Antiepileptic drugs

Hello friends. In this PPT I am talking about antiepileptic drugs. If you like it, please do let me know in the comments section. A single word of appreciation from you will encourage me to make more of such videos. Thanks. Enjoy and welcome to the beautiful world of pharmacology where pharmacology comes to life. This video is intended for MBBS, BDS, paramedical and any person who wishes to have a basic understanding of the subject in the simplest way.

1. Antiepileptic drugs Dr. Karun Kumar Assistant Professor Dept. of Pharmacology

2. Definitions Seizure  (from the Latin sacire, “to take possession of ”) is a transient occurrence of signs or symptoms due to abnormal excessive or synchronous neuronal activity in the brain Epilepsy  C ondition in which a person has a risk of recurrent seizures due to a chronic, underlying process. Clinical phenomenon rather than a single disease entity.

3. Types of seizures Focal seizures  O riginate within networks limited to one brain region (partial seizures NO longer used) Generalized seizures  A rise within and rapidly engage networks distributed

4. Classification of seizures (2017 ILAE) Focal Onset (having intact or impaired awareness, motor or nonmotor onset, or evolve from focal to bilateral tonic clonic) Generalized Onset a. Motor  Tonic-clonic, Other motor (e.g., atonic, myoclonic) b. Nonmotor (absence) 3. Unknown Onset a. Motor, nonmotor, or unclassified

5. Classification of AED

6. Exam diagram

7. Excitatory synapse

8. Inhibitory synapse

9. Approach to the patient History and examination 1 st goal  D etermine whether the event was truly a seizure In-depth history is essential, because in many cases the diagnosis of a seizure is based solely on clinical grounds—the examination and laboratory studies are often normal

10. Plan of action LFT, RFT

11. AED

12. PNES or PNEE Pseudoseizures , psychogenic seizures, and hysterical seizures are older terms Clinically resemble epileptic seizures but occur without the excessive synchronous cortical electroencephalographic activity that defines epileptic seizures These terms reinforce the idea that the events are not epileptic seizures and are of psychiatric origin

13. Phenytoin MOA  Prevents repetitive detonation of normal brain cells (↑ inact . state of VGSC) Also, ↓ presynaptic release of glutamate ↑ GABA release ↓ Ca 2+ influx

14. Adverse effects-PHENYTOIN Plasma level monitoring needed (0 order k.) Hypertrophy of gums Enzyme induction Neutropenia and other hypersensitivity reactions Young girls beware ! Causes hirsutism, coarsening of facial features and acne Teratogenic Osteomalacia

15. Interference with folate absorption leads to megaloblastic anemia Neurological manifestations at higher doses  Ataxia, vertigo, nystagmus, diplopia

16. Uses Used only when better tolerated newer drugs cannot be used Trigeminal neuralgia  2 nd choice drug to Carbamazepine

17. Interactions Phenobarbitone competitively inhibits phenytoin metabolism, while by enzyme induction both enhance each other’s degradation—unpredictable overall interaction Carbamazepine and phenytoin induce each other’s metabolism Valproate displaces protein bound phenytoin and decreases its metabolism  Plasma level of unbound phenytoin increases

18. 4. Chloramphenicol, Isoniazid, Cimetidine and Warfarin inhibit phenytoin metabolism  C an precipitate its toxicity 5. Phenytoin induces microsomal enzymes and increases degradation of steroids (failure of oral contraceptives), Doxycycline, Theophylline

19. Fosphenytoin Water soluble prodrug of Phenytoin has been introduced to overcome the difficulties in i.v. administration of Phenytoin, which it has replaced for use in status epilepticus. On i.v. injection it is less damaging to the intima While Phenytoin cannot be injected in a drip of glucose solution (because it gets precipitated), fosphenytoin can be injected with both saline and glucose

20. Carbamazepine 1 st line AED for focal seizures and trigeminal neuralgia (MOA  ↑ inact . state of VGSC) Manic depressive illness and acute mania  A s an alternative to Lithium Carbamazepine produces dose-related neurotoxicity  sedation, dizziness, vertigo, diplopia and ataxia Hypersensitivity  R ashes, photosensitivity, hepatitis, lupus like syndrome and rarely agranulocytosis, aplastic anemia

