Antiepileptics (New) - drdhriti


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An updated power point presentation on “Antiepileptics” suitable for undergraduate MBBS level medical students

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  • Paroxysmal: Periodic attack of disease or sudden outburst of disease
  • Antiepileptics (New) - drdhriti

    2. 2.  In 400 B.C., the early physician Hippocrates suggested that epilepsy was a disorder of the brain  Famous Persons Afflicted:  ALEXANDER THE GREAT  JULIUS CAESAR  NAPOLEON  LEWIS CARROLL
    3. 3.  Definition: These are Group of disorders of the CNS characterized by paroxysmal cerebral dysrhythmia, manifesting as brief episodes (seizure) of loss or disturbance of consciousness, with or without characteristic body movements (convulsions), sensory or psychiatric phenomena  Focal origin and Disease of lightening (JH Jackson)  What is a seizure?  A seizure is a transient alteration of behaviour due to the disordered and synchronous firing of populations of brain neurons. Seizure can be non-epileptic and can be evoked in normal brain  A seizure is a paroxysmal behavioral spell generally caused by an excessive disorderly discharge of cortical nerve cells
    4. 4. • Epilepsy is a syndrome of two or more unprovoked or recurrent seizures on more than one occasion • Epileptic seizures range from clinically undetectable (electrographic seizure) to convulsions • Not to be confused: Remember its Not only falling down and unconsciousness of patients: Alteration in mental state, tonic or clonic movements, convulsions, and various other psychic symptoms
    5. 5.  Types: Generalized and Partial (focal) Seizures  Generalized: 1. Generalized tonic-clonic seizure 2. Absence seizure 3. Tonic seizures 4. Atonic Seizure 5. Myoclonic seizure 6. Infantile spasm
    6. 6.  Partial (focal) Seizures: 80% of Adult epilepsies  Simple Partial Seizures  Complex Partial Seizures  Simple partial or complex partial secondarily generalized
    7. 7. 1. Generalized tonic-clonic  GTCS/major epilepsy/grand mal  Commonest of all  Lasts for 1-2 minutes  Aura-cry-unconsciousness-tonic phase-clonic phase  Usually occurs in both the hemispheres  Manifestations are determined by cortical site of seizure occurrence  2 phases: tonic phase followed by clonic phase  Tonic phase:  Sustained powerful muscle contraction (involving all body musculature) which arrests ventilation  Clonic phase:  Alternating contraction and relaxation, causing a reciprocating movement which could be bilaterally symmetrical
    8. 8.  Tonic: Rythmic high frequency, high voltage discharges with cortical neurons undergoing sustained depolarization, with protracted trains of action potentials – depolarization shift  Clonic: Characterized by groups of spikes on the EEG and periodic neuronal depolarizations with clusters of action potentials
    9. 9.  Absence seizure:  Also called minor epilepsy/petit mal  Usually in Children and lasts for 1-2 minutes  Typical generalized spike-and-wave type discharges at 3 per second (3 Hz)  Momentary loss of consciousness (not convulsion), patient stares at one direction  No motor (muscular component)  No convulsions  Minor muscular twitching restricted to eyelids (eyelid flutter) and face  No loss of postural control.
