Pharmacology of anticonvulsant drugs

This chapter tries to address Section K2(iii) of the 2023 CICM Primary Syllabus, which expects the exam candidate to somehow "understand the pharmacology of anti-convulsant drugs". That's probably something of a tall order, as the scientific community still has no idea about how half of them work. The ones for which the mechanism of action is clear are usually brutally stupid general anaesthetics (like barbiturates and benzodiazepines) or sodium-channel-blocking local anaesthetics (like phenytoin), where the mechanism of antiepileptic action is clearly "put an end to all neuronal activity, including seizure activity". For the rest, the only thing we can be sure of is the pharmacokinetics and the clinical side effects, with minimal pharmacodynamic material available.

Phenytoin and levetiracetam together have the greatest representation  in past paper SAQs:

So, apart from the drug-specific comparison question, it is not inconceivable that one day the college could bring back a classification SAQ which 67% of the candidates would again probably fail. In fact they already have, in Question 4 from the second paper of 2023, but the classification section was only 30% of the marks.  preparation for that dark day, a classification system is offered here, based on Hanada (2014).

Mechanism/class Drug target Examples

Ion channel modulators:

reduce neuronal excitability by altering the resting membrane potential,  stabilising the channels involved in the conduction of action potentials, or inhibiting the intracellular calcium flux which triggers  excitatory neurotransmitter release.

 K+ channels
  • Retigabine (ezogabine)
Ca2+ channels
  • Ethosuximide
  • Gabapentin
  • Pregabalin
  • Paramethadione 
  • Zonisamide
Na+ channels
  • Phenytoin
  • Carbamazepine
  • Lacosamide
  • Lamotrigine
  • Rufinamide
  • Sodium valproate
  • Topiramate
GABA potentiators: Increased inhibitory neurotransmission by either directly affecting the GABA ligand-gated chloride channel, decreasing the reuptake of GABA from the synapse, or decreasing the breakdown of GABA. GABAA
  • Benzodiazepines
  • Barbiturates
  • Clobazam
  • Primidone
GABA reuptake transporter
  • Tiagabine
GABA catabolism
  • Vigabatrin
  • Sodium valproate
Presynaptic neurotransmitter release modulators: decrease the release of neurotransmitters SV2A
  • Levetiracetam
Postsynaptic inhibitors of neurotransmission: decrease the effect of released neurotransmitter ligands on their receptors AMPA 
  • Perampanel
  • Topiramate
NMDA
  • Ketamine
  • Sodium valproate
  • Magnesium
God only knows what effect  
  • Paraldehyde
  • Potassium bromide

Other potential classification systems abound. For example, on the Wikipedia page for anticonvulsants, the drugs are listed according to their chemistry, which is surely one way of doing it (you won't miss anything), but has the disadvantage of being difficult to remember and moreover tells you nothing about the drugs' clinical behaviour. 

From the perspective of the CICM trainee, a laborious exploration of these classification systems would not be essential. There are only two other drugs in common use which have been explored in previous exam questions (valproate and carbamazepine) and they do have some interesting pharmacological features worth discussing.

Sodium valproate

Sodium valproate (or specifically valproic acid, as the sodium does nothing) was discovered accidentally in the course of testing potential antiepileptic agents, when Pierre Eymard used it as a solvent for his test drugs in 1962. Chemically, valproic acid (2-n-propylpentanoic acid) is a simple branched-chain fatty acid, and there are several other such acids (substituted butyric, pentanoic and hexanoic acids) which all seem to have some anticonvulsant activity. Cutting top the chase, its most usual pharmacological properties are:

  • Very small VOD: according to Klotz & Antonin (, its volume of distribution is essentially limited to the extracellular water, particularly that of blood (i.e. 0.1-0.4 L/kg). Partly, this is because it is highly protein-bound to blood albumin (90%).
  • Highly protein bound: this feature becomes both harmful and helpful in overdose; on one hand there is more toxic drug in the circulation, but on the other this makes it easier to remove valproate by dialysis.
  • Almost exclusively metabolised by the liver: almost none of the unchanged drug can be reclaimed from the urine, i.e. this drug does not rely on the kidneys for clearance, and can be given to chronic renal failure patients with little concern.
  • Narrow therapeutic index: the levels need to be in a range of 50-100 mcg/mL, anything higher than that will result in some degree of toxicity. For this reason, monitoring of drug levels is usually required.
  • Hyperammonaemia in overdose results from interference with urea cycle enzymes and can give rise to truly preposterous ammonia levels, coma, cerebral oedema, and death. Valproate overdose is very popular with CICM Fellowship examiners, and has been the subject of at least two questions from the Second Part exam, but has never been explored in the First Part.

