L2 Clinical Pharmacology Anti-Epileptic Drugs

Overview

This lecture covers Epilepsy as a disorder of neuronal excitation/inhibition balance, how seizures are classified and diagnosed, the epidemiology and prognosis of the condition, the general treatment strategy (stepwise monotherapy), the three broad mechanistic classes anti-epileptic drugs work through, and the specific mechanisms, indications, side effects, and interactions of the four core drugs (levetiracetam, phenytoin, valproate, gabapentin), before finishing with benzodiazepines for acute seizure management and the underlying GABAergic inhibitory circuitry that both AEDs and benzodiazepines act on.

Epilepsy: Definition, Pathophysiology, and Diagnosis

Epilepsy is a family of neurological disorders characterised by seizures (though seizures also occur outside epilepsy). An epileptic seizure is the clinical manifestation of an abnormal, paroxysmal, synchronous pattern of brain activity.

• Core pathophysiology: an imbalance between inhibition and excitation, with too much excitatory brain activity driving the seizure.
• Both extremes of inhibition are pathological: a spectrum runs from more inhibition (coma, death) through a “good balance” zone (sleep, arousal) to less inhibition (epilepsy, death) — illustrating that normal brain function sits in a narrow balanced range.
• In the normal brain, excitation (glutamate) and inhibition (GABA) are balanced (illustrated as a level seesaw); in the epileptic brain, excitation outweighs inhibition (seesaw tips toward excitation).
• 1/3 of people with epilepsy will not respond to medication and have uncontrolled seizures.

Diagnostic criteria (any one of):

1. At least 2 unprovoked seizures occurring more than 24 hours apart, OR
2. 1 unprovoked seizure with a probability of further unprovoked seizures similar to the recurrence risk after 2 unprovoked seizures (i.e. at least 60%) over the next 10 years, OR
3. A diagnosis of an epilepsy syndrome.

Seizure types are classified as focal, generalised, or unknown.

Neuronal Excitation and Inhibition: the Underlying Mechanisms

• Activation of AMPA (glutamate) receptors causes an influx of Na+, making the membrane potential more positive → an action potential initiates.
• Activation of GABAA receptors causes an influx of Cl-, making the membrane potential more negative → inhibition of the action potential.

	GABAA	GABAB
Receptor type	Cl- ion channel	Gi-coupled GPCR
Activation time	Milliseconds	~100 milliseconds
Effect	Inhibition of action potential	Inhibition of action potential

Glutamate handling:

• Glutamine is converted to glutamate by the enzyme glutaminase (reaction: glutamine + H2O + ATP → glutamate + NH4+ + ADP + PO4^3- via glutaminase).
• In the synapse: glutamine is transported from astrocytes into the nerve terminal, converted to glutamate by glutaminase, packaged into vesicles via VGLUT, and released into the synaptic cleft to act on postsynaptic glutamate receptors.
• Glutamate is cleared from the cleft by transporters (EAAT3 on the neuron; EAAT1/EAAT2 on astrocytes), taken up by astrocytes, and converted back to glutamine by glutamine synthetase — completing the glutamate–glutamine cycle.

Glutamate excitotoxicity

Glutamate can cause lesions in any brain area when injected, and cultured neurons die within hours of exposure to high glutamate levels. Domoic acid, a toxic amino acid found in red algae, has high specificity for glutamate ion channels (AMPA and kainate receptors) and can bioaccumulate in shellfish; a documented poisoning of ~100 people in Canada from blue mussels caused mental confusion and short-term memory loss. Domoic acid poisoning in seagulls is believed to have inspired Alfred Hitchcock’s film The Birds.

Causes of Neuronal Hyperactivity and Ideal Drug Targets

• Increased synaptic excitation
• Reduced synaptic inhibition
• Increased intrinsic excitability
• Some combination of the above

Anti-epileptic drugs would ideally reduce hyperactivity without affecting normal neuronal activity.

Three main mechanisms by which anti-epileptic drugs act:

1. Inhibiting electrical excitability of cell membranes via blockade of use-dependent sodium channels.
2. Inhibiting T-type calcium channels (relevant to absence seizures) and presynaptic calcium channels.
3. Increasing GABA-mediated inhibition.

