ANTIEPILEPTICS - drdhriti

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A power point presentation on antiepileptics (newer - 2011) suitable for reading by UG medical students

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ANTIEPILEPTIC DRUGS: 

ANTIEPILEPTIC DRUGS Department of Pharmacology NEIGRIHMS, Shillong, India

History of Epilepsy: 

History of Epilepsy 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

What are Epilepsies?: 

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

Epilepsies – Clinically: 

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 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: 

Classification of Epileptic Seizures Generalized: Generalized tonic- clonic seizure Absence seizure Tonic seizures Atonic Seizure Myoclonic seizure Infantile spasm

Types of seizures – contd.: 

Types of seizures – contd. Partial (focal) Seizures: 80% of Adult epilepsies Simple Partial Seizures Complex Partial Seizures Simple partial or complex partial secondarily generalized

Generalized seizures: 

Generalized seizures 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

EEG changes in GTCS: 

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

Generalized Seizures – contd.: 

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.

Generalized seizures – contd.: 

Generalized seizures – contd. 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

Partial (focal) Seizures: 

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

Scheme of Seizure Spread: 

Scheme of Seizure Spread Simple (Focal) Partial Seizures Contralateral spread

Partial (focal) Seizures – contd.: 

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

Complex partial seizure – contd.: 

Complex partial seizure – contd. ….Deja vu …

Partial (focal) Seizures – contd.: 

Partial (focal) Seizures – contd. Secondarily generalized (Jacksonian): Partial seizures initially Followed by generalized tonic-clonic seizure

Scheme of Seizure Spread: 

Scheme of Seizure Spread Complex Partial Seizures Complex Secondarily Generalized Partial Seizures

Partial (focal) Seizures – contd.: 

Partial (focal) Seizures – contd.

Status epilepticus: 

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

Experimental Models: 

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

Why Epilepsy occurs?: 

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. 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 .

Classification of Antiepileptic drugs: 

Classification of 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:: 

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 – Cl - Channel. Glutamate receptor antagonism (NMDA, AMPA, or kainic acid) Genetic mechanism

Slide 23: 

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. m gate h gate

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: 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

Anticonvulsant mechanism – contd.: 

Anticonvulsant mechanism – contd. The GABA mediated CL- channel opening Drugs: barbiturates, benzodiazepines, vigabatrin, gabapentin and valproate

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 GABA A 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 t 1/2 (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 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.

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 epilepsy is suppressed but no change in EEG and aura.. In CVS – depresses ventricular automaticity, accelerates AV conduction

Phenytoin – contd.: 

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 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 – contd.: 

Phenytoin – 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. Phenytoin Toxicities 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 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

Carbamazepine (Tegretol/Tegrital): 

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 MOA: Stabilizes Na+ channel (Voltage gated) in inactivated state – less excitability Potentiation of GABA receptor

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 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

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 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 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

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 Pharmacokinetics: 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 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.)

Gabapentin: 

Gabapentin GABA derivative and can cross BBB Enhances GABA release, but not agonist of GABA A 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

Gabapentin – contd.: 

Gabapentin – contd. 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.

Lamotrigine: 

Lamotrigine 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

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. Daily dose – 100 to 300 mg

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 Uses: GTCS, SP and CPS as supplement drug in refractory cases

BenzoDiazepines: 

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

Diazepam: 

Diazepam 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

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 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

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 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

3. Choice of Drugs: According to the seizure types: 

3. Choice of Drugs: According to the seizure types Seizure types 1 st choice 2 nd 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 -

Treatment of Epilepsies – contd.: 

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

Generalized Onset Seizures – drug therapy: 

Generalized Onset Seizures – drug therapy 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 Seizures - treatment: 

Partial Seizures - treatment 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 Seizures – contd.: 

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

Status Epilepticus: 

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

Important to study: 

Important to study 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

HAVE A NICE DAY ! : 

HAVE A NICE DAY ! Thanks