L4 - Pharmacokinetic & Pharmacodynamic Considerations – Comprehensive Lecture Notes

Learning Objectives

• Distinguish pharmacokinetics (PK) from pharmacodynamics (PD) and explain their respective roles in pharmacotherapy.
• Identify key physiological and patient-specific factors that alter drug absorption, distribution, metabolism and excretion (ADME).
• Explain the clinical implications of altered PK/PD on efficacy, toxicity and treatment failure.
• Evaluate pharmacist-led strategies to manage variability in drug response (therapeutic drug monitoring, dose individualisation, PK or PD monitoring, patient education).

Fundamental Definitions and Conceptual Overview

• PK = “What the body does to the drug.”
  • Steps: ingestion → absorption → distribution → metabolism → clearance.
• PD = “What the drug does to the body.”
  • Events: receptor binding → post-receptor activation → cellular/metabolic change → therapeutic/ adverse effects.
• ADME mnemonic (PK) versus Receptor binding / signal transduction (PD).

Core Differences Between PK and PD

• Focus
  • PK: drug concentration–time profile in body compartments.
  • PD: concentration–effect relationship.
• Clinical relevance
  • PK governs onset, intensity and duration (via half-life t_{1/2}).
  • PD governs therapeutic benefit and adverse effects once the target is reached.
• Limiting steps
  • Poor PK can negate even a potent PD drug (e.g.
    drug never reaches site).
  • Ineffective PD (wrong target, polymorphic receptor) yields poor outcomes despite optimal PK.
• Patient variability drivers
  • PK: organ function (renal/hepatic), age, genetics, drug–drug interactions (DDIs).
  • PD: receptor polymorphisms, disease state, resistance mechanisms.

Overview of Variability in Drug Response

• Causes: renal/hepatic disease, pregnancy, obesity, age extremes, genetics, DDIs, environmental factors, adherence.
• Pharmacist response toolkit
  • Therapeutic drug monitoring (TDM).
  • Dose individualisation (e.g. DoseMe™ software).
  • PD monitoring (biomarkers, clinical response).

Pharmacokinetic Step-by-Step Challenges

1 Absorption

• Influencing factors
  • Drug properties: solubility, particle size, formulation.
  • Route of administration.
  • GI environment: pH, enzymes, motility, microbiota, food effect.
  • Physiological: blood flow, surface area, disease states.
• Key clinical scenarios & actions
  • Chelation: tetracyclines / quinolones / levothyroxine + Ca²⁺, Fe²⁺, antacids → ↓ absorption → counsel on dose separation.
  • pH-dependent drugs: itraconazole, atazanavir need acidity; PPIs ↓ absorption → consider alternative drug or stop PPI.
  • Bariatric surgery & malabsorption → ↓ surface area / ↑ transit time → use liquids or non-oral route.
  • Variability in IM/SC absorption due to local blood flow.

2 Distribution

• Determinants: body composition (fat vs water), plasma protein binding, tissue blood flow, capillary permeability, disease states, special barriers (BBB, placenta, fibrotic tissue).
• Age-related shifts
  • Neonates: ↑ total body water, ↓ protein binding.
  • Elderly: ↑ body fat, ↓ total water, altered albumin.
• Example problems & pharmacist actions
  • Digoxin (hydrophilic): ↓ body water → ↑ plasma levels → toxicity. Action: dose adjust to renal function + hydration status.
  • Phenytoin & warfarin (high protein binding): hypo-albuminaemia → ↑ free drug → neurologic toxicity / bleeding. Action: dose reduction, monitor levels/INR.
• Pregnancy – placental transfer
  • Favour crossing: low MW (< 500 Da) e.g. paracetamol, warfarin; high lipophilicity (diazepam); low protein binding.
  • Late gestation ↑ permeability; e.g. NSAIDs contraindicated in 3rd trimester (bleeding risk).
• Breast-feeding – milk transfer
  • Small, lipophilic, weak bases (erythromycin, theophylline) concentrate.
  • Milk:plasma ratio (M:P) 0.1 – 1; high for metronidazole, low for heparin.

