Antiseizure Drugs-01

1. Antiseizure Drugs-01 Kaukab Azim, MBBS, PhD & DR.Farooq,MBBS,M.Phil

2. Drug Groups

3. Seizure Disorders A seizure is the physical findings or changes in behavior that occur after an episode of abnormal electrical activity in the brain. The term "seizure" is often used interchangeably with "convulsion." Convulsions are when a person's body shakes rapidly and uncontrollably. During convulsions, the person's muscles contract and relax repeatedly. There are many different types of seizures. Some have mild symptoms and no body shaking. During a seizure some neurons of the brain begin to fire in massive synchronized bursts. After few seconds or minutes the inhibitory mechanisms of the brain regain control and the seizurestops.

4. Epilepsy • The term epilepsy includes disorders or syndromes with widely variable pathophysiologic findings, clinical manifestations, treatments, and prognoses. • Individuals with epilepsy are identified by the tendency for and occurrence of recurrent seizures. • A seizure is a paroxysmal(abrupt worsening of sumptoms OR recurrence of disease), hypersynchronous, excessive neuronal discharge of variable extent.

5. The word seizure is not synonymous with the word epilepsy. • Any brain can generate a single or even multiple seizures under appropriate provocative circumstances. It is the tendency to have recurrent seizures, not necessarily with provocation, that makes the diagnosis of epilepsy. • More than one seizure must occur before the diagnosis of epilepsy is made.

6. Treatment Goals • No seizures • No side effects • Monotherapy • Once daily dosing • No blood tests

7. What actually happens • 70% seizure free with one drug • With careful monitoring and adjustment • 5% to 10% seizure free with two or more drugs • 20% still have seizures

8. Principals of pharmacological treatment 1 • Use the right drug for the seizure type • Use one drug and increase the dose until a therapeutic effect is gained or toxicity appears (maximum tolerated dose) • Monitor treatment including blood levels • If required add a second drug. • If a response consider slowly removing the first drug

9. Principals of pharmacological treatment 2 • If monotherapy fails use two drugs • Review and replace the combinations used • Add in a third drug if necessary • Be prepared to accept that a significant reduction in seizure frequency maybe as good as it gets

10. Antiseizure Drugs Antiseizure (also called anticonvulsant, antiepileptic) drugs :The inhibition of seizure activity in the CNS is accomplished without major disturbances in the normal electrical activity. Sustained, high frequency, repetitive firing are inhibited much more effectively than low-frequency, non-repetitive firing. Antiseizuredrugs do not cure epilepsy; they just suppress seizures on a temporary basis. Therefore most patients must take them for life. The therapeutic index of most antiseizure drugs is low and adverse effects are common. They are usually mild, but most antiseizure drugs may cause occasionally life-threatening adverse reactions.

11. Most antiseizure drugs can cause malformations :when given during pregnancy. Since also seizures per se can cause malformations a careful assessment of the risk/benefit ratio is mandatory in each epileptic woman who want to have a baby. The mechanisms of action of antiseizure drugs are still not well understood but they have been found to concern mainly: a) voltage-gated ion channels b) inhibitory and excitatory synaptic functions

12. Drug Groups

13. Carbamazepine and Congeners Drugs Carbamazepine, oxcarbazepine. Mechanism of action • Frequency-dependent and voltage-dependent blockade of inactivated Na+ channels (most likely the main mechanism). • Interaction with other ion channels and several neurotransmitters (at high doses. Their contribution to its antiseizure effects is uncertain) Pharmacological Effects • Inhibition of post tetanic potentiation, which may prevent the spread of seizure from the epileptic focus (the discharge of the focus itself is not prevented and therefore aura(forewarning of an epileptic attack) and EEG alterations are not eliminated) • Analgesic actions (in some type of neuropathic pain). • Antidepressant actions (mechanism likely similar to that of tricyclic antidepressants) • Strong PYC3A4 inducing action (which leads to many pharmacokinetics interactions).

14. Carbamazepine and Congeners Pharmacokinetics • Oral bioavailability: . 90% • Biotransformation: 99% by the PYC3A4 (biotransformation rate is low). Adverse effects • Dizziness, drowsiness, blurred vision ,diplopia, ataxia (common & dose related). • Neutropenia, thrombocytopenia, agranulocytosis, aplastic anemia (the risk of these reactions is 5-8 times greater in patients treated with carbamazepine than in the general population) • Confusion, agitation, hallucinations (after high doses).

