Lecture 3- ADME Flashcards
permeation
movement of drug through barriers
aqueous/passive
no energy required: high to low conc
ficks law
“helps determine how well drugs can cross membranes” involves aqueous diffusion and passive diffusion of molecules down a conc. gradient
faster diffusion/absorption occurs when (ficks)
larger conc. gradients,
large area,
thin membrane
c1 (ficks law)
higher conc.
c2 (ficks law)
lower conc.
area (ficks law)
that diffusion is occurring
permeability coefficient (ficks)
measure of the mobility of drug mol. in the medium of diffusion path
thickness (ficks)
length of the diffusion path
the bigger the area, the thinner the membrane the ____ diffusion
faster diffusion
charged drugs are lipid ___ and water ____
insoluble, soluble
uncharged drugs are lipid ___ and water ___
soluble, insoluble
pKa
acid dissociation constant
HA
protonated acid, uncharged
A
unprotonated acid, charged
BH+
protonated base, charged
B
unprotonated base, uncharged
if pH equals pKa
50% protonated 50% unrpotonated
in order to cross membrane weak acids need to be _____ and weak bases need to be____; thus both are ____
protonated (acids)
unprotonated (bases)
both are uncharged
endocytosis
cell engulf
-occurs when substance is too large or insoluble or impemeant to cell by pinching it off
exocytosis
cell directs the contents of secretory vesicles out of the cell membrane, releasing a substance from the cell
volume distribution
how far the drug distributes out into body tissue; either bloodstream (SMALL) or out into tissues (HIGH vd)
Vd (L) equation
(D)amt of drug in body/conc. in plasma (C0)
a high VD indicates
out into tissues = lipophilic (fat lovin)
how can vd be decreased
plasma protein binding, dehydration
how can vd be increased
renal failure or liver failure
metabolism
mechanism that terminates/alters the biologic activity of a substance
prodrug
an inactive substance that must be converted by metabolism (liver) before it has biologic activity
sites of metabolism
liver***
lungs, GI, skin, kidney
what is the goal of metabolism
to convert xenobiotics into more water-soluble (polar) components for excretion
phase 1 rxn
makes more water soluble (polar) either for the kidneys or for a phase 2 rxn
major classes of phase 1 rxns
oxidation, reduction, hydrolysis
phase 2 rxn
add/alter molecule to increase water sol.
-conjugation, glucuronidation, sulfation
define CYP2D6
CYP- cytochrome P450
2- family
D- subfamily
6- individual enzyme
cyp 3A4
most drug interactions
gut flora
vitamin K absorption
what can impair hepatic drug metabolism
-liver dz: alcoholics, cirrhosis, hepatitis, Renal dz- fluid backup affecting liver -cardiac dz -endocrine -genetic -diet -age gender -any dz that lower blood flow
whats the most important enzyme system in liver
Cytochrome P-450 system
what organ does elimination mainly occur?
kidneys
where are weak acids excreted in?
alkaline urine
where do weak bases excrete faster in?
acidic urine
if weak acids are charged
less reabsorption occurs
where does “trapping” occur
stomach, SI, breast milk, aqueous humar, vaginal/prostatic secretions
clearance
volume of blood cleared of drug per unit time
what happens to cr Clearance if age goes up
it declines
what happens to crCl when wight increases
it goes up
what happens when Serum clearance increases
crCl goes down
half life (t1/2)
time it takes for the body to get rid half of the drug out of the system
steady state
amount of drug coming in during a period of time is equal to the amount leaving the body at that same time frame
first order elimination
elimination percentage-proportional to concentration
-most drugs follow
zero-order (cap limited)
elimination of constant AMOUNT
-independent of conc.
what is Ke
elimination constant
= cl/Vd
=(peak/trough)/changeintime
what happens to Ke when Cl increases
cl/vd
ke increases
what happens to Ke when vd increases
cl/vd
ke decreases
formula for t1/2 and ke
t1/2= 0.693/ke ke= cl/vd
..
t1/2=0.693*vd/cl
a larger vd has what effect on half life
increase
a smaller cl will have what effect on half life?
increase
what constant makes the avg steady state plasma drug level equal to the rate of drug admin?
clearance
equation for avg conc. (steady state)
Css= Dose/( Cl*dosing interval)
what effect does dose have on the Css
proportional, increase =increase
what effect does increasing the dose interval have on Css?
decrease css
how long is time to steady state
4-5 half-lives
loading dose
gets pt to steady state immediately
-skipping 4-5 half lives by big dose, then intermittent
amidirone
takes a year for elimination or something like that lol
maintenance dose
administrating drug in such a way to maintain a steady state of a drug in body
(given after load dose)
what is the best cure to toxicity, why?
tincture of time-gives body time to metabolize
provides good supportive care
graph of zero order vs first order
zero order- straight line down (CONSTANT amount)
first order- curve line down (percent of drug)
