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59 Cards in this Set

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What is a prodrug?
A drug that after administration needs to go through biotransformation into pharmacologically active metabolites (ex. prednisone, cortisone)
Prodrugs may be designed to do what? Give an example.
Prodrugs may be designed to increase systemic absorption. (ex. levodopa crosses the bbb before being transformed into active L-dopamine)
For a given drug, the rate and/or pathway of biotransformation may be variable between what?
May be variable between species.
Between populations or individuals of the same species, there may be variations in what?
There may be variations in drug elimination.
Review:

What is variable between species?

What is variable between pop.s or individuals of same species?
Species = biotransformation

Pop/indiv./same species = drug elimination
What is pharmacogenetics?
Pharmacogenetics is the study of genetic differences responsible for differences in drug elimination and responses to drugs.
Recall, most drugs follow what kind of elimination? What does this type of elimination equal?
Most drugs follow first order elimination.

Drug elimination = drug metabolism + drug excretion
In first order elimination how do you figure out the percent of drug metabolized?
% drug metabolized = (km/k)100
In first order elimination how do you figure out the percent of drug excreted? What about the fraction of drug excreted?
% drug excreted = (ke/k)100

Fraction of drug excreted = fe = ke/k
In first order drug elimination how do you figure out the fraction of drug metabolized?
Frac. of drug metab. = (1-fe)
GFR is fairly ?.
Constant
What is a difference between drugs eliminated largely by kidneys when compared to drugs that are largely eliminated thru metabolism?
Unlike drugs eliminated largely by kidneys (GFR fairly constant), drugs that are largely eliminated thru metabolism (eg, lidocaine, theophylline) have variable t1/2s between individuals (genetic effect).
What is the main site of drug metabolism?
The main site of drug metabolism is the liver (biotransformation).
In hepatic metabolism drugs are typically transformed into what? What is a benefit of this?
Drugs are typically transformed into more polar forms. These polar forms then lend themselves better to renal excretion.
What are the 2 phases of hepatic metabolism?
Phase I : a functional group is introduced or exposed

Phase II : a polar moiety gets appended to the drug
Hepatic clearance of drugs is defined how?
It is defined as the volume of liver-perfusing blood that gets cleared of a drug per unit time.
What is the equation for total body clearance?
Clt = Clnr + Clr

Clr = renal "
Clnr = nonrenal "
What is hepatic clearance approximately equivalent to?
Clnr
What is the equation for hepatic clearance?
Clh = Clt - Clr
For drugs with a high ER (ex. propranolol) what does a change in blood flow influence?
The rate of metabolism.
What is intrinsic clearance (Clint)?
It is a measure of the inherent capacity of the liver to metabolize a drug in absence of flow limitations.
How are most drugs cleared by the liver?
Most drugs are restrictively cleared by the liver. When protein-bound, they do not easily cross cell membranes and so are not easily metabolized.
Although most drugs are restrictively cleared by the liver some are removed how?
Some are non-restrictively removed. For example, propranolol and morphine. For such drugs the ER > fu (the fraction of unbound drug)
Generally, what occurs when a restrictively cleared drug is displaced from plasma protein binding?
Generally, when a restrictively cleared drug is displaced from plasma protein binding, clearance increases if it was highly protein bound.
For protein bound drugs what do changes in fu and Cl'int PROPORTIONALLY affect?
For protein bound drugs, changes in fu and Cl'int proportionally affect hepatic clearance.

(Cl'int = the intrinsic clearance of free drug)
For drugs with high intrinsic clearance, Clh is INDEPENDENT of ? ? and DEPENDENT on ? ?.
For drugs with high intrinsic clearance, Clh is independent of protein binding and dependent on hepatic blood flow.
Drugs administered via a route of administration other than oral get distributed prior to what?
Drugs administered via a route of administration other than oral get distributed prior to liver metabolism.
When administered orally drugs typically get absorbed in the ? ? and transported to the ? via the ? ? ? prior to entrance into the ? ? ?.
When administered orally, drugs are typically absorbed in the small intestine and transported to the liver via the hepatic portal vein prior to entrance into the general systemic circulation.
What is the first pass effect?
When some ORALLY administered drugs get rapidly metabolized by the intestinal mucosal cells and the liver before entry into the general circulation.
What is the first pass effect aka?
Pre-systemic elimination.
Orally administered drugs that display the first pass effect achieve only low what?
Orally administered drugs that display the first pass effect achieve only low plasma levels after oral administration.


