Antiepileptic/Antiseizure Drugs

Samra Bashir
 Learning objectives
At the end of the session, the students should be able to discuss
the use of the antiepileptic drugs with
 their mechanism of action,
 Pharmacokinetics
 while identifying their important side effects
 Epilepsy
• Epilepsy : periodic and unpredictable occurrence of seizures
• Seizure: transient alteration of behavior due to the disordered, synchronous,
and rhythmic firing of populations of brain neurons.
• Worldwide prevalence 1%
• 2nd most common neurological disorder after stroke
• Epilepsy is not a single entity-it is a family of different recurrent seizure
disorders
• The neuronal discharge in epilepsy results from the firing of a small no of
neurons in a specific area-primary focus
• The site of electrical discharge determines the types of symptoms produced
• This results in abnormal movements or perceptions-short duration-recurrent
• Epileptic seizures may involve convulsions-motor cortex
• Epileptic seizures may include visual, auditory, olfactory hallucinations-
parietal or occipital cortex
 Causes of epilepsy
Primary epilepsy
• No specific anatomic cause such as trauma or neoplasm is evident
• May be produced by inherited abnormality in the CNS
• Patients are treated chronically with antiepileptic drugs -Often for life
Secondary epilepsy
• May be caused by a no of reversible disturbances, such as
• 1. Tumors
• 2. Head injury
• 3. Hypoglycemia
• 4. Meningeal infection
• 5. Rapid withdrawal of alcohol from alcoholic
• Antiepileptic drugs are given until the primary cause is corrected
• Seizures secondary to stroke or trauma may cause irreversible CNS
damage
 Classification of epilepsy
• Seizures have been classified in two
broad groups
1. Partial or focal Genearalized Partial seizures
epilepsy
• Simple partial (focal aware seizures)
• Complex partial (focal impaired
awareness seizures)
2. Generalized Partial seizures
with secondary
generalization

Choice of drug treatment is based on

the type of seizure being treated
 Partial/focal seizures
Simple partial
• Confined to a single locus in the brain
• Electrical charge does not spread
• Patient does not lose consciousness
• Patient exhibits abnormal activity of a single limb or muscle
group
• May occur at any age
Complex partial
• Not simple, a little complex
• Show complex sensory hallucinations, distortions
• Patient may lose consciousness
• Patient exhibits motor dysfunctions-chewing movements,
dirrhea and urination
• 80% patients-below 20 years
 Generalized epilepsy
Produced locally but rapidly spread throughout the
cerebral cortex
Tonic-clonic (grand mal)
• Most common, most dramatic form of epilepsy
seizures-loss of consciousness-tonic-clonic
phases---followed by a period of confusion and
exhaustion
Absence (petit mal)
• Brief, abrupt and self-limiting loss of
consciousness, staring and rapid eye blinking for
3-5 seconds, 4-10 years of age until puberty
 Generalized epilepsy
Myoclonic
• Short episodes of muscle contraction for
several minutes, rare, occur at any age as
a result of permanent neurologic damage
secondary to hypoxia, uremia, encephalitis or
drug poisoning
Febrile seizures
• In young children-3 months to 5 years-seizures with high fever, febrile seizures consists of
generalized tonic-clonic seizures of short duration, often look threatening but actually
benign and do not cause death, injury or learning disorders, rarely require medication
Status epilepticus
• Rapidly recurrent seizures
 Therapy of epilepsy
• Drug therapy is most widely effective
mode of treatment
• With standard therapy seizures can be
controlled in 2/3rd of the patients
 Classification of antiepileptic drugs
• Barbiturates: phenobarbitone
• Deoxy-barbiturates: Primidone
• Hydantoin- phenytoin, phosphenytoin
• Iminostilbene – carbamazepine, oxcarbazepine
• Succinimide – ethosuximide
• Aliphatic carboxylic acid – valproic acid, diovalproex
• Benzodiazepines – clonazepam, diazepam, Lorazepam, clobazam
• Phenytriazine – lamotrigine
• Cyclic GABA analogue – Gabapentin
• Newer drugs – Vigabatrin, topiramate, tiagabine, zonisamide, levetiracetam
 Mechanism of action of antiepileptic drugs
• Inhibit the local generation of seizure discharges, both by
reducing the ability of neurons to fire action potentials at high
rate as well as reducing neuronal synchronization.
