Antiepileptic drugs

Seizures Various forms (depending on the part of the brain affected) Result from episodic high-frequency discharge of a group of neurons (excitotoxicity) Starting locally May then spread to other areas of the brain recurrent seizures

Nature of Epilepsy The neurochemical basis of the abnormal discharge is not well understood. It may be associated with enhanced excitatory amino acid transmission, impaired inhibitory transmission, or abnormal electrical properties of the affected cells. The glutamate content in areas surrounding an epileptic focus is often raised.

Nature of epilepsy Abnormal electrical activity during seizure can be detected by electroencephalograph (EEG) Recording from electrodes distributed over the surface of the scalp Can recognize various types of seizures.

Symptoms Range from a brief lapse of attention to a convulsion (several minutes) Depends on the function of the region of the brain that is affected

Affected brain regions Motor cortex (convulsion) Hypothalamus (peripheral autonomic discharge) Reticular formation in the upper brainstem (loss of consciousness)

Epilepsy Recurrent seizures Treated mainly with drugs Brain surgery may be used for severe cases

Causes of epilepsy No recognizable cause May develop after brain damage Trauma, infection or tumor growth Or other kinds of neurological disease

Epileptogenesis Excitatory transmission is facilitated (e.g. glutamate) Inhibitory transmission is reduced (e.g. GABA) Abnormal electrical properties of the affected cells

EPILEPSY affects 5–10% of the general population. It is due to sudden, excessive depolarization of some or all cerebral neurons. This may be: localized (focal or partial seizure); spread to cause a secondary generalized seizure; may affect all cortical neurons simultaneously (primary generalized seizure).

Classification of seizures EEG Cortex: F – frontal O – occipital T – temporal Rang et al. Pharmacology – 5th Ed. (2003) Classification of seizures

Types of epilepsy Two major seizure categories: Partial Generalized Both can be classified as: Simple (if consciousness is not lost) Complex (if consciousness is lost) The type of seizure determines the choice of drug!

Partial seizures Discharge begins locally (often remain localized) EEG discharge is normally confined to one hemisphere

Partial seizures Symptoms include: Involuntary muscle contraction Abnormal sensory experiences Autonomic discharge Or effects on mood and behavior

Simple partial seizures

Complex partial seizures Loss of consciousness Discharge in the brainstem reticular formation Are among the commonest types of epilepsy

Complex partial seizures

Jacksonian epilepsy In motor cortex Repetitive jerking of particular muscle group May spread to involve much of the body Losses voluntary control of the affected parts of the body Does not necessarily loss consciousness

Psychomotor epilepsy In temporal lobe The attack may consist of movements such as: Rubbing movements Dressing or walking or hair-combing Lasts for a few minutes Recover with no recollection of the event The behavior during the seizure can be bizarre and accompanied by a strong emotional response

Generalized seizures Involve the whole brain, including the reticular system characterized by immediate loss of consciousness Producing abnormal electrical activity throughout both hemispheres

Generalized seizures Two important categories: Tonic-clonic seizures (grand mal) Absence seizures (petit mal)

Tonic-clonic seizures (grand mal) EEG shows Generalized continuous high-frequency activity in the tonic phase (2) An intermittent discharge in the clonic phase (3)

Tonic-clonic seizures (grand mal) Tonic phase: An initial strong contraction of the whole musculature, causing a rigid extensor spasm Respiration stops, defecation, micturition, salivation often occur Lasts for about 1 minute Tonic phase (stiffening of the body)

Tonic-clonic seizures (grand mal) Clonic phase: A series of violent, synchronous jerks after the tonic phase Gradually dies out in 2-4 minutes Clonic phase (the body jerks)

Tonic-clonic seizures (grand mal) The patient stays unconscious for a few more minutes and then gradually recovers, feeling ill and confused Post-convulsive phase (exhaustion)

Absence seizures (petit mal) Occur in children Much less dramatic May occur more frequently (many seizures each day) than tonic-clonic seizures

Absence seizures (petit mal) The patient ceases whatever he was doing Sometimes stopping speaking in mid-sentence Stares vacantly for a few seconds, with little or no motor disturbance. The patient is unaware of his surrounding Recovers with no after-effects

Absence seizures (petit mal)                                                                                  

Absence seizures (petit mal) EEG pattern shows a characteristic rhythmic discharge during the period of seizure The rhythmicity appears to be caused by oscillatory feedback between the cortex and the thalamus

Absence Seizures

Absence seizures (petit mal) Thalamic neurons activity depends on the calcium channels that they express Treated by blocking calcium channels

Lennox-Gastaut Syndrome (LGS: Lennox Syndrome) Severe kind of epilepsy Occurs in children Causes excitotoxic neurodegeneration Associated with progressive mental retardation

Antiepileptic drugs Effective in controlling seizures in about 70% of patients Their use is often limited by side-effects

