Drugs for Epilepsy

1. Drugs for Epilepsy

2. Epilepsy • Seizure • Brief episode of abnormal electrical activity in nerve cells of the brain • Convulsion • Involuntary spasmodic contractions of any or all voluntary muscles throughout the body, including skeletal and facial muscles • Epilepsy • Chronic, recurrent pattern of seizures

3. Epilepsy • The third most common neurologic disorder after cerebrovascular and Alzheimer’s disease. • the sudden, excessive, and synchronous discharge of cerebral neurons. • This abnormal electrical activity may result in a variety of events, including loss of consciousness, abnormal movements, atypical or odd behavior, and distorted perceptions that are of limited duration but recur if untreated.

4. ETIOLOGY OF SEIZURES • Primary (idiopathic) • Cause cannot be determined • More than 50% of epilepsy cases • Secondary (symptomatic) • Distinct cause is identified Trauma, infection, cerebrovascular disorder Focal areas that are functionally abnormal may be triggered into activity by changes in physiologic factors, such as an alteration in blood gases, pH, electrolytes, and blood glucose and changes in environmental factors, such as sleep deficiency, alcohol intake, and stress.

5. Classification of Epilepsy • A. Focal (Partial-onset seizures) • involve only a portion of the brain, typically part of one lobe of one hemisphere. • The symptoms depend on the site of neuronal discharge and on the extent to which the electrical activity spreads to other neurons in the brain. • Focal seizures may progress to become generalized tonic–clonic seizures.

6. A. Focal (Partial-onset seizures) 1. Simple partial: The electrical discharge does not spread, and the patient does not lose consciousness. The patient often exhibits abnormal activity of a single limb or muscle group that is controlled by the region of the brain. Simple partial seizures may occur at any age.

7. A. Focal (Partial-onset seizures) 2. Complex partial: • These seizures exhibit complex sensory hallucinations and mental alteration. • Motor dysfunction may involve chewing movements, diarrhea, and/or urination. Consciousness is altered. • Complex partial seizures may occur at any age.

8. B. Generalized • May begin locally and then progress to include abnormal electrical discharges throughout both hemispheres of the brain. • It may be convulsive or nonconvulsive, and the patient usually has loss of consciousness. 1. Tonic–clonic: These seizures result in loss of consciousness, followed by tonic (continuous contraction) and clonic (rapid contraction and relaxation) phases.

9. 2. Absence: involve a brief, rapid, and selflimiting loss of consciousness. The onset generally occurs in patients at 3 to 5 years of age and lasts until puberty or beyond. The patient exhibits rapid eye-blinking, which lasts for 3 to 5 seconds. • 3. Myoclonic: short episodes of muscle contractions that may recur for several minutes. Myoclonic seizures occur at any age but usually begin around puberty or early adulthood.

10. 4. Clonic: consist of short episodes of muscle contractions that may closely resemble myoclonic seizures. Consciousness is more impaired with clonic seizures as compared to myoclonic. • 5. Tonic: involve increased tone in the extension muscles and are generally less than 60 seconds long. • 6. Atonic: also known as drop attacks and are characterized by a sudden loss of muscle tone.

12. Status epilepticus: • A series of seizures (usually tonic-clonic) without recovery of consciousness between attacks; it is a life-threatening emergency.

14. PHARMACOKINETICS • A. Phenytoin • Phenytoinmetabolism is nonlinear; elimination kinetics shift from first-order to zero order • The metabolism of phenytoin is enhanced in the presence of inducersof liver metabolism (eg, phenobarbital, rifampin) and inhibitedby other drugs (eg, cimetidine, isoniazid). • Phenytoin itself induces hepatic drug metabolism, decreasing the effects of other antiepileptic drugs including carbamazepine, clonazepam, and lamotrigine. • Fosphenytoinis a water-soluble prodrugform of phenytoin that is used parenterally.

15. B. Carbamazepine • Carbamazepine induces formation of liver drug-metabolizing enzymes that increase metabolism of the drug itself and may increase the clearance of many other anticonvulsant drugs including clonazepam, lamotrigine, and valproicacid. • Carbamazepine metabolism can be inhibited by other drugs (eg, propoxyphene,valproicacid). • A related drug, oxcarbazepine, is less likely to be involved in drug interactions.

16. C. Valproic Acid • In addition to competing for phenytoin plasma protein binding sites, valproic acid inhibits the metabolism of carbamazepine, ethosuximide, phenytoin, phenobarbital, and lamotrigine. • Hepatic biotransformation of valproic acid leads to formation of a toxic metabolite that has been implicated in the hepatotoxicity of the drug.

17. D. Other Drugs • Gabapentin, pregabalin, levetiracetam, and vigabatrin • Eliminated by the kidney, largely in unchanged form. • These agents have virtually no drug-drug interactions. • Tiagabine, topiramate, and zonisamide undergo both hepatic metabolism and renal elimination of intact drug. • Lamotrigineis eliminated via hepatic glucuronidation.

