ANTIEPILEPTIC DRUGS

• Convulsions:
Involuntary/paroxysmal skeletal muscle contractions.
• Not present in all forms of epilepsy/seizures (sensory/behavioral symptoms).
• Seizure:
Cerebral neurons → fire rapidly/synchronized bursts → episodes of
Sudden/transient disturbances → cerebral excitation.
• Epilepsy:
Chronic neurologic disorder → recurrent seizures.
• Group/focus of hyperexcitable/irritable neurons → spontaneous discharge → epileptic seizure.
• 5-10 people in 1000 → most common neurological disorder.
• Cause:
• Stroke/tumor/encephalopathy/head trauma/ CNS injury/congenital
abnormality/birth trauma/genetic factor/systemic metabolic disorder
(infection/hypoglycemia/hypoxia/uremia) → damage to neurons → altered
threshold.
• Metabolic disorder (infection/hypoglycemia/hypoxia/uremia) → precipitate
seizures.
• Diagnostic Aids:
• Electroencephalography (EEG/intracranial ECG).
• Treatment Options:
• Surgery.
• Drug therapy (primary → 50% patients cured/25% patients substantially reduced
seizure activity).
• Neural stimulation.
• Dietary control.
CLASSIFICATION OF
EPILEPTIC SEIZURES
RATIONALE FOR DRUG
TREATMENT
• Individual seizures → self-limiting.
• Uncontrolled reoccurring seizures → further damage to already
injured neurons/harmful to healthy neurons.
• Seizures → functional changes in neuronal pathways → impaired
cerebral activity/ ↑ susceptibility to more seizures.
• Seizure → lose consciousness/convulsions → injury due to falling.
• Seizure → cardiac irregularities → cardiac arrest → fatal.
• Minor seizure → embarrassment → social interaction
compromise → social withdrawal.
DRUGS USED TO TREAT
EPILEPSY
• ↓ firing of neurons:
• ↑ inhibitory effects of GABA.
• ↓ effects of excitatory neurotransmitters (glutamate/aspartate).
• Altering movement of ions (sodium/calcium).
Barbiturates
• Phenobarbital/mephobarbital → all types of adult seizures (generalized tonic-clonic
seizures/complex partial seizures).
• Primidone → generalized tonic-clonic seizures unresponsive to other drugs.
• Safe/effective.
• ↑ sedation.
• Mechanism of Action:
• ↑ inhibitory effects of GABA.
• ↓ Ca+ in excitatory presynaptic neurons.
• ↓ release of excitatory neurotransmitters → glutamate.
• Adverse Side Effects:
• Sedation.
• Nystagmus.
• Ataxia.
• Folate deficiency.
• Vitamin-K deficiency.
• Skin problems.
• Children:
• Paradoxical ↑ in seizures.
• ↑ in hyperactivity.
Benzodiazepines
• Diazepam/lorazepam → status epilepticus.
• Clonazepam → absent seizures (Lennox-Gastaut variant)/minor generalized
seizures (akinetic spells/myoclonic jerks).
• Clorazepate → adjunct in partial seizures.
• Mechanism of Action:
• Inhibitory effects of GABA.
• Adverse Side Effects:
• Sedation.
• Ataxia.
• Behavioral changes.
Hydantoins
• Phenytoin → first-line therapy for most seizures (partial seizures/generalized
tonic-clonic seizures).
• Mephenytoin toxicity > phenytoin toxicity + similar properties.
• Ethotoin → absent seizures.
• Mephenytoin/ethotoin → if patient in unresponsive to other < toxic drugs.
• Fosphenytoin → IV → in emergency → continuous/uncontrolled seizures (status
epilepticus).
• Mechanism of Action:
• ↓ Na+ entry in rapidly firing neurons → ↓ neuronal excitability → stabilized neuronal
membrane.
• ↓ ability of Na+ channels to reset from inactive state → active state (after firing of action
potential).
• ↓ reactivation of Na+ channels → ↑ absolute refractory period (time between action
potentials) → ↓ firing rate to normal.
• ↑ dose → movement of K+/Ca+ → ↑ GABA effects (at doses > therapeutic dose).
• Adverse Side Effects:
• Gastric irritation.
• Confusion.
• Sedation.
• Dizziness.
• Headache.
• Cerebellar signs (nystagmus/ataxia/dysarthria).
• Gingival hyperplasia.
• Hirsutism (↑ body hair).
• Skin disorders.
Iminostilbenes
• Carbamazepine → all except absence seizures/first-line in partial/tonic-clonic
seizures.
• Efficacy/side effects = phenytoin → substitute for phenytoin (patient response).
• Oxcarbazepine → partial seizures in adults (adjunct for children 4-16 yrs.).
• Mechanism of Action:
• ↓ recovery of Na+ channels firing too rapidly (like phenytoin).
• Carbamazepine → ↓ presynaptic reuptake/release → norepinephrine.
• Adverse Side Effects:
• Dizziness.
• Drowziness.
• Ataxia.
• Water retention ( ↑ ADH release).
• Cardiac arrhythmias.
• CHF.
Succinimide
Ethosuximide/phensuximide/methsuximide.
• Absence (petit mal) seizures (ethosuximide).
• Mechanism of Action:
• ↑ seizure threshold → ↓ electrical activity in the brain.
• ↓ Ca+ influx → thalamic neurons.
• Spontaneous rhythmic Ca+ entry → thalamic neurons →partial seizures.

