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PAI > ADME > Flashcards

ADME Flashcards

1
Q

What is the most commonly used analgesic?

A

Paracetamol

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2
Q

What concentration does analgesic effects of paracetamol start?

A

10 mcg/ml

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3
Q

MOA of paracetamol

A

Central inhibition of COX-2 + prostaglandin synthase

Anti-pyretic via CNS inhibition of PGE2

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4
Q

Paracetamol commonly causes ________ failure

A

Acute liver failure

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5
Q

Draw metabolism of paracetamol

A
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6
Q

What is the maximum therapeutic dose of paracetamol?

A

4g/day

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7
Q

What dose does paracetamol toxicity start?

A

5g/day

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8
Q

What does paracetamol overdose lead to?

A

Hepatic toxicity

Hepatic failure

Encephalopathy + death within days

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9
Q

In terms of metabolism, what makes paracetamol toxic?

A

NAPQI, generated by cytochrome p450, covalently binds cellular proteins altering cell function leading to cell injury and death

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10
Q

What detoxifies NAPQI?

A

Glutathione

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11
Q

Describe paracetamol overdose + the phases of toxicity

A

Normal conjugation metabolism routes are saturated e.g. glucuronidation + sulfation, which leads to an increase in NAPQI production

Glutathione reserves are less than 30%, therefore, unable to detoxify all NAPQI leading to cellular injury

4 phases of toxicty

  1. 0-24hr = asymptomatic, N+V, abdominal pain
  2. 24-72hr = 1st symptoms resolve but liver injury evolve (elevation of LFTs e.g. bilirubin)
  3. N+V reoccur, maximal manifestatioon of hepatic injury, AST/ALT in 10,000s, coma + anuria (failure of kidneys to produce urine) leading to death
  4. >4 days is recovery phase, may take weeks for LFTs to return to normal
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12
Q

Function of NAC

A

Restores glutathione allowing NAPQI detoxification to produce non-toxic metabolites + increase sulfation reaction

NAC is a direct antioxidant improving organ function + limits hepatocyte damage

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13
Q

When is NAC best administered?

A

If adminitered within 8 hours + all patients have early signs of toxicity but normal AST

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14
Q

What receptor do opioids commonly bind to?

A

Mu-opioid receptor

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15
Q

List opioid side effects

A

Respiratory depression

Euphoria

Sedation

Decrease in GI motility

Urinary retention

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16
Q

What is the antidote for opioids?

A

Naloxone

Competitive Mu-opioid receptor antagonist

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17
Q

What morphine metabolite is the major contributor to the overall morphine analgesic effect?

A

Morphine-6-glucuronide

18
Q

How does renal function affect morphine?

A

When renal function is impaired,

increase in M6G, which leads to an increase in effects

19
Q

Name a morphine metabolite which is…

  • active?
  • non-active?
A

Active = M6G, morphine, normorphone

Inactive = M3G, codeine, norcodeine

20
Q

Pharmacology of M6G

A

Active metabolite

Potency depends on route of administration

21
Q

Pharmacology of M3G

A
22
Q

Why is M6G better than morphine?

A

Has better analgesic effect than morphine

Fewer side effects

  • Decrease in resp. depression, nausea + anti-emetic use + sedation in the first 4 hours
23
Q

Disadvantage of M6G

A

Expensive

24
Q

Phase1: What morphine metabolites are metabolised by CYP450 2D6?

A

Codeine

Oxycodone

Hydrocodone

25
Q

What morphine metabolites are metabolised by CYP450 34A?

A

Fentanyl

Methadone

26
Q

What morphine metabolites are metabolised by UGT?

What does UGT stand for?

A

Morphine

Hydromorphine

Oxymorphone

27
Q

How is morphine excreted?

Where are other morphine metabolites excreted?

A

Mostly renal

Glucuronide conjugates excreted in bile

Methadone excreted in faeces

28
Q

Enzymes that mediate phase 1 + 2 metabolism are called…

What do these type of enzymes modify?

A

Polymorphic

Polymorphisms alter safety + efficacy of drugs

29
Q

What is Cytochrome P450’s?

  • Function
  • Where does it take place
  • How does genetic polymorphisms affect CYP450?
A

Involved in drug metabolism + bioactivation

Carry out degradation of xenobiotics

happens in liver

P450s transform drugs, which leads to, soluble molecules that can be excreted

Genetic polymorphisms affect drug metabolism + response

30
Q

What are the effects of codeine + how does it come about?

What catalyses reaction of morphine to codeine?

A
31
Q

Describe the allelic variant in CYP isoform

A
32
Q

Describe CYP2D6 poor metaboliser

A

Decrease activation of CYP2D6-dependent analgesic prodrugs e.g. codeine

They do not get any analgesic benefits from codeine

They do have same frequency of side effects than normal metabolism

33
Q

Describe CYP2D6 ultrarapid metaboliser

A

Potential for increased morphine production from codeine + might be at a greater risk for opioid related ADR + benefit from a lower does

ADRs include respiratory depression, shock, cardiac arrest, death etc

34
Q

What do CYP2D6 single nucleotide polymorphisms influence?

A

Patient outcomes

35
Q

What is the only tramadol metabolite with analgesic activity?

A

M1

36
Q

What are the pharmacological effects of tramadol + its metabolites?

A
37
Q

What influences ADRs of NSAIDs?

A

Liver metabolism via CYP2C9

38
Q

What is an issue with patients with low CYP2C9?

A

They cannot metabolise celecoxib efffectively

Ths leads to increased blood level + ADR due to drug accummulation

39
Q

How does OPRM1 + A118G allele affect patient?

A

Increase meds + decrease pain relief

40
Q

What do formation of tramadol metabolites depend on?

A

CYP2D6 + CYP3A4

PAI (17 decks)

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