Pharmacology of Antiepileptic agents with

Antiepileptics

1. Antiepileptic drugs paroxysmal cerebral dysrhythmia disturbance of consciousness (seizures) with or without characteristic body movements (convulsions) These are group of disorders of CNS characterized by Epilepsy It is a Chronic medical condition produced by sudden changes in the electrical function of the brain. Sreenu Thalla Associate Professor Department of Pharmacology

2. Classification Barbiturate – Phenobarbitone Deoxybarbiturate – Primidone Hydantoin – Phenytoin , Fosphenytoin Iminostilbene – Carbamazepine , Oxcarbazepine Succinimide – Ethosuximide Aliphatic carboxylic acid – Valproic acid, Divalproex Benzodiazepenes – Clonazepam , Diazepam, Lorazepam , Clobazepam Phenyltriazene – Lamotrigine Cyclic GABA analogue – Gabapentin Newer drugs – Vigabatrin , Topiramate,Tiagabine , Zonisamide , Levetiracetam

3. Drugs Seizure disorder Carbamazepine or Valproate or Phenytoin or Phenobarbital Tonic- clonic (Grand mal) Drug of Choice Topiramte Lamotrigine (as adjunct or alone) Gabapentin (as adjunct) Alternatives: Carbamazepine or Topiramte or Phenytoin or Valproate Partial (simple or complex) Drug of choice Phenobarbital Lamotringine (as adjunct or alone) Gabapentin (as adjunct ) Alternatives: TREATMENT

4. Valproate or Ethosuximide Absence ( petit mal) Drug of choice Clonazepam Lamotrigine Alternatives: Valproate Myoclonic , Atonic Drug of choice Clonazepam Alternatives: Diazepam, i.v. or Phenytoin, i.v. or Vaproate Status Epilepticus Drug of choice Phenobarbital, i.v Alternatives: Diazepam, rectal* Diazepam ,i.v Valproate Febrile Seizures * Preferred

5. Mechanism of action Current antiepileptic drugs are thought to act mainly by three main mechanisms: Reducing electrical excitability of cell membranes, mainly through use-dependent block of sodium channels Enhancing GABA-mediated synaptic inhibition; this may be achieved by an enhanced postsynaptic action of GABA, by inhibiting GABA transaminase , or by drugs with direct GABA agonist properties Inhibiting T-type calcium channels (important in controlling absence seizures). Newer drugs act by other mechanisms yet to be elucidated. Drugs that block glutamate receptors are effective in animal models but are unsuitable for clinical use

6. Phenytoin is the most important member of the hydantoin group of compounds, which are structurally related to the barbiturates. It is highly effective in reducing the intensity and duration of electrically induced convulsions in mice, although ineffective against PTZ-induced convulsions. Despite its many side effects and unpredictable pharmacokinetic behaviour , Phenytoin is widely used, being effective against various forms of partial and generalised seizures, although not against absence seizures, which may even get worse. PHENYTOIN Mechanism of Action Membrane stabilization by blocking Na + & Ca +2 influx into the neuronal axon. Or I nhibits the release of excitatory amino acids via inhibition of Ca +2 influx

7. Well absorbed when given orally, however, it is also available as iv. (for emergency) 80-90% protein bound Induces liver enzymes (Very Important) Metabolized by the liver to inactive metabolite Metabolism shows saturation kinetics and hence t ½ increases as the dose increased Excreted in urine as glucuronide conjugate Plasma t ½ approx. 20 hours Pharmacokinetics . Pharmacokinetic Interactions Inhibitors of liver enzymes elevate its plasma levels e.g. Chloramphenicol , INH Inducers of liver enzymes reduce its plasma levels e.g. Carbamazipine ; Rifampicin .

