AntiEpileptic Drugs
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Transcript of AntiEpileptic Drugs
ANTI EPILEPTIC DRUGS
DR. KAUSHIK MUKHOPADHYAY
DEPT. OF PHARMACOLOGY, ESI-PGIMSR
SEIZURE VS EPILEPSY
• Seizure is a paroxysmal event due to abnormal excessive or synchronous neuronal activity in the brain.
• Epilepsy describes a condition in which a person has recurrent seizures due to a chronic, underlying process.
this definition implies that a person with a single seizure, or recurrent seizures due to correctable or avoidable circumstances, does not necessarily have epilepsy.
ACTION POTENTIAL
Seizu
reFocal
Seizure
Without Dyscognitive Symptoms
With Dyscognitive Symptoms
GeneralizedSeizure
Absence
Typical
Atypical
Generalized Tonic Clonic Seizure
Tonic
Clonic
Atonic
Myoclonic
Focal, Generalizedor Unclear
(Epileptic spasms)
GENERATION OF SEIZURES
Absence Seizure
GTCSTonic 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
MECHANISMS OF ANTISEIZURE DRUGS:
• 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)
SODIUM CHANNEL – 3 STATES
• PHENYTOIN• CARBAMAZEPINE• VALPROATE• TOPIRAMATE• LAMOTRIGINE• LACOSAMIDE
GABA MEDIATED
• BARBITURATE• BZD• VALPROATE• TIAGABINE• VIGABATRINE
T-TYPE CA2+ CHANNELS @ THALAMUS
PHENYTOIN(DILANTIN/EPSOLIN/EPTOIN)
Pharmacological actions:• Not CNS depressant• Abolish tonic phase of GTC seizure• 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.Mechanism of action:• Prevents repetitive detonation of normal brain cells
during `depolarization shift`• Prolonging the inactivation of voltage gated Na+ channel• At concentrations 5- to 10-fold higher - reduction of
spontaneous activity and enhancement of responses to GABA
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 • Monitoring of plasma concentration
PHENYTOIN – CONTD.Adverse effects:• Hirsutism, coarsening of facial features • Gum hypertrophy and Gingival hyperplasia.• Hypersensitivity – rashes, lymphadenopathy• Megaloblastic anaemia• Osteomalacia• Hyperglycaemia• Cognitive impairment• Fetal Hydantoin Syndrome
Toxicity
• Ataxia, Vertigo, Confusion, Disorientation • i.v – local vascular injury, arrhythmia
PHENYTOIN – CONTD.
DDI:• CBZ & Phenytoin – induce each other’s metabolism• Valproate, Cimetidine, Isoniazid – inhibits metabolism• Acidic drug displaces from protein binding sites
Fosphenytoin
• Aqueous soluble prodrug
CARBAMAZEPINE (TEGRETOL/TEGRITAL)
• Chemically related to imipramine• Trigeminal neuralgia• Lithium like action – mood stabilizer• Resembles phenytoin in pharmacological actions• MOA:
• Stabilizes Na+ channel (Voltage gated) in inactivated state – less excitability
• Potentiation of GABA receptor
CARBAMAZEPINE – CONTD.
• Pharmacokinetics:• Poorly water soluble and
oral absorption is low• 75% bound to plasma
protein• Metabolized in liver• Substrate and inducer of
CYP3A4• Half life – 20 to 40hrs.
Decreases afterwards due to induction
• Adverse effects:• Autoinduction of metabolism• Hypersensitivity – rash,
photosensitivity, hepatitis, • granulocyte suppression and
aplastic anemia• ADH action enhancement –
hyponatremia and water retention
• Teratogenicity• Exacerbates absence seizures
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
VALPROIC ACID(ENCORATE/VALPARIN)
• Broad spectrum anticonvulsant• 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.
• Adverse effects:• Elevated liver enzymes• Abdominal pain and
heartburn• Tremor, hair loss,
weight gain• hepatotoxicity• In Girls – polycystic
ovarian disease and menstrual irregularities
• 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
ETHOSUXIMIDE
• Drug of choice for absence seizures• 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
BZD
• 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.
• Status epilepticus – Diazepam, Lorazepam may be used as alternative
• 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
PHENOBARBITONE• First effective organic antiseizure agent• Mechanism:
• GABAA receptor mediated like other Barbiturates• Pharmacokinetics:
• Slowly absorbed and long t1/2 (80 – 120 hrs)• Metabolized in liver and excreted unchanged in kidney
• Uses:• Many consider them the drugs of choice for
seizures only in infants• GTC
• Dose:• 60 mg 1-3 times a day• Child: 3-6 mg/kg/day
PHENOBARBITONE – CONTD.
• 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
NEWER ANTIEPILEPTICS
1. Lamotrigine2. Topiramate3. Levetiracetam4. Tiagabine5. Vigabatrine6. Gabapentin7. Lacosamide
LAMOTRIGINE
• Phenyltriazine derivative, newer agent• CBZ like, Broad spectrum activity
• 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
• Uses: Partial (simple and complex) and secondarily generalized, absence seizure, myoclonic seizure in youngs• Mood Stabilizer
• ADR: Rash
TOPIRAMATE
• Broad spectrum antiseizure drug• Pharmacological effects and MOA:
• Carbonic anhydrase inhibitor• Multiple actions – Na+ channel, K+ channel, 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
GABAPENTIN
• GABA derivative and can cross BBB• MOA - Enhances GABA release, but not agonist of GABAA
Binds a protein in cortical membrane – similar to L type of voltage sensitive Ca++ channel, but do not alter Ca++ currents
• Pharmacokinetics:• Absorbed orally• Not metabolized in humans• Not bound to plasma proteins and excreted unchanged in urine
• ADR:• Sedation, dizziness
Thank You