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See all Premium member Presentation Transcript Antiepileptic Drugs : Antiepileptic Drugs Pharmacology, NEIGRIHMS SOME FAMOUS PEOPLE WHO WERE AFFLICTED : SOME FAMOUS PEOPLE WHO WERE AFFLICTED ALEXANDER THE GREAT JULIUS CAESAR NAPOLEON What are Epilepsies? : What are Epilepsies? 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 are seizures? : What are seizures? A seizure is a transient alteration of behaviour due to the disordered, synchronous, and rythmic firing of populations of brain neurones. Seizure can be nonepileptic 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. What are Epilepsies – Clinically? : What are Epilepsies – Clinically? 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. How many types? : How many types? Generalized: Generalized tonic-Clonic Seizures Absence Seizure Atonic Seizures Myoclonic Seizures Infantile Spasms Types of seizures – contd. : Types of seizures – contd. 2. Partial (focal) Seizures Simple Partial Seizures Complex Partial Seizures 1. Generalized seizures : 1. Generalized seizures A. 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 occurence Slide 9: Tonic phase: - Sustained powerful muscle contraction (involving all body musculature) which arrests ventilation. EEG: Rythmic high frequency, high voltage discharges with cortical neurons undergoing sustained depolarization, with protracted trains of action potentials. Generalized Seizures – contd. Slide 10: Clonic phase: - Alternating contraction and relaxation, causing a reciprocating movement which could be bilaterally symmetrical. EEG: Characterized by groups of spikes on the EEG and periodic neuronal depolarizations with clusters of action potentials. Generalized Seizures – contd. Generalized Seizures – contd. : Generalized Seizures – contd. Generalized Seizures – contd. : Generalized Seizures – contd. Generalized Seizures – contd. : Generalized Seizures – contd. B. 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, 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. Generalized Seizures – contd. : Generalized Seizures – contd. C. Atonic Seizures: Unconsciousness with relaxation of all muscles Patient falls down Loss of postural tone, with sagging of the head or falling D. 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 Generalized Seizures – contd. : Generalized Seizures – contd. E. 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 2. Partial (focal) Seizures : 2. Partial (focal) Seizures A. Simple partial seizure Lasts for 20 – 60 seconds 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 Partial (focal) Seizures – contd. : Partial (focal) Seizures – contd. B. 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 Motor activity appears as non-reflex actions. Automatisms (repetitive coordinated movements). Wide variety of clinical manifestations Consciousness is impaired Complex partial seizure – contd. : Complex partial seizure – contd. Deja vu Partial (focal) Seizures – contd. : Partial (focal) Seizures – contd. C. Secondarily generalized: (Jacksonian) Partial seizures initially Followed by generalized tonic-clonic seizure Secondarily generalized seizure : Secondarily generalized seizure Partial (focal) Seizures – contd. : Partial (focal) Seizures – contd. Types of Seizure: Summery: : Types of Seizure: Summery: Status epilepticus : Status epilepticus Continuous seizure activity for more than 30 minutes, or 2 or more seizures without recovery of consciousness. Emergency: Recurrent tonic-clonic convulsions without recovery in between. Causes of Epilepsy : Causes of Epilepsy ACUTE CONGENITAL Causes of Epilepsy – contd. : Causes of Epilepsy – contd. ACUTE EPILEPSY CORTICAL DAMAGE TRAUMA STROKE NEOPLASM AUTOIMMUNE EFFECTS Causes of Epilepsy – contd. : Causes of Epilepsy – contd. 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. ExperimentalModels : ExperimentalModels Maximal electroshock seizures: tonic phase abolished by drugs effective in GTCS PTZ clonic seizures (Pentylenetetrazole): Can be prevented by drugs effective in absence seizure Chronic focal seizure: alumina cream in monkey Kindled seizures: bursts of weak electrical impulses – tonic-clonic seizure Classification – antiepileptic drugs : Classification – antiepileptic drugs 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 Mechanisms of seizure & antiseizure drugs: : Most common ones: Modification of ion conductance Prolongation of Na+ channel inactivation Inhibition of `T` type Ca++ current Increase inhibitory (GABAergic) transmission. Glutamate receptor antagonism (NMDA, AMPA, or kainic acid) Genetic mechanism Mechanisms of seizure & antiseizure drugs: Slide 30: 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. Na+ Na+ Na+ Sustain channel in this conformation Anticonvulsant