Exam 4 Flashcards
protein surfaces are mostly ___________ with _________ crevices (hydrophobic/hydrophilic)
hydrophilic, hydrophobic
_______ (high/low) protein content in blood plasma
high
protein binding results in non-uniform distribution of a drug in the body and hence affects which pharmacokinetic parameter?
Vd
the _______ (majority/minority) of drug molecules in plasma are bound to plasma proteins
majority
______ (free/bound) drug molecules are pharmacologically active and in equilibrium with other type of drug - free or bound
free
clinical labs report total plasma as the plasma drug concentration, what is the total plasma concentration equal to?
bound + unbound
this type of drug cannot easily pass through membranes, has a restrictive distribution and elimination, therapeutically inactive
bound drugs
this type of drug crosses cell membranes, has a larger distribution, therapeutically active
free/unbound drugs
major protein component of plasma and ECF, acidic and basic drugs bind to this
albumin
plasma protein that basic drugs bind to
AAGP
plasma proteins that lipophilic drugs bind to
lipoproteins
what percentage of plasma protein binding means low binding?
less than 50%
what percentage of plasma protein binding means high binding?
greater than 80%
what does fu mean?
fraction unbound drug in plasma
what does fut mean?
fraction unbound drug in tissues
what does fu equal (what’s the equation)?
[unbound]/[unbound]+[bound]
what does Vp mean?
plasma volume
what does Vt mean?
tissue volume
fu is _____ (higher, lower, constant) as Cp increases for drugs bound to albumin
constant
the number of albumin protein binding sites is _______ (greater/less) than the drug molecules available for binding
much greater than
at very ______ (high/low) Cp binding sites are saturated so fu increases as Cp increases
high
if the fu value is 0.01, what is the percent protein binding?
99%
if the fu value is 0.9, what is the percent protein binding?
10%
highly bound drugs have a ________ (high/low) fu, and drugs with this fu have a _______ (high/low) Vd
low, low
a greater Vd causes what change in Cp?
decrease in Cp because greater Vd means more moves into tissues so there is less drug in the plasma (decreased Cp)
changes in fu imply changes in the unbound drug concentration in plasma which can enter tissues and exert a pharmacological or toxicological effect but it can also be eliminated by what?
glomerular filtration
for drugs whose fu increases and are subject to _______ elimination, the increased unbound drug concentration is SOMETIMES cancelled out by the increase in elimination by GFT
restrictive
what is Ka?
affinity constant
a ______ (high/low) Ka value means strongly bound drugs (decreased fu) so larger dose needed
high
drug affinity (Ka and fu) is altered in what disease state?
uremia (consequence of severe renal disease)
any factor that alters protein binding becomes clinically important when a drug is _______ (highly/not highly) protein bound, when fu is _______ (greater than/less than) 0.1
highly, less than
_________ (increase/decrease) in albumin during hepatic failure, renal failure, burns, stress/trauma, pregnancy, decreased binding of phenytoin for example (decreased Cp)
decrease
______ (increase/decrease) in AAGP during myocardial infarction, renal failure, arthritis, surgery, increase in Cp of quinidine for example
increase
_____ (increase/decrease) in tissue binding affinity in uremia, increased Cp of digoxin for example
decrease
when 2 drugs compete for the same binding site, one drug kicks out the other drug
displacement
these drugs achieve high concentrations in plasma and bind to albumin/AAGP, displace other drugs from tissue sites
displacers
“non-synthetic” or “functionalization” reactions, introduce or uncover a hydrophilic functional group
phase I of biotransformation
“synthetic” or “conjugation” reactions, drug or drug metabolite is attached to endogenous water-soluble molecule
phase II of biotransformation
drug metabolite is eliminated from cell via transporters in cell membrane
phase III of biotransformation
the phases of biotransformation ______ (do/do not) imply sequence
do not
examples of this are oxidation, hydrolysis, reduction, and demethylation
phase I reactions
ester hydrolysis, amidase, epoxide hydrolase are enzyme examples of which type of reaction?
hydrolysis, phase I
CYP450 and FAD monooxygenase (FMO) are enzyme examples of which type of reaction?
oxidation, phase I
CYP450 and Azo reductase are enzyme examples of which type of reaction?
reduction, phase I
CYP450 only is an enzyme example of which type of reaction?
demethylation, phase I
examples of this are glucuronidation, sulfonation, glutathione conjugation, and acetylation
phase II reactions
UDP-glucuronosyltransferase (UGT) is an enzyme example of what type of reaction?
glucuronidation, phase II
PAPS-sulfotransferase (SULT) is an enzyme example of what type of reaction?
sulfonation, phase II
glutathione-S-transferase is an enzyme example of which type of reaction?
glutathione conjugation
N-Acetyltransferase (NAT) is an enzyme example of which type of reaction?
acetylation, phase II
multidrug resistance proteins (MRP), P-glycoprotein (P-gp or MDR1), and solute carrier transporters (OATP, OCT) are examples of this
phase III reactions
chemical conversion of a drug into another chemical form (metabolite)
biotransformation/metabolism
what is km?
first-order rate constant for metabolism
what is ke?
excretion rate constant
how do you determine ke?
unchanged (not metabolized) drug in the urine
what is fe?
fraction of drug excreted
how to find fraction of drug metabolized?
