Epilepsy.pdf

ANTI EPILEPSY DR A.E * Types of epilepsy: A) Partial = Focal Seizures: Epileptic focus Local discharge - Simple Partial (Jacksonian Epilepsy): NO loss of consciousness. Focus in Frontal lobe Clonic jerking of single limb or a muscle group lasting for about 2 minutes. There may be some sensory...

ANTI EPILEPSY DR A.E * Types of epilepsy: A) Partial = Focal Seizures: Epileptic focus Local discharge - Simple Partial (Jacksonian Epilepsy): NO loss of consciousness. Focus in Frontal lobe Clonic jerking of single limb or a muscle group lasting for about 2 minutes. There may be some sensory disturbance. B) Generalized Seizures: Abnormal Discharge affects both hemispheres. 1- Tonic-clonic (Grand mal) Epilepsy: Aura Clonic jerking Flaccid relaxation Loss of consciousness Confusion & Fatigue Tonic spasm (1 min.) Sleep. 2- Absence (Petit mal) Epilepsy: Brief sudden attack of loss of consciousness lasting only for 10-15 seconds with mild or no motor disturbances. Begins in childhood (2-12 years), may stop at age of 20 or change to Grand mal epilepsy. 3- Myoclonic seizures: Short jerking of the whole body or one of the extremities with OUT loss of consciousness. A) Goal of Therapy: 1- Selective inhibition of the Epileptogenic focus. 2- Prevent spread of the abnormal impulses in the surrounding normal brain tissue. 3- Treatment should be continued for 2-3 years fit-free. 4- Withdraw Anti-Epileptic drugs gradually to avoid Status Epilepticus. Mechanism of Action of Anti-Epileptic Drugs: 1- Block of Na+-channels Delay recovery Carbamazepine, Lamotrigine & Valproate. Treat Partial & Grand Mal e.g. Phenytoin, 2- Block of voltage dependent T-Calcium channels Trimethadione & Valproate. Treat Petit Mal e.g. Ethosuximide, 3- Enhance GABA-Transmission: a- GABA-Potentiators e.g. Barbiturates & Benzodiazepines. b- GABA metabolism e.g. Vigabatrin & Valproate. 4- Block excitatory transmitters (Glutamate & Aspartate) e.g. Felbamate. 1 ANTI EPILEPSY DR A.E 1- Phenytoin (Diphenyl-Hydantoin, Epanutin) Kinetics: 1- Absorption: a- Oral: - Irritant (Used after meals) & affected by particle shape & size (Polymorphism). b- I.M. Irregular absorption. c- Slow I.V. in Status epilepticus. 2- Distribution All-over the body. Highly bound to plasma albumin (80-90%) 3- Metabolized by Hepatic Microsomal Enzymes glucuronic acid: Hydroxylation then conjugation with a- Small dose First-Order Kinetics Constant t ½ b- Large dose Zero-Order Kinetics t ½ with Dose. Uses : 1- Grand Mal Epilepsy & Partial seizures (No Sedation) 2- Status Epilepticus (15 20 mg / kg body weight Slow I.V.). 3- Treatment of Trigeminal neuralgia. 4- Class-1 Group-B Anti-Arrhythmic Useful in treatment of Ventricular arrhythmia with Heart Block Drug of Choice in Digitalis-Induced arrhythmia * Adverse Effects of Phenytoin: 1- CNS: Confusion & Hallucinations. Ataxia, Nystagmus & Vertigo. 2- GIT: Gastric irritation (highly alkaline) Used after meals. 3-Blood: Megaloblastic anemia& Hypoprothrombinemia 4-Bone: Osteomalacia. 5- Hirsutism (Androgenic effect). 6- Hepatotoxicity. 7- Hypersensitivity 8- Hormones Lymphadenopat Release of A.D.H. & Insulin Hyperglycemia. 9- Gum (Gingival) Hyperplasia especially in Children Irreversible Consult Dentists. 10- During Pregnancy: a- First trimester Teratogenic Fetal Hydantoin Syndrome b- Before labor Hypoprothrombinemia in baby Bleeding Hare lip & Cleft palate Prevented & treated by Vit-K 2 ANTI EPILEPSY DR A.E - Drug Interactions: a- Phenytoin Hepatic Microsomal Enzyme Inducer: - Its own metabolism Tolerance & Failure of Anti-Epileptic activity. - Metabolism of Other Anti-Epileptic drugs e.g. Barbiturates & Carbamazepine. - Metabolism of other drugs e.g. Oral contraceptives. - Metabolism of Folic Acid & Its intestinal absorption Megaloblastic anemia & Toxicity of Methotrexate (Folate antagonist). - Metabolism of Vit D Hypocalcemia Osteomalacia. - Metabolism of Vit K Hypoprothrombinemia. b- HME Inducers e.g. Phenobarbitone & Carbamazepine c- HME Inhibitors e.g. Valproate, Cimetidine & Isoniazide Metabolism of Phenytoin. Metabolism of Phenytoin. d- Phenytoin displaces Thyroxin & Tricyclic Anti-Depressants from plasma proteins. e- Aspirin, Sulfa & Valproate Displace phenytoin from plasma proteins. Fosphenytoin : the prodrug form of phenytoin with the advantage over phenytoin: 1-less vascular irritation 2-ability to be injected faster 3-greater physical compatibility with IV and IM solutions to dilute it 4-can be given IM 3 ANTI EPILEPSY DR A.E 2- Carbamazepine (Tegretol) - Related to Tri-cyclic Anti-depressants Useful as Mood Stabilizer in patients with Manic-Depressive (Bipolar affective) Disorders. Uses : a- Grand Mal Epilepsy & Partial seizures (No Sedation) b- Treats Trigeminal neuralgia. c-Mood Stabilizer Adverse Effects: a- Allergy b- Ataxia, Nystagmus & Vertigo c- Anorexia Cerebello-Vestibular G.I.T. upset d- Anti-diuretic Fluid retention e- Hepatitis f- Teratogenic Similar to Fetal Hydantoin Syndrome. g- Bone marrow inhibition - Drug interaction : Hepatic Microsomal Enzyme Inducer (see Phenytoin) NB) Oxcarbazepine (Trileptal) 600 1200 mg / day Related to carbamazepine But less toxic & Less HME induction Eslicarbazepine acetate: similar to carbazepine but shown to be effective when given once daily and may be more rapidly to active metabolite 4 ANTI EPILEPSY DR A.E 3- Valproic Acid & Sodium Valproate (Depakene) 1- Mechanism of Action: a- Block Na+-channels b- Block T-Ca2+-Channels c- Similar to Phenytoin Effective in Partial & Grand Mal epilepsy. Similar to Ethosuximide GABA-transaminase enzyme Effective in Absence seizures. GABA. d- Antagonize excitatory transmitters e.g. Aspartate. 2- Therapeutic use : a- Broad spectrum Anti-epileptic useful in Partial seizures, Grand mal & Petit mal epilepsy (Not drug of choice Sedation & Hepatotoxic). b- Drug of choice in patients with: - Mixed Petit mal + Grand mal epilepsy. - Myoclonic epilepsy. 3- Other Uses: a- Mood stabilizer in Bipolar Affective disorders. b- Migraine headache. 3- Adverse Effects: a- C.N.S. Sedation b- G.I.T. Nausea & Vomiting. c- blood: Thrombocytopenia & Platelet aggregation Hemorrhage. d- Hepatotoxicity. e- Temporary loss of hair f- Teratogenic Thin curly hair. Spina bifida. g- Allergy 4- Drug Interaction: - Enzyme inhibitor Metabolism of Phenytoin ,carbamazepine & barbiturates. - Displaces phenytoin from plasma proteins. 5 ANTI EPILEPSY DR A.E 4-Phenobarbitone: Effective in sub-hypnotic dose (100-300 mg/Day). * Mechanism Anti-Epileptic Effects: 1- Facilitate GABAA transmission 2- Cl- influx Hyperpolarization Ca2+ influx by presynaptic nerve endings Postsynaptic inhibition. Release of excitatory mediators. 3- block Na channels. * Use in Epilepsy: 1- Grand Mal & Partial seizures NOT drug of choice 2- Phenobarbitone 10 20 mg / kg Slow I.V. Sedation, Tolerance & Dependence. Status Epilepticus * Adverse Effects: 1- Tolerance & Dependence. 2- S E D A T I O N. 3-CNS Ataxia, Nystagmus & Vertigo. 4-Blood: Megaloplastic anemia& Hypoprothrombinemia 5-Bone: Osteomalacia. * drug interactions:Hepatic Microsomal Enzyme Induction: NB) Barbiturates, Phenytoin & Carbamazepine: 1- Treat Partial & Grand Mal Epilepsy. 2- Worsens Petit Mal Epilepsy. 3- H.M.E. Inducers. 5-Ethosuximide (Zarontin). 1- Anti-Epileptic: a- Block Voltage dependent T-Calcium channels. b- Drug of Choice in Absence Seizures = Petit Mal Epilepsy c- Worsens Grand Mal Epilepsy. 2- Adverse Effects: a- C.N.S. Drowsiness, Lethargy & Behavioral changes. b- G.I.T: anorexia ,nausea and vomiting c- Allergy leukopenia and thrombocytopenia. 6 ANTI EPILEPSY DR A.E 6-Benzodiazepines 1- Mechanism of Action GABA-A transmission Cl- influx Hyperpolarization Post-synaptic inhibition. 2-USES: - lorazepam & Diazepam 10 mg SLOW I.V. Drug of Choice in Status epilepticus. - Clonazepam: a- Slow I.V. 1 mg treat Status epilepticus. b- Orally 4 mg Broad spectrum anti-epileptic in Partial, Grand mal, Petit mal & Myoclonic epilepsy Not drug of choice. 