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Anti-Seizure Drugs Dr. Mohammed Samir Hussein BCs of Pharmaceutical Science MD of Clinical Pharmacology
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Anti-Seizure Drugs PHL421-1440-1441 Edited By: Dr. Mohammed Samir Hussein BCs of Pharmaceutical Science MD of Clinical Pharmacology +201003256675
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Definitions Epilepsy: is a chronic disorder of brain function characterized by recurrent seizures of a particular pattern unprovoked by any immediate identified cause. Seizures: a single occurrence results from abnormal neuronal discharge in the central nervous system produced by either focal or generalized disturbances of brain tissue. They result in abnormal phenomena of motor (convulsion), sensory, autonomic, or psychic origin.
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Classification of Seizures
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Spreading pathways and Symptoms of seizure
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Etiology and Mechanisms of Epilepsy Increased activity of voltage-gated ion channels (Na+, K+ & Ca++ channels) 2. Decreased inhibitory (GABA) neurotransmission 3. Increased excitatory neurotransmission (glutamate receptors) 4. Alteration of extracellular ion concentration (K+, Ca++) Epileptic seizures are result from hyperexcitable neurons caused by:
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Molecular Targets of Antiseizure Drugs 1- Modification of ion conductance: AP is generated by activation on Na+ ch. in Cortex, an Ca++ ch. in Thalamus Prolong Inactivation state of voltage-dependent Na+ channels in a use-dependent fashion (all types except Absence Seizer ) Inhibition of Ca++ currents on T-type Ca++ ch. (Absence Seizer only ). 2- Increase inhibitory (GABAergic) transmission 3- Decrease excitatory (glutamatergic) activity Inhibition of excitatory glutamate transmission via ionotropic receptors
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Therapeutic goal is complete cessation of seizures without side effects using a single drug (monotherapy) and a dosing schedule that is easy for the pt to follow Important Concepts: Choice of drug depends on seizure type Single drug therapy tried first Titration of dose necessary Monitor plasma drug concentrations Therapy tailored to individual Drugs treat symptoms; do not cure underlying cause Therapeutic failure can be due to many causes (poor compliance most common) How to Manage Epilepsy?
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Life-long treatment may be necessary. It may take weeks to establish adequate drug plasma levels and to determine the adequacy of therapeutic improvement. Lack of compliance is responsible for many treatment failures.
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I. Na+ Channel Inhibitors Phenytoin and Fosphenytoin Carbamzepine and Oxcarbazepine Valproic Acid Lamotrigine Topiramate Zonisamide Blocks voltage-gated Sodium Channels by selectively binding To Channel in the Inactive State and slowing its rate of recovery in cortex Epileptic patient has a higher number of channel and they makes more cycles than normal
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Indications: First choice for partial and generalized tonic-clonic seizures. Some efficacy in clonic, myoclonic & atonic no effect on infantile spasms or absence seizures. 1. Phenytoin Drug Interactions: Phenytoin is 90% bound to plasma protein, Phenylbutazone, sulfonamides can displace phenytoin can result in intoxication. High affinity for thyroid-binding protein. Measurement of TSH levels is best for phenytoin patients.
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Pharmacokinetics: -Phenytoin used orally, low water soluble and so cause tissue damage and necrosis if injected IV or IM -The prodrug Fosphenytion which is highly water soluble. - After IV adminsteration Rapidly converted to phenytoin in the blood, providing high levels of phenytoin within minutes. - Fosphenytoin may also be administered intramuscularly (IM). Fosphenytoin (prodrug) Indication: Fosphenytoin is the drug of choice and standard of care for IV and IM administration.
