Antiepileptic Drugs

1. Antiepileptic Drugs By YOGENDRA MAVAI Department of Pharmacology Shri Ram College of Pharmacy Banmore

2. Introduction Epilepsy (from the Ancient Greek (epilēpsía) — "seizure") is a common chronic neurological disorder characterized by seizures. These seizures are transient signs and/or symptoms of abnormal, excessive or hypersynchronous neuronal activity in the brain. Epilepsy is more likely to occur in young children, or people over the age of 65 years; however, it can occur to anyone at any time.. Epilepsy is usually controlled, but not cured, with medication. However, over 30% of people with epilepsy do not have seizure control even with the best available medications. Surgery may be considered in difficult cases..

3. Introduction • Epilepsy affects about 0.5% of the population. • The characteristic event is the seizure, which is often associated with convulsion, but may occur in many other forms. • The seizure is caused by an abnormal high-frequency discharge of a group of neurons, starting locally and spreading to a varying extent to affect other parts of the brain.

4. Introduction • Seizures may be partial or generalised depending on the location and spread of the abnormal neuronal discharge. The attack may involve mainly motor, sensory or behavioural phenomena. Unconsciousness occurs when the reticular formation is involved.

5. Types of Epilepsy Partial seizures • The discharge begins locally, and often remains localised. Produce relatively simple symptoms without loss of consciousness. • Two major categories, namely partial and generalised seizures; there is some overlap and many varieties of each.

6. Types of Epilepsy Generalised seizures • Involve the whole brain, including the reticular system, thus producing abnormal electrical activity throughout both hemispheres. Immediate loss of consciousness.

8. Tonic-clonic=stiffening of the limbs-jerking of the limbs and face Myoclonic seizures are rapid, brief contractions of bodily muscles (1 arm & 1 foot), sudden jerk of a foot during sleep Atonic seizures (drop attacks, astatic or akinetic seizures )= loss of muscle tone,head drops, loss of posture or sudden collapse Tonic seizures =stiffness or rigidity in all muscles,a fall with injuries (sleep and are resistant to drug therapy). Infantile Spasms (myoclonic-tonic seizures) = repetitive seizures by quick, sudden movements

9. Nature of Epilepsy • Two common forms of generalised epilepsy are the tonic-clonic fit (grand mal) and the absence seizure (petit mal). Status epilepticus is a life- threatening condition in which seizure activity is uninterrupted.

11. Nature of Epilepsy • Repeated epileptic discharge can cause neuronal death (excitotoxicity). • Current drug therapy is effective in 70-80% of patients.

12. Animal Models of Seizures • Chemical-induced: Pentylenetetrazole, Kainic Acid, • Maximal electrochock • Kindling

13. Epilepsy syndromes are further divided by presumptive cause: Idiopathic: genetic abnormalities Symptomatic : effects of an epileptic lesion Cryptogenic: presumptive lesion that is otherwise difficult or impossible to uncover during evaluation.

14. There are over 40 different types of epilepsy, including: benign Rolandic epilepsy, frontal lobe epilepsy, infantile spasms, juvenile myoclonic epilepsy, juvenile absence epilepsy, childhood absence epilepsy (pyknolepsy), hot water epilepsy, Lennox-Gastaut syndrome, Landau-Kleffner syndrome, mitochondrial disorders, progressive myoclonic epilepsy, reflex epilepsy, Rasmussen's syndrome, temporal lobe epilepsy, limbic epilepsy, status epilepticus, abdominal epilepsy, massive bilateral myoclonus, catamenial epilepsy, Jacksonian seizure disorder, Lafora disease, photosensitive epilepsy, etc.

