ADME Flashcards
What is the most commonly used analgesic?
Paracetamol
What concentration does analgesic effects of paracetamol start?
10 mcg/ml
MOA of paracetamol
Central inhibition of COX-2 + prostaglandin synthase
Anti-pyretic via CNS inhibition of PGE2
Paracetamol commonly causes ________ failure
Acute liver failure
Draw metabolism of paracetamol
What is the maximum therapeutic dose of paracetamol?
4g/day
What dose does paracetamol toxicity start?
5g/day
What does paracetamol overdose lead to?
Hepatic toxicity
Hepatic failure
Encephalopathy + death within days
In terms of metabolism, what makes paracetamol toxic?
NAPQI, generated by cytochrome p450, covalently binds cellular proteins altering cell function leading to cell injury and death
What detoxifies NAPQI?
Glutathione
Describe paracetamol overdose + the phases of toxicity
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
- 0-24hr = asymptomatic, N+V, abdominal pain
- 24-72hr = 1st symptoms resolve but liver injury evolve (elevation of LFTs e.g. bilirubin)
- 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 days is recovery phase, may take weeks for LFTs to return to normal
Function of NAC
Restores glutathione allowing NAPQI detoxification to produce non-toxic metabolites + increase sulfation reaction
NAC is a direct antioxidant improving organ function + limits hepatocyte damage
When is NAC best administered?
If adminitered within 8 hours + all patients have early signs of toxicity but normal AST
What receptor do opioids commonly bind to?
Mu-opioid receptor
List opioid side effects
Respiratory depression
Euphoria
Sedation
Decrease in GI motility
Urinary retention
What is the antidote for opioids?
Naloxone
Competitive Mu-opioid receptor antagonist
What morphine metabolite is the major contributor to the overall morphine analgesic effect?
Morphine-6-glucuronide
How does renal function affect morphine?
When renal function is impaired,
increase in M6G, which leads to an increase in effects
Name a morphine metabolite which is…
- active?
- non-active?
Active = M6G, morphine, normorphone
Inactive = M3G, codeine, norcodeine
Pharmacology of M6G
Active metabolite
Potency depends on route of administration
Pharmacology of M3G
Why is M6G better than morphine?
Has better analgesic effect than morphine
Fewer side effects
- Decrease in resp. depression, nausea + anti-emetic use + sedation in the first 4 hours
Disadvantage of M6G
Expensive
Phase1: What morphine metabolites are metabolised by CYP450 2D6?
Codeine
Oxycodone
Hydrocodone
What morphine metabolites are metabolised by CYP450 34A?
Fentanyl
Methadone
What morphine metabolites are metabolised by UGT?
What does UGT stand for?
Morphine
Hydromorphine
Oxymorphone
How is morphine excreted?
Where are other morphine metabolites excreted?
Mostly renal
Glucuronide conjugates excreted in bile
Methadone excreted in faeces
Enzymes that mediate phase 1 + 2 metabolism are called…
What do these type of enzymes modify?
Polymorphic
Polymorphisms alter safety + efficacy of drugs
What is Cytochrome P450’s?
- Function
- Where does it take place
- How does genetic polymorphisms affect CYP450?
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
What are the effects of codeine + how does it come about?
What catalyses reaction of morphine to codeine?
Describe the allelic variant in CYP isoform
Describe CYP2D6 poor metaboliser
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
Describe CYP2D6 ultrarapid metaboliser
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
What do CYP2D6 single nucleotide polymorphisms influence?
Patient outcomes
What is the only tramadol metabolite with analgesic activity?
M1
What are the pharmacological effects of tramadol + its metabolites?
What influences ADRs of NSAIDs?
Liver metabolism via CYP2C9
What is an issue with patients with low CYP2C9?
They cannot metabolise celecoxib efffectively
Ths leads to increased blood level + ADR due to drug accummulation
How does OPRM1 + A118G allele affect patient?
Increase meds + decrease pain relief
What do formation of tramadol metabolites depend on?
CYP2D6 + CYP3A4