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Hirsutism, Acne & coarsening of facial features. Diplopia, ataxia common dose related effects. Mild peripheral neuropathy Gingival hyperplasia (20-40%). Decreased serum concentrations of thyroxine, and vitamin K with long-term use. Macrocytic anemia (folic acid absorption and metabolism inhibitor) Long-term use interfere with Vit. D absorption and cause Osteoporosis Purple glove syndrome. Adverse Effects of Phenytoin
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Phenytoin Teratogenicity Fetal hydantoin syndrome: Includes growth retardation, microencephaly, and craniofacial abnormalities (e.g., cleft palate) and is possibly due to an epoxide metabolite of phenytoin. Cleft lip, cleft palate Congenital heart disease Slowed growth Mental retardation
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Indications: First choice for complex partial and generalized tonic-clonic seizures (because of its dual action suppression of seizure foci and prevention of spreading of activity). It is also used to treat trigeminal neuralgia and in bipolar disease. 2. Carbamzepine (Tricyclic antidepressant) Contraindication : May exacerbate absence or myoclonic seizures. Blood disorders- aplastic anemia/agranulocytosis. Erythematous skin rash.
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Drug Interaction: CBZ metabolism is affected by many drugs, and CBZ affects the metabolism of many drugs. Adverse Effects: Common: Diplopia and ataxia (most common), gastrointestinal disturbances; sedation at high doses Occasional: Retention of water and hyponatremia; rash, agitation in children, Aplastic anemia , Agranulocytosis ( decrease in WBCs) so increase incidence of infection Rare: Idiosyncratic blood dyscrasias and severe rashes - SJS 2. Carbamzepine
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Carbamazepine Teratogenicity Carbamazepine has been implicated as a cause of craniofacial anomalies and spina bifida.
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Indications: - Partial seizures - Complex partial seizures - Primary & secondarily generalized tonic-clonic seizures Pharmacokinetic : - Is a prodrug whose actions are similar to those of carbamazepine - it has a short half-life of 1—2 hour. - Fewer adverse effects than CBZ and phenytoin 3. Oxcarbazepine
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Indications: - Adjunct therapy (ages 2 & up): - Simple & complex partial seizures - Generalized seizures of Lennox-Gastaut Syndrome -Monotherapy (adults): Simple & complex partial seizures Contraindication : May make myoclonic seizures worse Adverse effect : Rash (10%) Rare progression to serious systemic illness Increased alertness 4. Lamotrigine
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Other Mechanism of Action: Some inhibition of T-type Ca2+ channels Increases GABA production and decreases GABA metabolism. Indications: Absence seizures, myoclonic seizures, Simple or complex partial, primary generalized tonic-clonic, & atonic seizures. Highly effective for photosensitive epilepsy and juvenile myoclonic epilepsy. Used when we cannot detect type of Epilepsy, or with Mixed Epilepsy (more than one type of Epilepsy) Other uses of valproate include management of bipolar disorder and migraine prophylaxis. 5. Valproic Acid
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Contraindication : Liver disease. Drug Interactions: Affects metabolism of many drugs through liver enzyme inhibition. Adverse Effects: Weight gain (30-50%) Dose-related tremor Transient hair loss. Polycystic ovary syndrome and menstrual disturbances Bone loss - Ankle swelling Neural tube defects - spina bifida Weight loss & anorexia. 5. Valproic Acid
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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. 6. Topiramate
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Contraindication : History of kidney stones. Drug Interactions: CBZ, phenytoin, phenobarbital, & primidone decrease blood levels. Adverse Effects: Nervousness & paresthesia. Psychomotor slowing, word-finding difficulty, impaired concentration, interference with memory. Weight loss & anorexia. 6. Topiramate
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Other Mechanism of Action: Inhibits T-type Ca2+ currents. Binds to GAB 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 7. Zonisamide
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Drug Interactions: Phenytoin and carbamazepine decrease its half-life by half. Adverse Effects: Weight loss Abnormal thinking Nervousness Agitation/irritability. 7. Zonisamide
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II. Enhancement of GABA Inhibition Phenobarbital Primidone Benzodiazepine Tiagabine Enhancement of inhibitory effects of GABAA Receptors, allowing Cl ion to enter neuron and producing HYPERPOLRIZATION leading to inhibition of CNS
