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Pharmacology > metabolism > Flashcards

metabolism Flashcards

1
Q

Biotransformation

A

the sum if all processed whereby a compound is transformed chemically within a living organism

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2
Q

what does primary transformation do?

A

makes a lipophilic compound more hydrophilic

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3
Q

are detoxification and biotransformation the same thing?

A

NO

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4
Q

biotransformation products

A

may get more or less potent/ biologically active

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5
Q

detoxification products

A

always get less potent

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6
Q

what is phase one of metabolism called?

A

oxidation step known as bioconversion

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7
Q

what happens in phase 1 of metabolism?

A

polar functioning group such as a hydroxyl group introduced into the lipophilic drug making it more hydrophilic

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8
Q

what enzyme normally carries out phase 1?

A

cytochrome P450 mono oxygenases

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9
Q

what happens in phase 2 of metabolism?

A
  • Metabolites produced in phase 1 are covalently linked to naturally occurring endogenous species – eg sugars, peptides and sulfides
  • Makes the metabolites quite water soluble and non toxic – readily excreted
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10
Q

what happens to the molecular weight of drugs as they exit phase 2?

A

it increases as theyre being added to

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11
Q

where does the name cytochrome P450 come from

A

Cytochrome: it is a coloured intracellular protein
P: it is pink
450: its absorption spectrum has a maximum at 450 nm

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12
Q

what are the Cytochrome P450 Monooxgenases involved in?

A

in the liver, they’re in the smooth ER, drug metabolism

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13
Q

what are Cytochrome P450 Monooxgenases also known as?

A

microsomal enzymes, this is because of the fraction that they are found in when you homogenise the cell

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14
Q

what is the main function of the Cytochrome P450 Monooxgenases in phase 1 of metabolism?

A

give the drug 1 oxygen from molecular oxygen, and the other oxygen is released as water – makes the drug more hydrophillic

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15
Q

equation for phase 1

A

R-H + O2 + H+ – NADPH/Enzyme –> R-OH + NADP+ + H2O

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16
Q

Hydroxylation

A

is a chemical process that introduces a hydroxyl group (-OH)

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17
Q

Epoxidation

A

a conversion of a usually unsaturated compound into an epoxide

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18
Q

Dealkylation

A

removal of an alkyl groups

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19
Q

Deamination:

A

removal of an amino group

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20
Q

Sulfoxidation

A

reaction with, or conversion to a sulfoxide

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21
Q

Desulfuration

A

the process of removing sulphur

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22
Q

what is Epoxie

A

cyclic ether with 3 rings

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23
Q

what is Epoxie

A

cyclic ether with 3 rings

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24
Q

different levels of CYP2D6 which catalyse the reaction of iodine to morphine depend on?

A

genetic polymorphisms

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25
Q

people who are poor metabolisers of codine

A

coding is ineffective as they don’t break down enough coding into morphine

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26
Q

ultra rapid metabolisers of coding are at risk of

A

morphine toxicity

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27
Q

ultra rapid metabolisers of coding have how many copies of the gene CYP2D6?

A

2 or more

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28
Q

why are there reports of children dying from having coding?

A

they don’t have the correct levels of CYP2D6 in their livers, so break down too much coding and get poised from the high levels of morphine

can overdose even from receiving the milk of mothers containing codine

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29
Q

if the enzyme that breaks down a drug is inhibited what is the effect on the drug?

A

increased activity of the drug

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30
Q

which drug would increase the activity of the enzyme which breaks down warfrin? effect?

A

carbemazepine

reduces the activity of warfarin due to enhanced metabolism

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31
Q

which drug would decrease the activity of the enzyme which breaks down warfrin? effect?

A

erythromycin

increase the activity of warfarin due to impaired metabolism

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32
Q

a safer drug has a …

A

high therapeutic index, large lethal dose and a small effective dose

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33
Q

dangerous drugs have

A

lower therapeutic index, requires regular monitoring, minor modification could cause toxic effects

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34
Q

which drugs could be toxic with minor adjustments?

A

warfarin, lithium, digoxin

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35
Q

what is the equation for therapeutic index?

A

LD50/ED50

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36
Q

ED50 -

A

the effective dose in 50% of the population

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37
Q

when would 2 drugs reacting be dangerous when affecting the theraputic index?

A

when they make the therapeutic index smaller

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38
Q

what enzymes are requires for phase 2 of metabolism?

A

transferase enzymes

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39
Q

what are also required for phase 2 metabolism>

A

cofactors

40
Q

what are the 2 important things required for phase 2?

A

cofactors and transferase enzymes

41
Q

what is glutathione important in?

A

cofactor which is important in phase 2 of metabolism

42
Q

what is glutathione made of?

A

glutamic acid, cysteine, glycine

43
Q

what are the 2 important cofactors required for conjugation in phase 2?

A

UDP-GA and PAPS

44
Q

which transferase enzyme add glutaronic acid? using which cofactor?

A

glucuronyl transferase

using UDP cofactor

45
Q

which transferase enzyme add sulphate groups to amino or hydroxyl compounds? using which cofactor?

A

Sulphotransferase

– requires PAPS to be a sulfur donor

46
Q

what does Glutathione S transferase do?

A

conjugates electrophilic metabolites

47
Q

what is the issue with first pass metabolism?

