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5. Metabolism and Biotransformation of Drugs. > Metabolism. > Flashcards

Metabolism. Flashcards

1
Q

Why must some drugs be metabolised?

A

So they can then be absorbed.

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2
Q

What is the difference between metabolism and biotransformation?

A

They both mean exactly the same thing.

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3
Q

Is metabolism species specific?

A

Yes, as the process of metabolism relies on enzymes and not all species have the same enzymes.

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4
Q

Metabolism mainly occurs in what organ of the body?

A

The liver.

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5
Q

What is produced when a drug is broken down by an enzyme?

A

Different metabolites.

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6
Q

Why will many drugs be metabolised in more than one area of the body?

A

As each different area will also produce different metabolites.

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7
Q

What happens when a drug becomes biologically active?

A

You go from an active drug to an active metabolite or from an inactive drug to an active metabolite.

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8
Q

What name is given to the process where a drug becomes biologically active?

A

Bio-activation.

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9
Q

Will all the metabolites from drug metabolism be active?

A

No.

Some metabolites might have limited or no biological activity.

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10
Q

Can some of the the metabolites produced from a drug be toxic?

A

Yes.

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11
Q

How does the body handle drugs that produce toxic metabolites?

A

The drug is normally converted to make it more water soluble and this hopefully means that the toxic substance is eliminated very quickly.

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12
Q

What must we ensure before we administer a drug to an animal?

A

We must be sure that that animal can metabolise that drug.

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13
Q

Why do we want to get rid of drugs from the body?

A

So the metabolites do not remain in the body forever.

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14
Q

What enzymes are involved in phase 1 metabolism?

A

Cytochrome P-450 enzymes.

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15
Q

In phase 1 metabolism, what are the toxins and drugs converted into by the cytochrome-P450 enzymes?

A

Into intermediary metabolites which are polar and not lipid soluble making them easier to eliminate.

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16
Q

What are the 3 categories of metabolites that can be produced following drug metabolism in the liver?

A

Biologically active substances.

Metabolites with limited or no biological activity.

Toxic metabolites.

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17
Q

What percentage of all common drugs are metabolised by the body?

A

Around 50%.

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18
Q

Will phase 1 of drug metabolism always occur before phase 2?

A

No.

Some drugs can enter phase 2 metabolism straight away.

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19
Q

Will all drug that undergo phase 1 metabolism undergo phase 2 metabolism?

A

No.

Some of the drugs from phase 1 metabolism can be excreted.

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20
Q

How are metabolites from phase 2 metabolism excreted?

A

The metabolites can be converted to bile and excreted in faeces.

Or they will be re-absorbed into the blood and travel to the kidney where they are eliminated in urine.

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21
Q

What happens to metabolites that enter phase 2 metabolism?

A

They are conjugated to another group.

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22
Q

What are most of the reactions that occur in phase 1 metabolism?

A

Redox reactions and hydrolytic reactions.

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23
Q

What is the main group of enzymes involved in phase 1 metabolism?

A

The cytochrome P-450 enzymes.

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24
Q

What is always required by the cytochrome P-450 enzymes?

A

Oxygen and NADPH as a co-factor.

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25
Q

What is meant by the term that all phase 1 reactions are stereospecific and enantiomer specific?

A

If 2 forms of a drug are present then only 1 form of the drug will be metabolised.

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26
Q

What are the categories of cytochrome CYP3A4?

A

3 = Family.

A = Subfamily.

4 = The individual enzyme.

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27
Q

What is meant when it is said the cytochrome P-450 enzymes are inducible?

A

It means we can up-regulate the amount of enzymes present.

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28
Q

Do all species have the same cytochrome P-450 enzymes?

A

No.

All species have different C-P-450’s.

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29
Q

Is enzyme induction a fast or slow process?

A

A slow process.

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30
Q

What happens when cytochrome P-450 enzymes are inhibited?

A

They stop working.

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31
Q

Is cytochrome P-450 inhibition a quick or slow process?

A

It happens almost instantly.

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32
Q

What causes polymorphisms to occur in cytochrome P-450 enzymes?

A

The genetic make up of the animal.

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33
Q

When will a particular C-P-450 enzyme be up-regulated?

A

If we administer a drug that is used by a particular C-P-450 over a long period of time then that enzyme will be upregulated.

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34
Q

What will drugs compete against to get into the active site of their cytochrome P-450?

A

Against endogenous substrates.

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35
Q

What must be present for an enzyme to be up-regulated?

A

A large amount of substrate must be present for a long time.

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36
Q

How does the up-regulation of enzymes affect overall metabolism?