Carbamazepine

Carbamazepine is basically a tricyclic antidepressant with antiepileptic properties (and no antidepressant effect). Its most memorable features include:

  • Minimal water solubility: in fact so difficult was it to create an injectable formulation that early papers on this drug (eg. Albani, 1995) were not able to report the bioavailability because no parenteral option was available to act as the denominator.
  •  Sodium channel blocker: Carbamazepine appears to bind to voltage-gated sodium channels in their inactive state, stabilising this state and keeping the channels closed. This is sufficiently similar to what phenytoin does for the two drugs to be classed together, but on the other hand Kuo et al (1997) were able to find enough differences in their receptor-binding kinetics to suggest that carbamazepine might be more useful for one sort of seizures, whereas phenytoin might be more useful for another. 
  • It is self-enzyme-inducing. Carbamazepine is metabolised exclusively in the liver, by CYP3A4 - for which it is both a substrate and an activator. With sustained use, increased CYP3A4 activity results in the need for higher and higher doses of the drug, and a shorter and shorter interval between doses, such that chronic users end up having to take it twice a day (i.e the half-life decreases from 40 to about 8 hours)
  • It is a pro-drug. Carbamazepine is metabolised into carbamazepine-epoxide, which has about the same activity as the parent drug.
  • In overdose, it does classical tricyclic things, with sodium channel blocking QRS prolongation and anticholinergic features. Helpfully, some of the usual point-of-care urine drug screen tests will also often be positive for tricyclics. The bowel, paralysed by the anticholinergic effects, will hopefully store a large bezoar of undissolved tablets, which will be susceptible to whole bowel lavage or doses of charcoal.

Gabapentin

This thing (1-aminomethy1 cyclohexaneacetic acid) is basically a structural analogue of GABA, but it does nothing GABA-like, and its mechanism of action seems to have nothing to do with GABA.

  • Absorption is weird and dose-dependent because transport across the gut wall is facilitated by a saturable L-amino acid transporter, so oral bioavailability is approximately 60% after a 300-mg dose and 40% after a 600-mg dose. This was reported by McLean (1995) but not subsequently, and StatPearls seem to believe it has an oral bioavailability of 90% irrespective of dose.
  • It is actively transported into the brain by this exact same active transport system, which causes it to become concentrated there by up to ten times in plasma concentration (Taylor et al, 1998)
  • Mechanism of action has weirdly little to do with GABA, as the drug target mainly seems to be calcium channels. By affecting these, the release of excitatory neurotransmitters is decreased. There are also several other possible mechanisms
  • It is not metabolisd, and binds no proteins. Gabapentin does not seem interested in interacting with anything in the body, and is eliminated in its unchanged form.

References

Hanada, Takahisa. "The AMPA receptor as a therapeutic target in epilepsy: preclinical and clinical evidence." Journal of Receptor, Ligand and Channel Research 7 (2014): 39-50.

Löscher, Wolfgang. "Basic pharmacology of valproate." CNS drugs 16.10 (2002): 669-694.

Chapman, Astrid G., Brian S. Meldrum, and Etienne Mendes. "Acute anticonvulsant activity of structural analogues of valproic acid and changes in brain GABA and aspartate content." Life sciences 32.17 (1983): 2023-2031.

Perucca, Emilio. "Pharmacological and therapeutic properties of valproate." CNS drugs 16.10 (2002): 695-714.

Zaccara, Gaetano, Andrea Messori, and Flavio Moroni. "Clinical pharmacokinetics of valproic acid—1988.Clinical pharmacokinetics 15.6 (1988): 367-389.

Albani, F., R. Riva, and A. Baruzzi. "Carbamazepine clinical pharmacology: a review." Pharmacopsychiatry 28.06 (1995): 235-244.

Tomson, Torbjörn. "Clinical pharmacokinetics of carbamazepine." Cephalalgia 7.4 (1987): 219-223.

Kuo, Chung-Chin, et al. "Carbamazepine inhibition of neuronal Na+ currents: quantitative distinction from phenytoin and possible therapeutic implications." Molecular pharmacology 51.6 (1997): 1077-1083.

McLean, Michael J. "Gabapentin.Epilepsia 36 (1995): S73-S86.

Taylor, Charles P., et al. "A summary of mechanistic hypotheses of gabapentin pharmacology." Epilepsy research 29.3 (1998): 233-249.