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📚 Comprehensive MBBS Learning Note: Pharmacokinetics & Pharmacodynamics

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PART 1: PHARMACOKINETICS (PK)

The simple definition: Pharmacokinetics is what the body does to the drug — how it moves, changes, and is removed. The classic mnemonic is ADME: Absorption → Distribution → Metabolism → Excretion.

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1.1 — ABSORPTION

Key concept: Passive diffusion governs most absorption

• Lipophilic (fat-soluble) — crosses the lipid bilayer easily
• Uncharged / non-ionized — charged molecules are repelled by the hydrophobic membrane interior

The pH-Partition Hypothesis

Henderson-Hasselbalch equation: For a weak acid: pH = pKa + log([A⁻]/[HA])

Other Factors Affecting Absorption

• Gastric emptying rate — faster emptying → faster drug delivery to intestine → faster absorption
• Blood flow — more blood = faster removal of absorbed drug = maintained concentration gradient
• Particle size / formulation — finer particles dissolve faster
• Drug interactions — antacids, food, other drugs can chelate, bind, or alter pH
• Gut motility — diarrhea reduces absorption; constipation may increase it

Routes of Administration & Their Significance

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1.2 — BIOAVAILABILITY (F)

• IV has F = 1 (100%) by definition
• Oral F may be reduced by:
  1. Poor absorption (lipophilic, low solubility)
  2. Gut wall metabolism (intestinal CYP3A4)
  3. First-pass effect (hepatic)

First-Pass Effect (Pre-systemic Elimination)

• GTN (nitroglycerin) has >90% first-pass extraction → must be given sublingually or transdermally
• This is why oral morphine doses are much higher than IV doses

Bioequivalence

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1.3 — DISTRIBUTION

Key Factors in Distribution

1. Blood flow to organ — highly perfused organs (brain, heart, kidneys, liver) receive drug first
2. Plasma protein binding — drugs bind to albumin (acidic drugs) or α₁-acid glycoprotein (basic drugs)
3. Tissue binding — drugs may accumulate in fat, bone, etc.
4. Lipophilicity — lipophilic drugs penetrate cell membranes and CNS easily
5. Drug ionization — non-ionized form crosses membranes

Plasma Protein Binding

• Most drugs reversibly bind to plasma proteins (mainly albumin)
• Only the free (unbound) fraction is pharmacologically active, can diffuse to tissues, and can be metabolized/excreted
• Protein binding is saturable and drugs can compete for binding sites

• Warfarin is ~99% protein-bound → adding another highly protein-bound drug can displace it → more free warfarin → bleeding risk
• Hypoalbuminemia (liver disease, nephrotic syndrome) → more free drug → enhanced effect or toxicity

Volume of Distribution (Vd)

• Large Vd → drug hard to remove by dialysis (it's sequestered in tissues)
• Loading dose = Vd × target concentration

Redistribution

• Rapid onset of anesthesia (seconds) — brain is highly perfused
• Effect wears off in minutes — redistribution to muscle then fat
• Drug is still in body; repeated doses cause cumulation and prolonged effect

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1.4 — METABOLISM (Biotransformation)

Key principle: Metabolism usually (not always) inactivates drugs and makes them more hydrophilic for excretion. But there are important exceptions.

Where does metabolism occur?

• Liver — primary site (richest in CYP enzymes)
• Gut wall (intestinal CYP3A4)
• Kidneys, lungs, plasma (minor)

Phase I Reactions — Functionalization

Phase II Reactions — Conjugation

Important Pharmacokinetic Concepts Related to Metabolism

• Codeine → morphine (by CYP2D6)
• Clopidogrel → active thiol metabolite (by CYP2C19)
• Enalapril → enalaprilat
• Prednisone → prednisolone

• Paracetamol → NAPQI (N-acetyl-p-benzoquinoneimine) via CYP2E1 at high doses → hepatotoxicity; rescued by N-acetylcysteine (NAC)
• Methanol → formaldehyde → formic acid → blindness/death

Genetic Polymorphisms (Pharmacogenomics)

• Ultrarapid metabolizers — duplicate gene copies; drug metabolized too fast → reduced effect (e.g., codeine → excessive morphine accumulation in UMs!)
• Extensive metabolizers — normal (most people)
• Intermediate metabolizers
• Poor metabolizers — loss-of-function alleles; drug accumulates → toxicity