A

When more enzymes are present then metabolism will be more efficient.

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37
Q

Why will the up-regulation of enzymes affect the pharmacodynamics of a drug?

A

As it is used up and excreted much quicker as more enzymes are working on it.

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38
Q

What must we change is the pharmacodynamics of the drug have changed?

A

We must make the dose larger or more frequent.

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39
Q

Why must we increase the dose of the drug if the amount of enzymes that metabolise that drug have been up-regulated?

A

Because the effects of the drug will be felt by the body for a shorter period of time as the drug is being used up much more quickly.

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40
Q

How does enzyme inhibition affect drug metabolism?

A

When the enzyme is inhibited the drug is not metabolised.

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41
Q

What are the 4 pathophysiological parameters that influence the activity of drug metabolising enzymes?

A

Age.

Gender.

Diet.

Disease.

42
Q

What kind of organisms will have a low expression rate of cytochrome 9-450 enzymes?

A

Neonates and geriatrics.

43
Q

Why must the dose size be adjusted in elderly and newborn animals?

A

As they have fewer cytochrome P-450 enzymes.

44
Q

Other than drug metabolism, what is the other role of the cytochrome P-450 enzymes?

A

They are also used in hormone synthesis and deactivation.

45
Q

What must the drug compete with for access to cytochrome P-450 enzymes?

A

With hormone substrates.

46
Q

Do cytochrome P-450 enzymes have a higher affinity for drugs or steroid hormones?

A

Steroid hormones and this can slow down the rate of metabolism.

47
Q

Can constituents from the diet influence drug metabolism?

A

Yes. This means the drug will be metabolised more slowly.

48
Q

When will phase 1 enzyme be down regulated?

A

During periods of fever and this means there are fewer enzymes available to metabolise the drug.

49
Q

Will phase 2 enzymes be affected by fevers?

A

No, but they are affected by liver disease.

50
Q

What causes 70% of all side effects?

A

Variations in biotransformation of the drug.

51
Q

Where will phase 1 metabolism occur without cytochrome P-50 enzymes?

A

In the liver, lungs and kidneys.

52
Q

Phase 1 metabolism in the liver, lungs and kidneys will be carried out by what enzymes?

A

Non-microsomal enzymes that do not require NADPH as a cofactor.

53
Q

What are examples of the non-microsomal enzymes that carry out phase 1 metabolism?

A

Alcohol dehydrogenase.

The enzymes involved in aldehyde oxidation.

The enzymes involved in xanthine oxidation.

The enzymes involved in amine oxidation.

54
Q

What are the groups of non-microsomal enzymes involved in phase 1 metabolism?

A

Dehydrogenase’s along with some mono-oxygenase’s, peroxidase’s and aromatase’s.

55
Q

What reactions are involved in phase 2 of metabolism?

A

Conjugation reactions.

56
Q

What is the drug usually conjugated to in phase 2 metabolism?

A

Glucuronic acid.

Glutathione.

Sulphate.

Methyl groups.

Acetyl groups.

Methionine.

57
Q

What happens during a conjugation reaction in phase 2 metabolism?

A

A group such as glucuronic acid binds to the drug and becomes a functional group on the drug.

58
Q

What enzyme catalyses the addition of glucuronic acid to the drug in phase 2 metabolism?

A

UDP-glucuronosyltransferase.

59
Q

What is the aim of adding glucuronic acid to the drug in phase 2 metabolism?

A

It makes the drug more water soluble.

60
Q

What enzyme adds gulucronic acid to the drug in phase 5 of metabolism?

A

Uridine-5-diphospho glucuronysyl transferase.

61
Q

What enzyme adds glutathione to the drug in phase 5 of metabolism?

A

Glutathione S transferase.

62
Q

What enzyme adds sulphate groups to the drug in phase 5 of metabolism?

A

Sulphate transferase.

63
Q

What enzyme adds acetyl groups to the drug in phase 5 of metabolism?

A

Different acetylase’s.

64
Q

What enzyme adds methyl groups to the drug in phase 5 of metabolism?

A

Different methyl transferase’s.

65
Q

What enzyme adds methionine groups to the drug in phase 5 of metabolism?

A

Different peptidase’s.

66
Q

Are drugs that are conjugated to something else biologically active?

A

No.

Except for 6-morphine glucuronide.

67
Q

What kind of conjugates are excreted in bile?

A

Conjugates with a high molecular weight.

68
Q

What kind of conjugates are excreted in urine?

A

Conjugates with a low molecular weight.

69
Q

What animals will glucurodination not occur in?

A

In cats.

