Pharmacokinetics

Definitions:

• • How the body processes the drug. The actions of the body on the drug, including absorption, distribution, metabolism, and excretion. Elimination of a drug may be achieved by metabolism or by excretion. Biodisposition is the same as pharmacokinetics.

  • Relationship of drug concentration and time.

  • Volume of distribution (apparent): The ratio of amount of drug in the body to its concentration in the plasma of blood.

    • Vd = Amount of drug in the body / Plasma drug conc. (units = vol)

  • Clearance: The ratio of rate of elimination of the drug to its concentration in plasma or blood

    • CL = Rate of elimination of drug / Plasma drug conc. OR Vd x Ke (elimination constant) - in drugs that follow first-order elimination/kinetics.

    • (units = vol per unit time)

  • Half-life: The time it takes for the amount or concentration of a drug to fall to 50% of an earlier measurement; this number is constant, regardless of concentration, for drugs eliminated by first-order kinetics (the great majority of drugs). Half-life is not a constant and therefore not particularly useful for drugs eliminated by zero-order kinetics (e.g, ethanol, aspirin, phenytoin)

    • t_1/2 = 0.7 x Vd / CL (units = time)

    • Property of first-order elimination.

      • # of half-lives: 1:50%; 2:75%; 3:87.5%; 4:93.75%

  • Bioavailability: The fraction (or percentage) of the administered dose of a drug that reaches the systemic circulation.

    • F = 1 or 100% in drugs given through the IV route.

  • Therapeutic Window: is the safe "opening" between minimum therapeutic conc and the minimum toxic conc of a drug. The minimum effective conc will usually determine the desired trough levels of a drug given intermittently, while the minimum toxic conc determines the permissible peak plasma conc.

Dosage calculations:

The dosing plan of drug administration is based on knowledge of both the minimum therapeutic and minimum toxic concentrations of the drug, as well as clearance and volume of distribution.

• • Loading dose = Vd x Cp / F (Vd: vol of distribution; Cp: desired plasma conc; F: biovailability)

  • Maintenance dose = Cp x CL/F (CL: clearance)

  • Adjustment of dosage when elimination is altered by disease:

    • Corrected dose = Average dose for a normal person x Pt's creatinine clearance/normal creatinine clearance

      • This approach ignores non-renal routes of clearance that may be significant. If a drug is partly cleared by the kidney and partly cleared by the liver or other non-renal dose, the above equation should be applied to that part of the dose that is eliminated by the kidney.

      • E.g. If the creatinine clearance is reduced by 1/3rd normal, reduce dose by 1/3rd.

    • E.g.: Mr. Jones is admitted to Hospital with pneumonia due to GNB. The ABx tobramycin is ordered. The CL and Vd of tobramycin in Mr. Jones are 80 mL/min and 40 L respectively. What is the IV loading dose to achieve the therapeutic plasma conc of 4 mg/dL rapidly, and what is the maintenance dose administered IV q6hrs to obtain average steady state plasma conc of 4 mg/L.

      • Loading dose = Vd x Cp / F

      • Loading dose = 40 x 4/1 = 160 mg

      • Maintenance dose = Cp x CL/F

      • Maintenance dose = 4 x 0.08 / 1 = 0.32 mg/min

      • When given at q6h intervals:

        • 0.32 x 60 x 6 = 115.2 mg q6h.

  • Plasma conc. of drug given by constant IV infusion will show smooth rise in concentration with time, and always reaches 50% of steady state after one half-life, 75% after two half-lives, 87.5% after three half-lives, and so on. The decline in conc. after stopping the drug administration follows the same: 50% is left after one-half life, 25% after two half-lives, etc.