1-fe
for a drug eliminated by kidneys and liver, how does fe change with renal failure? liver cirrhosis?
decrease, constant (because no effect of liver on kidney processes)
for a drug eliminated by kidneys and liver, how does ke, km, and k change with renal failure? liver cirrhosis?
renal failure: ke decreases, km constant (because no effect of kidney on liver processes), k decreases
liver cirrhosis: ke constant (because no effect of liver on kidney processes), km decreases, k decreases
for a drug eliminated by kidneys and liver, k is approximately equal to what in renal failure? how about in liver cirrhosis?
renal failure: k about equal to km
hepatic cirrhosis: k about equal to ke
what does total clearance equal?
nonrenal clearance (Clnr) + renal clearance (Clr)
what are some sites of drug metabolism outside the liver (extrahepatic metabolism)?
small intestine (CYP3A4, UGT), vascular smooth muscle (GST), skin (SULT), kidneys (CYP450)
if Clnr is _________ (greater/less) than or equal to 1500 mL/min - the average hepatic blood flow - then drug is metabolized faster than the rate of hepatic blood flow, therefore extrahepatic metabolism is present, need to compare Clnr with HBF not Clr
greater
first pass effect _____ (increases/reduces) drug bioavailability, _____ (less/more) [systemic drug], AUCIV is greater than AUCoral, for drugs given orally the absolute bioavailability is less than or equal to 1
reduces, less
fraction of drug extracted by the liver
hepatic extraction ratio (ERH)
a _____ (high/low) ERH implies poor bioavailability due to extensive first pass effect
high
what value indicates a low ERH?
less than 0.3
what value indicates a high ERH?
greater than 0.7
factors that affect hepatic clearance
blood flow, intrinsic clearance, protein binding
variable Q, varies due to diet, physical activity, drugs (beta blockers decrease this and ultimately decrease Clh)
blood flow
what is F’?
reduced bioavailability (amount of drug systemically absorbed after liver extraction)
for drugs with ______ (high/low) ER the rate of drug metabolism is almost as high as the blood flow perfusing the liver, influenced by alterations in blood flow - flow dependent - for example beta blockers decrease Q and Clh resulting in increased Cp
high
for drugs with ______ (high/low) ER the rate of drug metabolism is lower, flow independent, influenced by changes to enzyme function (induction, inhibition)
low
reflects the inherent activities of all the enzymes involved in a drug’s biotransformation/metabolism
intrinsic clearance (Clint)
______ (high/low) ERH drugs are affected by Clint
low
for high ER drugs what is the main determinant of Clh?
Q, blood flow
for low ER drugs what is the main determinant of Clh?
Clint
bile produced in hepatic cells and enters gallbladder, active process so saturable, drug and metabolite excretion in bile depends on molecular weight (MW) and polarity
biliary excretion
drugs/metabolites with a molecular weight of greater than 500 are excreted primarily through ______ (bile/ urine/both)
bile
drugs/metabolites with a molecular weight of 300-500 are excreted primarily through ______ (bile/urine/both)
both
drugs/metabolites with a molecular weight less than 300 are excreted primarily through ______ (bile/urine/both)
urine
reabsorption of drug into the blood, polar glucuronides hydrolyzed back to less polar parent drug, intestinal beta-glucuronidase, evidenced by a secondary peak, important in multiple dosing or large single doses because can lead to drug accumulation to toxic levels (leflunomide), examples of drugs that do this –> morphine, indomethacin, pregnenolone, sulindac
enterohepatic circulation
which CYP450 has the most genetic variation?
CYP2D6
______ (poor/ultra) metabolizers have a higher incidence of side effects/toxicity
poor
______ (poor/ultra) metabolizers have a greater chance of therapeutic failure
ultra
by affecting the absorption, metabolism, distribution, and elimination processes that a drug is subject to genetic polymorphisms can significantly change PK parameters, this may necessitate changing the dosage regimen which is constituted by what?
DL (loading dose, to enable Css to be quickly attained), DM (maintenance dose, to keep Css within therapeutic range), tau (to maintain Css and reduce fluctuation and accumulation)
the relationship between the dose and the time course of drug concentration in body
pharmacokinetics
the relationship between drug concentration at the site of action and the effects of the drug
pharmacodynamics
is it possible to directly measure drug levels at the site of action?
no
whe rapid equilibrium exists between plasma drug concentration and drug concentration at site of action the drug concentration in the _______ can be used in the modeling process
blood
what does E represent?
intensity of the effect
what does C represent?
the drug concentration at the site of action
what does S represent?
the slope parameter that reflects the potency of the drug (greater slope greater potency)
what does E0 represent?
the effect in the absence of drug or the baseline effect, blood pressure for example exists in the absence of drug
what does Emax represent?
the maximum effect resulting from the drug (intrinsic activity)
what does EC50 represent?
the drug concentration when the effect is 50% of the maximum effect (a measure of the drug potency)
what does n represent?
the parameter affecting the shape of the curve, related to the number of drug molecules bound to the receptor (greater n means greater number of drug molecules bound to receptor)
the PK model estimates drug concentration in ______ (central/peripheral) compartment
peripheral
causes of this include drug concentration effect relationship changes with time, drug may produce an effect by an indirect mechanism (like anticoagulants), prodrugs can cause this, may result in a hysteresis loop
drug effect time profile may not relate to drug concentration time profile
arrows represent a series of observations, at a given plasma [drug] the drug effect will be different depending on whether the [drug] is high or low, time-dependent pharmacological response
hysteresis loop
used when there is a time delay between plasma [drug] and effect, hypothetical compartment that links PK and PD models, drug transfer from plasma to effect compartment does not affect PK of drug, drug transfer is first order, drug effect determined by [drug] in this
effect compartment
_______ (increasing/decreasing) the dose prolongs the duration of effect and duration ____ (is/isn’t) proportional to administered dose
increasing, isn’t