• Carbamazepine, valproate, and phenytoin are believed to inhibit repetitive firing by increasing the number of Na+ channels in the inactivated state.
• Ethosuximide and valproate inhibit T-type Ca2+ channels.
• Levetiracetam’s mechanism is currently unknown, but it inhibits presynaptic Ca2+ influx, reducing neurotransmitter release.
• Vigabatrin inhibits GABA transaminase (the enzyme that breaks down GABA), increasing GABA in the synaptic cleft.
• Tiagabine inhibits GABA reuptake, increasing GABA in the synaptic cleft.
• Benzodiazepines act as positive allosteric modulators at GABAA receptors.

Seizure Classification and Types

By onset:

• Focal seizures: ictal activity from a distinct brain region; can include loss of consciousness; can progress to a generalised seizure.
  • Focal aware seizures (FAS): no loss of consciousness.
  • Focal impaired awareness seizures (FIAS): impaired awareness at some point.
  • Focal to bilateral tonic-clonic: starts as FAS or FIAS and may progress to unilateral motor movements or bilateral tonic-clonic movements.
• Generalised seizures: ictal activity originating in both hemispheres; can include muscle jerking (tonic-clonic) or reduced muscle tone.
  • Generalised tonic-clonic seizures (GTCS).
  • Absence seizures: brief loss of consciousness.
• Unknown: clinical and EEG data cannot determine whether focal or generalised.

The ILAE-style classification diagram further subdivides focal onset into aware vs impaired awareness, and motor vs non-motor onset (with possible progression to focal-to-bilateral tonic-clonic); generalised onset is subdivided into motor (tonic-clonic, other motor) and non-motor (absence seizures). Footnote definitions given: “aware” = awareness during the seizure with intact consciousness of self and environment; “motor” = movement or motion; “unclassified” = seizures not fitting other categories or with insufficient information to classify.

By clinical presentation:

• Tonic-clonic (sometimes “generalised tonic-clonic,” GTC): muscle tightening followed by convulsions. Two phases are shown: a rigid/arched “tonic phase,” followed by a jerking/convulsing “clonic phase.”
• Clonic: convulsions.
• Myoclonic: muscle jerks.
• Atonic: reduced muscle tone.
• Absence: staring into space, lip smacking, chewing.

Symptoms by brain region (focal seizure symptoms depend on the area affected; brainstem seizures are the most serious):

• Frontal lobe: movement, emotions, memory, language, social/sexual behaviour, personality.
• Parietal lobe: bodily sensations.
• Occipital lobe: processing vision.
• Temporal lobe: hearing, speech, memory, and emotions.
• Brainstem/cerebellum region: balance and coordination; breathing, heart rate, and temperature.

EEG comparison: a normal EEG is contrasted with a focal seizure EEG (high-amplitude rhythmic spiking confined to a subset of channels) and a generalised seizure EEG (high-amplitude spiking across all channels).

Epidemiology, Associations, and Prognosis

• 0.5–1% of people have epilepsy.
• Alzheimer’s disease increases epilepsy risk 2–3x; late-onset epilepsy increases Alzheimer’s risk 2–3x.
• 3% of traumatic brain injury (TBI) patients develop epilepsy over a 12-month period.
• 12% of stroke patients develop epilepsy over a 10-year period.
• 80% of patients with brain tumours develop epilepsy.

Prognosis:

• Recurrent seizures are associated with injuries in 28–40% of patients.
• Recurrent seizures are associated with a 1.6–9-fold increase in mortality in the first 2 years after diagnosis.
• 64–82% of patients with generalised seizures become seizure-free.
• 25–75% of patients with focal seizures become seizure-free.
• 5-year seizure-free periods have remained unchanged over the past 20 years despite the release of 17 anti-epileptic drugs — i.e. newer drugs have not improved seizure-free rates, though [transcript implies, not stated explicitly on this slide] side effects are more tolerable.
• Poor adherence/compliance occurs in 30–40% of patients and is estimated to cause 45% of breakthrough seizures.

Principles of Treatment

• Start with an anti-epileptic drug as monotherapy at a low dose, to minimise adverse events.
• If a seizure recurs, increase the dose until seizures stop.
• If seizures persist at maximal drug doses, add another anti-epileptic drug.
• Anti-epileptic drugs are effective in controlling only about 70% of seizures overall (stated as ~67% in the lecture summary).

