Factors Affecting Drug Response

Why This Matters

When you're tested on pharmacology, you're not just being asked to recall drug names—you're being evaluated on whether you understand why the same drug can work beautifully in one patient and cause serious harm in another. The factors affecting drug response sit at the intersection of pharmacokinetics (what the body does to the drug) and pharmacodynamics (what the drug does to the body). Mastering these concepts means understanding absorption, distribution, metabolism, and excretion (ADME) and how patient-specific variables alter each step.

Think of drug response as an equation with dozens of variables: genetics, organ function, body composition, timing, and even what the patient ate for breakfast. Exam questions will ask you to predict how changing one variable affects the outcome—or to identify which factor explains an unexpected drug response. Don't just memorize that "elderly patients need lower doses"—know why (reduced hepatic blood flow, decreased renal clearance, altered body composition). That mechanistic understanding is what separates strong exam performance from guesswork.

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Pharmacokinetic Modifiers: How the Body Handles Drugs

These factors alter how drugs are absorbed, distributed, metabolized, or excreted—changing the concentration of active drug that reaches its target. The core principle: anything that affects ADME will shift drug levels, potentially causing toxicity or therapeutic failure.

Age

• Neonates and elderly patients have immature or declining organ function—infants lack fully developed hepatic enzymes, while older adults show reduced liver mass and blood flow
• Volume of distribution shifts with age as body water decreases and fat increases in elderly patients, affecting hydrophilic versus lipophilic drug concentrations
• Renal clearance declines predictably with age—the Cockcroft-Gault equation estimates this decline, making it essential for dosing renally-cleared drugs

Body Weight and Composition

• Volume of distribution ($V_d$) scales with body size—larger patients may need higher loading doses to achieve therapeutic concentrations
• Obesity alters pharmacokinetics unpredictably because lipophilic drugs accumulate in fat tissue while hydrophilic drugs may not distribute proportionally
• Lean body mass determines clearance for many drugs, meaning dosing by total body weight in obese patients can cause toxicity

Liver and Kidney Function

• Hepatic impairment reduces first-pass metabolism—drugs normally cleared by the liver reach systemic circulation at higher concentrations
• Renal impairment prolongs half-life of drugs eliminated by the kidneys, requiring dose reduction or extended intervals
• Child-Pugh score and creatinine clearance are the clinical tools used to guide dosing adjustments in organ dysfunction

Dosage and Route of Administration

• Bioavailability varies dramatically by route—IV administration provides 100% bioavailability while oral drugs face first-pass metabolism
• First-pass effect can eliminate 90%+ of some oral drugs before they reach systemic circulation, explaining why certain medications require alternative routes
• Onset and duration depend on route—sublingual and inhaled routes bypass first-pass metabolism and provide rapid onset for emergency situations

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Genetic and Biological Variation

Individual differences in enzyme activity, receptor sensitivity, and physiological state create predictable patterns of altered drug response. Pharmacogenomics explains why "standard doses" fail in certain populations.

Genetic Factors (Pharmacogenomics)

• CYP450 polymorphisms create poor, intermediate, and ultra-rapid metabolizers—a poor metabolizer of codeine gets no pain relief (can't convert to morphine), while an ultra-rapid metabolizer risks overdose
• Drug transporter variants (P-glycoprotein, OATP) affect how much drug enters target tissues or gets pumped back into the gut lumen
• HLA variants predict severe drug reactions—HLA-B*5701 screening before abacavir prevents life-threatening hypersensitivity

Sex Differences

• Women generally have higher body fat percentage and lower $V_d$ for water-soluble drugs, potentially requiring dose adjustments
• Hormonal fluctuations affect CYP enzyme activity—estrogen inhibits certain pathways while progesterone may induce others
• QT prolongation risk is higher in women, making sex a consideration when prescribing drugs that affect cardiac conduction

Individual Variations in Drug Metabolism

• Enzyme activity exists on a spectrum—even without identified genetic variants, patients show 10-fold differences in drug clearance
• Age, sex, genetics, and disease all converge to create each patient's unique metabolic profile
• Therapeutic drug monitoring (TDM) measures actual drug levels when variability is high and therapeutic windows are narrow

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Drug-Drug and Drug-Environment Interactions

External factors—other medications, food, toxins, and timing—can dramatically alter drug response through predictable mechanisms. These are highly testable because they're preventable with proper clinical awareness.

