ANTIEPILEPTIC DRUGS
Hiwa K. Saaed, BPharm, HD, MSc, PhDDepartment of Pharmacology & Toxicology
College of Pharmacy
University of Sulaimani 2019-20
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Antiepileptic drugs (AEDs)
ØDefinitions and Terminology
ØEtiologies and risk factors
ØClassification of epileptic seizures
ØManagement of epilepsy
ØPrinciples of treatment
ØHistorical overview
ØClassification of AntiepilepticØMechanism of Antiepileptic drug
ØSpecial cases: pregnancy
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Epilepsy:
Epilepsy: is a chronic disorder of cerebral cortex characterized by recurrent (periodic and unpredictable) seizures, often accompanied by episodes of unconsciousness and/or amnesia.Seizures are sudden, transitory, and uncontrolled episodes of brain dysfunction, resulting from abnormal electrical discharge in cerebral neuronal cells, associated with prolonged depolarisation of cerebral neurons result in motor, sensory or behavioral changes loss of consciousness, abnormal movements, atypical or odd behavior, and distorted perceptions that are of limited duration but recur if untreated.
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Approximately 10% of the population has at least one seizure in their lifetime. Globally, epilepsy is the fourth most common neurologic disorder after migraine, cerebrovascular disease (stroke), and Alzheimer’s disease. Epilepsy is not a single entity but an assortment of different seizure types and syndromes originating from several mechanisms that have in common the sudden, excessive, and synchronous discharge of cerebral neurons.
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Epilepsy:
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SeizuresThe site of origin of the abnormal neuronal firing determines the symptoms that are produced. For example, qif the motor cortex is involved, the patient may experience abnormal
movements or a generalized convulsion.qSeizures originating in the parietal or occipital lobe may include visual,
auditory, and olfactory hallucinations. Seizures may Remain localised (focal epilepsy) OR Spread (generalised
epilepsy)
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ETIOLOGY OF SEIZURES
• Epilepsy can be due to an underlying genetic, structural, or metabolic cause or an unknown etiology.
• Idiopathic: In most cases, epilepsy has no identifiable cause. • The neuronal discharge in epilepsy results from firing of a small
population of neurons in a specific area of the brain referred to as the “primary focus.”
• Focal areas that are functionally abnormal may be triggered into activity by changes in physiologic factors, such as:⎯ an alteration in blood gases, pH, electrolytes, and blood glucose ⎯ changes in environmental factors, such as sleep deprivation, alcohol intake,
and stress. • A number of causes , can precipitate seizures such as:
⎯ illicit drug use, ⎯ tumor, head injury, meningeal infection, ⎯ hypoglycemia, ⎯ and the rapid withdrawal of alcohol
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I. Partial (Focal) Seizures
1. Partial (focal) seizures (60%): they start locally in a certain site, its divided into:
A. Simple partial: may occur at any age, without loss of consciousness, 1. Jacksonian motor epilepsy: convulsion in single group of
muscles or limb. 2. Jacksonian sensory epilepsy or paraesthesia in some localized
region.B. Complex partial (psychomotor or temporal lobe):• it is associated with loss of consciousness for about 30 seconds to
2 minutes.• Disturbances of cognitive, affective, and psychomotor (chewing
movement, diarrhoea, urination) or sensory hallucinations (smell or taste).
• 80% of individuals experience their initial seizures before 20 years of age.
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II. Generalized Seizures
begin locally, rapidly spread, affect the whole brain, both hemispheres, may be convulsive or non convulsive, immediate loss of consciousness. It is divided into:1. Tonic-clonic (grand-mal): Patient fall in convulsion & may
bite his tongue & may lose control of his bladder or bowel.
