Antiepileptic drugs


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Antiepileptic drugs

  1. 1. Central nervous system Dr . Shadab Khan
  2. 2. The brain The spinal cord
  3. 3. Anatomical classification  Cerebral hemispheres  Diencephalon  Thalamus  Hypothalamus  Brain stem  Midbrain  Pons  Medulla  Cerebellum  Spinal cord
  4. 4. Cerebrum cerebral cortex thalamus cerebrum hypothalamus mid-brain cerebellum pons varolii spinal cord medulla oblongata Acknowledgement: Picture of model from Mentone Educational Centre C15
  5. 5. The functional areas of the cerebrum  sensory areas interpret impulses from receptors.  motor areas control muscular movements.  association areas are involved with intellectual and emotional processes.
  6. 6. Functional areas of the cerebral cortex Primary sensory area Primary motor area Speech Visual association area Motor area for speech Primary auditory area Auditory association area Acknowledgement: Picture of model from Mentone Educational Centre C15 Primary visual area
  7. 7. functions of cerebrum         thinking reasoning learning memory intelligence sense of responsibility perception of the senses initiation and control of voluntary muscle contraction
  8. 8. simplified…  Back of brain: perception  Top of brain: movement  Front of brain: thinking
  9. 9. Hypothalamus cerebral cortex thalamus cerebrum hypothalamus mid-brain cerebellum pons varolii spinal cord medulla oblongata Acknowledgement: Picture of model from Mentone Educational Centre C15
  10. 10. The hypothalamus regulates:           heart rate body temperature movement of food through the alimentary canal food and water intake patterns of waking and sleeping contraction of the urinary bladder sexual cycles sensory information from internal organs associated with fear and anger the release of hormones from the pituitary gland
  11. 11. BASAL GANGLIA Include: •Caudate nucleus •Globus pallidus •Putamen •Amygdaloid Claustrum Partly •Substancia nigra •Subthalamic nucleus
  12. 12. Brain Stem  Midbrain  Pons  Medulla oblongata
  13. 13. The medulla oblongata regulates:  heartbeat through its cardiovascular centre  breathing rhythm through its respiratory centre  the diameter of blood vessels through its vasomotor centre
  14. 14. Cerebellum Two major hemispheres: three lobes each • Anterior • Posterior • Floculonodular Vermis: midline lobe connecting hemispheres Separated from brain stem by 4th ventricle
  15. 15. Functions of cerebellum     Smooths, coordinates & fine tunes bodily movements Helps maintain body posture Helps maintain equilibrium Also some role in cognition  Damage: ataxia, incoordination, wide-based gait, overshooting, proprioception problems
  16. 16. Spinal cord
  17. 17. Spinal nerves  Divided based on vertebral locations  8 cervical  12 thoracic  5 lumbar  5 sacral  1 coccygeal  Cauda equina (“horse’s tail”): collection of nerve roots at inferior end of vertebral canal
  18. 18. The action of the spinal cord Sensory neurons pick up signals from the skin and transfer that information to connector neurons in the spinal cord and/or brain. This information is relayed on to the motor neurons in the spinal cord to illicit a response.
