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2 Epilepsy A group of chronic CNS disorders characterized by recurrent seizures. 3 Epilepsy Seizures are sudden, transitory, and uncontrolled episodes of brain dysfunction resulting from abnormal discharge of neuronal cells Associated with motor, sensory or behavioral changes. 4 Seizures The causes for seizures can be multiple, from infection, to neoplasms, to head injury. In a few subgroups it is an inherited disorder. 5 Seizures Febrile seizures or seizures caused by meningitis are treated by antiepileptic drugs Although they are not considered epilepsy (unless they develop into chronic seizures). 6 Seizures Seizures may also be caused by acute underlying toxic or metabolic disorders, 7 The EEG in seizure of Epilepsy Generalized Tonic-Clonic Seizures Spike wave Absence Seizures 3 Hz Paradoxical discharge Psychomotor seizures 1.etiology (1) primary epilepsy: inherited abnormality. (2) secondary epilepsy: such as brain tumors, head injury, hypoglycemia, meningeal infection, rapid withdrawal of alcohol from an alcoholic. 2.Pathogenesis sudden, excessive and abnormal discharge of cerebral neurons which diffuses to local or whole brain in short time over-excitement. 3. clinic manifestation regional or whole brain dysfunction: • motor • vegetative and mental episodes • loss of consciousness etc. Neuronal Substrates of Epilepsy The Synapse ions The Brain The Ion Channels/Receptors 12 Classification of Epileptic Seizures I. Partial (focal) Seizures A. Simple Partial Seizures B. Complex Partial Seizures II. Generalized Seizures A. Generalized Tonic-Clonic Seizures B. Absence Seizures C. Tonic Seizures D. Atonic Seizures E. Clonic and Myoclonic Seizures 13 I. Partial (Focal) Seizures A. B. Simple Partial Seizures Complex Partial Seizures. 14 Scheme of Seizure Spread Simple (Focal) Partial Seizures Contralateral spread 15 I. Partial (Focal) Seizures A. Simple Partial Seizures (Jacksonian) Involves one side of the brain at onset. Focal motor, sensory or speech disturbances. Confined to a single limb or muscle group. 16 I. Partial (Focal) Seizures A. Simple Partial Seizures (Jacksonian) Seizure-symptoms don’t change during seizure. No alteration of consciousness. EEG: Excessive synchronized discharge by a small group of neurons. Contralateral discharge. 17 Scheme of Seizure Spread Complex Partial Seizures Complex Secondarily Generalized Partial Seizures 18 B. Complex Partial Seizures (Temporal lobe epilepsy or Psychomotor Seizures) Produces confusion and inappropriate or dazed behavior. Motor activity appears as non-reflex actions. Automatisms (repetitive coordinated movements). 19 B. Complex Partial Seizures (Temporal Lobe epilepsy or Psychomotor Seizures) Wide variety of clinical manifestations. Consciousness is impaired or lost. EEG: Bizarre generalized EEG activity with evidence of anterior temporal lobe focal abnormalities. Bilateral. 20 II. Generalized Seizures A. B. C. D. E. Generalized Tonic-Clonic Seizures Absence Seizures Tonic Seizures Atonic Seizures Clonic and Myoclonic Seizures. 21 In Generalized seizures, both hemispheres are widely involved from the outset. Manifestations of the seizure are determined by the cortical site at which the seizure arises. 22 23 A. Generalized Tonic-Clonic Seizures Recruitment of neurons throughout the cerebrum Major convulsions, usually with two phases: 1) Tonic phase 2) Clonic phase 24 Tonic phase: - Sustained powerful muscle contraction (involving all body musculature) which arrests ventilation. 25 Tonic phase: EEG: Rythmic high frequency, high voltage discharges with cortical neurons undergoing sustained depolarization, with protracted trains of action potentials. 26 Clonic phase: - Alternating contraction and relaxation. 27 Clonic phase: EEG: Characterized by groups of spikes on the EEG and periodic neuronal depolarizations with clusters of action potentials. 28 B. Absence Seizures (Petite Mal) Brief and abrupt loss of consciousness. Sometimes with no motor manifestations. 29 B. Absence Seizures (Petite Mal) Typical 2.5 – 3.5 Hz spike-and-wave discharge. Usually of short duration (5-10 sec), but may occur dozens of times a day. 30 C. Tonic Seizures Opisthotonus, loss of consciousness. Marked autonomic manifestations D. Atonic Seizures (atypical) Loss of postural tone, with sagging of the head or falling. May loose consciousness. 31 Neuronal Substrates of Epilepsy The Synapse ions The Brain The Ion Channels/Receptors 32 Pharmacotherapy of Seizures Goals: Block repetitive neuronal firing. Block synchronization of neuronal discharges. Block propagation of seizure. 