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Biochemistry > Drug metabolism > Flashcards

Drug metabolism Flashcards

1
Q

What is drug metabolism and what is its main purpose?

A

The biotransformation of pharmaceutical substances in the body so that they can be eliminated more easily. This happens in the liver.

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2
Q

What are xenobiotics?

A

Foreign substance to the body e.g. drugs, plant metabolites, food additives etc.
1. Water soluble are easily excreted in urine.
2. Lipophilic: some are not easily excreted and are deposited in adipose tissue or have to be metabolised to water soluble products.

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3
Q

Discuss the 2 phases of liver detoxification.

A

Phase 1: compound is oxidised, reduced, hydrolysed then excreted.
Phase 2: compound is conjugated to hydrophilic molecule then excreted.

*some compounds go through both phases

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4
Q

What is liver activation?

A

Compound goes through phase 1 but instead of detoxification & excretion, we have an inactive drug that is transformed into an active metabolite/ toxin.

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5
Q

What type of oxidation reaction happens in phase 1 reaction?

A

Monooxygenase (enzymes) reactions that require cytochrome p450.

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6
Q

What is cytochrome p450?

A

They’re electron carriers that have a porphyrin structure (haem group with fe3+).

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7
Q

Discuss the Cytochrome P450 nomenclature.

A
  • Name derived from their absorption spectrum.
    It has a max frequency of 450 nanometres in complex with carbon monoxide.
  • It has 18 families, 43 subfamilies and 57 genes.
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8
Q

What is cytochrome p450’s primary role?

A
  • Hormone synthesis & breakdown
  • Metabolism & detoxification of compounds after ingestion
  • Drug biotransformation & drug metabolism
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9
Q

Discuss the control of cytochrome p450?

A
  1. Inhibition:
    - p450 2B6 - orphenadrine, thiotepa, ticlopidine
    - p450 2e1- Disulfiram, ritonavir.
  2. Induction:
    - p450 2B6 - Phenobarbitone, phenytoin, primidone, Rifampin
    - p450 2E1- ethanol, isoniazid.
  3. Genetic variation (from person to person)
    - Genetic variants exist with a frequency of at least 1%
    - Lack of functional activity = Specific drug toxicity or Inactivity of pro-drug
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10
Q

Discuss drug interactions with CYP P450: activation.

A
  • Some drugs activate P-450 e.g. Phenobarbitone (sedative) induces CYP2C9.
    -For patients on warfarin, may lead to low levels of warfarin. – Increased risk of clotting.
  • Warfarin is metabolised by multiple cytochromes including CYP2C9 and CYP3A
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11
Q

Discuss drug interactions with CYP P450: inhibition.

A
  • Some drugs inhibit P-450, leads to increased levels of other drugs.
  • E.g. patients on warfarin taking the anti-fungal ketoconazole have increased warfarin levels as ketoconazole inhibits CYP3A4. Increased risk of bleeding.
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12
Q

What is CYP3A4?

A
  • CYP3A4 is the major isoform in human liver, it oxidatively metabolises > 50% of drugs.
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13
Q

What is the fruit that interacts greatly with drugs?

A

-Grapefruit juice naturally contains CYP3A4 inhibitors (furanocoumarins).
-More than 85 drugs that may interact with the fruit 45 with have serious side-effects (death, AKI).
- Simvastatin combined with a 200 ml glass of grapefruit juice once a day for three days, produces a 330 per cent rise in the systemic concentration of the drug.

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14
Q

Recall the types of reaction involved in phase I drug metabolism.

A
  1. Introduction of functional groups; -OH, -NH2, -COOH
  2. Prepare substance for conjugation (Phase II metabolism)
  3. Reactions: Reduction, Hydrolysis, Oxidation
  4. Oxidation: most common phase I reaction type.
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15
Q

Phase I Reactions – Reduction.

A
  • Chloramphenicol is a broad-spectrum antibiotic which is reduced by nitro-reductase.

*Reduction implies the addition of two hydrogens to the molecule nitro is the chemistry name given to the –NO2 functional group.

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16
Q

Phase I Reactions – Hydrolysis.

A
  • Aspirin at pH 7 is hydrolysed by esterases to salicylate and acetate.

*Hydrolysis implies the addition of water (H2O) to the molecule resulting in the breaking of the molecule into two parts.

17
Q

Phase I Reactions: Oxidation.

A
  • Many oxidation reactions are catalysed by the mixed function oxidase (MFO) system – (Cytochrome P450, NADPH & molecular O2).
  • Reaction: RH + O2 + 2H+ + 2e- = ROH + H2O (where R is the drug)
  • Oxidation can occur by: Hydroxylation, Dehydrogenation, Oxidative dealkylation.
18
Q

Phase I Reactions: Hydroxylation.

A
  • Addition of “OH” group.
  • E.g. RH + O2 + NADPH + H+ = ROH + H2O + NADP+
  • Take place mainly on the endoplasmic reticulum of liver cells.
  • Lipophilic → hydrophilic compounds → more readily excreted.
19
Q

Example of hydroxylation reaction: lidocaine.

A

Metabolism involves addition of an - OH group as a first step via P450, NADPH, O2.