  19. 19. Major fiber tracts in white matter of spinal cord sensory Damage: to motor areas – paralysis motor
  20. 20.  Ascending pathways: sensory information by multi-neuron chains from body up to more rostral regions of CNS  Dorsal column  Spinothalamic tracts  Spinocerebellar tracts  Descending pathways: motor instructions from brain to more caudal regions of the CNS  Pyramidal (corticospinal) most important to know  All others (“extrapyramidal”)
  21. 21. Blood-Brain Barrier  Tight junctions between endothelial cells of brain capillaries, instead of the usual permeability  Highly selective transport mechanisms  Allows nutrients, O2, CO2  Not a barrier against uncharged and lipid soluble molecules; allows alcohol, nicotine, and some drugs including anesthetics
  22. 22. Drugs Acting on the Central nervous System
  23. 23. ANTIEPILEPTIC DRUGS Dr Shadab Khan
  24. 24. What is Epilepsy?  Epilepsy is a collective term for a group of disorders characterised by paroxysmal cerebral dysrthmia, menifesting as brief episodes (seizures) of loss or disturbance of conciousness with or without characteristic body movements(convulsions)sensory or psychiatric phenomina
  25. 25. Convulsion – Involuntary spasmodic contractions of any or all voluntary muscles throughout the body, including skeletal and facial muscles. Seizures – Brief episode of abnormal electrical activity in the nerve cells of the brain -- detected on EEG Epilepsy – Chronic, recurrent pattern of seizures
  26. 26. Classification • Generalized • Partial
  27. 27. Generalised seizures 1.Generalised tonic clonic seizures (GTCS) Grand mal epilepsy • Major epilepsy1-2 min • Commonest • Aura –cry –unconciousness –tonic spasm of all body muscles-tonic jerking • Prolongrd sleep and depression of all CNS functions
  28. 28. 2.Absence Seizures Minor epilepsy, petit mal •½ minute •Children •Apparent freezing •EEG: 3 cycle per second spike and wave pattern 3. Atonic Seizures Akinetic Epilepsy ,Drop Attack •Sudden loss of postural tone •Unconciousness •Excessive inhibitory discharges
  29. 29. 4.Myoclonic seizures Shock like momentary contraction of muscles of a limb or the whole body 5. Infantile Spasms Hypsarrhythmias
  30. 30. Partial seizures 1.Simple partial seizures 2.Complex Partial seizures 3. Simple Partial or complex partial seizures secondarily generalized
  31. 31. Classification: Classification: 1. Drugs used to abolish seizures(anticonvulsants) 1. Drugs used to abolish seizures(anticonvulsants) 1. Drugs to prevent seizures (prophylaxis) 1. Drugs to prevent seizures (prophylaxis)
  32. 32. Chemical Classification 1. Barbiturate: phenobaritone 2. Deoxybarbiturate : Primidone 3. Hydantoin: Phenytoin 4. Iminostillbene : Carbama zepine 5. Succinimide: Ethosuximide 6. Aliphatic Carboxylic acid: Valproic acid 7. Benzodiazepines: Clonazepam , Diazepam 8. Phenyltriazine : Lamotrigine 9. Cyclic GABA analogue: Gabapentine 10. Newer Drugs: vigabatrine ,Zonisamide
  33. 33. Mechanism of Action ION Theory – movement of K+, Na+, Ca+, Mg+: Stabilizes neurons:  from becoming hyperexcited  prevents excessive impulses to adjacent neurons 1. Increase threshold of activity in the motor cortex Makes it more difficult to excite; reduces response 2. Depress the seizure discharge from its origin Suppress transmission of impulses from one nerve to the next 3. Decrease the speed of nerve impulse conduction within a given neuron
  34. 34. Indications •Prevention or control of seizure activity •Long-term maintenance treatment of epilepsy •Acute treatment of convulsions and status epilepticus Status epilepticus: common seizure disorder – life-threatening emergency characterized by tonic-clonic convulsions that occur in succession. Loss of consciousness, hypotension, hypoxia, cardiac dysrhythmias – brain damage and death may quickly result Once controlled, long term therapy is begun to prevent future seizures •Brain Surgery - Head injuries = prophylactic AED Therapy