• Slow acetylators (common in Europeans, Middle Eastern) — isoniazid accumulates → peripheral neuropathy (prevented by pyridoxine)
• Fast acetylators (common in Asians) — may have reduced isoniazid efficacy

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1.5 — EXCRETION

Renal Excretion (most important route)

• Alkalinization of urine (with NaHCO₃) traps weak acids in ionized form → more excretion. Used in aspirin/salicylate overdose and phenobarbital overdose.
• Acidification of urine traps weak bases → more excretion. (Historically used in amphetamine overdose; now rarely done)

• Drugs with high renal excretion accumulate in renal failure → dose reduction needed
• Examples: aminoglycosides, digoxin, lithium, metformin (lactic acidosis risk)

Biliary Excretion & Enterohepatic Circulation

• Some drugs are conjugated (mainly glucuronides) in the liver and secreted into bile → intestine
• In the intestine, gut bacteria hydrolyze the conjugate → releases the parent drug → reabsorbed → back to liver
• This enterohepatic recycling prolongs the drug's half-life
• Examples: estrogens (in OCP), morphine, digoxin, bile acids
• Clinical significance: Antibiotics that kill gut flora (e.g., ampicillin) can disrupt enterohepatic circulation of OCP estrogens → reduce contraceptive efficacy (though this is now debated)

Other Routes of Excretion

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1.6 — CLINICAL PHARMACOKINETICS

Half-Life (t½)

• Vd = volume of distribution
• CL = clearance
• 0.693 = ln 2

• After 1 t½: 50% remains
• After 2 t½: 25% remains
• After 3 t½: 12.5% remains
• After 4–5 t½: ~97% eliminated (clinically considered fully eliminated)
• Drugs reach steady state (accumulation equilibrium) after 4–5 half-lives

• A drug with t½ = 4 hours reaches steady state in 20 hours → when to check levels
• A drug with t½ = 8 days (e.g., amiodarone: t½ up to 40 days!) takes weeks to clear

Clearance (CL)

• Total body clearance = hepatic CL + renal CL + other CL
• Clearance determines the maintenance dose required to maintain a target concentration

Zero-Order vs First-Order Kinetics

Area Under the Curve (AUC)

• The AUC represents the total drug exposure over time
• Used to calculate bioavailability, clearance
• Higher AUC = more drug exposure = potentially more effect AND toxicity

Loading Dose vs Maintenance Dose

Steady State

• Reached after 4–5 t½
• At steady state, Cmax (peak) and Cmin (trough) remain constant between doses
• Trough levels are measured just before the next dose — used for TDM (therapeutic drug monitoring) of vancomycin, aminoglycosides, digoxin, phenytoin, lithium

Therapeutic Drug Monitoring (TDM)

• Narrow therapeutic index (TI) — small difference between effective and toxic dose
• High inter-individual variability in pharmacokinetics
• Concentration-dependent toxicity

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PART 2: PHARMACODYNAMICS (PD)

The simple definition: Pharmacodynamics is what the drug does to the body — how it produces its effect at the molecular and tissue level.

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2.1 — DRUG RECEPTORS

What is a Receptor?

Drug-Receptor Bonds

Drug Shape, Stereochemistry & Chirality

• Most drugs are chiral (over half of all useful drugs) — they exist as enantiomeric pairs
• Often only one enantiomer is pharmacologically active
• Examples:
  • (S)-warfarin is 3–5× more potent than (R)-warfarin
  • (S)-amlodipine is the active form
  • Levodopa — only L-DOPA is active (not D-DOPA)
  • Thalidomide — (R) form is sedative; (S) form was teratogenic — but they interconvert in vivo

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2.2 — RECEPTOR TYPES (The Four Superfamilies)

Type I — Ligand-Gated Ion Channels (Ionotropic Receptors)

• Mechanism: Ligand binding directly opens an ion channel
• Signal speed: Milliseconds — fastest signaling
• Location: Cell surface
• Examples:

Type II — G-Protein-Coupled Receptors (GPCRs / Metabotropic Receptors)

• Structure: 7 transmembrane-spanning domains (7-TM receptors)
• Mechanism: Ligand → activates coupled G-protein (Gα subunit dissociates) → activates/inhibits effector enzyme → second messenger cascade
• Speed: Seconds to minutes
• ~50% of all drugs target GPCRs