Drugs by seizure type:

• Focal and generalised seizures: valproate, lamotrigine, levetiracetam, carbamazepine, phenytoin, topiramate, gabapentin.
• Absence seizures: ethosuximide (not effective for other seizure types), valproate.
• Status epilepticus: midazolam, diazepam, phenytoin, phenobarbital.

Core Anti-Epileptic Drugs

Indications summary (drug list drugs):

Drug	Indications	Notes
Levetiracetam	Focal and GTC seizures	May worsen myoclonic seizures; often first-line
Phenytoin	Focal and GTC seizures	May worsen myoclonic seizures; not first-line
Valproate	Focal, GTC, absence, and myoclonic seizures	Broadest coverage of the four; also used for bipolar mania
Gabapentin	Focal and GTC seizures	May worsen myoclonic seizures; lower efficacy than the others; second-line

Levetiracetam

• Mechanism of action is unproven; hypothesised to inhibit synaptic vesicle protein 2A (SV2A).
• SV2A regulates the readily releasable pool size (the number of vesicles containing neurotransmitters, e.g. glutamate); inhibition reduces this pool size, so less glutamate is released and excitatory activity decreases.
• Use with caution in patients with mood disorders and kidney dysfunction.
• Often first-line anti-epileptic; limited drug interactions.
• Side effects: dizziness, headache, irritability, loss of strength and energy, mood and behavioural changes, sleepiness; also lethargy/fatigue, motor coordination problems, and behavioural abnormalities including sometimes suicidal ideation.

Valproate

• Inhibits GABA transaminase, the enzyme that breaks down GABA, decreasing GABA breakdown and increasing GABA levels in the brain.
• Used for focal, GTC, absence, and myoclonic seizures; also indicated to treat mania in bipolar disorder.
• Side effects: feeling tired, dizziness, upset stomach, vomiting, tremor, hair loss, weight gain, changes in behaviour; also nausea, and rarely severe hepatic toxicity; associated with congenital birth defects.
• Drug interactions: carbapenem antibiotics (e.g. meropenem) increase valproate excretion, decreasing valproate blood concentration and increasing seizure risk. Valproate inhibits lamotrigine metabolism, increasing lamotrigine blood concentration and side effects.

Gabapentin

• Inhibits voltage-gated L-type Ca2+ ion channels, preventing calcium influx in neurons; the membrane potential cannot become more positive, so depolarisation does not occur, no neurotransmitter is released, and excitatory activity decreases.
• Approved for focal and GTC seizures; second-line therapy; lower efficacy than the other core drugs; also indicated for neuropathic pain.

Phenytoin

• Blocks voltage-gated Na+ ion channels, preventing sodium influx in axons; the membrane potential cannot become more positive, so depolarisation does not occur and no neurotransmitters are released, decreasing excitatory activity.
• Not a first-line drug due to side effects and drug interactions.
• Side effects (presumed to be phenytoin’s, per the flag above): jerking movements of the eyes, decreased coordination, shaking of the hands, slowed thinking and movement, memory problems, slurred speech, poor concentration. Also separately stated: mild effects include vertigo, ataxia, headache, nystagmus; severe effects include confusion, cognitive dysfunction, and gum hyperplasia.
• Drug interactions: phenytoin is an inducer of CYP3A4 (~40% of drugs are metabolised by CYP3A4), leading to decreased plasma levels of many co-administered drugs.

Why drug interactions matter

23% of people aged 65–74 and 39% of people aged 75–84 take 5 or more long-term medicines, raising the relevance of enzyme-inducing/inhibiting AEDs like phenytoin and valproate in polypharmacy. [The lecture poses but does not answer whether older people are more likely to take seizure medication.]

Benzodiazepines and Acute Seizure Management

• Benzodiazepines (diazepam, midazolam) are used to treat acute seizures.
• They are positive allosteric modulators of the GABAA receptor: they increase the frequency of GABAA channel opening when GABA is bound, increasing Cl- influx, making the membrane potential more negative, and decreasing neurotransmission.
• Benzodiazepines have no effect in the absence of GABA (they require GABA to be bound to have an effect).
• They bind to a different site than the endogenous agonist GABA: the α–γ subunit junction of the GABAA receptor (which also has separate ethanol and barbiturate binding sites, with GABA binding at the α subunit and benzodiazepines at the γ subunit).
• Three functional states of the GABAA chloride channel: no Cl- influx (nothing bound); normal Cl- influx (GABA bound alone); increased Cl- influx (GABA and benzodiazepine bound together) — illustrating the potentiating effect of benzodiazepines on GABA-mediated inhibition.

