Antiepileptic Drugs (AEDs)

Dr. Barry Boland, PhD

Reading Resources:
• Rang, Dale and Ritter: Ch. 46 (9th Ed.)
•Nestler et al: Ch.21
 Epileptic Seizures

• Definition: Episodic high frequency discharges by a localised

group of neurons in the brain.
• Symptoms produced depend on brain areas affected:
* Motor cortex → Convulsions
* Hypothalamus → Peripheral autonomic effects
* Reticular formation (upper brainstem) → Loss of consciousness

• Seizure activity may or may not spread to other brain regions

• Treatment:
Epilepsy can be controlled but rarely cured by
medication
Drug treatment effective in ~ 70% of patients
Side-effects from chronic use (benefit-risk balance)
 Epilepsy
Incidence: Approx. 0.5% of the general population (1:200)
Primary Epilepsy: Idiopathic (cause unknown): Genetic ⇔ Environment

Secondary Epilepsy: Result of brain damage

Possible Causes of Epilepsy

 Forms of Epilepsy
1. Partial Seizures (Local, Focal)
• Discharge localised to one brain region and hemisphere
(i) Simple: Consciousness not affected (i) Motor (ii) Sensory
(ii) Complex: Consciousness affected e.g. Temporal lobe (hippocampus)

Normal EEG Partial Seizure EEG

Normal
a-rhythm:
9-13 spikes/sec
(Hertz, Hz)

Note: 30% of patients with partial seizures can sometimes experience generalised seizure
Partial → Secondarily Generalised Seizure
 Forms of Epilepsy
2. Generalised Seizures
Discharge involves both hemispheres & reticular system → Consciousness affected

(i) Absence / Petit mal seizures Absence / Petit mal

• Most common in children, staring spells
• 3 “spike and wave” discharges/sec
• Oscillating feedback between cortex & thalamus

(ii) Tonic-clonic / Grand mal seizures

Tonic-clonic / Grand mal
• Tonic phase (2): Muscle spasm, respiration stops,
bowel/bladder discharge
• Clonic phase (3): Release
• Physical signs: Violent jerking, unable to stand

Images from RDR Pharm, 9th Ed.

 Aetiology of Epilepsy
Complex: Genetic component e.g. V-gated and Ligand-gated ion channels in
neurons.
Altered Neurotransmission:
• Increased excitatory neurotransmission
• Decreased inhibitory neurotransmission
• Repeated discharge → Excitotoxicity → Long-term effects on brain

Excessive Glutamate: Local levels of glutamate elevated

Neurotrophins: Possible role for neurotrophin BDNF

• BDNF causes increased membrane excitability & synapse formation
(block?)

Animal models: Useful predictors of antiepileptic drug effect in humans.

Chemical: ICV Kainate injections (glutamate agonist)
Physical: Kindling: Repeated low intensity brain
stimulation (electrodes)
Surgical removal of damaged area: Resection
 Antiepileptic Drugs (AEDs)
Main Aims: Reduce electrical excitability of excitatory neurons (glutamate)
Increase inhibitory (GABA) neurotransmission
Main Mechanisms:
1. Use-dependent Na+ channel block
• Phenytoin, carbamazepine, lamotrigine, (valproate)

2. Ca2+ channel inhibition

• Ethosuximide, gabapentin, (phenytoin, valproate)
3. Increase GABA-mediated neural inhibition
Enhance GABAA activation: Phenobarbital, benzodiazepines
Inhibit GABA deaminase: Valproate, vigabatrin
Inhibit GABA re-uptake: Tiagabine
4. Inhibit glutaminergic transmission
• NMDA, AMPA, mGluR antagonists effective in animal models – needed
for normal neural function – adverse effects
 Other AED Approaches

• Carbonic Anhydrase Inhibitors

• Hormones
• Cannabidiol (CBD): Approved for Dravett’s syndrome
(mutation in voltage-gated sodium channel Na(V)1.1)
• Ketogenic Diet: High Fat, Adequate Protein
Low Carbohydrate
 AEDs: Na+ Channel Blockers

• Voltage-dependant Na+ channels

Exist in three states: Na+
(i) Resting
(ii) Open
(iii)
Inactivated
• Drug stabilises rec. in its inactivated state
Drug
• Drug action is use-dependant
• Preferentially inhibits neurons that fire
repetitively with high frequency
• Mainly affect neurons with high-
frequency discharge e.g. seizure
• Little interference with low-frequency Voltage-dependant
neurons in normal state Na+ channel
 AEDs: Na+ Channel Blockers
(i) Carbamazepine (CBZ)
Most widely-used antiepileptic
Chemically related to TCAs – tricyclic antidepressants
Use-dependent Na+ channel inhibitor

