1. EPILEPSY -I Department of Pharmacology College of Pharmacy King Saud University

3. Definitions Epilepsy: is a chronic neurological disorder of brain function characterized by a periodic recurrent, and unpredictable occurrence of unprovoked seizures. Epilepsy: is a chronic neurological disorder of brain function characterized by a periodic recurrent, and unpredictable occurrence of unprovoked seizures. Seizure: transient alteration of behavior due to disordered and rhythmic firing of population of brain neurons. Seizure: transient alteration of behavior due to disordered and rhythmic firing of population of brain neurons. These seizures are usually distressful and often incapacitating. These seizures are usually distressful and often incapacitating. Seizures occur when there is abnormal, excessive, synchronized firing of neurons. Can be local or generalized Seizures occur when there is abnormal, excessive, synchronized firing of neurons. Can be local or generalized Convulsion: The major motor manifestations of a seizure (rhythmic jerking of the limbs) Convulsion: The major motor manifestations of a seizure (rhythmic jerking of the limbs)

4. Etiology is usually unknown (>70%). Seizures are signs of underlying neurological disturbances

5. Etiology or First Cause Birth and perinatal injuries Vascular insults Head trauma Congenital malformations Metabolic disturbances (serum Na +, glucose, Ca 2+, urea) Drugs or alcohol (including withdrawal from barbiturate, CNS depressants) Neoplasia (tumors) Infection or fever Genetic ( >25 single gene mutations identified)

6. Pathophysiology of Epilepsy  High frequency discharge of impulses by interconnected cerebral neurons  Starts locally then spread  Enhancement of excitatory transmission  Reduction of inhibitory transmission

7. Symptoms of Epilepsy  Convulsion (motor cortex involvement)  Peripheral autonomic discharge (hypothalamus involvement )  Loss of consciousness (reticular formation involvement)  Others, staring,, jerking movements of the arms and legs and amnesia

8. Diagnostic Tools Electroencephalogram (EEG) The most important tool for diagnosis epilepsy Measures brain waves Should be performed with 24 hours of seizure Repeated EEGs are often required Computerized Tomography (CT) Scans Usually the first test ordered for first-time seizures Magnetic Resonance Imaging (MRI) Strongly recommended for children with first-time seizures Also for seizures associated with significant mental or motor problems May help to determine if the disorder can be treated with surgery

9. EEG Figure 1. Electroencephalograph (EEG) records in epilepsy

10. Distinguishing between seizure types is important because different types of seizure may have different causes, prognoses and treatments.

11. Seizure types Classified into two broad categories organized according to the source of the seizure within the brain: Partial (localized to one region of the brain) Generalized (distributed throughout the brain).

12. Types of Epilepsy   Partial seizures Simple partial seizures: These seizures begin from a small area in your brain and don't result in loss of consciousness (20-60”) Complex partial seizures: These seizures also begin from a small area of your brain. They alter consciousness and usually cause memory loss (amnesia) and nonpurposeful movements, such as repeated hand rubbing, lip smacking (30”-2 min.) Secondary generalized seizures (partial seizures with secondary generalization): These seizures occur when simple or complex seizures spread to involve your entire brain (1-2 min.)

13. Types of Epilepsy; cont.  Generalized seizures Absence (petit mal seizures): These seizures are characterized by sudden loss of consciousness, staring, & stopping of body activities (<30”) Myoclonic seizures: These seizures usually appear as sudden jerks of arms and legs Atonic seizures: Also known as drop attacks, these seizures cause sudden collapse or fall down. After a few seconds, consciousness is regained Generalized tonic-clonic (grand mal seizures): They're characterized by a loss of consciousness, sustained muscles contraction followed by periods of muscle relaxation

14. Types of Epilepsy; cont.   Status epilepticus: Characterized by convulsions without cessation (lasting greater than 30 minutes) Characterized by convulsions without cessation (lasting greater than 30 minutes) Mortality: 5 -15% Causes: hyponatremia, pyridoxine deficiency, abrupt withdrawal of anticonvulsants or fever

15. Animal Models of Epilepsy   Genetic strains that show epilepsy-like characteristics   Transgenic mouse strains   Local cortical damage   Convulsant drugs (pentylenetetrazol)   Kindling model   Kainate model

16. Kindling Repeated low-level electrical stimulation to some brain sites in animals can lead to permanent increases in seizure susceptibility In other words, a permanent decrease in seizure "threshold.” Amygdala and parahippocampal regions are particularly susceptible Chemical stimulation may cause this too (repeated exposure to pesticides can induce seizures in humans) Changes in anatomy and cell morphology (loss of critical components in the neural circuit)

17. Nature of epilepsy Epilepsy affects about 0.5% of the population. The characteristic event is the seizure, which is often associated with convulsions but may occur in many other forms. The seizure is caused by an asynchronous high-frequency discharge of a group of neurons, starting locally and spreading to a varying extent to affect other parts of the brain. In absence seizures, the discharge is regular and oscillatory. Partial sizures affect localised brain regions, and the attack may involve mainly motor, sensory or behavioural phenomena. Unconsciousness occurs when the reticular formation is involved. Generalised seizures affect the whole brain. Two common forms of 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.

