Compare and contrast the pharmacology of valproic acid and carbamazepine
Both these agents are listed as “level B” in the syllabus pharmacopeia and as such a general
understanding of each class and relevant pharmacokinetics and pharmacodynamics was
expected. Most candidates had better knowledge of valproate than carbamazepine. Some
description of the toxicological features for intensive care practitioners was expected.
|Chemistry||Branched-chain fatty acid||Tricyclic|
|Routes of administration||Oral and IV||Oral only|
|Absorption||Almost 100% absorbed when given orally, and has almost 100% oral bioavailability due to minimal first pass metabolism||Oral absorption is very slow, peak dose may be achieved as late as 24 hours following administration, but overall the bioavailability is good: something like 85%|
|Solubility||pKa 4.8; slightly water-soluble (much more lipid soluble)||Reported pKa varies from 7 to 13; minimally water soluble (but hihgly lipid-soluble)|
|Distribution||VOD=0.2 L/kg, i.e. essentially confined to the extracellular compartment of the blood). Highly protein bound (90%)||VOD=0.7-1.4L/kg; 75-80% protein bound|
|Target receptor||Multiple molecular targets, particularly sodium channels, enzymes responsible for the catabolism of GABA, and NMDA receptors||Mainly voltage-gated sodium channels, which are stabilised in their inactive state by this drug|
|Metabolism||Hepatic metabolism: extensively metabolised by microsomal glucuronide conjugation, mitochondrial β-oxidation and cytochrome P450-dependent oxidation.||Hepatic metabolism; metabolised by CYP3A4 into carbamazepine-epoxide, which has similar activity to the parent drug. Carbamazepine also acts as a CYP3A4-inducer, which means that the dose needs to be increased with sustained treatment in order for the same level to be maintained.|
|Elimination||Minimal renal excretion||Minimum renal excretion; both the parent drug and the active metabolite undergo minimal renal excretion|
|Time course of action||Half-life is 9 to 18 hours||Half-life is up to 40 hours, but become shorter with prolonged courses of therapy|
|Mechanism of action||Multiple anticonvulsant mechanisms: sodium valproate increases the activity of GABA (mainly by inhibiting its catabolism) and stabilises neuronal membranes by its activity on sodium channels, as well as reducing the high-frequency firing of neurons by voltage-gated sodium, potassium, and calcium channel blockade.||By binding to voltage gated sodium channels and stabilising them in their inactive state, carbamazepine decreases the excitability of excitable tissues and prevents the generation and propagation of action potentials|
|Clinical effects||Especially effective for partial seizures and for discrete epileptogenic foci. Also indicated for bipolar disorder. Side effects include hepatoxicity, SIADH, thrombocytopenia, hyperammonaemia and aplastic anaemia.||Indicated for generalised tonic-clonic seizures. Acute toxicity resembes phenytoin in lower doses (ataxia, nystagmus), but progressively remembles TCA toxicity, with anticholinergic syndrome features and QRS prolongation due to sodium channel blockade|
|Single best reference for further information||Rahman & Nguyen, 2021||Thomson, 1987|
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