2. Absence (petit-mal): Loss of consciousness without involving motor area. Most common in children ( 4-12 yrs. ).
3. Tonic: Some patients, after dropping unconscious experience only the tonic or clonic phase of seizure.
4. Atonic ( akinetic): Starts between the ages 2-5 yrs. The pt’s legs simply give under him & drops down.
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5. Myoclonic: rare, occur at any age؛ Sudden, brief shock like contraction which may involve the entire body or be confined to the face, trunk or extremities. May reoccur for several minutes.
6. Clonic: These seizures consist of short episodes of muscle contractions that may closely resemble myoclonic seizures. Consciousness is more impaired with clonic seizures as compared to myoclonic.
7. Febrile Seizures: young children (3M-5 years) with illness accompanied by high fever. Consist of generalized tonic-clonic convulsion with short duration.
8. Status epilepticus (reoccurring seizure): Continuous (a series of rapid recurrent seizures) tonic-clonic without intervening return of consciousness. It is life-threatening emergency.
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II. Generalized Seizures
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Classification of Epileptic Seizures
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First aid for seizures
Do• Remove harmful objects nearby• Cushion their head• aid breathing by gently placing them in recovery positionDon’t• Restrain the person movement• Put anything in the person’s mouth• Give them anything to eat and drink until they are fully
recovered
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Therapy is symptomatic in that the majority of drugs prevent seizures, but neither effective prophylaxis or cure is available.The goal of the therapy is to improve the patient’s quality of life through maximizing the seizure control & minimizing drug side effects In general, seizures can be controlled with one medication in approximately 75% of patients. Patients may require more than one medication in order to optimize seizure control, and some patients may never obtain total seizure control.Antiepileptics are indicated when there is two or more seizures occurred in short interval (6m-1year)Drug choice is based on:1. Classification of seizures. 2. Patient’s age & health state3. Data on efficacy, tolerability, safety and pharmacokinetics
Management of Epilepsy
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Starting Treatmentstart low, go slow
• Rx should always be started with a single drug at a small dose
• All common side-effects must be discussed
• Teratogenicity and contraception if applicable
• Importance of compliance should be stressed
• Careful titration is a must
- start low, go slow
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• Modern treatment of seizures started in 1850 with the introduction of bromides, which was based on the theory that epilepsy was caused by an excessive sex drive.
• In 1910, phenobarbital , became the drug of choice for many years. • A number of medications similar to Phenobarbital were developed,
including primidone.• In 1940, phenytoin has become a major first-line antiepileptic drug (AED) in
the treatment of partial and secondarily generalized seizures.• In 1968, carbamazepine (CBZ) was approved, initially for the treatment of
trigeminal neuralgia; later, in 1974, it was approved for partial seizures. • Ethosuximide has been used since 1958• Valproate (VPA) was licensed in Europe in 1960 and in the United States in
1978, and now is widely available throughout the world.
Historical overview
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Classification of Antiepileptics (AEDs)Classical before 1990PhenytoinPhenobarbitalPrimidoneCarbamazepineEthosuximideValproic AcidBenzodiazepines
Newer after 1990Felbatol (felbamate) 1993Neurontin (gabapentin) 1994Lamictal (lamotrigine) 1995Topamax (topiramate) 1996Gabitril (tiagabine) 1998Keppra (levetiracetam) 1999Trileptal (oxcarbazepine) 2000Zonegran (zonisamide) 2000Lyrica (pregabalin) 2005Potiga (Ezogabine)Aptiom (Eslicarbazepine)Banzel (Rufinamide), VIMPAT (Lacosamide), Brivaracetam، Perampanelother
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Antiepileptic drugs (AEDs)
AEDS act by:I. Block the initiation of the electrical discharge from the focal areaII. Prevent the spread of abnormal electrical discharge to adjacent brain areaAEDs prevent depolarisation of neurones by:
• Modification of ion conductance (direct membrane stabilisation) • inhibition of excitatory (glutamergic) activity • stimulation of inhibitory (GABAergic) transmission.