70
Q

What happens to any drugs that are glucurodinated if they are given to a cat?

A

They are toxic to cats and they will stay in the cats body longer.

71
Q

What animals does very little acetylation take place in?

A

In dogs.

72
Q

What animals does very little sulphylation take place in?

A

Pigs.

73
Q

In what animals will there be no glutathione conjugation?

A

Guinea pigs.

74
Q

What happens in cats if they are given any compounds that need to be glucurodinated?

A

They tend to be sulphonated.

Sulphonating compounds takes much longer and this means the drug stays in the body for a longer time.

75
Q

What are the 8 drugs that require glucurodination and that cats are sensitive to?

A

Acitaminophen.

Phenytoin.

Hexobarbital.

Propfol.

Carbamates.

Chloramphenicol.

Sulphonamides.

Ketones.

76
Q

What transporter transports organic ions into the bile duct or PCT?

A

MDR-1 (PGP).

77
Q

What transporter transports glucuronides and sulphates into the bile duct or PCT?

A

MRP-2.

78
Q

What transporter transports glucuronides into the bile duct or PCT?

A

BSEP.

79
Q

What transporter transports phospholipids into the bile duct or PCT?

A

MDR-3.

80
Q

What transporter transports glucuronides and cations into the bile duct or PCT?

A

BCRP.

81
Q

What is the 1st pass effect?

A

The elimination of drugs before they reach the systemic circulation.

82
Q

How does the first pass effect occur?

A

If we give a drug orally it is absorbed into the portal circulation which takes it to the liver.

Some of the drug is metabolised in the liver and a smaller amount of the active drug reaches the systemic circulation.

Some of the drug has been inactivated by the liver and this is the 1st pass effect.

83
Q

How does a drug enter systemic circulation if there is no first pass effect?

A

There is no hepatic metabolism and the same amount of drug that was absorbed will reach the systemic circulation.

84
Q

What drugs are most likely to be affected by the first pass effect?

A

Oral drugs.

85
Q

What are factors other than hepatic metabolism that contribute to the first pass effect?

A

Transport proteins.

Cytochrome P-50 enzymes in the GI.

86
Q

How can we see the first pass effect in drugs that are inhaled?

A

When they are partially metabolised by cytochrome P-450 enzymes in the lungs.

87
Q

What happens to any drug that is not absorbed in the GI tract?

A

It will be excreted in the faeces.

88
Q

What contributes to the first pass effect of drugs that are administered orally?

A

Outward ABC transporters.

The inactivation of drugs in the gut wall.

The metabolism of drugs in the liver.

89
Q

When does the 1st pass effect become clinically relevant?

A

When there are changes in liver metabolism.

90
Q

Why does the 1st pass effect only become clinically relevant when there are changes in liver metabolism?

A

As drug companies have already taken the 1st pass effect into account.

91
Q

How will giving a drug in conjunction with a drug that mobilises hepatic enzymes affect the 1st pass effect?

A

There will be more of a first pass effect.

92
Q

Do we worry about the 1st pass effect in healthy patients?

A

No.

93
Q

When does the first pass effect become clinically relevant?

A

When there is a problem with the inactivation technique for the drug.

I.e. If we administer a drug then the first pass effect is taken into account and a certain amount of drug will be de-activated.

But, if the deactivation process is faulty then more drug enters the body and this can lead to side effects.

94
Q

Enterohepatic circulation occurs with routes of administration?

A

All routes of administration.

95
Q

When does enterohepatic circulation occur?

A

After the drug has entered the systemic circulation and has undergone biotransformation in the liver.

96
Q

The enterohepatic circulation only involves what kind of drugs?

A

Glucurodinated drugs.

97
Q

What happens to glucurodinated drugs in the enterohepatic circulation?

A

They are taken into bile and excreted into the GI tract.

However, bacteria in the gut break down the glucurodinated drugs.

This breaks the bond between the glucurodinic acid and the drug and we have an active drug once again.

This active drug can be re-absorbed in the large intestine.

98
Q

When does the enterohepatic circulation become clinically relevant?

A

When there is a problem with glucurodination or if there are no bacteria in the GI tract.

99
Q

What happens in the enterohepatic circulation if there is a problem with glucurodination?

A

All of the drug will be absorbed and this will be a higher dose than intended and could be toxic.

100
Q

What happens in the enterohepatic circulation if there are no bacteria present?

A

The drug will not be recycled and there will be a lower dose than normal.

101
Q

Do we need to worry about enterohepatic circulation in the healthy animal?

A

No.

5. Metabolism and Biotransformation of Drugs. (1 decks)

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