• Inhibit the spread of epileptic activity to nearby and distant
sites, either by strengthening the inhibitory surround mediated
by GABAergic interneurons or by reducing glutamate-mediated
excitatory neurotransmission (the means through which a
presynaptic neuron depolarizes and excites a postsynaptic
follower neuron).
 Mechanism of action of antiepileptic drugs
Partial and generalized tonic-clonic seizures
• Inactivation of voltage-activated sodium channel
• enhanced ϒ-amino butyric acid (GABA)-mediated synaptic
inhibition
• Anti-glutaminergic activity
Absence seizures
• Inhibition of voltage-activated Ca2+ channel (T current)
Targets of antiepileptic drugs
Calcium channel
blockade
 Primary antiepileptic drugs
• Phenytoin, fosphenytoin
• Carbamazepin
• Valproic acid
• Ethosuximide
• Primidone
 Adjunct/second-line/alternative antiepileptic drugs
• Gabapentin
• Pregabalin
• Lamotrigine
• Phenobarbitone
• Tiagabine
• Topiramate
• Zonisamide
• Felbamate
• Viagabatrin
• Levetiracetam
 Phenytoin
(diphenylhydantoin)
Mechanism of action
• One of the widely used antiepileptic drugs.
• Blocks voltage-gated sodium channels (blocks high
frequency firing of neurons by prolonging the inactivated
state of voltage sensitive neuronal Na+ channel thus
prolong the refractory period of the neuron)

Block of sustained high frequency repetitive firing of action potentials

 Phenytoin
(diphenylhydantoin)
Pharmacokinetics
• Chronic admin is always oral
• Oral absorption is slow
• IV-status epilepticus (fosphenytoin)
• Metabolism- cytochrome P450 system to inactive metabolites, only 5% excretes unchanged through urine.
• At low dose t1/2 is 24 hrs
• At relatively larger doses-toxicity due to saturation of metabolizing enzymes- thus monitoring of plasma
concentration is very helpful in tailoring dose.
• Plasma protein binding 90%
• low volume of distribution (0.6–0.7 L/kg in adults).
• Inducer of hepatic microsomal enzymes
 Phenytoin
Indications
• First line drug for Prevention of Partial seizures (Simple and complex) and Tonic-clonic (generalized and secondarily generalized)
• Treatment of Status epilepticus (recurrent tonic-clonic) as second line drug
• Prevention and treatment of seizures that may occur during and after nerosurgery.
• May worsen absence epilepsy, juvenile myoclonic epilepsy, and Dravet’s syndrome.
Adverse effects
Early signs
• Depression of CNS--Cerebellum and vestibular system leading to nystagmus , diplopia and ataxia
• GIT--Nausea and vomiting
• Gingival hyperplasia (most common, 20%)
• Hirsutism, acne
Long term use
• Coarsening of facial fetures, mild peripheral neuropathy
• Osteomalasia
• Megaloblastic anemia and low folate levels
• Sedation at higher plasma levels
• Inhibition of insulin release--Hyperglycemia and glucosuria
 Phenytoin
Hematologial complications are rare and may cause agranulocytosis with fever and rash.
Idiosyncratic and allergic reactions
• Skin rash, fever and lymphadenopathy
Foetal hydantoin syndrome (mental and physical birth defects)

Drug-drug interactions
• Valproic acid, phenylbutazone, and sulfonamides can displace phenytoin for binding to plasma proteins.
• Valproic acid also inhibits phenytoin metabolism. The combined effect can result in marked increases in free phenytoin.
• In all of these situations, patients may exhibit signs of toxicity when total drug levels are within the therapeutic range.
• Phenytoin stimulates the rate of metabolism of valproic acid, tiagabine, ethosuximide, lamotrigine, topiramate, oxcarbazepine,
zonisamide, felbamate and many benzodiazepines.
• Autoinduction of its own metabolism, however, is insignificant.
