Question 4

Classify the mechanisms of action of anti-convulsant drugs (30% marks). Outline the pharmacology of gabapentin (70% marks)

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College Answer

The first part of this question required candidates to correlate the mechanism of action of anti epileptic drugs with atleast one example under each section. These included GABA potentiation (Barbiturates/Tiaganbine), reduction in excitory transmission (including NMDA/AMPA antagonists) and modification of ionic conductances (sodium channel blockade-Phenytoin, Calcium channel blockadeLamotrigine, Gabapentin, activation of potassium channels- Retigabine). The second part of this question involved an overview of gabapentin pharmacology. Gabapentin is an amino acid analogue of GABA utilised in neuropathic pain and epilepsy. There a multiple proposed mechanisms of action including Ca+ antagonism, inhibited glutamate release and anatagonism and increased GABA concentrations.. Important pharmacokinetic properties included dose dependent absorption, minimal protein binding, no metabolism with renal clearance and requirement for dose reduction in renal failure. It has largely central neurological side effects with a rare but important association with steven johnson syndrome or toxic epidermal necrolysis.

Discussion

There is no accepted classification system for anticonvulsants like there is for antiarrhythmics,  but Hanada (2014) offers something that looks a little like this:

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

For gabapentin,

Name Gabapentin
Class Antiepileptic
Chemistry Structural analogue of GABA
Routes of administration Oral only
Absorption Variable oral bioavailability; 60% in small doses, 40% in large doses, mainly because it is absorbed by saturable facilitated transport (L-amino acid transporter)
Solubility pKa is around 10.7; modestly soluble in water (10%) but extremely fat soluble. Also a substrate for L-amino acid transporters in the CNS, which means that it is concentrated in the brain, by up to ten times the plasma concentration
Distribution VOD=0.8L/kg; not bound to any plasma proteins
Target receptor Voltage-hated calcium channels, which therefore decreases the release of excitatory neurotransmitters
Metabolism Not metabolised
Elimination Eliminated 100% unchanged in the urine
Time course of action Half-life is around 5-09 hours
Mechanism of action By inhibiting the voltage-gated calcium channels in the CNS, gabapentin reduces the release of excitatory neurotransmitters (mostly noradrenaline, dopamine and serotonin), and therefore decreases epileptogenesis.
Clinical effects Indicated for prevention of partial seizures, for restless leg syndrome, in neuropathic pain, for post-heppetic neuralgia, as a co-analgesic, and in alcohol withdrawal. Adverse effects are few, but do include Steven-Johnson syndrome, but more commonly just ataxia and somnolence.
Single best reference for further information McLean, 1995

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.

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.