Treatment Monotherapy with anticonvulsant Increase dose gradually until seizures are controlled or adverse effects become unacceptable. Multiple-drug therapy may be required. Achieve steady-state kinetics Monitor plasma drug levels Avoid sudden withdrawal

Primary generalized seizures AED Treatment Options Partial seizures Primary generalized seizures Tonic- Clonic Simple Complex Secondary Generalized Tonic Myoclonic Atonic Absence phenytoin, carbamazepine, phenobarbital, gabapentin, oxcarbazepine, pregabalin Ethosuximide valproic acid, lamotrigine, topiramate, (levetiracetam, zonisamide)

ANTISEIZURE DRUGS 1. Carboxamides (enzyme inductors – CYP450): Carbamazepine (+ neuropathic pain – n. trigeminus, postherpetic pain, etc.), Oxcarbazepine 2. Hydantoins: Phenytoin (enzyme inductor), 3. Barbiturates (Phenobarbital – enzyme inductors) and their analogues (Primidone – prodrug) 4. Succinimides: Ethosuximide (petit mal) 5. Valproates (enzyme inhibitors): Sodium valproate (Depakin®) 6. Benzodiazepines: Clonazepam, Clorazepate, Diazepam Lorazepam, Nitrazepam 7. GABA analogues: Gabapentin, Tiagabine 8. Hetereogenic anticonvulsants: Lamotrigine, Levetiracetam, Pregabalin (partial seizures, peripheral neuropathic pain), Topiramate, Vigabatrin ANTISEIZURE DRUGS

MECHANISM OF ACTION OF ANTIEPILEPTIC DRUGS Antiepileptics inhibit the neuronal discharge or its spread in one or more of the following ways: (1) Enhancing GABA synaptic transmission: barbiturates, benzo- diazepines, gabapentin, levetiracetam, tiagabine, vigabatrin, topira- mate, valproate; the result is increased permeability to chloride ion, which reduces neuronal excitability. Valproate and topiramate block GABA transaminase and tiagabine blocks reuptake of GABA. (2) Reducing cell membrane permeability to voltage-dependent sodium channels: carbamazepine, lamotrigine, oxcarbazepine, phenytoin, topiramate, valproate. (3) Reducing cell membrane permeability to calcium T-channels: valproate, ethosuximide; the result is diminishing of the generation of action potential. (4) Inhibiting excitory neurotransmitter glutamate: lamotrigine.

Treatment of Seizures Strategies: Modification of ion conductances. Increase inhibitory (GABAergic) transmission. Decrease excitatory (glutamatergic) activity.

Antiepileptic drugs Three main mechanisms: Other mechanisms include: Enhancement of GABA action Inhibition of sodium channel function Inhibition of calcium channel function Other mechanisms include: Inhibition of glutamate release Block of glutamate receptors

GABA Na+ Ca2+ Barbiturates Benzodiazepines Gabapentin Levetiracetam Tiagabine Topiramate Valproate Vigabatrin Na+ Ca2+ Carbamazepine Lamotrigine Oxcarbazepine Phenytoin Topiramate Valproate Ethosuximide Levetiracetam Pregabalin Valproate

Na+ Channel Inhibitors blocks voltage-gated sodium channels by selectively binding to the channel in the inactive state and slowing its rate of recovery Antiseizure drugs, enhanced Na+ channel inactivation Goodman & Gilman's The Pharmacologic Basis of Therapeutics - 11th Ed. (2006)

Na+ Channel Inhibitors Phenytoin (Dilantin, Phenytek) Fosphenytoin (Cerebyx) Carbamzepine (Tegretol, Carbatrol) Oxcarbazepine (Trileptal) Valproic Acid (Valproate; Depakene, Depakote) Lamotrigine (Lamictal) Topiramate (Topamax) Zonisamide (Zonegran)

Na+ Channel Inhibitors Phenytoin (Dilantin, Phenytek): Oldest nonsedative antiepileptic drug. Narrow therapeutic window (~ 40-100 μmol/l) Well absorbed. Indications: First choice for partial and generalized tonic-clonic seizures Some efficacy in clonic, myoclonic, atonic, No effect on infantile spasms or absence seizures Drug Interactions: Decreases blood levels of many medications Increases blood levels of phenobarbital & warfarin

Na+ Channel Inhibitors Phenytoin (Dilantin, Phenytek): Adverse Effects: Hirsutism & coarsening of facial features Acne Gingival hyperplasia (20-40%) Megaloplastic anemia. (corrected by folic acid) Decreased serum concentrations of folic acid, thyroxine, and vitamin K with long-term use. “Fetal hydantoin syndrome”: teratogenic includes growth retardation, microencephaly, and craniofacial abnormalities (e.g., cleft palate) and is possibly due to an epoxide metabolite of phenytoin.