• phenobarbital and carbamazepine, cause decreases in phenytoin steady-state concentrations through induction of hepatic
microsomal enzymes.

Dose: 100 mg BD, maximum 400 mg/day; Children 5-8 mg/kg/day.

 Iminostilbenes - Carbamazepine
Mechanism of action
• Similar to phenytoin - Inactivation of voltage-gated sodium channels (prototype sodium channel blocker)
Pharmacokinetics
• Route of adm: oral
• absorption is slow after oral administration but once absorbed, quickly crosses BBB due to high lipid solubility
• Patients can better tolerate the drug if taken after meal as low peak plasma levels are achieved due to slow
absorption.
• Plasma protein binding 70%
• Metabolism- CYP3A4, only 5% is excreted unchanged.
• Induces drug metabolizing enzyme CYP3A4 and thus its own metabolism
• Thus initial half life of 36 hrs reduces to 8-12 hours after chronic use. This requires the dosage adjustment
after continuous use
• It increases the metabolism of many other antiepileptic drugs
 Carbamazepine
Indications
First choice drug for
• Partial/focal seizures
1. Simple
2. Complex (most effective)
3. Focal-to-bilateral tonic-clonic seizures
• Generalized Tonic-clonic (grand mal)
• Not effective in absence and myoclonic seizures and can exacerbate these conditions.
Additional uses: Drug of choice for trigeminal neuralgia, bipolar disorders (as mood stabilizer)
Adverse effects
• Dose-dependent mild gastrointestinal discomfort
• Dose related neurotoxicity: dizziness, vertigo, diplopia and ataxia – most common
• Sedation at higher doses.
• Vomiting, diarrhea and worsening of seizures at higher doses.
• Idiosyncratic reactions: Erythematous skin rash, Blood dyscrasias--Leukopenia and aplastic anemia
• In elderly, it may cause hyponatremia and water retention as it enhances ADH action
• Minor fetal malformation if taken during pregnancy
• Liver toxicity--Patient should have frequent blood and liver function tests
 Carbamazepine
Drug-drug interaction
• carbamazepine induces CYP 1A2/2C9/ 3A4 enzymes, and increases metabolism of its
own and the concomitant antiseizure drugs including primidone, phenytoin,
ethosuximide, valproic acid, and clonazepam.
• Valproic acid may inhibit carbamazepine clearance and increase steady-state
carbamazepine blood levels.
• Phenytoin and phenobarbital, may decrease steady-state concentrations of
carbamazepine through enzyme induction.
• These interactions may require dosing changes.
• No clinically significant protein binding interactions have been reported.
Dose: 200-400 mg TDS; Children 15-30 mg/ kg/day
 Oxcarbazine
• Oxcarbazepine is a keto analogue of carbamazepine.
• It is prodrug that is rapidly converted to eslicarbazepine which is extensively converted to the active metabolite S-
licarbazepine.
• Oxcarbazepine is inactivated by glucuronide conjugation, is eliminated by renal excretion, and has a short t1/2 of only about 1–
2 h.
• Mechanism of action is same as carbamazepine.
• But it is less potent enzyme inducer than carbamazepine
• It induces CYP 3A4 thus reduces the levels of steroid oral contraceptives but does not affect the plasma levels of warfarin.
• It does not increase its own metabolism.
• Therapeutic uses: As monotherapy or adjunct therapy of focal seizures in adults and 2-16 year old children
• Most adverse effects are similar to that with carbamazepine, but hyponatremia may occur more commonly with
oxcarbazepine than with carbamazepine.
• Fewer hypersensitivity reactions have been associated with oxcarbazepine, and cross-reactivity with carbamazepine does not
always occur.
• Eslicarbazepine Acetate
• It is also a prodrug but it is more rapidly converted to the active metabolite S-licarbazepine than its parent drug oxcarbazine
• Rest of the properties are same as oxcarbazine
 Valproic acid
Mechanism of Action
• Valproate is a first-line broad-spectrum antiseizure drug that is thought to offer
protection against many seizure types.
