11.1 Pharmacokinetics & Pharmacodynamics
Key Takeaways
- Steady-state plasma concentration (Css) is achieved after 4 to 5 elimination half-lives (t1/2), independent of dosing rate or administration route.
- The loading dose equation LD = (Ctarget x Vd) / F depends on Volume of Distribution (Vd), which for digoxin is ~7 L/kg, requiring major dose reduction in elderly patients and renal impairment.
- Phenytoin exhibits zero-order (capacity-limited) kinetics at therapeutic concentrations (10–20 mg/L); small dose increments can lead to disproportionate serum level increases and severe neurotoxicity.
- Co-administration of potent CYP3A4/CYP2C9 inducers (e.g., rifampicin, carbamazepine, phenytoin) accelerates substrate clearance over 1–2 weeks, whereas CYP inhibitors (e.g., clarithromycin, amiodarone, ketoconazole) rapidly increase substrate concentrations.
- Therapeutic Drug Monitoring (TDM) targets include vancomycin trough 15–20 mg/L for severe MRSA, gentamicin once-daily trough <1 mg/L, and lithium therapeutic range 0.6–1.0 mmol/L.
Principles of Pharmacokinetics (ADME)
Pharmacokinetics evaluates the quantitative timeline of drug movement through the human body. Mastering absorption, distribution, metabolism, and elimination (ADME) allows clinicians to individualize therapy, calculate loading and maintenance doses, and anticipate therapeutic failure or drug toxicity in medical inpatients.
Absorption and Bioavailability ($F$)
Bioavailability ($F$) represents the fraction of an administered drug dose that reaches the systemic circulation in active, unchanged form. Intravenous (IV) administration delivers $100%$ bioavailability ($F = 1.0$). For oral formulations, $F$ is limited by incomplete intestinal absorption and first-pass hepatic metabolism.
- High first-pass metabolism: Drugs like propranolol ($F \approx 26%$), morphine ($F \approx 30%$), lidocaine ($F < 3%$), and verapamil ($F \approx 20%$) undergo extensive presystemic degradation by intestinal mucosal and hepatic CYP3A4 enzymes and P-glycoprotein (P-gp/MDR1) efflux transporters. Consequently, oral doses of morphine or propranolol are significantly higher than equivalent IV doses.
- Factors altering absorption: Gastrointestinal motility, gastric pH (e.g., co-administration of proton pump inhibitors reducing ketoconazole absorption), mucosal edema in congestive heart failure, and enteral feeding interactions (e.g., tube feeds binding oral phenytoin).
Volume of Distribution ($V_d$)
Volume of Distribution ($V_d$) is a hypothetical fluid volume required to contain the total body content of a drug at the same concentration as present in vascular plasma:
[ V_d = \frac{\text{Total amount of drug in body } (D)}{\text{Plasma concentration } (C)} ]
The magnitude of $V_d$ provides crucial insights into anatomical drug distribution:
- Low $V_d$ ($< 0.2 \text{ L/kg}$ or $14 \text{ L}$ in a $70 \text{ kg}$ adult): Confined predominantly to the vascular space or extracellular fluid. Highly plasma protein-bound or large hydrophilic molecules exhibit low $V_d$ (e.g., warfarin $0.14 \text{ L/kg}$, unfractionated heparin, gentamicin, aspirin).
- High $V_d$ ($> 1 \text{ L/kg}$ or $> 70 \text{ L}$): Extensively distributed into peripheral tissues, fat, or skeletal muscle. Lipophilic or tissue-bound drugs demonstrate massive $V_d$ (e.g., digoxin $\approx 7 \text{ L/kg}$, chloroquine $> 100 \text{ L/kg}$, tricyclic antidepressants). Hemodialysis is ineffective for removing drugs with high $V_d$.
Metabolism: Phase I and Phase II Reactions
Hepatic drug clearance involves two main enzymatic processes:
- Phase I Reactions (Functionalization): Oxidation, reduction, and hydrolysis reactions primarily mediated by the Cytochrome P450 (CYP450) monooxygenase superfamily situated in smooth endoplasmic reticulum. Phase I converts lipophilic compounds into more polar metabolites.
- CYP3A4: Metabolizes $>50%$ of prescribed drugs (statins, calcium channel blockers, immunosuppressants).