A

Drugs extracted so efficiently by the liver or gut wall – amount reaching systemic system much less than that is absorbed

48
Q

how does individual variation affect first pass metabolism?

A

in the activities of drug-metabolising enzymes and also as a result of variation in hepatic blood flow.

49
Q

some drugs which undergo substantial elimination through first pass

A

aspirin, salbutamol, morphine,

50
Q

Zero-order elimination kinetics

A

Elimination of a constant quantity per time unit of the drug quantity present in the organism - straight line

51
Q

First order elimination kinetics

A

Elimination of a constant fraction per time unit of the drug quantity present in the organism. The elimination is proportional to the drug concentration

52
Q

which order of kinetics do most drugs follow

A

first order

53
Q

which drugs follow zero order kinetics? why?

A

alcohol, aspin, phenytoin

when saturated and drug one excess

54
Q

why would a drug follow zero order kinetics?

A

limited number of enzymes available for metabolism of drug – limit reached – metabolism happens at constant rate – always a straight line - alcohol

55
Q

Half-life

A

Time it takes for the plasma concentration or the amount of drug in the body to be reduced by 50%.

56
Q

how much drug should be remaining after 3 half lives?

A

12.5%

57
Q

Elimination rate constant (K):

A

Fractional rate of drug removal from the body

58
Q

what should the elimination rate constant be in first order kinetics

A

constant

59
Q

Clearance

A

The volume of plasma in the VASCULAR COMPARTMENT cleared of drug per unit time by the processes of metabolism and excretion

60
Q

clearances are addictive - what is the CLtotal equation

A

CL renal + CL non renal

could be different for other organs???

61
Q

clearance as a product of first order elimination…

A

constant (k) and Volume distribution

62
Q

what is the CLtotal equation

A

k+Vd

63
Q

what is the CLtotal equation

A

k+Vd

64
Q

(O1) rate of elimination is proportional to

A

plasma concentration

65
Q

zero order alcohol metabolism is

A

linear not exponential

66
Q

why in zero order does conc. of drug become a constant value?

A

enzymes are saturated and cannot metabolise any more alcohol

67
Q

doesn’t matter how much you have in your body elimination will be

A

approximately 4mili mol / litre / hour

68
Q

what is the oxidation factor in alcohol metabolism?

A

alcohol dehydrogenase – requires cofactor NAD+ that isnt produced constantly – produced over period of time – enzymes cant work without

69
Q

slow elimination means … half life

because

A

long half life

- large Vd, large fraction of drug located in tissues not accessible to organs of elimination, long HL

70
Q

rapid elimination means … half life

because

A

short half life

- small Vd, small fraction in the tissues, more assemble to organs elimination, short HL

71
Q

Most drugs follow first order kinetics

A

Metabolism rate is proportional to drug plasma concentration

Drug concentration drops by fixed percentage in a given time

72
Q

A few drugs follow zero order kinetics

A

Metabolism removes a fixed amount of drug in a given period
Drug concentration drops linearly
Overdoses take longer to clear
Example: alcohol

73
Q

Repeated administration

A

Drug administration of a fixed dose at a regular time interval, through a given route

74
Q

Loading dose

A

In urgent situations, the steady state plasma concentration must be reached more rapidly. A higher dose can then be administered on treatment initiation, to compensate for accumulation.

75
Q

accumulation occurs when

A

the drug is administered before the previous dose is completely eliminated

76
Q

concentration steady state av equation

A

= (f x dose) / (CL x J)

77
Q

what guides maintenance dosage intervals/

A

drug half life

78
Q

warren half life

A

37 hours, so should be taken daily

79
Q

drugs with 1/2 life less than 30 mins should be given

A

by infusion

80
Q

Drugs ½ life 30 min should be taken

A

every 8 hours but should consult the therapeutic index

81
Q

if the drug has a low therapeutic index, must be given every

A

1/2 life by INFUSION

82
Q

½ life 8-24 hours

A

give every ½ life

83
Q

total clearance of a drug is the fundamental parameter describing

A

its elimination

84
Q

the rate of elimination equals

A

CLtotal x plasma conc

85
Q

CL total determines

A

steady stat plasma conc. (CLss)

86
Q

CLss =

A

rate drug administration/ CLtot

87
Q

most dugs follow

A

1st order kinetics - exponential

88
Q

Vd

A

where the body is treated as one well stirred compartment.

Vd is the parent volume linking the amount of drug in the body at any time to the plasma conc.

89
Q

elimination half life is

A

directly proportional to Vd and inversely proportional to CLtot

90
Q

within how many half lives with repeated dosing does plasma conc. reach a steady value?

A

3-5 HLs

91
Q

how would a therapeutic dose be reached rapidly in urged situations?

A

by giving a loading dose

92
Q

Loading dose is achieved in plasma conc. determined by

A

L = Ctarget x vd

93
Q

what would a 2 compartment model mean for kinetics

A

they become biexponential

94
Q

what do the 2 compartment in the 2compartment model represent?

A

process of transfer between plasma and tissues (a phase)

elimination from the plasma (B phase)

95
Q

some drugs show non-exponential kinetics - important clinical consequences …

A

disproportionate increase in steady state plasma conc. when daily dose inc.

Pharmacology (18 decks)

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