• Proposed mechanisms of action are
• Inactivation of voltage-activated sodium channels
• Reduction of low-threshold (T) Ca2+ current
• Enhancement of GABA levels in brain
Pharmacokinetics
• Orally absorbed, bioavailability > 80%
• Drug is better tolerated if administered after meal.
• Metabolized by liver, plasma t1/2 9-18 hrs
• PP binding is 90%
 Valproic acid
Indications
• As alternative/adjuvant drug for Tonic-clonic seizures
• Drug of choice for myoclonic seizures, atonic seizures
• absence seizures but second as choice due to hepatotoxicity, however, preferred to ethosuximide when the patient
has concomitant generalized tonic-clonic seizures.
• It is also effective against focal/partial seizures but less than carbamazepine and phenytoin.
Adverse effects
• Nausea, vomiting, abdominal pain and heart burn (most common)
• Idiosyncratic reactions: Hepatic toxicity, thrombocytopenia
• Less frequent (Rash, alopecia, sedation, ataxia, tremors)
• Teratogenic (spina bifida and neural tube defects), It should not be used in females with child bearing potential.
• Long-term use in young girls results in higher incidence of polycystic ovarian disease and menstrual irregularities.
• It inhibits metabolism of phenobarbital, carbamazepin and ethosuximide
Dose: Adults-start with 200 mg TDS, maximum 800 mg TDS; children-15-30 mg/kg/day.
 Divalproex
• It is a mixture of valproic acid with sodium valproate (1:1).
• Oral absorption is slower, but bioavailability is the same.
• Gastric tolerance may be better.
• However valproic acid is much less expensive than divalproex
 Succinimides: Ethosuximide
Primary agent for the treatment of generalized absence seizures
Mechanism of Action
• Blocks low-voltage-activated T-type of Ca2+ channels in thalamic neurons that underlie the 3-Hz spike-wave discharges of
generalized absence seizures.
Indication
• First line drug for the treatment of generalized absence seizures.
• If ethosuximide monotherapy does not lead to seizure control, the drug can be combined with valproate or other agents such
as benzodiazepines.
Pharmacokinetics
• Well absorbed orally
• Metabolized by liver, 25% is excreted unchanged in urine
• Does not induce P450
• Does not bind with PPs
• Plasma t1/2 is 40-50 hrs in adults and 30 hrs in children
Adverse effects
• GIT (Gastric distress, including pain, nausea, and vomiting) and CNS (drowsiness, lethargy, euphoria, dizziness, headache, and
hiccough) are most common
• Restlessness, agitation, anxiety, aggressiveness, inability to concentrate in patients with history of psychiatric disturbances.
• Urticaria, SLE, Stevens-Johnson syndrome, Leukopenia, thrombocyctopenia and aplastic aneamia
• Valproic acid inhibits its metabolism resulting in decreased clearance and increased steady state concentration.
 Primidone
(2-desoxyphenobarbital)
Mechanism of action
• It is a derivative of phenobarbital
• Mechanism of action is same as phenobarbital i.e. potentiation of GABA
Pharmacokinetics
• Well absorbed orally
• Poor protein binding
• Metabolized by liver to active metabolites phenobarbital and
phenylethylemalonamide, which have longer half life than parent drug
• Activity is mainly because of these metabolites.
• Used with carbamazepin and phenytoin allowing smaller doses of these agents to be
used
 Primidone
Indications
• Generalized tonic-clonic and partial seizures mainly as adjunct
to carbamazepine or phenytoin
Adverse effects
• CNS - Nystagmus, ataxia, sedation, vertigo
• GIT - Nausea and vomiting
• Agitation and confusion at high doses
• Rebound seizures may occur
 Benzodiazepines
• Benzodiazepines potentiate GABA induced Cl- influx
• Clonazepam: Primarily used in absence seizures and as an adjunct for the
treatment of myoclonic and atonic seizures. However, tolerance develops
to its therapeutic effects within 6 months or so.
• Clobazam: It is 1,5-benzodiazepine. It is generally used as adjuvant to
phenytoin, carbamazepine, valproic acid and phenobarbital in refectory
epilepsy (partial, secondary-generalized tonic-clonic, absence, myoclonic
and atonic)
• Diazepam: the drug of choice for emergency control of convulsions, e.g.
status epilepticus, tetanus, eclampsia, convulsant drug poisoning, etc.