• cAMP pathway: Drug → Gs → ↑ adenylyl cyclase → ↑ cAMP → activates PKA → phosphorylates proteins → effect
• IP₃/DAG pathway: Drug → Gq → ↑ PLC → IP₃ (releases Ca²⁺ from ER) + DAG (activates PKC)

Type III — Enzyme-Linked Receptors (Receptor Tyrosine Kinases, RTKs)

• Structure: Single transmembrane domain; intracellular enzymatic domain
• Mechanism: Ligand binding → receptor dimerization → autophosphorylation of tyrosine residues → downstream signaling (MAPK, PI3K/Akt pathways)
• Speed: Minutes to hours
• Examples:

• Ligand → receptor dimerization → JAK activation → phosphorylates STAT transcription factors → gene expression
• Targets: ruxolitinib (JAK1/2 inhibitor) for myelofibrosis, tofacitinib for RA

Type IV — Nuclear Receptors (Intracellular / Transcription Factor Receptors)

• Location: Cytoplasm or nucleus
• Mechanism: Drug/ligand enters cell (must be lipophilic), binds intracellular receptor → receptor-ligand complex moves to nucleus → binds DNA response elements → alters gene transcription
• Speed: Hours to days (slowest onset; but effects can persist long)
• Examples:

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2.3 — DOSE-RESPONSE RELATIONSHIPS

Graded Dose-Response Curve

• Threshold dose: Minimum dose producing a measurable effect
• EC₅₀ (Effective Concentration 50%): Concentration producing 50% of the maximal effect — indicates potency
• Emax: Maximum achievable effect — indicates efficacy (intrinsic activity)

Effect
  |                           ___________Emax
  |                       __/
  |                   ___/
  |               ___/
  |           ___/
  |_______---/
  |_________________________ Log [Dose]
              ↑
             EC50

Potency vs Efficacy — A Critical Distinction

MBBS exam trick: A drug can be low-potency but high-efficacy (e.g., aspirin — needs grams but fully anti-inflammatory). Or high-potency but low-efficacy (e.g., a partial agonist — little drug needed but ceiling effect).

Quantal Dose-Response Curve

• ED₅₀ — Dose effective in 50% of the population
• TD₅₀ — Dose toxic in 50% of the population
• LD₅₀ — Lethal dose in 50% of the population

• High TI = safer drug (wide therapeutic window) — e.g., penicillin
• Low TI = dangerous drug (narrow window) — e.g., digoxin, warfarin, lithium, phenytoin, aminoglycosides, cyclosporine

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2.4 — AGONISTS AND ANTAGONISTS

Agonists

• Buprenorphine as an analgesic: ceiling on respiratory depression (safer in overdose) but also ceiling on analgesia
• Pindolol (partial β-agonist): has intrinsic sympathomimetic activity (ISA) — doesn't lower resting heart rate as much as pure β-blockers

Antagonists

Competitive Antagonists

• Compete with agonist for the same binding site (orthosteric site)
• Surmountable — increasing agonist concentration overcomes the block
• Shift the dose-response curve to the right (parallel shift) — Emax unchanged, EC₅₀ increased

Non-Competitive Antagonists

• Bind to a different site (allosteric site) on the receptor, OR bind irreversibly to the orthosteric site
• Insurmountable — even high agonist concentrations cannot fully overcome the block
• Reduce the Emax (flatten the curve) without shifting the EC₅₀ (unless allosteric, in which case both shift and depress the curve)

• Phenoxybenzamine (irreversible α-blocker) — used in pheochromocytoma
• Ketamine (non-competitive NMDA antagonist — blocks the channel pore)
• Amlodipine (binds to a different site than verapamil on voltage-gated Ca²⁺ channels)

Functional/Physiological Antagonism

• Adrenaline vs histamine (for anaphylaxis — adrenaline counteracts the histamine-mediated bronchoconstriction and vasodilation)
• Glucagon vs insulin (opposing effects on blood glucose)

Chemical Antagonism

• Protamine sulfate neutralizes heparin (ionic interaction)
• Chelating agents (EDTA, desferrioxamine) bind metal ions

Pharmacokinetic Antagonism

• Activated charcoal — reduces gut absorption of another drug
• Enzyme inducers (rifampicin) — increase metabolism of another drug

