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Introduction to Clinical Pharmacology

1. What is Clinical Pharmacology?

• Pharmacokinetics (PK) – what the body does to the drug
• Pharmacodynamics (PD) – what the drug does to the body
• Therapeutic monitoring – optimizing dosing in individual patients
• Rational pharmacotherapy – evidence-based, goal-directed drug prescribing

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2. Fundamentals of Rational Pharmacotherapy

Core Principles

The WHO Model of Rational Drug Use

• Polypharmacy without indication
• Inappropriate dose/duration
• Underuse of effective drugs (e.g., underprescribing statins in high CV-risk patients)
• Failure to account for drug interactions

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3. Pharmacokinetics (PK)

"The processes of absorption, distribution, metabolism, and excretion — collectively termed drug disposition — determine the concentration of drug delivered to target effector molecules." — Harrison's Principles of Internal Medicine, 21st Ed., p. 1884

ADME Framework

Drug administered → Absorption → Distribution → Metabolism → Excretion

A — Absorption

• Transfer of drug from the site of administration into systemic circulation
• Governed by bioavailability (F): fraction of administered dose reaching systemic circulation
  • IV route: F = 100%
  • Oral route: reduced by first-pass hepatic metabolism
• Key factors: lipophilicity, molecular size, ionization (pH-partition theory), GI motility, formulation

D — Distribution

• Movement of drug from blood into tissues
• Volume of distribution (Vd) = theoretical volume needed to contain total body drug at plasma concentration
  • Small Vd (e.g., warfarin ~10 L): confined to plasma, highly protein-bound
  • Large Vd (e.g., chloroquine ~200–800 L): extensive tissue accumulation
• Factors: protein binding (albumin, α₁-acid glycoprotein), tissue perfusion, blood-brain barrier, lipophilicity

M — Metabolism (Biotransformation)

• Primarily hepatic; also GI wall, lung, kidney
• Phase I reactions: oxidation, reduction, hydrolysis (CYP450 enzymes, especially CYP3A4, CYP2D6, CYP2C9, CYP2C19)
• Phase II reactions: conjugation (glucuronidation, sulfation, acetylation) → increased water solubility → easier excretion
• Prodrugs: require metabolism for activation (e.g., codeine → morphine via CYP2D6; clopidogrel → active thienopyridine via CYP2C19)
• Enzyme induction (e.g., rifampicin, carbamazepine) → accelerated drug metabolism → sub-therapeutic levels
• Enzyme inhibition (e.g., fluconazole, erythromycin) → reduced clearance → drug toxicity

E — Excretion

• Renal (main route for hydrophilic drugs): glomerular filtration, tubular secretion, tubular reabsorption
• Biliary/fecal: for large molecules, conjugated drugs; enterohepatic recirculation prolongs effect
• Others: lungs (volatile agents), breast milk, sweat

Key PK Parameters

Steady State

• Achieved after ~5 half-lives of repeated dosing
• At steady state: rate of input = rate of elimination
• Loading dose can be used to achieve therapeutic levels rapidly when t½ is long (e.g., amiodarone, digoxin)

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4. Pharmacodynamics (PD)

Drug-Receptor Interactions

• Most drugs act on receptors (proteins on cell surfaces or intracellularly)
• Types of receptors:
  • Ligand-gated ion channels (e.g., nicotinic ACh receptor, GABA-A): fast effects (milliseconds)
  • G-protein-coupled receptors (GPCRs) (e.g., β-adrenergic, muscarinic): second messenger systems (cAMP, IP₃/DAG)
  • Receptor tyrosine kinases (e.g., insulin receptor): phosphorylation cascades
  • Nuclear receptors (e.g., glucocorticoid receptor): gene transcription regulation

Key PD Concepts

Dose-Response Relationships

• Graded dose-response: continuous relationship between dose and effect in an individual
• Quantal dose-response: all-or-none response in a population → ED50, TD50, LD50

Tolerance and Tachyphylaxis

• Tolerance: diminished response with repeated exposure (e.g., opioids, nitrates)
• Tachyphylaxis: rapid development of tolerance within hours (e.g., ephedrine, amphetamines)
• Mechanisms: receptor downregulation, desensitization, increased metabolism, physiological adaptation

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5. Therapeutic Drug Monitoring (TDM)

Indications for TDM

1. Narrow therapeutic index – small margin between effective and toxic concentrations
2. Large inter-individual PK variability – genetic polymorphisms, organ impairment
3. Non-linear pharmacokinetics – dose-proportional changes do not apply (e.g., phenytoin, ethanol)
4. Concentration-effect relationship is well established
5. Clinical endpoint is difficult to assess (e.g., seizure prophylaxis, immunosuppression)

Drugs Commonly Monitored

Timing of Blood Samples

• Trough level: drawn just before the next dose → reflects minimum concentration; most commonly used
• Peak level: drawn at defined time after dose → reflects maximum concentration; important for aminoglycosides (concentration-dependent killing)
• AUC-based monitoring: gold standard for vancomycin and some antifungals

Factors Affecting Interpretation

• Protein binding (only free drug is pharmacologically active)
• Timing of sample relative to last dose
• Route and formulation
• Drug interactions
• Organ function (renal, hepatic impairment)
• Genetic polymorphisms (pharmacogenomics)

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6. Pharmacogenomics

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7. Drug Interactions

Pharmacokinetic Interactions (alter drug levels)

• Absorption: antacids chelate fluoroquinolones/tetracyclines
• Protein binding: warfarin displaced by NSAIDs (modest clinical significance)
• Metabolism (CYP): rifampicin (inducer) reduces efficacy of OCP, antivirals; azole antifungals (inhibitors) increase levels of statins, cyclosporine
• Renal excretion: probenecid inhibits tubular secretion of penicillins

Pharmacodynamic Interactions (alter drug effect without changing levels)

• Synergism: cotrimoxazole (sulfamethoxazole + trimethoprim both block folate synthesis)
• Antagonism: naloxone reverses opioid effects
• Additive toxicity: NSAIDs + ACE inhibitors + diuretics → triple whammy nephrotoxicity

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8. Special Populations

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Summary Diagram (Conceptual)

Drug Administered
      ↓
Absorption (Bioavailability F)
      ↓
Systemic Circulation ←→ Distribution (Vd, protein binding)
      ↓
Metabolism (CYP450, Phase I/II)
      ↓
Excretion (Renal, Biliary)

      ↕  [Drug at site of action]
      ↕
Receptor Binding (Affinity, Emax, EC50)
      ↓
Pharmacological Effect (PD)
      ↓
TDM: Monitor plasma levels → adjust dose → achieve therapeutic goal

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