2 First Generation Drugs Second Generation Drugs Drug GroupsFirst Generation DrugsSecond Generation DrugsOthersFor Partial and Generalized Tonic-Clonic SeizuresFor Absence SeizuresGabapentinFelbamateLevetiracetamLamotrigineTiagabineTopiramateZonisamideAcetazolamideACTHGlucocorticoidsCarbamazepineValproic acidPhenytoinClonazepamDiazepamLorazepamEthosuximide
3 Learning OutcomesBy the end of this course the students should be able to:List the main classes of anti-epileptic drugsExplain the mechanism of action of each drug in each groupDescribe the pharmacological effects of each drug in each groupDescribe the main pharmacokinetic features or each drug in each groupDescribe the main adverse effects of each drug in each groupList the main contraindications of antiseizure drugsOutline the main therapeutic uses of antiseizure drugs
4 Classification of epilepsy GeneralizedTonic clonic seizureAbsence seizureMyoclonicTonicAtonicPartialSimpleComplexPartial with secondary generalization
5 Antiseizure DrugsAntiseizure (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.
6 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 channelsb) inhibitory and excitatory synaptic functions
7 1. Carbamazepine and Congeners DrugsCarbamazepine, oxcarbazepine.Mechanism of actionFrequency-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)
8 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).
9 Carbamazepine and Congeners PharmacokineticsOral bioavailability: . 90%Biotransformation: 99% by the CYP3A4 (biotransformation rate is low).Adverse effectsDizziness, 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).Cardiac arrhythmias.Heart failure, after long treatments (rare).Water retention and hyponatremia, after long treatments.Hepatic failure, after long treatments (rare).Allergic reactions: skin rash (. 5%), Stevens-Johnson syndrome, lupoid syndrome, aplastic anemia (rare).The risk of malformations (mainly related to neural tube defect) is increases 2-3 fold during pregnancy[Adverse effects of oxcarbazepine are similar but less frequent]
10 Carbamazepine – Therapeutic Uses 1. EpilepsyIt 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).Diabetes insipidusRarely used to treat pituitary diabetes insipidus. The drug is not effective in nephrogenic diabetes insipidus, which indicates that functional V2 receptors are required for the antidiuretic effect of the drug.
11 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 disorderAs an alternative to lithium for the therapy of acute mania and the prophylactic treatment of bipolar disorder.
12 2. Phenytion and Congeners DrugsPhenytoin, fosphenytoin (a prodrug rapidly converted to phenytoin in plasma)Mechanism of actionFrequency-dependent and voltage-dependent blockade of inactivated Na+ channels (most likely the main mechanism).Induction of hepatic microsomal enzymes.
13 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).
14 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.Elimination: is dose dependent, i.e. first order at low doses, but zero order at high doses. (This means that when the maximum capacity of the liver to metabolize the drug is approached, even a small further increase in dosage may cause a very large increase in blood levels of the drug).
15 Phenytoin – Adverse Effects Central nervous systemNystagmus (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 systemGingival hyperplasia (30-40% of patients)Hepatitis, hepatic necrosis (rare)Inhibition of folate absorption (after long treatments)
16 Gastrointestinal system Gingival hyperplasia (30-40% of patients)Inhibition of folate absorption (after long treatments)Endocrine systemHyperglycemia (due to decreased insulin secretion)Osteomalacia (due to increased metabolism of vit D and reduced intestinal Ca++ absorption)Hematopoietic systemBlood dyscrasias (megaloblastic anemia, aplastic anemia) (rare)Lymphoadenopathy, pseudolymphoma (after long treatments)Malignant lymphoma (?), Hodgkin's disease (?)
17 Phenytoin – Adverse Effects Other systemsSkin hyperpigmentation, hirsutism (mainly in women)Coarsening of facial features (mainly in children)PregnancyRisk of malformations increases 2-3 foldA "fetal hydantoin syndrome" (cleft lip, cleft palate, congenital heart disease, slowed growth and mental deficiency)Allergic skin reactionsSkin rashes, erythema multiformeExfoliative dermatitis, Stevens-Johnson syndrome, lupoid syndrome (very rare)
18 Phenytoin – Therapuetic Uses EpilepsyFirst 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 neuralgiasCarbamazepine remain the preferred agent for these conditions but phenytoin is a second choice drug and can achieve good results.Cardiac arrhythmiasUsed mainly when arrhythmias are due to digitalis toxicity.
19 3. Phenobarbital Mechanism of action Enhancement of GABA-mediated inhibition (the opening of Cl- channels is prolonged by facilitating GABA action)Blockade of AMPA receptorsDirect opening of Cl- channels (after high doses)Blockade of Na+ and Ca++ channels (at high doses)
20 Pharmacological effects Suppression of the excessive discharge of the seizure focusPrevention of the spread of excitation from seizure focus.All other effects of the barbiturate class.PharmacokineticsOral 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)
21 Adverse effects, contraindications All the adverse effects and contraindications of barbiturate class (dependence occurs with barbiturates, but not with phenobarbital)Therapeutic usesSecond choice drug for:Partial seizures,Generalized tonic-clonic seizuresStatus epilepticus.
