L2-3: Pharmacokinetics Flashcards
water soluble + lipid soluble drugs penetrate cellular membranes through ____ diffusion
passive (simple)
3 types of carrier-mediated trasnport
- structure specific
- competition
- Tmax
a ______ drug in an acidic medium (like stomach) is ______ ionized and more lipid soluble = rapidly absorbed
weak acidic drug
less ionized
if a drug is less ionized, how does this affect its ability to be absorbed
less ionized = absorbed quickly
what happens if a weak basic drug diffuses into an acidic medium
drug becomes ionized and will accumulate
why aren’t strong acids and bases lipid souble (cannot penetrate lipid membranes by passive diffusion)
they are always ionized in the body
ionized = not lipid soluble
what is ion trapping
acids accumulate in basic env
bases accumulate in acidic env
what causes an increase in the elimination of bases in urine
making the urine more acidic w/ ammonium chloride
what causes an increase in the elimination of acids in urine
making the urine more basic by sodium bicarbonate
the amount of active drug available at the site of action
bioavailability
what is the bioavailability of IV administered drugs
100%
disadvantages of oral administration
- emesis (irritation of intestinal mucosa)
- irregularities in abs
- metabolism by intestinal flora
- abs drug is exposed to liver
- gastric emptying time
- binidng to food
sites in body where drugs accumulate
Fat, Tissues, Bone
what is the main goal of biotransformation
promotion of elimination from the body
what does permeability glycoprotein (Pgp) aka multidrug resistance protein 1 (MDRI) do?
uses ATP to pump out substrates across cellular membranes
it is extensively distributed
factors affecting absorption
- solubility
- dissolution
- concentration
- blood flow
- absrobing surface
- pH
- contact time
bioavailability is a result of ….
- decomposition/inactivation of drug in intestine
- degree of absorption
- metabolism in gut wall or liver
- transport of drug by P glycoproteins back to the lumen of the gut
term for the initial metabolism of drug as it passes through gut and liver
first pass effect
what are the sites of drug exclusion
- CSF
- ocular fluid
- endolymph fluid
- fetal fluid
- pleural fluid
what is the apparent volume of distribution (Vd)?
total amount of drug in body / concentration of drug in plasma
what does a very low Vd indicate about the presence of a drug
drug is mostly present in the plasma (blood)
what does a high Vd indicate about the presence of a drug
drug is extensively distributed and binds extensively with peripheral tissues
drugs with very high plasma protein binding have ______ Vd
low
common characteristics of most pharmacologically active drugs
- lipid soluble
- unionized or partially ionized
- storngly bound to plasma proteins and other tissues
- not readily excreted by kidney
- remain in body for a long time
Phase I reactions convert ______ soluble parent compounts into more _________ metabolites (meaning they are ______ soluble)
lipid solible compounds into more polar metabolites = less lipid solible
phase I metabolites are usually _______ and readily ________
inactive, excreted
phase I reactions usually introduce or unmask certain ___________
functional groups
ex: OH, SH, NH2
what are the 2 types of Phase I reactions?
Microsomal: inducible reactions that occur in the ER
Non-microsomal: non inducible
Phase I reactions are NOT _______ specific
compound
type of Phase I reactions that come from ER, layers of enzyme+lipid layers that can metabolize lipid soluble drugs
Microsomal
Phase II reactions make drugs…
more polar, of larger molecular weight, and more inactive
what is the only Phase II reaction which is microsomal (therefore inducible)
Glucuronidation
what are the 2 most common CYP450 enzymes
CYP 3A4 and CYP 2D6
Phase II reactions are the _________ of drug via __________ enzymes
(Ex: glucuronidation, acetylation, sulfation, methylation, etc)
conjugation
transferase
what type of biotransformtion (phase I or II) do glucuronidation, acetylation, sulfation, methylation fall under
phase II
what are the types of enzymes that fall into non-microsomal phase I reactions
- esterases + amidases
- monoamine oxidases
- alcohol and aldehyde dehydrogenases
endogenous amines (Catecholamines, serotonin) are what type of nonmicrosomal enzymes
monoamine oxidases
CYP 450 inducers ?
Riley
Barfs
Penis
Goo
She just wont (swallow)
rifampin
barbiturates
phenytoin
glucocorticoids
st. john’s worts
what are the P450 inhibitors?
Candy Dildos Keep Every Vagina Functioning
cimetidine
diltiazem
ketoconazole
erythromycin
verapamil
fluoxetine
3 methods of renal excretion of drugs and drug metabolites
- glomerular filtration in the PT
- active tubular secretion or reabsorption
- passive diffusion across tubular epithelium
measure of the capacity of the body to remove the drug
clearancce
proportionality constant that relates the rate of drug elimintation to its plasma concentration
clearance
Explain the Two Compartment Model (biexponential) of drug pharmacokinetics
- distribution of drug is not instantaneous
- Vd (distribution of volume) becomes larger until equilibrium is reached
- intial decline in drug [ ] is fast due to elimination and distribution occurring
- the later decline in the plasma drug [ ] is only due to elimination (slower)
in the two compartment model, the intitial decline in drug [ ] is due to what?
fast elimination and distribution
in the two compartment model, the secondary decline in drug [ ] is due to what?
elimination only (slower)
the elimination of most drugs from the body follows ______ kinetics, meaning that a constant proportion of the drug is eliminated per unit of time
exponential
what assumptions are made when describing a drug’s half life ?
- body is a single compartment
- body size is = to Vd
- drug is distributed equally throughout body
- drug in plasma is in equilibrium w/ total volume
what type of elimination does this graph show
zero order elimination
elimination process gets saturated after a high dose
what type of elimination does this graph show
first order
to reach immediate therapeutic concentration, a ____________ dose is used
loading
Loading Dose = _____ x _____
Vd x TC (target concentration)
is a loading dose dependent on the half life or clearance of a drug?
no
repeated administration (same dose at same dosing intervals) results in a _________ concentration of the drug in plasma
steady state
it takes at least _______ half lives to obtain a steady state plasma level
5
shortening the _______interval will result in a higher steady state concentration
dosing
what is the effect on steady state concentration of the dosing interval length is increased
lower steady state
is the time required to reach steady state levels related to the size of the dose?
no
where is permeability glycoprotein (P-gp) expressed
- intestinal mucosa
- hepatocytes
- renal proximal tubular cells
- adrenal gland
- capillary endothelial cells of the BBB
Do Vd values represent their actual distribution in the body fluid
no
Vd is a conceptual figure
