5 - Drug Metabolism Flashcards

1
Q

Why would you want a drug to be lipophilic or water soluble?

A

Lipophilic - in order to access tissues (therapeutic effect)

Water soluble - so it can be retained in the blood and excreted

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2
Q

What are the two stages of drug metabolism?

A

Phase 1 - Adding a reactive group to increase polarity

Phase 2 - Adding a water soluble conjugate onto the reactive site

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3
Q

What are the possible Phase 1 reactions?

A

Oxidation (creating) - [most common, starts with hydroxylation] electrophiles, R=0 R-O-R [triangle]

Hydrolysis/reduction (unmasking) - nucleophiles, R-OH R-SH R-NH2

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4
Q

Where are most Phase 1 reactions carried out?

A

In the liver, by the cytochrome P450 enzymes (SER of hepatocytes)
There are 57 subtypes of P450.

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5
Q

What is aspirin converted to in Phase 1?

A

Salicylic acid (hydrolysis unmasking)

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6
Q

What is nicotine converted to in Phase 1?

A

Cotinine (oxidation)

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7
Q

What is cocaine converted to in Phase 1?

A

Ecgonine Methyl Ester + Benzoic Acid (hydrolysis)

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8
Q

What is chloral hydrate converted to in Phase 1?

A

Trichloroethanol (reduction)

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9
Q

What can Phase 1 metabolites be?

A

Inert
Active e.g. cannabis, prolongs effects
Active (from prodrug) e.g. codeine to morphine

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10
Q

What are the possible Phase 2 reactions?

A

For oxidation:
glutathione conjugation R-SG, glutathione, electrophiles

For hydrolysis/reduction
glucuronidation R-GI, UDP-glucuronic acid, OH NH2 SH COOH
acetylation R-Ac, Acetyl CoA, OH NH2
sulfation R-SO2H, 3’ phosphoadenosine 5’ phosphoadenosine, OH NH2

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11
Q

Which is the most common Phase 2 reaction?

A

Glucuronidation

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12
Q

Describe glucuronidation and sulfation in terms of their affinity and capacity?

A

Glucuronidation is low affinity/high capacity - more likely to occur at high drug doses e.g. aspirin

Sulfation is high affinity/low capacity e.g. low dose paracetamol

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13
Q

Explain the basis of paracetamol overdose

A

Paracetamol is first metabolised via sulfation.
As more paracetamol is taken glucuronidation is used (low affinity/high capacity)

However, electrophile and subsequent glutathione conjugates are very reactive.

Paracetamol, NAPQI , conjugate

When overdosing, the glutathione stores are depleted and NAPQI begins to build up. NAPQI is highly toxic.

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14
Q

Name some other less common Phase 2 pathways

A

Acetylation (aromatic amines), N-acetyl transferase (NAT enzyme), Acetyl CoA e.g. Isoniazid

Methylation, methyltransferases e.g. Levodopa

Amino acid conjugation, react with carboxylic acid or amine group of amino acid

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15
Q

Why is drug metabolism so important?

A

Biological half-life is decreased

Duration of exposure is reduced

Accumulation of the compound in the body is avoided

Potency/duration of the biological activity of the chemical can be altered

The pharmacology/toxicology of the drug can be governed by its metabolism

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