Antiseizure Drugs

Kaukab Azim, MBBS, PhD

Drug Groups

First Generation Drugs Second Generation Drugs Others

For Partial and Generalized Tonic-Clonic Seizures For Absence Seizures Gabapentin

FelbamateLevetiracetamLamotrigineTiagabineTopiramateZonisamide

AcetazolamideACTHGlucocorticoidsCarbamazepine

Valproic acidPhenytoinClonazepamDiazepamLorazepam

EthosuximideValproic acid

Learning Outcomes

By the end of this course the students should be able to:• List the main classes of anti-epileptic drugs• Explain the mechanism of action of each drug in each group• Describe the pharmacological effects of each drug in each

group• Describe the main pharmacokinetic features or each drug in

each group• Describe the main adverse effects of each drug in each

group• List the main contraindications of antiseizure drugs• Outline the main therapeutic uses of antiseizure drugs

Classification of epilepsy1. Generalized

A. Tonic clonic seizureB. Absence seizureC. Myoclonic D. TonicE. Atonic

2. Partial A. Simple B. Complex

3. Partial with secondary generalization

Antiseizure Drugs• Antiseizure (also called anticonvulsant, antiepileptic)

drugs are compounds fully effective in controlling seizures in 50-80 % of patients.

• The inhibition of seizure activity in the CNS is accomplished without major disturbances in the normal electrical activity.

• Sustained, high frequency, repetitive firing are inhibited much more effectively than low-frequency, non-repetitive firing.

• Antiseizure drugs do not cure epilepsy; they just suppress seizures on a temporary basis. Therefore most patients must take them for life.

• The therapeutic index of most antiseizure drugs is low and adverse effects are common. They are usually mild, but most antiseizure drugs may cause occasionally life-threatening adverse reactions.

• Most antiseizure drugs can cause malformations when given during pregnancy. Since also seizures per se can cause malformations a careful assessment of the risk/benefit ratio is mandatory in each epileptic woman who want to have a baby.

• The mechanisms of action of antiseizure drugs are still not well understood but they have been found to concern mainly:

a) voltage-gated ion channels

b) inhibitory and excitatory synaptic functions

1. Carbamazepine and Congeners

DrugsCarbamazepine, oxcarbazepine.

Mechanism of action• Frequency-dependent and voltage-dependent

blockade of inactivated Na+ channels (most likely the main mechanism).

• Interaction with other ion channels and several neurotransmitters (at high doses. Their contribution to its antiseizure effects is uncertain)

Pharmacological Effects

• Inhibition of post tetanic potentiation, which may prevent the spread of seizure from the epileptic focus (the discharge of the focus itself is not prevented and therefore aura and EEG alterations are not eliminated)

• Analgesic actions (in some type of neuropathic pain).• Antidepressant actions (mechanism likely similar to

that of tricyclic antidepressants)• Strong CYP3A4 inducing action (which leads to many

pharmacokinetics interactions).

Pharmacokinetics• Oral bioavailability: . 90%• Biotransformation: 99% by the CYP3A4

(biotransformation rate is low).Adverse effects• Dizziness, drowsiness, blurred vision diplopia, ataxia

(common, dose related).• Neutropenia, thrombocytopenia, agranulocytosis,

aplastic anemia (the risk of these reactions is 5-8 times greater in patients treated with carbamazepine than in the general population)

• Confusion, agitation, hallucinations (after high doses).

Carbamazepine and Congeners

Carbamazepine – Therapeutic Uses

1. Epilepsy• It is a first choice drug for partial seizures and for

generalized tonic-clonic seizures (It has been the most widely prescribed anticonvulsant drug world wide. No newer drug has been found to be superior in efficacy).

• In complex partial seizures it prevents the attacks in 60-65% of patients.

• The antiepileptic effect can undergo tolerance in 10-20% of patients.

• (Absence, myoclonic, tonic and atonic seizures may worsen in patients treated with carbamazepine).

2. Trigeminal and related neuralgias.• Carbamazepine is the first choice drug for

trigeminal neuralgia (result are good in 70% of patients).

• In refractory cases the addition of phenytoin can be useful.

3. Bipolar affective disorder• As an alternative to lithium for the therapy of

acute mania and the prophylactic treatment of bipolar disorder.

2. Phenytion and Congeners

DrugsPhenytoin, fosphenytoin (a prodrug rapidly converted to phenytoin in plasma)

Mechanism of action• Frequency-dependent and voltage-dependent

blockade of inactivated Na+ channels (most likely the main mechanism).

Pharmacological effects• Inhibition of post tetanic potentiation, which

may explain the prevention of the spread of seizure from the epileptic focus (the excessive discharge of the focus itself is not prevented and therefore aura and EEG alterations are not eliminated)

• Cerebellar-vestibular stimulation (with high doses).

• Analgesic actions (in some type of neuropathic pain).

Phenytoin - Pharmacokinetics

• Oral bioavailability: . 90% (absorption speed depends on pharmaceutical preparation)

• Administration: oral (fosphenytoin is more soluble and available for parenteral use)

• Biotransformation: 98% by the liver P450 system (biotransformation rate is low).