8. Side effects Ataxia, headache, but not sedation. Marked confusion with intellectual deterioration occurs Hyperplasia of the gums often develops gradually, as does hirsutism Megaloblastic anaemia (Decreased RBC production) Hypersensitivity reactions, mainly rashes, are quite common. Severe idiosyncratic (unexpected sensitivity) reactions, including hepatitis Skin reactions and neoplastic lymphocyte disorders Clinical Uses Used for partial Seizures & generalized tonic- clonic seizures. But not effective for absence Seizures

9. Carbamazepine One of the most widely used antiepileptic drugs, is chemically derived from the tricyclic antidepressant drugs Was found in a routine screening test to inhibit electrically-evoked seizures in mice. Pharmacologically and clinically, its actions resemble those of Phenytoin although it appears to be particularly effective in treating complex partial seizures (e.g. psychomotor epilepsy). It is also used to treat other conditions, such as neuropathic pain and manic-depressive illness Pharmacokinetics Carbamazepine is well absorbed. Its plasma half-life is about 30 hours when it is given as a single dose. A slow-release preparation is used for patients who experience transient side effects coinciding with plasma concentration peaks

10. Adverse effects Drowsiness , dizziness and ataxia to more severe mental and motor disturbances. It can also cause variety of gastrointestinal and cardiovascular side effects. The incidence and severity of these effects is relatively low. Severe bone marrow depression, causing neutropenia (low levels of neutrohills ) Hypersensitivity reaction can occur but are very rare. Treatment is usually started with a low dose, which is built up gradually to avoid dose-related toxicity

11. Phenobarbital Mechanism of Action Increases the inhibitory neurotransmitters ( e.g : GABA ) and decreasing the excitatory transmission. Also, it also prolongs the opening of Cl - channels. Pharmacokinetics Well absorbed, and about 50% of the drug in the blood is bound to plasma albumin. It is eliminated slowly from the plasma (half-life, 50-140 hours). About 25% is excreted unchanged in the urine.

12. Clinical uses Used in adults because of sedation. For some years, it was widely used in children, including as prophylaxis following febrile convulsions in infancy. It can cause behavioural disturbances and hyperkinesia , and is now seldom used at all in newly diagnosed patients Adverse effects Some degree of tolerance to the sedative effect seems to occur. C ognition and motor performance show impairment even after long-term treatment. M egaloblastic anaemia , mild hypersensitivity reactions O steomalacia (softening of bones). I t must not be given to patients with porphyria ( distubance of metabolism). In overdose, P henobarbital produces coma and respiratory and circulatory failure, as do all barbiturates

13. Ethosuximide Which belongs to the succinimide class, is another drug developed empirically by modifying the barbituric acid ring structure. Pharmacologically and clinically, however, it is different from the drugs so far discussed, in that it is active against PTZ-induced convulsions in animals and against absence seizures in humans, with little or no effect on other types of epilepsy. It supplanted Trimethadione , the first drug found to be effective in absence seizures, which had major side effects. Ethosuximide is used clinically for its selective effect on absence seizures. Mechanism of action The main effect described is inhibition of T-type calcium channels, which may play a role in generating the 3/second firing rhythm in thalamic relay neurons that is characteristic of absence seizures.

14. Pharmacokinetics Ethosuximide is well absorbed, and metabolised and excreted much like P henobarbital, with a plasma half-life of about 50 hours Side effects Nausea and anorexia, sometimes lethargy and dizziness, and it is said to precipitate tonic- clonic seizures in susceptible patients. Very rarely, it can cause severe hypersensitivity reactions.

15. Sodium Valproate It is a simple monocarboxylic acid, chemically unrelated to any other class of antiepileptic drug In 1963 it was discovered quite accidentally to have anticonvulsant properties in mice. It inhibits most kinds of experimentally induced convulsions and is effective in many kinds of epilepsy, being particularly useful in certain types of infantile epilepsy. Like Carbamazepine,Valproate is also used in psychiatric conditions such as bipolar depressive illness

16. Mechanism It causes a significant increase in the GABA content of the brain and is a weak inhibitor of two enzyme systems that inactivate GABA, namely GABA transaminase and succinic semialdehyde dehydrogenase , but in vitro studies suggest that these effects would be very slight at clinical dosage. Other more potent inhibitors of these enzymes (e.g. vigabatrin ) also increase GABA content and have an anticonvulsant effect in experimental animals. There is some evidence that it enhances the action of GABA by a postsynaptic action, but no clear evidence that it affects inhibitory synaptic responses. It also inhibits sodium channels, but less so than Phenytoin

17. Unwanted effects It causes thinning and curling of the hair in about 10% of patients. The most serious side effect is hepatotoxicity . An increase in serum glutamic oxaloacetic transaminase , which signals liver damage of some degree, commonly occurs, but proven cases of valproate -induced hepatitis are rare. The few cases of fatal hepatitis in valproate -treated patients may well have been caused by other factors. Valproate is teratogenic , causing spina bifida and other neural tube defects. Pharmacokinetics Valproate is well absorbed orally and excreted, mainly as the glucuronide , in the urine, the plasma half-life being about 15 hours.