    10. 10.  Atonic Seizures:  Unconsciousness with relaxation of all muscles  Patient falls down  Loss of postural tone, with sagging of the head or falling  Myoclonic Seizures:  Isolated clonic jerks associated with brief bursts of multiple spikes in the EEG  Momentary contractions of muscles of limbs or whole body  No loss of postural control  Infantile spasm:  An epileptic syndrome  Characterized by brief recurrent myoclonic jerks (muscle spasm) of the body with sudden flexion or extension of the body and limbs  Progressive mental deterioration
    11. 11.  Simple partial seizure (Jacksonian)  Lasts for 20 – 60 seconds  Motor, sensory, vegetative or psychic symptomatology  Typically consciousness is preserved  Confined to a group of muscles or localized sensory disturbances depending on area of cortex involved  For example – if motor cortex of the left thumb then jerking movement of left thumb, and if it is sensory cortex then paresthesia of left thumb.  No alteration of consciousness  EEG: Excessive synchronized discharge by a small group of neurons. Contralateral discharge
    12. 12. Simple (Focal) Partial Seizures Contralateral spread
    13. 13.  Complex partial seizure (temporal lobe/psychomotor epilepsy)  Focus is located in temporal lobe  Confused behaviour and purposeless movements and emotional changes lasting for 30 seconds to 2 minutes  An aura often present  Automatisms (repetitive coordinated movements)  perioral and hand automatisms  Wide variety of clinical manifestations and Consciousness is impaired
    14. 14. ….Deja vu …
    15. 15.  Secondarily generalized (Jacksonian):  Partial seizures initially  Followed by generalized tonic-clonic seizure
    16. 16. Complex Partial Seizures Complex Secondarily Generalized Partial Seizures
    17. 17. 1. Maximal electroshock seizures (MES): tonic phase abolished by drugs effective in GTCS and also Partial seizures 2. PTZ clonic seizures (Pentylenetetrazole): Can be prevented by drugs effective in absence seizure (Petit mal) 3. Chronic focal seizures: Aluina cream on motor cortex of Monkey 4. Kindled seizures: bursts of weak electrical impulses – tonic- clonic seizure (genesis of clinical epilepsy)
    18. 18.  Idopathic  Children: Birth traumas, infections – meningitis and congenital abnormalities  Middle age: Alcohol, infections, head injury and Drugs like cocaine, low blood sugar, low oxygeen, low blood Na+ and low Ca+ etc.  Elderly: Stroke, tumors etc.  Congenital:  Hippocampus DYSGENESIS (FAILURE OF CORTEX TO GROW PROPERLY)  VASCULAR MALFORMATIONS  AT LEAST EIGHT SINGLE LOCUS GENETIC DEFECTS ARE ASSOCIATED WITH EPILEPSY – motor cortex, somatosensory cortex, visual cortex, auditory cortex, temporal lobe cortex and olfactory.
    19. 19.  Hydantoins: phenytoin, phosphenytoin  Barbiturates: phenobarbitone  Iminostilbenes: carbamazepine, oxcarbazepine  Succinimides: ethosuximide  Aliphatic carboxylic acid: Valproic acid, divalproex  Benzodiazepines: clonazepam, diazepam, lorazepam  New compounds: gabapentin, lamotrigine, tiagabine, topiramate, vigabatrin, zonisamide, felbamate
    20. 20. Most common ones:  Modification of ion conductance  Prolongation of Na+ channel inactivation  Inhibition of `T` type Ca++ current  Increase inhibitory (GABAergic) transmission – Cl- Channel.  Glutamate receptor antagonism (NMDA, AMPA, or kainic acid)  Genetic mechanism
    21. 21. The Sodium Channel: A. Resting State B. Arrival of Action Potential causes depolarization and channel opens allowing sodium to flow in. C. Refractory State, Inactivation – reduce the rate of recovery. Na+ Na+ Na+ Sustain channel in this conformation Anticonvulsant mechanism – contd. m gate h gate
    22. 22. Drugs acting via this channel: Phenytoin, Sodium Valproate, Carbamezepine, Lamotrigine, Topiramide and Zonisamide
    23. 23. T type Ca++ current inhibition:  Thalamic neurons exhibit prominent T current which is a low threshold Ca++ current  T type current is responsible for 3 Hz spike-and-wave  Throughout the thalamus `T` current has large amplitudes – thalamocortical oscillations  Bursts of action potential is by action of T current  In absence seizure  Drugs – ethosuximide, valproate and trimethadione
    24. 24.  The GABA mediated CL- channel opening  Drugs: barbiturates, benzodiazepines, vigabatrin, gabapentin and valproate
    25. 25.  First effective organic antiseizure agent  Mechanism:  Mechanism of CNS depression like other barbiturates, but less effect on Ca++ channel and glutamate release – less hypnotic effect  GABAA receptor mediated like other Barbiturates  Continued use – sedation effect lost but not anticonvulsant action  Raises seizure threshold and limits spread  Suppresses kindled seizures  Pharmacokinetics:  Slowly absorbed and long t1/2 (80 – 120 hrs)  Metabolized in liver and excreted unchanged in kidney  Single dose after 3 wks. – steady state
    26. 26.  Adverse effects:  Sedation  Behavioural abnormalities  Hyperactivity in children  Rashes, megaloblastic anaemia and osteomalacia  Primidone:  Deoxybarbiturate  Converted to Phenobarbitone and PEMA Short half life 6-14 hrs  Uses:  Many consider them the drugs of choice for seizures only in infants  GTC  SP and CPS  Dose:  60 mg 1-3 times a day Child: 3-6 mg/kg/day  Available as tabs – 30/60mg, syr. and inj.
