Metabolism Of Drugs Flashcards
What are the 3 types of metabolism of drugs?
1) drug metabolism as a mechanism of termination of drug action
2) drug metabolism as a mechanism of drug activation
3) drug elimination without metabolism
How does drug metabolism as a mechanism of termination of drug action work?
Action of drug is terminated before excreted b/c they are metabolized to biologically inactive derivatives, resulting in more polar, less lipid-soluble drugs, making for less renal reabsorption and more drug excreted
How does drug metabolism as a mechanism of drug activation work?
- Some drugs are inactive as they are administered (prodrugs), having to be metabolized in the body to become active
- Many drugs are active as administered and have active metabolites as well
- other drugs have toxic metabolites
How does drug elimination without metabolism work?
Some drugs such as lithium are not modified by the body, and continue to act until they are excreted
How is phase 1 of metabolism accomplished?
By enzymes (cytochrome P450) found in smooth endoplasmic reticulum; these enzymes make slight modification to the drug to make it more water-soluble, making it easier to get rid of
What type of reactions do phase 2 types of metabolism involve?
Conjugation reactions, where an endogenous substrate is conjugated to the drug via the actions of a transferase enzyme (attach another substance with similar high molecular weight = transferase enzyme)
In phase 2 types of metabolism, what is the relative size of the drug-conjugate in order to facilitate elimination?
The drug-conjugate has increased size
Who is the phase 2 metabolism system lacking in?
Neonates (little kids and babies)
The phase 2 type of metabolism is lacking in neonates, which makes them susceptible to what?
To drugs metabolized in this manner
What is the most important organ for drug metabolism?
Liver
Metabolism occurs via enzymes located in or on what?
- Smooth endoplasmic reticulum = SER (Phase 1 reactions)
- Cytoplasm (Phase 2 reactions)
- mitochondria, cell membrane
What phase reaction occurs in the smooth ER?
Phase 1 reactions
What phase reaction occurs in the cytoplasm?
Phase 2 reactions
Starting with the endoplasmic reticulum, explain how you see heme
ER –> oxidoreductase-CYP complex (enzymes) –> CYP-oxidoreducatase complex (heme complex) –> iron-protoporphryrin IX (Heme)
What enzymes are named with the root CYP?
Cytochrome p450 enzymes
Cytochrome p450 enzymes are named with a root ____ followed by a number designating the family, letter denoting the subfamily, and another number designating the form.
CYP (“sip”)
What is the family, subfamily, and gene number for CYP3A4?
Family = 3
Subfamily = A
Gene number = 4
How many CYPs are there that metabolize drugs in humans?
12
What are the most active CYPs for drug metabolism?
CYP2C
CYP2D
CYP3A (which CYP3A4/5 metabolizes about 50% of all drugs)
Which phase of metabolism reactions involves oxidation, reduction, and hydrolysis?
Phase 1 reactions
Phase 1 reactions utilize what type of oxidation?
Cytochrome P450-dependent oxidation
Drugs which increase the expression of p450 enzymes (induce liver to make more enzymes)
CYP Inducers
Drugs which will reduce the plasma level and therefore the effectiveness of the substrate drug (assuming metabolism inactivates the substrate)
CYP inducers
What does reducing the effectiveness of the substrate drug do for the drug?
It reduces the drug, metabolizing more of them
Examples of CYP Inducers:
-Benzopyrenes (induce liver to make more enzymes) in cigarette smoke
-Chronic ethanol
-Barbiturates
-Carbamazepine (seizure drug)
-Rifampin (antibiotic used for Tuberculosis)
“Smoking and drinking in Barb’s Car Rif’s her Fin”
Example:
In a patient taking oral contraceptives who is later prescribe rifampin for a bacterial infection, predict what happens next:
- induce more liver enzymes –> decreases BC drug’s effectiveness –> PREGGO!!!
- instead, use different antibiotic or use other contraceptives
Drugs which decrease the expression of p450 enzymes
CYP Inhibitors
Drugs which will increase the plasma level, and therefore increase the toxicity risk of the substrate drug (assuming metabolism inactivates the substrate)
CYP Inhibitors
When does watching taking CYP inhibitors matter most?
When the other drug you’re taking has a really low therapeutic index
Examples of CYP inhibitors:
- Cimetidine
- Erythromycin (popular antibiotic)
- Grapefruit juice (NOT GRAPE JUICE!!!!)
Example:
In a patient taking warfarin as an anticoagulant who is later prescribed cimetidine for peptic ulcers, predict what happens next:
Pt is more susceptible for bleeding out (blood in urine and bruising easily)
For CYP inhibitors and CYP inducers, can one exposure change the enzymes too much?
Not really; you have to have regular exposure to change the enzymes
What are the 3 main phase 2 reactions of metabolism?
1) glucoronidation
2) sulfation
3) acetylation
What enzyme is associated with the phase 2 reaction of glucuronidation?
Glucuronosyl transferase
Why do neonates have problems with phase 2 reactions?
They have reduced glucuronosyl transferase activity, not allowing them to add glucuronosyl transferase to the drug
What enzyme is associated with the phase 2 reaction of sulfation?
Sulfotransferase
What’s an example of an addition of a sulfate group to the drug in a sulfation phase 2 reaction?
Minoxidil
What enzyme is associated with the phase 2 reaction of acetylation?
Acetyltransferase
Acetylation has genotype count variation. What does this mean?
Slow or fast acetylators
(Slow = don’t have a lot of enzymes = long 1/2 life = slow metabolism
–> can cause drug-induced lupus)
What can cause drug-induced lupus?
Too much administration of the slow acetylator in the phase 2 reaction, acetylation
What do all of the examples of acetyl drugs for phase 2 reactions cause?
SLE
When you administer UDP-glucuronosyl transferase to salicylic acid, which is UDP-glucuronic acid +, what happens to the size of the drug?
It pretty much doubles in size because you’re adding more +UDP, allowing you to more readily get rid of the drug
The first step in aspirin metabolism is in what phase?
Phase 1
The second step in aspirin metabolism is in what phase?
Phase 2
What phases are being used when aspirin goes through hydrolysis and then oxidation?
Phase 1 (hydrolysis) Phase 1 (oxidation)
What phases are being used when aspirin goes through hydrolysis and then glucuronide (salicyl acyl)?
Phase 1 (hydrolysis) Phase 2 (glucuronide = salicyl acyl)
What phases are being used when aspirin goes through hydrolysis and then glycine (salicyluric acid)?
Phase 1 (hydrolysis) Phase 2 (glycine = salicyluric acid)
