Q21

What is the mechanism of action of the non steroidal anti-inflammatory drugs (NSAIDs)?

  • NSAIDs serve to suppress inflammation chiefly by inhibiting prostaglandin synthesis
  • In so doing, they decrease the sensitivity of vessels to bradykinin and reverse the vasodilation of inflammation

Pass Criteria:

  • Inhibit COX, thus decrease prostaglandin synthesis – and in so doing the response to inflammation is modulated.

How does aspirin differ from other NSAIDs in its action on COX?

  • Cyclo-oxygenase (COX) is the key catalyst for arachidonic acid conversion to prostaglandins. NSAIDs inhibit COX, thus inhibiting this conversion.
  • Aspirin (original NSAID) irreversibly inhibits COX, whilst the newer NSAIDs (ibuprofen, diclofenac) reversibly inhibit COX.
  • 2 types of COX exist – COX 1 is expressed in most cells, and COX 2 is inducible, its expression varies depending on stimulus
  • Selective COX 2 inhibitors (celecoxib) do not affect platelet function at usual doses, whilst the other NSAIDs do inhibit platelet aggregation.

Pass Criteria:

  • Irreversible vs reversible

What are the adverse effects of NSAIDs?

  • GI effects
    • GI irritation
    • Ulcers
    • Abdominal pain
    • Nausea and vomiting
  • Bleeding
    • Secondary to platelet effects
  • Renal
    • Nephrotoxicity
    • Hyperkalaemia
  • Allergy
    • Rash
    • Pruritus
  • Cardiovascular

    • Selective COX 2 inhibitors – implicated in increased risk of cardiovascular thrombotic events
    • Fluid retention, oedema, hypertension
  • CNS
    • Headaches
    • Tinnitus
    • Dizziness
    • Stroke
  • Pulmonary
    • Asthma
  • Haematological
    • (rare)
    • Thrombocytopaenia
    • Neutropaenia
  • Hepatic
    • Abnormal LFTs

Pass Criteria:

  • 3 of 4 bold plus one other to pass – namely GI effects, bleeding and renal effects plus any one of the others

Q22

What is the mechanism of action of morphine?

  • Act on receptors: mu/delta/kappa
  • Reduce presynaptic neurotransmission (especially glutamate)
  • Inhibits post-synaptic neurons
  • Central (thalamic action)

Pass Criteria:

  • Mu + 1 other mechanism of action to pass

Why do opiates cause respiratory depression?

  • Inhibition of brainstem respiratory controls allowing less response to hypercapnoea

Pass Criteria:

  • Bold

How is morhpine metabolised?

  • Conjugated in liver
    • morphine-3-glucuronide = most
  • Small amount (10%)
    • morphine-6-glucuronide = increased analgesic potency
  • Renal excretion

Pass Criteria:

  • Bold

Q23

What is the mechanism of action of aspirin?

  • Irreversible non-selective cyclooxygenase inhibition (Cox 1 & 2) resulting in:
    • Platelets
      • Irreversible inhibition of COX 1 results in reduction in thromboxane A2 and inhibition of platelet aggregation for the life of the platelet (10 days)
    • Tissue
      • Inhibits prostaglandin synthesis (COX2)
      • Results in anti-inflammatory action, analgesic, and antipyretic effects

Pass Criteria:

  • Bold, need to mention platelet effect (COX1) AND tissue (COX2) anti-inflammatory or analgesic effect

Describe the pharmacokinetics of aspirin.

  • Rapidly absorbed from stomach and intestinte
  • Aspirin hydrolyzed to salicylic acid in plasma and blood
  • Peak plasma level within 1-2 hours
  • Serum half-life of aspirin 15 minutes
  • Low protein binding
  • Saturable metabolism with increasing doses (switches from first to zero order metabolism)
  • Urinary alkalinisation increases excretion of salicylate and it’s conjugates

Pass Criteria:

  • Bold plus 2

Outline the adverse effects of aspirin.

