19th May 2025

Anti-epileptic drugs

Antiepileptic drugs (AEDs) form a group of drugs that encompasses a wide range of medications which fall into several discrete classes of drugs. The drug classes have differing pharmacological properties and mechanisms of action, and hence differing side effect profiles. Here, some of the commonest mechanisms of action of AEDs will be reviewed, then some of the more commonly used AEDs and their side effect profiles will be discussed individually.

Mechanisms of action

AEDs may be classified on the basis of their mechanism, although it should be noted that several drugs exert their effects via multiple mechanisms; furthermore, for some specific drugs the mechanism is unknown.

Drugs which block sodium currents

The most common mechanism via which AEDs act is via voltage-gated sodium-channel inhibition. Voltage-gated sodium channels contribute to the generation and propagation of action potentials in neurons. Sodium channels in the brain have roles within both inhibitory interneurons and excitatory neurons. When neurons are hyperpolarised, voltage-gated sodium channels are closed (resting); during depolarisation they open; and they close again and become inactivated in the period after depolarisation. The action of most AEDs which influence voltage-gated sodium channels results from binding when the channel is in the inactivated state, thus prolonging the period of inactivity and delaying the transition from the inactivated state to the resting state. Prolongation of this inactivated state inhibits high-frequency repetitive firing of action potentials. This inhibition of repetitive firing acts to inhibit seizure-related neuron firing.

Examples:

Phenytoin
Carbamazepine
Lamotrigine
Oxcarbazepine
Lacosamide
Topiramate

Drugs which block calcium currents

AEDs may also act to inhibit voltage-gated calcium channels. There are two ways in which this effect may inhibit seizure activity; first, through inhibition of T-type calcium channels, which are normally involved in the generation of oscillatory neuronal activity in thalamo-cortical pathways, and are of particular benefit in the treatment of absence seizures; second, via inhibition of neuronal N- and P/Q type calcium channels, thus reducing the release of glutamate into the synapse.

Examples:

Ethosuximide
Valproate
Gabapentin
Pregabalin

Drugs which enhance GABA-ergic chloride currents

GABA is an inhibitory neurotransmitter acting on GABAA and GABAB receptors. GABAA receptors mediate neuronal excitability through tonic and phasic inhibition. Phasic inhibition refers to the modulation of transient, rapidly degrading currents, while modulation of longer-lasting, slowly degrading currents is known as tonic inhibition. GABAergic AEDs act by enhancing inhibitory activity; this is through a variety of effects, including allosteric binding to GABAA which increasing the affinity of GABA binding, increasing the concentration of synaptic GABA, and prolonging the duration and/or increasing the frequency of chloride channel activation that occurs as a result of GABAA activation.

Examples:

Valproate
Benzodiazepines
Vigabatrin
Topiramate

Drugs which block glutamatergic currents

Glutamate is an excitatory neurotransmitter. Glutamate binds to postsynaptic receptors and hence increase cationic conductance and promote neuronal depolarisation. Although few AEDs act exclusively at glutamate receptors, several exert some of their action via this pathway by blocking receptor binding and blocking excitatory glutamatergic activity. Several AEDs also exert an inhibitory effect on neuronal firing through inhibition of presynaptic glutamate release. This effect is a result of blockade of sodium and calcium channels.

Examples:

Topiramate
Levetiracetam
Phenobarbital

Specific AEDs and their associated adverse effects

Benzodiazepines

Sedation
Withdrawal seizures with abrupt cessation
Ataxia
Dysarthria
Depressed mood
Behavioural changes / aggression

Carbamazepine

Bone marrow suppression
Toxic epidermal necrolysis (TEN) or Stevens-Johson Syndrome (SJS)
Hyponatraemia
Rash
Fluid retention
Nausea and vomiting
Diarrhoea

Phenytoin / fosphenytoin

Gingival hyperplasia
Rash – rarely SJS / TEN
Increase in body hair
Reduced bone mineral density
Folate deficiency
Confusion
Diplopia
Ataxia
Peripheral neuropathy
Sexual dysfunction

Valproate

Nausea and vomiting
Ecchymosis
Weight gain
Metabolic syndrome
Thrombocytopenia
Subclinical hypothyroidism
Polycystic ovarian syndrome
Teratogenic effects
Acute liver injury
Acute pancreatitis
Hyperammonaemic encephalopathy

Ethosuximide

Sleep disturbance
Sedation
Nausea and vomiting

Gabapentin

Sedation
Ataxia
Weight gain
Risk of respiratory depression in overdose and concurrent opioid administration

Pregabalin

Sedation
Ataxia
Dizziness
Increased body habitus
Fluid retention
Diplopia
Weakness
Tremor
Mood disturbance

Lacosamide

PR interval prolongation on electrocardiogram (ECG) – therefore caution advised in patients with pre-existing conduction disease and other medications which may enhance this effect
Nausea and vomiting
Ataxia
Vertigo

Topiramate

Cognitive impairment
Sedation
Fatigue
Weight loss
Mood disturbance
Metabolic acidosis
Renal calculi
Reduced bone mineral density
Ophthalmological effects including acute angle closure glaucoma and acute myopia