |
Drugs That Cause Photosensitivity
SAT For Very Annoying Skin: Sulfonamides, Amiodarone, Tetracyclines, Fluoroquinolones, Voriconazole, 5-Aminolevulinic acid, St. John's wort.
Drugs That Cause SJS / TEN
Most common: Allopurinol, sulfonamides, anticonvulsants (carbamazepine, phenytoin, lamotrigine, phenobarbital), NSAIDs (piroxicam), nevirapine. HLA-B*5801 testing recommended before allopurinol. HLA-B*1502 in East Asians before carbamazepine.
Drugs That Prolong QT
| Class | Specific Drugs |
|---|---|
| Antiarrhythmics | Sotalol, dofetilide, quinidine, procainamide, amiodarone |
| Antibiotics | Macrolides (erythromycin, azithromycin), fluoroquinolones (moxifloxacin > levofloxacin) |
| Antipsychotics | Haloperidol, droperidol, ziprasidone, thioridazine |
| Antidepressants | Citalopram, TCAs (amitriptyline) |
| Other | Methadone, ondansetron, hydroxychloroquine, sumatriptan |
Mechanisms of Drug Allergy
| Type | Mechanism | Timing | Drug Example |
|---|---|---|---|
| Type I (Immediate / anaphylaxis) | IgE-mediated mast cell degranulation | Minutes | Penicillin anaphylaxis, cephalosporin allergy |
| Type II (Cytotoxic) | IgG/IgM antibodies against drug-coated cells | Hours–days | Methyldopa (autoimmune hemolytic anemia), heparin (HIT type II) |
| Type III (Immune complex) | Drug–antibody complex deposition | Days–weeks | Serum sickness (penicillin, sulfonamides), drug-induced lupus |
| Type IV (Delayed / cell-mediated) | T-cell mediated | Days–weeks | Contact dermatitis, SJS/TEN, DRESS syndrome |
Drug Suffixes — Monoclonal Antibody Nomenclature
| Suffix | Source | Examples |
|---|---|---|
| -ximab | Chimeric (mouse/human) | Infliximab (anti-TNF), rituximab (anti-CD20) |
| -zumab | Humanized | Trastuzumab (anti-HER2), bevacizumab (anti-VEGF), omalizumab (anti-IgE) |
| -umab | Fully human | Adalimumab (anti-TNF), nivolumab (anti-PD-1), denosumab (anti-RANKL) |
Drugs Used in Rheumatology & Autoimmune Disease
| Drug | Mechanism | Key Uses | Toxicity |
|---|---|---|---|
| Methotrexate | Folate antagonist (↓dihydrofolate reductase) | RA (first-line DMARD), psoriasis, ectopic pregnancy | Myelosuppression, hepatotoxicity, pneumonitis, mucositis; give with folic acid supplementation; rescue with leucovorin |
| Hydroxychloroquine | Immunomodulatory (inhibits TLR signaling, ↓cytokines) | SLE, RA | Retinal toxicity (annual eye exam), QT prolongation, neuromyopathy |
| TNF-α inhibitors | Block TNF-α (cytokine driving inflammation) | RA, Crohn's, psoriasis, ankylosing spondylitis | Infection risk (reactivation TB — screen before starting), demyelination, HF exacerbation, lymphoma risk |
| Colchicine | Binds tubulin → inhibits microtubule polymerization → ↓neutrophil migration | Acute gout, FMF, pericarditis | Diarrhea (most common), myelosuppression at high doses; narrow TI |
| Allopurinol / Febuxostat | Xanthine oxidase inhibitors → ↓uric acid production | Chronic gout prophylaxis, tumor lysis syndrome prevention | Allopurinol: SJS (especially HLA-B*5801), rash; reduce dose of 6-MP/azathioprine (XO metabolizes these) |
Rapid-Fire Clinical Pearls
Digoxin toxicity is enhanced by hypokalemia (digoxin and K+ compete for the same binding site on Na+/K+-ATPase). Classic ECG signs: scooped ST segments ("Salvador Dali mustache"), increased PR interval, bidirectional VT. Treatment: correct K+, digoxin-specific Fab fragments.
Nitroglycerin tolerance develops with continuous exposure (24-hour patches). The mechanism involves sulfhydryl group depletion and neurohormonal activation. Prevent tolerance with a 10–12-hour nitrate-free interval daily (typically overnight). This is a board-tested concept.
Rifampin is the most potent CYP inducer and turns all body fluids orange (urine, tears, sweat). It reduces the efficacy of oral contraceptives, warfarin, HIV protease inhibitors, cyclosporine, and virtually every CYP-metabolized drug. Always screen for rifampin interactions.
Metformin should be held before iodinated contrast procedures (risk of lactic acidosis in AKI from contrast nephropathy). Resume 48 hours after the procedure if renal function is stable. This is a common clinical practice question.
Aminoglycosides exhibit concentration-dependent killing: higher peak concentrations produce greater bactericidal activity. The post-antibiotic effect (PAE) allows extended-interval dosing (once-daily gentamicin), which improves efficacy and reduces nephrotoxicity by lowering trough levels. Monitor: peak levels for efficacy, trough levels for toxicity. Synergy with cell wall agents (penicillins) is used in endocarditis treatment.
Isoniazid (INH) is the cornerstone of TB therapy. Key facts: metabolized by N-acetyltransferase (NAT2) — slow acetylators (50% of Caucasians) are at higher risk for peripheral neuropathy (pyridoxine/B6 prophylaxis required) and hepatotoxicity. INH also inhibits CYP enzymes and is a monoamine oxidase inhibitor. Drug-induced lupus occurs with chronic use (anti-histone antibodies).
Warfarin is one of the most heavily tested drugs. Key interactions: (1) CYP2C9 inhibitors increase warfarin levels (fluconazole, amiodarone, metronidazole, TMP-SMX). (2) CYP inducers decrease warfarin levels (rifampin, carbamazepine, phenytoin, barbiturates). (3) Vitamin K–rich foods (leafy greens) decrease INR. (4) Broad-spectrum antibiotics kill gut flora that produce vitamin K → increase INR. Always check INR when adding/removing interacting drugs.
Lithium is the gold standard for bipolar disorder maintenance. Its narrow therapeutic index (0.6–1.2 mEq/L) means small changes in clearance cause toxicity. Anything that reduces renal lithium clearance is dangerous: thiazide diuretics, NSAIDs, ACE inhibitors, dehydration. Signs of toxicity: coarse tremor, ataxia, confusion, seizures, nephrogenic DI. Treatment: IV saline, hemodialysis for severe toxicity.
Azathioprine and 6-mercaptopurine are metabolized by xanthine oxidase. Co-administration with allopurinol (an XO inhibitor) dramatically increases levels of these drugs, causing severe myelosuppression. Reduce the azathioprine/6-MP dose by 75% if allopurinol must be used concurrently, or switch to an alternative agent. TPMT (thiopurine methyltransferase) polymorphisms also affect 6-MP metabolism — test before initiating therapy.
Exam Strategy
For pharmacology questions: (1) Identify the drug class from the stem (mechanism clues, suffix). (2) Know the mechanism of action — this predicts both therapeutic effects and side effects. (3) Recognize toxidromes and antidotes. (4) Understand pharmacokinetic principles (first-order vs zero-order, loading dose, CYP interactions). (5) Be comfortable with receptor pharmacology (G-protein subtypes, agonist vs antagonist curves). These five skills will answer the vast majority of pharmacology questions on any exam.