9/10 ch.3 required reading quiz 2

two basic pharmacokinetic parameters

Volume of distribution and Clearance

volume of distribution

the measure of the apparent space in the body that a drug seems to distribute into

clearance (CL)

measure of the ability of the body to eliminate the drug

clearance (CL) predicts

rate of elimination in relation to the drug concentration (C)

CL_b

clearance of blood

CL_p

clearance of plasma

CL_u

unbound in water

Elimination of drug from the body may involve processes

in the kidney, the lung, the liver, and other organs

rate of elimination =

CL x C

First-order elimination

body eliminates a constant percentage of the drug per unit of time

area under the curve (AUC)

represents the body's total exposure to the drug over time

first order elimination clearance

dose/AUC

Large AUC

lots of drug remains in the blood over time → low clearance

Small AUC

drug disappears from the blood quickly → high clearance

Capacity-limited elimination

the enzymes or transporters responsible for eliminating a drug have a maximum capacity

Capacity-limited elimination is also known

mixed-order, saturable, nonlinear, and Michaelis-Menten elimination

V_max (maximum elimination capacity)

maximum elimination capacity

K_m

drug concentration at which the rate of elimination is 50% of V_max

concentrations that are high relative to the K_m

the elimination rate is almost independent of concentration—a state of “pseudo-zero order” elimination

flow-dependent elimination

the organ is so good at removing the drug that the limiting factor is how quickly blood can bring the drug to the organ

two aspects to the pharmacokinetics of proteins (large molecules)

long half life and target-mediated drug disposition (TMDD)

long half life

Large molecules tend to stay in the body for a long time, like a couple of weeks

target-mediated drug disposition (TMDD)

for large molecules the drug binds its target, and that interaction helps remove the drug from the body

Half-life (t_1/2)

time required to change the amount of drug in the body by one-half during elimination (or during a constant infusion)

Half-life (t_1/2) equation

0.7xV/CL

drug accumulation

give the next dose before the previous dose has been completely eliminated, some of the old drug is still present., the new dose adds on top of it

Accumulation is inversely proportional

to the fraction of the dose lost in each dosing interval

accumulation factor (AF)

how much higher the drug level becomes with repeated dosing compared with a single dose

Bioavailability (F)

fraction of the administered drug dose that reaches the systemic circulation unchanged

Why is IV bioavailability 100%

When you give a drug intravenously (IV), you're putting it directly into the bloodstream

orally administered drugs

don't get fully absorbed from the GI tract bc drugs need right balance of water and lipid solubility and P-glycoprotein can pump drugs back in intestine

-decreases bioavailability

first-pass elimination

when a drug is metabolized before entering systemic circulation, can be metabolized in blood or in liver (can excrete drug in bile)

extraction ratio (ER)

fraction of the drug the liver removes during one passage through the liver

extraction ratio (ER) formula

CLliver​ = hepatic clearance

QQ = blood flow through the liver

systemic bioavailability of the drug (F)

can be predicted from the extent of absorption (f) and the extraction ratio (ER)

rate of absorption

determined by the site of administration and the drug formulation

Zero-order absorption

constant amount of drug is absorbed per unit time

first-order rate of absorption

constant fraction (percentage) of the remaining drug is absorbed per unit time

after four absorption half-lives

almost all of the dose will have been absorbed

choose a route other than oral

avoid first-pass metabolism by the liver

topical, patch, sublingual, rectal, inhalation

Sublingual

under the tongue and largely avoids first pass

Transdermal

patch on skin and largely avoids first pass

Rectal

only partially avoids first pass , 50% pass

inhalation

bypass the hepatic first-pass effect but lung may also serve as a site of first-pass loss