Pharmacokinetics

Topic Overview

Pharmacokinetics (PK) describes what the body does to a drug — how it is absorbed, distributed, metabolized, and excreted. Mastery of PK is essential for selecting correct doses, predicting drug interactions, and monitoring therapy. On FNP exams and in clinical practice, PK principles guide dosing adjustments in renal/hepatic impairment, loading doses, and choosing routes of administration.

Key Concepts and Definitions

  • Absorption — Movement of drug from site of administration into systemic circulation. Depends on route, drug formulation, blood flow, and solubility.
  • Bioavailability (F) — Fraction of administered dose that reaches systemic circulation unchanged. IV = 100%; oral varies due to first-pass metabolism.
  • Distribution — Reversible transfer of drug between bloodstream and tissues. Influenced by protein binding, blood flow, and lipid solubility.
  • Volume of Distribution (Vd) — Apparent space into which a drug distributes. High Vd = drug leaves plasma (e.g., lipophilic drugs). Low Vd = stays in plasma (e.g., highly protein-bound drugs).
  • Metabolism (Biotransformation) — Enzymatic conversion of drug into metabolites, primarily in liver (CYP450 system). Can activate or inactivate drugs.
  • Excretion — Removal of drug from body, mainly via kidneys. Also bile, lungs, sweat.
  • Half-life (t½) — Time for drug concentration to decrease by 50%. Determines dosing interval and time to steady state (~4–5 half-lives).
  • Steady State (Css) — Plateau reached when rate of drug administration equals rate of elimination. Takes ~4–5 half-lives.
  • Clearance (Cl) — Volume of plasma cleared of drug per unit time. Main determinant of maintenance dose.
  • First-pass effect — Oral drugs absorbed from gut travel via portal vein to liver, where a portion is metabolized before reaching systemic circulation.

Core Principles and Processes

The ADME Framework

  1. Absorption — Factors: route (IV bypasses absorption), food, GI pH, drug interactions. Exam tip: Enteric-coated and sustained-release formulations resist gastric acid.
  2. Distribution — Protein binding: only free (unbound) drug is pharmacologically active. Albumin binds acidic drugs; alpha-1-acid glycoprotein binds basic drugs. Competition for binding sites can raise free drug levels (e.g., warfarin + aspirin).
  3. Metabolism — Phase I (oxidation, reduction, hydrolysis via CYP450) and Phase II (conjugation). Cytochrome P450 system is high-yield: CYP3A4 metabolizes ~50% of drugs. Know common inducers (e.g., rifampin, phenytoin, carbamazepine) and inhibitors (e.g., ketoconazole, erythromycin, grapefruit juice).
  4. Excretion — Renal: glomerular filtration + tubular secretion + reabsorption. Key for exams: Creatinine clearance (CrCl) used to dose renally cleared drugs (e.g., gentamicin, metformin). Non-renal: bile (enterohepatic recirculation), lungs (volatile anesthetics), milk (lactation considerations).

First-Order vs. Zero-Order Kinetics

  • First-order (most drugs): Clearance proportional to concentration. Constant fraction eliminated per unit time. Linear elimination.
  • Zero-order (saturation kinetics): Constant amount eliminated per unit time, independent of concentration. Seen with ethanol, phenytoin, aspirin at high doses. Risk of toxicity due to unpredictable accumulation.

Loading Dose vs. Maintenance Dose

  • Loading dose: One-time large dose to reach therapeutic level quickly. Used when rapid effect needed (e.g., amiodarone, digoxin). Formula: Load = (Vd × desired concentration) / F.
  • Maintenance dose: Regular dose to keep concentration steady. Based on clearance. Formula: Maintenance = (Cl × Css) / F.

Clinical Application and Assessment

In primary care, FNP must consider PK changes in special populations:

  • Renal impairment: Reduce dose or lengthen interval for renally excreted drugs. Monitor CrCl.
  • Hepatic impairment: Reduce doses of hepatically metabolized drugs (e.g., warfarin, opioids). Use with caution.
  • Elderly: Decreased liver blood flow, reduced renal function, increased Vd for lipophilic drugs → lower doses often needed.
  • Pediatrics: Immature liver/kidney function in neonates; different body composition.
  • Pregnancy: Increased Vd, increased renal clearance, altered metabolism. Many drugs require dose adjustments.

Safety Precautions and Complications

  • Drug interactions affecting PK: CYP450 inducers/inhibitors, protein binding displacement, changes in GI pH (antacids reduce absorption of many drugs).
  • Toxicity risks: Narrow therapeutic index drugs (lithium, digoxin, warfarin) require monitoring of serum levels.
  • Patient education: Take medications consistently with regard to food, avoid grapefruit juice (CYP3A4 inhibitor), report side effects early.
  • Therapeutic drug monitoring (TDM): Essential for drugs like phenytoin, valproic acid, vancomycin. Know timing of peak (after absorption) and trough (just before next dose).

Exam Tips and High-Yield Points

  • PK is frequently tested in questions about dosing adjustments, drug interactions, and selecting routes.
  • Memory aid for CYP450 inducers: “Rifampin, Phenytoin, Carbamazepine, St. John’s Wort” — think “RPC-St. John”.
  • Memory aid for CYP450 inhibitors: “Ketoconazole, Erythromycin, Cimetidine, Grapefruit, Amiodarone” — “KECGA” sounds like “keg-ah.”
  • Half-life rule: After 4 half-lives ~94% eliminated; steady state also reached after 4–5 half-lives.
  • Bioavailability of oral drugs is rarely 100% due to incomplete absorption and first-pass effect. Exception: Some drugs have high bioavailability (e.g., levofloxacin ~99%).
  • Know Vd relationship: If a drug has a very large Vd (e.g., >500 L), it is extensively distributed into tissues and not easily removed by dialysis.
  • Zero-order kinetics = risk of accumulation. If you see ethanol, phenytoin, aspirin overdose on exam, think zero-order.
  • For renally cleared drugs: When CrCl drops, either decrease dose or increase interval. Most common strategies on exams: lengthen interval (e.g., every 12h → every 24h).
  • Steady state concentration is proportional to dose rate (maintenance dose / interval) and inversely proportional to clearance.
  • Practice interpreting scenarios: A patient on warfarin starts taking aspirin → increased bleeding risk (free warfarin ↑ due to protein binding displacement).