  35. 35. Phenobarbitone  First efficatious antiepileptic 1912  Mechanism: GABA receptor mediated synaptic inhibition  Raises seizure threshold as well as limits spread and suppresses kindled seizures  Long plasma t1/2 (80-120 hrs) Drawback : • Sedative action • Behaviouralar abnormalities • Diminution of intelligence • Impairment of learning • Hyperactivity in children • Mental confusion in older people
  36. 36. Uses: Generalised tonic Clonic seizures Simple partial Seizures Complex partial Seizures Gardinal ,syr Luminal
  37. 37. Phenytoin (Diphenylhydantoin) Synthesised in 1908 as a barbiturate analogue Mechanism of Action •The drug slows the recovery of voltage-dependent sodium channels(stabilising effect) on all neuronal membranes including the peripheral nerves as well as on all non-excitable & excitable membranes •It inhibits the spread of seizure discharges in the brain & shortens the duration of after discharge •It reduces the neuronal sodium concentration leading to a reduction in PDS •Decreases post tetanic potentiation which is responsible for the spread of seizure activity
  38. 38. Pharmacokinetics •Slowly absorbed from the gut •Plasma peak level 3-12 hrs after ingestion •70-95% albumin bound •Metabolised mainly by parahydroxylation in the liver •About 94% of a single dose is excreted in urine in 48 hrs •The dose increments must be smaller with increasing dosage since plasma concentration rises dispropotionately to the dose increment
  39. 39. Adverse Effects At therapeutic level: a) Gum Hypertrophy:Commonest b) Hirsutism,Acne,coarsening of facial hair c) Hypersensitivity reactions d) Megaloblastic Anemia e) Osteomalacia f) Hyperglycemia g) During pregnancy: fetal hydantoin syndrome Hypoplastic phalanges Cleft palate Hare lip Microcephaly
  40. 40. At High plasma levels a) Cerebellar & vestibular menifestations b) Drowsiness, behavioral alterations,mental confiusion,hallucinations,disorientations and rigidity c) Epigastric pain,nausea and vomiting d) IV injections – local vascular injury • Intimal damage ang thrombosis of vein • Edema and discoloration of the injected limb • Rate of injection should not exceed 50mg/min • Fall in BP and cardiac arrhythmias
  41. 41. Interactions a. Phenobarbitone inhibits phenytoin metabolism b. Carbamazepine and phenytoin increase each others metabolism c. Valproate decreases its metabolism d. Chloramphenicol, isoniazid,cemitidine,dicumaroland warfarin inhibit phenytoin metabolism e. It inhibits warfarin metabilism f. Inceases degradation of steroids,digitixin,doxycycline,theophylline g. Sucralfate decrease it absorption
  42. 42. Uses a) Generalised tonic-clonic,simple and complex partial seizure 100 mg BD max 400mg /day 5-8 mg /kg/day for children b) Status epilepticus c) Trigeminal neuralgia DILACTIN ,EPTON,EPSOLIN , SYR FENTOIN –ER
  43. 43. Fosphentoin: • • • • • Water soluble prodrug of phenytoin To overcome the difficulties in I.V administration of phenytoin in status epilepticus Few vascular complications Can be injected at a faster rate Can be injected with both saline and glucose FOSOLIN 50mg /ml in 2ml, 10 ml injection
  44. 44. Carbamazepine 1960 mechanism of action similar to that of phenytoin Pharmacological actions Specific for trigeminal neuralgia Effective in differentiation pain in diabetic neuropathy,cancer and multiple sclerosis Pharmarmacokinetic: Oral absorption slow Metabolised by liver (98%) Potent hepatic microsomal enzyme inducer
  45. 45. Adverse Effects 1. 2. 3. 4. 5. 6. Nausea, sedation,dizziness,vertigo,diplopia anorexia Coma, convulsions and cardiovascular collapse Hypersensitivity reactions Agranulocytosis and aplastic anemia Water retention and hyponatremia in elderly Minor fetal malformations
