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Anti epileptic drugs
- 1. Anti-Epileptic Drugs Dr Kushagra Sharma PharmD, RPh.
- 2. Epilepsies The group of disorder of the CNS characterized by paroxysmal cerebral dysrhythmia, manifesting as brief episodes (Seizures) of loss or disturbance of consciousness, with or without body movement (Convulsions), sensory or psychiatric phenomena. These episodes are unpredictable and their frequency is highly variable. Recognised as “Disease of lightening” by JH Jackson.
- 3. Classification of Seizures Generalized Seizures Generalized Tonic-Clonic Seizures. Absence Seizures. Atonic Seizures. Myoclonic Seizures. Partial Seizures Simple partial Seizures. Complex partial Seizures. Complex/Simple Partial Seizure secondary generalized.
- 4. Generalised Tonic-Clonic Seizures Major Epilepsy. Commonest Lasts about 1-2 min. Sequence is aura-cry-unconsciousness-tonic spasm of all body muscles-clonic jerking followed by prolonged sleep and depression of all CNS functions. Absence Seizures Minor Epilepsy. Prevalent in children Lasts about 1-2 min. Loss of consciousness, Patient freezes and stares at one direction, little bilateral jerking. EEG shows 3 cycle per sec. wave length.
- 5. Atonic Seizures Akinetic Epilepsy. Sudden loss of postural tone. Patient ma fall off sudden. EEG shows diffused slow waves correlate with loss of muscle tone. Myoclonic Seizures Sudden skeletal muscle contraction that may involve the entire body or one part of the body. Patients complaints sudden jerking movements during sleep. EEG shows 2 Hz spikes and wave pattern per sec.
- 6. Simple Partial Seizures Also known as Jacksonian Seizures or Jacksonian motor Seizures . Begins with one group of muscles and spread gradually to adjacent level. No loss of Consciousness. Patient may have symptoms like auditory, visual or olfactory hallucinations, “Pins & Needle” sensations with no reason. Complex Partial Seizures Partial loss of Consciousness. Patient behaves as partially conscious like- He may get up, put on his clothes, start walking or even drive his car but does not follow your command and does not even recollect the events after the attack is over. Complex/Simple Partial Seizure secondary generalized These are the type when partial seizers progress to generalised/tonic/clonic/tonic-clonic seizures.
- 7. Classification of Anti-Epileptic Drugs Barbiturate -Phenobarbitone Deoxybarbiturate -Primidone Hydantoin -Phenytoin, Fosphenytoin Iminostilbene -Carbamazepin, Oxcarbazepin Succinimide -Ethosuximide Aliphatic Carboxylic Acid -Valproic acid(Sodium valproate), Divalproex Benzodiazepines -Clonazepam, Diazepam, Lorazepam, Clobazam Phenyltriazine -Lamotrigine Cyclic GABA analogous -Gabapentin, Pregabalin Newer Drugs -Topiramate, Zomisamide, Lacosamide, Levetiracetam, Vigabetrin, Tiagabine
- 8. Phenobarbitone First Anti-Epileptic Drug, 1912. Mechanism of Action: It primarily acts on GABA. Benzodiazepine (BZD) receptor- Cl- Channel complex and potentiate GABAergic inhibition by using lifetime of Cl- Channel opening induced by GABA. Barbiturates act on alpha & beta sub units.
- 9. It has anti-convulsant activity which is not entirely dependent on general CNS depression. T- Half is 80 – 120 hours. Complete metabolized in liver and excretes unchanged from kidney. Steady state concentration can be reach in 2 – 3 weeks and single dose can be used for maintenance. The major drawback is its sedative action. Side Effects- Behavioural Abnormalities, Diminution of Intelligence, Impairment of learning and memory, Hyperactivity in children, Mental Confusion, Rashes, Megaloblastic Anaemia, Osteomalacia. Uses- Cheapest and least toxic. Used in GTC, SP, CP, seizures in 60 mg as 1 to 3 times a day (Adults). 3 to 5 mg per day for children (per Kg). Less popular due to its side effects.
- 10. Primidone- After administration it is converted by liver in phenobarbitone and phenyl ethyl malonamide (PEMA). T – Half is 6 – 14 hours. 1/3 of drug is eliminated by kidney. Frequently used in GTCS and Partial epilepsy. Adverse Effect- Anaemia, Leukopenia, Psychotic reactions, lymph nodes enlargements. Dose- 250 – 500 mg BD (Adults). 10 – 20 mg/kg/day (Children).
- 11. Phenytoin- Major Anti-Epileptic Drug, 1938. Not a CNS depressant. Drug of Choice. Toxic doses produce excitement & muscular rigidity. It limits spread of seizures. It should not inject with glucose solution (forms Ppts.). Mechanism of Action It prolonged the inactivated state of voltage sensitive neuronal sodium channel.
