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39 Cards in this Set

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  • Back
Name 4 consequences of drug metabolism.
1. Elimination
2. Facilitation of Excretion
3. Alters drug activity
4. Produces toxic or carcinogenic metabolites
Describe facilitation of excretion as a consequence of drug metabolism.
Metabolism converts drug molecule to a less lipophilic, more water soluble compound. Thus, the new compound is less likely to be reabsorbed and more likely to be excreted.
Describe alteration of drug activity as a consequence of drug metabolism.
Most drugs interact with receptors to produce their effects so converting a drug to an inactive metabolite inhibits it from interacting with receptors. EXCEPTION: prodrugs are metabolized to biologically active cmpds
Describe elimination as a consequence of drug metabolism.
The original drug molecule is chemically modified and no longer present, thus, eliminated.
Give 4 examples of "portals of entry". Why are they important?
Liver, lung, skin, GI
They are impt because they are primarily responsible for metabolism
Of the various portals of entry, why is the liver the most important?
1. size
2. perfusion
3. location
4. cell type (hepatocytes have high concentration of enzymes)
In simple terms, describe Phase I and Phase II reactions.
A. Phase I = pre-synthetic; add nothing greater than MW=18 (water) to drug
B. Phase II = synthetic; add higher MW compounds
Name 3 general examples of Phase I reactions.
1. Oxidations
2. Reductions
3. Hydrolysis
What is the most important Phase I reaction?
Microsomal Mixed-Function Oxidase System
Name the 2 components of the MMFOS. Which is more important and why?
1. NADPH Cytochrome P450 Reductase
2. Cytochrome P450: the most impt b/c it is the site of drug substrate binding & oxygen activation
In terms of enzyme properties, why is Cytochrome P450 unusual?
has a very broad substrate specificity - thus the ability to metabolize many different compounds
"Mixed Function Oxidase" means that molecular oxygen is split into 2 atoms. Where do these atoms end up?
1 atom is on the drug metabolite and 1 atom forms water
Since there are close to 60 human P450's and each P450 is a separate gene product, a classification scheme was devised. Use the scheme to define CYP3A4.
CYP3A4
3 = family
A = subfamily
4 = individual enzyme
What happens to the concentration of a CYP following chronic drug administration?
CYP is induced & its concentration increases.
5 things to keep in mind about CYP induction...
1. induction requires a finite amt of time
2. induction process is reversed when inducing agent is withdrawn
3. induction can lead to enhanced rate of metabolism of the inducing agent itself and/or a 2nd drug
4. CYP induction is basis of some drug-drug intrxns
5. non-prescription drugs can also induce CYP
Know how phenobarbital affects bishydroxycoumarin & how grapefruit juice affects felodipine.
Administering phenobarbital decreases concetration of coumarin while grapefruit juice increases concentration of felodipine.
Name 4 examples of Phase II reactions.
1. Glucuronide synthesis by glucuronosyl transferase
2. Sulfate formation
3. Acetylation
4. Glutathione S-transferases
Of the Phase II reactions, which is most important and why?
Glucuronide syn by glucuronosyl transferase is most important b/c (1) induced by many of the same drugs that induce CYPs (2) end product - glucuronide - is much more hydrophilic compared to its precursor
Where are sulfotransferases and glutathione S-transferases located? Are the enzymes inducible?
Both are located in cytoplasm and glutathione S-transferases are induced by drugs & xenobiotics.

(note: glucuronosyl transferases are also inducible but they are microsomal enzymes - not cytosolic)
Why are glutathione S-transferases important?
Glutathione-S-transferase catalyzes the nucleophilic
conjugation of glutathione (GSH) with many diverse electrophilic
substrates. Glutathione conjugation is a major mechanism
of detoxification in mammals.
Understand the importance of environmental factors on drug metabolism.
In terms of adjusting a patient's dose, there is not a good test for determing how well a patient metabolized the drug due to environmental and genetic factors.
Sulfotransferases produce sulfates. Are sulfates highly ionized or highly non-ionized at physiological pH? How does this affect their water solubility?
Sulfates are highly ionized at physiological pH, leading to increased water solubility.
The initial step in mercapturic acid synthesis is catalyzed by this family of Phase II enzymes.
Glutathione S-transferases
If a specific P450 is required to inactivate a drug but a person has very little amounts of the P450 due to variant alleles, how will this affect the drug response in the person? Will it be diminished or exaggerated?
It will be exaggerated b/c the P450 is not inactivating it
Are pharmacologically active molecules more lipophilic or lipophobic?
lipophilic

thus, to facilitate excretion, drug metabolism converts the molecules into less lipophilic and more water-soluble compounds
Describe metabolism of prodrugs.
Prodrugs are metabolized to biologically active compounds
Phase I hydrolysis reactions can occur in these 2 locations.
plasma
liver
Acutely, how does alcohol affect drug metabolism?
acutely, alcohol can inhibit drug metabolism
Does chronic alcohol consumption induce P450 system?

And what about excessive chronic consumption?
Chronic consumption can induce P450 (specifically, can induce CYP2E1 which makes acetaminophen more hepatotoxic).

Excessive chronic alcohol intake, however, can cause decreased metabolism and eventually liver cirrhosis.
These polymorphic Phase II enzymes produce acetylated cysteines.
glutathione S-transferases
Does P450 catalyze demethylation, methylation or conjugation?
demethylation
Where is P450 located within a cell?
endoplasmic reticulum
Which introduces active centers?

Phase I
Phase II
Phase I
Which of the Phase II reactions are inducible?
Glucuronosyl transferase

Glutathione S-transferase
Prodrugs are activated by this system.

Phase I or Phase II
Phase I
These reactions generally terminate drug action.

Phase I or Phase II
Phase II
TRUE OR FALSE

P450 converts NADP+ to NADPH.
FALSE

NADPH supplies reducing equivalents for reduction of oxygen to water.
Which enzyme does the following:

1) N-dealkylation
2) Aromatic hydroxylation
3) Aliphatic hydroxylation
Cytochrome P450
Name the 2 polymorphic Phase II enzymes
N-acetyltransferase

Glutathione S-transferase