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LCRS Pharmacology and Therapeutics > Drug metabolism- Notes > Flashcards

Drug metabolism- Notes Flashcards

1
Q

Why do we need drug metabolism?

A

Most drugs tend to be lipophilic and lipid soluble drugs must be metabolised to become more water soluble so they can be excreted easier
Metabolism eliminates or reduces pharmacological and toxicological activity and converts drugs into something more polar/soluble so it can be more easily excreted by the kidneys

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2
Q

What is the major organ for drug metabolism?

A

Liver

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3
Q

What is hepatic first pass metabolism?

A

Metabolic conversion of the drug into something that is different before the drug enters general circulation

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4
Q

How can you avoid the problem of extensive first pass metabolism of a drug?

A

Give the drug intravenously

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5
Q

What are the three stages of metabolic change?

A

Phase I
Phase II
Excretion

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6
Q

What are the three types of phase I chemical activity?

A

Oxidation
Reduction
Hydrolysis

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7
Q

What are phase II reactions for?

A

To add big polar groups to the molecule to make it more polar so it can be excreted

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8
Q

Give some examples of phase II chemical activity?

A 
Glucorinidation
Acetylation
Amino acid conjugation
Sulphation
Methylation
Glutathione conjugation
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9
Q

What is the purpose of phase I reactions?

A

Releasing or making functional groups
Oxidation/reduction creates new functional groups
Hydrolysis unmasks functional groups

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10
Q

What is the drug called when it is activated by phase I?

A

Prodrug

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11
Q

In what form is a prodrug administered?

A

Pharmacologically inactive so you’re relying on liver to convert it

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12
Q

Where do phase I reactions primarily occur?

A

In the liver

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13
Q

What is the main enzyme system in the liver involved in drug metabolism called?

A

Cytochrome P450

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14
Q

How many enzymes are involved in the cytochrome P450 system?

A

57

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15
Q

What process does cytochrome p450 specifically have an effect on?

A

Phase I oxidising reactions

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16
Q

What other compounds is P450 involved in the metabolism of?

A

Endogenous compounds- steroids and oestrogens

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17
Q

What is the basic reaction of CYP450?

A

RH (drug) + NADPH + O2 + H+ –> ROH (oxidised drug) + NADP+ + H2O

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18
Q

What is needed for this oxidation reaction?

A

Drug
NADPH
Molecular oxygen
Source of protons

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19
Q

What is at the centre of P450’s catalytic site?

A

Catalytic iron in the oxidised state (Fe3+)

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20
Q

What do all P450 enzymes have at its active site?

A

Porphyrin ring and iron (Fe3+)

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21
Q

What does the drug bind to in P450??

A

The iron in the catalytic site

22
Q

What happens after the drug binds?

A

An electron is donated by NADPH which is picked up by the P450 complex and reduces Fe3+ to Fe2+

23
Q

What happens after the reduction of iron?

A

Oxygen binds to the catalytic site so P450 now has oxygen and Fe2+ bound

24
Q

What happens after oxygen binding?

A

The Fe2+ loses an electron to become Fe3+ and the oxygen picks up the other electron and becomes unstable

25
Q

What happens after the oxidation?

A

Another electron is sent in from NADPH which is picked up by Fe3+ to become Fe2+ which donates this to oxygen again so the oxygen becomes very unstable

26
Q

What happens after the oxygen becomes very unstable?

A

The drug is converted into the hydroxylated derivative and the reactive oxygen is lost as water by picking up two protons

27
Q

What happens after conversion of the drug?

A

It is released and the P450 returns to the cycle with iron in its Fe3+ state ready to undergo the next cycle

28
Q

What is N-demethylation?

A

Oxidation of a methyl group in a nitrogen environment-

29
Q

What is N-oxidation?

A

Oxidation of the nitrogen group itself

30
Q

What does N-oxidation generate?

A

An amine oxide

31
Q

What enzyme catalyses N-oxidation?

A

Flavin containing monooxygenase (works in a similar way to P450 but has a different catalytic site

32
Q

Why does flavin containing monooxygenase have a medical relevance?

A

Fish odour syndrome (Flavin containing monooxygenase deficiency)

33
Q

Why does fish odour syndrome occur?

A

Humans generate trimethylamine in their GI tract (from protein metabolism) which smells terrible and in the liver flavin containing monooxygenase converts it to trimethylamine N-oxide which odourless and polar so can be excreted but people with FCMO deficiency can’t metabolise trimethylamine but sweat and breathe it out so smell bad

34
Q

What order kinetics does both P450 and FCMO have?

A

First

35
Q

What is alcohol metabolised by and into?

A

Metabolised by alcohol dehydrogenase into acetaldehyde then to acetic acid which is removed

36
Q

Where is FCMO and P450 found?

A

Inner membrane of endoplasmic reticulum

37
Q

Where is alcohol dehydrogenase found?

A

Cytoplasm (soluble)

38
Q

Why does reduction work effectively in the GI tract?

A

It is a low oxygen environment

39
Q

Why do reduction reactions tend to take place in the GI tract?

A

Most reductases are bacterial enzymes that are colonising in our gut

40
Q

What is procainamide?

A

Local anaesthetic

41
Q

How is procainamide metabolised?

A

Around the amine function to generate a carboxylic acid and amine

42
Q

How do you work out the enzyme name for phase II stages?

A

Take the name of the reaction and add transferase on the end

43
Q

What is the conjugate from the phase II reactions like?

A

Usually inactive
Less lipid soluble
More polar
Easier to excrete

44
Q

What are conjugating agents?

A

Large, polar, endogenous chemicals that are used in phase II reactions which target specific types of functional group

45
Q

What is the most common phase II reaction?

A

Glucuronidation

46
Q

What is glucuronidation?

A

Addition of sugar to a foreign compound

47
Q

Why is glutathione conjugation one of the most important processes toxicologically?

A

Glutathione reacts with electrophiles- damaging species that are often generated during metabolism, they must be removed because they can damage DNA and proteins

48
Q

Why do glucuronidation products have a problem with glomerular filtration?

A

Makes large molecular weight products

49
Q

How are large molecular weight molecules often excreted?

A

In bile

50
Q

How does methylation affect polarity?

A

Decreases it

LCRS Pharmacology and Therapeutics (33 decks)

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