  • GI upset
  • Gastrointestinal bleeding from gastritis or peptic ulceration
  • Heptotoxicity
  • Hypersensitivity reactions (asthma, angioedema, rash), prolonged bleeding time from platelet inhibition

Pass Criteria:

  • Bold + 1 other

Q24

Describe the mechanism of action of fentanyl.

Synthetic opioid that acts on the u opioid receptor.

Pass Criteria:

  • Bold to pass.

Describe the pharmacokinetics of fentanyl.

  • High first pass metabolism – metbaolised by P450 CYP3A4 with no active metabolites
  • Duration of action is 1 – 2 hours
  • Transdermal, muscosal, and IM absorption are all good
  • May be given IV, IM, IN, SC, SL/buccal (with lozenge), transdermal patch, epidural

Pass Criteria:

  • Bold plus 2 routes to pass.

Describe its potency relative to morphine.

Fentanyl is 100 times more potent than morphine. 0.1 mg of fentanyl = 10 mg of morphine.

Pass Criteria:

  • Potency (in the range 100 – 200) to pass.

List the adverse effects of fentanyl.

  • Respiratory depression
  • Nausea
  • Vomiting
  • Dysphoria
  • Cough
  • Sedation
  • Constipation
  • Urinary retention
  • Itch
  • Urticaria
  • Chest wall and laryngeal rigidity

Pass Criteria:

  • Name 4 to pass.

Q25

Describe the mechanism of action of bupivacaine.

Amide local anaesthetic that blocks voltage-gated Na channels.

Pass Criteria:

  • Bold to pass.

Describe the pharmacokinetics of bupivacaine.

  • Metabolised by the liver
  • Distribution half-life of 28 minutes
  • Elimination half-life of 3.5 hours
  • Large Vd of 72 L, 95% protein bound, lipophilic
  • Duration of action of 4 to 8 hours (longer than lignocaine or ropivicaine)

Pass Criteria:

  • Bold to pass.

Give examples of its clinical use.

Use as a nerve block in low concentrations (0.25%) for:

  • Local infiltration
  • Digital ring block
  • Femoral block
  • Intercostal block
  • Intrapleural block
  • Epidural (post-operative)
  • Brachial plexus block
  • Sciatic nerve block
  • Intra-articular analgesia

Pass Criteria:

  • Name 2 to pass (will not accept IV regional anaesthesia).

List some of its toxic effects.

  • Sedation
  • Visual and auditory disturbance
  • Cardiac arrythmia
  • Hypotension/arrest
  • Seizure

Pass Criteria:

  • Bold to pass.

Q26

Describe the pharmacokinetics of paracetamol.

  • Rapid absorption
  • Bioavailability of 70 – 90%
  • Peak concentration after 30 – 60 minutes (slight ppb)
  • Partial metabolism by hepatic MEs to paracetamol glucoronide and sulphate (90%)
  • First order kinetics – half-life of 2 – 3 hours
  • <5% is excreted unchanged

Pass Criteria:

  • 4 points to pass.

What is its mechanism of action?

Selective COX-2 inhibitor.

Pass Criteria:

  • Bold to pass.

What is the mechanism of paracetamol toxicity?

  • Zero order kinetics
  • Paracetamol is conjugated with glucoronide and sulphate (by transferase enzymes) – this pathway becomes saturated in overdose
  • Paracetamol is then metabolised by the smaller CYP2E1 pathway to NAPQI – this is detoxified by glutathione, which becomes depleted, resulting in high levels of the toxic metabolite (NAPQI) 

Pass Criteria:

  • Bold and concept to pass.

Extra question: What are the clinical manifestations of toxicity?

  • Nausea
  • Vomiting
  • Abdominal pain
  • Liver failure
  • Renal failure (tubular necrosis)
  • HAGMA
  • Coma (in large doses)

Pass Criteria:

  • 4 to pass.

 


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