How pharmacokinetics is tested on Step 1

Expect one-step calculations and qualitative "what happens if" questions.

AbsorptionBioavailability (F); IV = 100%; first-passmetabolism lowers oral FDistributionVd; protein binding, lipid solubility, tissuebindingMetabolismPhase I (CYP450) and phase II (conjugation) in theliverExcretionKidney (filtration, secretion) and bile; clearance
ADME. Older adults lose phase I activity first; phase II conjugation is relatively preserved.
QuantityEquationKey point
Volume of distributionVd = amount in body ÷ plasma concentrationLow Vd: large or charged or highly protein-bound drugs stay in blood
ClearanceCL = elimination rate ÷ plasma concentration = Vd × kFalls with kidney or liver disease
Half-lifet½ = 0.7 × Vd ÷ CLLonger if Vd rises or CL falls
Loading doseLD = Cp × Vd ÷ FDepends on Vd; unchanged in kidney disease
Maintenance doseMD = Cp × CL × τ ÷ FLower it when clearance falls
Therapeutic indexTI = TD50 ÷ ED50Narrow TI: warfarin, digoxin, lithium, theophylline, aminoglycosides

Cp = target plasma concentration; τ = dosing interval; F = bioavailability.

Elimination kinetics

Most drugs follow first-order kinetics until their elimination enzymes saturate.

First orderConstant fraction removed per hourFixed half-lifeRate depends on concentrationExponential decline (straight on logplot)Most drugsZero orderConstant amount removed per hourNo fixed half-lifeElimination is saturatedLinear declineEthanol, high-dose aspirin, phenytoinvs
Elimination kinetics. Small dose increases of a zero-order drug can cause large rises in level and toxicity.
  • Urine pH and ion trapping: weak acids (aspirin, phenobarbital, methotrexate) are excreted faster in alkaline urine, so sodium bicarbonate treats overdose; weak bases (amphetamines) are trapped in acidic urine.
  • Phase II and acetylation: slow acetylators are more likely to develop drug-induced lupus from hydralazine, procainamide, and isoniazid.

CYP450 interactions

Inducers lower the levels of other drugs; inhibitors raise them.

CYP450InducersRifampin, carbamazepine,phenytoin, St. John's wort,chronic alcoholInhibitorsAzoles, macrolides,ritonavir, grapefruit,amiodaroneCommon victimsWarfarin, oralcontraceptives, cyclosporine
CYP450. Rifampin lowers warfarin and oral contraceptive levels; clarithromycin or fluconazole raises warfarin levels and bleeding risk.

Pharmacodynamics

Dose-response curves show potency (position) and efficacy (maximum effect).

Drug effectPotency (EC50)Efficacy (Emax)Example
Competitive antagonistDecreases (curve shifts right)Unchanged; overcome by more agonistNaloxone vs opioids
Noncompetitive antagonistUnchangedDecreasesPhenoxybenzamine (irreversible α blocker)
Partial agonistCan be higher or lowerLower than a full agonistBuprenorphine at μ-opioid receptors
Inverse agonistNot applicableOpposite of agonist effectSome antihistamines at H1

Potency is how much drug is needed; efficacy is the maximum effect a drug can produce.

Worked example

Use the equations step by step.

functions Worked example — dosing an IV antibiotic

An IV drug has Vd 40 L and clearance 5 L/h. The target plasma concentration is 10 mg/L. What are the loading dose, the maintenance dose every 12 hours, the half-life, and the time to steady state?

  1. IV drug, so F = 1. Loading dose = 10 mg/L × 40 L = 400 mg.
  2. Maintenance dose = 10 mg/L × 5 L/h × 12 h = 600 mg every 12 hours.
  3. Half-life = 0.7 × 40 L ÷ 5 L/h ≈ 5.6 hours.
  4. Steady state takes 4–5 half-lives, about 22–28 hours, without a loading dose.

Answer. Loading dose 400 mg; 600 mg every 12 hours; t½ ≈ 5.6 h; steady state in roughly a day.