How GABA Inhibits Neurotransmission (broader circuit view)

• GABAergic neurons can inhibit neurotransmission at synapses throughout the brain; ~20% of neurons in the brain are GABAergic.
• Mechanism: influx of Cl- causes hyperpolarisation, preventing neurons from depolarising and releasing neurotransmitters; this interrupts the action potential and stops neurotransmission.
• This inhibitory action occurs at presynaptic terminals, postsynaptic neurons, and interneurons.
• Illustrated via a GABAergic interneuron synapsing onto a glutamatergic presynaptic terminal (containing AMPA, VDCC, NMDAR, and mGluR2/3), which synapses onto a postsynaptic neuron; GABAA-mediated Cl- influx and GABAB signalling at the postsynaptic membrane block the Na+/AMPA-mediated depolarisation pathway.

Summary Points

• Epilepsy is a serious condition requiring pharmacotherapy.
• Pharmacotherapy is effective in about 67% of patients (compare with the ~70% figure given earlier in the lecture for seizure control generally).
• Anti-epileptics can have poor compliance, significant side effects, and drug interactions.
• Anti-epileptics have varied mechanisms of action but generally work to decrease neurotransmission.
• Levetiracetam is typically first-line, followed by valproate, gabapentin, and phenytoin.

Self-test

1. Define epilepsy and state the core pathophysiological imbalance underlying an epileptic seizure.
2. State the diagnostic criteria for epilepsy (all three qualifying scenarios).
3. Describe the two-step mechanism by which activation of AMPA leads to an action potential, and by which activation of GABAA inhibits one.
4. Distinguish GABAA from GABAB in terms of receptor type, activation speed, and effect.
5. Describe the glutamate–glutamine cycle at the synapse, from glutamine uptake into the presynaptic terminal to glutamate’s return to the astrocyte.
6. Explain why domoic acid poisoning causes mental confusion and memory loss, referencing its receptor target.
7. List the three main mechanisms by which anti-epileptic drugs act on neuronal excitability.
8. Distinguish focal from generalised seizures in terms of where ictal activity originates and give one example presentation of each.
9. List the five clinical seizure types described and give the defining feature of each.
10. A patient has a focal seizure and the medical team says the deficits are the “most serious” possible for a focal seizure. Which brain region is most likely involved, and why would this location be more serious than, say, the occipital lobe?
11. Describe the stepwise approach to starting and adjusting anti-epileptic drug therapy.
12. Describe levetiracetam’s proposed mechanism of action, from receptor/protein target to the resulting change in neurotransmitter release.
13. Explain how valproate increases GABA levels in the brain, and give one other clinical indication (besides epilepsy) for valproate.
14. Describe the mechanism by which gabapentin reduces excitatory neurotransmission.
15. Describe the mechanism by which phenytoin reduces excitatory neurotransmission.
16. A patient stabilised on several long-term medications is newly started on phenytoin for focal seizures, and several of her other drug levels subsequently fall. Explain the pharmacological basis for this interaction.
17. A patient on valproate is prescribed meropenem for a severe infection, and her seizures return despite good adherence. Explain the likely mechanism.
18. Explain why benzodiazepines have no anticonvulsant effect in the total absence of GABA, referencing their receptor binding site.
19. Describe the three functional states of the GABAA chloride channel shown in the lecture (no ligand, GABA alone, GABA plus benzodiazepine) and the resulting difference in chloride influx.
20. Integrative: A first-time seizure patient is diagnosed with focal epilepsy and started on monotherapy. Using the lecture’s treatment algorithm and drug indication table, explain which core drug would typically be tried first and why, and describe what happens next if seizures continue at the maximum dose.

