25B19: Exam Report

Outline the following pharmacology of phenytoin:

  1. Dosage (15% of marks)
  2. Mechanism of action (15% of marks).
  3. Adverse effects (30% of marks)
  4. Pharmacological considerations relevant to safe and effective use (40% of marks)

21% of candidates passed this question.

The information asked for in this question is the information directly relating to its safe use in intensive care. Phenytoin is an exemplar drug for multiple essential pharmacological principles that apply to the safe prescription of drugs in critical illness.

The best answers succinctly demonstrated understanding of these concepts within the structure provided. In general, in the first part exam including in this question, more serious, important or more common side effects or pharmacological considerations ie.

Cardiac S/E or the contribution of zero vs first order pharmacokinetics to the narrow therapeutic window, would be weighted higher in the mark distribution within their subsections.

K2iii / 25B19: Outline the following pharmacology of phenytoin

a) Dosage

  • PO 200-600mg/day
  • IV loading 15-20mg/kg + maintenance 100mg TDS

b) mechanism of action

  • Anticonvulsant
  • Blocks voltage-gated sodium channels to stabilise in its inactivated state → ↓ AP generation

c) Adverse Effects

CNS

Ataxia, nystagmus, tremor, slurred speech, confusion

→ Signs of acute toxicity

CVS

Bradycardia, hypotension, heart block

→ Cardiac monitoring during IV loading, avoid in patients with pre-existing HB

Haem

Aplastic anaemia, agranulocytosis

→ Avoid if bone marrow suppression risk

Other

Peripheral neuropathy, drug-induced lupus, hepatitis, gum hypertrophy (chronic use)

Osteomalacia, vitamin D deficiency

Hypersensitivity rash, SJS / TENS, DRESS syndrome

d) Pharmacological considerations relevant to safe and effective use

PC

Pharmacological Points

IV formulation has propylene glycerol + ethanol as solvent

Highly alkaline pH 12

Considerations

  • Phenobarbital
  • Topiramate

PK

A

Pharmacological Points

  • Oral bioavailability 90%
  • Food affects oral absorption

Considerations

  • Pause enteral feeds 1-2hrs prior to administration

D

Pharmacological Points

  • High PB 90% to albumin

Considerations

  • ↑ free fraction in hypoalbuminaemia

M / E

Pharmacological Points

  • Metabolised via hepatic CYP450 by hydroxylation to inactive metabolites → saturable

  • Enterohepatic recirculation

Considerations

  • First-order to zero-order kinetics once enzymes are saturated
  • ↓ dose in hepatic failure

T 1/2

Pharmacological Points

  • Long – 22hrs

Considerations

  • Loading required to reach steady state faster

PD

Pharmacological Points

CYP450 inducer

Considerations

  • ↑ metabolism of some drugs → ↓ drug levels (eg. NOAC, warfarin)

Pharmacological Points

Narrow therapeutic window 10-20µg / mL

Considerations

  • Due to saturable PK
  • Use free drug levels for monitoring as toxicity can occur with normal total level due to hypoalbuminaemia

Pharmacological Points

Teratogenic (Category D) → congenital malformations, Fetal Hydantoin Syndrome

Considerations

  • Adequate folic acid supplementation
  • Specialist advice

Author: Bonnie Lau