• Elimination: is dose dependent, i.e. first order at low doses, but zero order at high doses.

Phenytoin – Adverse EffectsCentral nervous system

• Nystagmus (frequent), diplopia, ataxia, dyskinesia, vertigo, tremor, hyperreflexia, dystonic reactions, blurring of vision.

• Hyperactivity, nervousness.• Sedation, drowsiness (with high drug plasma levels).• Peripheral neuropathy (7-30% of patients treated for

long time).• Phenytoin encephalopathy (with high drug plasma

levels).

Gastrointestinal system

• Gingival hyperplasia (30-40% of patients) • Inhibition of folate absorption (after long treatments)

Endocrine system

• Hyperglycemia (due to decreased insulin secretion)• Osteomalacia (due to increased metabolism of vit D and

reduced intestinal Ca++ absorption)Hematopoietic system

• Blood dyscrasias (megaloblastic anemia, aplastic anemia) (rare)

• Lymphoadenopathy, pseudolymphoma (after long treatments)

• Malignant lymphoma (?), Hodgkin's disease (?)

Phenytoin – Adverse EffectsOther systems

• Skin hyperpigmentation, hirsutism (mainly in women)

• Coarsening of facial features (mainly in children)

Pregnancy

• Risk of malformations increases 2-3 fold• A "fetal hydantoin syndrome" (cleft lip, cleft

palate, congenital heart disease, slowed growth and mental deficiency)

Phenytoin – Therapuetic UsesEpilepsy

• First or second choice drug for partial and generalized tonic-clonic seizures.

• Fosphenytoin is drug of choice for the emergency treatment of status epilepticus.

• (Absence, myoclonic and akinetic seizures may worsen in patients treated with phenytoin).

Trigeminal and related neuralgias

• Carbamazepine remain the preferred agent for these conditions but phenytoin is a second choice drug and can achieve good results.

Cardiac arrhythmias

• Used mainly when arrhythmias are due to digitalis toxicity.

3. Phenobarbital

Mechanism of action

• Enhancement of GABA-mediated inhibition (the opening of Cl- channels is prolonged by facilitating GABA action)

• Blockade of AMPA receptors• Direct opening of Cl- channels (after high doses)• Blockade of Na+ and Ca++ channels (at high

doses)

Pharmacological effects

• Suppression of the excessive discharge of the seizure focus

• Prevention of the spread of excitation from seizure focus.• All other effects of the barbiturate class.Pharmacokinetics

• Oral bioavailability: 100%

• Biotransformation: 75% by the liver (biotransformation rate is low)

• Excretion by the kidney: 25% (in acid urine) up to 75% (in alkaline urine)

Adverse effects, contraindications

• All the adverse effects and contraindications of barbiturate class (dependence occurs with barbiturates, but not with phenobarbital)

Therapeutic uses

Second choice drug for:

1. Partial seizures,2. Generalized tonic-clonic seizures3. Status epilepticus.

4. Valproic Acid

Mechanism of action• The drug likely acts with multiple mechanisms,

including:1. State-dependent blockade of inactivated

Na+ channels.2. Blockade of NMDA receptor mediated

excitation.3. Blockade of T type Ca++ channels in

thalamic neurons.

Pharmacological effects• A broad spectrum antiepileptic drug • The drug can inhibit CYP2C9 and

glucuronosyltransferase, so inhibiting the biotransformation of many drugs.

Pharmacokinetics• Oral bioavailability: 100%• Biotransformation: > 95% by the liver (some

metabolites are active)

Valproic Acid – Adverse EffectsCNS

• Sedation, drowsiness (when given with other CNS depressants)

• Dizziness, tremor, ataxia, nystagmus , diplopia, dysarthria

• Nervousness, agitation (mainly in children).

Gastrointestinal system

• Nausea, vomiting, anorexia, weight gain (up to 20%).

• Hyper-ammon-emia (50%), fulminant hepatitis

Hematopoietic system

• Thrombocytopenia, mainly-dose related (up to 30% of patients).

Allergic reactions

• Skin rashes, photosensitivity, erythema multiforme

Reproductive system.

• Menstrual disturbances (up to 20% of patients).

• Increased risk of neural tube defect (up to 20 fold) when given during pregnancy. Spina bifida can ensue.

Therapeutic Uses1. Epilepsy

• Valproic acid can be considered a first or second line therapy in all forms of epilepsy in all age groups.

• It is the best drug available to control myoclonic seizures (results are good and sometimes excellent) and atonic seizures (results are sometimes rather good)

• It is a first line agent (together with carbamazepine and phenytoin) for tonic-clonic seizures.

• It is a first line agent (together with ethosuximide) in absence seizures (for uncomplicated absence seizures ethosuximide is preferred because of valproate hepatotoxicity)

• It is the preferred drug in patients with absence seizures and concomitant grand mal seizures.

• It is considered equally effective as carbamazepine in simple and complex partial seizures.

• It is an alternative drug in infantile spasms and Lennox Gastaut syndrome.

2. Bipolar affective disorder

• It is considered a drug of choice (together with lithium) for the therapy of acute mania and the prophylactic treatment of bipolar disorder, especially in rapid cycling patients.

