Antiseizure Drugs Kaukab Azim, MBBS, PhD. Drug Groups First Generation Drugs Second Generation Drugs Others For Partial and Generalized Tonic- Clonic.

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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 Felbamate Levetiracetam Lamotrigine Tiagabine Topiramate Zonisamide Acetazolamide ACTH Glucocorticoids Carbamazepine Valproic acid Phenytoin Clonazepam Diazepam Lorazepam Ethosuximide Valproic 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

Seizure Disorders A 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.

Epilepsy The 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 Drugs Antiseizure (also called anticonvulsant, antiepileptic) drugs are compounds fully effective in controlling seizures in % 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 Congeners Drugs Carbamazepine, 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 Congeners Drugs Phenytoin, 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 - 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 Effects Central 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 Effects Hematopoietic 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 Uses Epilepsy 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.

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 (see barbiturates).

Phenobarbital 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 seizures 3.Status epilepticus.

Valproic Acid Mechanism 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 Effects CNS 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 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 Uses 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.

Valproic Acid – Therapeutic Uses 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. 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.

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 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.

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.

Carbonic Anhydrase Inhibitors Drugs Acetazolamide is the drug most frequently used Mechanism of action Inhibition of carbonic anhydrase increases the CO 2 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)

Lamotrigine Mechanism 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%). La MOE tri jeen

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. 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. toe PYRE a mate

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 Gabapentin ga ba pen tin

Gabapentin Adverse 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).

Felbamate Mechanism of action Likely multiple, including a.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.

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 Therapeutic uses Adjunct or second choice drug for partial seizures. (Absence, myoclonic and akinetic seizures may worsen in patients treated with tiagabine) tye AG a been

Zonisamide Mechanism 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 uses Second choice or adjunct or drug for: a.Partial and tonic clonic seizures. b.Myoclonic seizures c.Lennox Gastaut syndrome d.Infantile spasms zoe NIS a mide)

FDA Pregnancy Risk for Antiseizure Drugs DrugFDA CategoryDrugFDA Category CarbamazepineDLamotrigineC PhenytoinDTopiramateC Valproic acidDLevetiracetamC PhenobarbitalDFelbamateC ClonazepamDGabapentinC EthosuximideCTiagabineC AcetazolamideCZonisamideC