Principles of Clinical Pharmacology

Principles of Clinical Pharmacology - Drug's Journey

Pharmacokinetics (PK): What body does to drug (ADME).

• Absorption: Drug entry to systemic circulation.
  • Bioavailability ($F$): Fraction of unchanged drug reaching systemic circulation. $F = (\text{AUC}\text{oral} / \text{AUC}\text{IV}) \times (\text{Dose}\text{IV} / \text{Dose}\text{oral})$.
  • First-pass metabolism: Pre-systemic hepatic metabolism (↓$F$ oral).
• Distribution: Drug movement from blood to tissues.
  • Volume of Distribution ($V_d$): Apparent volume drug occupies. $V_d = \text{Dose} / C_0$.
  • Protein binding: Influences free drug.
• Metabolism: Chemical drug alteration.
  • Phase I: Oxidation, reduction, hydrolysis (CYP450).
  • Phase II: Conjugation (glucuronidation).
• Excretion: Drug removal.
  • Routes: Renal, hepatic.
  • Clearance ($Cl$): Plasma volume cleared per unit time. $Cl = k \times V_d$.
  • Half-life ($t_{1/2}$): Time for drug conc. to halve. $t_{1/2} = (0.693 \times V_d) / Cl$.

⭐ Zero-order kinetics drugs: Warfarin, Aspirin, Phenytoin, Ethanol, Theophylline - 📌 WAP-ET Zero.

Principles of Clinical Pharmacology - Drug's Power Play

• Pharmacodynamics (PD): Drug's action on body; mechanisms.
• Receptors: Cellular targets for drugs.
  • Types: Ion channels, GPCRs, Enzyme-linked, Intracellular.
• Drug-Receptor Interactions:
  • Agonist: Activates receptor (Full, Partial, Inverse).
  • Antagonist: Blocks agonist action (Competitive, Non-competitive).
• Dose-Response Curve (DRC): Relates dose to effect.
  • Graded: Effect intensity vs. dose.
    • Efficacy ($E_{max}$): Maximum possible effect.
    • Potency ($ED_{50}$): Dose for 50% of $E_{max}$.
  • Quantal: All-or-none response (e.g., $ED_{50}$, $LD_{50}$).
  • Therapeutic Index (TI): $TI = TD_{50} / ED_{50}$; drug safety margin.

⭐ Spare receptors increase sensitivity to agonists, allowing maximal response without occupying all receptors.

• Key Concepts:
  • Tolerance: Decreased drug effect with repeated use.
  • Tachyphylaxis: Rapidly diminishing response.
  • Synergism: Enhanced combined effect (1+1 > 2). and potency (ED50))

Principles of Clinical Pharmacology - It Depends!

Drug response varies significantly due to multiple factors, necessitating individualized therapy.

• Age:
  • Pediatrics: Immature organ function (e.g., Gray baby syndrome - chloramphenicol).
  • Geriatrics: ↓ renal/hepatic function, polypharmacy, ↑ sensitivity (e.g., benzodiazepines).
• Pharmacogenomics: Genetic variants impact drug metabolism/response.
  • E.g., CYP2D6 (codeine), TPMT (azathioprine), NAT2 (isoniazid).
• Disease States:
  • Renal/Hepatic dysfunction: Requires dose adjustments (e.g., ↓ digoxin in renal failure).
• Drug Interactions: One drug alters another's effect.

  Type	Mechanism	Example
  Pharmacokinetic	Altered ADME (e.g., CYP enzyme activity)	Rifampicin (inducer) ↓ warfarin effect
  Pharmacodynamic	Additive/Opposing effects at target	Beta-blockers + Verapamil → severe bradycardia

⭐ Grapefruit juice is a potent CYP3A4 inhibitor, significantly increasing levels of drugs like statins and calcium channel blockers.

Principles of Clinical Pharmacology - Safety First

• Adverse Drug Reactions (ADRs): Harmful drug effects.
  • 📌 Mnemonic: Augmented, Bizarre, Chronic, Delayed, End-of-use, Failure.
  • Types:

    Type	Description	Example
    A	Augmented, dose-dependent	Insulin hypoglycemia
    B	Bizarre, non-dose-dependent	Penicillin allergy
    C	Chronic, dose & time-related	NSAID nephropathy
    D	Delayed, time-related	Carcinogenesis
    E	End-of-use, withdrawal	Opioid withdrawal
    F	Failure of therapy	Antibiotic resistance

  ⭐ Type B (Bizarre) ADRs are unpredictable, not dose-dependent, and often immune-mediated (e.g., penicillin allergy).

• Pharmacovigilance (PV): ADR detection, assessment, understanding, prevention. Report to PvPI.

• Therapeutic Drug Monitoring (TDM): Optimizes dose via drug levels. For NTI drugs (Digoxin, Lithium, Phenytoin).
• Rational Drug Use (RDU): Right drug, dose, duration, cost.

High‑Yield Points - ⚡ Biggest Takeaways

• Pharmacokinetics (ADME) defines drug journey; Pharmacodynamics its action and effects.
• Bioavailability (F): fraction reaching circulation; reduced by first-pass metabolism.
• Half-life (t½) determines dosing frequency and steady state achievement (typically 4-5 half-lives).
• Therapeutic Index (TI): crucial for safety; narrow TI drugs demand close monitoring.
• Volume of Distribution (Vd) indicates tissue penetration; Clearance (CL) reflects elimination efficiency.
• Drug action involves receptors: agonists activate, antagonists inhibit.
• Dose-response relationships quantify drug efficacy and potency.