Metabolism:
• Epoxidation to CBZ-10,11-epoxide
→ Hydrolysis to CBZ-10,11-trans-dihydrodiol
• Strong inducer of P450 enzymes
→ Increases metabolism of phenytoin, warfarin, oral contraceptives and
more…
• Autoinducer of its own metabolism: Half-life of 30 hr for single dose,
decreasing to 15 hr on repeated dosing
Side Effects:
Neurological: Drowsiness, dizziness, ataxia, cognitive and motor disturbances
 AEDs: Na+ Channel Blockers

(ii) Oxcarbazepine O

• Pro-drug analogue of CBZ

N

• Monotherapy: Partial Seizures (Children > 4yrs) O NH2

• Adjunct Therapy: Partial Seizures (Adults)

• Less P450 induction than CBZ → Less drug interactions

- Interacts with oral contraceptives
- Does not interact with warfarin, cimetidine and erythromycin

Note: Both carbamazepine and oxcarbamazepine also act as GABA

receptor agonists and have been used for neuropathic pain and
schizophrenia.
 AEDs: Na+ Channel Blockers NH
O
(iii) Phenytoin O N
H

• Na+ and Ca2+ channel inhibitor

plasma concentration
• Introduced in 1938 Toxic range
• First-line treatment for partial & secondary + displacement
generalised seizures Therapeutic range

Pharmacokinetic Considerations:
• Highly bound to plasma albumin (80-90%) Normal
• Displaced by other drugs e.g. valproate time

Metabolism:
Non-linear elimination kinetics: 2
Saturated at higher dose → Increased half life (> 20 hr) Toxic range
3 1
Variations in plasma concentration for patients (1, 2, 3)

Plasma conc.
Therapeutic range
Drug Interactions: Common
• Phenytoin is both metabolised by and induces CYP450
enzyme expression + activity.
• Increased metabolism of CBZ, phenobarbital, valproate, Dose

etc.).
 AEDs: Na+ Channel Blockers

(iii) Phenytoin
Narrow therapeutic range (40-100 μM)

Side Effects:
• Plasma conc. > 100 μM: Vertigo, ataxia, headache
• Plasma conc. > 150 μM: Confusion, intellectual deterioration
• Hypersensitivity reactions (skin, liver)
• Gum hyperplasia
• Vitamin D deficiency
• Teratogenesis

Fosphenytoin (Prodrug): Safer, better tolerated, but expensive

 AEDs: Na+ Channel Blockers
(iv) Lamotrigine

• Triazine; structurally unrelated to other drugs in this group

• Also inhibits presynaptic depolarisation of glutaminergic

neurons ➙ Less glutamate release

• Minimal effect on metabolizing enzymes

• Effective & well-tolerated; usually combined with valproate

• Low CNS toxicity ➙ Preferred in elderly

• Non-teratogenic ➙ Can be used in pregnancy

 AEDs: Na+ Channel Blockers

(v) Zonisamide O
N
• Structurally related to sulfonamides
• Inhibit both Na+ & Ca2+ channels CH 2 SO 2NH 2

• Neuroprotective by free radical scavenging

• Metabolised by CYP450, then glucuronidation
- Non-inducer
- Inactive metabolite
• Half-life 60 hr; less when combined with phenytoin, CBZ, valproate.
• Useful where poor compliance
• Well tolerated; not prone to serious drug-drug interactions
 AEDs: Ca2+ Channel Inhibition

Ca2+ channels: L-, N- & T-type

Low threshold T-channels implicated in
periodic discharges of partial seizures
H2 H2
Ethosuximide H3C C C
O
• Inhibits T-type Ca channels
2+ H3C
NH
Ca2+
O
(Pre-synaptic and post-synaptic)
• Other effects:
Inhibits Na+/K+-ATPase
Inhibits GABA deaminase
• Side Effects
Nausea, anorexia, lethargy, dizziness
Sometimes hypersensitivity reactions
 AEDs: Ca2+ Channel Inhibition
COOH

COOH NH 2 COOH NH 2 NH 2

GABA Gabapentin Pregabalin

Gabapentin
• Structural analogue of GABA but not active at GABA receptors.
• Pre-synaptic L-type Ca2+ channel inhibitor:
Binds a2d-subunit of Ca2+ channels in cerebral neocortex, hippocampus & spinal
cord (so also useful in treating pain).
• ↓ Release of Glutamate + associated modulators / co-transmitters
• Increases GABA levels (Mild stimulation of glutamic acid decarboxylase (GAD))

• Prodrug pregabalin is more potent.