18. NEWER ANTIEPILEPTIC DRUGS Vigabatrin The first 'designer drug' in the epilepsy field, is a vinyl-substituted analogue of GABA. Designed as an inhibitor of the GABA- metabolising enzyme GABA transaminase . Extremely specific for this enzyme and works by forming an irreversible covalent bond. In animal studies, vigabatrin increases the GABA content of the brain and also increases the stimulation-evoked release of GABA, implying that GABA transaminase inhibition can increase the releasable pool of GABA and effectively enhance inhibitory transmission. In humans, vigabatrin increases the content of GABA in the cerebrospinal fluid. Although its plasma half-life is short, it produces a long-lasting effect because the enzyme is blocked irreversibly, and the drug can be given by mouth once daily.

19. Evidence of neurotoxicity was found in animals but has not been found in humans, removing one of the main question marks hanging over this drug. The main drawback of vigabatrin is the occurrence of depression, and occasionally psychotic disturbances, in a minority of patients; otherwise, it is relatively free from side effects. Vigabatrin has been reported to be effective in a substantial proportion of patients resistant to the established drugs, and may represent an important therapeutic advance

20. Levetiracetam Developed as an analogue of piracetam , a drug used to improve cognitive function, and discovered by accident to have antiepileptic activity in animal models. Unusually, it lacks activity in conventional models such as electroshock and PTZ tests, but is effective in the kindling model. It has little or no effect on known targets (ion channels and GABA-related mechanisms), and its mechanism of action is unknown. It is excreted unchanged in the urine.

21. Gabapentin Designed as a simple analogue of GABA that would be sufficiently lipid-soluble to penetrate the blood-brain barrier. It turned out to be an effective anticonvulsant in several animal models but, surprisingly, not by acting on GABA receptors. Its main site of action appears to be on T-type calcium channel function, by binding to a particular channel subunit (α 2 δ), and it inhibits the release of various neurotransmitters and modulators, but the details remain unclear. The side effects of G abapentin (mainly sedation and ataxia) are less severe than with many antiepileptic drugs. The absorption of G abapentin from the intestine depends on the amino acid carrier system and shows the property of saturability , which means that increasing the dose does not proportionately increase the amount absorbed. This makes G abapentin relatively safe and free of side effects associated with overdosing.

22. Pharmacokinetics Its plasma half-life is about 6 hours, requiring dosing two to three times daily. It is excreted unchanged in the urine and is free of interactions with other drugs. These drugs are excreted unchanged in the urine, and so must be used with care in patients whose renal function is impaired. Uses It has limited efficacy when used on its own, so is used mainly as add-on therapy. It is also used as an analgesic to treat neuropathic pain. A recently introduced follow-up drug, Pregabalin is more potent than Gabapentin but otherwise very similar.

23. Clinical uses Cardiac dysrhythmias - phenytoin Bipolar disorder - valproate , carbamazepine , oxcarbazepine , lamotrigine topiramate Migraine prophylaxis - valproate , gabapentin Anxiety disorders - gabapentin Neuropathic pain - gabapentin , carbamazepine , lamotrigine Tonic- clonic (grand mal) seizures: carbamazepine , phenytoin , valproate Use of a single drug is preferred, when possible, to avoid pharmacokinetic interactions newer agents include vigabatrin , lamotrigine , felbamate , gabapentin Partial (focal) seizures : carbamazepine,valproate,alternatives are clonazepam or phenytoin .

24. Absence seizures (petit mal): ethosuximide or valproate valproate is used when absence seizures coexist with tonic- clonic seizures, because most other drugs used for tonic- clonic seizures can worsen absence seizures. Myoclonic seizures : diazepam intravenously or (in absence of accessible veins) rectally. Neuropathic pain : for example carbamazepine , gabapentin . To stabilise mood in mono- or bipolar affective disorder (as an alternative to lithium): for example carbamazepine , valproate