- CYP2D6: Polymorphic enzyme (poor vs ultra-rapid metabolizers); processes codeine, tamoxifen, beta-blockers, and SSRIs.
- CYP2C9/2C19: Metabolizes warfarin, phenytoin, omeprazole, and clopidogrel.
- Phase II Reactions (Conjugation): Covalent attachment of polar endogenous groups (glucuronide, sulfate, acetate, glutathione) to produce hydrophilic, inactive conjugates excreted by kidneys or bile.
- Acetylation (NAT2): Genetic polymorphism determines slow vs. fast acetylator status. Slow acetylators receiving isoniazid, hydralazine, or procainamide face high risks of drug-induced lupus erythematosus and peripheral neuropathy.
Clinical Table: CYP450 Inducers and Inhibitors
| Category | High-Yield Agents | Clinical Mechanism & Impact |
|---|---|---|
| Potent Inducers | Rifampicin, Carbamazepine, Phenytoin, Phenobarbital, St John’s Wort, Chronic Alcohol, Griseofulvin | Accelerates CYP expression over 7–14 days. Decreases plasma levels of warfarin, DOACs, OCPs, tacrolimus, leading to therapeutic failure. |
| Potent Inhibitors | Sodium valproate, Isoniazid, Cimetidine, Ketoconazole/Azoles, Fluoxetine/SSRIs, Erythromycin/Clarithromycin, Diltiazem/Verapamil, Grapefruit juice, Amiodarone, Ciprofloxacin | Immediately blocks CYP catalytic sites. Increases plasma levels of statins, digoxin, warfarin, theophylline, precipitating acute drug toxicity. |
Elimination Kinetics: First-Order vs. Zero-Order
Drug elimination occurs through hepatic metabolism, renal excretion, or biliary elimination.
First-Order Kinetics (Linear Elimination)
- Mechanism: A constant fraction (percentage) of drug is eliminated per unit time. The rate of elimination ($V_e$) is directly proportional to plasma concentration ($C$).
- Half-life ($t_{1/2}$): Constant and independent of dose.
- Steady-State ($C_{ss}$): Achieved when the rate of drug administration equals the rate of elimination. Reaching $C_{ss}$ requires 4 to 5 half-lives.
- Calculations: [ t_{1/2} = \frac{0.693 \times V_d}{CL} \quad \text{and} \quad \text{Loading Dose (LD)} = \frac{C_{target} \times V_d}{F} ] [ \text{Maintenance Dose Rate} = \frac{C_{ss} \times CL}{F} ]
Zero-Order Kinetics (Non-linear / Capacity-Limited Elimination)
- Mechanism: Metabolic clearance pathways become saturated at therapeutic plasma concentrations (Michaelis-Menten kinetics). A constant amount (mass) of drug is eliminated per unit time, regardless of concentration.
- Half-life ($t_{1/2}$): Variable; half-life increases as dose increases.
- Clinical Risk: Dose increases produce unpredictable, non-linear, exponential jumps in plasma drug levels.
- Classic Zero-Order Drugs: Phenytoin (saturates near therapeutic levels of 10–20 mg/L), Ethanol, High-dose Aspirin (salicylates), and Theophylline.
Pharmacodynamics: Receptor Kinetics and Efficacy
Pharmacodynamics examines the biochemical and physiological effects of drugs on target receptors.
- Full Agonist: Binds receptor, induces maximal conformational change, and achieves maximal efficacy ($E_{max} = 100%$).
- Partial Agonist: Binds receptor with lower intrinsic activity ($E_{max} < 100%$), functioning as a competitive antagonist in the presence of full agonists (e.g., buprenorphine at $\mu$-opioid receptors, pindolol in adrenergic receptors).
- Competitive Antagonist: Competitively binds the active site. Shifts dose-response curve to the right (increases $EC_{50}$, potency decreases), but $E_{max}$ remains achievable with higher agonist concentrations.
- Non-Competitive Antagonist: Binds allosteric site or irreversibly covalently binds active site. Reduces maximal response ($E_{max}$ decreases), while $EC_{50}$ remains unchanged.
Therapeutic Drug Monitoring (TDM) Targets
Drugs with narrow therapeutic indices ($TI = TD_{50} / ED_{50}$) demand routine serum concentration monitoring to balance efficacy against severe toxicity.