3. Migraine prophylaxis

• It has been approved by FDA for the prevention of migraine attack (mechanism is still uncertain).

• There is no evidence that it might be useful in treatment of acute migraine attack.

5. Ethosuximide

Mechanism of action• Blockade of voltage-sensitive T type Ca++

channels in thalamic neurons • The T type Ca++ current is thought to provide

a pacemaker current in thalamic neurons responsible for generating the rhythmic cortical discharge of an absence attack.

Pharmacological effects

• Suppression of the oscillating discharge of the thalamic seizure focus.

• Prevention of the spread of excitation through thalamocortical and corticothalamic circuits.

• Other brain circuits are unaffected at therapeutic concentrations.

Pharmacokinetics

• Biotransformation: 75% by the liver

• Half-life: 45 hours

Therapeutic uses

• It is the preferred drug in absence seizures (it prevents the attacks in more than 60% of patients and diminishes their frequency in 20-30% of patients).

• The earlier is the treatment, the greater the efficacy of the therapy (best results are obtained if therapy is started within 1-3 months since the beginning of attacks).

• It is considered a second choice drug in myoclonic and atonic seizures.

6. Benzodiazepines

• All benzodiazepines have antiseizure properties but some selectivity seems to exist since certain compounds, like clonazepam, appear more effective than others in specific seizure types.

• Diazepam and clonazepam are the drugs most frequently used as anticonvulsants

Mechanism of action

• Enhancement of GABA-induced increased frequency of bursts of openings of chloride channels.

Pharmacological effects

• Prevention of the spread of excitation from seizure focus

• All other effects of benzodiazepine class.

7. Carbonic Anhydrase InhibitorsDrugs• Acetazolamide is the drug most frequently used

Mechanism of action• Inhibition of carbonic anhydrase increases the

CO2 content in the brain.• Decrease in tissue pH seems to inhibit Na+

entrance into the cells.• Anticonvulsant effects (which are similar to those

of carbon dioxide) rapidly undergo tolerance.

Toxicity• Paresthesias, drowsiness (10%)• Nephrolithiasis• Hyperchloremic metabolic acidosis (with high

doses)• Sulfonamide-type allergic reactionsTherapeutic uses• As an alternative drug in all type of seizures

(efficacy is low and tolerance limit the use).• The drug may have special role in epileptic

women with seizure exacerbation at the time of menses.

Second Generation Antiseizure Drugs

• All second generation drugs are effective when taken in addition to another anti-seizure drug (adjuvant therapy).

• All drugs can be used as second choice in tonic-clonic seizures

• Most drugs can be used as first-choice in simple partial seizures

• Some drugs can be used as first choice in generalized seizures:

a) Tonic clonic seizures (lamotigrine, topiramate, levetiracetam)

b) Absence seizure (lamotigrine)

1. LamotrigineMechanism of action

• The drug likely acts with multiple mechanisms, including:

a. Voltage- and frequency-dependent blockade of Na+ channels (most likely the main mechanism).

b. Blockade of voltage-gated Ca++ channels

Adverse effects

• Generalized skin rash (8%, incidence, higher in children)

• Severe rash and Sevens-Johnson syndrome (up to 0.8%).

2. Topiramate

Mechanism of action

• Likely multiple, including:

A. Blockade of voltage-gated Na+ and Ca++ channels

B. Potentiation of inhibitory effects of GABA at GABA-A receptors.

Adverse effects

• Most common (10%) and dose-related: drowsiness, dizziness, fatigue, ataxia, aphasia, nystagmus, paresthesias.

• Occasional: ocular hypertension, angle-closure glaucoma, metabolic acidosis.

Contraindications and precaution

• Glaucoma, COPD, nephrolithiasis, porphyria.

Other uses

• Migraine prophylaxis.

Mechanism of action

• Still uncertain. It may involve:A. Decreased release of glutamate from presynaptic terminals

(most likely due to blockade of presynaptic voltage-gated Ca++ channels)

Adverse effects

• Most common (10%) and dose-related: fatigue, drowsiness, dizziness, ataxia.

• Abrupt discontinuation can cause a withdrawal reaction (anxiety, insomnia, sweating).

Other uses

• Essential tremor.• Neuropathic pain (post-herpetic neuralgia).

3. Gabapentin

5. Levetiracetam

Mechanism of action

• Still uncertain. The drug binds selectively to a synaptic vesicular protein.

• This can likely modify the synaptic release of glutamate and GABA.

6. Tiagabine

Mechanism of action

• Inhibition of GABA reuptake in both neurons and glia, so enhancing GABAergic transmission.

Adverse effects

• Most common (10%) and dose-related: nervousness, dizziness, fatigue, tremor.

• Increased incidence of status epilepticus in patients with refractory partial epilepsy.

FDA Pregnancy Risk for Antiseizure Drugs

Drug FDA Category Drug FDA Category

Carbamazepine D Lamotrigine C

Phenytoin D Topiramate C

Valproic acid D Levetiracetam C

Phenobarbital D Felbamate C

Clonazepam D Gabapentin C

Ethosuximide C Tiagabine C

Acetazolamide C Zonisamide C