Antiepileptic  drugs (new) - drdhriti
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Antiepileptic drugs (new) - drdhriti



A Power Point presentation on ANTI EPILEPTICS suitable for Medical undergraduate level students

A Power Point presentation on ANTI EPILEPTICS suitable for Medical undergraduate level students



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  • Paroxysmal: Periodic attack of disease or sudden outburst of disease

Antiepileptic drugs (new) - drdhriti Presentation Transcript

    Department of Pharmacology NEIGRIHMS, Shillong
  • 2. History of Epilepsy
    In 400 B.C., the early physician Hippocrates suggested that epilepsy was a disorder of the brain
    Famous Persons Afflicted:
  • 3. What are Epilepsies?
    Definition: These are Group of disorders of the CNS characterized by paroxysmal cerebral dysrhythmia, manifesting as brief episodes (seizure) of loss of consciousness, with or without characteristic body movements (convulsions), sensory or psychiatric phenomena
    What is a seizure?
    A seizure is a transient alteration of behaviour due to the disordered, synchronous, and rhythmic 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. Epilepsies – Clinically
    • Epilepsy is a syndrome of two or more unprovoked or recurrent seizures on more than one occasion
    • 5. Epileptic seizures range from clinically undetectable (electrographic seizure) to convulsions
    • 6. 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
  • Classification of Epileptic Seizures
    • Generalized:
    Generalized tonic-clonic seizure
    Absence seizure
    Tonic seizures
    Atonic Seizure
    Myoclonic seizure
    Infantile spasm
  • 7. Types of seizures – contd.
    Partial (focal) Seizures: 80% of Adult epilepsies
    Simple Partial Seizures
    Complex Partial Seizures
    Simple partial or complex partial secondarily generalized
  • 8. Generalized seizures
    Generalized tonic-clonic
    • GTCS/major epilepsy/grand mal
    • 9. Commonest of all
    • 10. Lasts for 1-2 minutes
    • 11. Aura-cry-unconsciousness-tonic phase-clonic phase
    • 12. Usually occurs in both the hemispheres
    • 13. Manifestations are determined by cortical site of seizure occurrence
    • 14. 2 phases: tonic phase followed by clonic phase
    • 15. Tonic phase:
    • 16. Sustained powerful muscle contraction (involving all body musculature) which arrests ventilation
    • 17. Clonic phase:
    • 18. Alternating contraction and relaxation, causing a reciprocating movement which could be bilaterally symmetrical
  • EEG changes in GTCS
    Tonic: Rythmic high frequency, high voltage discharges with cortical neurons undergoing sustained depolarization, with protracted trains of action potentials
    Clonic: Characterized by groups of spikes on the EEG and periodic neuronal depolarizations with clusters of action potentials
  • 19. Generalized Seizures – contd.
    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.
  • 20. Generalized seizures – contd.
    • Atonic Seizures:
    • 21. Unconsciousness with relaxation of all muscles
    • 22. Patient falls down
    • 23. Loss of postural tone, with sagging of the head or falling
    • 24. Myoclonic Seizures:
    • 25. Isolated clonic jerks associated with brief bursts of multiple spikes in the EEG
    • 26. Momentary contractions of muscles of limbs or whole body
    • 27. No loss of postural control
    • 28. Infantile spasm:
    • 29. An epileptic syndrome
    • 30. Characterized by brief recurrent myoclonic jerks (muscle spasm) of the body with sudden flexion or extension of the body and limbs
    • 31. Progressive mental deterioration
  • Partial (focal) Seizures
    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
  • 32. Scheme of Seizure Spread
    Simple (Focal) Partial
    Contralateral spread
  • 33. Partial (focal) Seizures – contd.
    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
  • 34. Complex partial seizure – contd.
    ….Deja vu …
  • 35. Partial (focal) Seizures – contd.
    Secondarily generalized (Jacksonian):
    Partial seizures initially
    Followed by generalized tonic-clonic seizure
  • 36. Scheme of Seizure Spread
    Complex Partial Seizures
    Complex Secondarily Generalized Partial Seizures
  • 37. Partial (focal) Seizures – contd.
  • 38. Status epilepticus
    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
  • 39. Experimental Models
    Maximal electroshock seizures (MES): tonic phase abolished by drugs effective in GTCS and also Partial seizures
    PTZ clonic seizures (Pentylenetetrazole): Can be prevented by drugs effective in absence seizure (Petit mal)
    Kindled seizures: bursts of weak electrical impulses – tonic-clonic seizure
  • 40. Why Epilepsy occurs?
    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.
    AT LEAST EIGHT SINGLE LOCUS GENETIC DEFECTS ARE ASSOCIATED WITH EPILEPSY – motor cortex, somatosensory cortex, visual cortex, auditory cortex, temporal lobe cortex and olfactory.
  • 41. Classification of Antiepileptic drugs
    Hydantoins: phenytoin, phosphenytoin
    Barbiturates: phenobarbitone
    Iminostilbenes: carbamazepine, oxcarbazepine
    Aliphatic carboxylic acid: Valproic acid, divalproex
    Benzodiazepines: clonazepam, diazepam, lorazepam
    New compounds: gabapentin, lamotrigine, tiagabine, topiramate, vigabatrin, zonisamide, felbamate
  • 42. Mechanisms of seizure & antiseizure drugs:
    Most common ones:
    Modification of ion conductance
    • Prolongation of Na+ channel inactivation
    • 43. Inhibition of `T` type Ca++ current
    Increase inhibitory (GABAergic) transmission – Cl- Channel.
    Glutamate receptor antagonism (NMDA, AMPA, or kainic acid)
    Genetic mechanism
  • 44. Anticonvulsant mechanism – contd.
    The Sodium Channel:
    Resting State
