General Pharmacology

🟢 Lite — Quick Review (1h–1d)

Rapid summary for last-minute revision before your exam.

General Pharmacology — Key Facts for FMGE Core concept: Understanding how drugs are absorbed, distributed, metabolized, and excreted (ADME) determines dosing and toxicity High-yield point: First-pass metabolism, zero-order vs first-order kinetics, and therapeutic index are commonly tested ⚡ Exam tip: Most FMGE pharmacology questions ask you to identify drug interactions or contraindications based on pharmacokinetic principles

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🟡 Standard — Regular Study (2d–2mo)

Standard content for students with a few days to months.

General Pharmacology — FMGE Study Guide

Pharmacokinetics (ADME)

Absorption

Routes of administration:

• Oral: Most common; subject to first-pass metabolism (liver)
• IV: Bypasses first-pass; immediate effect; no absorption phase
• IM: Better absorption than SC; depends on blood flow
• SC: Slower than IM; useful for depot preparations
• Topical: Local effect; some systemic absorption
• Inhalation: Rapid absorption via alveoli; no first-pass

Factors affecting absorption:

• Bioavailability (F): Fraction of drug reaching systemic circulation unchanged
  • F = (AUC oral)/(AUC IV) × 100
  • IV = 100% (absolute bioavailability)
  • High first-pass = low bioavailability (e.g., propranolol, nitroglycerin)
• Ionization: Weak acids (aspirin) absorbed better in acidic stomach; weak bases in intestine
• Lipophilicity: More lipophilic drugs cross membranes more easily

First-pass metabolism:

• Drug absorbed from GI tract → portal circulation → liver → systemic circulation
• Some drugs extensively metabolized in liver on first pass → low bioavailability
• Examples: Propranolol (60-80%), morphine (20-40%), lidocaine (35%)
• Drugs with high first-pass should not be given orally in acute situations (IV instead)

Distribution

Volume of distribution (Vd):

• Vd = (Amount of drug in body)/(Plasma concentration)
• Theoretical volume that would be needed to contain total drug at plasma concentration
• High Vd (>40 L): Drug distributes into tissues (deep compartment) - amphiphilic, highly lipid-soluble
• Low Vd (<20 L): Drug remains primarily in plasma (albumin-bound)

Protein binding:

• Albumin: Binds acidic drugs (warfarin, sulfonamides, NSAIDs)
• Alpha-1 glycoprotein: Binds basic drugs (propranolol, lidocaine)
• Displacement interactions: Two drugs compete for binding sites → increased free concentration of one drug
  • Example: Warfarin + sulfonamides → bleeding (sulfonamides displace warfarin from albumin)
• Only free (unbound) drug is pharmacologically active

Blood-brain barrier:

• Tight junctions between endothelial cells
• Only lipophilic, non-ionized drugs cross
• Example: Dopamine (polar) doesn’t cross; L-dopa (less polar) crosses and is converted to dopamine in brain

Placental transfer:

• Most drugs can cross placenta to some extent
• Category X (contraindicated): Thalidomide, isotretinoin, methotrexate, warfarin
• Category A (safest): Folate, levothyroxine

Metabolism

Phase I reactions (Functionalization):

• Oxidation, reduction, hydrolysis by cytochrome P450 system (CYP450)
• CYP450 enzymes: Located in liver smooth ER (Heme iron in active site)
• CYP3A4: Most abundant; metabolizes ~50% of drugs
• CYP2D6: Polymorphic; codeine (prodrug) → morphine (in CYP2D6 extensive metabolizers)
• Inducers (increase CYP activity): Rifampin, carbamazepine, phenytoin, chronic alcohol, St. John’s wort
• Inhibitors (decrease CYP activity): Ketoconazole, erythromycin, cimetidine, grapefruit juice, acute alcohol

Phase II reactions (Conjugation):

• Glucuronidation, sulfation, acetylation, methylation
• Generally makes drug more water-soluble for renal excretion
• Example: Morphine → morphine-6-glucuronide (active metabolite)

Zero-order kinetics:

• Constant amount of drug eliminated per unit time (regardless of concentration)
• Occurs at high drug concentrations when enzymes are saturated
• Examples: Phenytoin, aspirin at high doses, ethanol
• T1/2 increases as concentration increases (unlike first-order)

First-order kinetics:

• Fraction of drug eliminated per unit time is constant
• Most drugs follow first-order kinetics
• T1/2 is constant regardless of concentration
• First-order equation: C = C0 × e^(-kt)

Loading dose calculation:

• Loading dose = (Vd × target plasma concentration) / bioavailability (F)
• Used when rapid attainment of steady state is needed

Steady state:

• Reached after 4-5 half-lives (97% of steady state)
• Constant rate infusion: Steady state = (Clearance × desired plasma concentration) / infusion rate

Excretion

Renal excretion:

• Glomerular filtration (free drug + bound drug? → only free drug filtered)
• Tubular secretion (active transport - increases elimination)
• Tubular reabsorption (passive - drugs reabsorbed if reabsorb water; acidification increases excretion of basic drugs)
• Cockcroft-Gault equation: Estimates creatinine clearance (used for drug dosing in renal impairment)

Biliary excretion:

• Some drugs excreted in bile → feces
• Enterohepatic circulation: Drug secreted in bile → absorbed from intestine → back to liver
• Prolongs drug effect
• Example: Digoxin (some biliary excretion), some estrogens

Other routes:

• Pulmonary: Volatile anesthetics (exhaled)
• Saliva, sweat, breast milk (important for lactating mothers)

Pharmacodynamics

Mechanisms of Drug Action

Agonists:

• Bind to receptor and produce response
• Full agonist: Maximal response
• Partial agonist: Submaximal response even at high concentrations (e.g., buprenorphine)
• Inverse agonist: Produces opposite effect to agonist (e.g., some antihistamines)

Antagonists:

• Bind to receptor without producing effect
• Competitive antagonist: Reversible; can be overcome by increasing agonist concentration
• Non-competitive antagonist: Irreversible; cannot be overcome by increasing agonist
• Physiological antagonist: Acts at different receptor to produce opposite effect (e.g., histamine vs epinephrine for anaphylaxis)

Receptor Types

G-protein coupled receptors (GPCR):

• Gs: ↑cAMP → stimulatory effects (β-agonists, glucagon)
• Gi: ↓cAMP → inhibitory effects (α2-agonists, adenosine)
• Gq: ↑IP3/DAG → ↑intracellular Ca²⁺ (α1-agonists, muscarinic M1, M3)
• G11: Opening of Ca²⁺-activated K⁺ channels (muscarinic M2)

Ligand-gated ion channels:

• Nicotinic ACh receptors (Na⁺ influx)
• GABA-A receptors (Cl⁻ influx → hyperpolarization)
• NMDA/glutamate receptors (Ca²⁺ influx)

Enzyme-linked receptors:

• Insulin receptor (tyrosine kinase)
• ANP receptor (guanylyl cyclase → ↑cGMP)

Nuclear receptors:

• Steroid hormones, thyroid hormone (intracellular receptors → gene transcription changes)
• Slower onset but longer duration of effect

Therapeutic Index

Therapeutic Index (TI) = TD50/ED50

• Higher TI = safer drug (wide margin between effective and toxic doses)
• Low TI drugs: Warfarin (2-3), digoxin (2), lithium (3), theophylline (4)
• Narrow therapeutic index drugs: Require therapeutic drug monitoring

Half-maximal effective concentration (EC50):

• Concentration at which 50% of maximal effect is achieved
• Lower EC50 = more potent drug

Drug Interactions

Pharmacokinetic interactions:

• Absorption: Antacids chelate tetracyclines; cholestyramine binds other drugs
• Distribution: Sulfonamides displace warfarin
• Metabolism: CYP450 inducers/inhibitors
• Excretion: Probenecid blocks uric acid secretion (and other drugs)

Pharmacodynamic interactions:

• Synergistic: Two drugs with similar effects (e.g., benzodiazepine + alcohol = CNS depression)
• Additive: Sum of effects
• Antagonistic: One drug reduces effect of another

Adverse Drug Reactions

Type A (Predictable, dose-dependent):

• Extensions of pharmacological effect
• Examples: Respiratory depression with opioids, bleeding with warfarin
• Can be avoided by careful dosing

Type B (Unpredictable, dose-independent):

• Idiosyncratic: Genetic deficiency (G6PD + sulfonamides = hemolysis)
• Allergic/immune: IgE-mediated (penicillin anaphylaxis)
• Pseudoallergic: Direct mast cell degranulation (radiocontrast, vancomycin “red man syndrome”)

Teratogenicity:

• Thalidomide: Limb defects (phocomelia)
• Isotretinoin: Severe malformations
• Warfarin: Warfarin embryopathy (nasal hypoplasia, stippled epiphyses)
• ACE inhibitors: Fetal renal damage
• Category X drugs: Contraindicated in pregnancy

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