ANTIEPILEPTIC DRUGS OBJECTIVES Define the following terms: Absence (petit mal) seizures © Generalized tonic-clonic (grand mal) seizures © Myoclonic jerking © Partial and generalized seizures «Status epilepticus You should be able to: * List the major drugs used for partial and generalized tonic-clonic seizures and describe their main adverse effects, © List the major drugs used for absence seizures and describe their main toxic effects * Describe the pharmacokinetic factors that must be considered in designing a dosage regimen for antiepileptic drugsANTIEPILEPTIC DRUGS 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 seizures 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, * 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. * 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. The glutamate content in areas surrounding an epileptic focus may be increased. «Repeated epileptic discharge can cause neuronal death (excitotoxicity). * Current drug therapy is effective in 70-80% of patients 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; > Enhaneing 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 not yet developed for clinical use. THE MAJOR ANTIEPILEPTIC DRUGS * The main drugs in current use are: phenytoin, carbamazepine, valproate and ethosuximide. © Phenytoin: > Acts mainly by use-dependent block of sodium channels > Effective in many forms of epilepsy, but not absence seizures, > Metabolism shows saturation kinetics; therefore, plasma concentration can vary widely and monitoring is needed> Drug interactions are common > Main unwanted effects are confusion, gum hyperplasia, skin rashes, anaemia, teratogenesis > Widely used in treatment of epilepsy; also used as antidysrhythmic agent. © Carbamazepine: > Derivative of tricyclic antidepressants > Similar profile of 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 enzyme-inducing agent; therefore, many drug interactions > Low incidence of unwanted effects; principally sedation, ataxia, mental disturbances, water retention. © Valproate: > Chemically unrelated to other antiepileptic drugs > Mechanism of action not clear; weak inhibition of GABA transaminase; some effect on sodium channels > Related few unwanted effects: baldness, teratogenicity, liver damage (rare but serious). © Bthosuximide > 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 * Secondary drugs include: > Phenobarbital: highly sedative > Various benzodiazepines (e.g, clonazepam); diazepam used in treating status epilepticus. NEW ANTIEPILEPTIC DRUGS + Vigabatrin > Acts by inhibiting GABA transaminase > Effective in patients unresponsive to conventional drugs > Main side-effects: drowsiness, behavioural and mood changes. « Lamotrigine > Acts by inhibiting sodium channels > Broad therapeutic profile > Main side-effects are hypersensitivity reaction (especially skin rashes). © Felbamate > Mechanisms of action unknown > Broad therapeutic profile > Use limited to intractable disease because of the risk of severe hypersensitivity reactions. © Gabapentin > Mechanism of action unknown > Saturable absorption; therefore, itis safe in overdose > Relatively free of side-effects © Tiagabine > GABA-uptake inhibitor> Side-effects are dizziness and confusion > Not yet fully evaluated © Topiramate > Complex actions, not fully understood » Similar to phenytoin with fewer side-effects and simpler pharmacokinetics > Risk of teratogenesis. CLINICAL USES OF ANTIEPI * Tonic-clonic (grand mal) seizures: > Carbamazepine (preferred because of low incidence of side-effects), phenytoin, valproate > Use of a single drug is preferred when possible to avoid pharmacokinetic interactions > Newer agents (not yet fully assessed) include vigabatrin, lamotrigine, felbamate. gabapentin, * Partial (focal) seizures: carbamazepine, valproate, clonazepam or phenytoin are alternatives, * Absence seizures (petit mal): ethosuximide or valproate > Valproate is used when absence seizures coexist with tonic-clonic seizures, since most other drugs used for tonic-clonic seizures can worsen absence seizures, + Myoclonie seizures: diazepam intravenously or (in absence of accessible veins) rectally, * Neuropathic pain carbamazepine, gabapentin. * To stabilise mood (as an alternative to lithium) carbamazepine, valproate, PTIC DRUGSseg vanuade9@9 pene agra ese sutinowey Spee 340) BUS poow pur jnoIRNeG "wonPES nna, soudazerpoziag 295 | auoypess arian uonepas [sme jomuo> 0 posn undo 7 ‘undocnp “undazeuo(> 3) _soudezerporueg rougnegouous _penursnsoing one srvounsien vv smonten ere sasn NIV aoe wD sede vvave, ‘pave ON souanprooviwavid | gana IVI, s NOLLDV 40 ALIS ostuang VAC OLLdTWGaLINY NIV RL 40 SaILwadOud