 Benzodiazepines
• For this purpose 0.2-0.5 mg/kg slow i.v. injection is followed by repeated
doses as required; maximum 100 mg/ day.
• Adverse effects of iv administration are thromboflebitis of injected vein,
marked fall in BP and respiratory depression. Resuscitative measures
should be at hand before the drug is injected.
• Lorazepam: An alternative to diazepam in status epilepticus or for
emergency control of convulsions of other etiology.
• 0.1 mg/kg injected i.v. at a rate not exceeding 2 mg/min. The action of
lorazepam after i.v. injection is more sustained than that of diazepam
which is rapidly redistributed.
Adjunct/second-line/alternative anti-epileptics
 Gabapentin and pregabalin
Mechanism of Action
• It is a GABA analogue but does not mimic GABA-ergic action
• Increases GABA release in the brain
• It inhibits pre-synaptic glutamate release probably by binding with α2δ subunit of voltage activated calcium channels.
Indications
• Adjunct therapy for partial seizures with or without progression to generalized tonic-clonic seizures
• Also used in prophylaxis of migraine and treatment of chronic pain, diabetic neuropathy and postherpatic neuralgia
Pharmacokinetics
• Absorb after oral administration
• Does not bind with PP
• Elimination is as unchanged drug through kidneys. Dose adjustment is needed with reduced renal functions.
• Does not induce hepatic enzymes so no interaction with other antiepileptic drugs
• Half life 6 hrs
Adverse effects
• Somnolence, dizziness, ataxia, headache, and tremor (most common)
• However, there is very low incidence of serious toxic effects.

Dose: Gabapentin: 900-1800 mg in 3 divided doses, or in some patients upto 3600 mg. Pregabalin 300 mg/day
 Lamotrigine
Mechanism of Action
• Blocks voltage-gated sodium channels and
• voltage-gated Calcium channels
Pharmacokinetics
• Well absorbed orally
Steven-Johnson syndrome
• Metabolized by liver by glucronidation with plasma t1/2 of 24-36 hrs
• Its half life is decreased by enzyme inducers such as carbamazepine, phenytoin and phenobarbital and increased by valproic acid
• However, metabolism of other anticonvulsants ·and oral contraceptives is not altered.
• Reduce the dose of lamotrigine to half in patients taking valproic acid.
Indications
• It is effective as monotherapy or adjunct therapy in partial, generalized tonic-clonic seizures, absence seizures (though less effective than ethosuximide
and valproic acid) and Lennox-Gestaut.
Adverse effects
• Dizziness, ataxia, blurred or double vision, nausea, vomiting
• Potentially fatal rash (Stevens-Johnson syndrome) particularly in children requiring withdrawal
• Disseminated intravascular coagulation
Dose
• As adjunt with CYP-inducing ASD (e.g., carbamazepine, phenytoin, phenobarbital, or primidone, but not valproate) initial dose is 50 mg/d for 2 weeks
followed by 50 mg twice per day for 2 weeks and then increased to a maintenance dose of 300–500 mg/d divided into two doses.
 Phenobarbitone
First efficacious antiepileptic drug introduced in 1912.
Mechanism of action
• Potentiation of synaptic inhibition through an action on the GABA A receptor (most important), Limits sustained repetitive firing at higher dose.
• higher anticonvulsant: hypnotic ratio than other barbiturates
Indications
• Generalized tonic-clonic seizures, partial seizures (SP and CP)
• Status epilepticus (however response is slow to develop)
One of the cheapest and least toxic antiepileptic drug, however, it has become less popular than carbamazepine, phenytoin and valproic acid
Pharmacokinetics
• Slow but complete oral absorption
• Clearance is 75% hepatic and 25% renal
• long plasma t1/2 (80-120 hours)
• Steady-state concentrations are reached after 2-3 weeks, and a single daily dose can be used for maintenance.
• Induces hepatic CYPs-increased metabolism of oral contraceptives, phenytoin.
