Antiseizure Drugs

Antiseizure Drugs

Kaukab Azim, MBBS, PhD

Drug Groups

First Generation Drugs Second Generation Drugs Others

For Partial and Generalized Tonic-

Clonic SeizuresFor Absence Seizures

GabapentinFelbamateLevetiracetamLamotrigineTiagabineTopiramateZonisamide

AcetazolamideACTHGlucocorticoids

CarbamazepineValproic acidPhenytoinClonazepamDiazepamLorazepam

EthosuximideValproic acid

Learning OutcomesBy 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

Seizure DisordersA seizure is the physical findings or changes in behavior that occur after an episode of abnormal electrical activity in the brain.

The term "seizure" is often used interchangeably with "convulsion." Convulsions are when a person's body shakes rapidly and uncontrollably. During convulsions, the person's muscles contract and relax repeatedly. There are many different types of seizures. Some have mild symptoms and no body shaking.

During a seizure some neurons of the brain begin to fire in massive synchronized bursts. After few seconds or minutes the inhibitory mechanisms of the brain regain control and the seizure stops.

EpilepsyThe term epilepsy includes disorders or syndromes with widely variable

pathophysiologic findings, clinical manifestations, treatments, and

prognoses. Individuals with epilepsy are identified by the tendency for and

occurrence of recurrent seizures. A seizure is a paroxysmal,

hypersynchronous, excessive neuronal discharge of variable extent.

However, the word seizure is not synonymous with the word epilepsy. Any

brain can generate a single or even multiple seizures under appropriate

provocative circumstances. It is the tendency to have recurrent seizures,

not necessarily with provocation, that makes the diagnosis of epilepsy.

More than one seizure must occur before the diagnosis of epilepsy is

made.

Antiseizure DrugsAntiseizure (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

Carbamazepine and CongenersDrugsCarbamazepine, 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 PYC3A4 inducing action (which leads to many pharmacokinetics interactions).

Pharmacokinetics• Oral bioavailability: . 90%• Biotransformation: 99% by the PYC3A4 (biotransformation

rate is low).

Adverse effects• Dizziness, drowsiness, blurred vision diplopia, ataxia

(common, doserelated).• 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

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).

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.

Bipolar affective disorder• As an alternative to lithium for the therapy of acute mania and the prophylactic

treatment of bipolar disorder.

Phenytion and CongenersDrugsPhenytoin, fosphenytoin (a prodrug rapidly converted to phenytoin in plasma)

Pharmacodynamics

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 - PharmacokineticsOral 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)Endocrine system• Hyperglycemia (due to decreased insulin secretion)• Osteomalacia (due to increased metabolism of vit D and reduced

intestinal Ca++ absorption)

Phenytoin – Adverse EffectsHematopoietic system• Blood dyscrasias (megaloblastic anemia, aplastic anemia) (rare)• Limphoadenopathy, pseudolymphoma (after long treatments)• Malignant lymphoma (?), Hodgkin's disease (?)Other 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.

PhenobarbitalMechanism 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 (see barbiturates).

PhenobarbitalPharmacokinetics

• 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, contraindicationsAll the adverse effects and contraindications of barbiturate class(dependence occurs with barbiturates, but not with phenobarbitalTherapeutic usesSecond choice drug for:

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

Valproic AcidMechanism of action• The drug likely acts with multiple mechanisms, including:

a) State-dependent blockade of inactivated Na+ channels.

b) Blockade of NMDA receptor mediated excitation.

c) Blockade of T type Ca++ channels in thalamic neurons.

Pharmacological effects• A broad spectrum antiepileptic drug (see therapeutic uses)• 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.

Valproate Hepatitis• The occurrence is about 1 in 37000 patients if the

drug is given alone, but 1 in 6500 patients if other drugs are given concurrently.

• Children below 2 years of age (or with mental retardation or congenital neurological disease) are especially at risk.

• Hepatitis appears usually after two months of therapy, but it may show after few days or after six months.

• Pathogenesis is unknown (most likely idiosyncratic)

Valproic Acid – Therapeutic UsesEpilepsy• 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.

Valproic Acid – Therapeutic UsesBipolar 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.

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.

EthosuximideMechanism 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• Oral bioavailability: > 90 %• Biotransformation: 75% by the liver• Half-life: 45 hours

Ethosuximide

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.

BenzodiazepinesAll 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.

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 reactions

Therapeutic 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)

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

Pharmacokinetics

• Oral bioavailability: 98%• Administration: oral

Adverse effects

• Most common (10%) and dose-related: drowsiness, dizziness,• fatigue, ataxia, diplopia.• Generalized skin rash (8%, incidence, higher in children)

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

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TopiramateMechanism 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.

c. Blockade of AMPA glutamate receptors.

d. Inhibition of carbonic anhydrase.

Pharmacokinetics

• Oral bioavailability: .80%.• About 50% is eliminated unchanged by the kidney• Administration: oral

Adverse effects

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

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

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Topiramate

Contraindications and precaution

• Glaucoma, COPD, nephrolithiasis, porphyria.

Antiseizure uses

• First or second choice or adjunct drug for:a. Simplex and complex partial seizures.

b. Tonic-clonic seizures.

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)b. Increased brain GABA concentration (possibly via nonvesicular

release of GABA)

Pharmacokinetics

• Intestinal absorption by a L-amino acid carrier protein.• Most drug is eliminated unchanged by the kidney• Administration: oral

Gabapentinga ba pen tin

GabapentinAdverse effects

• Most common 10%) and dose-related: fatigue, drowsiness, dizziness, ataxia.• Abrupt discontinuation can cause a withdrawal reaction (anxiety, insomnia,

sweating).

Antiseizure uses

Second choice or adjunct drug for:• Partial seizures, tonic-clonic seizures• (Absence, myoclonic and akinetic seizures may worsen in patients treated

with gabapentin)

Other uses

• Essential tremor.

• Neuropathic pain (post-herpetic neuralgia).

FelbamateMechanism of action

• Likely multiple, includinga. Blockade of NMDA glutamate receptors

b. Potentiation of GABA responses

Adverse effects

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

• Aplastic anemia (0.03%) and severe hepatitis (0.01%)(these serious adverse effects limit felbamate use)

Therapeutic uses

Second choice drug for:

a. Atonic seizures

b. Lennox Gastaut syndrome

Levetiracetam(Le- ve-teer-A-se-tam)

Mechanism of action

• Still uncertain. The drug binds selectively to a synaptic vescicular protein. This can likely modify the synaptic release of glutamate and GABA.

Adverse effects

• Drowsiness, fatigue ,dizziness, ataxia.

Therapeutic uses

First or second choice or adjunct drug for:

a. Partial seizures, tonic clonic seizures

b. Myoclonic seizures.

TiagabineMechanism 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

Therapeutic uses

Adjunct or second choice drug for partial seizures.

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

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ZonisamideMechanism of action• Likely multiple, including

a. Blockade of Na+ channels

b. Blockade of T type CA++ channels.

c. Enhancement of GABAergic transmission

d. Inhibition of glutamatergic transmission

Adverse effects• Drowsiness, dizziness, headache, irritability.• Allergic reactions (the drug is a sulfonamide

Therapeutic usesSecond choice or adjunct or drug for:

a. Partial and tonic clonic seizures.

b. Myoclonic seizures

c. Lennox Gastaut syndrome

d. Infantile spasms

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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