Pharmacokinetics

Volumes and protein binding

Volumes and protein binding Which of the following alteration in protein binding is likely to be the most clinically significant acutely? A. Volume of distribution=2, fut is increased B. Volume of distribution=150, fut is decreased C. Volume of distribution=2, fut is decreased D. Volume of distribution=150, fup is increased B. Protein displacement is only relevent if the unbound Vd (Vu) is significantly decreased. This is only relevant for drugs with small volume of distribution that are displaced from plasma protein binding OR for drugs with Large Vd where displacement occurs from tissue binding sites.

Volumes and protein binding If fup is increased, which of the following situations would most likely require a change in MD? A. Low E drug IV B. Low E drug PO C. High E drug IV D. High E drug PO Only C. This is really the only concern!

Volumes and protein binding When do you see a “spike” on the time vs concentration graph (aka transient increase) when fup is increased? A. Both PO and IV Low E drugs B. High E drug given IV C. Only Low E drug given IV D. High E drug given PO E. Both A and D This happens because the increase in fup causes a decrease in total Css, but no change in Css,u (takes a little time to go back to normal). This acute change also ONLY occurs if the drug has a low Vd. Also, for high E PO, fup’s also cancel out.

Volumes and protein binding When are you likely to see a clinically significant effect if fup is changed? Low or High protein binding? Wide or narrow therapeutic index? High or Low E drug? IV or PO? Know this chart!!

Volumes and protein binding Which of the following would result in the most clinically significant (concerning) situation? A. Nonlinear elimination B. Nonlinear plasma protein binding C. Both D. Neither A, because if you double dose, increase Css more than double b/c decreased Clint. B would result in increased CL, so you’d get less than doubling.

Volumes and protein binding Describe the phases of nonlinear protein binding: A= low concentrations. Constant fup. Doesn’t change. Most drugs. B= increase Cu now increase fup (for a drug that binds to a saturable protein). Few drugs C= Toxic range. Higher concentration because protein is now saturated

Dose dependence

Dose dependence CL,T=300 ml/min, fe=0.1. If this drug exhibits non-linear pharmacokinetics, what will be affected causing an increase in AUC? A. Because it is a high extraction drug, the CL will be affected B. Because it is a low extraction drug, the CL will be affected C. Because it is a high extraction drug, the F will be affected D. Because it is a low extraction drug, the F will be affected. B CL (low e drugs)= fup*CLint

Dose dependence High Extraction Drugs Low Extraction Drugs CL= F*= Non-linear PK manifests in: Terminal slope will be: Half life: CL= F*= Non-linear PK manifests in: Terminal slope will be: Half-life: High non-linear Pk affects F, while for low E drugs, non-linear PK affects CL *Terminal slope for high E drugs will be the same, since CL=k*V…not affecting CL, only affecting F.

Dose dependence

Dose dependence

Dose dependence

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