Drug Metabolism Overview (DM12)

Question 1

What is metabolism?

Answer 1

Biotransformation, bioconversion, change

Question 2

What is xenobiotics?

Answer 2

Foreign biotics

Question 3

What is inhibition?

Answer 3

To prohibit (chemically)

Question 4

What is Phase 1 Metabolism?

Answer 4

Functionalization

Question 5

What is Phase II metabolism?

Answer 5

Conjugation

Question 6

Why is Drug Metabolism important?

Answer 6

It informs the physician/pharmacist/patient on: fate of drugs in vivo, dose adjustments, drug interactions, therapy failure, side effects, duration of action, etc

Question 7

Pharmacist must consider DM because?

Answer 7

Non-therapeutic effects or side effects of drugs
Optimization of drug therapy
Duration of action alterations
Chronic drug therapy
polypharmacy issues
“One dose fits all paradigm” does not work
In vivo drug stability

Question 8

Rarely is only one metabolite produced from a single drug. T/F

Answer 8

True

Question 9

Drug metabolism is not required for the elimination of most drugs. T/F

Answer 9

False

Question 10

What are the fates of a drug that undergoes metabolism?

Answer 10

Activation, Inactivation, Bio-activation to toxicity

Question 11

What are drugs that are withdrawn due to reactive metabolites?

Answer 11

Benoxaprofen, Iproniazid, Nefazodone, Tienilic acid,Troglitazone

Question 12

What are black boxed drugs due to reactive metabolites?

Answer 12

Dacarbazine, Dantrolene, Felbamate, Flutamide, Isoniazid, Ketoconazole, Tolcapone, Valproic Acid

Question 13

What are some of the charateristics of drug metabolizing enzymes?

Answer 13

multiple enzyme families (CYP1-50)
polymorphic (multiple forms of the same enzyme)
Cyto-protective role
Constitutively expressed
Most are inducible
Broad substrate specificity
Stereo-selectivtiy

Question 14

What are some of the sites of drug metabolism on an organ level?

Answer 14

Liver, Small Intestine, Kidneys, Skin, Lungs & Nasal Passage, and Plasma

Question 15

What are some sites of drug metabolism on a cellular level?

Answer 15

Microsomal (ER), Cytosol, and Mitchondiral

Question 16

What are prodrugs?

Answer 16

Inactive, bio-reversible derivatives of active parent drugs.
Undergo enzymatic or chemical conversion in vivo to afford the active drug.
Improve delivery, taste, toxic profile, overcome formulation issues, etc.

Question 17

What is an ester prodrug?

Answer 17

Enalapril (prodrug) turns into Enalaprilat (potent Antihypetensive)

Question 18

What is an Azo prodrug?

Answer 18

Sulfasalazine is cleaved by bacterial reductases to make sulfapyridine which allows it to be absorbed from the intestine and places the drug at the desired sight of action.

Question 19

What is an example of a similarly active agent?

Answer 19

Clarithomycin (Broad spectra macrolide antibiotic)
Fluoxetine
Propranolol (antihypertensive)

Question 20

What is an example of alteration of drug activity?

Answer 20

Iproniazid (Antidepressant-withdrawn) is metabolized into Isoniazid (Antitubercular Agent)

Question 21

What is an example of bio-activation to toxicity?

Answer 21

Haloperidol to BCPP or Quaternary pyridinium metabolite (toxic to brain Dopamine Cells)
Acetaminophen to n-Acetylbenzo-quinoneimine(causes liver necrosis)

Question 22

What is an example of bio-activation to carcinogenicity?

Answer 22

Benzopryene or B(a)P
Aflatoxin
2-acetylaminofluorene(AAF) to N-hydroxy

Question 23

What CYPs can activate Pro-carcinogens?

Answer 23

CYP1A1, CYP1A2, CYP2E1, CYP3A4

Question 24

What is an example of bio-activation to tetratogenicity?

Answer 24

Thalidomide now used for Leprosy, as an Anticancer agent

Question 25

Which one of the DM outcomes, which one would have the highest benefit to a patient administered a long acting drug to control chronic pain? A. Drug metabolizing enzyme induction B. Bio-activation to toxicity C. Rapid termination of drug action D. Formation of similarly active metabolites E. Alteration in drug activity

Answer 25

D. Formation of similarly active metabolites

Question 26

What are the common inducers?

Answer 26

``` Barbiturates Carbamazepine Phenytoin Rifampin St Johns Wort Ethanol Tobacco ```

Question 27

What are the common inhibitors?

Answer 27

``` Clarithromycin Erythomycin Ketoconazole Itraconazole Cimetidine Protease Inhibitors Grape fruit juice Omeprazole ```

Question 28

serum concentrations?

Answer 28

It lowers it.

Question 29

What is the mechanism for DME induction?

Answer 29

Receptor mediated transcriptional activation

Question 30

What are the types of DME inhibition?

Answer 30

Competitive & Non-competitive

Question 31

What does a competitive inhibitor do?

Answer 31

Interferes with active site of enzyme so substrate cannot bind.

Question 32

What does a noncompetitive inhibitor do?

Answer 32

Changes shape of enzyme so it cannot bind to substrate

Question 33

What is special about mechanism based inhibition?

Answer 33

metabolites are irreversibly bound

Question 34

What occurs in complexation inhibition?

Answer 34

Metabolite or intermediate form a complexation and therefore the enzyme is no longer available for further oxidation.

Question 35

What occurs when Omeprazole and Warfarin are coadministrated?

Answer 35

Omeprazole, an inhibitor, delays removal of warfarin from systemic circulation leading to an increase of warfarin in the blood levels which may lead to increased bleeding.

Question 36

``` What is the potential complication of taking erythromycin and glyburide(an antidiabetic drug) together? A. Hyperglycemia B. Hypoglycemia C. CNS depression D. Liver failure ```

Answer 36

B. Hypoglycemia