Adverse effects
• Sedation (most common)
• Nystagmus and ataxia (higher doses)
• Long term administration may produce, diminution of intelligent, impairment of learning and memory and Irritability and hyperactivity in children, and agitation and
confusion in the elderly
• Rashes, megaloblastic anaemia and osteomalacia (similar to that with phenytoin) occur in some patients on prolonged use.
 Tiagabine
• This newer anticonvulsant potentiates GABA mediated neuronal
inhibition by depressing GABA transporter GAT-1 which removes
synaptically released GABA into neurons and glial cells.
• It is approved only for add-on therapy of partial seizures with or
without secondary generalization, when not adequately
controlled by standard antiepileptic drugs alone.
• Adverse effects are mild sedation, nervousness, asthenia,
amnesia and abdominal pain.
 Topiramate
• Broad spectrum anticonvulsant
Mechanism of action
• prolongation of Na+ channel inactivation,
• GABA potentiation by a postsynaptic effect on GABA-A receptor and
• antagonism of AMPA-kainate subtype of glutamate receptors.
Indications
• As monotherapy (more than 10 year old) and adjuvant (more than 2 year old) in refractory SPS, CPS, GTCS and Lennox-
Gastaut syndrome.
• For prophylaxis of migraine headache in adults.
Pharmacokinetics
• Topiramate is readily absorbed orally
• Primarily excreted unchanged in urine with an average t1/2 of 24 hours.
Adverse effects
• impairment of attention, sedation, ataxia, word finding difficulties, psychiatric symptoms,
• weight loss, paresthesias and renal stones.
 Zonisamide
• A sulfonamide derivative and broad spectrum anti-seizure drug
Mechansim of action
• Prolong inactivation state of voltage-gated sodium channles and T-
type Ca2+ current
• Inhibition of neurotransmitter release
• Inhibits carbonic anhydrase and is free radical scavenger
Indications
• It is indicated as add-on therapy in refractory partial seizures in adults
and 12 years or olders.
 Felbamate
Mechanism of Action
• Blockade of sodium channels
• Inhibits NMDA receptors
• Prevents AMPA mediated signaling
• Potentiates GABAergic transmission
Indications
• Treatment of focal seizures and Lennox-Gestaut syndrome in patients who have inadequately responded to
alternative ASDs (as 3rd line drug)
Pharmacokinetics
• About half of the administered dose appears in urine as metabolites
• Carbamazepin and phenytoin may decrease its levels
Adverse effects
• It can cause liver and bone marrow toxicities including drug-induced aplastic anemia and liver failure.
Dose: 1-4 g/day
 Vigabatrin
Mechanism of Action
• Irreversible inhibitor of GABA-aminotransferase (enzyme responsible for metabolism of
GABA) => Increases inhibitory effects of GABA.
• S(+) enantiomer is active
Pharmacokinetics
• Absorption is rapid, bioavailability is ~ 60%, T 1/2 6-8 hrs, eliminated by the kidneys.
Indications
• As adjunct therapy for partial seizures with or without generalization and West’s
syndrome (as 3rd line drug).
• Contraindicated if preexisting mental illness is present.
Adverse effects
• Drowsiness, Dizziness, Weight gain, Agitation, Confusion, Psychosis
Dose: 2-4 g daily; children -10-100 mg/kg/day.
 Levetiracetam
Mechanism of action:
Levetiracetam binds selectively to SV2A (synaptic vesicle integral membrane protein), which reduces
the release of the excitatory neurotransmitter glutamate during trains of high-frequency activity.
Therapeutic uses:
Levetiracetam is a broad-spectrum antiseizure agent and one of the most commonly prescribed drugs
for epilepsy, primarily because of its perceived favorable adverse effect profile, broad therapeutic
window, favorable pharmacokinetic properties, and lack of drug-drug interactions.
Levetiracetam is effective in the treatment of
• focal seizures in adults and children,
• primary generalized tonic-clonic seizures, and
• the myoclonic seizures of juvenile myoclonic epilepsy.
 Levetiracetam
Pharmacokinetics
• Oral absorption of levetiracetam is rapid and nearly complete, with peak plasma concentrations
in 1.3 hours. Food slows the rate of absorption
• PP binding <10% Kinetics are linear
• The plasma half-life is 6–8 hours, but may be longer in the elderly.