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Enhancement of GABA Inhibition
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Enhancement of GABA Inhibition
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Enhancement of GABA Inhibition
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Inhibit low-threshold (T-type) Ca2+ currents, especially in thalamic neurons that act as pacemakers to generate rhythmic cortical discharge. III. Calcium Channel Blockers Ethosuximide Gabapentin Pregabalin
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Indications: First line for absence seizures Contraindication : May exacerbate partial & tonic-clonic seizures Adverse Effects: Psychotic behavior Blood dyscrasias Persistent headaches Anorexia and hiccups Lupus-like syndromes Toxicity: Parkinson-like symptoms - photophobia 1. Ethosuximide
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Other Mechanism of Action: Originally designed to be a centrally acting GABA agonist. Selective inhibition of v-g Ca2+ channels containing the α2δ1 subunit. Indications: Adjunct therapy in adults and children with partial & secondarily generalized seizures. Also effective as monotherapy Contraindication : Can exacerbate myoclonic & absence seizures Adverse Effects: Weight Gain (5%) with ankle edema Irritability Behavioral problems in children (6%) Has been associated with movement disorders 2. Gabapentin
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Other Mechanism of Action: Same as gabapentin. Indications: Adjunct therapy for partial & secondarily generalized seizures. Prescribed for neuropathic pain, fibromyalgia. 3. Pregabalin
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IV. the N-methyl-D-aspartate (NMDA) glutamate receptor Channel Blockers Felbamate has a broad spectrum of anticonvulsant action. The drug has multiple proposed mechanisms including blocking voltage-dependent sodium channels. competing with the glycine-agonist binding site on the N-methyl-D-aspartate (NMDA) glutamate receptor. blocking calcium channels. potentiation of GABA actions. It is reserved for use in refractory epilepsies (particularly Lennox-Gastaut syndrome) because of the risk of aplastic anemia (about 1:4000) and hepatic failure Felbamate
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Other/Unknown MOA Indications: An adjunct therapy for adults with partial seizures. Some patients have success with monotherapy Contraindication : Renal dysfunction Adverse Effects: Asthenia Infection Behavioral problems Levetiracetam
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Pharmacokinetics Summary Most classical antiepileptic drugs exhibit similar pharmacokinetic properties. Good absorption. Low plasma protein binding (except for phenytoin, BDZs, valproate, and tiagabine). Conversion to active metabolites (carbamazepine, primidone, fosphenytoin). Cleared by the liver but with low extraction ratios. Distributed in total body water. At high concentrations phenytoin exhibits zero order kinetics.
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Adverse Reactions Summary 1. Minor Reactions (common) Gastrointestinal disturbances (most drugs). Sedative effects (most drugs). Ataxia (many drugs). Visual disturbances (several drugs) Weight gain/loss (several drugs). 2. Drug- Specific Reactions Gingival hyperplasia (phenytoin). Hirsutism (phenytoin). Inhibition of platelet aggregation (valproic acid). Altered behavior in children and elderly (barbiturates). Kidney stones & hypohidrosis (↓sweating) (zonisamide, tiagabine).
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Adverse Reactions Summary 3. Serious reactions (rare) Skin eruptions (hypersensitivity) (most drugs). Blood dyscrasias (most drugs) very rare. Hepatitis (phenytoin, valproic acid, carbamazepine). Alopecia (valproic acid) rare. Absence status epilepticus (rare; clonazepam + valproic acid; tiagabine?). Serum sickness (immune reaction). Teratogenic (most established drugs; probably new drugs as well?).
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Drug Interactions Summary 1. Induction of Hepatic Drug metabolizing enzyme: Phenytoin, Phenobarbital and Primidone resulting in a decrease the plasma concentration of a variety of other drugs such as antibiotics, other antiseizure drugs, oral anticoagulants, oral contraceptives, etc. 2. Competition for the same drug metabolizing enzyme Phenytoin, valproic acid, phenobarbital and primidone are all metabolized by the same P450 and affect the metabolism of each other as well as other drugs such as dicoumarol or sulfonamides. 3. Displacement of drugs bound to Plasma Proteins Phenytoin and valproic acid are highly bound to plasma proteins and can increase the concentration of other or drugs like diazepam or warfarin that are bound to plasma protein.
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THANK YOU FOR YOUR ATTENTION
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