Lec 50 Pharmacokinetics Flashcards
What is pharmacokinetics vs pharmacodynamics?
pharmacokinetics = what body does to drug pharmacodynamics = what drug does to bidy
What are the four processes of pharmacokinetics? mnemonic?
ADME
- absorption
- distribution
- metabolism
- excretion
What is definition absorption?
movement of drug from site of administration [GI tract] to systemic circulation
What is definition distribution?
movement of drug from systemic circulation to perfused tissue and between compartments
What is definition metabolism?
biotransformation of administered drug
mainly hepatic
What is definition excretion
removal drugs and their metabolites from body – mainly in urine or bile
What type of administration of drug bypasses the absorption process?
intravenous
What are 4 mechanisms of absorption?
- diffusion through membranes
- diffusion through aqueous intercellular spaces [capillary fenestrations]
- through membrane channels
- active transport via membrane carriers
What types of drugs can diffuse through membrane readily? which not?
small, non-polar, uncharged molec pass through easily
polar molec not as well
charged molec not at all
What happens to concentration of drug in systemic circulation for IV vs extravascular administration?
IV: will start high and decrease
extravascular: will start low as it is absorbing will increase to peak and then decrease
What is bioavailability [F] of a drug? What are its possible values?
- fraction of dose that reaches systemic circulation
- ranges from 0 to 1
What factors can limit oral bioavailability?
- incomplete absorption from GI tract
- first-past metabolism
Why would you get incomplete absorption from GI tract?
- some of dose undergoes metabolism within intestinal epithelial cells
- some of dose excreted in feces
What is first pass metabolism?
- drug absorbed through GI enters portal circulation first and passes by liver before reaching the rest of systemic circulation
- drug may be metabolized within liver so less bioavailability
Which types of administration have first pass metabolism?
- only oral
- sublingual, intramuscular do not
What is CYP3A4?
- enzyme in GI epithelial cell and in liver
- inactivates some percentage of drug that enters
How do you calculate bioavailability for time vs plasma concentration graph?
bioavailability can be calculated by area under the curve [AUC]
Is AUC for IV drug bigger smaller or same as for oral?
bigger AUC = higher bioavailability for IV drug
Where in the GI tract can drugs be absorbed?
- can take place in all segments of GI tract
How does pH affect drug absorption?
- many drugs are weak acids or weak bases
- those ionized in the stomach’s acidic environment will be poorly absorbed there
What is the major site of absorption for most oral drugs?
small intestine [particularly duodenum]
What 3 things determine why most drugs are absorbed in duodenum?
- large surface area
- longer transit time relative to stomach
- pH in range that leaves week acids and bases mostly non-polarized so can pass through membranes
How do extended-release drugs affect their absorption?
often designed to be released from tablet at various location along GI
What 2 factors influence drug distribution?
- binding to plasma proteins
2. vascularity of tissue
What are the 2 most important plasma proteins for drug binding?
- albumin
- a1-acid glycoprotein
How does binding to plasma proteins affect drug distribution?
- almost all drugs bind plasma proteins [often 95-99% of total drug in plasma is bound]
- only free fraction of drug is available for distribution
- drug that binds protein more will have smaller Vd
How does vascularity of tissue affect drug distribution?
- drugs distribute faster to highly perfused tissues [brain and heart]
- distribution slower to muscle
- slowest to adipose tissue and bone
What is redistribution?
- drugs distribute between tissues, mediated by return to bloodstream
What does VRG stand for?
vessel-rich group = brain and heart
What is the volume of distribution?
Vd = volume of distribution Vd = A/C A = amount of drug in body C= plasma concentration of drug Vd is the apparent volume = the volume of plasma you would need to hold the amount of drug administered
What is relationship between amount of drug accumulated in tissue and Vd?
more drug accumulated in tissue = bigger Vd
can often be much bigger than plasma volume
What specific type of drugs in particular have large Vd?
lipophilic drugs that accumulate in adipose tissue
What are two methods of drug elimination?
- metabolism
- excretion
What are the two major organs of elimination?
- liver most important metabolizer, kidney also does some metabolizing
- kidney plays role in drug elimination primarily by excreting unchanged drug
What is difference elimination and excretion?
- once drug undergoes metabolism it has been eliminated even if metabolites still present in body
- excretion is elimination only when the excreted drug is unchanged
- excretion of already metabolized drug by urine or bile is NOT elimination
What is the rate of elimination?
amount of drug removed from body per unit time
What is relationship rate of elimination and plasma drug concentration [C]? What order process?
- first order process [linear]
- rate of elimination directly related to plasma drug concentration [C]
rate of elim = C* Cl
What is pharmacokinetic definition of clearance [Cl]?