    27. 27.  Pharmacological actions:  Not CNS depressant  But muscular rigidity and excitement at toxic doses  Abolish tonic phase of GTC seizure  No effect on clonic phase  Prevents spread of seizure activity  Tonic-clonic epilepsy is suppressed but no change in EEG and aura..  In CVS – depresses ventricular automaticity, accelerates AV conduction
    28. 28.  Mechanism of action:  Prevents repetitive detonation of normal brain cells during `depolarization shift`  Prolonging the inactivation of voltage sensitive Na+ channel  No high frequency discharges  Na+ channel recovers  No interference with kindling – only on high frequency firing  Pharmacokinetics:  Slow oral absorption  80-90% bound to plasma protein  Metabolized in liver by hydroxylation and glucoronide conjugation  Elimination varies with dose – first order to zero order  T1/2 life is 12 to 24 hrs  Cannot metabolize by liver if plasma conc. Is above 10 mcg/ml  Monitoring of plasma concentration
    29. 29. Adverse effects:  Hirsutism, coarsening of facial features and acne  Gum hypertrophy and Gingival hyperplasia.  Hypersensitivity – rashes, lymphadenopathy  Megaloblastic anaemia  Osteomalacia  Hyperglycaemia  Cognitive impairment  Exacerbates absence seizures  Fetal Hydantoin Syndrome
    30. 30. Phenytoin Toxicities Fetal Hydantoin Syndrome
    31. 31.  Uses: It is the first line antiepileptic for  GTCS, no effect in absence seizure  Status epilepticus  Trigeminal neuralgia – 2nd to Carbamazepine  Available as caps/tabs/inj 25 to 100 mg caps and tabs  Drug Interactions:  Phenytoin and carbamazepine increases each others metabolism  Induces microsomal enzyme – steroids, digitoxin etc  Phenytoin metabolism inhibition – by warfarin, isoniazide etc.  Sucralfate – decreases phenytoin ebsorption
    32. 32.  Chemically related to imipramine  Trigeminal neuralgia  Lithium like action – mood stabilizer  Resembles phenytoin in pharmacological actions  Unlike phenytoin – inhibits kindling, modifies electroshock seizures and raises threshold to PTZ and electroshock  MOA:  Stabilizes Na+ channel (Voltage gated) in inactivated state – less excitability  Potentiation of GABA receptor
    33. 33.  Pharmacokinetics:  Poorly water soluble and oral absorption is low  75% bound to plasma protein  Metabolized in liver: active 10-11 epoxy carbamazepine  Substrate and inducer of CYP3A4  Half life – 20 to 40hrs. Decreases afterwards due to induction  Adverse effects:  Autoinduction of metabolism  Nausea, vomiting, diarrhoea and visual disturbances  Hypersensitivity – rash, photosensitivity, hepatitis, granulocyte suppression and aplastic anemia  ADH action enhancement – hyponatremia and water retention  Teratogenicity  Exacerbates absence seizures
    34. 34.  Uses:  Complex partial seizure  GTCS and SPS  Trigeminal and related neuralgias  Manic depressive illness and acute mania  Available as tabs (100mg 200, 400 etc.) and syr.  Oxcarbamazepine  Interactions:  Enzyme inducer – reduce efficacy of OCPs and others  Metabolism is induced by – phenobarbitone, phenytoin, valproate  Inhibits its metabolism – isoniazide and erythromycin
    35. 35.  Drug of choice for absence seizures  Does not modify maximal electroshock seizure or inhibit kindling  High efficacy and safety  Not plasma protein or fat binding  Mechanism of action involves reducing low threshold Ca2+ channel current (T-type channel) in thalamus At high concentrations:  Inhibits Na+/K+ ATPase  Depresses cerebral metabolic rate  Potentiates GABA  Phensuximide = less effective  Methsuximide = more toxic
    36. 36.  Toxicity:  Gastric distress, including, pain, nausea and vomiting  Lethargy and fatigue  Headache  Hiccups  Euphoria  Skin rashes  Doses:  20-30mg/kg/day  Available as syr./caps.
    37. 37.  Broad spectrum anticonvulsant  Effects on chronic experimental seizure and kindling  Potent blocker of PTZ seizure  Effective in partial, GTCS and absence seizures  Mechanism:  Na+ channel inactivation  Ca++ mediated `T` current attenuation  Inhibition of GABA transaminase  Pharmacokinetics: well absorbed orally, 90% bound to plasma protein and completely metabolized in liver and excreted in urine t1/2 is 10-15 hrs.