• Two-thirds of the drug is excreted unchanged in the urine and the remainder as the inactive
deaminated metabolite 2-pyrrolidone-N-butyric acid. Metabolism occurs in the blood.
• Does not induce metabolizing enzymes , and drug interactions are minimal.
Adverse effects
• somnolence, asthenia, ataxia, infection (colds), and dizziness.
• Less common but more serious are behavioral and mood changes, such as irritability,
aggression, agitation, anger, anxiety, apathy, depression, and emotional lability.
 General principles of epilepsy treatment
• Antiepileptic drugs control seizures but do not cure disease
• Epilepsy may fadeout after years of successful control.
• The aim of drug therapy is to control and totally prevent seizure activity at an acceptable level of
side effects.
• Underlying cause of seizures should be investigated in a patient and treated if found, to end the
seizures in secondary epilepsy.
• It may not be necessary to initiate ASDs after an isolated tonic-clonic seizure in a healthy young
adult who lacks a family history of epilepsy and who has a normal neurological exam, a normal EEG,
and a normal brain MRI scan
• If antiepileptic drugs are to be used, the below given general principles should be followed
1. Choice of the drug and dose is according to the seizure type and need of the patient.
2. Treatment should be initiated early as each seizure episode increases the propensity to future
attacks.
 General principles of epilepsy treatment
3. Start with a single drug, preferably at low dose- gradually increase dose with
monitoring of plasma levels till full control of seizures or side effects appear
4. If full control is not achieved at maximum tolerated dose of one drug,
substitute another drug.
5. Use combinations when all reasonable monotherapy fails.
6. Combining drugs with different mechanisms of action, such as those which
prolong Na+ channel inactivation with those facilitating GABA appears more
appropriate.
7. Pharmacokinetic interactions among anticonvulsants are common; dose
adjustments guided by therapeutic drug monitoring are warranted.
 General principles of epilepsy treatment
• Compliance with a properly selected, single drug in maximal tolerated dosage results
in complete control of seizures in about 50% of patients.
• If seizures occur despite of optimal plasma drug levels, physicians should assess the
presence of potential precipitating factors.
• If compliance has been confirmed yet seizures persist, substitute another drug.
• The second should preferably of different mechanism of action than the first one.
• If therapy with a second single drug also is inadequate, combination therapy is
warranted.
• The two simultaneously used drugs should have different mechanism of action.
• Most crucial for successful management is patient adherence to the drug regimen;
noncompliance is the most frequent cause for failure of therapy with ASDs.
 General principles of epilepsy treatment
• Once initiated, ASDs are typically continued for at least 2 years.
• Tapering and discontinuing therapy should be considered if the patient is seizure free after 2 years;
tapering should be done slowly over several months.
• Factors favourable to withdrawal are-childhood epilepsy, absence of family history, primary generalized
tonic-clonic epilepsy, recent onset at start of treatment, absence of cerebral disorder and normal EEG.
• Even then recurrence rates of 12-40% have been reported.
• Though, most anti-seizure drugs can cause birth defects, antiseizure drug should not be stopped if a
women on antiepileptic drugs conceive. An attempt to reduce the dose of drugs should be cautiously
made. lt may be advisable to substitute valproate.
• valproate, phenobarbital, and topiramate should not be used in women with child bearing potential
• Prophylactic folic acid supplementation in 2nd and 3rd trimester along with vit. K in the last month of
pregnancy is recommended to minimize neural tube defects and bleeding in newborn.
 General principles of epilepsy treatment
• Some antiepileptic drugs such as primidone, levetiracetam,
gabapentin, lamotrigine, and topiramate penetrate into breast
milk in relatively high concentrations. Other antiseizure drugs
that are highly protein bound, such as valproate, phenobarbital,
phenytoin, and carbamazepine, do not penetrate into breast
milk substantially.
• As a general rule, breastfeeding should not be discouraged
given the lack of evidence of harm and the known positive
benefits.
 Treatment of various types of seizures
• Generalized tonic-clonic and simple partial seizures

Ethosuximide
 Questions ???

Thank you