K2iii / 17A17 / 14B02 : Compare and contrast the pharmacology of phenytoin and levetiracetam

17A17: Exam Report

Compare and contrast the pharmacology of phenytoin and levetiracetam.

35% of candidates passed this question.

A table was useful to answer this question. Comparing and contrasting the pharmacology was required to score well rather than listing various aspects of pharmacology. The key properties of the drugs which demonstrate their importance to ICU was required.

14B02: Exam Report

Describe the pharmacology of Phenytoin (75% of marks) and Levetiracetam (25% of marks).

35% of candidates passed this question.

The knowledge of phenytoin was often superficial and many answers were too brief and didn’t adequately cover the required material. The knowledge around levetiracetam seemed very limited with many candidates guessing (incorrectly) what the pharmacokinetics might be. Most answers demonstrated a structured approach to this type of question.

Better answers were able to distil major issues such as the narrow therapeutic window for phenytoin or the potential clinical impact of differing ordered kinetics or altered metabolism. Candidates are reminded to read each question carefully; levetiracetam should not be confused with levosimendin.

K2iii / 17A17 / 14B02: Compare and contrast the pharmacology of phenytoin and levetiracetam

Drug

Pheytoin

Levetiracetam

Use

Pheytoin

  1. Tx seizures
  2. Anti-arrhythmias
  3. Trigeminal neuralgia tx

Levetiracetam

Tx epilepsy

Owing to is MoA, Phenytoin can be used as an anti-arrythmic and for neuropathic pain.  Levetiracetam used solely for epilepsy

Route

Pheytoin

PO/IV

PO = slow absorption & unpredictable

Levetiracetam

PO/IV

Equal dosing for PO & IV preparations of Levetiracetam therefore easier to prescribe

Phenytoin owing to long t1/2 requires loading to reach SS

Onset

Pheytoin

IV immediate → peaks 1hr

PO unknown (variable) → Peaks 1 – 3hrs

Levetiracetam

1hr → reaches SS after 2days of BD dosing

MoA

Pheytoin

Binds & stabilises INACTIVE Na+ channels to prevent further generation of AP

Potentiates GABA

↓Ca2+ influx → ∴ ↓excitability

 Strong affinity for CNS binding

Levetiracetam

Binds synaptic vessel protein SV2A

Inhibits Ca2+ channel

↓NT release

∴impedes impulse conduction

PD

Pheytoin

CNS – stabilises membrane → prevents the spread of seizure

 CVS

  • Blocks fast Na+ channel
  • ↓slope of Ph 0
  • ↓amplitude of AP
  • ∴ ↓ conduction velocity (-ve inotropy)
  • GI – ↓BGL, deranged LFTs

Levetiracetam

CNS – ↓seizures, impedes impulse conduction

Pheytoin – owing to MoA on Na channels has a broader spectrum of PD

PK

Pheytoin

A

Slow but good

90% OBA

D

90% PPB high!

Low VD 0.6L/kg

M

Liver CYP450

Hydroxylation

E

Metabolites in urine

t ½ B 9 – 24hrs 

Levetiracetam

A

Excellent

100% OBA

Delayed by food

D

<10% PPB

VD 0.5L/kg

M

Enzymatic hydrolysis of acetamide group

No active metabolite

No CYP450 metabolism

E

Leve doesn’t compete w other drugs for binding, whereas this is a big problem for phenytoin

Metabolism of Phenytoin =saturabtable;

First order kinetics then ∆ Zero order kinetics

Levetiracetam is more favourable for metabolism as largely excreted unchanged.  However, L requires dose adjustment with renal impairment. 

P requires dose adjustment for [albumin] and liver fn

Adverse Effects

Pheytoin

*** Narrow therapeutic range: 10 = 20mcg/mL**

  • Large genetic variability
  • Ther & Toxic dose very close
  • Requires monitoring

Levetiracetam

Fatigue

Weakness

Irritability

(all worse in first month)

L has a much more favourable drug side effect profile and less drug interactions cf P