Pharm 6: Clinical Pharmacokinetics 1

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Clearance (CL)

a measure of the body's ability to eliminate the drug = Rate of elimination (amount/time) / plasma drug concentration (amount/volume) -> units = volume per unit time -> how much volume of blood you have to clear per unit time to get rid of the drug

First order elimination

rate of elimination = CL x C -> most drugs follow this with low plasma drug concentration (at high concentrations there is a VMAX because the transporters are saturable)

Extraction ratio (ER)

the ratio of the hepatic clearance of a drug (CL-liver) to the hepatic blood flow (Q) = CL-liver/Q -> Q = 1.5 L/min in a person weighing 70kg -> ratio of drug that when it enters the liver is cleared by the liver in one pass -> high > .7, low <.3

High extraction ratio

clearance is blood flow dependent, have large first pass effect -> bioavailability is low after oral administration -> morphine, Lidocaine, verapamil, propanolol and nitroglycerin

Low extraction ratio

clearance capacity limited (liver controls the clearance) -> phenytoin and warfarin -> clearance is relatively independent of hepatic blood flow (not efficiently cleared by liver), primarily determined by the metabolizing capacity of the liver and by the free drug fraction\

Drugs with intermediate extraction ratios

hepatic clearance is dependent on hepatic blood flow, metabolizing capacity of liver and free drug fraction -> aspirin, quinadine, codeine, nortriptyline

Bioavailability (F)

the fraction of drug absorbed as such into the systemic circulation = f x (1-ER) where f is the fraction of drug absorbed and (1-ER) is the fraction of drug that escapes extraction by the liver

Volume of distribution (VD)

the volume that would be required to contain all of the drug in the body at the same concentration as in the blood or plasma = amount of drug in the body / plasma drug concentration -> if the plasma drug concentration is maintained at a low level this will be very large (e.g. Quinacrine -> bound to peripheral tissues), if it is contained within the blood at a high concentration this will be very small

Half life

the amount of time it takes to change the amount of drug in the body by 50% during elimination (or during a constant infusion) = .693 x VD/CL -> determines the rate at which blood concentration rises during a constant infusion and falls after administration is stopped (in clinical situations steady state is said to be attained after 4 of these) -> DOES NOT depend on the dose

Calculate the volume of distribution (VD) given a loading dose and the plasma drug concentration at time zero

= Dose/C0 -> extrapolate the curve back to the y axis to get C0 (plasma drug concentration at time 0)

KE

= CL/VD = rate constant for elimination of the drug -> bigger clearance the faster elimination happens, the larger the VD the slower elimination happens = .693/(t1/2)

Describe the concept of steady-state with regard to plasma drug concentrations (saturation kinetics)

rate of elimination = (Vmax x C) / (Km + C), at high drug concentrations, the rate of elimination approaches Vmax (zero order kinetics -> constant amount of drug is eliminated per unit time)

List examples of drugs that follow zero-order kinetics

aspirin at high doses, ethanol and phenytoin regardless of the concentration, the elimination is always the same -> clearance will increase as concentration drops (desaturation of the enzymes)

Maintenance dose

= dosing rate x dosing interval -> used to maintain a steady state of drug in the body -> dosing rate = rate of elimination = CL x TC / F -> TC = target concentration

Loading dose

= VD x target concentration / F

Calculate the drug plasma levels reached after a given number of half lives during drug administration

1 t1/2 = 50%, 2 t1/2 = 75%, 3 t1/2 = 87.5%, 4 t1/2 = 93.75% (after 4 it is assumed that we have reached steady state)

Calculate the drug plasma levels reached after a given number of half lives after drug administration is discontinued

1 t1/2 = 50%, 2 t1/2 = 25%, 3 t1/2 = 12.5%, 4 t1/2 = 6.25% (after 4 it is assumed that we have reached steady state)

Given the half-life of a drug, calculate the accumulation factor (AF)

= 1 / (fraction lost in one dosing interval) = 1 / (1 - fraction remaining) -> predicts the ratio of the peak concentration at steady state to the peak concentration after the first dose -> for a drug given once every half life this will = 1/.5 = 2, 2 half lives will = 1/.25 = 4

Peak concentration at steady state (PKSS)

= peak concentration after the first dose x AF

Pharmacokinetic equations

see page 12 for chart of pharmacokinetic equations

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