- 12. Pharmacokinetics- Absorption (Oral) is slow due to poor aqueous solubility. Distributed 80 – 90 % in a body. T- Half is 12 – 24 hours. Only 5% phenytoin excretes in urine (Unchanged). Adverse Effect- Therapeutic Level- Gum Hypertrophy, acne, Hypersensitivity reactions, Megaloblastic anaemia, Osteomalacia, Hyperglycaemia, Foetal hydration syndrome (Pregnancy). Dose related Toxicity- Cerebellar & Vestibular Manifestation (Ataxia, Vertigo, Diplopia), Drowsiness, behavioural alteration, mental confusion, hallucination, epigastric pain, nausea, vomiting, low blood pressure, cardiac arrhythmia(IV). Neurotoxicity due to steep raise in plasma concentration. Uses- GTC, Simple & complex partial seizures. Dose- 100 – 400 mg/day (Adults), 5 – 8 mg/kg/day (Children).
- 13. Fosphenytoin- Water soluble product of phenytoin. Introduce to overcome difficulties in IV administration of phenytoin (used in epileptics). Doses are phenytoin equivalents. Can be injected at faster rates (150 mg/min.). Required regular ECG monitoring. Injected by both saline & Glucose. Dose- 50 mg/ml in 2 ml, 10 ml injection. Carbamazepine- In 1960s for trigeminal neuralgia. Chemically related to imipramine. First line drug. It inhibits kindling.
- 14. Pharmacokinetics- Oral absorption is slow. Poor water solubility. 75 % bound with plasma protein & metabolized in liver by oxidation. T- Half is 20 – 40 hours. Adverse Effect- Dose related neurotoxicity – Sedation, Dizziness, Vertigo, Diplopia, Ataxia. Vomiting, Diarrhoea, worsening of seizures with high dose. Acute Intoxication causes coma, convulsions, cardio collapse. Hypersensitivity reaction. Rarely agranulocytosis & aplastic anaemia. Interactions- Oral Contraceptives, lamotrigine, Valproate & topiramate, Phenobarbitone, Phenytoin, Erythromycin, Fluoxetine & Isoniazid. Uses- CPS, GTCS & SPS.
- 15. Ethosuximide- Most prominent action is agonism of PTZs induced clonic seizures. Clinically it is effective only in absence seizures. It suppresses T current without affecting other types of calcium & sodium currents. Does not potentiate GABA at therapeutic concentration. Adverse Effect- Gastro – Intolerance, tiredness, mood changes, agitation, headache, drowsiness & inability to concentrate. Uses- Only used for absence seizures. Doses- 20 – 30 mg/kg/day.
- 16. Valproic Acid Branched chai aliphatic carboxylic acic with broad spectrum anti – convulsant action. More potent in PTZ Seizures. It shows little sedation. Effective in Partial seizure, GTCS, Absence seizures. Mechanism of Action It acts by multiple mechanism- 1. Like Phenytoin (Prolongation of sodium channel inactivation). 2. Like Ethosuximide (Weak attenuation of calcium mediated T current). Pharmacokinetics- Oral absorption is good. 90 % bound to plasma protein, completely metabolized in liver by oxidation. T- Half is 10 – 15 Hours.
- 17. Adverse Effect- Toxicity is low. Anorexia, vomiting, loose motions & heartburn. Alopecia, curling of hair & increased bleeding tendency have been noticed. Uses- Uses while pregnancy should be avoided. Drug of choice for absence seizures. Alternative drug for GTCS, SPS, CPS. Interactions- Increases plasm level of phenobarbitone & lamotrigine by inhibiting their metabolism. Phenytoin toxicity. Carbamazepine. Clonazepam & Valproic acid may for Ppts. Foetal abnormalities.
- 18. Clonazepam It is benzodiazepine with anti – convulsant properties. Blocks PTZ seizures at doses which produces mild sedation. Mechanism of Action- It potentiate GABA induced Chlorine influx to produce sedation. Pharmacokinetics- Oral absorption is good. 85 % bound with plasma protein. T- Half is 24 Hours. Adverse Effect- Sedation & Dullness, Lack of concentration, irritability, Temper & behavioural changes in children. Salivation & Increase Respiratory secretion may be complained off. Uses- Absence Seizures. Dose- 0.5 – 5 mg TDS (Adults). 0.02 – 0.2 mg/kg/day (Children).
- 19. Choice of Drugs
- 20. SNo. Types of Seizures First Choice Second Choice Alternative Choice 1. GTCS/ Simple partial with or without generalised Carbamazepine Phenytoin Valproate Phenobarbitone Gabapentin Lamotrigine Levetiracetam Topiramate Primidone 2. Complex partial with or without generalized Carbamazepine Valproate Phenytoin Gabapentin Lamotrigine Levetiracetam Clobazam Topiramate Zonisamide 3. Absence Valproate Ethosuximide Lamotrigine Levetiracetam Clonazepam 4. Myoclonic Valproate Lamotrigine Topiramate Levetiracetam Clonazepam 5. Atonic Valproate Clonazepam Clobazam Lamotrigine 6. Febrile Seizures Diazepam (Rectal) - - 7. Status Epilepticus Diazepam (IV) Lorazepam (IV) Fosphenytoin (IV) Phenobarbitone (IV or IM) General Anaesthesia
- 21. Thank You…