Pharmokinetics and Pharmodynamics Flashcards
What is the clearance rate?
VD X Kel OR (0.693 X Vd) / (T 1/2)
What is the elimination rate?
Kel= Cl/Vd
What is the Half-life eqn?
(0.693 X Vd)/ Cl = 0.693/Kel
What is the Css eqn?
Css=F x D / (Cl x dose interval)
What is dosing rate eqn?
Css X Cl/ F
What is the maintenance dose?
(dosing rate/ F) x dosing interval
What is the loading dose eqn?
Css x Vd/ F
What kind of drugs can pass through lipid membranes?
unionized
If pH is less than pKa then (blank) forms predominate
protonated
When pH is greater than pKa the (blank) forms predominate
deprotonated
When pH=Pka then what does that mean?
HA=A- and BH+=B
When you give a drug where does it go first?
brain, heart, liver and kidneys
WHen you give a drug where does it stay the longest?
adipose tissue
When you give a drug, where will it be most concentrated between 15-30 minutes?
skeletal muscle and skin
What is the volume of distribution?
the amount of drug that is no longer in the serum (i.e. you can only check the serum where you put the drug in so if there is less drug in there then it has clearly been distributed in the tissues)
How do you calculate the volume of distribution?
Vd= Dose/ (concentration in the blood)
What is the central volume of your blood?
5.5 L
What is Central volume?
Vc=dose/peak serum level
Why is knowing the central volume helpful?
because it tells us the distribution of drug to non-vascular compartments and about the elimination that may occur before a sample can be taken.
What is often referred to as the central compartment?
the Vc of your blood (5.5L) when given IV drug admin.
How does drug get retains in the central compartment?
via proten binding an partitioning
Does high protein binding mean the drug will be less available?
not necessarily because the binding is reversible, it is low affinity but high capacity binding
when drugs bind to RBCs is this reversible?
no so it will affect pharmokinetics
What is peripheral volume?
sum of all the spaces outside the central compartment in which the drug distributes
Drugs taken (blank) or (blank) will first move into the central volume before distributing to the periphera compartment
orally
administered IV
Peripheral volume plus central volume = ?
apparent volume of distribution
If you double your volume of distribution what will happen?
your t 1/2 will increase and your concentration in the plasma will decrease
What is the peripheral volume?
the sum of all the spaces outside the central compartment
What organ metabolizes drugs?
liver
What are the transporters on hepatocytes?
ABC, NTCP, OAT, OATP, OCT
On hepatocytes is an OATP receptor which many drugs can bind to. Name 3 common types
HMG-CoA reductase inhibitors (statins), ACE-inhibitors, and chemotherapeutics
Several members of the OATP superfamily are expressed in the human liver including …..?
OATP1B1
OATP1B3
OATP2B1
Which one of the OATP superfamily receptors is only found on the liver?
OATP1B1
OATP2B1 and OATP1B3 have been detected in several tissues
Which one of the OATP superfamily receptors is only found in brain, intestine, placenta, heart and platelets
OATP2B1
Which one of the OATP superfamily receptors is only found in the placenta stomach, colon and prostate?
OATP1B3
Soooo… what two subfamily transporters are of particular importance for hepatic drug disposition?
OATP2B1
OATP1B
What is a potent inhibitor of OATP2B1 and OATP1B1?
cyclosporin A
What besides an inhibitor of OATP2B1 and OATP1B1 is cyclosporin A?
It is a substrate of CYP3A4 and functions as a competitive inhibitor thus resulting in increased levels of CYP3A4 substrates in the blood
(blank) interacts with ABCB1 and ABCC2
cyclosporin A
The ABC efflux pumps expressed in the (blank) of hepatocytes influence biliary elimination of substrate drugs.
canalicular membrane
What happens if your ABC transporters on your hepatocytes are inhibited?
you will get increased heptaocellular accumulation
Inhibition of intestinal ABCB1 or ABCC2- mediated drug efflux may lead to (blank)
enhanced intestinal absorption of co-admin drugs
(blank) has a narrow therapeutic window
Digoxin
(blank) has a narrow therapeutic window and lots of drug interactions
digoxin
What 2 transporters does cyclosporine (cicloral) inhibit the substrates of?