  46. 46. Interactions a) Reduces efficacy of haloperidol,oral contraceptives,lamotrigine and topiramate b) Metabolism of carbamazepines induced by phenobarbitone,phenytoin,valproate and vice versa. c) Erythromycin, flouxetine,isoniazid inhibit metabolism of carbamazepines Uses 1.Grand mal & petit mal seizures 2.Trigeminal and related neuralgias 3.Manic depressive illness and acute mania Dose : 200-400mgTDS 15-30mg /kg/day TEGRATOL,MAZETOL
  47. 47. OXCARBAZEPINE •Newer congener of carbamazepine • better tolerated OXETOL, OXCARB,OXEP 150,300,600MG TABS
  48. 48. ETHOSUCCIMIDE most frequently used succinimide Mechanism of Action The drug reduces the low threshold calcium currents in the thalamic neurones which are responsible for the generation of the absence seizures Pharmacological actions Effective only in petit mal epilepsy , does not induce liver enzymes
  49. 49. Pharmacokinetics •Completely absorbed from GIT •20% excreted unchanged in urine •Rest metabolised by liver Adverse Reactions: Anorexia, Nausea, Vomiting, Drowsiness, dizziness, skin rashes etc Uses Drug of Choice in petit mal epilepsy Dose 20-30mg /kg/day ZARONTIN 250mg/5ml syr
  50. 50. Valproic Acid : Sodium Valproate Mechanism of Action •It’s a broad spectrum antiepileptic which probably acts at multiple sites •Actions similar to that of ethosuccimide and phenytoin •Inhibits the T type Ca++ current and also delays the recovery of the inactivated Na++ channels •It also inhibits GABA transaminase thus increasing the GABA Pharmacokinetics •Rapidly and completely absorbed from the GI •More than 90% is metabolised in liver
  51. 51. Adverse Reactions •Nausea, vomiting •Increases apetite and causes weight gain •Dose related hair loss •Hypoalbunemia •Hepatotoxicity with death Uses •Petit mal •Combined grand mal and petit mal •Myoclonic epilepsy •Partial epilepsy •Mania and bipolar illnesses DIPROEX, VALANCE 125,250,500mg tabs
  52. 52. Clonazepam Benzodiazepine with prominent anticonvulsant properties Potentiate GABA induced Cl- influx to produce sedation and anticonvulsant properties Pharmacokinetics Good oral absorption Completely metabolised in liver t1/2 24 hrs
  53. 53. Uses Absence seizures Adjuvant in myoclonic and akinetic epilepsy Infantile spasm Dose: A0.5-5mg tds Children: 0.02-0.2mg/kg/day LONAZEP, CLONAPAX,RIVOTRIL 0.5, 1.0,2.0mg tab
  54. 54. CLOBAZAM 1,5 benzodiazepine Uses Adjuvant to other antiepileptic drugs FRISIUM, LOBAZAM, CLOZAM 5,10,20,mg capsules
  55. 55. Diazepam Drug of choice for emergency control of convulsions •Status epilepticus •Tetanus •Eclampsia •Convulsant drug poisoning Dose 0.2-0.5mg/kg injected i.v slowly Maximum 100mg/day Febrile convulsions in children : rectal instillation Lorazepam :alternative to diazepam
  56. 56. Gabapentine Lipophyllic GABA derivative Mechanism of action Crosses to the brain and enhances GABA release
  57. 57. Uses Dose : start with 300mg OD & increase to 300-600 mg tds as required NEURONTIN , GABANTIN •Reduces seizurepartial seizures with or without generalization •First line drug for pain due to diabetic neuropathy and post herpetic neuralgia • frequency in refractory Prophylactic effect in migraine
  58. 58. Vigabatrin Inhibitor of GABA transaminase •Anticonvulsant activity due to increase in synaptic GABA concentration •Effective in many cases of refractory epilepsy •Adjuvant medication
  59. 59. Adverse effects •Behavioral changes •Depression •Psychosis Dose : 2-4g daily Children : 40-100mg /kg/day
  60. 60. Conclusion Choice of drug and dose according to type of seizures and need of individual patients Initiate treatment early starting with low dose and gradually increasing it Treatment should be as simple as possible  All drug withdrawal should be gradual except in case of toxicity