3 Metabolism

• Greatest inter-individual variability; driven by CYP450 genotype, liver disease, DDIs.
• Phases
  • Phase I (oxidation/reduction/hydrolysis): ↑ polarity, create reactive intermediates.
  • Phase II (conjugation): ↑ water solubility → excretion.
• Clinically significant alterations & management
  • Hepatic impairment + morphine → ↓ first-pass → toxicity. Dose reduce.
  • Rifampin (CYP inducer) + warfarin → ↑ metabolism → sub-therapeutic INR → monitor INR / switch rifampin.
  • Clarithromycin (CYP3A4 inhibitor) + simvastatin → ↑ statin levels → myopathy. Switch statin or antibiotic.
  • Codeine in CYP2D6 ultra-rapid metabolisers → excess morphine → respiratory depression. Avoid codeine; use non-opioid.
  • Warfarin & CYP2C9 polymorphisms → unpredictable anticoagulation. Genotype-guided dosing.

4 Excretion

• Routes: renal (major), biliary/hepatic.
• Influencing factors: renal/hepatic function, urinary pH, protein binding, age, hydration, genetics.
• Renal dosing parameters
  • Two non-interchangeable metrics: eGFR vs Cl_{cr}.
  • Always match parameter to guideline; may change dose thresholds.
  • Cockcroft–Gault for Cl{cr}: Cl{cr}= \frac{(140 - \text{age})\times \text{weight}_{kg}}{72 \times SCr}\ (\times 0.85\ \text{if female}).
• High-risk renally-cleared drugs
  • Gentamicin → nephro/ototoxicity → TDM + dose adjust.
  • Morphine → M6G accumulation → respiratory depression → dose reduce, monitor.
  • Metformin → lactic acidosis if eGFR<30 mL/min/1.73 m² → contraindicated or dose ↓.
  • Lithium & digoxin (narrow TI) → toxicity with ↓ GFR → TDM + renal monitoring.
• Hepatically-cleared examples: erythromycin, diazepam, diltiazem, methadone, propranolol → dose adjust in hepatic impairment, monitor LFTs.

Pharmacodynamic Challenges

Variable Drug Sensitivity

• Same exposure → different response due to age, genetics, disease, sex, DDIs.
• Examples
  • Elderly ↑ sensitivity to benzodiazepines / opioids (sedation), anticholinergics (confusion, retention, constipation).
• Mechanisms
  • Receptor number/affinity variations.
  • Receptor down-regulation / desensitisation.
  • Impaired baroreflex / end-organ function (e.g. reduced β-adrenergic response with age).
• Pharmacist approach: “Start low, go slow”; titrate cautiously.

Tolerance vs Tachyphylaxis

• Tolerance
  • Gradual decrease in response over long-term repeated dosing.
  • Examples: opioids (need dose escalation); nitrates (24-48 h tolerance → schedule drug-free interval).
• Tachyphylaxis
  • Acute, rapid reduction in response after only a few doses.
  • Example: oxymetazoline nasal spray → rebound congestion within days.
• Management
  • Educate on timing/duration, monitor for dose creep, implement washouts or rotation.

Pharmacodynamic Interactions & Homeostatic Impairment

• PD interactions
  • Synergism: benzodiazepine + opioid → additive CNS/respiratory depression.
  • Antagonism: NSAID + ACE-I → NSAID blunts antihypertensive effect (fluid retention).
• Homeostatic impairment
  • Heart failure: diminished response to vasodilators.
  • Thyroid disease: altered β-agonist response (danger in asthma).
  • Frailty: unpredictable or amplified drug effects.
• Pharmacist actions
  • Screen for interactions (Rx & OTC), adjust therapy, counsel patients, tailor to comorbidities.

Pharmacist-Led Strategies for Optimised Therapy

• Interpret PK/PD data, lab values, TDM results.
• Choose appropriate dosing metric (eGFR vs Clcr) and calculation tool (AMH, AVQ calculators).
• Identify DDIs and receptor-level interactions; recommend alternatives.
• Educate on adherence, timing (drug–food, drug–drug separation), duration, and monitoring plans.
• Employ dose individualisation software, genotype data, biomarkers.

Key Take-Home Messages

• PK and PD together dictate efficacy and safety; both must be considered in every patient.
• Age, organ function, genetics, comorbidities and DDIs create variability → mandate personalised therapy.
• Ongoing monitoring (clinical, laboratory, TDM) and patient education are essential to manage variability.
• Pharmacists play an active role in detecting problems, modifying regimens, and ensuring optimal outcomes.