18. MECHANISMS OF ACTION • Effect of antiseizure drugs is to suppress repetitive action potentials in epileptic foci in the brain. A. Sodium Channel Blockade • Phenytoin, carbamazepine, lamotrigine, and zonisamideblock voltage-gated sodium channels in neuronal membranes. results in prolongation of the inactivated state of the Na+ channel and the refractory period of the neuron. • Phenobarbitaland valproicacid may exert similar effects at high doses.

19. B. GABA-Related Targets • Benzodiazepinesinteract with specific receptors on the GABAA receptor–chloride ion channel (facilitate the inhibitory effects of GABA). • Phenobarbital also enhance the inhibitory actions of GABA but interact with a different receptor site on chloride ion channels that results in an increased duration of chloride ion channel opening.

20. B. GABA-Related Targets • GABA aminotransaminase(GABA-T) is an enzyme in the termination of action of GABA. The enzyme is irreversibly inactivated by vigabatrinand can also be inhibited by valproicacid. • Tiagabine inhibits a GABA transporter (GAT-1) in neurons and glia prolonging the action of the neurotransmitter. • Gabapentinis GABA analog, but it does not activate GABA receptors directly. • Felbamate, topiramate, and valproicacid facilitate the inhibitory actions of GABA.

21. C. Calcium Channel Blockade • Ethosuximide inhibits low-threshold (T type) Ca2+ currents , especially in thalamic neurons. • A similar action is reported for valproic acid, as well as for both gabapentin and pregabalin. D. Other mechanisms • valproic acid causes neuronal membrane hyperpolarization, possibly by enhancing K+ channel permeability. • Phenobarbital , Topiramate, and Felbamateacts as an antagonist at glutamate NMDA receptors.

22. CLINICAL USES • Up to 80% of patients can expect partial or complete control of seizures with appropriate treatment. • Antiepileptic drugs suppress but do not cureor prevent seizures • Antiepileptics are indicated when there is two or more seizures occurred in short interval (6m -1 y) • An initial therapeutic aim is to use only one drug (monotherapy)

23. A. Generalized Tonic-Clonic Seizures • Valproic acid, carbamazepine, and phenytoin are the drugs of choice for generalized tonic-clonic (grand mal) seizures. • Phenobarbital(or primidone) is now considered to be an alternative agent in adults but continues to be a primary drug in infants. • Lamotrigine and topiramateare also approved drugs for this indication.

24. B. Partial Seizures • The drugs of first choice are carbamazepine (or oxcarbazepine) or lamotrigine or phenytoin. • Alternatives include felbamate, topiramate,phenobarbital, and valproic acid. • Many of the newer anticonvulsants can be used adjunctively including gabapentin and pregabalin, a structural congener.

25. C. Absence Seizures • Ethosuximide or valproic acid are the preferred drugs because they cause minimal sedation. • Valproicacid is particularly useful in patients who have concomitant generalized tonic-clonicor myoclonic seizures. • Clonazepamis an alternative drug (disadvantages sedation and tolerance). • Lamotrigine, levetiracetam, and zonisamide are also effective in absence seizures.

26. D. Status Epilepticus • I.V diazepam or lorazepamis usually effective providing short-term control. • For prolonged therapy, I.V phenytoin (highly effective and less sedating). • Phenytoin may cause cardiotoxicity, and fosphenytoin (water soluble) is a safer parenteral agent. • Phenobarbital used in status epilepticus, especially in children. • In very severe status epilepticusthat does not respond to these measures, general anesthesia may be used.

27. E. Other Clinical Uses • Valproic acid is used as a first-line drug in the treatment of mania. Carbamazepine and lamotrigine have also been used successfully in bipolar disorder. • Carbamazepine is the drug of choice for trigeminal neuralgia. • Gabapentin and Pregabalin have efficacy in pain of neuropathic origin, including postherpetic neuralgia, and, like phenytoin, may have some value in migraine. • Topiramateis also used in the treatment of migraine.

28. TOXICITY: • A. Teratogenicity ; congenital malformations. Neural tube defects (eg, spina bifida) are associated with the use of valproicacid. • carbamazepine has been implicated as a cause of craniofacial anomalies and spinabifida. • A fetal hydantoin syndrome has been described after phenytoin use by pregnant women, also Gingival hyperplasia.

29. B. Overdosage Toxicity • Most of the commonly used anticonvulsants are CNS depressants, and respiratory depression may occur with overdosage. Management is primarily supportive (airway management, mechanical ventilation), and flumazenil may be used in benzodiazepine overdose.

30. C. Life-Threatening Toxicity • Fatal hepatotoxicity with valproicacid (risk to children younger than 2 years and patients taking multiple anticonvulsant drugs). • Lamotriginehas caused skin rashes and life-threatening Stevens-Johnson syndrome or toxic epidermal necrolysis. Children are at higher risk (1–2% incidence), especially if they are also taking valproic acid. • Reports of aplastic anemia and acute hepatic failure have limited the use of felbamate to severe, refractory seizure states.