2.2 Pharmacokinetics & Pharmacodynamics

Why This Matters

Pharmacokinetics (PK) answers "what the body does to the drug," and pharmacodynamics (PD) answers "what the drug does to the body." NAPLEX uses these concepts to test dosing in renal or hepatic impairment, loading-dose decisions, and therapeutic drug monitoring. Calculation items in Area 1 frequently combine a PK formula with a clinical scenario, so the equations must be automatic.

ADME Overview

• Absorption — movement from the administration site into the blood. Affected by formulation, gastric pH, food, and the first-pass effect (hepatic/gut metabolism before systemic circulation).
• Distribution — movement from blood into tissues; governed by perfusion, lipophilicity, and protein binding.
• Metabolism — chemical transformation, mostly hepatic. Phase I (CYP450 oxidation) and Phase II (conjugation, e.g., glucuronidation) generally make drugs more water-soluble.
• Excretion — elimination, mainly renal. Renal impairment prolongs the half-life of renally cleared drugs (e.g., aminoglycosides, vancomycin).

Bioavailability (F)

Bioavailability (F) is the fraction of an administered dose that reaches the systemic circulation unchanged.

• Intravenous (IV) dosing has F = 1 (100%) by definition.
• Oral F is reduced by incomplete absorption and first-pass metabolism. Drugs with high first-pass extraction (e.g., propranolol, morphine, nitroglycerin) have low oral bioavailability and often require much higher oral than IV doses.

Converting Routes

When switching IV to oral, adjust for F:

Oral dose = IV dose / F

Example: if a drug's oral F is 0.5 and the IV dose is 100 mg, the equivalent oral dose is 100 / 0.5 = 200 mg.

Volume of Distribution (Vd)

The volume of distribution (Vd) is an apparent volume relating the amount of drug in the body to the plasma concentration:

Vd = amount of drug in body / plasma drug concentration

Vd is not a real anatomic volume. A highly lipophilic or tissue-bound drug (digoxin Vd ≈ 7 L/kg) has a large Vd; a drug confined to plasma (warfarin) has a small Vd near plasma volume.

Clinical relevance: drugs with a large Vd are poorly removed by hemodialysis because most drug sits in tissue, not plasma. Vd also drives the loading dose.

Clearance and Half-Life

Clearance (CL) is the volume of plasma cleared of drug per unit time (e.g., L/hr). Total clearance is the sum of hepatic, renal, and other routes. Clearance — not half-life — determines the maintenance dose rate.

For a one-compartment, first-order drug:

t1/2 = (0.693 x Vd) / CL

Key implications:

• A larger Vd lengthens half-life; higher clearance shortens it.
• Steady state is reached in about 4-5 half-lives of constant dosing.
• After stopping a drug, about 4-5 half-lives are needed for ~97% elimination.

First-Order vs. Zero-Order Kinetics

• First-order kinetics: a constant fraction of drug is eliminated per unit time. Rate is proportional to concentration, half-life is constant, and most drugs behave this way at therapeutic doses.
• Zero-order kinetics: a constant amount is eliminated per unit time because an enzyme or transporter is saturated. There is no true constant half-life; small dose increases produce disproportionately large concentration increases.

Capacity-limited (zero-order) examples on the NAPLEX: phenytoin, ethanol, and high-dose aspirin (salicylates). Phenytoin is the classic test case — a small dose increase near the top of the range can push levels into toxicity, so adjust by small increments and monitor levels.

Loading and Maintenance Doses

Use Vd for the loading dose and clearance for the maintenance rate:

Loading dose = (Vd x target concentration) / F

Maintenance dose rate = (CL x target concentration) / F

Worked Example

A drug has Vd = 50 L, CL = 5 L/hr, F = 1 (IV), and a target plasma concentration of 4 mg/L.

• Loading dose = (50 L x 4 mg/L) / 1 = 200 mg given once to reach target quickly.
• Maintenance rate = (5 L/hr x 4 mg/L) / 1 = 20 mg/hr to keep the level steady.

A loading dose is used when waiting 4-5 half-lives to reach steady state is clinically unacceptable (e.g., loading dose of digoxin or vancomycin).

Protein Binding and the Free-Drug Concept

Only unbound (free) drug is pharmacologically active and available for metabolism and elimination. Many drugs bind plasma proteins — albumin (acidic drugs like phenytoin, warfarin) and alpha-1-acid glycoprotein (basic drugs like lidocaine).

• Hypoalbuminemia (cirrhosis, nephrotic syndrome, critical illness) raises the free fraction of highly bound drugs, increasing effect at the same total level. For phenytoin, correct the measured total concentration for low albumin (or measure free phenytoin) before deciding the level is "low."
• Displacement interactions transiently raise free drug, but for most drugs autoregulation and increased clearance blunt clinical significance; the classic teaching example is highly bound, low-Vd, narrow-index drugs.
• Protein binding does not change a drug's potency at the receptor — it changes how much reaches the receptor.

Renal Function Estimation and Dose Adjustment

Because renally cleared drugs accumulate when kidney function falls, the Cockcroft-Gault estimate of creatinine clearance (CrCl) is the workhorse for renal dose adjustment on the exam:

CrCl (mL/min) = [(140 - age) x weight in kg] / (72 x serum creatinine), x 0.85 if female

Worked Example

A 70-year-old woman weighs 60 kg with a serum creatinine of 1.0 mg/dL.

• Numerator: (140 - 70) x 60 = 70 x 60 = 4,200
• Divide: 4,200 / (72 x 1.0) = 4,200 / 72 = 58.3
• Female multiplier: 58.3 x 0.85 = about 49.6 mL/min

Use an appropriate body weight (often ideal or adjusted in obesity), and round serum creatinine cautiously in older or low-muscle-mass patients to avoid overestimating CrCl. The exam frequently gives a CrCl and asks you to pick the renally adjusted dose or to avoid a contraindicated agent (for example, restricting metformin or dose-adjusting a DOAC at low CrCl).

Therapeutic Drug Monitoring (TDM)

Therapeutic drug monitoring (TDM) measures serum levels to keep concentrations within a narrow therapeutic window. TDM is justified when a drug has a narrow therapeutic index, variable PK, a measurable level that correlates with effect or toxicity, and no easy clinical endpoint.

Commonly monitored drugs: vancomycin (trough or AUC-guided), aminoglycosides, digoxin, phenytoin, lithium, warfarin (via INR, a pharmacodynamic surrogate), tacrolimus, and theophylline.

Sampling Principles

• Draw trough levels just before the next dose; draw peak levels after distribution is complete.
• Wait until steady state (about 4-5 half-lives) before interpreting a routine level unless toxicity is suspected.
• For highly protein-bound drugs (phenytoin), correct the total level for low albumin or measure free drug.