Anticonvulsants Antiseizure

Transcription

1 Anticonvulsants Antiseizure

2 Seizure disorders Head trauma Stroke Drugs (overdose, withdrawal) Brain tumor Encephalitis/ Meningitis High fever Hypoglycemia Hypocalcemia Hypoxia genetic factors

3 Epileptic seizure spread Focal Focal +secondary generalization Generalized

4 Epileptic seizure types Partial Simple Symptoms Muscle contraction Abnormal sensory experience No loss of consciousness Complex Late loss of consciousness General Tonic-clonic Myoclonic Absence Immediate loss of consciousness Spasm convulsions convulsions In children: no motor involvement

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7 Antiepileptic drugs GABA action Na + channel Ca 2+ channel Use-depending blockers Glutamate action

8 Glutamate GABA

9 First line Valproic acid / Valproate GABA transaminase inhibitor (GABA ) GABA synthesis Blocks Na and Ca channels Adverse effects: Hepatotoxicity, not given to children<2 years old Pregnancy: Birth defects (folate metabolism- neural tube deffects) Drug interactions: Inhibits metabolism of Lamotrigine, Phenobarb., Primidone Valproic acids serum levels decreased by CBZ, Phenytoin Use: Almost all seizurs Mood stabilizer in bipolar instead of Li

10 First line Na + channel-blockers Iminostilbenes Hydantoines

11 First line Carbamazepine Blocks Na channels- stops the propagation of the seizure Adverse effects: Structural similarity to TCAs- reuptake of NA - mood elevation Pregnancy: Birth defects (spina bifida, facial) Drug interactions: Induces it s own metabolism and also of Phenytoin, Valproic acid, Lamotrigine, Topiramate Use: Partial and tonic-clonic seizures (NOT in absence) Mood stabilizer in bipolar instead of Li Trigeminal neuralgia

12 First line Phenytoin/ Fosphenytoin Blocks Na channels- stops the propagation of the seizure Adverse effects: Gingival hyperplasia, hirsutism, osteomalacia, CNS depression Aplastic anemia Pregnancy: Birth defects (folate metabolism)- fetal hydantoin syndrome (cardiac deffects, face malformations, retardation ) Drug interactions: Induces metabolism of Valproic acid, Lamotrigine,Topiramate and also of: Digoxin, Steroids, Vit.K There is a polymorphism in phenytoin metabolism Use: Partial and tonic-clonic seizures (NOT in absence), should be avoided in children

13 Second line drugs Barbiturates (Phenobarbital, Primidone) GABA action Primidone blocks Na channels Adverse effects: Cognitive slowing, rash (allergic reaction) Use: Partial and tonic-clonic seizures

14 Clorazepate prodrug of Diazepam, tolerance Felbamate- NMDArec. block, the seizure can t start. Aplastic anemia- life threatening side eff. Gabapentin- GABA analog, no direct action on GABA rec. Lamotrigine- Blocks Na channels- stops the propagation of the seizure Side effects: cerebellar dysfunction, Stevens-Johnson syndrome (especially with valproic acid) Interactions: CYP450 Uses: Partial and also tonic-clonic seizures, atonic, absence Topiramate- Blocks Na channels, potentiates GABAa rec activation by GABA, blocks Glutamate rec. Uses: partial, also as monotherapy (in trials) Tiagabine- GABA reuptake inhibitor Vigabatrine- irreversible inhibitor of GABA transaminase

15 Abscence seizures: ethosuximide Ca2+ channel-blocker, thalamic neurons Long t1/2 Drug interactions: valproic acid inhibits ethosuximide s metabolism Use: Generalized absence in children Benzodiazepines (clonazepam, diazepam) Uses: absence, myoclonic, atonic Side eff.- sedative

16 Treatment options Absence Partial and Tonic Clonic Status Epilepticus Ethosuximide Valproic acid Clonazepam Lamotrigine Topiramate Phenytoin Carbamazepine Oxcarbazepine Valproic acid Phenobarbital Primidone Lamotrigine Gabapentin Levetiracetam Topiramate IV Diazepam/Lorazepam IV Fosphenytoin IV Phenobarbital

17 Special Cases: Pregnancy Seizures in pregnancy constitute major risk to mother and fetus Must maintain therapy (carbamazepine drug of choice) Requires careful monitoring change in plasma protein binding change in hepatic drug metabolism interaction with OCP Drugs are secreted in small quantities into breast milk but not usually sufficient to prevent breast feeding (phenobarbitone significantly) Teratogenicity Antiepileptic drugs associated with increased (2-3 fold) incidence of birth defects (cleft lip/palate and cardiac defects) Significant risk of neural tube defects (altered folate metabolism)

18 STATUS EPILEPTICUS Definition - generalised tonic-clinic fit lasting more than 30 minutes or repeated fits without recovery of normal alertness in between. Prompt treatment is required to prevent hypoxic cerebral damage metabolic complications hypoglycaemia lactic acidosis Treatment: IV Lorazepam/ Diazepam Phenytoin Phenobarbital

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21 Drug Main action Epilepsy type Side-effect Barbiturates Phenobarbital Primidone (not in use) Benzodiazepines Clonazepam Clobazam Diazepam Dialkylacetates Valporic acid Iminostilbenes Carbamazepine Hydantoins Phenytoin GABA GABA GABA transaminase inhibitor Na + channel Na + channel all types except absence all types most types, including absence all types except absence most widely used all types except absence Sedation Depression Allergy (primidone) Sedation Withdrawal syndrome then other drugs Nausea Weight gain Birth defects Sedation Ataxia Birth defects Allergy arrhythmias Gum hypertrophy Succinimides Ethosuximide Oxazolidinediones Trimethadione Ca 2+ channel only absence Nausea Anorexia Mood changes

22 Newer drugs Drug Main action Epilepsy type Side-effect GABA analogue Gaba-pentin unknown mechanism with other antiepileptics safe at overdose Phenyltriazine d. Lamotrigine Dicarbamate Felbamate Na + channel unknown mechanism all types epilepsy unresponsive to other drugs Nausea dizziness, ataxia Hypersensitivity skin rashes Nausea Insomnia Aplastic Anemia Hepatitis

23 Drugs used for epilepsy Seizure type Primary Drug Secondary drug Partial Generalized tonic-clonic Absence Carbamazepine Phenytoin Ethosuximide Valporic acid Phenobarbital Valporic acid Clonazepam Myoclonic Valporic acid Primidone