Core Science

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-HT_1B/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 K_d, the dissociation constant — lower K_d = 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 (E_max)	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 E_max)	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, GABA_A, 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
G_s	Stimulates adenylyl cyclase → ↑cAMP → PKA activation	β₁, β₂, D₁, H₂, V₂
G_i	Inhibits adenylyl cyclase → ↓cAMP	α₂, M₂, D₂, GABA_B, μ/δ-opioid
G_q	Activates phospholipase C → ↑IP₃ + DAG → Ca²⁺ release + PKC	α₁, M₁, M₃, H₁, V₁, AT₁

High-Yield Mnemonic

G_s = "Stimulatory" → ↑cAMP. G_i = "Inhibitory" → ↓cAMP. G_q = "qPLC" → IP₃/DAG/Ca²⁺. Remember: HAV₁ M₁AM₃ = H₁, α₁, V₁, M₁, AT₁, M₃ couple to G_q.

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
V_d	Volume of distribution — theoretical volume needed to contain total drug at plasma concentration
t_1/2	Half-life — time for plasma concentration to decrease by 50%
C_ss	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
E_max	Maximal effect achievable by a drug
K_d	Dissociation constant — concentration at which 50% of receptors are occupied
pK_a	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 (pK_a)	Non-ionized (uncharged) form crosses membranes	Aspirin (weak acid, pK_a 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 = (AUC_oral / AUC_IV) × 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 (V_d) = Amount of drug in body / Plasma drug concentration. V_d is a theoretical volume: a large V_d means the drug distributes extensively into tissues (is not primarily in plasma); a small V_d means it stays in the vascular compartment.

V_d Range	Interpretation	Examples
<5 L (~plasma volume)	Confined to plasma, high protein binding	Warfarin (V_d ~8 L), heparin
5–15 L (~ECF)	Distributes into extracellular fluid	Aminoglycosides (V_d ~15 L)
15–40 L (~TBW)	Distributes into total body water	Ethanol, phenytoin
>40 L	Extensive tissue binding/sequestration	Chloroquine (V_d ~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 = V_d × k_e	Determines maintenance dose: Dose rate = CL × C_ss
Half-life (t_1/2)	t_1/2 = 0.693 × V_d / CL	Steady state reached at ~4–5 half-lives; loading dose bypasses wait
Loading dose	LD = (V_d × C_target) / F	Achieves therapeutic level immediately (independent of clearance)
Maintenance dose	MD = (CL × C_ss) / 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% E_max — measure of potency), E_max (maximal achievable effect — measure of efficacy). Potency compares EC₅₀ values between drugs: a lower EC₅₀ means higher potency (left-shifted curve). Efficacy compares E_max values: a higher E_max 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), E_max unchanged	Decreased E_max, 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 N_N)	ACh (nicotinic N_N)
Postganglionic NT	Norepinephrine (NE) [exception: sweat glands use ACh]	ACh (muscarinic M_1–5)
Adrenal medulla	ACh (N_N) → releases epinephrine (80%) and NE (20%)	N/A

Adrenergic Receptor Subtypes

Receptor	G-Protein	Location	Effect of Stimulation
α₁	G_q	Vascular smooth muscle, iris dilator, bladder sphincter	Vasoconstriction, mydriasis, urinary retention
α₂	G_i	Presynaptic nerve terminals, CNS	↓NE release (negative feedback), sedation, ↓sympathetic outflow
β₁	G_s	Heart (SA node, AV node, myocardium)	↑HR (chronotropy), ↑contractility (inotropy), ↑conduction velocity
β₂	G_s	Bronchial smooth muscle, uterus, vasculature, liver	Bronchodilation, vasodilation, glycogenolysis, tocolysis
β₃	G_s	Adipose tissue, bladder detrusor	Lipolysis, bladder relaxation

Muscarinic Receptor Subtypes

Receptor	G-Protein	Location	Effect
M₁	G_q	CNS, gastric parietal cells, enteric neurons	CNS excitation, ↑gastric acid secretion
M₂	G_i	Heart (SA node, AV node, atrial muscle)	↓HR, ↓conduction velocity, ↓atrial contractility
M₃	G_q	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 M_1–5; 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	α_1A 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 (t_1/2 ~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 t_1/2 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 t_1/2 ~8 hrs) drops before factors II, IX, X (longer t_1/2). 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 (I_f) 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 GABA_A 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 t_1/2)	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 GABA_A 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-HT_2A 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-HT_2A 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)	G_i	Analgesia (supraspinal), euphoria, respiratory depression, miosis, constipation, physical dependence	Morphine, fentanyl, methadone, heroin
κ (kappa)	G_i	Analgesia (spinal), sedation, dysphoria, miosis	Butorphanol, nalbuphine, pentazocine
δ (delta)	G_i	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 t_1/2 (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 t_1/2 (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 t_1/2 (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: GABA_A (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 GABA_A, 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 N_M 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)	↑GABA_A 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 K_ATP 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 → G_s → ↑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 t_1/2 — 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; t_1/2 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 V_d for lipophilic drugs (longer t_1/2), decreased V_d 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 V_d 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 E_max); non-competitive antagonists reduce E_max
2	Potency = EC₅₀ (left on curve = more potent); Efficacy = E_max (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	G_s → ↑cAMP (β₁, β₂, D₁, H₂, V₂); G_i → ↓cAMP (α₂, M₂, D₂, opioid); G_q → PLC/IP₃/DAG (α₁, M₁, M₃, H₁, V₁)
9	Benzodiazepines increase frequency of GABA_A 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.