21. Lupus like syndrome Autoimmune disorder caused by a reaction to certain medications Symptoms are muscle and joint pain sometimes with swelling;flu-like symptoms of fatigue and fever SHIP drugs are responsible Sulfonamides incl. dapsone and PAS Hydralazine Isoniazid Procainamide

22. Interactions Carbamazepine is an enzyme inducer; can reduce efficacy of Haloperidol, oral contraceptives Metabolism of Carbamazepine is induced by Phenobarbitone, Phenytoin, Valproate and vice versa Erythromycin, Fluoxetine, Isoniazid inhibit metabolism of carbamazepine

23. Oxcarbazepine Newer congener of carbamazepine Toxic effects due to the epoxide metabolite are avoided Drug interactions and auto induction of own metabolism are less marked, because it is a weak enzyme inducer Risk of hepatotoxicity is estimated to be lower than carbamazepine; but that of hyponatremia is more Indications are the same as for carbamazepine, but it may be better tolerated Dose to dose it is 1½ times less potent

24. Eslicarbazepine Prodrug Rapidly converted in liver to the same active metabolite as is oxcarbazepine Same range of therapeutic and toxic effects Once daily dosing Add-on drug for focal seizure with or without generalization only in adults

25. Valproic acid (Sodium valproate) Valproate appears to act by multiple mechanisms: A phenytoin-like frequency-dependent prolongation of Na + channel inactivation. Weak attenuation of Ca 2+ mediated ‘T’ current (Ethosuximide like) Augmentation of release of inhibitory transmitter GABA by inhibiting its degradation (by GABA-transaminase) Blockade of excitatory NMDA type of glutamate receptor

26. Uses Drug of choice for Generalised tonic clonic seizures Absence seizures Myoclonic seizures Atonic seizures Alternative/adjuvant drug for focal seizures Mania and bipolar illness  As alternative to Lithium

27. Adverse effects (VALPROATE) Vomiting Alopecia Liver toxicity Pancreatitis Rash Obesity Agranulocytosis Teratogenic (Neural tube defects in offspring)

28. E ( dEntist )  Dentist may face excess bleeding while executing a dental procedure as Valproate causes increased bleeding tendency E  Epigastric pain

29. Interactions ↑ plasma levels of Phenobarbitone and Lamotrigine Displaces Phenytoin from protein binding site Inhibits hydrolysis of active epoxide metabolite of Carbamazepine Concurrent administration of Clonazepam and valproate is C/I (absence status may be pptd .) Foetal abnormalities are more common if Valproate and Carbamazepine are given concurrently

30. Divalproex ( Semisodium valproate) Coordination compound of valproic acid with sodium valproate (1:1) Oral absorption is slower, but bioavailability is the same Gastric tolerance may be better Primarily used in mania and bipolar illness May be used like Valproate

31. Lamotrigine Blocks voltage sensitive Na + channels Broad-spectrum antiepileptic S/E  S leepiness, dizziness, diplopia, ataxia and vomiting. Rash may be a severe reaction, particularly in children, requiring withdrawal Dose of lamotrigine should be reduced to half in patients taking Valproate

32. Uses Drug of choice for Generalised tonic clonic seizures Absence seizures Myoclonic seizures Atonic seizures Focal seizures

33. Gabapentin Enhances GABA release, but does not act as agonist at GABA A receptor Adjunctive therapy in focal seizures 1 st line drug for neuralgic pain due to diabetic neuropathy and postherpetic neuralgia Prophylactic effect in migraine Alternative drug for phobic states S/E  S edation, tiredness, dizziness, tremors & unsteadiness

34. Pregabalin Similar to gabapentin Used for Neuropathic pain (diabetic neuropathy, postherpetic neuralgia, complex regional pain syndrome (CRPS) Chronic pain S/E  Poo r concentration, rashes and allergic reactions have been complained

35. Levetiracetam 1 st line drug  F ocal seizures 2 nd line drug  GTCS and typical absence seizures MOA  B inds selectively to a synaptic vesicular protein ‘SV2A’, and this may alter release of glutamate and/or GABA across the synapse, thereby exerting anti-seizure effect S/E  S leepiness, dizziness, weakness

36. Topiramate 1 st line drug in atypical absence, myoclonic and atonic seizures 2 nd line drug in GTCS and focal seizures Broad spectrum anticonvulsant drug acting by :- Prolongation of Na + channel inactivation Suppression of repetitive neuronal firing GABA potentiation Antagonism of certain glutamate receptors Neuronal hyperpolarization through K + channels

