Pharmacokinetics of Elimination

Question 1

1. Explain the derivation and clinical relevance of pharmacokinetic parameters and be able to use them in designing dosage regimens and predicting changes in drug plasma levels and drug response, including: bioavailability (F), volume of distribution (Vd), clearance (CL), half-life (t1/2), elimination rate constant (ke), and first-order and zero-order kinetics.

Answer 1

• Rate of elimination proportional to Cp in 1st order kinetics (Cp doesn’t affect rate of elimination in zero-order).
• Cp vs. time estimates rate of elimination–> reflects how rates change over time.

-Clearance (CL): Selecting maintenance dose, dosage adjustments necessitated by alteration of kidney or liver function.
-The Vd (volume of plasma) that is completely cleared of drug in a given period using all the potential elimination processes.
Proportionality constant that makes Cpss = rate of administration.
-Hepatic clearance varies with blood flow to liver, protein-drug binding, and intrinsic hepatic metabolic activity (can be induced or inhibited).
-With blood flow, low extraction drug (metabolism inefficient), changes don’t affect clearance.
-High extraction drugs have efficient metabolism, and changes do have an effect on clearance.
-Renal function varies as kidney function varies, so estimate with SCr and CrCL.
-If kidney function changes, have to accommodate for renal dosing.

• Half-life (t1/2): Time to steady state or removal from body, selecting dosage intervals, relation to fluctuations in plasma drug levels between drug doses (difference between Cp max and Cp min).
• Characteristic of 1st order kinetics; it’s a constant fraction that is independent of the total amount of drug present.
• Time it takes for drug to be eliminated and reach steady state = 4-5 half lives.
• The greater half lives in the dosing interval, the more fluctuations you’ll have.
• If half life is too high and you can’t wait, can administer a loading does to reach steady state quicker.
• Don’t do higher maintenance doses because you don’t get proper Cpss sooner, just have a higher value.
• If tau < t1/2, plasma levels fluctuate less than 50%.
• If tau > t1/2, drug is eliminated before the next dose fluctuation.

Elimination rate constant (ke):

• Depends on the slope from the beta elimination phase.
• Describes the fraction of drug leaving the body/unit time.

First-order and zero-order kinetics:

• Implications for chronic dosing regimens.
• In 1st order kinetics, the rate of elimination is proportional to the plasma concentration, which complicates things because as drug is being eliminated, Cp is changing.
• 1st order kinetics is actually mediated by biological processes.
• In zero-order kinetics, rate is constant regardless of Cp.
• The amount of drug removed is constant, and the rate of elimination is independent of the amount of drug in the body.
• This happens due to saturation of hepatic metabolism. -Drugs in this system don’t have half-lives.

Question 2

2. Describe the relevance of pharmacokinetic concepts to clinical drug actions including: first-order elimination, zero-order elimination, volume of distribution, steady-state plasma concentration, clearance, and bioavailability.

Answer 2

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