 AEDs: GABA synthesis/breakdown

Valproate H2 O
OH
 Increases GABA in the brain O C C C L-glutamate
CH C OH
 Stimulates glutamate decarboxylase
H2N H2
 Inhibits GABA deaminase
H2 H2 Glutamate
H3C C C
 Weak block of Na+ & Ca2+ channels H2 C COOH decarboxylase
H3C C C
 Side effects H2 CO2
H2 O
Hepatotoxicity, teratogenesis Valproic Acid C C Gamma-aminobutric acid
OH (GABA)
CH 2 C
H2N H2
Vigabatrin
 Increases GABA in the brain GABA
deaminase
 Irreversibly inhibits GABA
deaminase H2 O
C C
H2
 Side-Effects H
H 2C C C COOH CH C OH
CH C O H2
Depression H2 Succinate semialdehyde
NH 2
Psychotic disturbances Vigabatrin
 AEDs: GABA Reuptake Inhibition

Tiagabine
S S

• Lipophilic GABA analogue; penetrates BBB COOH

(rational drug design) N

• Irreversibly inhibits GABA-transporter 1 (GAT-1)

in neurons & glia
Prevents GABA re-uptake
Prolongs GABA effect at inhibitory synapses
• Adjunct therapy in partial epilepsy

• Side-Effects:
Dizziness, confusion
 AEDs: GABAA Receptor Response

Main Aim: Increase GABAA receptor response O

C
C2H5 C N
Phenobarbital C C
O N O
• Strong P450 inducer → Drug interactions
Phenobarbital
• Side-Effects
* Sedation, tolerance
* Hypersensitivity reactions (skin, liver)
* Overdose: severe respiratory & circulatory depression, coma

Benzodiazepines e.g. Diazepam, lorazepam, clonazepam

• Fast-acting; used i.v. in emergency (status epilepticus)
• Tolerance develops over longer-term
• Sedative
 AEDs: Glutamate Receptor Antagonists
Note: AEDs effective at Glutamate ion channel receptors

Felbamate
• NMDA Glutamate Receptor antagonist
Also weakly blocks Na+- & Ca+-channels

Topiramate
• AMPA Glutamate Receptor antagonist
• D-fructose analogue
• Also various other effects:
Na+ channel inhibition
Raises GABA levels
Weak carbonic anhydrase inhibitor
AEDs acting on Excitatory Synapses

Image From: Bialer M, White HS. Nat Rev Drug Discov. 2010
 AEDs acting on Inhibitory Synapses

Image From: Bialer M, White HS. Nat Rev Drug Discov. 2010

Note: Fenbamate and Topiramate act on both excitatory (inhibit) and inhibitory (activate) neurons!
 Overview of Antiepileptic Drugs

Image from: Löscher and Schmidt D. Nat Rev Neurol. 2012 Dec;8(12):661-2

Note: Pre-synaptic neuron in image represents different Glutamate and GABA producing neurons
 AEDs: Carbonic Anhydrase Inhibition

Acetazolamide:
Mechanism of action: Inhibits carbonic anhydrase → Increases carbonic acid
↓ Intracellular pH causes ↑ K+ ions to leave neurons

•Neurons become more negative → Hyperpolarised

• ↑ Seizure Threshold

Uses: Adjunct therapy when poor response to other drugs

•Effective for focal, tonic-clonic and absence seizures.

•Also used for menstrual-related seizures, certain episodic disorders and to enhance other
AEDs.

•Not used for children

 AEDs: Hormones and Lipids

Effect of Sex Hormones on Seizures

Progesterone Oestrogen
Anticonvulsant Proconvulsant
Increases GABAA conductance Reduces GABAA conductance
Reduces glutaminergic excitation NMDA agonist in hippocampus
Alters GAD & GABAA expression

Cannabidiol (CBD)
• Dravett’s Syndrome: Severe myoclonic epilepsy of infancy (SMEI)
• CBD is non-psychoactive component of cannabis plant
• Oil extracted from a plant high in CBD, low in THC: Charottle’s Web
• FDA Approved Clinical Trials:
https://clinicaltrials.gov/ct2/results?term=epilepsy&cond=%22Dravet+Syndrome%22
 AEDs: Clinical Use and Effectiveness

Partial Generalised

(i) Simple
Tonic-Clonic Absence
(ii) Complex

Valproate Ethosuximide
Phenytoin
Carbamazepine
Lamotrigine

• Na+-channel blockers better in partial seizures

• Ca2+-channel blockers better in generalised seizures
• Status Epilepticus: I.v. admin. of diazepam / phenobarbital / phenytoin