    38. 38.  Adverse effects:  Elevated liver enzymes including own – rise in serum transaminase  Nausea and vomiting  Abdominal pain and heartburn  Tremor, hair loss, weight gain  Idiosyncratic hepatotoxicity  In Girls – polycystic ovarian disease and menstrual irregularities  Negative interactions with other antiepileptics  Teratogenicity: spina bifida  Drug Interactions:  Valproate and carbamazepine induce each others metabolism  Inhibits phenobarbitone metabolism and increases its plasma level  Displaces phenytoin from protein binding sites and thereby decreases its metabolism – phenytoin toxicity  Available as tabs. (200/300/500, syr. and inj.)
    39. 39.  GABA derivative and can cross BBB  Enhances GABA release, but not agonist of GABAA  Originally designed to be centrally active GABA agonist – rapid transfer across BBB  Binds a protein in cortical membrane – similar to L type of voltage sensitive Ca++ channel, but do not alter Ca++ currents  Pharmacological Effects:  Inhibits hindlimb extension in ME seizure  Inhibits clonic seizures induced by PTZ  Efficacy is equal to valproic acid but different from carbamazepine and phenytoin
    40. 40.  Pharmacokinetics:  Absorbed orally  Not metabolized in humans  Not bound to plasma proteins and excreted unchanged in urine  Half life is 4 to 6 hrs.  No known drug interaction  Uses:  Partial seizures with or without secondary generalization in addition to other drugs  900-1800mg/day is equivalent to 300 mg/day of carbamazepine if used alone  Usual starting dose is 300mg/day  Adverse effects: somnolence, dizziness, ataxia etc.
    41. 41.  Phenyltriazine derivative, newer agent  Carbamazepine like action profile and modify MES seizures  Originally, as antifolate agent  Mechanisms:  Delays recovery from inactivation of Na+ channels prolong Na+ channel inactivation  Glutamate and aspartate inhibition: By directly blocking Na+ channels - stabilizes pre synaptic membrane and prevent release by excitatory neurons  Inhibition of Ca++ in neurons  Actions: Broad spectrum activity – action in areas other than Na+ channels, suppresses tonic hind limb extension in ME seizure, no action on PTZ seizures,  Uses: Partial (simple and complex) and secondarily generalized, absence seizure, myoclonic seizure in youngs
    42. 42.  Pharmacokinetics:  Completely absorbed from GIT and metabolized by glucoronidation  Plasma half-life – 15 to 30 hrs  Phenobarbitone, carbamazepine and phenytoin – reduces half life  Valproate – increases plasma concentration but its concentration reduces  Together with Carbamazepine – increase in 10,11-epoxide and toxicity  Uses: Monotherapy and add on therapy in simple partial and secondarily generalized seizures. Daily dose – 100 to 300 mg
    43. 43.  Sulfamate substituted monosaccharide  Pharmacological effects and MOA:  Broad spectrum antiseizure drug  Carbonic anhydrase inhibitor  Antiseizure activity against PTZ, ME seizure and partial and secondarily generalized tonic-clonic kindling  Multiple actions – Na+ channel, K+ channel, GABAA, AMPA-kainate subtypes of glutamate  Pharmacokinetics:  Rapidly absorbed orally, 10-20% bound to plasma protein, excreted unchanged in urine  Metabolized by hydroxylation, glucoronidation and hydrolysis  Reduction in estradiol level  Uses: GTCS, SP and CPS as supplement drug in refractory cases
    44. 44.  Mainly used agents – Clonazepam, Diazepam, Lorazepam and Clobazam  Common Antiseizure properties:  Prevents PTZ induced seizures prominently and modifies electroshock seizure pattern  Clonazepam has potent effect on PTZ induced seizures but almost nil action on ME seiures  Suppress the spread of kindled seizures and generalized convulsions  Do not abolish abnormal discharges at site of stimulation
    45. 45.  Diazepam:  Commonly used as anticonvulsant in a variety of convulsions  But, not used for long term – sedation effect  Mechanism of anticonvulsant is mediated by same mechanism of sedation: Cl- channel  Used in emergency control of convulsion – status epilepticus, tetanus, febrile convulsion etc.  Usually given 0.2 to 0.5 mg/kg body weight IV followed by repeated doses if required – maximum dose 100 mg/day  Rectal diazepam