3- Adverse Effects: - Sedation & Behavioral changes - Tolerance & Dependence - Secretions Salivary & Bronchial - Other Anti-Epileptic Drugs - May be used as Monotherapy or as Add-on in resistant cases of Eilepsy. - most of them used as mood stabilizer and to control neuropathic pain. 1- Lamotrigine (Lamictal: a- Block Na+ and Ca++ channels & Antagonizes excitatory transmitters e.g. Glutamate & Aspartate. b- Adverse effects Skin rash & Dermatitis. 2- Topiramate (Topamax): a- Block Na+-channel & Antagonize excitatory transmitters e.g. Glutamate & Aspartate. b- Adverse effects Sedation & confusion. 3- levetiracetam a- binds to synaptic vesicular protein to modify the release of glutamate and GABA. b- Adverse effects : nervousness, dizzeness and depression 4- Gabapentin a- Release of GABA. b- Side effects Sedation & Ataxia -pregabalin: similar to Gabapentin 5- Tiagabin GABA uptake. Adverse effects : nervousness, dizzeness and depression 6-Zonnisamide: Block Na+ channels. Side effects cognitive impairment 7) Lacosamide : sodium channel blocker used in focal seizures. Toxicity: Dizziness, headache, nausea . small increase in PR interval 8) Rufinamide : Sodium channel blocker and other mechanisms used in focal seizures Toxicity: Somnolence, vomiting, pyrexia, diarrhea 7 ANTI EPILEPSY DR A.E 9) Primidone Sodium channel blocker-like but converted to phenobarbital used in Generalized tonic-clonic seizures, partial seizures Toxicity: Sedation, cognitive issues, ataxia, hyperactivity Interactions: Similar toPhenobarbital. 10) Retigabine: Opens potassium channels. Used in Focal seizures Toxicity : Dizziness, somnolence, confusion, blurred vision 11) Perampanel: non-competitive block of AMPA receptors, Used in focal and focal-to-bilateral tonic-clonic seizures, generalized tonic-clonic seizures Toxicity: Dizziness, somnolence, headache; psychiatric syndrome * Choice of Anti-Epileptic Drugs: A) Grand Mal Epilepsy &Partial Seizures: 1- First Choice: Carbamazepine & Phenytoin. 2- Alternative: Valproate 3- Phenobarbital B) Absence Seizures = Petit Mal Epilepsy: 1- First Choice: Ethosuximide 2- Alternative: a- Valproate. b- Lamotrigine as Add-on c- Clonazepam. C) Mixed Petit mal + Grand mal epilepsy Drug of Choice Valproate. D) Myoclonic Seizures Drug of Choice Valproate. Alternative Clonazepam E) Febrile convulsions in children (after antipyretics): Valproate, Phenobarbitone, Diazepam F) Drug-induced Seizures: (as antidepressants, stimulants, isoniazid poisoning and antihistamines): 1- Benzodiazepines is the first line anticonvulsant therapy. 2- barbiturates and propofol. 3- If isoniazid poisoning, pyridoxine is given G) Status Epilepticus: 1- Diazepam 10 mg Slow I.V. 2- Lorazepam 1 mg Slow I.V. 3- Phenytoin 15-20 mg / kg Slow I.V. 4-fosphenytoin. 5- Phenobarbitone 10 20 mg / kg Slow I.V. 6-if resistant cases: IV general anesthesia midazolam or propofol. N.B. Buccal midazolam for the termination of acute prolonged seizures in children. Continuous infusion of one or more anticonvulsants may be required in refractory status epilepticus 8 ANTI EPILEPSY DR A.E * Effect of AED on adverse pregnancy outcomes 1- Epilepsy doubles the incidence of adverse pregnancy outcomes 2- More than 90% of women have satisfactory outcomes 3- Some AEDs have teratogenic effects a. Barbiturates and phenytoin cause congenital heart malformations, orofacial clefts. b. Valproic acid & carbamazepine can cause spina bifida and hypospadias, c. Other effects include low birth weight and retardation (growth, psychologic developmental) d. The risk increases with high AED doses, plasma conc, polytherapy & family history 4- Many of these teratogenicity can be prevented by a. adequate folate supplementation with higher dose if there is history of previous defects. b. Determination of the most suitable AED from start in women c. New AEDs have less risk 5- Neonatal hemorrhagic disorders: give vitamin K during the last month of pregnancy 9