ANTIEPILEPTIC DRUGS copy.pptx.drugssssss

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1. ANTIEPILEPTIC DRUGS I Dr.Swathi Acharya Associate professor Department of pharmacology

2. Seizure: Transient alteration in behavior because of disordered firing of groups of brain neurons. Epilepsy: Is a chronic disorder of brain function characterized by recurrent seizures often accompanied by episodes of unconsciousness and amnesia. 5/4/22 and 5/5/22 Dr.Swathi Acharya 2

3. Classification of seizures Seizure types Epilepsy syndrome Seizure types: Generalized , Partial Generalized Partial GTCS/Major epilepsy/ Grandmal seizure Simple partial seizure Petitmal /Absence seizure Complex partial seizure Atonic seizure , Myoclonic seizure SPS/CPS with secondary generalization. Clonic seizure , Tonic seizure 5/4/22 and 5/5/22 Dr.Swathi Acharya 3

4. Classification Hydantoin: Phenytoin Barbiturates: Phenobarbitone Deoxybarbiturate : Primidone Iminostilbene : Carbamazepine Succinimide : Ethosuximide GABA Transaminase inhibitor: Valproic acid, Vigabatrin Benzodiazepines: Diazepam, Clonazepam, Lorazepam Newer agents: Gabapentin, Pregabalin, Vigabatrin, Lamotrigine, Levetiracetam, Lacosamide , Felbamate, Topiramate, Zonisamide . 5/4/22 and 5/5/22 Dr.Swathi Acharya 4

5. Drug enhancing GABA mediated inhibition 5/4/22 and 5/5/22 Dr.Swathi Acharya 5

6. Blockade of Na + channels and prolongation of their inactivated state 5/4/22 and 5/5/22 Dr.Swathi Acharya 6

7. Blockade of low threshold Ca 2+ current in thalamic neuron 5/4/22 and 5/5/22 Dr.Swathi Acharya 7

8. PHENYTOIN Oldest Non sedative antiepileptic drug MOA: 1.Prolongation of inactivated state of VG Na + channel: Therapeutic dose 2.High dose: Ca 2+ influx, Inhibition of Glutamate release, Facilitates GABA response Route: Oral , IV, Not IM 5/4/22 and 5/5/22 Dr.Swathi Acharya 8

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10. Pk : Bioequivalence varies with preparation 80-90% PPB Saturation kinetics Potent enzyme inducer- CYP 3A4,Inhibits-CYP2C19 Free drug excreted through saliva A/E: Therapeutic level Gum H ypertrophy H irsutism/Acne H ypersensitivity reaction 5” H ” H yperglycemia Fetal H ydantoin syndrome 5/4/22 and 5/5/22 Dr.Swathi Acharya 10

11. Megloblastic anaemia Vitamin K deficiency Osteomalacia Discontinuation “ withdrawal seizures” High plasma level: Cerebellar / Vestibular manifestation Drowsiness, behavioural alterations , Mental confusion, Hallucination, Disorientation, Rigidity Gastric intolerance IV inj : Fall in BP, Cardiac arrhythmia, Local vascular injury 5/4/22 and 5/5/22 Dr.Swathi Acharya 11

12. Drug interaction: Enzyme inducers : Corticosteroids, OCP , Vit D CBZ & Phenytoin , Phenobarbitone & phenytoin Induce each other metabolism Valproate Increase level: Inhibition metabolism, Displacement Sucralfate : Reduction in absorption Inhibition of Warfarin metabolism 5/4/22 and 5/5/22 Dr.Swathi Acharya 12

13. Uses: Antiepileptic use: GTCS,SPS/CPS, Status epilepticus CI in Absence/ Myoclonic seizure 2. Non Antiepileptic use: Trigeminal Neuralgia: 2 nd choice Ventricular arrhythmia due to digitalis toxicity Dose:300 mg/day 5/4/22 and 5/5/22 Dr.Swathi Acharya 13

14. Fosphenytoin : Water soluble prodrug of Phenytoin More potent, Less cardiotoxic Adv: Minor vascular complication/Faster injection Injected both with glucose/Saline. Can be given IM 5/4/22 and 5/5/22 Dr.Swathi Acharya 14

15. CARBAMAZEPINE I st line antiepileptic drug MOA: 1.Blocks use dependent Na + channel 2.Lithium like effect 3.Antidiuretic action Pk : Slow oral absorption 75% Bound to plasma proteins Substrate as well as inducer of CYP3A4 Autoinduction of metabolism. 5/4/22 and 5/5/22 Dr.Swathi Acharya 15