mechanism – contd. The Sodium Channel – contd. : The Sodium Channel – contd. Drugs acting via this channel: Phenytoin, Sodium Valproate, Carbamezepine, Lamotrigine, Topiramide and Zonisamide Anticonvulsant mechanism – contd. : Anticonvulsant mechanism – contd. T type Ca++ current inhibition: T type current is responsible for 3 Hz spike-and-wave Throughout the thalamus `T` current has large amplitudes Bursts of action potential is by action of T current In absence seizure Drugs – ethosuximide, valproate and trimethadione Anticonvulsant mechanism – contd. : Anticonvulsant mechanism – contd. The GABA mediated CL- channel opening Drugs: barbiturates, benzodiazepines, vigabatrin, gabapentin and valproate Individual Drugs : Individual Drugs Phenobarbitone : Phenobarbitone 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 Pharmcokinetics: Slowly absorbed and long t1/2 (80 – 120 hrs) Metabolized in liver and excreted unchanged in kidney Single dose after 3 wks. – steady state Phenobarbitone – contd.(Gardenal/Luminal) : Phenobarbitone – contd.(Gardenal/Luminal) Adverse effects: Sedation Behavioural abnormalities Hyperactivity in children Rashes, megaloblastic anaemia and osteomalacia Primidone: deoxybarbiturate 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. Phenytoin(Dilantin/Epsolin/Eptoin) : 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 phase is suppressed but no change in EEG and aura In CVS – depresses ventricular automaticity, accelerates AV conduction Phenytoin sodium – contd. : Phenytoin sodium – 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 Phenytoin sodium – contd. : Phenytoin sodium – contd. 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 Phenytoin sodium – contd. : Phenytoin sodium – contd. 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 Phenytoin sodium – contd. : 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. Phenytoin sodium – contd. : Phenytoin sodium – contd. 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 Phenytoin sodium – contd. : Phenytoin sodium – contd. Phenytoin sodium – contd. : Phenytoin sodium – contd. Phenytoin Toxicities Fetal Hydantoin Syndrome Images of Phenytoin preparations : Images of Phenytoin preparations Carbamazepine (Tegretol/Tegrital) : Carbamazepine (Tegretol/Tegrital) Chemically related to imipramine Trigeminal neuralgia Resembles phenytoin in pharmacological actions Unlike phenytoin – inhibits kindling, modifies electroshock seizures and raises threshold to PTZ and electroshock Carbamazepine – contd. : Carbamazepine – contd. 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 Carbamazepine – contd. : Carbamazepine – contd. Adverse effects: Autoinduction of metabolism Nausea, vomiting, diarrhoea and visual disturbances Hypersensitivity – rash, photosensitivity, hepatitis, granulocyte supression and aplastic anemia ADH action enhancement – hyponatremia and water retention Teratogenicity Exacerbates absence seizures Carbamazepine – contd. : Carbamazepine – contd. 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 Carbamazepine – contd. : Carbamazepine – contd. Interactions: Enzyme inducer – reduce efficacy of OCPs and others Metabolism is induced by – phenobarbitone, phenytoin, valproate Inhibits its metabolism – isoniazide and erythromycin Ethosuximide : 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 lowthreshold 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 Ethosuximide – contd. : Ethosuximide – contd. 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. Valproic acid(Encorate/Valparin) : 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 Mechanism: Na+ channel inactivation Ca++ mediated `T` current attenuation Inhibition of GABA transaminase Pharmacokinrtics: well absorbed orally, 90% bound to plasma protein and completely metabolized in liver and excreted in urine t1/2 is 10-15 hrs. Valproic acid – contd. : 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 Available as tabs. (200/300/500, syr. and inj.) Valproic acid – contd. : Valproic acid – contd. 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 Benzodiazepines : Benzodiazepines Mainly used agents – Clonazepam, Diazepam, Lorazepam and Clobazam 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 Benzodiazepines – contd. : Benzodiazepines – contd. Pharmacokinetic properties: Well absorbed orally (peak 1-4 hrs) IV administration – redistribution Diazpam rapid redistribution (1 hr) Diazepam – 99%, Clonazepam – 85% bound to plasma protein N-desmethyldiazepam (metabolite) is less active than diazepam – partial agonist Diazepam and NDD – hydroxylated to active metabolite – oxazepam – t1/2 is 1 to 2 days Clonazepam – reduction of nitro group to inactive 7-amino derivatives Lorazepam – conjugation with glucoronic acid – t1/2 is 14hrs Benzodiazepines – contd. : 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 Benzodiazepines – contd. : Benzodiazepines – contd. Therapeutic uses: Cloonazepam 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 Benzodiazepines – contd. : Benzodiazepines – contd. Gabapentin : Gabapentin GABA molecule covalently bound to a cyclohexane ring Originally designed to be centrally active GABA agonist – rapid transfer across BBB Pharmaqcological 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 Gabapentin – contd. : Gabapentin – contd. Mechanism of action: Unknown Does not mimic GABA Probably, promotes nonvesicular release of GABA Binds a protein in cortical membrane – similar to L type of voltage sensitive Ca++ channel But, do not alter Ca++ currents Does not reduce repetitive firing of action potentials Gabapentin – contd. : Gabapentin – contd. Pharmacokinetics: Absorbeed 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. Lamotrigine : Lamotrigine Phenyltriazine derivative Originally, as antifolate agent Pharmacological Effects and Mechanisms: Suppresses tonic hindlimb extension in ME seizure Partial and secondarily generalized in kindling No action on PTZ seizures Delays recovery from inactivation of Na+ channels – carbamazepine and phenytoin Effective against partial and secondarily generalized seizures Broad spectrum activity – action in areas other than Na+ channels Inhibition of glutamate release Lamotrigine – contd. : Lamotrigine – contd. 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 Topiramate : 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 Pharmacokinetics: Rapidly absorbed orally, 10-20% bound to plasma protein, excreted unchanged in urine Metabolized by hydroxylation, glucoronidation and hydrolysis Reduction in estradiol level Major Drug Interactions : Major Drug Interactions Phenytoin: With P.barbitone – unpredictable overall reaction With Carbamazepine – increases each other`s metabolism With Valproate – displaces phenytoin from protein binding Mainly significant interactions are due to displacement of protein binding - sulfonamides Carbamazepine: Increase in metabolism of other drugs like primidone, phenytoin, ethosuximide, valproic acid, and clonazepam Phenobarbitone and Phenytoin increases its metabolism Significant interactions are due to enzyme induction Major Drug Interactions – contd. : Major Drug Interactions – contd. Valproate: Due to Protein binding and inhibition of metabolism Phenytoin is displaced from binding Inhibits metabolism of phenobarbitone, phenytoin and carbamazepine Ethosuximide: Valproate inhibits metabolism and clearance Other uses of AEDs: : Other uses of AEDs: Gabapentin, carbamazepine — neuropathic pain Lamotrogine, carbamazepine — bipolar disorder Valproate, topirimate, gabapentin — migraine Diazepam – Tetanus, eeclampsia and convulsant drug poisoning Treatment of Epilepsies : 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 Choice of Drugs: According to the seizure types. Treatment of Epilepsies – Drug choices : Treatment of Epilepsies – Drug choices Treatment of Epilepsies – contd. : Treatment of Epilepsies – contd. 3. 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 Treatment of Epilepsies – contd. : Treatment of Epilepsies – contd. 4. Seizure diary 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 Treatment of Epilepsies – contd. : Treatment of Epilepsies – contd. 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 Generalized Onset Seizures : Generalized Onset Seizures 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 Partial Onset Seizures : Partial Onset Seizures 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) Partial Onset Seizures—New Drugs : Adjunctive (add-on) therapy: newer drugs felbamate, gabapentin, lamotrigine, levetiracetam, oxcarbazepine, tiagabine, topiramate, and zonisamide Phenytoin and carbamazepine failure: Lamotrigine, oxcarbazepine, felbamate approved for monotherapy – Refractory partial seizures: Topirimate can be effective. Partial Onset Seizures—New Drugs Status Epilepticus : Status Epilepticus Defn.: Continuous seizure activity for more than 30 minutes, or 2 or more seizures without recovery of consciousness. Recurrent tonic-clonic convulsions without recovery in between 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 Status Epilepticus – contd. : Status Epilepticus – contd. 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) or Phenytoin slow IV in saline (25-50mg/min) Resistant cases (refractory): IV anaesthetics General supportive measures Attentions : Attentions Selection of an appropriate antiseizure agent Use of single drug Withdrawal Toxicity Fetal malformations Slide 81: Thank You You do not have the permission to view this presentation. In order to view it, please contact the author of the presentation.