- Clearance [Cl] is the constant that relates the rate of elimination to plasma concentration
- vol of plasma from which drug eliminated per unit time [plasma volume/time - L/hr]
How does clearance [Cl] change as drug administered or eliminated?
- it does not
- clearance is constant, provides single value to characterize the drug’s elimination
What is equation for Cl?
Cl = Rate of elimination / Concentration [C]
What puts max limit on clearance?
- limited by plasma perfusion
- Cl cannot exceed volume that passes through that organ
What is max value for clearance of a drug by combined hepatic and renal elimination?
1600 mL/min
96 L/hr
How does plasma kidney perfusion differ from GFR?
- clearance by filtration limited to GFR
- renal secretion and metabolism combined with this allow kidney to have higher clearance
What is extraction ratio [E] of organ?
- E is an index of its efficiency in eliminating drug
- fraction of plasma cleared of drug during each pass through organ
- ranges from 0 [no elimination] to 1 [removes all drug from plasma in single pass]
What is equation for E [extraction ratio]?
E = (Cin - Cout) / Cin
Cin and Cout = drug concentration in plasma as it enters and leaves organ respectively
What does E=0 mean?
no elimination by the organ
What does E = 1 mean?
all drug eliminated from plasma in single pass through the organ
What is equation for specific organ clearance?
Cl = Q*E Cl = clearance Q = plasma flow E = extraction ratio
What is renal clearance?
Cl = QE = (UV)/P
What is another equation for the extraction ratio of kidney?
E = U/P
What is a high extraction drug?
drug with E >= 0.7
What is limiting factor of clearance of high-extraction drugs?
= flow limited
- sensitive to perfusion rate of organ since efficiency of organ already very high
How is it possible that even some highly protein-bound drugs can have high extraction ratios?
as free drug eliminated within organ, bound drug dissociates and can be eliminated
What is relationship high extraction and oral availability?
high extraction = low oral bioavalaibility because 70%+ of drug metabolized during first pass elimination
What is a low extraction drug?
- drug with E < = 0.3
How does clearance of low extraction drug change with perfusion rate?
- low extraction drug relatively insensitive to perfusion rate
- reduced perfusion –> increases extraction ratio by giving elimination more time to act on drug
What is limiting factor of clearance of low extraction drugs?
- capacity-limited
- sensitive to enzyme regulation [induction or inhibition]
What is equation for total clearance of drug?
Cl tot = Cl hepatic + Cl renal + Cl other
What are phase I drug metabolism rxns?
- oxidation/reduction rxns that add or expose active group of drug
- produce more polar molec
What is consequence of phase 1 rxn?
- metabolite less active than parent drug [often no activity]
- polar mole more likely to be excreted by kidney
- active group provides substrate for phase II conjugation rxns
What type of enzymes catalyzes most phase I rxns?
CYP450s
What enzyme in GI works to limit drug absorption?
CYP3A4 [a type of CYP450]
What is relationship rifampin and CYP450?
rifampin is a drug induces CYP450 so increases elimination of many other drugs
What is an relationship CYP3A4 and grapefruit juice?
grapefruit juice inhibits CYP3A4 in guit
- increases absorption of CYP3A4 substrates
Are phase I or phase II rxns catalyzed by CYP450 enzymes?
phase I
What are phase II metabolic rxn?
- conjugation endogenous metabolite [glucoronic acid, acetic acid, etc] to active group of drug
Are conjugated [phase II products] active or inactive? Whats an example of an active one?
- usually inactive
- exception: morphine glucoronide is active analgeisc
Does phase II rxn require phase I rxn already complete?
No - some drugs already have active group present so don’t need phase I rxn
What drugs mainly excreted in hepatobiliary excretion?
- mainly high molecular weight drugs and metabolites
What types of drugs are excreted via glomerular filtration?
- only unbound drugs
- clearance limited by GFR
What limits clearance of drugs excreted via glomerulus?
- limited by GFR
What is path of drug renal excretion?
- glomerular filtration or secretion [active transport in PT]
- then either excreted or reabsorped in PT/DT via passive diffusion or active transport
What is fraction excreted unchanged [FEU]?
- fraction of drugs excreted unchanged in urine
- represents net outcome filtration, reabsorption, secretion
What is equation for renal clearance of drug [excluding renal metabolism]?
Cl renal = FEU * Cl total
What is ion trapping?
- due to pH difference between urine and plasma, ionization of drug in urine can reduce drug reabsorption [and increase excretion]
- only uncharged species can be reabsorbed by diffusion
What is the henderson hassleback equations?
pH = pKa + log [unprotonated]/[protonated]
= pKa + log [A]/[HA]