15. Carbamazepine – Therapeutic Uses Epilepsy • It is a first choice drug for partial seizures and for generalized tonic-clonic seizures (It has been the most widely prescribed anticonvulsant drug world wide. No newer drug has been found to be superior in efficacy). • In complex partial seizures it prevents the attacks in 60-65% of patients. • The antiepileptic effect can undergo tolerance in 10-20% of patients. (Absence, myoclonic, tonic and atonic seizures may worsen in patients treated with carbamazepine). Trigeminal and related neuralgias. • Carbamazepine is the first choice drug for trigeminal neuralgia (result are good in 70% of patients). In refractory cases the addition of phenytoin can be useful. Bipolar affective disorder • As an alternative to lithium for the therapy of acute mania and the prophylactic treatment of bipolar disorder.

16. Phenytion and Congeners Drugs Phenytoin, fosphenytoin(a prodrug rapidly converted to phenytoin in plasma) Pharmacodynamics Mechanism of action • Frequency-dependent and voltage-dependent blockade of inactivated Na+ channels (most likely the main mechanism). Pharmacological effects • Inhibition of post tetanic potentiation, which may explain the prevention of the spread of seizure from the epileptic focus (the excessive discharge of the focus itself is not prevented and therefore aura and EEG alterations are not eliminated) • Cerebellar-vestibular stimulation (with high doses) • Analgesic actions (in some type of neuropathic pain)..

17. Phenytoin - Pharmacokinetics Oral bioavailability: . 90% (absorption speed depends on pharmaceutical preparation) Administration: oral (fosphenytoin is more soluble and available for parenteral use) Biotransformation:98% by the liver P450 system (biotransformation rate is low). Elimination:is dose dependent, i.e. first order at low doses, but zero order at high doses.

18. Phenytoin – Adverse Effects Centralnervoussystem • Nystagmus(eye) (frequent), diplopia, ataxia, dyskinesia, vertigo, tremor, hyperreflexia, dystonic reactions, blurring of vision. • Hyperactivity, nervousness. • Sedation, drowsiness (with high drug plasma levels). • Peripheral neuropathy (7-30% of patients treated for long time). • Phenytoin encephalopathy (with high drug plasma levels). Gastrointestinal system • Gingival hyperplasia (30-40% of patients) Endocrinesystem • Hyperglycemia (due to decreased insulin secretion) • Osteomalacia(due to increased metabolism of vit D and reduced intestinalCa++ absorption)

19. Phenytoin – Adverse Effects Hematopoietic system • Blood dyscrasias (megaloblastic anemia, aplastic anemia) (rare) • Limphoadenopathy, pseudolymphoma (after long treatments) • Malignant lymphoma (?), Hodgkin's disease (?) Other systems • Skin hyperpigmentation, hirsutism (mainly in women) • Coarsening of facial features (mainly in children) Pregnancy • Risk of malformations increases 2-3 fold • A "fetal hydantoin syndrome" (cleft lip, cleft palate, congenital heart disease, slowed growth and mental deficiency)

20. Phenytoin – Therapuetic Uses Epilepsy • First or second choice drug for partial and generalized tonic-clonicseizures. • Fosphenytoinis drug of choice for the emergency treatment of status epilepticus. • (Absence, myoclonic and akinetic seizures may worsen in patients treated with phenytoin). Trigeminal and related neuralgias • Carbamazepine remain the preferred agent for these conditions but phenytoin is a second choice drug and can achieve good results. Cardiacarrhythmias • Used mainly when arrhythmias are due to digitalis toxicity.

21. Phenobarbital Mechanism of action • Enhancement of GABA-mediated inhibition (the opening of Cl- channels is prolonged by facilitating GABA action) • Blockade of AMPA receptors • Direct opening of Cl- channels (after high doses) • Blockade of Na+ and Ca++ channels (at high doses) Pharmacological effects • Suppression of the excessive discharge of the seizure focus • Prevention of the spread of excitation from seizure focus. • All other effects of the barbiturate class.

22. Phenobarbital Pharmacokinetics • Oral bioavailability: 100% • Biotransformation: 75% by the liver (biotransformation rate is low) • Excretion by the kidney: 25% (in acid urine) up to 75% (in alkaline urine) Adverse effects, contraindications All the adverse effects and contraindications of barbiturate class(dependence occurs with barbiturates, but not with phenobarbital) Therapeuticuses Second choice drug for: • Partial seizures, • Generalized tonic-clonic seizures • Status epilepticus.