20
Q

What is Cytochrome P450’s Mechanism of action?

A
  1. Incorporates one atom of molecular oxygen into substrate creating an -OH group
  2. The other O is reduced to water
  3. NADPH provides reducing equivalents.
  4. Hydroxylation may activate/inactivate a drug or make a drug more soluble
  5. Or act as a site for conjugation (Phase II) e.g. glucuronidation
21
Q

Describe the complete metabolism of ethanol.

A

This is a Phase I reactions via dehydrogenation = Elimination of hydrogen (H2).

22
Q

Why is a deficiency in aldehyde dehydrogenase important in ethanol metabolism?

A
  • Leads to Acetaldehyde accumulation
  • Symptoms: vasodilation, facial flushing & tachycardia.
23
Q

Explain the mechanism of action of disulfiram (treatment for alcohol abuse).

A
  • Helps to maintain abstinence
  • Highly lipid soluble (accumulates in adipose tissue) & has 80% bioavailability after an oral dose.
  • MOA: Irreversibly inhibits the oxidation of acetaldehyde by competing with cofactor NAD.
  • Causes a 5-10 fold ^ in acetaldehyde concentration which produces unpleasant side effects.
24
Q

Phase I Reaction: oxidative dealkylation.

A

Removal of alkyl group from an organic compound. E.g. metabolism of Codeine.
1. Oxidative dealkylation: alkyl group of codeine is oxidised to an aldehyde.
2. 10% of codeine converted to morphine
3.The analgesic effect of codeine due to its conversion to morphine.

25
Q

How does a deficiency in CYP2D6 affect codeine metabolism?

A
  • Codeine is a prodrug that requires activation.
  • It is metabolised to morphine by P450 2D6
  • CYP2D6 has different polymorphisms present in the population. Deficiency = poor/ no activation.
26
Q

Describe the types of conjugation reactions involved in phase II drug metabolism.

A
  • More common following preliminary modification and makes compound more polar = easily excreted in urine or bile.
  • Main conjugation reactions are:
    1. Glucuronic acid conjugation (glucuronidation)
    2. Sulfate conjugation
    3. Glycine conjugation
    4. Glutamine conjugation
    5. Glutathione conjugation
27
Q

Discuss Phase II Reaction: Glucuronidation.

A
  • Most common form of conjugation.
  • Common for drugs with OH, COOH & NH2 groups
  • Glucuronic acid is transferred to the drug from uridine diphosphate glucuronic acid (a reactive intermediate)
28
Q

Discuss Phase II Reaction: Sulfation.

A
  • Common for phenols
  • Sulfate is transferred to the drug from the reactive intermediate (PAPS), in the presence of sulfotransferase.
  • Glucuronide formation & sulfation often compete for the same substrate e.g. paracetamol.
29
Q

Discuss Phase II Reaction: Glycine and glutamine conjugation.

A
  • Glycine conjugation is common for drugs with –COOH groups.
  • Glutamine can also be conjugated to drugs with COOH groups.
30
Q

Discuss Phase II Reaction: Glutathione metabolism.

A
  • Detoxification products containing Sulphur atom derived from Glutathione
  • Glutathione tripeptide - Glu, Gly, Cys (Glu & Gly released).
  • Final step – acetylation and End product – Mercapturates
31
Q

What are foreign compounds?

A

Foreign compounds include: aromatic nitro- & halogenated compounds & Phase l oxidation products of polycyclic hydrocarbons, aliphatic halides & epoxides.

32
Q

Describe the metabolism of aspirin.

A
  • Aspirin is readily hydrolysed to salicylic acid, both enzymatically and non-enzymatically. Salicylic acid undergoes conjugation reactions generating the major metabolites salicyluric acid.
33
Q

Describe the metabolism of paracetamol.

A
  • 5% excreted unchanged. 90% conjugated with glucuronide & sulphate before excretion.
  • 5% oxidised via Cytochrome P450 (CYP2E1, CYP1A2 subfamilies) to N-acetyl-p-benzoquinoneimine (NAPQI) & combined with glutathione
  • Metabolised to cysteine & mercapturate compounds before excretion.
34
Q

Explain why some drugs e.g. paracetamol are toxic at high doses.

A
  • Hepatotoxicity – due to 5% that is oxidised
  • Time to become depleted of glutathione – 3-4 days (dependent on nutritional status)
  • Few overt symptoms during early stage – in suspected overdose, treat before symptoms appear
  • Liver injury following single dose of 15g (30 standard tablets).
35
Q

Treatment of paracetamol overdose.

A
  • Treatment within 12 hr highly effective, some benefit up to 48 hr
  • Administration of n-acetylcysteine (NAC) which acts as a glutathione substitute.
36
Q

Define prodrugs.

A
  • A pharmacologically inactive chemical entity that when metabolised or chemically transformed by the mammalian system is converted into a pharmacologically active substance.
37
Q

In what situations are prodrugs used?

A
  • To alter/ improve absorption
  • To alter biodistribution
  • To alter metabolism
  • To alter elimination.
  • To improve patient acceptability (decrease pain on injection).

Biochemistry (30 decks)

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