Drug Metabolism 1+2

Question 1

what are the two main organs used for metabolising and eliminating drugs?

Answer 1

Kidney and Liver

Question 2

what usually happens to drugs before elimination from the body?

Answer 2

undergoes a chemical change mainly by an enzymatic process.

Question 3

which is more readily eliminated and more water soluble; drug or metabolite?

Answer 3

metabolite

Question 4

what are the therapeutic consequences of drug metabolism?

Answer 4

• Accelerated drug excretion
• Drug inactivation
• Increased therapeutic action
• Parent drug inactive but metabolite is active (Activation of prodrug)
• Toxic variations

Question 5

which genetic factors influence metabolism?

Answer 5

• Differences between species
• Differences between
individuals

Question 6

which physical factors influence metabolism?

Answer 6

• Age
• Gender
• Nutritional state
• Disease state
• Pregnancy

Question 7

which pharmacodynamic factors influence metabolism?

Answer 7

• Dose
• Frequency
• Route of administration
• Extent of protein binding

Question 8

which environmental factors influence metabolism?

Answer 8

• Co-administration of another drug

* Drug interactions

Question 9

what happens if the rate of metabolism decreases?

Answer 9

• Increased intensity and duration of drug action
• Increased accumulation in the plasma
• Increased toxicity risk

Question 10

what happens if the rate of metabolism increases?

Answer 10

• Decreased intensity and duration of drug action

* Rare cases (toxicity increases)

Question 11

what happens to drugs at the Liver?

Answer 11

first pass metabolism

Question 12

what are some general metabolic pathways?

Answer 12

• Hydrolytic Reactions
• Oxidation
• Reduction

Question 13

what happens during phase 1 metabolism?

Answer 13

• Introduction of polar functional groups into molecules

- providing a site for phase 2 metabolism as doesn’t always produce metabolites for excretion

Question 14

by what processes does phase one occur?

Answer 14

1. hydrolysis/hydration
2. oxidation
3. reduction
4. isomerisation (conversion from 1 functional group to another)

Question 15

explain how esters, amides and their isosteres are hydrolysed?

Answer 15

OH from water ends up on the carboxylic acid or its isostere and the H ends up on amines

Question 16

what enzymes hydrolyse esters?

Answer 16

non-microsomal hydrolases

Question 17

what enzymes hydrolyse amides?

Answer 17

liver microsomal amidases, esterases and deacylases.

Question 18

what influences the rate of hydrolysis?

Answer 18

In relation to carbxylic acid/ester/amide/isosteres:
-electrophilicity of the carbonyl carbon
-nature of heteroatom
-substituents on the carbonyl carbon
-substituents on the heteroatom
In relation to attacking species (e.g. water):
-nucleophilicity of attacking species
-electronic charge
-nature of nucleophile and its steric factors

Question 19

What happens in phase 1 oxidation with cytochrome-p450 enzymes?

Answer 19

• addition of an oxygen atom
• makes use of oxidases or monooxygenases located in the liver hepatocyte endoplasmic reticulum
• requires NADH or NADPH and O2 as cofactors

Question 20

what does the cytochrom 450 enzyme contain?

Answer 20

heme

Question 21

Describe the iron containing porphyrin?

Answer 21

• four pyrrole rings joined by one carbon bridges
• iron ion at the active site
• ligated by the four nitrogen atoms of the porphyrin
• sharing of nonbonding electrons with the metal atom
• accepts or donates electrons to do redox reactions
• normally present as either Fe2+ or Fe3+

Question 22

what is the primary reaction mediated by CYP450?

Answer 22

hydroxylation

Question 23

what happens during hydroxylation?

Answer 23

• cleavage of the Carbon - heteroatom bond resulting in dealkylation
• requires an availabe hydrogen on the atom that gets hydroxylated.