33 Pharmacotherapy of Seizures Goals: Minimize side effects with the simplest drug regimen. MONOTHERAPY IS RECOMMENDED IN MOST CASES 34 Strategies of treatment Modification of ion conductances. Increase inhibitory (GABAergic) transmission. Decrease excitatory (glutamatergic) activity. 35 Pharmacokinetics of antielpileptics Most classical antiepileptic drugs exhibit similar pharmacokinetic properties. Good absorption (although most are sparingly soluble). 36 Pharmacokinetics of antielpileptics Low plasma protein binding (except for phenytoin, BDZs, valproate, and tiagabine). Conversion to active metabolites 37 Pharmacokinetics of antielpileptics Cleared by the liver but with low extraction ratios. Distributed in total body water. Plasma clearance is slow. At high concentrations phenytoin exhibits zero order kinetics. 38 Pharmacokinetic Parameters 39 I Stabilize membrane and prevent depolarization by action on ion channels 40 PHENYTOIN (Dilantin) 41 Phenytoin 【pharmacokinetics】 • high concentrations in brain, • high plasma albumin binding, • half-life: 24 hours. Actions of Phenytoin on Na+ Channels Na+ A. B. C. Resting State Arrival of action potential causes depolarization and channel opens allowing sodium to flow in. Na+ Refractory State, Sustain channel Inactivation Na+ in this conformation 43 Phenytoin 【mechanism of action】 to decrease Na+ conductance in neurons to stabilize nervous cellular membranes. Phenytoin 【mechanism of action】 to reduce the influx of calcium ions during depolarization suppresses high-frequency repetitive firing halts seizure activity. 【Pharmacologic effects】 1.antiepileptic effect effective for tonic-clonic and partial seizures 2. Anti-peripheral neuralgia 3. antiarrhythmia 【therapeutic uses】 1. epilepsy. • highly effective for all partial seizures, tonic-clonic seizures and status epilepticus(First line). • not effective for absence seizure. 【therapeutic uses】 2. peripheroneural pain. Trigeminal neuralgia, glossopharyngeal neuralgia and sciatic neuralgia etc.. 3. arrhythmia Phenytoin 【Adverse effects】 Digestive system Gingival hyperplasia Nervous system Hematological Skeletal system Allergic response Others Phenytoin 【Adverse effects】 Digestive system: anorexia, nausea, vomiting and abdominal pain (recommend to take it after meal). It may cause phlebitis after IV. Phenytoin 【Adverse effects】 Gingival hyperplasia: occurs in children and teenagers after long term use, the incidence rate is about 20%. Generally, this effect can resolve after drug withdraw 3 to 52 Phenytoin 【Adverse effects】 Nervous system: nystagmus, diplopia, vertigo, ataxia (usually only at very high concentration). Severe patient occurs language disorder, mental confusion and Phenytoin 【Adverse effects】 inhibit the absorption of folinic acid and accelerate its metabolism. inhibit folic cid reductase. Hematological system: Phenytoin 【Adverse effects】 Hematological system: cause megaloblastic anemia after long-term use (recommend to pretreat with folinic acid). Phenytoin 【Adverse effects】 Skeletal system: enhance vitamin D metabolism so Phenytoin may increase the risk of hypocalcemia, rickets after long-term treatment(pretreat with Phenytoin 【Adverse effects】 Allergic response: rash, thrombocytopenia Others: lymphadenectasis. Fosphenytoin A Prodrug of phenytoin, more soluble, for parenteral use. rapidly converted to in the body. Avoids local complications associated with phenytoin: vein irritation, tissue damage,et al. 58 Fosphenytoin Can be injected with both saline and glucose While phenytoin cannot be injected with glucose 59 CARBAMAZEPINE (Tegretol) 60 Carbamazepine 1.The actions and mechanism are similar to those of phenytoin. • highly effective for all partial seizure as first-choice drug(for complex partial seizures) Carbamazepine • highly effective for tonic-clonic seizures, • effective for trigeminal neuralgia etc.. Carbamzepine 【Adverse effects】 CNS: somnolence, disequilibrium Gastrointestinal tract: nausea, vomiting and anorexia. Rash and hepatic lesion. OXCARBAZEPINE (Trileptal) Structure & mechanism Closely related to carbamazepine With improved toxicity profile Less potent than carbamazepine Active metabolite 64 OXCARBAZEPINE (Trileptal) Use in partial and generalized seizures as adjunct therapy. Toxicity: •Hyponatremia May aggravate •Less hyper-sensitivity and induction myoclonic and of hepatic enzymes than with absence seizures. carbamazepine 65 LAMOTRIGINE (Lamictal) like phenytoin, block repetitive firing involving Na+ channels Effective in myoclonic & generalized seizures in childhood and absence attacks. 