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They do their actions by:
↓ axonal conduction by preventing Na+ influx through fast Na+ channelsExample: Carbamazepine, oxcarbamazepine, phenytoin, also at high doses
barbiturates and valproate. Lamotrigine, felbamate, topiramate
↓ presynaptic Ca+2 influx through type T channels in thalamic neuronsExample: Ethosuximide, valproic acids, lamotrigine
↑ inhibitory tone through 1. facilitation of GABA-mediated hyperpolarization (Barbs,
BZs), 2. inhibiting GABA metabolism valproic acid and vigabatrin 3. or action on the reuptake of GABA (as with tiagabine)
↓ excitatory effects of glutamic acid1. lamotrigine, topiramate (block AMPA receptors); 2. Felbamate, Phenobarbital (blocks NMDA receptors)
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GABA Neurons
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Glutamate Neurons
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Ion Channels#Na+: Phenytoin, Carbamazepine, LamotrigineTopiramateValproic acid# For general tonic-clonicand partial seizuresCa++ #: EthosuximideValproic acidZonisamide# For Absence seizures
Enhance Inhibitory aa #Benzodiazepines(diazepam, clonazepam) Barbiturates (phenobarbital)Valproic acid GabapentinVigabatrinTopiramateFelbamate# Most effective in myoclonic but also in tonic-clonic and partialClonazepam: for Absence
Inhibit Excitatory aaFelbamateTopiramate
Classification of AEDs
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PHENYTOINPhenytoin (diphenylhydantoin)Fosphenytoin (IM, IV)Considered drug of choice (DOC) for• Tonic-clonic seizures• partial seizures (simple and complex)• initial Tx in adultsAlso used for• cardiac arrhythmias• trigeminal neuralgicPharmacokinetics• 90% plasma protein bound• Saturable (zero order) kinetics in therapeutic dose range• potent hepatic enzyme inducer (interaction with inhibitors)
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MECHANISM OF ACTIONReduces the propagation of abnormal impulses in the brain by:• Blocks voltage-gated Na+
channels by selectively binding to the channel in the inactive state and slowing its rate of recovery.
• At much higher concentrations, block voltage-dependent Ca+2 channels and interfere with the release of monoaminergic NTs
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PHENYTOIN Adverse effects
Ataxia and nystagmus.Cognitive impairment.HirsutismGingival hyperplasia, Coarsening of facial features.folate dependent megaloblastic anaemia,Osteomalacia, Inhibition of ADH,inhibition of insulin secretion→ hyperglycemia and glycosuriaHypoprothrominemia—coagulopathyExacerbates absence seizures.
PHENYTOIN TERATOGENICITY
Fetal hydantoin syndrome include:• cleft lip, cleft palate • congenital heart disease• slowed growth • mental deficiency
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CARBAMAZEPINE Pharmacokinetics
Blocks voltage-gated Na+ ChannelsIndications: Considered DOC for tonic-clonic, partial seizures, trigeminal neuralgias, prophylaxis of manic depressive illnessPharmacokinetics:• Absorbed slowly, enters brain rapidly• Potent inducer of hepatic drug metabolising enzymes
• own half life reduces over 2-3 weeks• increases metabolism of theophylline, warfarin and various
hormones• complex drug interactions with other anticonvulsant agents
Adverse effects• Stupor, coma, respiratory depression, drowsiness, dizziness, vertigo,
ataxia, • blurred vision, diplopia, bradycardia, skin rashes, GI upsets. • Hyponatremia in elderly.• The 10,11-epoxide metabolite →blood dyscrasias (leukopenia and
aplastic anaemia), and serious liver toxicity.
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OXCARBAZEPINE (Trileptal)
10-KETO DERIVATIVE OF CARBAMAZEPINEWith improved toxicity profile.Less potent than carbamazepine.Active metabolite.Mechanism of action, similar to carbamazepine Adverse effects: • Hyponatremia, • Less hypersensitivity, and induction of hepatic enzymes
than with carbamazepine.