    Arrival of Action Potential causes depolarization and channel opens allowing sodium to flow in.
    Refractory State, Inactivation – reduce the rate of recovery.
    m gate
    h gate
    Sustain channel in this conformation
  • 45. The Sodium Channel – contd.
    Drugs acting via this channel:
    Phenytoin, Sodium Valproate, Carbamezepine, Lamotrigine, Topiramide and Zonisamide
  • 46. Anticonvulsant mechanism – contd.
    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
  • 47. Anticonvulsant mechanism – contd.
    The GABA mediated CL- channel opening
    Drugs: barbiturates, benzodiazepines, vigabatrin, gabapentin and valproate
  • 48. Phenobarbitone
    First effective organic antiseizure agent
    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
    Slowly absorbed and long t1/2 (80 – 120 hrs)
    Metabolized in liver and excreted unchanged in kidney
    Single dose after 3 wks. – steady state
  • 49. Phenobarbitone – contd.(Gardenal/Luminal)
    Adverse effects:
    Behavioural abnormalities
    Hyperactivity in children
    Rashes, megaloblastic anaemia and osteomalacia
    Converted to Phenobarbitone and PEMA Short half life 6-14 hrs
    Many consider them the drugs of choice for seizures only in infants
    SP and CPS
    60 mg 1-3 times a day
    Child: 3-6 mg/kg/day
    Available as tabs – 30/60mg, syr. and inj.
  • 50. Phenytoin(Dilantin/Epsolin/Eptoin)
    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
  • 51. Phenytoin – contd.
    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
    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
  • 52. Phenytoin – contd.
    Adverse effects:
    Hirsutism, coarsening of facial features and acne
    Gum hypertrophy and Gingival hyperplasia.
    Hypersensitivity – rashes, lymphadenopathy
    Cognitive impairment
    Exacerbates absence seizures
    Fetal Hydantoin Syndrome
  • 53. Phenytoin sodium – contd.
    Fetal Hydantoin Syndrome
    Phenytoin Toxicities
  • 54. Phenytoin sodium – contd.
    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 phenytoinebsorption
  • 55. Carbamazepine (Tegretol/Tegrital)
    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
    Stabilizes Na+ channel (Voltage gated) in inactivated state – less excitability
    Potentiation of GABA receptor
  • 56. Carbamazepine – contd.
    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
    Exacerbates absence seizures
  • 57. Carbamazepine – contd.
    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.
    Enzyme inducer – reduce efficacy of OCPs and others
    Metabolism is induced by – phenobarbitone, phenytoin, valproate
    Inhibits its metabolism – isoniazide and erythromycin
  • 58. Ethosuximide
    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
  • 59. Ethosuximide – contd.
    Gastric distress, including, pain, nausea and vomiting
    Lethargy and fatigue
    Skin rashes
    Available as syr./caps.
  • 60. Valproic acid(Encorate/Valparin)
    Broad spectrum anticonvulsant
    Effects on chronic experimental seizure and kindling
    Potent blocker of PTZ seizure
    Effective in partial, GTCS and absence seizures
    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.
  • 61. Valproic acid – contd.
    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.)
  • 62. Gabapentin
    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
  • 63. Gabapentin – contd.
    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
    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.
  • 64. Lamotrigine
    Phenyltriazine derivative, newer agent
    Carbamazepine like action profile and modify MES seizures
    Originally, as antifolate agent
    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
  • 65. Lamotrigine – contd.
    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
  • 66. Topiramate
    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
    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
  • 67. BenzoDiazepines
    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
  • 68. 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
  • 69. BenzoDiazepines – contd.
    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
  • 70. Treatment of Epilepsies
    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
    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
  • 71. 3. Choice of Drugs: According to the seizure types
  • 72. Treatment of Epilepsies – contd.
    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
    Seizure diary
    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
    Care during attacks: tonic-clonic seizures
    Surgical removal
  • 73. Generalized Onset Seizures – drug therapy
    Tonic-clonic, myoclonic, and absence seizures:
    1st line drug is usually valproate
    Generalized seizures:
    Phenytoin and carbamazepineare 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
  • 74. Partial Seizures - treatment
    Without generalization
    Phenytoin and carbamazepinemay be slightly more effective
    With secondary generalization
    First-line drugs are carbamazepineand phenytoin(equally effective)
    Valproate, phenobarbital, and primidone are also usually effective
    Phenytoin and carbamazepine can be used together (but both are enzyme inducers)
  • 75. Partial Seizures – contd.
    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
  • 76. Status Epilepticus
    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
  • 77. Important to study
    Mechanism of action and Adverse effects/Uses of Phenytoin/Valproate/Carbamazepine/ETHSX
    Short Notes: Gabapentine, Lamotrigine, Topiramate
    Pharmacotherapy of Status Epilepticus
    Pharmacotherapy of GTCS
    Reasoning Questions:
    Valproic acid in absence seizure
    Phenytoin is not used in absence seizure
    Benzodiazepines as anticonvulsant
  • 78. HAVE A NICE DAY !