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303 MEDIMAGE > 3a. Metabolism - ADME II: elimination of drugs > Flashcards

3a. Metabolism - ADME II: elimination of drugs Flashcards

1
Q

what is metabolism

A

biotransformation of drugs

enzyme mediated chemical change to the drug molecule, either building molecule up or breaking down

parent (unchanged) -> metabolites

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2
Q

how does metabolism help drug elimination

A

altering chemical structure of molecule often means its ability to move around the body is altered so its easier to excrete or a change in its effects making its ability to bind to receptors (making it inactive)

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3
Q

many drugs are lipophilic to aid what and what does this means for elimination of parent form

A

lipophilic o aid absorption and distribution = high reabsorption in kidney and poor elimination in their parent form

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4
Q

metabolism produces more ___ metabolites that are better/harder excreted from body

A

hydrophilic polar meetabolites

better excreted

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5
Q

does metabolism abolish activity of drug

A

usually but not always

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6
Q

what are the 3 things that drug metabolism can result in

A

promotion of activity
no change
toxic

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7
Q

what is metabolism resulting in promotion of activity

A

drug metabolized to metabolites that are more pharmacologically active

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8
Q

what is metabolism resulting in no change in activity

A

metabolite formed is equally biologically active as parent drug

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9
Q

what are the 5 major sites of drug metabolism

A 
liver
intestinal wall
GI tract
plasma
lungs
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10
Q

why is the liver a possible site of drug metabolism

A

high levels of metabolising enzymes

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11
Q

why is the intestinal wall a possible site of drug metabolism

A

CYP450 enzymes

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12
Q

why is the GI tract a possible site of drug metabolism

A

gut bacteria and proteases

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13
Q

why is the plasma a possible site of drug metabolism

A

esterases - prodrug activation

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14
Q

why is the lungs a possible site of drug metabolism

A

metabolism of aerosol sprays

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15
Q

what happens to drugs administered orally in the part of the organs

what effect does metabolism in the digestive organs have on bioavail

A

Drugs administered orally will need to traverse GI tract, move across gut wall pass through portal vein and reach liver before reaching systemic circulation

Metabolism that occurs during this passage means not all oral dose is absorbed

Some orally admin drugs may greatly affect bioavailability by first pass that diff routes must be used to achieve therapeutic levels

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16
Q

what does first pass metabolism affect

A

affects the bio avail/fraction of dose that will reach systemic circulation

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17
Q

can drugs adminstered in IV form still udnergo metabolism

A

cant occur with first pass metabolism but can undergo systemic metabolism

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18
Q

first pass metabolism is before/after systemic circualtion

A

before

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19
Q

systemic metabolism is before/after systemic circualtion

A

after

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20
Q

what are the 4 types of metabolism reactions

A

oxidation
reduction
hydrolysis
conjugation

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21
Q

what is an oxidation metabolism reaction

A

increase proportion of oxygen on the molecule

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22
Q

what is an reduction metabolism reaction

A

loss of oxygen

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23
Q

what is an hydrolysis metabolism reaction

A

water molecule is added to compound usually resulting in bond cleavage

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24
Q

what are the 3 functionalization reactions for metabolism and what do they all do

A

create/modify a functional group

oxidation, reduction, hydrolysis

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25
Q

what is conjugation metabolism reaction

A

addition of endogenous substrate

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26
Q

what are the 4 types of conjugation metabolism reaction

A

glucuronidation
sulphataion
acetylation
glutathionylation

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27
Q

what does conjugation metabolism reactions do to the molecular mass, polarity and excretion

A

increase molecular mass
polarity/water solubility increase
increase likelihood of excretion

28
Q

what are the phase 1 reactions

A

oxidation, hydrolysis and reduction

29
Q

what is a phase 2 reaction

A

conjucation

30
Q

functionalisation reactions can result in metabolites that are more prone to what

A

more prone to undergo conjugation reaction

31
Q

what is the misconception about phase 1 and 2 reactions names

A

phase 1 isnt always before phase 2

32
Q

what are the 4 paths that a parent drug can take regarding functionalization and conjugation reactions on their way to excretion

is it as simple as this?