15. Etiology During the neonatal period and early infancy -hypoxic-ischemic encephalopathy, CNS infections, trauma, congenital CNS abnormalities, and metabolic disorders. During late infancy and early childhood, febrile seizures are fairly common -CNS infections and trauma. During childhood, well-defined epilepsy syndromes are generally seen. During adolescence and adulthood-CNS lesion, Other causes are stress, trauma, CNS infections, brain tumors, illicit drug use and alcohol withdrawal. In older adults, cerebrovascular disease is a very common cause. Other causes are CNS tumors, head trauma, and other degenerative diseases that are common in the older age group, such as dementia.

16. Pathophysiology Mutations in several genes have been linked to some types of epilepsy. Several genes that code for protein subunits of voltage-gated and ligand-gated ion channels have been associated with forms of generalized epilepsy and infantile seizure syndromes. One speculated mechanism for some forms of inherited epilepsy are mutations of the genes that code for sodium channel proteins; these defective sodium channels stay open for too long, thus making the neuron hyper-excitable.

17. Glutamate, an excitatory neurotransmitter, may, therefore, be released from these neurons in large amounts, which — by binding with nearby glutamatergic neurons { located in hippocampus) — triggers excessive calcium (Ca2+) release in these post-synaptic cells. Such excessive calcium release can be neurotoxic to the affected cell. Another possible mechanism involves mutations leading to ineffective GABA (the brain's most common inhibitory neurotransmitter) action. Epilepsy-related mutations in some non-ion channel genes have also been identified.

18. Epileptogenesis is the process by which a normal brain develops epilepsy after trauma, such as a lesion on the brain. One interesting finding in animals is that repeated low-level electrical stimulation to some brain sites can lead to permanent increases in seizure susceptibility: in other words, a permanent decrease in seizure "threshold." This phenomenon, known as kindling (by analogy with the use of burning twigs to start a larger fire) was discovered by Dr. Graham Goddard in 1967.

19. In short • The Interictal Spike (paroxysmal depolarization shift) • Increased excitability • Membrane depolarization, potassium buildup • Increased excitatory (EAA, glutamate) input • Decreased inhibitory (GABA) input

20. Evidence for the Pathophysiology of Seizures • Increased EAA • Increased Excitatory Amino Acid Transmission • Increased sensitivity to EAA • Progressive increase in glutamate release during kindling • Increased glutamate and aspartate at start of seizure • Upregulation of NMDA receptors in kindled rats • Decreased GABA • Decreased binding of GABA and benzodiazepines • Decreased Cl- currents in response to GABA • Decreased glutamate decarboxylase activity (synthesizes GABA) • Interfere with GABA causes seizures

21. Medications The mainstay of treatment of epilepsy is anticonvulsant medications. Often, anticonvulsant medication treatment will be lifelong and can have major effects on quality of life. The choice among anticonvulsants and their effectiveness differs by epilepsy syndrome. Availability - Currently there are 20 medications approved by the Food and Drug Administration for the use of treatment of epileptic seizures in the US

24. Strategies in Treatment • Stabilize membrane and prevent depolarization by action on ion channels • Increase GABAergic transmission • Decrease EAA transmission

25. Mechanism of Action • Current antiepileptic drugs are thought to act mainly by two main mechanisms:

26. Mechanism of Action • Reducing electrical excitability of cell membranes, possibly through inhibition of sodium channel. • Enhancing GABA-mediated synaptic inhibition. This may be achieved by an enhanced pre- or post- synaptic action of GABA, by inhibiting GABA-transaminase, or by drugs with direct GABA-agonist properties.

27. Mechanism of Action • A few drugs appear to act by a third mechanism, namely inhibition of T-type calcium channels. • Newer drugs act by other mechanism, yet to be elucidated. • Drugs that block excitatory amino acid receptors are effective in animal models, but not yet developed for clinical use.

28. Phenytoin • Mechanism of Action: acts by stabilizing membranes • Blocking voltage-dependence Na+ channel • (2) Blocking voltage-dependence Ca2+ channel • (3) Inhibiting calcium-induced secretory processes, including release of hormones and neurotransmitters. • (4) Inhibiting post tetanic potentiation (PTP).