16. A/E: Dose related neurotoxicity Hypersensitivity reaction Antidiuretic action Teratogenicity : Risk low: Finger Nail hypoplasia , Craniofacial defect, Delayed development Valproic acid doubles the risk of Teratogenicity Drug interaction: 1 .CBZ& Phenytoin induce each other metabolism 2.Enzyme inducer 3.Enzyme inhibitors precipitates its toxicity 5/4/22 and 5/5/22 Dr.Swathi Acharya 16

17. Uses: 1. Antiepileptic use: GTCS,PS 2. Non antiepileptic use: a. Trigeminal Neuralgia: 1 st choice b. Post herpetic Neuralgia c. Glossopharyngeal neuralgia By interrupting temporal summation of afferent impulse d. Maniac depressive psychosis as alternative to Li + Dose: 200-400 mg TDS 5/4/22 and 5/5/22 Dr.Swathi Acharya 17

18. OXCARBAZEPINE Newer congener of Carbamazepine Metabolism only by glucuronidation ,no oxidation Toxic effects of Epoxide metabolites are reduced Drug interaction and autoinduction less Low Risk of hepatotoxicity 5/4/22 and 5/5/22 Dr.Swathi Acharya 18

19. VALPROIC ACID(SODIUM VALPROATE) Broad spectrum antiepileptic agent MOA: 1. Prolongation of frequency dependent Na + channel inactivation 2. GABA activity by inhibiting degradation, increasing synthesis. 3. Blocks Ca 2+ mediated “T” current 5/4/22 and 5/5/22 Dr.Swathi Acharya 19

20. Pk : Oral absorption is good 90-95% Plasma protein bound Potent enzyme inhibitor A/E: Dose related: Weight gain, GIT distress, reversible alopecia, Ataxia, Drowsiness, Tremor Idiosynchratic toxicity: Hepatotoxicity(Fatal in children < 3 yrs),Pancreatitis, Thrombocytopenia Pregnancy: High risk of NTD’s , Spina bifida. 5/4/22 and 5/5/22 Dr.Swathi Acharya 20

21. Drug interaction: 1.Phenytoin toxicity 2.Inceased plasma level of Phenobarbitone & Lamotrigine 3.Doubles risk of terotogenicity of CBZ 4.Potentiates CNS depressant action of BZD & Barbiturates 5/4/22 and 5/5/22 Dr.Swathi Acharya 21

22. USES: 1. Antiepileptic use: Broad Spectrum Antiepileptic DOC for absence seizure Alternative/Adjuvant in GTCS,SPS,CPS Myoclonic , Atonic seizure 2. Non antiepileptic uses: a. Maniac depressive bipolar disorder b. Prophylaxis for Migraine and cluster headache c. An alternative to CBZ in trigeminal neuralgia 200 mg TDS to 800 mg TDS 5/4/22 and 5/5/22 Dr.Swathi Acharya 22

23. ANTIEPILEPTIC DRUG PART II 5/4/22 and 5/5/22 Dr.Swathi Acharya 23

24. PHENOBARBITONE MOA: 1.Enhancement of GABA A receptor mediated synaptic inhibition 2.Blocks AMPA receptor High dose : Block L-Ca 2+ channel Use dependent Na + channel Pk : Potent enzyme inducer, Tolerence to sedative action 5/4/22 and 5/5/22 Dr.Swathi Acharya 24

25. A/E: Sedation, Behavioural abnormalities, Impairement in learning &memory, Hyperactivity in children, Mental confusion. Uses: GTCS,SPS,CPS,prophylaxis of febrile seizure,Status epilepticus 5/4/22 and 5/5/22 Dr.Swathi Acharya 25

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27. BENZODIAZEPINES MOA: Increased frequency of GABA mediated Cl - channel opening Draw back: Sedative effect, Tolerence to anticonvulsant action Diazepam: a. 1 st line emergency control of convulsions Status epilepticus,Tetanus , Eclampsia , Drug poisoning b. Febrile seizure A/E: Thrombophlebitis,Fall in BP,Respiratory depression. 5/4/22 and 5/5/22 Dr.Swathi Acharya 27

28. Clonazepam : Potent ,Long acting Absence seizure Adjuvant in Myoclonic & Akinetic epilepsy A/E: Lack of concentration, irritability, Behavioural abnormality, Motor disturbance, ataxia,Salivation . Clobazam : Less sedative long acting Partial, Secondarily Generalised TCS, Absence, Atonic seizure Generally used as adjuvant drugs. 5/4/22 and 5/5/22 Dr.Swathi Acharya 28

29. Lorazepam : a. Status epilepticus/Emergency control of convulsion Adv: Less thrombophlebitis ,Sustained action 5/4/22 and 5/5/22 Dr.Swathi Acharya 29

