ANTI-EPILEPTIC DRUGS

Dr.Nasser A. H. Al-Harchan Asst. Prof. of Pharmacology College of Medicine Baghdad University

introduction
Seizure Seizures are sudden, transitory, and uncontrolled episodes of brain dysfunction resulting from abnormal discharge of neuronal cells with associated motor, sensory or behavioral changes. Epilepsy A group of chronic CNS disorders characterized by recurrent seizures.

Classification of Epileptic Seizures

I. Partial (focal) Seizures A. Simple Partial Seizures B. Complex Partial Seizures C. Partial with secondary generalized tonic classic seizure II. Generalized Seizures A. Generalized Tonic-Clonic Seizures B. Absence Seizures C. Myoclonic Seizures

Pathological Basis
o o o o

Abnormal electrical discharge in the brain Coordinated activity among neurons depends on a controlled balance between excitation and inhibition Any local imbalance will lead to a seizure Imbalances occur between glutamate-mediated excitatory neurotransmission and gammaaminobutyric acid (GABA) mediated inhibitory neurotransmission Generalised epilepsy is characterised by disruption of large scale neuro-networks in the higher centres.

Strategies in Treatment
Stabilize membrane and prevent depolarization by action on ion channels Increase GABAergic transmission Decrease EAA (Excitatory Amino Acid) Transmission

Classification of Anticonvulsants

Classification of Anticonvulsants
Classical
Phenytoin Phenobarbital Primidone Carbamazepine Ethosuximide Valproic Acid Trimethadione

Newer
Lamotrigine Felbamate Topiramate Gabapentin Tiagabine Vigabatrin Oxycarbazepine Levetiracetam Fosphenytoin Others

Phenytoin
Limited water solubility not given i.m. Slow, incomplete and variable absorption. Extensive binding to plasma protein. Metabolized by hepatic ER by hydroxylation. Chance for drug interactions. Therapeutic plasma concentration: 10-20 g/ml Shift from first to zero order elimination within therapeutic concentration range.

Phenytoin Toxicity and Adverse Events

Acute Toxicity High i.v. rate: cardiac arrhythmias hypotension; CNS depression. Acute oral overdose: cerebellar and vestibular symptoms and signs:
nystagmus, ataxia, diplopia vertigo.

Phenytoin Toxicity
Chronic Toxicity Dose related vestibular/cerebellar effects Behavioral changes Gingival Hyperplasia GI Disturbances Sexual-Endocrine Effects:
Osteomalacia Hirsutism Hyperglycemia

Phenytoin Toxicity and Adverse Events

Chronic Toxicity Folate Deficiency - megaloblastic anemia Hypoprothrombinemia and hemorrhage in newborns Hypersenstivity Reactions could be severe. SLE, fatal hepatic necrosis, Stevens-Johnson syndrome. Pseudolymphoma syndrome Teratogenic Drug Interactions: decrease (cimetidine, isoniazid) or increase (phenobarbital, other AEDs) rate of metabolism; competition for protein binding sites.

Carbamazepine (Tegretol)
Second - most commonly prescribed anticonvulsant Structurally related to tricyclic antidepressants Uses:
partial and tonic-clonic seizures neuropathic pain management Schizophrenia, bipolar disorder

May be used in combination with Dilantin or Phenobarbital

Carbamazepine (Tegretol)
all types except absence seizures; particularly useful for generalized tonic-clonic, simple and complex partial inhibition of voltage-gated Na+ channels oral, slow and erratic, 75% plasma protein bound; t1/2=36 hrs initially, decreasing to 20 hrs following continuous therapy (autoinduction), active metabolite excreted diplopia and ataxia, GI upset, hypersensitivity, serious toxicity including aplastic anemia, agranulocytosis drug interactions are many, related to the hepatic enzyme inducing properties of carbamazepine

Carbamazepine (Tegretol)
Toxicity similar to phenytoin Adverse effects
CNS:
Restlessness, irritability, agitation Dizziness, confusion, ataxia, encephalopathy

Renal
Renal failure, urinary frequency Water retention (stimulates ADH)

Visual changes

Carbamazepine (Tegretol)
Agranulocytosis Lupus Arrhythmia & cardiac conduction abnormalities Toxicity: bone marrow depression, hepatic dysfunction, visual changes

Carbamazepine (Tegretol)
Numerous drug interactions Erratically absorbed, better absorption on full stomach

Phenobarbital
The only barbiturate with selective anticonvulsant effect. Bind at allosteric site on GABA receptor and duration of opening of Cl channel. Ca-dependent release of neurotransmitters at high doses.
Inducer of microsomal enzymes drug interactions. Toxic effects: sedation (early; tolerance develops); nystagmus & ataxia at higher dose; osteomalacia, folate deficiency and vit. K deficiency. In children: paradoxical irritability, hyperactivity and behavioral changes. Deoxybarbiturates: primidone: active but also converted to phenobarbital. Some serious additional ADRs: leukopenia, SLE-like.

Valproic Acid
Effective in multiple seizure types. Blocks Na and Ca channels. Inhibits GABA transaminase. Increases GABA synthesis. Toxicity: most serious: fulminant hepatitis. More common if antiepileptic polytherapy in children < 2 years old. (?) Toxic metabolites involved. Drug interactions: inhibits phenobarbital and phenytoin metabolism.

Ethosuximide
Second - most commonly prescribed Drug of choice for Absence. Blocks Ca++ currents (Tcurrents) in the thalamus. Not effective in other seizure types GI complaints most common CNS effects: drowsiness lethargy). Has dopamine antagonist activity (? In seizure control) but causes Parkinsonian like symptoms. Potentially fatal bone marrow toxicity and skin reactions (both rare)

Benzodiazepines
Diazepam (Valium) IV, IM Lorazepam (Ativan) IV
Used to terminate status epilepticus Close medical supervision & resuscitative equipment should be available qpotentiates GABAA receptor function via a distinct allosteric binding site on the protein termed the benzodiazepine receptor. frequency of opening of Cl channel.

Benzodiazepines
diazepam (i.v.)- drug of choice for the treatment of status epilepticus clonazepam and clorazepate- long-term treatment of absence, myoclonic, akinetic and atonic seizures; tolerance to anticonvulsive action limits clinical usefulness of benzodiazepines potentiates GABAA receptor function via a distinct allosteric binding site on the protein termed the benzodiazepine receptor oral, t1/2 : clonazepam=1 day; clorazepate=2 hrs; i.v. diazepam=12 days); very high plasma protein binding, N-desmethyldiazepam (t1/2=3 days) is active metabolite of diazepam and clorazepate, clonazepam is primarily reduced to inactive metabolites sedation, ataxia; hyperactivity and irritability in children; high therapeutic index, low incidence of toxicity additive or synergistic effects with other sedative hypnotics

Enhancers of GABA Transmission

Gabapentin: Developed as GABA analogue. Mechanism: Increases release of GABA by unknown mechanism. Vigabatrin: Irreversible inhibitor of GABA transaminase. Potential to cause psychiatric disorders (depression and psychosis). Tiagabine: decreases GABA uptake by neuronal and extraneuronal tissues.

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