A

1/ parent drug -> functionalisation and then excretion
2/ parent drug -> function -> conjugation -> excretion
3/ parent drug -> exception
4/ parent drug -> conjugation -> excretion

not as simple as sometimes conjugate metabolite forms from conjugate reaction can be substrate for another functionalization

33
Q

what is the most important functionalisation reaction

A

oxidation

34
Q

what is the enzyme that facilitates oxidation

A

CYP450

35
Q

what are the 3 families of CYP involved with drug metabolism and how many isoforms are responsible for majority of phase 1 reactions

A

CYP1,2, and 3

4 isoforms

36
Q

what 3 things does exidation require and which is the reducing agent

A

O2, NADPH (reducing agent), cytochrome p450

37
Q

what is the nomenclature of CYP family eg CYP3A4

A 
C = cytochrome
P = P450 wavelength
3 = family
A = subfamily
4 = isoform
38
Q

what are conjugation reactions

A

synthetic reactions as it involves adding an endogenous molecule onto drug

39
Q

what is the endogenous molecule in a conjugation reaction normally

A

carbohydrate, an amino acid or something derived from the 2

40
Q

what does conjugation reactions do to the property of the molecule

A

makes it larger

increase water solubility

41
Q

what is glucouronidation and what compounds is it common for

A

endogenous compounds and drugs

42
Q

what is the key enzyme for glucouronidation

A

UGTs

43
Q

what does UGTs do

A

transfer polar glucose derivative onto target molecule

44
Q

what is sulfonation carried out by

A

sulphotransferases

45
Q

what are major areas of high activity for sulphotransferases

A

SI, colon, liver, pancreas

46
Q

what does sulfonation do to the property of molecule and what is this good for

A

increases water solubility of molecule

improves excretability in bile and urine

47
Q

what do sulphotransferase transfer

A

sulphonate from donor PAPs onto acetyl or hydroxyl group of receiving molecule

48
Q

what is a limitng factor for sulfonation

A

PAPS is synthesised in all almost all tissues but its depletion limits sulfonation

49
Q

for sulphotransferases what are forms associated with the cell membrane involved in

A

housekeeping

50
Q

what is glutathione conjugation done via

A

glutathione S transferases

51
Q

what does glutathione conjugation do

A

clean up system for reactive species generated in cells as well as other functions

52
Q

what does acetylation do to the properties of the compound and what does this achieve

A

generally decreases water solubility so that its more difficult to excrete metabolites in the urine

53
Q

what functions does acetylation have

A

housekeeper and homeostasis

54
Q

what does methylation do

A

adds lipophilic methly group to decrease water solubility

55
Q

what is methylation used for in terms of the types of compounds it facilitates

A

small endogenous compounds

56
Q

why are there variations seen in metabolism

A

drug dose required to achieve effective therapeutic blood levels can be diff in diff people

metabolism rate in people

genetic and non genetic factors

57
Q

what will extensive and poor metabolism have an effect on in term of the drug level

A

extensive = low drug levels to produce therapeutic effect

poor = higher drug level and may result in increased risk of an adverse drug reaction

58
Q

how does induction of enzymes lead to metabolism variability

A

induction may mean drug effect is reduced as more metabolism means faster clearance and there is less active drug to cause effect

59
Q

how does inhibition of enzymes lead to metabolism variability

A

mean drug effect is decreased as less metabolism means slower clearance so more active drug to cause effect

60
Q

what are the 2 types of inhibition of enzymes in metabolism

A

reversible when inhibitor is competitive

irreversible inhibition as metabolized by enzyme and then that metabolite irreversibly binds enzyme rendering it inactive

61
Q

how does genetic variability lead to metabolism variability

A

polymorphism alter expression and activity

gene mutation result in altered proteins and altered phenotype

62
Q

what are 4 non genetic reasons for metabolism variability

A

age/immaturity

sex

pregnancy

disease

63
Q

how does age/immaturity affect metabolism variability

A

younger means there is reduced avail of endogenous cofactors needed for metabolism and enzyme systems arent fully developed

64
Q

how does sex affect metabolism variability

A

differences in steroid hormones can affect the expressions of different drug metabolizing enzymes.

Sex influences weight and fat distribution and these physiological diff can affect pharmacokinetics

65
Q

how does pregnancy affect metabolism variability

A

opposing changes in drug metabolism that can occur during pregnancy

some enzyme activities are increased in pregnancy

66
Q

how does disease affect metabolism variability

A

liver disease and cardiac disease may limit blow flow to liver

Impact liver enzymes and perfusion that’s important for distributing drugs so limited blood flow to liver can impact extent and rate of drug metabolism

303 MEDIMAGE (14 decks)

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