Analgelsics: Non opioids Flashcards
How is paracetamol metabolised?
Liver, mainly into sulfate and glucuronide conjugates.
Small amount is metabolised by CYP2E1 into a highly reactive intermediate called N-acetyl-P-benzoquinone imine (NAQPI), which is conjugated by glutathione to become inactivated
What are the side effects of paracetamol?
Paracetamol overdose is one of the most common causes of acute liver failure
With toxic doses of paracetamol, sulfate and glucuronide pathways of metabolism are saturated 🡪 more paracetamol is metabolised by CYP2E1 into NAQPI 🡪 when glutathione is depleted (level falls by 70-80% after being consumed by NAQPI) 🡪 NAQPI reacts with hepatocytes to cause irreversible oxidative damage 🡪 hepatocellular centrilobular necrosis/
What is the antidote to paracetamol overdose?
Antidote: N-acetylcysteine (NAC)
Administer based on prediction of hepatotoxicity (time from ingestion and serum paracetamol concentration are used together with a modified Rumack-Matthew nomogram to determine risk of hepatotoxicity and guide the administration of NAC)
What is the MOA of NSAIDs?
Inhibitor of prostaglandin synthesis, through their effect on COX
2 COX isoforms (COX-1, COX-2)
- COX-1 is expressed under physiological conditions, COX-2 is induced by inflammation
- Most of the adverse effects of NSAIDs are based on its inhibition of the physiological prostaglandins produced by COX-1
What are the side effects of NSAIDs?
Gastrointestinal: dyspepsia, peptic ulcer disease (PUD), BGIT
- Inhibition of COX-1 🡪 decreased gastric prostaglandins, which are gastroprotective 🡪 BGIT, perforation
Haematological: increased bleeding tendencies
- COX-1 inhibition 🡪 loss of TXA2 🡪 platelet dysfunction (qualitative defect)
Renal: renal impairment, renal failure
Cardiovascular: major adverse cardiovascular events (MACE), AMI, CVA
- Risk of thrombotic events are increased with long-term NSAID use, particularly the COX-2 inhibitors
Aspirin-exacerbated respiratory disease (AERD), asthma exacerbation due to shunting of arachidonic acid to leukotriene pathway
What are the risk factors for NSAID induced gastropathy?
- Duration and dose of NSAID (hence prescribe lowest dose for shortest possible duration)
Increasing age - Previous NSAID-induced gastropathy
- Previous PUD
- Concomitant use of corticosteroids
- Concomitant use of antiplatelets or anticoagulants
What are the risk factors for NSAID induced nephropathy?
- Chronic kidney disease (CKD)
- Hypovolaemia (e.g. bleeding, dehydration, aggressive diuresis)
- Decreased effective circulating volume (e.g. congestive heart failure (CHF), nephrotic syndrome, liver cirrhosis)
- Concomitant use of other nephrotoxic agents, e.g. diuretics, ACEI, ARB
- Increasing age
What are the MOA of gabapentinoids, e.g. gabapentin, pregabalin?
Works on α2δ subunit of voltage-gated Ca2+ channels 🡪 decreased Ca2+ influx 🡪 decreased release of excitatory neurotransmitters (e.g. glutamate, noradrenaline, substance P)
What are the uses of gabapentinoids, e.g. gabapentin, pregabalin?
- Antiepileptic drug (AED)
- Can be used to treat neuropathic pain
- Increasingly being used in acute pain for opioid sparing effect
what are the side effects of gabapentinoids?
Sedation, dizziness, weight gain, peripheral oedema
What is the MOA of TCAs?
- Inhibits reuptake of serotonin, noradrenaline
- Also blocks cholinergic, adrenergic, histamine, and Na+ channels
What are the side effects of TCAs?
Anticholinergic, e.g. dry mouth, dry eyes, urinary retention, constipation, impaired vision, sedation
Use with caution in pre-existing glaucoma and CVS disease
What is the MOA of ketamine?
NMDA antagonist
What are the uses of ketamine?
Anaesthetic agent (main use, at higher doses)
Analgesic (secondary use, at lower doses), to decrease or prevent central sensitisation
what are the side effects of ketamine?
CNS: hallucinations, sedation, impaired memory
CVS: sympathetic stimulation (dose-dependent)