OATP
BCRP
(blank) is a substrate of OATP1B1/1B3 and BCRP. Cyclosporin (increases/decreases) exposure 4.6 fold
Pitavastatin
increases
(blank) is inhibited by other OATP or BCRP inhibitors.
Rosuvastatin (crestor)
(blank) increases rosuvastatin exposure 2 fold.
Lopinair/ritonavir (kaletra)
Lopinavir/ritonavir are inhibitors of (blank).
OATP1B1/1B3
What are the phases of metabolism in the liver?
phase 1 “oxygenases”
phase 2 “transferases”
What are the oxygenases in the liver?
cyctochrome P450
Flavin-containing monooxygenases (mEH, sEH)
What are the transferases in the liver?
Sulfotransferase UDP-glucuronosyltransferases (UGT) Glutathione-S-transferases (GST) N-acetyltransferases (NAT) Methyltransferases (MT)
What does this:
C and O oxidation, dealkylation, others
Cyctochrome P450s
What does this:
N, S, and P oxidation
Flavin-containing monooxygenase (FMO)
What does this:
Hydrolysis of epoxides
Epoxide hydrolases (mEH, sEH)
What does this:
addition of sulfate
Sulfotransferases (SULT)
What does this:
addition of glucuronic acid
UDP-glucuronyosyltransferase
What does this:
addition of acetyl group
n-acetyltrasnferases (NAT)
What does this:
addition of a methyl group
methyltransferases (MT)
What reduces alcohol in the liver?
What reduces aldehyde in the liver?
what reduces quinones in the liver?
alcohol dehydrogenase
aldehye dehydrogenase
NADPH quinone oxioreductase (NQO)
What is this
~57 genes, 18 families, 43 subfamilies
CYPs
Which CYP families are responsible for drug metabolism? are the rates of metabolism fast or slow?
1 2 3
slow
Competition among drugs for CYPs leads to (blank)
adverse drug reaction and Drug/drug interacions
polymorphisms (SNP) and differing expression levels explain individual differences in (blank)
drug clearance
What do the numbers and letters after CYP stand for?
ex. CYP2D6 2=family D= sub-family 6= specific gene \+++++note++++ nomenclature is genetically based NOT FUNCTIONALLY
Which CYP has the most SNPs? Does this metabolize a large number of drugs?
CYP2D6
yes
Which CYP can metabolize the most drugs? How many clinically relavent SNPs of this have been found?
CYP3A4
46
When you have 2 copies f the CYP2D gene are you going to be a slow or fast metabolizer?
super fast
WHy is it important to understand SNPS and CYPs
because different SNPs make different CYPs fast or slow metabolizers which means some drugs wil be excreted quickly without ever reaching a therapeutic level and some drugs may just stay in your body and be slowly excreted reaching dangerous levels
Why dont you absorb a lot of drug in the stomach?
because the surface area is small
WHere do you absorb most of the drug?
small intestine
What is first pass?
its when you swallow a drug and then it goes to your GI tract where you excrete 80% and absorb only 20% that is first pass;
Ex. you swallow a 1000mg tablet, then you en up with 200 mg at first pass
Clearance is the same thing as (blank)
elimination
Most drugs are eliminated in a (blank) order elimination process. Why is this important
first
the amount of drug eliminated per unit time is directionally proportional to the drug concentration
What do you want to reach in chronic therapy?
steady state
the amount going in is replacing the exact amount that is being excreted (Css)
Drugs are cleared primarily by the (blank) and (Blank)
liver and kidneys
Excretion into the (blank) is a major route of elimination for metabolites as well as unchanged drug.
urine
with (blank) elimination, the amount of drug eliminated is directly proportional to the serum drug concentration
first order
In first order elimination, the amount of drug eliminated changes but the fraction of a drug eliminated remains (blank)!!
constant!!!!