Drug Interactions

• Enzyme induction (e.g., rifampin, carbamazepine) accelerates metabolism of co-administered drugs, potentially causing therapeutic failure
• Enzyme inhibition (e.g., ketoconazole, grapefruit juice) slows metabolism, increasing drug levels and toxicity risk
• Competition for plasma protein binding can transiently increase free drug concentration, though this effect is often overstated clinically

Diet and Nutrition

• Grapefruit juice inhibits intestinal CYP3A4—a single glass can increase statin or calcium channel blocker levels several-fold
• High-fat meals increase absorption of lipophilic drugs while delaying gastric emptying and slowing overall absorption
• Vitamin K-rich foods antagonize warfarin by providing substrate for clotting factor synthesis, requiring consistent dietary intake

Environmental Factors

• Smoking induces CYP1A2—smokers require higher doses of theophylline, clozapine, and caffeine; quitting can cause sudden toxicity
• Occupational exposures to solvents or heavy metals can alter hepatic enzyme activity unpredictably
• Adherence barriers (cost, access, health literacy) affect whether prescribed doses actually reach the patient

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Temporal and Adaptive Factors

Drug response changes over time due to biological rhythms, repeated exposure, and physiological adaptations. These factors explain why the same dose stops working or why timing matters.

Circadian Rhythms (Chronopharmacology)

• Hepatic enzyme activity fluctuates over 24 hours—some drugs are metabolized faster in the morning than at night
• Blood pressure follows a circadian pattern, making evening dosing of antihypertensives more effective at preventing morning cardiovascular events
• Corticosteroid timing mimics natural cortisol release—morning dosing reduces HPA axis suppression

Tolerance and Dependence

• Pharmacodynamic tolerance occurs when receptors downregulate or desensitize after repeated agonist exposure, requiring dose escalation
• Pharmacokinetic tolerance results from enzyme induction—the body learns to metabolize the drug faster
• Physical dependence reflects neuroadaptation—abrupt discontinuation unmasks compensatory changes, causing withdrawal

Pregnancy and Lactation

• Increased plasma volume and cardiac output during pregnancy dilute drug concentrations and accelerate renal clearance
• Placental transfer follows lipophilicity rules—small, lipophilic, un-ionized drugs cross readily to the fetus
• FDA pregnancy categories (now replaced by narrative labeling) guide risk-benefit decisions, but many drugs lack adequate human data

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Psychological and Subjective Factors

The mind-body connection influences measurable drug outcomes through mechanisms that are increasingly well-understood. These factors are especially relevant in clinical trials and pain management.

Placebo Effect

• Placebo responses involve real neurobiological changes—endorphin release, dopamine signaling, and measurable brain activation patterns
• Expectation and conditioning drive magnitude—patients who expect relief show greater placebo response
• Clinical trial design must control for placebo through blinding and randomization to isolate true drug effects

Disease States

• Pathophysiology alters pharmacokinetics—heart failure reduces hepatic blood flow; burns increase $V_d$ through capillary leak
• Receptor expression changes in disease—beta-receptor downregulation in heart failure reduces response to beta-agonists
• Polypharmacy in chronic disease multiplies interaction risk and complicates attribution of adverse effects

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Quick Reference Table

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Self-Check Questions

1. A patient stabilized on warfarin suddenly shows elevated INR after starting a new medication. Which two factors could explain this, and what mechanism do they share?

2. Compare and contrast how age and obesity affect volume of distribution—which types of drugs are most affected by each?

3. An ultra-rapid CYP2D6 metabolizer is prescribed codeine for pain. Predict the clinical outcome and explain the pharmacogenomic principle involved.

4. Why might a drug requiring hepatic metabolism need increased dosing during pregnancy despite the goal of minimizing fetal exposure?

5. A patient reports that their blood pressure medication "stopped working" after they quit smoking. Which factor explains this, and what's the underlying mechanism?