Answers

Reveal answers

1. Epilepsy is a family of neurological disorders characterised by seizures; the core pathophysiology is an imbalance between inhibition and excitation, with too much excitatory brain activity driving the seizure.
2. (a) At least 2 unprovoked seizures more than 24 hours apart, OR (b) 1 unprovoked seizure with a recurrence probability similar to that after 2 unprovoked seizures (at least 60% over the next 10 years), OR (c) a diagnosis of an epilepsy syndrome.
3. AMPA activation causes Na+ influx, making the membrane potential more positive, which triggers an action potential. GABAA activation causes Cl- influx, making the membrane potential more negative, which inhibits an action potential.
4. GABAA is a Cl- ion channel activating within milliseconds; GABAB is a Gi-coupled GPCR activating over ~100 milliseconds; both produce inhibition of the action potential, but GABAA is fast and GABAB is slow.
5. Glutamine is transported from astrocytes into the nerve terminal, converted to glutamate by glutaminase, packaged into vesicles via VGLUT, and released into the synaptic cleft to act on postsynaptic glutamate receptors. Glutamate is cleared by EAAT3 (neuronal) and EAAT1/EAAT2 (astrocytic) transporters; astrocytes convert the taken-up glutamate back to glutamine via glutamine synthetase, completing the cycle.
6. Domoic acid has high specificity for glutamate ion channels (AMPA and kainate receptors); overstimulating these causes glutamate excitotoxicity, which the lecture notes can cause lesions and neuronal death, consistent with the confusion and memory loss reported in the Canadian shellfish poisoning cases.
7. (1) Blockade of use-dependent sodium channels to reduce membrane excitability; (2) inhibition of T-type calcium channels (absence seizures) and presynaptic calcium channels; (3) increasing GABA-mediated inhibition.
8. Focal seizures originate from a distinct brain region (may include loss of consciousness and may progress to generalised); generalised seizures originate in both hemispheres simultaneously (may include muscle jerking/tonic-clonic activity or reduced muscle tone).
9. Tonic-clonic (muscle tightening then convulsions), clonic (convulsions), myoclonic (muscle jerks), atonic (reduced muscle tone), absence (staring into space, lip smacking, chewing).
10. The brainstem/cerebellum region, since it controls balance/coordination and breathing, heart rate, and temperature — vital autonomic functions — making brainstem seizures the most serious, per the lecture.
11. Start with one anti-epileptic drug as monotherapy at a low dose to minimise adverse events; if a seizure recurs, increase the dose until seizures stop; if seizures persist at the maximal dose, add a second anti-epileptic drug.
12. Levetiracetam is hypothesised to inhibit SV2A, which regulates the readily releasable pool size of neurotransmitter-containing vesicles; inhibiting SV2A reduces this pool size, so less glutamate is released and excitatory activity decreases (the mechanism is officially unproven).
13. Valproate inhibits GABA transaminase, the enzyme that breaks down GABA, so GABA breakdown decreases and GABA levels in the brain rise. It is also indicated to treat mania in bipolar disorder.
14. Gabapentin inhibits voltage-gated L-type Ca2+ channels, preventing calcium influx; without the resulting depolarisation, no neurotransmitter is released, reducing excitatory activity.
15. Phenytoin blocks voltage-gated Na+ channels, preventing sodium influx in axons; the membrane potential cannot become more positive, so depolarisation and neurotransmitter release do not occur, reducing excitatory activity.
16. Phenytoin is an inducer of CYP3A4, an enzyme that metabolises ~40% of drugs; inducing it increases enzyme production and accelerates metabolism of co-administered drugs, lowering their plasma levels.
17. Carbapenem antibiotics such as meropenem increase valproate excretion, lowering valproate blood concentration; the resulting drop in drug level increases seizure risk.
18. Benzodiazepines are positive allosteric modulators that bind the α–γ subunit junction of the GABAA receptor (a different site from GABA itself); as allosteric modulators they only enhance the receptor’s response when GABA is already bound, so with no GABA present there is nothing for them to potentiate.
19. No ligand bound: no Cl- influx (channel closed). GABA bound alone: normal Cl- influx. GABA and benzodiazepine bound together: increased Cl- influx (channel opens more/wider) — showing benzodiazepines potentiate rather than replace GABA’s effect.
20. Levetiracetam would typically be tried first, as the lecture states it is often first-line and, along with phenytoin and gabapentin, is indicated for focal and GTC seizures. If seizures continue despite up-titration to the maximum dose of levetiracetam, per the treatment algorithm a second anti-epileptic drug (e.g. valproate, gabapentin, or phenytoin, per the lecture’s stated order after levetiracetam) would be added rather than substituted outright.