AUCoral < AUCiv
What is absolute bioavailability in relation to oral absorption?
In the event of 100% absorption following oral administration, if the same dose of the drug is administered IV: AUCoral=AUCiv
What does F equal in the event of a first pass effect?
F < 1. However, other factors can also cause a reduction in F value. So a more direct measure is ER (extraction ratio)
In the event of a first pass effect what is the ER equivalent to?
ER < 1.

ER = (Ca - Cv)/Ca

Ca and Cv are the blood drug conc entering and leaving the liver respectively.
When you see F" in an equation what does it represent?
The fraction of drug removed by non-hepatic processes.
What does ER enable if an IV dose is known?
Er enables the determination of an equivalent oral dose of a drug if the IV dose is known.
What is hepatic blood flow?
A bioavailability factor estimated from the Clh and the blood flow (Q).
What is a typical hepatic blood flow?
1.5L/min

(ranges between 1 and 2L/min depending on physical activity, drug and food intake)
What is ER?
Extraction Constant (same as Eh or Extraction Ratio
Drugs with a high ER have poor what?
Drugs with a high ER have poor bioavailability when administered orally because of the first pass effect.
Drugs that dissolve slowly when administered po are more susceptible to what?
They are more susceptible to the first pass effect.
3 ways to overcome the first pass effect.
1. Change route of administration.

2. Increase oral dose

3. Use a more rapidly absorbable formulation.
Before enzyme saturation, metabolism is what kind of process? Upon saturation, metabolism is what kind of process?
Before enzyme saturation, metabolism is a first order process.

Upon saturation, metabolism is a zero-order process.
Generally in michaelis-menten enzyme kinetics a drug with a high Km needs what to achieve saturation?
Generally, a drug with a high Km needs a high concentration to achieve saturation.
When the enzyme gets saturated, the reaction proceeds at the ? rate and that rate depends upon what?
When the enzyme gets saturated, the reaction proceeds at the maximum rate and that rate depends on the amount of free enzyme.
The michaelis menten eqn produces what kind of curve? What is the reciprocal of this?
A non-linear curve. The reciprocal eqn is the lineweaver-burk eqn, it is linear and may be used to determine Km and Vmax.
Define competitive inhibition.
Drug and inhibitor compete for the same active site on enzyme; drug and inhibitor may have similar chemical structures; inhibition may be overcome by increasing drug concentration; change in km but not Vmax.
Define non-competitive inhibition.
Inhibitor acts at a site other than active enzyme site; inhibitor may combine equally well with the enzyme or with the drug-enzyme complex; Km is the same but V max is lower.
Define uncompetitive inhibition.
Inhibitor combines only with the drug-enzyme complex.
How could you confirm the pharmacokinetics parameters for two different metabolites?
Each metabolite may be administered by IV bolus separately to confirm the pharmacokinetic parameters separately.
Secretion of drugs into bile is what kind of process?
Secretion into bile is an active process.
Drugs that are excreted into bile have a ? molecular wt.
Drugs that are excreted into bile have a high mw.
MW > 500 excreted how?
bile only
300 < MW < 500 excreted how?
bile and kidney, a decrease in excretion via one route causes a compensatory increase in use of alternative excretory route.
MW < 300 excreted how?
Renal only
Drugs excreted in bile have ? ? groups.
Drugs excreted in bile have strongly polar groups. (ex. metabolites such as glucoronide conjugates)
If a drug is normally excreted in bile, any compound that stimulates bile production would do what?
If a drug is normally excreted in bile, any compound that stimulates bile production would increase that drug's excretion.
Give an example of a drug that increases bile flow?
Phenobarbitol
If a drug is given ?, it is more likely to be excreted in bile than if it is given ?.
If a drug is given ORAL, it is more likely to be excreted in bile than if it is given IV.