• Adverse Side Effects:

• GI distress (nausea/vomiting).
• Headache.
• Dizziness.
• Fatigue.
• Lethargy.
• Movement disorders (dyskinesia/bradykinesia).
• Skin rashes.
• Itchiness.
Carboxylic Acids (Valproic Acid)
• Absence seizures/generalized tonic-clonic seizure (second-line agent)/bipolar
disorder (manic disorder).
• Mechanism of Action:
• ↑ GABA.
• ↑ K+ conductance/efflux → ↑ hyperpolarization/ ↓ excitability.
• ↓ Na+ entry → limit Na+ entry in rapidly firing neurons.
• Adverse Side Effects:
• GI distress.
• Temporary hair loss.
• Weight gain/loss.
• Impaired platelet function.
 NEWER “SECOND-
GENERATION” AGENTS
Prototypic drug → Felbamate
Same efficacy/desirable ADME/mild side effects/adjunct “add-on” therapy.
Felbamate
• Partial seizures (adults/children) + generalized absence seizures in children (Lennox-
Gastaut syndrome).
• Mechanism:
• NMDA receptor antagonism.
• Excitatory neurotransmitter influence blockage (glutamate).

• Adverse Side Effects:

• Severe:
• Aplastic anemia/liver failure.
• Common:
• Insomnia.
• Headache.
• Dizziness.
• GIT problems (anorexia/nausea/vomiting).
Gabapentin
• Partial seizures (adults/children).
• Mechanism:
• GABA receptor agonism (↑ GABA release).
• Other unknown mechanism.
• Adverse Side Effects:
• Sedation.
• Fatigue.
• Dizziness.
• Ataxia.
Lamotrigine
• Partial/generalized seizures (adults/children) + adjunct in partial seizures
(children).
• Mechanism:
• Stabilize Na+ channels (carbamazepine/phenytoin).
• Inhibit Na+ entry (presynaptic neuron) → inhibit release of excitatory neurotransmitters.
• Adverse Side Effects:
• Dizziness.
• Headache.
• Ataxia.
• Vision problems.
• Skin rash.
Levetiracetam
• Adjunct in partial seizures.
• Adverse Side Effects:
• Sedation.
• Dizziness.
• Generalized weakness.
Tiagabine
• Adjunct in partial seizures (uncontrolled by traditional drugs).
• Mechanism:
• ↓ reuptake of GABA.
• ↑ GABA concentration in synaptic cleft.
• Adverse Side Effects:
• Dizziness.
• Weakness.
• Psychiatric disorders (anxiety/depression).
Topiramate
• Partial seizures (adult).
• Mechanism:
• ↓ Na+ channel opening.
• ↓ excitatory amino acid receptor.
• ↑ GABA receptor.
• Adverse Side Effects:
• Sedation.
• Ataxia.
• Dizziness.
• Fatigue.
Zonisamide
• Adjunct in partial seizures (adult).
• Mechanism:
• Stabilize Na+ channels.
• ↓ Ca+ entry into rapidly firing neurons.
• Adverse Side Effects:
• Sedation.
• Ataxia.
• Fatigue.
• Loss of appetite.
 SELECTION OF A
SPECIFIC ANTIEPILEPTIC
AGENTS
Patient-patient basis.
SINGLE-DRUG THERAPY
VS. DRUG
COMBINATION IN
EPILEPSY
 Monotherapy Combination Therapy
• Low levels of: • Common because newer drugs have
• Side effects. predictable pk/side-effects profile.
• Drug interactions.
• Cost.

• Easy management of ADR.

• Better adherence.
PHARMACOKINETICS
• Oral administration (3-4 divided doses).
• Dose → drug/severity of seizures.
• Uniform distribution.
• Hepatic microsomal oxidase enzyme biotransformation.
PRECAUTIONS FOR
PREGNANCY
• Complications:
• Stillbirth.
• Microencephaly.
• Mental retardation.
• Infant seizures.
• Congenital malformations (cleft plate/cardiac defects/neural tube defects).
• Risk management:
• Monotherapy.
• Lowest possible dose.
• Optimal prenatal care (folic acid/exercise/rest).
• Monitor drug-related effects (withdrawal symptoms/development delays).
STATUS EPILEPTICUS
Medical Emergency → one long/extended seizure.
 Seizures occurring without any appreciable period of recovery.
• Precipitating Factors:
• Sudden withdrawal of antiepileptic drug.
• Cerebral infarct.
• Systemic/intracranial infection.
• Withdrawal from addictive drugs (alcohol).
• Prognosis:
• Permanent damage/death (generalized/tonic-clonic).
• Treatment:
• Standard emergency procedures (maintaining airways/start IV line).
• First-line drugs:
• Lorazepam/ diazepam (IV).
• Phenytoin (IV).
• Uncontrolled seizure:
• Phenobarbital (IV).
• General anesthesia (halothane).
WITHDRAWAL OF
ANTISEIZURE
MEDICATION
• 60%-70% patients remain seizure free (after withdrawal).
• Taper off medication over an extended period (6 months).
• Indicators of successful withdrawal:
• Seizure free while on medication (at least 2yrs).
• Normal neurological examination prior to withdrawal.
• Young age upon onset of seizure.
 SPECIAL
CONSIDERATIONS IN
REHABILITATION
PATIENTS
• Evaluate patient history/risk factors for predisposition to seizures.
• Evaluate antiepileptic therapy goals are achieved (note changes in nature of seizure/side
effects).
• Complications:
• Cerebral Side effects (ataxia) → inability to participate in functional activates.
• Solutions → dose adjustment/drug substitution/coordination exercises.
• Skin conditions (rash/dermatitis).
• Risks Management for Epileptic Patients:
• Potential Complications:
• Headache.
• Dizziness.
• Sedation.
• GI disturbances (nausea/vomiting).
• Management:
• Reschedule time/day of therapy.
• Remove exacerbating factors/stimuli → light/sound.
References
1. Pharmacology In Rehabilitation - Charles D. Ciccone.
2. Lippincott Pharmacology- Richard Harvey.