Phenytoin Induced Gingival Hyperplasia 17 year old boy treated with 300mg/day phenytoin for 2 years (unsupervised) Partial recovery at 3 months after discontinuation

Fosphenytoin is a prodrug rapidly converted to phenytoin in the blood, providing high levels of phenytoin within minutes. Fosphenytoin may also be administered intramuscularly (IM). Phenytoin sodium should never be given IM because it can cause tissue damage and necrosis. Fosphenytoin is the drug of choice and standard of care for IV and IM administration. Due to sound-alike and look-alike names, there is a risk for medication error to occur. The trade name of fosphenytoin is Cerebyx® Celebrex®, the cyclooxygenase-2 inhibitor Celexa®, the antidepressant.

Na+ Channel Inhibitors Carbamzepine (Tegretol, Carbatrol): Derived from Tricyclic, antidepressant (bipolar) Indications: First choice for complex partial and generalized tonic-clonic seizures. Contraindications: May exacerbate absence or myoclonic seizures. Blood disorders Liver disorders

Na+ Channel Inhibitors Carbamazepine (Tegretol, Carbatrol): Drug Interactions: A powerful inducer of hepatic microsomal enzymes CBZ metabolism is affected by many drugs, and CBZ affects the metabolism of many drugs. oral contraceptives, warfarin, corticosteroids, etc. Determination of plasma levels and clearance may be necessary for optimum therapy. Adverse Effects: Common: Diplopia and ataxia (most common), gastrointestinal disturbances; sedation at high doses Occasional: Retention of water and hyponatremia; rash, agitation in children Rare: Idiosyncratic blood dyscrasias and severe rashes

Na+ Channel Inhibitors Oxcarbazepine (Trileptal): FDA approved in 2000 for partial seizures Complex partial seizures Primary & secondarily generalized tonic-clonic seizures Is a prodrug whose actions are similar to those of carbamazepine; it has a short half-life of 1—2 hour. Its activity is due to a 10-hydroxy metabolite with a half-life of 10 hours. Fewer adverse effects than CBZ, phenytoin

Na+ Channel Inhibitors Valproic Acid (Valproate; Depakene, Depakote): Other Mechanisms of Action: 1) Some inhibition of T-type Ca2+ channels. 2) Increases GABA production and decreases GABA metabolism. (Inhibition of GABA transaminase ) Indications: Simple or complex partial, & primary generalized tonic-clonic Also used for absence, myoclonic, and atonic seizures. Highly effective for photosensitive epilepsy and juvenile myoclonic epilepsy. Low toxicity and lack of sedative action Contraindications: Liver disease

Na+ Channel Inhibitors Valproic Acid (Valproate; Depakene, Depakote): Drug Interactions: Affects metabolism of many drugs through liver enzyme inhibition

Na+ Channel Inhibitors Valproic Acid (Valproate; Depakene, Depakote): Adverse Effects: Weight gain (30-50%) Dose-related tremor Transient hair loss Polycystic ovary syndrome (PCOS) and menstrual disturbances Bone loss Ankle swelling The most serious side-effect is hepatotoxicity An increase in serum glutamic oxaloacetic transaminase (sign of liver damage)

Na+ Channel Inhibitors Lamotrigine (Lamictal): Other Mechanism of Action: May inhibit synaptic release of glutamate. Indications: Adjunct therapy (ages 2 & up): Simple & complex partial seizures Generalized seizures of Lennox-Gastaut Syndrome Monotherapy (adults): Contraindications: May make myoclonic seizures worse.  

Na+ Channel Inhibitors Lamotrigine (Lamictal): Adverse Effects: Rash (10%) Rare progression to serious systemic illness Increased alertness

Na+ Channel Inhibitors Topiramate (Topamax): Other Mechanism of Action: Enhances post-synaptic GABAA receptor currents. Kainate receptor antagonist (blocks a certain type of glutamate channel) Indications: Adjunct therapy for partial and primary generalized seizures in adults and children over 2. Decreases tonic and atonic seizures in children with Lennox-Gastaut syndrome. Contraindications: History of kidney stones, teratogenic

Na+ Channel Inhibitors Topiramate (Topamax): Drug Interactions: CBZ, phenytoin, phenobarbital, & primidone decrease blood levels Adverse Effects: Nervousness & paresthesias Psychomotor slowing, word-finding difficulty, impaired concentration, interference with memory Weight loss & anorexia Metabolic acidosis

Na+ Channel Inhibitors Zonisamide (Zonegran): is a sulfonamide derivative that has a broad spectrum of action Other Mechanism of Action: Inhibits T-type Ca2+ currents. Binds to GABA receptors. Facilitates dopaminergic and serotonergic neurotransmission.

Na+ Channel Inhibitors Zonisamide (Zonegran): Indications: Approved for adjunct treatment of partial seizures in adults. Appears to have a broad spectrum: Myoclonic seizures Infantile spasms Generalized & atypical absence seizures Lennox-Gastaut Syndrome Drug Interactions: Phenytoin and carbamazepine decrease its half-life by half.

Na+ Channel Inhibitors Zonisamide (Zonegran): Adverse Effects: Weight loss Abnormal thinking Nervousness Agitation/irritability Usually well tolerated