18. Many animal models have been devised, including electrically and chemically induced generalised seizures, production of local chemical damage and kindling. These provide good prediction of antiepileptic drug effects in humans. Several susceptibility genes, mainly encoding neuronal ion channels, have been identified. The neurochemical basis of the abnormal discharge is not well understood. It may be associated with enhanced excitatory amino acid transmission, impaired inhibitory transmission, or abnormal electrical properties of the affected cells. Several susceptibility genes, mainly encoding neuronal ion channels, have been identified.. Repeated epileptic discharge can cause neuronal death (excitotoxicity). Current drug therapy is effective in 70-80% of patients.

19. Excitotoxicity and oxidative stress Excitatory amino acids (e.g. glutamate) can cause neuronal death. Excitotoxicity is associated mainly with activation of NMDA receptors, but other types of excitatory amino acid receptors also contribute. Excitotoxicity results from a sustained rise in intracellular Ca2+ concentration (Ca2+ overload). Excitotoxicity can occur under pathological conditions (e.g. cerebral ischaemia, epilepsy) in which excessive glutamate release occurs. It can also occur when chemicals such as kainic acid are administered.

21. Raised intracellular Ca2+ causes cell death by various mechanisms, including 1.activation of proteases, 2.formation of free radicals, 3. and lipid peroxidation. 4.Formation of nitric oxide and arachidonic acid are also involved.

22. Raised [Ca2+]i affects many processes, the chief ones relevant to neurotoxicity being 1. increased glutamate release 2. activation of proteases (calpains) and lipases, causing membrane damage 3. activation of nitric oxide synthase; while low concentrations of nitric oxide are neuroprotective, high concentrations in the presence of reactive oxygen species generate peroxynitrite and hydroxyl free radicals, which damage many important biomolecules, including membrane lipids, proteins and DNA 4. increased arachidonic acid release, which increases free radical production and also inhibits glutamate uptake (site 6).

23. Various mechanisms act normally to protect neurons against excitotoxicity, the main ones being : 1.Ca2+ transport systems, 2.mitochondrial function and 3.the production of free radical scavengers

24. Oxidative stress Oxidative stress refers to conditions (e.g. hypoxia) in which the protective mechanisms are compromised, reactive oxygen species accumulate, and neurons become more susceptible to excitotoxic damage.

25. Excitotoxicity due to environmental chemicals may contribute to some neurodegenerative disorders. Measures designed to reduce excitotoxicity include the use of 1.glutamate antagonists, 2. calcium channel-blocking drugs 3.free radical scavengers; none are yet proven for clinical use.

27. Mechanism of action of antiepileptic drugs 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).

28. 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

30. Phenytoin Mechanism of action: – –acts mainly by use-dependent block of sodium channels thus it blocks sustained high frequency repetitive firing of action potentials - Membrane stabilization – –effective in many forms of epilepsy, but not absence seizures – –metabolism shows saturation kinetics, therefore plasma concentration can vary widely; monitoring is therefore needed

32. – –drug interactions are common – –main unwanted effects are confusion, gum hyperplasia, skin rashes, anemia, teratogenesis – –widely used in treatment of epilepsy; also used as antidysrhythmic agent

33. Phenytoin Indications 1. 1. Generalized tonic-clonic (grand mal) and complex partial (psychomotor, temporal lobe) seizure 2. 2. Prevention and treatment of seizures occurring during or following neurosurgery 3. 3. Trigeminal neuralgia and migraine 4. 4. Ventricular tachycardia, paroxysmal supraventricular tachycardia and arrhythmias associated with digitalis glycoside toxicity 5. 5. Rheumatoid arthritis and discoid lupus erythematosus

34. Phenytoin Side Effects uncoordinated muscle or eye movement CNS: nystagmus, ataxia uncoordinated muscle or eye movement mental confusion, dizziness, insomnia, Cognitive impairment Immunologic: rashes and systemic lupus erythematosus GI system: Nausea, vomiting, constipation, toxic hepatitis and liver damage Hirsutism,, gingivial hyperplasia Connective tissues: gingival hyperplasia, coarsening of the facial features, and hypertrichosis Hirsutism,, gingivial hyperplasia Blood: thrombocytopenia, leukopenia, granulocytopenia and megaloblastic anemia Bone: osteomalacia

35. Precautions & Contraindications Precautions: Impaired liver function Elderly patients HyperglycemiaOsteomalaciaContraindications: hypersensitivy to phenytoin or other hydantoins

36. Pharmacokinetics Absorption: oral & slow Metabolism: By the hepatic mixed function oxidase system Excretion: Urine (  5% as unchanged drug); as glucuronides) Half-life elimination: Approximately 24 hours. High protein binding Enzyme inducer.