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2.5 — RECEPTOR REGULATION

Desensitization / Tachyphylaxis

• Rapid loss of response to an agonist with repeated or continuous exposure
• Mechanisms:
  • Receptor phosphorylation → uncoupling from G-protein (β-arrestin recruitment)
  • Receptor internalization (endocytosis) — reduces surface receptor number
  • Receptor downregulation — reduced synthesis or increased degradation
• Example: β₂-adrenergic receptor in asthma — overuse of salbutamol → tolerance → poorer symptom control
• Example: Tachyphylaxis to ephedrine (indirect sympathomimetic) — depletes noradrenaline stores

Sensitization / Supersensitivity

• Prolonged receptor blockade → upregulation of receptors (increased number + sensitivity)
• Example: Chronic use of β-blockers → upregulation of β-receptors → abrupt withdrawal → rebound tachycardia, angina, hypertensive crisis
• Denervation supersensitivity: after cutting a nerve, the target tissue becomes hypersensitive to the neurotransmitter (Cannon's law)

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2.6 — DRUG INTERACTIONS AT THE PHARMACODYNAMIC LEVEL

Synergism

• Additive: 1 + 1 = 2 (e.g., two ACE inhibitors at half doses)
• Supra-additive (potentiation): 1 + 1 > 2 (e.g., alcohol + benzodiazepines → extreme CNS depression; trimethoprim + sulfamethoxazole → synergistic antibacterial action against sequential steps in folate synthesis)

Antagonism

• Pharmacodynamic antagonism: β-blockers reduce efficacy of β-agonists in asthma
• Functional antagonism: Already described above

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2.7 — SPECIAL PHARMACODYNAMIC CONCEPTS

Efficacy vs Effectiveness

• Efficacy = how well a drug works under ideal (controlled trial) conditions
• Effectiveness = how well it works in real-world clinical practice

Tolerance

• Pharmacokinetic tolerance: Enzyme induction (e.g., alcohol induces CYP2E1 → metabolizes itself faster in chronic drinkers)
• Pharmacodynamic tolerance: Receptor downregulation/desensitization (e.g., opioid tolerance — requires escalating doses)
• Tachyphylaxis: Rapid tolerance after just a few doses (e.g., nitrates, ephedrine)

Drug Dependence

• Physical dependence: Withdrawal syndrome on stopping (e.g., opioids, alcohol, benzodiazepines, β-blockers)
• Psychological dependence: Craving without physical withdrawal
• Note: Physical dependence ≠ addiction; even cancer patients on opioids develop physical dependence

Idiosyncratic Reactions

• Primaquine → hemolytic anemia in G6PD-deficient patients
• Halothane → hepatitis (in susceptible individuals)
• Malignant hyperthermia with volatile anesthetics in RYR1-mutation carriers
• Aplastic anemia with chloramphenicol

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PART 3: INTEGRATION — PK/PD RELATIONSHIPS

3.1 — PK/PD Models

3.2 — Time-Dependent vs Concentration-Dependent Antibiotics

3.3 — Why PK/PD Matters Clinically

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PART 4: QUICK REFERENCE MNEMONICS & HIGH-YIELD SUMMARIES

ADME in one sentence:

Remembering CYP Inducers: "PC BRAS"

• Phenytoin
• Carbamazepine
• Barbiturates (phenobarbital)
• Rifampicin (most potent inducer)
• Alcohol (chronic)
• St John's Wort

Remembering CYP Inhibitors: "SICKFACES.COM"

• Sodium valproate
• Isoniazid
• Cimetidine
• Ketoconazole
• Fluconazole
• Alcohol (acute)
• Chloramphenicol
• Erythromycin / Clarithromycin
• Sulfonamides
• Ciprofloxacin
• Omeprazole
• Metronidazole

Narrow Therapeutic Index Drugs: "PLaTiNum DiGiTaL"

• Phenytoin, Lithium, Theophylline, New warfarin, Digoxin, Gentamicin (aminoglycosides), Tacrolimus / cyclosporine, Lamotrigine

Receptor Types — Easy Memory Aid:

• Type I = Ion channel = Instant (milliseconds)
• Type II = G-Protein coupled = Plenty of examples, Seconds
• Type III = Tyrosine kinase = Three domains, minutes
• Type IV = NucLear = Long time (hours)

Half-life Rule of 5:

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PART 5: EXAM-READY KEY FACTS AT A GLANCE

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