    46. 46.  Adverse effects:  Long term use of Clonazepam – drowsiness and lethargy – tolerance to antiseizure effects  Muscular incoordination and ataxia  Hypotonia, dysarthria and dizzziness  Behavoiural abnormalities in children – aggression, hyperactivity, irritability and difficulty in concentration  Increased bronchial and salivary secretions  Exacerbation of seizures  Therapeutic uses:  Clonazepam in absence seizure and myoclonic seizure in children (1 to 6 months)  Dose initial – 1.5mg/day, children – 0.01 to 0.03mg/kg/day  Status epilepticus – Diazepam, Lorazepam may be used as alternative
    47. 47. 1. Aim of the treatment:  Control and prevent all seizure activity (seizure - freedom and improvement in quality of life!)  To search the cause of epilepsy  Attempts to remove the causes  Symptomatic treatment with antiepileptic drugs  To consider status epilepticus as medical emergency and treat efficiently and promptly 1. Initiation of treatment:  Initiate therapy even if it is isolated tonic-clonic seizure with family history of seizure, abnormal neurological examination, abnormal EEG and an abnormal MRI  Treat with monotherapy, Substitute another drug if fails  Combination therapy – only when all monotherapy fail  Therapeutic monitoring of drugs – dose adjustments
    48. 48. Seizure types 1st choice 2nd choice Generalized tonic-clonic or simple partial seizure Carbamazepine, Phenytoin and Valproic acid Phenobarbitone and Valproate Absence seizure Valproate Ethosuximide Complex partial seizure with or without generalization Phenytoin, Carbamazepine and Valproate Gabapentin Lamotrigine Myoclonic Valproate Lamotrigine Topiramate Status epilepticus Diazepam Lorazepam Phenytoin IV Phosphenytoin IV Febrile convulsions Diazepam rectal 0.5mg/kg -
    49. 49. 4. Withdrawal of drugs:  Gradual withdrawal  Prolong therapy – life long/3yrs after last seizure  Withdrawal – childhood epilepsy, absence of family history, primarily generalized tonic-clonic seizure and normal EEG 5. Seizure diary 6. Antiepileptics and pregnancy  Drugs should not be stopped if conceive – status epilepticus  Fits during pregnancy – birth defects, mental retardation etc.  Folic acid and vit.K supplementation 7. Care during attacks: tonic-clonic seizures 8. Surgical removal
    50. 50.  Tonic-clonic, myoclonic, and absence seizures:  1st line drug is usually valproate  Generalized seizures:  Phenytoin and carbamazepine are effective on tonic-clonic seizures but not other types of seizures  Absence seizures:  Valproate and ethosuximide are equally effective in children, but only valproate protects against the tonic-clonic seizures that sometimes develop  Risk of hepatoxicity with valproate—should not be used in children under 2
    51. 51.  Without generalization  Phenytoin and carbamazepine may be slightly more effective  With secondary generalization  First-line drugs are carbamazepine and phenytoin (equally effective)  Valproate, phenobarbital, and primidone are also usually effective  Phenytoin and carbamazepine can be used together (but both are enzyme inducers)
    52. 52.  Adjunctive (add-on) therapy: newer drugs gabapentin, lamotrigine, levetiracetam, oxcarbazepine, tiagabine, topiramate, and zonisamide  Phenytoin and carbamazepine failure: Lamotrigine, oxcarbazepine, felbamate approved for monotherapy  Refractory partial seizures: Topiramate can be effective
    53. 53.  Continuous seizure activity for more than 30 minutes, or 2 or more seizures without recovery of consciousness  Its an Emergency Condition: Recurrent tonic- clonic convulsions without recovery in between
    54. 54.  Goal of therapy:  Rapid termination of seizure activity – more difficult to control – permanent brain damage  Prompt treatment with effective Drugs  Attention to hypoventilation and hypotension  Treatment is IV only  Diazepam 10mg IV bolus injection (2mg/min)  Fractional dose at every 10 min. or titrated dose by slow infusion  Lorazepam: 0.1mg/kg  Followed by Phenobarbitone IM/IV (100-200mg)/min or Phenytoin slow IV in saline (25-50mg/min)  Resistant cases (refractory): IV anaesthetics (Propofol or thiopentone)  General supportive measures
    55. 55.  Mechanism of action and Adverse effects/Uses of Phenytoin/Valproate/Carbamazepine/ETHSX  Short Notes: Gabapentine, Lamotrigine, Topiramate  Clinical:  Pharmacotherapy of Status Epilepticus  Pharmacotherapy of GTCS  Reasoning Questions:  Valproic acid in absence seizure  Phenytoin is not used in absence seizure  Benzodiazepines as anticonvulsant
    56. 56. Thanks