37. Drug interactions Alcohol intake, amiodarone, chloramphenicol, diazepam, H2-antagonists, isoniazid → increase phenytoin level Alcohol intake, amiodarone, chloramphenicol, diazepam, H2-antagonists, isoniazid → increase phenytoin level Phenylbutazone, salicylates, succinimides, sulfonamides → increase phenytoin level Phenylbutazone, salicylates, succinimides, sulfonamides → increase phenytoin level Carbamazepine and sucralfate → decrease phenytoin level Carbamazepine and sucralfate → decrease phenytoin level Corticosteroids, warfarin, digitoxin, doxycycline, estrogens, furosemide, oral contraceptives, quinidine, rifampin, theophylline, vitamin D → phenytoin decreases their level Corticosteroids, warfarin, digitoxin, doxycycline, estrogens, furosemide, oral contraceptives, quinidine, rifampin, theophylline, vitamin D → phenytoin decreases their level

38. Valproate Mechanism of action: 1. 1. Enhancement of GABA action 2. Weak inhibition of GABA transaminase, 3.Blocks voltage-dependent sodium channels 4.T-type Ca 2+ channel blockade Indications: Treatment of absence, myoclonic partial, and tonic-clonic seizure Migraine prophylaxis Bipolar disorder

41. Adverse Effects relatively few unwanted effects GI side effects: nausea, vomiting and anorexia GI side effects: nausea, vomiting and anorexia CNS: ataxia, tremors, sedation, CNS: ataxia, tremors, sedation, Rashes and alopecia Rashes and alopecia Elevates liver enzymes; hepatitis (rarely) Elevates liver enzymes; hepatitis (rarely) Acute pancreatitis Acute pancreatitis Hyperammonia Hyperammonia baldness, teratogenicity, liver damage (rare, but serious). The most serious side effect is hepatotoxicity

42. Precautions & Contraindications Precautions: Hepatic Dysfunction Hepatic Dysfunction Pancreatitis Pancreatitis Blood disorders Blood disorders Thrombocytopenia ThrombocytopeniaContraindications: Active liver disease Active liver disease Hypersensitivity to valproate Hypersensitivity to valproate Family history of severe hepatic dysfunction Family history of severe hepatic dysfunction

43. Pharmacokinetics Metabolism: hepatic via glucuronide conjugation and mitochondrial beta-oxidation Metabolism: hepatic via glucuronide conjugation and mitochondrial beta-oxidation Half-life elimination:adults(9-16 hrs) Half-life elimination:adults(9-16 hrs) Children(4-14hrs) Children(4-14hrs) Excretion: urine Excretion: urine Protein binding: 80%to90% Protein binding: 80%to90% Valproate is hepatic enzyme inhibitor Valproate is hepatic enzyme inhibitor

44. Drug interactions Valproate inhibits metabolism of phenobarbital, lamotrigine, lorazepam & phenytoin Valproate inhibits metabolism of phenobarbital, lamotrigine, lorazepam & phenytoin Valproate is displaced by aspirin from plasma protein Valproate is displaced by aspirin from plasma protein Plasma conc. Of valproate reduced by carbamazepine Plasma conc. Of valproate reduced by carbamazepine The concomitant use of valproic acid and clonazepam may induce absence status in patients with a history of absence type seizures The concomitant use of valproic acid and clonazepam may induce absence status in patients with a history of absence type seizures Cholestyramine reduces absorption of valproate Cholestyramine reduces absorption of valproate

45. Carbamazepine: derivative of tricyclic antidepressants Na + channel inactivation 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 strong inducing agent, therefore many drug interactions low incidence of unwanted effects, principally sedation, ataxia, mental disturbances, water retention.

46. Carbamazepine is a powerful inducer of hepatic microsomal enzymes, and thus accelerates the metabolism of many other drugs, such as phenytoin, oral contraceptives, warfarin and corticosteroids. In general, it is inadvisable to combine it with other antiepileptic drugs. Ozcarbazepine, introduced recently, is a prodrug that is metabolised to a compound closely resembling carbamazepine, with similar actions but less tendency to induce drug- metabolising enzymes.

47. Ethosuximide: the main drug used to treat absence seizures; may exacerbate other forms acts by blocking T-type calcium channels relatively few unwanted effects, mainly nausea and anorexia.

48. Secondary drugs include: phenobarbital: highly sedative various benzodiazepines (e.g. clonazepam ); diazepam used in treating status epilepticus.

49. Diazepam, given intravenously or rectally, is used to treat status epilepticus, a life-threatening condition in which epileptic seizures occur almost without a break. Its advantage in this situation is that it acts very rapidly compared with other antiepileptic drugs. With most benzodiazepines, the sedative effect is too pronounced for them to be used for maintenance therapy. Clonazepam and the related compound clobazam are claimed to be relatively selective as antiepileptic drugs. Sedation is the main side effect of these compounds, and an added problem may be the withdrawal syndrome, which results in an exacerbation of seizures if the drug is stopped abruptly Clonazepam and the related compound clobazam are claimed to be relatively selective as antiepileptic drugs. Sedation is the main side effect of these compounds, and an added problem may be the withdrawal syndrome, which results in an exacerbation of seizures if the drug is stopped abruptly

50. Newer agents that are becoming widely used because of their improved side effect profile include vigabatrin, lamotrigine, felbamate, gabapentin, pregabalin, tiagabine, topiramate and zonisamide