ADME

Question 1

What is the most commonly used analgesic?

Answer 1

Paracetamol

Question 2

What concentration does analgesic effects of paracetamol start?

Answer 2

10 mcg/ml

Question 3

MOA of paracetamol

Answer 3

Central inhibition of COX-2 + prostaglandin synthase

Anti-pyretic via CNS inhibition of PGE₂

Question 4

Paracetamol commonly causes ________ failure

Answer 4

Acute liver failure

Question 5

Draw metabolism of paracetamol

Question 6

What is the maximum therapeutic dose of paracetamol?

Answer 6

4g/day

Question 7

What dose does paracetamol toxicity start?

Answer 7

5g/day

Question 8

What does paracetamol overdose lead to?

Answer 8

Hepatic toxicity

Hepatic failure

Encephalopathy + death within days

Question 9

In terms of metabolism, what makes paracetamol toxic?

Answer 9

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

Question 10

What detoxifies NAPQI?

Answer 10

Glutathione

Question 11

Describe paracetamol overdose + the phases of toxicity

Answer 11

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

Question 12

Function of NAC

Answer 12

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

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

Question 13

When is NAC best administered?

Answer 13

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

Question 14

What receptor do opioids commonly bind to?

Answer 14

Mu-opioid receptor

Question 15

List opioid side effects

Answer 15

Respiratory depression

Euphoria

Sedation

Decrease in GI motility

Urinary retention

Question 16

What is the antidote for opioids?

Answer 16

Naloxone

Competitive Mu-opioid receptor antagonist

Question 17

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

Answer 17

Morphine-6-glucuronide

Question 18

How does renal function affect morphine?

Answer 18

When renal function is impaired,

increase in M6G, which leads to an increase in effects

Question 19

Name a morphine metabolite which is…

• active?
• non-active?

Answer 19

Active = M6G, morphine, normorphone

Inactive = M3G, codeine, norcodeine

Question 20

Pharmacology of M6G

Answer 20

Active metabolite

Potency depends on route of administration

Question 21

Pharmacology of M3G

Question 22

Why is M6G better than morphine?

Answer 22

Has better analgesic effect than morphine

Fewer side effects

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

Question 23

Disadvantage of M6G

Answer 23

Expensive

Question 24

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

Answer 24

Codeine

Oxycodone

Hydrocodone

Question 25

What morphine metabolites are metabolised by CYP450 34A?

Answer 25

Fentanyl Methadone

Question 26

What morphine metabolites are metabolised by UGT? What does UGT stand for?

Answer 26

Morphine Hydromorphine Oxymorphone

Question 27

How is morphine excreted? Where are other morphine metabolites excreted?

Answer 27

Mostly renal Glucuronide conjugates excreted in bile Methadone excreted in faeces

Question 28

Enzymes that mediate phase 1 + 2 metabolism are called... What do these type of enzymes modify?

Answer 28

Polymorphic Polymorphisms alter safety + efficacy of drugs

Question 29

What is Cytochrome P450's? * Function * Where does it take place * How does genetic polymorphisms affect CYP450?

Answer 29

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

Question 30

What are the effects of codeine + how does it come about? What catalyses reaction of morphine to codeine?

Question 31

Describe the allelic variant in CYP isoform

Question 32

Describe CYP2D6 poor metaboliser

Answer 32

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

Question 33

Describe CYP2D6 ultrarapid metaboliser

Answer 33

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

Question 34

What do CYP2D6 single nucleotide polymorphisms influence?

Answer 34

Patient outcomes

Question 35

What is the only tramadol metabolite with analgesic activity?

Answer 35

M1

Question 36

What are the pharmacological effects of tramadol + its metabolites?

Question 37

What influences ADRs of NSAIDs?

Answer 37

Liver metabolism via CYP2C9

Question 38

What is an issue with patients with low CYP2C9?

Answer 38

They cannot metabolise celecoxib efffectively Ths leads to increased blood level + ADR due to drug accummulation

Question 39

How does OPRM1 + A118G allele affect patient?

Answer 39

Increase meds + decrease pain relief

Question 40

What do formation of tramadol metabolites depend on?

Answer 40

CYP2D6 + CYP3A4