9/10 lecture drug absorption, distribution, and clearance

Oral drug pathway (from mouth to bloodstream)

Disintegration → Dissolution → Absorption

pharmacodynamics

what the drug does to the body, how drug produces its effect (esp. interactions w/ receptors)

pharmacokinetics

what the body does to the drug over time

ADME (absorption, distribution, metabolism, excretion)

Disintegration

break the dosage form apart in GI tract

capsule vs tablet, solid vs liquid, coating

Dissolution

drug dissolves in GI fluid

lipophilicity vs hydrophilicity, weak acid vs weak base

Absorption

drug has to cross the intestinal epithelial cell membrane and ultimately enter the bloodstream

active vs passive

Cmax

highest concentration of drug in the blood after the dose

Tmax

how long it takes to reach the peak (Cmax)

Half-life

time required for the drug concentration to decrease by 50%

C_plasma​×V_d

amount of drug in body

AUC (Area Under the Curve)

the total amount of drug exposure in the body over time

more=more overall drug exposure

less=less overall drug exposure

To dissolve in GI fluid

drug needs to be water-soluble in ionized form

To cross the GI membrane

drug needs to be lipid-soluble, non-ionized form

Transcellular transport

enters one side of the intestinal cell, travels through it, and exits the other side into the blood

non-ionized and lipophilic

Paracellular transport

goes b/t cells thru tight junctions

Influx pumps

transport proteins that help move certain drugs (like ionized drugs)

GI tract → enterocyte → toward bloodstream

Efflux pumps

pumps drugs back into GI lumen

P-glycoprotein

if P-glycoprotein is inhibited

less efflux of drugs back in lumen so more drug concentration in blood

first-pass metabolism

metabolism of an oral drug in the intestinal wall and/or liver before it reaches systemic circulation, which reduces the amount of active/unchanged drug reaching the bloodstream

decreases bioavailability

Bioavailability (F)

fraction or percentage of an administered drug dose that reaches systemic circulation unchanged

why we want high bioavailability

more drug reaches blood where the bloodstream can carry drug to tissue or organ where receptor is located

importance of blood

body’s transportation system for drug, why we want more drugs to reach bloodstream

relationship b/t first pass metabolism and bioavailability

inverse relationship

IV administration

drug is placed directly into systemic circulation so %100 bioavailability

value is used to determine bioavailability (F) value

bioavailability (F) formula

AUC oral/AUC iv x 10

Volume of Distribution (Vd)

how much a drug appears to leave the blood/plasma and distribute into the body's tissues

High Vd

more drug in tissues

Low Vd

more drug remains in blood/plasma

Plasma

liquid portion of your blood

Vd (L) formula

concentration of drug in body(mg) /concentration of drug in plasma(mg/L)

loading dose

larger initial dose given to quickly reach the desired drug concentration in the blood

affected mostly by Vd

loading dose formula

= desired concentration x Vd

Maintenance dose

keeps you in the therapeutic range by replacing the drug being eliminated

protein binding

drug in the blood attaches to proteins in the plasma, especially albumin, only free drug can do this

bound drug won’t be excreted by kidney

Vd and protein binding

when a drug is highly bound to plasma proteins, it tends to stay in the bloodstream instead of entering tissues which lowers Vd

Clearance (CL)

the volume of plasma that is completely cleared of drug per unit time

how efficiently the body removes a drug from the blood/plasma

Clearance (CL) formula

Rate of drug removal (mg/min) / Plasma concentration (mg/mL)

total Clearance (CL) formula

CLkidney + CLliver + CLother

two major ways the body clears drugs

kidneys clearance and liver clearance

kidney clearance

remove drug from the blood and put it into the urine

Liver clearance

chemically changes the parent drug into metabolites

phase I and phase II (conjugation)

Phase I

oxidation/reduction/hydrolysis, commonly involving CYP450

rate of drug administration

clearance (CL) x C_steady-state

Vd and half life relationship

proportional, high Vd = long half life , low Vd = short half life

k_e

first-order elimination rate constant

t_1/2 = 0.693 / k_e

Ke formula

ln (C2/C1) / t2-t1

Steady state

when the rate of drug entering the body equals the rate of drug being eliminated

rate in = rate out

4-5 half lives

to achieve steady state

Rate of drug removal formula

= k_e x C_plasma x V_d

amount of drug in body formula

C_plasma​×V_d

first-order elimination

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

half-life is constant

zero-order elimination

constant amount eliminated

half-life depends on concentration and CL is constant

saturable route of elimination

zero order where too much drug so elimination enzymes become saturated so they can’t any faster → fixed amount eliminated per hour

zero order graph

first order graph