66 LAMOTRIGINE (Lamictal) Add-on therapy with valproic acid Toxicity: •Dizziness Almost completely absorbed •Headache •Nausea T1/2 = 24 hrs •Somnolence •Life threatening rash “Stevens-Johnson” Low plasma protein binding 67 II Inhibitors of Calcium Channels 68 ETHOSUXIMIDE (Zarontin) Mechanism reducing low-threshold Ca2+ channel current (T-type channel) in thalamus 69 At high + + Inhibits Na /K ATPase. Depresses cerebral metabolic rate. Inhibits GABA aminotransferase. At high Choice for absence seizures. High efficacy and safety. Not plasma protein or fat binding Ethosuximide 1.effective for absence seizure(First -choice), no effective for other seizures. Ethosuximide 2.more adverse effects: Gastrointestinal intolerance Tiredness Mood change III Increase GABAergic transmission 74 CLONAZEPAM (Klonopin) A benzodiazepine. (+) frequency of Cl- channel opening. One of the most potent antiepileptic agents known. 75 CLONAZEPAM (Klonopin) Long acting drug with efficacy for absence seizures. Also effective in some cases of myoclonic seizures. 76 CLONAZEPAM (Klonopin) Has been tried in infantile spasms. Doses should start small. 77 Toxicity: Sedation is prominent. Ataxia. Behavior disorders. PHENOBARBITAL (Luminal) The oldest antiepileptic drug except for the bromides A safest drugs, it has sedative effects. Prolongs opening of Cl- channels. 79 PHENOBARBITAL (Luminal) Many consider them the drugs of choice for seizures only in infants. Useful for partial, generalized tonic-clonic seizures, and febrile seizures 80 PHENOBARBITAL (Luminal) Toxicity: Sedation. Cognitive impairment. Behavioral changes. Induction of liver enzymes. May worsen absence and atonic seizures. 81 VALPROATE (Depakene) Mechanism similar to phenytoin. (+) levels of GABA in brain. Facilitates glutamic acid decarboxylase Inhibits the GABA-transporter in neurons and glia (GAT). 82 VALPROATE (Depakene) Fully ionized at body pH, thus active form is valproate ion. One of a series of carboxylic acids with antiepileptic activity. 83 VALPROATE (Depakene) Toxicity: •Elevated liver enzymes including own. •Nausea and vomiting. •Abdominal pain and heartburn. Hepatotoxicity. 84 TOPIRAMATE (Topamax) Mechanism (-)voltage-dependent sodium channels (+) inhibition of GABA (acting at a site different from BDZs and BARBs). 85 DIAZEPAM (Valium) AND ClORAZEPAM (Ativan) Toxicity •Sedation •Children may manifest a paradoxical hyperactivity. •Tolerance Benzodiazepines. Given I.V. Lorazepam may be longer acting. for treating status epilepticus Have muscle relaxant activity. 86 Benzodiazepines Intravenous diazepam is used for epilepticism in adults( First-choice ). Clonazepam is used for absence and myoclonic seizure in children. PRIMARY GENERALIZED TONIC-CLONIC SEIZURES (Grand Mal) Drugs of choice: Carbamazepine Phenytoin Valproate* *Not approved except if absence seizure is involved 88 GENERALIZED ABSENCE SEIZURES Drugs of choice: Ethosuximide Valproate* * First choice if primary generalized tonic-clonic seizure is also present. 89 ATYPICAL ABSENCE, MYOCLONIC, ATONIC* SEIZURES Drugs of choice: Valproate Clonazepam Lamotrigine** * Often refractory to medications. **Not FDA approved for this indication. May worsen myoclonus. 90 INTERACTIONS BETWEEN ANTISEIZURE DRUGS With other antiepileptic Drugs: Carbamazepine with phenytoin Increased metabolism of carbamazepine phenobarbital Increased metabolism of epoxide. Phenytoin with primidone Increased conversion to phenobarbital. Valproic acid with clonazepam May precipitate nonconvulsive status epilepticus phenobarbital Decrease metabolism, increase toxicity. phenytoin Displacement from binding, increase toxicity. 91 Drug choice for The Therapy of Epilepsy 1. Accurate evaluation. 2. The drug choice for initial treatment of seizures . (1) grad mal and simple partial seizures Carbamazepine, phenytoin phenobarbital, primidone and valproic acid as alternative. Therapy for Epilepsy (2)Absence seizure ethosuxide, valproic acid, clonazepam. (3)Complex partial seizures Carbamazepine, phenytoin, primidone, valproic acid. Therapy for Epilepsy (4) Status epilepticus Diazepam iv, or plus lorazepam. or clonazepam, phenytoin and phenobarbital. (5)Tonic seizure: valproic acid (6)Myoclonic seizure Glucocorticoids, clonazepam. Therapy for Epilepsy 3. Duration of therapy: 2-3 years. 4. Change drug or add a second drug and/or combination ----gradually. 5. Withdrawn or discontinue ----gradually (half year). 6. Monitoring the serum drug level. Summary for this chapter 1. Choice of drugs for different patterns of epilepsies 2. Effects and uses of phenytoin