What does Kel represent?
fraction of drug eliminated per unit of time (remember this stays constant)
What is zero order elimination?
elimination of a constant quantity per unit time (rather than constant fraction like first order)
Most drugs are eliminated by first order elimination because the (blank) for elimination is not reached. In this case, the rate of elimination is directly proprotional to the concentrion of drug in the blood stream.
Km (substrate level at half the max rate of metabolism)
Some drugs such as alcohol exhibit (blank) elimination because the amout of drug exceeds the elimination rate constant
zero order
For a first order reaction what will a serum level curve look like?
For a first order reaction, what will a log scale of a serum level curve look like?
non linear
linear
What is the eqn for clearance?
Cl=Dose/AUC
Cl=(Rate of elimination)/ (Cp)
Do clearance rates change in a given patient?
no because elimination is not saturated in drugs used clinically
When we talk about clearance what are we talking about?
When we talk about overall clearance what are we talking about?
clearance from plasma
clearance rates of drugs from each tissue combined
What is the equation for elimination rate?
Cl X Cp
If you have a graph of concentration and time and you make a clearance curve out of it, it is not linear, how do you make it linear? What does this give you?
you measure the slow of the curve at by dividing concentration by time and plot that and you get a straight line
elimination rate constant
What wil Kel X Cp tell us?
how much drug is left
What eqn do you use to figure out the relationship between blood level and Kel?
slope= (ln Cp (2) - ln CP (1) )/ (t2-t1)
What eqn can you use to predict the time it takes to reach a specific serum level for our patient?
slope= (ln Cp (2) - ln CP (1) )/ (t2-t1)
just rearrange it for time
WHy would you want to know the time it takes to reach a specific serum level in a patient
so you can predict tau which is the ideal dosing interval.
tau=ln (Peak/trough)/ Kel
A critical parameter that relates to the rate of drug elimination is (blank). This is the time it taks for the concentration of drug in the plasma to fall by half.
half-life (T 1/2)
(blank) and (blank) reflect the same process, how quickly a drug is removed, and therefore, how often a dose has to be administered
T1/2 and Kel
What is the relationship between T1/2 and Kel?
T1/2=0.693/ Kel
Can you know the Vd or Cl of a drug base soley on its halflife?
nope you need both to find the Kel which will help you find the half life
(Kel= Cl/Vd)
(blank) are mathematical schemes that represent complex physiological spaces or process (important for determination of Kel)
pharmacokinetics
What are the 2 most commonly used pharmacokinetic models?
comparment 1
compartment 2
What is the one compartmental model?
Drug goes to central compartmetn before going to peripheral. Drug equilibrituates quickly within tissues and you use Vd to determine drug distribution
What is the two comparment model?
when you have slow equilibration within peripheral tissues-> have biphasic line (first slope is distribution to peripheral tissues, second slope is first order elimination)
Which is more unpredicatble, one compartment or 2?
2 because it doesnt obey linear kinetics
If you are looking at a drug concentration vs time graph, what is presented linearly a zero order or first order elimination?
zero order, first order is nonlinear
What is the goal of therapeutic drug monitoring?
to enhance the pnts chance of max benefit from a prescribed drug while minimizing the risks of toxicity
Characteristics of drugs associated with a need for therapeutic drug monitoring are: Digoxin.. why? Phenytoin... WHy? Warfarin...why? Lithium.... why?
narrow therapeutic range
unpredicatble dose/response relationship
signif consequences from toxicity
correlation between CSS and efficacy or toxicity
What is this:
As successive doses are administered, drug begins to accumulate in the body. With first order elimination, at a certain point in therapy, the amount of drug administered during a dosing interval exactly replaces the amount of drug excreted (rate in = rate out).
steady state
When this equilibrium occurs, the peak and trough drug concentrations are the same for each additional dose given. When peak and trough concentrations are the same with (blank) or more successive doses, steady-state is reached.
two or more
The time required to reach steady-state is approximately (blank) to (blank) half-lives.