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Eslicarbazepine
• Eslicarbazepine acetate is a prodrug that is converted to the active metabolite eslicarbazepine (S-licarbazepine) by hydrolysis.
• S-licarbazepine is the active metabolite of oxcarbazepine• It is a voltage-gated sodium channel blocker • It is approved for partial-onset seizures in adults. • linear pharmacokinetics and is eliminated via glucuronidation.• The side effect profile includes dizziness, somnolence, diplopia,
and headache. Serious adverse reactions such as rash, psychiatric side effects, and hyponatremia occur rarely.
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SODIUM VALPROATEMost effective and broad spectrum, DOC for tonic clonic, partial, absence and myoclonic seizures, inhibits P450 systemAdverse effects:
• Elevated liver enzymes including own.• Tremor, hair loss, changes in hair growth• increased appetite Weight gain.• coagulopathy (inhibition of platelet aggregation), • Idiosyncratic hepatotoxicity.• Negative interactions with other antiepileptics.• Teratogen: spina bifida
FELBAMATE (Felbatrol)Effective against partial seizures but has severe side effects.Thus, used only for refractory cases. One of the metabolites; α,β-unsaturated aldehyde, 2-phenylpropenal is chemically reactive, like acrolein covalently linking proteins as well as DNA,it can cause liver and bone marrow toxicity
• Blocks voltage gated Na+ channel, • may block Ca+2 Channel• Block GABA transaminase• Enhance GABAergic
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GABAPENTIN (Neurontin)
• Used as an adjunct in partial and generalized tonic-clonic seizures.• Does not induce liver enzymes.• not bound to plasma proteins.• drug-drug interactions are negligible.• Low potency.• An aa, Analog of GABA that does not act on GABA receptors, it may
however alter its metabolism, non-synaptic release and transport.• Alleviate both diabetic neuropathies pain and post herpetic pain
Adverse effects: Somnolence، Dizziness، Ataxia، Headache، Tremor.
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RX of Partial SeizuresInhibit GABA transaminaseADVERSE EFFECTS: Depression, psychosis, visual dysfunction
Vigabatrin
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LAMOTRIGINE (Lamictal) Adverse effects:• Dizziness• Headache• Diplopia• Nausea• Somnolence• Rash
Presently use as add-on therapy with valproic acid.Almost completely absorbedT1/2 = 24 hrsLow plasma protein binding Blocks sodium channels, & high voltage Ca+2 channelthus its effective in partial, generalized, myoclonic, absence seizures & Lennox-Gastaut syndrome (LGS).Approved for use in bipolar disorder
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Adjunct Rx of refractory Partial SeizureUnknown mechanism of action but binds to presynaptic vesicle proteinADVERSE EFFECT: Dizziness, sleep disturbances, headache, and asthenia (LACK OF ENERGY)
LEVETIRACETAM (Keppra)
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TIAGABINE (Gabatril)100% bioavailable,highly protein bound.T1/2 = 5 -8 hrsEffective against partial and generalized tonic-clonic seizures.GABA uptake inhibitor GAT-1.Adverse effects: Dizziness, Nervousness,Tremor, Difficulty concentrating, Depression, Asthenia, Emotional, Psychosis, Skin rash
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EZOGABINEEzogabine is thought to open voltage-gated M-type potassium channels leading to stabilization of the resting membrane potential. Ezogabine exhibits linear pharmacokinetics and no drug interactions at lower doses. Possible unique side effects are: urinary retention, QT interval prolongation, blue skin discoloration, retinal abnormalities.
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TOPIRAMATE (Topamax)
Adverse effects:• Somnolence• Fatigue• Dizziness• Cognitive slowing• Paresthesias• Nervousness• Confusion• Urolithiasis• Weight loss
• Broad spectrum antiseizure activity, also used in migraine
• Rapidly absorbed, bioav. is > 80%, has no active metabolites, excreted in urine.T1/2 = 20-30 hrs
• blocking of voltage-dependent sodium channels• Additionally ↑ the frequency of Cl- channel
opening by binding to GABA receptor.• High-voltage calcium currents (L-type) are reduced • Depresses excitatory action of kainate on AMPA
receptors.• Carbonic anhydrase inhibiter effect• Teratogenic in animal models.