30. PHARMACOKINETICS • Because phentoin is a weak acid, its intestinal absorption is variable and plasma concentration can vary widely. Monitoring is therefore needed • It is metabolized by the microsomal system and is excreted first in the bile and then in the urine.

31. Therapeutic uses • Antiseizure: used in the treatment of grand mal epilepsy and tonic-clonic seizure disorders, not in absence seizures. • Antiarrhythmias

32. Adverse effects • Gastrointestinal irritation • Ataxia • Blood dyscrasias. • Gingival hyperplasia, increased collagen proliferation.

33. Adverse effects • Hepatitis. • Drug interactions: increased plasma concentrations of phenytoin can occur by concurrent administration of chloramphenicol, isoniazid, cimetidine, zdicumarol, et al.

34. Carbamazepine • Derivative of tricyclic antidepressants • Similar profile to that of phenytoin, but with fewer unwanted effects • Effective in most forms of epilepsy (except absence seizures); particularly effective in psychomotor epilepsy; also useful in trigeminal neuralgia and mania.

35. Carbamazepine • Strong inducing agent; therefore many drug interactions • Low incidence of unwanted effects; principally sedation, ataxia, mental disturbances, water retention

36. Valproate • Valproate is very effective against absence seizure. • Mechanism: facilitate glutamic acid decarboxylase; inhibit GABA-transaminase; enhance synaptic responses. some effect on sodium channels • Relatively few unwanted effects: anorexia, nausea, teratogenicity, liver damage (rare, but serious)

37. Ethosuximide • The main drug used to treat absence seizures, may exacerbate other forms • Acts by blocking T-type Ca2+-channels • Relatively few unwanted effects, mainly nausea and anorexia. (mental disturbances)

38. Benzodiazepine • Diazepam: preferred drugs for Status epilepticus. • Nitrazepam: petit mal ,especially myoclonic seizures and infantile spasms. • Clonazepam: is one of the most effective in some cases of myoclonic seizures. Used in petit mal and status epilepticus

39. Barbiturates • Phenobarbital, Luminal: is useful in the treatment of generalized tonic-clonic seizures and statue epilepticus. • Mechanism:(1) block Ca2+ currents presynaptic membrane and decrease neurotransmitter release.(2) prolong the openings of the Cl- channel in postsynaptic membrane and decrease it’s response. • Adverse effects: sedation, depression, drug interaction.

40. Clinical Uses of Antiepileptic Drugs • Tonic-clonic (grand mal) seizures: carbamazepine preferred because of low incidence of side-effects, phenytoin, valproate. Use of single drug is preferred when possible, because of risk of pharmacokinetic interactions. • Partial (focal) seizures: carbamazepine, valproate; clonazepam or phenytoin are alternatives.

42. Clinical Uses of Antiepileptic Drugs • Absence seizures (petit mal): ethosuximide or valproate. Valproate is used when absence seizures coexist with tonic-clonic seizures, since most drugs used for tonic-clonic seizures may worsen absence seizures. • Myoclonic seizures: valproate or clonazepam. • Status epilepticus: must be treated as an emergency, with diazepam intravenously.

43. Surgery Epilepsy surgery is an option for patients whose seizures remain resistant to treatment with anticonvulsant medications who also have symptomatic localization-related epilepsy; a focal abnormality that can be located and therefore removed. The goal for these procedures is total control of epileptic seizures,although anticonvulsant medications may still be required.

44. Electrical stimulation Methods of anticonvulsant treatment are both currently approved for treatment and investigational uses. A currently approved device is vagus nerve stimulation (VNS). Investigational devices include the responsive neurostimulation system (RNS) and deep brain stimulation (DBS).

45. Attentions • Selection of an appropriate antiseizure agent • Use of single drug • Withdrawal • Toxicity • Fetal malformations

46. THANKS