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LCRS 1 - Pharmacology > Drug metabolism > Flashcards

Drug metabolism Flashcards

1
Q

Why do we need drug metabolism?

A
  • Drugs tend to be lipophilic
  • Must be metabolised to become more water soluble - excreted easily
  • Metabolism tends to eliminate or reduce pharmacological and toxiocological activity
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2
Q

What is the major organ for drug metabolism?

A

Liver

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3
Q

What organs are involved in drug metabolism?

A 
LIVER
Gut
Kidneys
Skin
Brain
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4
Q

What is hepatic first pass metabolism?

A

Metabolic conversion of drug into something different before drug enters general circulation

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5
Q

How can you combat the low bioavailability of a drug that undergoes extensive first pass metabolism?

A

IV admin

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6
Q

Why can first pass metabolism be pre-hepatic?

A

Intestines, stomach, oesophagus and buccal cavity have a small amount of metabolic capacity

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7
Q

What types of metabolic change are involved in phase I metabolism?

A

Oxidation
Reduction
Hydrolysis

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8
Q

What types of metabolic change are involved in phase II metabolism?

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

What is the role of phase I reactions?

A
  • Oxidation/reduction introduce new FGs
  • Hydrolysis unmasks FGs
  • These FGs serve as a point of attachment for phase II reactions
  • Often inactivate drugs but can also activate prodrugs
  • Sometimes produce toxic metabolites
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10
Q

What is the cytochrome p450 enzyme system?

A
  • Main system involved in phase I oxidising reactions
  • Involved in metabolism of most drugs + endogenous compounds
  • Humans - 57 enzymes
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11
Q

How can some drugs affect CYP450?

A
  • Drugs can inhibit or induce CYP450

- Bad because changes ability of system to handle certain drugs

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12
Q

Where is CYP450 predominantly found?

A

Liver

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13
Q

Describe the basic reaction of CYP450

A

RH + NADPH + O2 + H+ —-> ROH (oxidised drug) + NADP+ + H20

Any aqueous environment has source of protons

Oxidation reactions involve a hydroxylation step catalysed by P450

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14
Q

What is N-demethylation?

A
  • Oxidation of methyl group in nitrogen environment (N-methyl group)
  • Very effective way of removing pharmacological activity
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15
Q

What is O-demethylation

A

Oxidation of O-methyl group by C450

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16
Q

What is N-oxidation?

A
  • Generation of an amine oxide (oxide of tertiary amines)

- Enzyme = flavin containing monooxygenase

17
Q

What is the medical relevance of flavin containing monooxygenase?

A

FCMO deficiency (fish odour syndrome):

  • Humans generate trimethylamine in GIT (product of protein metabolism)
  • Trimethylamine smells terrible
  • In liver, FCMO converts trimethylamine into trimethylamine N-oxide (odourless) and polar tf can be excreted in urine
  • Defective FCMO - produce trimethylamine but can’t metabolise and excrete it so they sweat and breathe it out
18
Q

Where are FCMO and P450 enzymes found?

A

Inner membrane of ER

19
Q

What do reductive reactions form?

A

2 amines

Far less common than oxidation

20
Q

Where do reductive reactions usually happen and why?

A
  • GIT
  • Low oxygen environment
  • Most reductases are bacterial enzymes colonising our gut
21
Q

What is hydrolysis? What enzymes are involved?

A

Splitting a molecule with water
Esterases
Amidase

22
Q

What is the aim of phase II metabolism?

A

Make drug less lipid soluble, more polar and easier to excrete

23
Q

What do phase II enzymes need?

A

Conjugating agent
Usually large, polar, endogenous chemical
Target specific FG

24
Q

Explain glucuronidation

A

Addition of sugar to foreign compound
CA = UDPGA
Enzyme = glucuronyl transferase
Sugar derivative of xenobiotic is POLAR so can be removed

25
Q

What is the most common phase II reaction?

A

Glucuronidation

26
Q

Why are molecules that have undergone glucuronidation often excreted in the bile?

A

Glucuronidation makes quite large molecular weight products so problem with glomerular filtration

27
Q

Explain acetylation

A

Drug has amino group
CA = Acetyl CoA (acts as donor compound)
Enzyme = acetyl transferase
Acetyl group transferred to electron rich atom (N,O,S)

28
Q

Explain methylation

A

CA = S-adenosyl methionine (donor)
Enzyme = methyl transferase
Methyl group transferred to electron rich atom (N,O,S)
Decreases polarity

29
Q

Explain sulphation

A 
Xenobiotic is taken with PAPS (CA -
 sulphate donor)
Enzyme = sulphotransferases
Transfer of sulphur to substrates to produce sulphuric acid derivative
Very polar and water soluble
30
Q

Explain glutathione conjugation

A

One of the most important processes toxicologically
Enzyme = glutathione transferase
Glutathione = tripeptide - glycine, glutamine, cysteine
Cysteine has thiol - reactive part
Reacts with damaging electrophilic intermediates generated during metabolism

31
Q

Why is drug metabolism important?

A
  1. Reduces biological half-life of drug bc of phase I and II reactions
  2. Reduces duration of exposure
  3. Avoids accumulation of drug in body
  4. Can alter potency/duration of biological activity of chemical
  5. Pharmacology/toxicology of the drug is governed by its metabolism
32
Q

What effect do phase I reactions have on drug polarity?

A

Little effect

33
Q

What is PAPS?

A

3’-phosphoadenosine-5’-phosphosulphate

34
Q

What reactions target -OH and -NH2 groups?

A

Acetylation
Glucuronidiation
Methylation
Sulphation

35
Q

What functional group does amino acid conjugation target?

A

-COOH

36
Q

What functional groups does glucuronidation target?

A
  • OH
  • COOH
  • NH2
  • SH

LCRS 1 - Pharmacology (33 decks)

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