Clinical Table: Therapeutic Drug Monitoring Targets & Toxicity Features
| Drug | Target Therapeutic Window | Sampling Time | Clinical Toxicity Features |
|---|---|---|---|
| Digoxin | 0.5–0.9 mcg/L (HF)<br>0.8–2.0 mcg/L (AF) | $\ge 6 \text{ hours}$ post-dose | Nausea, xanthopsia (yellow-green vision), Mobitz Type I/II AV block, ventricular bigeminy. Toxicity exacerbated by hypokalemia, hypomagnesemia, hypercalcemia. |
| Gentamicin | Once-daily: Trough $< 1 \text{ mg/L}$ at 18–24h<br>Multiple daily: Peak 5–10 mg/L, Trough $< 2 \text{ mg/L}$ | Trough immediately pre-dose; Peak 30 min post-infusion | Vestibulo-ototoxicity (irreversible bilateral hair cell loss), acute tubular necrosis (ATN, non-oliguric AKI). |
| Vancomycin | Trough 15–20 mg/L (severe infection/MRSA endocarditis)<br>10–15 mg/L (uncomplicated SSTI) | Trough within 30 min prior to 4th dose | Nephrotoxicity, ototoxicity, Red Man Syndrome (histamine release from rapid infusion). |
| Lithium | 0.6–1.0 mmol/L (maintenance)<br>0.8–1.2 mmol/L (acute mania) | 12 hours post-dose (trough) | Coarse tremor, ataxia, dysarthria, seizures, nephrogenic diabetes insipidus. Toxicity triggered by dehydration, NSAIDs, ACE inhibitors, thiazides. |
| Phenytoin | 10–20 mg/L (total)<br>1–2 mg/L (free unbound) | Trough prior to dose | Nystagmus ($>20 \text{ mg/L}$), ataxia ($>30 \text{ mg/L}$), lethargy/encephalopathy ($>40 \text{ mg/L}$), gingival hyperplasia, peripheral neuropathy. |
| Theophylline | 10–20 mg/L | Trough prior to dose | Refractory seizures, fatal ventricular tachyarrhythmias, intractable vomiting. |
Exam Pearls
MRCPI Exam Pearl: Hypokalemia does not alter serum digoxin concentration, but it markedly increases myocardial sensitivity to digoxin by diminishing extracellular potassium competition for the $Na^+/K^+$-ATPase alpha subunit. Always check and correct potassium ($K^+ \ge 4.0 \text{ mmol/L}$) in suspected digoxin toxicity.
MRCPI Exam Pearl: Thiazide diuretics reduce renal clearance of lithium by $24-40%$ because compensatory proximal tubular sodium reabsorption in response to distal natriuresis leads to co-reabsorption of filtered lithium.
A 48-year-old man receiving chronic warfarin therapy for a mechanical aortic valve (target INR 2.5–3.5) is diagnosed with active pulmonary tuberculosis and initiated on rifampicin, isoniazid, pyrazinamide, and ethambutol. Ten days later, his INR drops from 3.1 to 1.3 despite strict adherence. What is the pharmacological mechanism responsible for this subtherapeutic INR?
An 82-year-old woman with chronic kidney disease (eGFR 22 mL/min/1.73 m²) and atrial fibrillation is admitted with confusion, severe nausea, and a heart rate of 38 bpm. Her ECG shows atrial fibrillation with a slow ventricular response and Mobitz Type I second-degree AV block. She takes digoxin 250 mcg daily. Laboratory values reveal serum potassium of 3.1 mmol/L and serum digoxin of 3.4 mcg/L (target 0.8–2.0 mcg/L). What combined pharmacological mechanisms account for her presentation?
A 29-year-old man with focal epilepsy is treated with oral phenytoin. His serum phenytoin concentration at a dosage of 300 mg daily is 8 mg/L (therapeutic range 10–20 mg/L). To achieve a therapeutic concentration, his physician increases the dose to 400 mg daily. Two weeks later, he presents to the emergency department with severe horizontal nystagmus, marked truncal ataxia, and a serum phenytoin level of 34 mg/L. Which kinetic principle explains this disproportionate rise in serum concentration?