30. Ethosuximide: MOA: Inhibition of low threshold “T” type Ca 2+ channels in thalamocortical system A/E: GI intolerence , Head ache, Dizziness, Tiredness, Mood changes, Agitation, Drowsiness, Inability to concentrate Interaction: Valproic acid inhibits the metabolism of Ethosuximide Use: Absence seizure 5/4/22 and 5/5/22 Dr.Swathi Acharya 30

31. NEWER ANTIEPILEPTIC DRUGS Advantages: Favourable safety profile Interms of a.Toxicity b.Teratogenicity c.Drug interaction Used as ADD on drugs a. Lamotrigine b. Gabapentin c. Pregabalin d. Topiramate e. Zonisamide f. Levetiracetam g. Lacosamide h. Tiagabine i . Vigabatrin 5/4/22 and 5/5/22 Dr.Swathi Acharya 31

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33. Lamotrigine MOA: 1.Block VG Na + Channel 2.Block “N” type Ca 2+ channel Interaction: a. Phenytoin,CBZ : Level b. Valproic acid: Level A/E: Dizziness, Atxia , Diplopia , Skin rash Uses: a . Absence, Akinetic , Myoclonic epilepsy b. Add on Refractory partial seizure, GTCS c. Add on to Bipolar disorder 5/4/22 and 5/5/22 Dr.Swathi Acharya 33

34. GABAPENTIN MOA: a. Increases GABA concentration in Brain by Increasing release and synthesis b. Inhibits “N” type of Ca 2+ channel A/E: Drowsiness , Fatigue, Dizziness, Wait gain , ataxia Use: a. Resistant partial seizure b. 1 st line drug – Neuralgic pain – DM Neuropathy c. Prophylactic in Migraine d. Alternative to Phobic state PREGABALIN Newer congener Adv: Less sedation Use: Neuropathic pain 5/4/22 and 5/5/22 Dr.Swathi Acharya 34

35. TOPIRAMATE MOA: a. Blocks use dependent “Na +” channel b. Activation of GABA Receptor c. Inhibits “AMPA” Receptor for Glutamate d. Neuronal hyperpolarisation through activation of K + channel A/E: Impairment in attention, Sedation, Ataxia, Poor memory ,Weight loss, Urolithiasis. Use: a. GTCS, SPS, CPS, Myoclonic epilepsy, Absence seizure b. Prophylactic in Migraine ZONISAMIDE MOA: a. Inhibition of use dependent “Na +” channel b Inhibition of “T” TYPE Calcium channel Use: Add on to Refractory Partial seizures A/E: Dizziness, Headache,Irritabiity,Anorexia,Renal stones 5/4/22 and 5/5/22 Dr.Swathi Acharya 35

36. LEVETIRACETAM MOA: Modifies synaptic release of glutamate /GABA by binding to specific synaptic vesicular protein “SV 2 A” A/E: Somnolnce,Asthenia,Dizziness Use: a. GTCS,CPS, Myoclonic epilepsy LACOSAMIDE MOA: a. Inhibition of use dependent “Na +” channel b Inhibition of “CRMP 2” Use: Partial seizures A/E: Dizziness, Headache, Nausea, Ataxia, Vertigo, Tremor, depression, arryhthmia . 5/4/22 and 5/5/22 Dr.Swathi Acharya 36

37. TIAGBINE MOA: Inhibits GABA uptake In the neuronal ang glial cell through GAT-1 A/E: Dizziness,Fatigue,Tremor,confusion Use: a. CPS with/without generalization VIGABATRIN MOA: a. Irreversible Inhibition of GABA Transaminase. Use: SPS/CPS with/without generalization A/E: Weight gain, visual field defects, Behavioral changes, depression, psychosis. 5/4/22 and 5/5/22 Dr.Swathi Acharya 37

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39. STATUS EPILEPTICUS a. Lorazepam 4mg IV @ 2mg/min Repeated after 10 min or Diazepam 10mg IV @ 2mg/min Repeated after 10 min , Damaging to the vein b. If seizure fails to respond in 20 min Fosphenytoin 100-150mg/min IV maximum 1000mg If Fosphenytoin not available Phenytoin sodium @25-50 mg/min An alternative to Fosphenytoin , Phenobarbitone sodium 50-100mg/min 5/4/22 and 5/5/22 Dr.Swathi Acharya 39

40. c. If seizure fails to respond in 40 min with Lorazepam,Fosphenytoin , Treat with Midazolam,Propofol,Thiopentone sodium With /without curarisation . d. General measures, Maintain airway, Oxygenation, Fluid electrolyte balance, Blood pressure ,Normal cardiac rhythm and euglycemia . 5/4/22 and 5/5/22 Dr.Swathi Acharya 40