PHR 481 Pharmacology II

Antiepileptic Drugs

By Dr. Rowaida Refaat

Intended learning outcomes (ILOs): By the end of this lecture students should be able to: 1- Identify epilepsy with respect to etiology and types of seizures. 2- Classify antiepileptic drugs according to their mechanisms of action. 3- Compare between standard and new antiepileptic drugs regarding their therapeutic uses, adverse effects and drug interactions. Antiepileptic drugs Epilepsy: A disorder of the brain function characterized by recurrent usually unprovoked seizures. Seizure: Sudden alteration in behavior or motor function caused by an abnormal electrical discharge from the brain. Symptoms depend on the site of the abnormal neuronal discharge. Antiepileptic drugs (AED): Drugs that decrease the frequency and/or severity of seizures in epilepsy. Etiology of epilepsy: Epilepsy can affect anyone one at any age, but most commonly occurs in children during the teenage years and early 20s and in the elderly. Idiopathic or primary (cryptogenic) epilepsy (most cases are idiopathic) May be due to an inherited abnormality of the CNS. Symptomatic or secondary As a result of head injury, hypoglycemia, hypoxia, brain tumors or alcohol withdrawal. Classification of seizures

Status epilepticus: Two or more seizures lasting for 30 minutes or longer without regain of full consciousness between them. It is life threatening and requires emergency treatment. Diagnosis of epilepsy: - Based on clinical description (eye witness) - EEG to test the electrical activity of the brain - Blood tests to exclude metabolic causes - MRI or CT scan Management of epilepsy: The goal of therapy is to maximize seizure control, minimize side effects and improve the patients quality of life. Therapy is started after the second seizure with 1 st line drug (monotherapy), and continued until seizures are controlled or toxicity occurs. If the first-line drug is ineffective, a switch to another drug or addition of a 2nd drug (combination therapy) is done. Therapy must be continued for at least 2 years after the last seizure, and then the drugs should be stopped gradually. Classification of antiepileptic drugs: First generation drugs (standard AED) E.g. phenytoin, carbamazepine, divalproex, phenobarbitone, primidone

ethosuximide,

Second generation drugs (new AED) E.g. lamotrigine, topiramate, felbamate, gabapentin, levetiracetam, tiagabine, zonisamide. Mechanism of action of antiepileptic drugs: Blockade of Na+ channels Blockade of Ca2+ channels Enhancement of inhibitory GABAergic transmission Interference with excitatory glutamate transmission

Phenytoin: - The oldest non-sedative antiepileptic drug. - It blocks the voltage-gated Na channels in the inactive state slowing their return to the resting state. - At very high concentrations it can block the voltage-gated Ca channels Pharmacokinetics: - Phenytoin is well absorbed orally, it is not given IM as it causes tissue necrosis. - Extensively bound to plasma albumin 90% - Metabolized by liver microsomal enzymes and metabolism follows saturation or zero order kinetics (small increase in a daily dose can produce a large increase in the plasma concentration leading to drug toxicity). Therapeutic uses: - Generalized tonic-clonic convulsions - Partial seizures - Status epilepticus Drug interactions: - Phenytoin is a hepatic microsomal enzyme inducer; it induces its own metabolism and the metabolism of concomitantly administered drugs e.g. oral contraceptives, oral anticoagulants & other antiepileptics. - Enzyme inducers and inhibitors affect the metabolism of phenytoin. - It interacts with other highly protein-bound drugs. Adverse effects: - Vertigo, nystagmus, ataxia, diplopia - Gingival hyperplasia, hirsutism - Megaloblastic anemia, teratogenesis - Hypoprothrombinemia and hemorrhage Fosphenytoin: A prodrug rapidly converted to phenytoin in the body high levels within minutes. Given IV or IM with toxicities similar to phenytoin.