37. A/E  Impairment of attention, sedation, ataxia, word finding difficulties, poor memory, weight loss, paresthesias and renal stones. Other uses Approved for prophylaxis of migraine (when β blockers/other prophylactics are C/I or ineffective)

38. Zonisamide Adjunctive therapy in GTCS and focal seizures MOA  Prolongation of Na+ channel inactivation S/E  S omnolence, dizziness, headache, irritability and anorexia. Metabolic acidosis and renal stones can occur. C/I  I n patients sensitive to Sulfonamides

39. Lacosamide Adjunctive therapy in focal seizures MOA  ↑ Na + channel inactivation and suppresses repetitive firing of neurons A/E  A taxia, vertigo, diplopia, tremor, depression and cardiac arrhythmia

40. Treatment of epilepsies Antiepileptic drugs suppress seizures, but do not cure the disorder Aim  C ontrol and prevent all seizure activity at an acceptable level of side effects Cause of epilepsy should be searched; if found and treatable, an attempt to remove it should be made Some general principles of symptomatic treatment with antiepileptic drugs are 

41. Start with one 1 st line drug Initiate treatment early Start at a low dose; gradually ↑ until Effective control of seizures is achieved OR Side-effects develop Optimise adherence (use minimum number of doses per day) If 1 st drug fails start second 1 st line drug, followed if possible by gradual withdrawal of 1 st If 2 nd drug fails, start 2 nd line drug in combination with the preferred baseline drug at maximum tolerated dose (beware interactions)

42. 7. If this combination fails, replace 2 nd line drug with alternative second-line drug 8. If this combination fails, check adherence and reconsider diagnosis (Are events seizures? Occult lesion? Treatment adherence/alcohol/drugs confounding response?) 9. Consider alternative, non-drug treatments (e.g. epilepsy surgery, vagal nerve stimulation) 10. Use minimum number of drugs in combination at any one time

43. Epilepsy in pregnancy Pre-conception counselling  B est; start folic acid (5 mg daily for 2 months) before conception to reduce the risk of fetal malformations. Risk of fetal malformation is minimised if a single drug is used. Carbamazepine and Lamotrigine have the lowest incidence of major fetal malformations Prophylactic folic acid supplementation in 2, 3 tri. Vit. K in the last month of pregnancy

44. Dental implications Dentists have to recognize and manage Phenytoin induced gum hypertrophy In an epileptic patient, dental procedure should be carried out only after ensuring that the patient is under adequate anticonvulsant drug cover and has taken his/her medication In the event of a patient developing an attack of GTCS during dental procedure, the first priority is to prevent injuries due to biting or fall. Ensure that the patient is secure on the flat dental chair or floor

45. Any denture or instrument should be immediately removed from the mouth The head should be turned to the side to prevent the tongue from falling back and obstructing the airway Give oxygen through a face mask to support respiration if any sign of cyanosis is seen Do not attempt to stop convulsive movements by restraining the patient In case the seizures do not stop or recur within 10-20 minutes, management is as for status epilepticus

46. Status epilepticus Continuous seizures or repetitive, discrete seizures with impaired consciousness in the interictal period GCSE (e.g., persistent, generalized electrographic seizures, coma, and tonic-clonic movements) Nonconvulsive status epilepticus (e.g., persistent absence seizures or focal seizures with confusion or partially impaired consciousness, and minimal motor abnormalities) Practical def.  D uration of seizures prompts the acute use of anticonvulsant therapy In GCSE  W hen seizures last beyond 5 min.

47. Febrile convulsions Some children (< 5 yrs.) develop convulsions during fever Attempt should be made to see that they do not develop fever, but when they do, temperature should not be allowed to rise by using paracetamol and external cooling DOC  R ectal diazepam 0.5 mg/kg In recurrent cases or those at particular risk of developing epilepsy  I ntermittent prophylaxis with diazepam (oral or rectal)

48. Infantile spasms (hypsarrhythmia) Therapy of this condition is unsatisfactory antiepileptic drugs are generally useless Corticosteroids afford symptomatic relief but cannot be used for long-term due to A/E Clonazepam, Valproate and Vigabatrin may afford some relief