METABOLISM

Question 1

what is the definition of biotransformation or metabolism.

Answer 1

A change in the chemical structure of an absorbed drug within a living organism, usually by enzyme-catalyzed reactions.

Question 2

what is the evolved purpose of the liver?

Answer 2

to process toxic substances from the diet and to process wastes from a variety of metabolic pathways. (it treats drugs the same way).

Question 3

why is drug metabolism important?

Answer 3

enzumes play a role in terminating drug action, they make drugs more excretable and inactivates many drugs.

Question 4

what kind of compounds are more readily excreted in urine and bile?

Answer 4

polar compounds

Question 5

what does metabolism often results to in terms of compounds?

Answer 5

they inactivate compounds

Question 6

why are certain drugs administered as inactive prodrugs?

Answer 6

because few drugs are activated by metabolism

Question 7

why are lipid-soluble drugs not readily excreted from the body?

Answer 7

they cross out of renal tubules through membranes and back into the blood.

Question 8

where are drugs metabolized?

Answer 8

the liver is the major site of metabolism of xenobiotics. Metabolism also occurs in other organs as well.

Question 9

biotransformation reactions are catalyzed by cellular enzymes that are located in which sections? (order of likely hood)

Answer 9

endoplasmic reticulum> cytoplasm> mitochondria > nuclear/cell membrane > lysosomes.

Question 10

where are drug metabolizing enzymes mainly found?

Answer 10

in the microsomes and in the cytosol.

Question 11

what are microsomes?

Answer 11

they are vesicles consisting of membranes of ER which contain membrane-bound P45- enzymes (phase 1 metabolism)

Question 12

what is cytosol?

Answer 12

supernatant consisting of cytoplasmic fluid and soluble phase 2

Question 13

what are the two phases in which enzyme reactions are involved in drug metabolism?

Answer 13

phase 1 reactions : drugs are converter to more polar metabolites then either excreted or onto phase 2.
Phase 2 reactions: ‘conjugation’ or ‘synthesis’ reactions in which a substance from the diet is attached to the functional group derived from phase 1 reactions.

Question 14

what are the 5 characteristics of phase 1 reactions?

Answer 14

1. makes drugs more reactive and capable of combining with polar conjugating groups.
2. substrates are lipid-soluble compounds of widely varied chemical structure.
3. metabolites are more water-soluble, can be circulated, excreted or undergo a phase 2 reaction.
4. involves one or more cytochrom P-450
5. P-450 heme-containig proteins that macimally absorbs light at 450 nm

Question 15

what are other other names for the P-450 enzyme?

Answer 15

microsomal or CYP enzyme system; mixed-function oxidases (MFO)

Question 16

what are the 5 steps to the cytochrom p450 cycle in drug oxidations?

Answer 16

1. Fe3+ is oxididze, and Fe2+ is reduced.
2. oxidized from combines with drug
3. NADPH-dependent cytochrome P450 reductase reduces p450
4. molecular oxygen is reduces to activated oxygen ->oxidized drug complex
5. activated oxygen is transferred to drug substrate to from oxidized product

Question 17

what ate the 3 types of phase 1 reactions?

Answer 17

1. oxidation (LEO says GER)
2. reduction
3. hydrolysis
   these reactions introduce or unmask functional groups.

Question 18

what are 3 characteristics of the phase 2 reactions?

Answer 18

1. couple drug with substrates from diet to produce conjugates
2. conjugates are often polar, inactive and readily excretable
3. some conjugating substances are glucuronic acid, sulfate, glutathione, methyl groups, glycine…

Question 19

what are the 4 types of phase 2 reactions?

Answer 19

1. glucuronic acid conjugation
2. sulphate conjugation
3. acetylation
4. glutathione conjugation

Question 20

describe clucuronic acid conjugation.

Answer 20

very important pathway
large drugs are excreted into bile for elimination in feces, but glucuronidases in gut bacteria can hydrolyze conjugate and free drug, which can be reabsorbed (enteroheptic recirculation)
for people who are deficient in this enzyme, they are slow to metabolize certain drugs

Question 21

give examples of sulphate conjugation

Answer 21

(sulfotransferases)

phenols and alcohols conjugated to sulphase (eg: acetaminophen)

Question 22

describe acetylation

Answer 22

(n-acetyltransferases)

it occurs in drugs with -NH2 group conjugated to COCH3 (eg. sulfonamide antimicrobial drugs)

Question 23

describe glutathione conjugation.

Answer 23

(glytathione s-transferases)

epoxides, arene oxides conjugated to glutathione (eg anticancer drugs)

Question 24

how can we counter act an acetaminophen overdose?

Answer 24

within limits, glutathione conjugation can inactive the reactive intermediate (NAPQI) -> physician will administer a source of glutathione (n-acetylcysteine) -> minimizes hepatic damage.

Question 25

what are 6 factors that can affect the rate of drug metabolism?

Answer 25

1. enzyme induction and inhibition
2. multidrug therapy
3. distribution
4. age
5. genetics
6. disease

Question 26

describe the process of induction of drug metabolism

Answer 26

it increases drug metabolism and intrun decreases drug action. it can also increase the drug-related toxicity depending on whether phase 1 or 2 enzyme are induced. (note balance between phase 1 and 2 is important.

Question 27

describe the process of inhibition of drug metabolism.

Answer 27

certain drugs can inhibit P450 activity mostly by competing fcor the same enzyme. eg some antifungal, antibiotics inhibit enzymes responsible for the metabolism of terfenadine.

Question 28

describe the process of multi-drug therapy.

Answer 28

because there is a finite number of hepatic enzymes, the system can be saturated, and this is most common when multiple drugs require the same metabolic enzyme, and they are taken at the same time. The drugs then compete for, or inhibit, the metabolizing enzymes.

Question 29

describe a possible distribution problem, in the body, which may inhibit metabolism.

Answer 29

drugs bound to plasma proteins or stored in fat are not available for metabolism.

Question 30

describe how age may affect drug metabolism.

Answer 30

infants and older people may be deficient in metabolic capacity, or may even have over production of certain metabolic enzymes.

Question 31

how can genetics effect the metabolism process?

Answer 31

process may very due to genetic polymorphism. eg CYP2D6 deficiency leads to a decrease in metabolism of some cardia drugs.

Question 32

how can health and disease effect drug metabolism in the body.

Answer 32

1. poor nutrition can lead deficienct in substances needed for conjugation.
2. endocrine diseases, liver disease, infectious/ inflammatory diseases can inhibit the metabolism of drug
3. heart disease can impair blood flow to liver