Carbamazepine: - Chemically related to TCAs. - Slowly absorbed after oral administration and 70% bound to plasma proteins. - It is a powerful enzyme inducer and has an active metabolite. Mechanism of action: Similar to phenytoin, it blocks Na+ channels preventing the generation of repetitive action potentials in the epileptic focus. Therapeutic uses: - Generalized tonic-clonic seizures - Partial seizures - Trigeminal neuralgia & bipolar disorder - It should not be used in absence seizures Adverse effects: - Bone marrow depression (aplastic anemia, agranulocytosis). - Hyponatremia especially in the elderly. Oxcarbazepine: - Closely related to carbamazepine and used in children & adults with partial seizures. - Oxcarbazepine is a prodrug that is rapidly reduced to 10-monohydroxy metabolite (MHD) which blocks the sodium channels. - It is a less potent enzyme inducer than carbamazepine. Divalproex: It is a combination of Na valproate & valproic acid. Mechanism of action: - Inhibition of GABA transaminase which is responsible for degradation of GABA - Blockade of the sodium & calcium channels Used in: partial & primary generalized seizures Adverse effects: hepatotoxicity, ataxia, weight gain, teratogenicity

Drug interactions: - Valproate inhibits the metabolism of other anti-epileptics. - > 90% bound to plasma proteins, so it causes significant interactions with other highly protein bound drugs (aspirin, phenytoin, TCAs). Ethosuximide: - Effective in treating only absence seizures. - Not effective in other seizure types therefore its use is limited. - It blocks T-type calcium channels . Phenobarbitone: It enhances the inhibitory effects of GABA (increases the duration of opening of Cl- channels leading to hyperpolarization and neuronal inhibition). Used in: - Status epilepticus IV - Febrile convulsions - Patients with refractory epilepsy (partial or generalized seizures) It is a potent enzyme inducer level of other drugs. Toxic effects: Sedation, nystagmus & ataxia, osteomalacia, folate deficiency and vitamin K deficiency Primidone - metabolized to phenobarbitone. - Its pharmacological properties, uses and side effects are similar to phenobarbitone. Used in: patients with refractory epilepsy. Benzodiazepines: - They bind to GABA inhibitory receptors to reduce firing rate (increase the frequency of opening of Cl - channels). - Diazepam is used IV in status epilepticus . - Lorazepam & diazepam are used as adjunctive therapy in myoclonic, partial and generalized tonic-clonic seizures.

 New antiepileptic drugs: Most of these drugs are used as adjunctive therapy in partial seizures. Lamotrigine: Blocks sodium channels & high voltage dependent calcium channels. Effective in: Partial seizures, generalized seizures, absence seizures & Lennox-Gastaut syndrome. Bipolar disorder. - Well tolerated by the elderly with partial seizures. - Rapid titration to high serum concentrations can cause a rash which may progress to life threatening reaction. Felbamate: It has multiple proposed mechanisms: Blockade of voltage-dependent sodium channels Weak activity against glutamate (NMDA) receptors Blockade of calcium channels Potentiation of GABA actions Used in: refractory epilepsy (Lennox-Gastaut) due to the risk of aplastic anemia & hepatic failure. Topiramate: Broad spectrum of antiseizure activity: Blocks voltage-dependent sodium channels Increases the frequency of Cl - channel opening by binding to GABA A receptor Reduces the high-voltage calcium currents It is a carbonic anhydrase inhibitor and may act at NMDA sites. Used in: partial and primary generalized seizures and also in migraine Gabapentin: Analog of GABA but doesnt work through the GABA pathway. Well tolerated by the elderly due to mild adverse effects and no pharmacokinetic drug interactions.

Zonisamide: Sulfonamide derivative with a broad spectrum of actions: Blocks voltage-gated Na channels & T-type Ca channels Also has a limited carbonic anhydrase activity Tiagabine: Blocks GABA uptake into presynaptic neurons Levetiracetam: Does not affect the pharmacokinetics of other antiepileptic drugs. Antiepileptic therapy in pregnancy: Therapy shouldnt be stopped during pregnancy Only one drug should be prescribed at the lowest effective dose, if possible. Antiepileptic drugs e.g. phenytoin, barbiturates & valproate increase the risk of congenital defects when given during the first trimester. All women should be on high doses of folic acid prior to conception & during the first trimester. Newborns of mothers receiving phenobarbitone or phenytoin may develop hypoprothrombinemia serious haemorrhage prevented by Vit K.

Vagal nerve stimulation: It is effective in the treatment of partial seizures in patients who are: Refractory to multiple drugs Sensitive to the adverse effects of antiepileptics Having difficulty to follow medication schedule The vagal nerve stimulator generates an electrical pulse to stimulate the nerve and prevent the abnormal activity of the brain. Patients activate the stimulator when they expect a seizure.