Q2i / 17B12 / 15B20: Compare and contrast aspirin and clopidogrel

17B12: Exam Report

Compare and contrast aspirin and clopidogrel.

68% of candidates passed this question.

Both of these commonly used agents are level A in the syllabus and thus a high level of detail was expected. Marks were awarded in the following areas – pharmaceutics, mechanism of action, pharmacokinetics (PK) and side effects. For the PK parameters a general description rather than exact values was sufficient (i.e. ‘high protein binding’ rather than ‘98% protein bound’). It was expected that candidates would mention the fact that clopidogrel is a pro-drug and the factors which influence its conversion to the active form. Additional marks were awarded for well-structured answers which attempted a comparison between the two drugs (helped by the use of a table).

15B20: Exam Report

Compare and contrast the pharmacology of aspirin and clopidogrel

46% of candidates passed this question.

Both agents are principally used as anti-platelet agents. Aspirin however has wider clinical applications. Mechanism of action of both agents involves irreversible inhibitions of enzymes and/or receptors. The inability of platelets to regenerate these means that physiological effects can not be fully explained by pharmacodynamics or pharmacokinetics alone. Candidates who followed a traditional template for pharmacology answers scored better, providing answers that covered the breath of the topic.

Q2I / 17B12 / 15B20: Compare and contrast aspirin and clopidogrel

Chemical

Salicylate

A thienopyridine

Use

Salicylate

  1. Pain
  2. IHD
  3. Prevent TIA, stroke, DVT
  4. Fever

A thienopyridine

↓atherothrombotic events in patients with atherosclerotic disease

Presentation

Salicylate

Tablets 75 – 600mg

A thienopyridine

Tablets

Dose

Salicylate

75mg – 100mg OD (antiplatelet)

300 – 400mg Q4h (analgesia) MAX 4g/day

A thienopyridine

Prophylactic: 75mg PO

ACS + aspirin: 300mg PO

Onset

Salicylate

30 mins

A thienopyridine

2hrs

DoA

Salicylate

3 – 6hrs

NB: aspirin is a prodrug → converted to SALICYLATE (active form) in stomach

A thienopyridine

Platelet aggregation returns to normal 5 days after Tx withdrawal → requires new platelet synthesis

MoA

Salicylate

  • Irreversible inhibition of COX enzyme
  • ↓synthesis PG, prostacyclin & thromboxane
  • Inhibits COX1 > COX2
  • ∴ more affinity for platelet COX
    • Antiplatelet activity
    • Antipyretic
    • Analgesia 

A thienopyridine

  • Inhibits binding of ADP to P2Y12 receptor
  • ∴ prevents ADP-mediated activation of GP IIb/IIIa
    Irreversible

PD

Salicylate

CNS

  • Analgesia
  • Antipyretic

CVS

  • Antiplatelet
  • ↑ blood loss post op
  • Exac HF

RESP – bronchospasm in sensitive individuals

GI – ↑risk GI ulcer & bleeding

GU

  • Proteinuria
  • Haematuria
  • Renal impairment

A thienopyridine

CVS: platelet aggregation inhibition

PK

Salicylate

A

  • Complete because weak acid & UNIONISED in stomach/GB
  • But 70% OBA 2° 1st pass metabolism

D

  • PPB 80%
  • VD15L/kg (small)
  • Hydrolysed rapidly to salicylate by esterases

M

  • 50% salicylic acid metabolised to salicyruvate in liver → SATURATABLE → ZERO ORDER KINETICS
  • 20% metabolised by conjugate to glucuronide → also SATURABLE
  • Due to 2 saturable metabolism pathways, NON LINEAR KINETICS

i.e. half life varies with dose

E

  • Salicylate metabolites in urine
  • 10% unchanged → via glom filtration, active prox secretion
  • Urinary excretion is pH dependent ↑pH 5 → 8
  • Traps ionised salicylate from 3% → 80%!

A thienopyridine

A

OBA 50%

D

98% PPB

M

85% hepatic esterases → INACTIVE

15% by Cytochrome P450 → ACTIVE DRUG

E

Metabolites excreted in urine & faeces

Adverse Effects

Salicylate

  • Crosses placenta! + gets trapped!
  • GI ulcer/lung
  • Hepatic impairment
  • Renal papillary necrosis
  • Bronchospasm
  • Aplastic AN
  • OD = mortality 2%
    • Alkalisation of urine ↑excretion of free salicylic acid
    • Removed by HD
  Contraindicated in spinal/epidural
  • Assoc w ↑periop blood loss → requires cessation
  • Last for lifespan of platelet = 10 days
    ∴ stop 5 – 10 days pre-op

A thienopyridine

  • ↑risk GI bleeding
  • TTP

INTERACTIONS

  • + any anti-clotting drug = HUGE risk of bleeding
  • CYP2C19 poor metabolisers → ↓response with Clopidogrel

AVOID OMEPRAZOLE because metabolised by CYP2C19