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PERAMPANEL
is a selective Blockers of AMPA glutamate receptors resulting in reduced excitatory activity. Perampanel has a long half-life enabling once-daily dosing. It is approved for adjunctive treatment of partial-onset seizures in patients 12 years or older.
RUFINAMIDEacts at sodium channels. It is approved for the adjunctive treatment of seizures associated with Lennox-Gastaut syndrome in children over age 4 years and in adults.Adverse effects: include the potential for shortened QT intervals. Patients with familial short QT syndrome should not be treated with rufinamide.
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ZONISAMIDE
• Sulfonamide derivative• Orally active half-life 50-60 hrs• Both focal and generalizedMECHANISM OF ACTION• Blocks voltage-gated Na+ channels and T-type Ca+2 current, • enhancement of GABA-receptor function ADVERSE EFFECTS:
• somnolence, Ataxia, • Oligohidrosis has been reported, and patients should be monitored for
increased body temperature and decreased sweating. hyperthermia (children)• Kidney stone
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STATUS EPILEPTICUS
Status epilepticus is life threatening and requires emergency treatment usually consisting of administration of a fast-acting medication such as a benzodiazepine, followed by a slower-acting medication such as phenytoin.
Special Cases: PregnancySeizure very harmful for pregnant women.Antiepileptic drugs associated with increased (2-3 fold) incidence of birth defects (cleft lip/palate and cardiac defects)Significant risk of neural tube defects, folic acid is recommended to be given for every pregnant women with epilepsyPhenytoin, sodium valproate are absolutely contraindicated. Oxcarbamazepine is better than carbamazepine.Fetal exposure to lamotrigine or levetiracetam may be safer with regard to cognition than other antiseizure drugs, and these two agents also have the lowest risks of major congenital malformations.Monotherapy usually better than drugs combination.
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Valproate is a known human teratogen. First-trimester exposure is associated with an approximately three-fold increased risk of major congenital malformations, most commonly spina bifida (absolute risk, 6–9%). Phenobarbital use during pregnancy is also associated with an elevated risk of major congenital malformation, most often cardiac defects. First-trimester in utero exposure to topiramate is associated with an approximately 10-fold increase in oral clefts risk (absolute risk, 1.4%).Newborns of mothers receiving phenobarbitone, or phenytoin may develop hypoprothrominemia, heamorrhage prevented by Vit. K
Special Cases: Pregnancy & Breastfeeding
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BREAST FEEDING• Some antiepileptic drugs such as primidone, levetiracetam,
gabapentin, lamotrigine, and topiramate penetrate into breast milk in relatively high concentrations. For example, in one study, plasma concentrations of lamotrigine in breastfeeding infants were 18.3% of maternal plasma concentrations.
• Other antiseizure drugs that are highly protein bound, such as valproate, phenobarbital, phenytoin, and carbamazepine, do not penetrate into breast milk substantially.
• Case series have not reported adverse effects on the newborn of antiseizure drug exposure via breast milk, although there are some reports of sedation with the barbiturates and benzodiazepines. As a general rule, breastfeeding should not be discouraged given the lack of evidence of harm and the known positive benefits.
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ANTISEIZURE DRUG INTERACTIONS
With other drugs:antibiotics á phenytoin, phenobarb, carb.anticoagulants phenytoin and phenobarb á
metabolism.cimetidine displaces pheny, V.A and BDZsisoniazid á toxicity of phenytoinoral contraceptives antiepileptics á metabolism.salicylates displaces phenytoin and v.a.theophyline carb and phenytoin mayâeffect.
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