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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
• Pharmacogenomics — how genetic variation affects drug response
• Clinical therapeutics — evidence-based application of drugs to treat disease

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2. Pharmacokinetics (PK): What the Body Does to the Drug

A. ADME Model

B. Key PK Parameters

• Bioavailability (F): Fraction of administered dose reaching systemic circulation. IV = 100%; oral varies by drug.
• Volume of Distribution (Vd): Apparent space the drug distributes into. High Vd = extensive tissue binding (e.g., digoxin, chloroquine).
• Clearance (CL): Rate of drug removal relative to plasma concentration. CL = Dose / AUC.
• Half-life (t½): Time for plasma concentration to fall by 50%. t½ = 0.693 × Vd / CL.
• Steady State: Reached after ~4–5 half-lives of repeated dosing; plasma levels plateau.
• Loading Dose: Used when rapid achievement of therapeutic levels is needed. LD = Vd × target concentration / F.

C. Routes of Administration

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3. Pharmacodynamics (PD): What the Drug Does to the Body

A. Drug-Receptor Interactions

• Agonists: Bind and activate receptors (e.g., morphine at opioid receptors)
• Antagonists: Bind but do not activate; block agonist effects (e.g., naloxone, beta-blockers)
• Partial agonists: Submaximal activation even at full receptor occupancy (e.g., buprenorphine)
• Inverse agonists: Reduce baseline receptor activity below basal level

B. Dose-Response Relationships

• Graded dose-response: Increasing drug dose → increasing effect (up to maximum)
• Emax: Maximum drug effect achievable
• EC50: Concentration producing 50% of Emax; reflects potency
• Efficacy: Maximum effect a drug can produce (ceiling effect)
• Potency vs. Efficacy: A drug can be potent (low EC50) but have low efficacy (low Emax), or vice versa

C. Therapeutic Index (TI)

• Wide TI (e.g., penicillin): Large margin between effective and toxic doses → safer
• Narrow TI (e.g., warfarin, digoxin, lithium, phenytoin): Small margin → requires monitoring

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4. Drug Metabolism and Enzyme Systems

CYP450 System (Hepatic)

Phase I vs. Phase II Metabolism

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5. Pharmacogenomics

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6. Special Populations: Altered Pharmacokinetics

Renal Impairment

• Reduced clearance of renally eliminated drugs
• Dose reduction required for: aminoglycosides, digoxin, metformin, NSAIDs
• Use eGFR (CrCl) to guide dosing

Hepatic Impairment

• Reduced metabolism of hepatically cleared drugs
• Reduced first-pass effect → increased bioavailability of oral drugs
• Use Child-Pugh or MELD score to guide adjustments

Elderly

• ↓ Renal clearance, ↓ hepatic function, ↓ albumin → higher free drug levels
• Increased Vd for lipid-soluble drugs, decreased Vd for water-soluble drugs
• Greater sensitivity to CNS drugs, anticoagulants

Pregnancy

• ↑ Plasma volume → lower drug concentrations
• ↑ Renal clearance
• Teratogenicity risk — FDA categories A/B/C/D/X (now replaced by labeling narrative)

Pediatrics

• Weight-based dosing; immature renal and hepatic function in neonates
• Allometric scaling: doses calculated per kg

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7. Adverse Drug Reactions (ADRs)

Classification (Rawlins-Thompson)

Drug Interactions

• Pharmacokinetic: Alteration of absorption, distribution, metabolism, or elimination (e.g., CYP450 interactions)
• Pharmacodynamic: Additive, synergistic, or antagonistic effects at receptor level (e.g., two CNS depressants)

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8. Fundamentals of Rational Pharmacotherapy

The WHO Framework for Rational Prescribing (6-Step Model)

Principles of Rational Drug Selection

1. Indication: Is there a clear clinical indication? Avoid polypharmacy without justification.
2. Efficacy: Is the drug proven effective for this indication (evidence-based)?
3. Safety: What is the ADR profile? Does the patient have risk factors for toxicity?
4. Suitability: Comorbidities, organ function, age, pregnancy, allergies, drug interactions.
5. Cost-effectiveness: Prefer generics where therapeutically equivalent; consider adherence.
6. Adherence: Choose regimens patients can realistically follow (once vs. four times daily).

Polypharmacy and Deprescribing

• Polypharmacy (typically ≥5 drugs) increases ADR risk, drug interactions, and non-adherence
• Deprescribing = systematic reduction of unnecessary medications, especially in elderly
• Tools: Beers Criteria (drugs to avoid in elderly), STOPP/START criteria

Monitoring Drug Therapy

• Therapeutic drug monitoring (TDM): Measure plasma drug levels for narrow-TI drugs
  • Aminoglycosides (peak/trough), vancomycin (trough/AUC), digoxin, phenytoin, lithium, cyclosporine
• Clinical endpoints: Blood pressure (antihypertensives), HbA1c (antidiabetics), INR (warfarin)
• Safety monitoring: LFTs (statins, antifungals), CBC (methotrexate), creatinine (ACE inhibitors, NSAIDs)

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9. Key Concepts Summary

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