4 to 5
The length of IV infusion will have a signif effect upon the (blank)
peak serum level
T or F, if we administer the same dose to the same patient at different rates, the peak levels will differ
T
If you infuse longer what will happen to your peak level?
it will decrease weirdly
How can you get a change in your half life?
rapid metabolization or liver damage, age
Impairment of (blank) will have a significant impact on the pharmacokinetic properties of drugs excreted renally.
kidney function
if you have excess creatine in your SERUM what does this tell us?
that you have renal function problems
In kidney disease, what all is impaired?
filtration, secretion, and reabsorption
(blank) is primarily filtered, NOT secreted or reabsorbed from the kidney. THerefore it can readily be used as an estimate of gomerular filtration rate.
creatinine
(blank) can be used as an overal estimate of renal function (since if filtration is impaired, then you know secretion and absorption will be equally impaired)
creatinine clearance
What is the y intercept (Knr) of Kel and CLcr graph?
it is the non-renal elimination rate i.e elimination rate when you have no renal function
What is the relationship between Ke and Clcr (creatinine clearance)?
linear
What is the calculated Kel for a particular drug and patient?
Kel=Knr + (B x CLcr)
If you have liver disfunction what can happen to your CLcr?
you CLcr can be OVerpridicted (so dont use equation with people with liver disease)
If you have a patient who is emaciated what can happen to your CLcr?
low serum creatinine secondary to decreased muscles mass, resulting in a signif over prediction of CLcr
If you have a patient who is elderly, what can happen to your CLcr?
They may have low serum creatinine concentrations secondary to decreased muscle mass, leading to a possible over predicition of CLcr
If you have a patient with unstable renal function, what can happen to your CLcr?
PK consult correcting for rising serum creatinine, may be more accurate in these patients
How do you estimate CLcr for males?
Wt(140-age) / (SCr X 72)
SCr= most recent serum creatinine
Wt=weight
How do you estimate CLcr for females?
85% of male value
What method for calculating CLcr is more accurate for patients with unstable renal function?
Jelliffe method:
What is an MIC?
the minimum concentration of drug that inhibits the growth of a microorganism
What happens when you are above the MIC?
you have time-dependent killing and minimal to moderate persistent effects
Even if you fall below tht MIC can you still have effects of the drug?
yes, this is called time-dependent killing
What if you have peak effects above MIC what kind of killing will you get?
concentration-dependent killing and prolonged or persistent effects
B-lactams have a kill rate that is (blank) as long as the concentration is above the MIC. WHat does this mean?
concentration-independent
This means these agent have no signif post-antibiotic effects.
What is Post antibiotic effect (PAE)?
The persistent suppression of bacterial growth following antibiotic exposure
So how should you use beta-lactams?
you should give small doses frequently OR give continuous IV infusion of Beta lactams
What is vancomysin and why do you use it?
it is an antibiotic used against methicillin-resistant staph or for penicillin allergic patients OR patients who have failed to respond to penicillin or cephalosporin.
What four drugs have a kill rate that is concentration-independent as long as the concentration is above the MIC?
vancomycin, carbapenems, macrolides, and clindamycin
vancomycin, carbapenems, macrolides, and clindamycin have an (blank) post-antibiotic effect, therefore serum levels may be allowed to drop below the MIC for a short period of time.
intermediate
How should you deal with vancomycin, carbapenems, macrolides, and clindamycin
maximize exposure time durin which the plasma concentration exceeds MIC. THis may be achieved by givng smaller doses more frequently.
