drug metabolism

Question 1

-aka Biotransformation
-plays a central role in the Elimination of drugs & other foreign compounds compounds

Answer 1

drug metabolism

Question 2

foreign compounds

Answer 2

xenobiotics

Question 3

most important organ in drug metabolism

Answer 3

Liver

Question 4

drug metabolism generally converts drugs into:

Answer 4

-pharmacologically active
-relatively nontoxic
-polar, readily excretable water-soluble products

Question 5

most drugs absorbed are:

Answer 5

lipophilic

Question 6

drug metabolism reaction have been divided into 2 categories

Answer 6

1- phase 1 or functionalization reactions

2- phase 2 or conjugation reactions

Question 7

phase 1 or functionalization reactions:

Answer 7

-oxidation (most common)
-reduction
-hydrolysis

Question 8

phase 2 or conjugation reactions

Answer 8

• glucoronidation - (most common)
  -sulfation
  -glysine conjugation
  -glutathione conjugation
  -acetylation
  -methylation

Question 9

phase 1 reaction purpose

Answer 9

-to introduce a functional group(s) into the xenobiotic molecule to produce a more water soluble compound

-this can be achieved by direct introduction of the functional groups (aromatic & aliphatic hydroxylation) or by Unmasking existing functionalities (reduction of ketones & aldehydes to alcohols)

Question 10

phase one reaction

Answer 10

may not produce sufficiently hydrophilic or inactive metabolites, they generally tend to provide a functional group or Handle on the molecule that can undergo subsequent phase 2 reactions

Question 11

-aka conjugation reactions
-to attach small, polar, & ionizable endogenous compounds (glucoronic acid, sulfate, glycine, & other amino acid) to the functional handles of phase 1 metabolites or parent compounds that already have suitable existing functional groups to form water soluble conjugated products

Answer 11

phase 2 reactions

Question 12

phase 2 reactions
Exceptions:

Answer 12

*methylation & acetylation
-terminate or attenuate biological activity
-not necessarily increase water solubility

*glutathione (GSH) conjugation
-protects the body against chemically reactive compounds or metabolites

Question 13

LUNA

Answer 13

Lipophilic
Un-ionized
Nonpolar
Absorbed

Question 14

HIPE

Answer 14

Hydrophilic
Ionized
Polar
Excreted

Question 15

VILEORA

Answer 15

Valence Increase
Loss of electrons
Oxidation
Reducing Agent

Question 16

VDGEROA

Answer 16

Valence Decrease
Gain of electrons
Reduction
Oxidizing agent

Question 17

Oxidation

Answer 17

-addition of Oxygen
-removal of hydrogen
-addition of electronegative element

Question 18

reduction

Answer 18

-removal of oxygen
-addition of hydrogen
-removal electronegative element

Question 19

Glucoronidation
cofactor
enzyme

Answer 19

-Uridine diphosphate glucorinic acid (UDPGA)
-glucoronosyltransferase (UDP)

Question 20

Sulfation
cofactor
enzyme

Answer 20

-phosphoadenosyl phosphosulfate (PAPS)
-sulfotransferase

Question 21

glycine conjugation
cofactor
enzyme

Answer 21

-glycine
-acyl-CoA glycinetransferase

Question 22

the first mammalian metabolite discovered from glycine conjugation

Answer 22

Hippuric Acid

Question 23

glutathione conjugation
cofactor
enzyme

Answer 23

-glutathione (GSH)
-GSH-S-transferase

Question 24

glutathione is composed of 3 amino acids:

Answer 24

1- glutamate
2- cysteine (SH)- responsible for detoxification
3-glycine

Question 25

methylation cofactor enzyme

Answer 25

- S-Adenosylmethionine (SAM) - transmethylases / methyltransferases

Question 26

Acetylation cofactor enzyme

Answer 26

Acetyl-CoA N-acetyltransferase

Question 27

not yet fully developed in neonates & children

Answer 27

glucoronidation

Question 28

results from the inability to conjugate chloramphinicol with glucoronic acid

Answer 28

gray baby syndrome

Question 29

results from the inability of newborns to conjugate biliburin with glucoronic acid

Answer 29

neonatal hyperbilirubinemia or kernicterus

Question 30

-excess bilirubin in blood -yellowing of skin and eyes

Answer 30

jaundice

Question 31

bilirubin moves from the bloodstream into the brain tissue

Answer 31

kernicterus

Question 32

metabolism of acetaminophen

Answer 32

-sulfation: major route in children -glucoronidation: major route in adults

Question 33

sulfation (major) lack of glucoronyltransferase enzymes

Answer 33

cat

Question 34

glucoronidation (major) lack of sulfotransferase enzymes

Answer 34

pigs

Question 35

conjugation pathway for benzoic acid

Answer 35

most animals: conjugation w/ glycine birds: conjugation w/ ornithine

Question 36

variation in acetylating ability caused mainly by differences in N-acetyltransfearase activity

Answer 36

acetylation polymorphism

Question 37

drugs that undergo acetylation (HIPS)

Answer 37

-hydralazine -Isoniazid -procainamide -sulfonamides

Question 38

slow acetylators

Answer 38

-egyptians, african americans, caucasians -tend to accumalate higher drug plasma concentrations -greater therapeutic response (higher cure rate)

Question 39

rapid acetylators

Answer 39

-eskimos & asians -eliminate drug more rapidly -more likely to show an inadequate therapeutic response to standard drug doses

Question 40

*accumulate higher drug concentrations of the un acetylated drug *more prone to drug induced toxicities: -hydralazine & procainamide: drug induced systemic lupus erythematosus syndrome (SLE) -isoniazid: peripheral nerve damage -sulfasalazine: hematologic disorders

Answer 40

slow acetylators

Question 41

-produce toxic metabolites more rapidly -more likely to develop isoniazid-associated hepatitis -acetylhydrazine: hepatotoxic metabolite of isoniazid

Answer 41

rapid acetylators