22 4. Valproic Acid Mechanism of action The drug likely acts with multiple mechanisms, including:State-dependent blockade of inactivated Na+ channels.Blockade of NMDA receptor mediated excitation.Blockade of T type Ca++ channels in thalamic neurons.ChemistryValproic acid is the dipropylacetic acid. Salts, ester and amides of this acid (i.e. sodium valproate) are also active antiseizure agents.Mechanism of actionThe 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.d) Increased GABA content in the brain (mechanism is uncertain)e) Opening K+ channels (at high doses)
23 Pharmacological effects A broad spectrum antiepileptic drugThe drug can inhibit CYP2C9 and glucuronosyltransferase, so inhibiting the biotransformation of many drugs.PharmacokineticsOral bioavailability: 100%Biotransformation: > 95% by the liver (some metabolites are active)
24 Valproic Acid – Adverse Effects CNSSedation, drowsiness (when given with other CNS depressants)Dizziness, tremor, ataxia, nystagmus , diplopia, dysarthriaNervousness, agitation (mainly in children).Gastrointestinal systemNausea, vomiting, anorexia, weight gain (up to 20%).Hyper-ammon-emia (50%), fulminant hepatitis
25 Hematopoietic systemThrombocytopenia, mainly-dose related (up to 30% of patients).Allergic reactionsSkin rashes, photosensitivity, erythema multiformeReproductive 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.
26 Therapeutic Uses 1. 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.
27 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.Lennox–Gastaut syndrome (LGS), also known as Lennox syndrome, is a difficult-to-treat form of childhood-onset epilepsy that most often appears between the second and sixth year of life, and is characterized by frequent seizures and different seizure types; it is often accompanied by developmental delay and psychological and behavioral problems.West syndrome or infantile spasms is a severe epilepsy syndrome composed of the triad of infantile spasms, an interictal electroencephalogram (EEG) pattern termed hypsarrhythmia, and mental retardation,
28 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 prophylaxisIt 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.
29 5. Ethosuximide Mechanism of action Blockade of voltage-sensitive T type Ca++ channels in thalamic neuronsThe 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.
30 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.PharmacokineticsBiotransformation: 75% by the liverHalf-life: 45 hours
31 Therapeutic usesIt 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.
32 6. 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
33 Mechanism of actionEnhancement of GABA-induced increased frequency of bursts of openings of chloride channels.Pharmacological effectsPrevention of the spread of excitation from seizure focusAll other effects of benzodiazepine class.
34 7. Carbonic Anhydrase Inhibitors DrugsAcetazolamide is the drug most frequently usedMechanism of actionInhibition 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.
35 ToxicityParesthesias, drowsiness (10%)NephrolithiasisHyperchloremic metabolic acidosis (with high doses)Sulfonamide-type allergic reactionsTherapeutic usesAs 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.
37 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 seizuresMost drugs can be used as first-choice in simple partial seizuresSome drugs can be used as first choice in generalized seizures:Tonic clonic seizures (lamotigrine, topiramate, levetiracetam)Absence seizure (lamotigrine)
38 1. Lamotrigine Mechanism of action The drug likely acts with multiple mechanisms, including:Voltage- and frequency-dependent blockade of Na+ channels (most likely the main mechanism).Blockade of voltage-gated Ca++ channelsAdverse effectsGeneralized skin rash (8%, incidence, higher in children)Severe rash and Sevens-Johnson syndrome (up to 0.8%).
39 2. Topiramate Mechanism of action Likely multiple, including: Blockade of voltage-gated Na+ and Ca++ channelsPotentiation of inhibitory effects of GABA at GABA-A receptors.
40 Adverse effectsMost common (10%) and dose-related: drowsiness, dizziness, fatigue, ataxia, aphasia, nystagmus, paresthesias.Occasional: ocular hypertension, angle-closure glaucoma, metabolic acidosis.Contraindications and precautionGlaucoma, COPD, nephrolithiasis, porphyria.Other usesMigraine prophylaxis.
41 3. Gabapentin Mechanism of action Still uncertain. It may involve: Decreased release of glutamate from presynaptic terminals (most likely due to blockade of presynaptic voltage-gated Ca++ channels)Adverse effectsMost common (10%) and dose-related: fatigue, drowsiness, dizziness, ataxia.Abrupt discontinuation can cause a withdrawal reaction (anxiety, insomnia, sweating).Other usesEssential tremor.Neuropathic pain (post-herpetic neuralgia).
42 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.
43 6. Tiagabine Mechanism of action Inhibition of GABA reuptake in both neurons and glia, so enhancing GABAergic transmission.Adverse effectsMost common (10%) and dose-related: nervousness, dizziness, fatigue, tremor.Increased incidence of status epilepticus in patients with refractory partial epilepsy.
44 FDA Pregnancy Risk for Antiseizure Drugs FDA CategoryCarbamazepineDLamotrigineCPhenytoinTopiramateValproic acidLevetiracetamPhenobarbitalFelbamateClonazepamGabapentinEthosuximideTiagabineAcetazolamideZonisamide