Download Anti Epileptic Drugs

Anti Epileptic Drugs
Prof S Kalyanaraman
OXCARBAZEPINE
OXCARBAZEPINE
1. What is the mechanism of action?
Blocks voltage dependant sodium channel
OXCARBAZEPINE
2. Describe the pharmacokinetics
• Bioavailability < 100 %
• Reduced in liver to the active metabolite,
monohydroxy derivative (MHD)
• 27 % excreted unchanged by kidneys
• Peak serum drug level 4 – 6 hours
• Peak serum metabolite level 8 hours
• Elimination half life 8 – 10 hours
• Time to steady state – 2 days
• Protein binding 38 %
OXCARBAZEPINE
3. What are the indications ?
• Partial seizures in adults
• All indications of Carbamazepine including
diabetic neuropathy
• Trigeminal neuralgia
• Mood stabiliser in affective disorders
OXCARBAZEPINE
4. What are the contraindications ?
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Hypersensitivity to Carbamazepine
Pregnancy, Lactation
Renal dysfunction, hepatic dysfunction
Hyponatremia (25 – 50 % of patients on chronic
therapy have Na levels below 135 but this is
usually asymptomatic. Hyponatremia is due to anti
diuretic effect and consumption of large volumes
of fluid is to be discouraged) (Serum sodium level
should be monitored regularly during therapy)
OXCARBAZEPINE
5. What are the side effects ?
Hyponatremia
Drowsiness
Dizziness
Ataxia
Diplopia
Dry mouth
Dyspepsia
Abdominal pain
Nausea
Vomiting
Constipation
Weight gain
Diarrhea
Alopecia
Fatigue
Tremor
Skin rash
OXCARBAZEPINE
6. What is the dosage?
• Starting dose 300 mg bd
• Increase dose by 600 mg / day at weekly
intervals
• Maximum 1200 mg bd
• Dosing interval twice daily
OXCARBAZEPINE
7. What is the cost ?
150 mg
Rs 3 / -
300 mg
Rs 5 / -
600 mg
Rs 10 / -
OXCARBAZEPINE
8. Name some proprietary preparations.
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Oxep (Nicholas Piramal)
Oxrate (Merind Pharma)
Oxetal (Sun Pharma)
Oxeptal (Stedman)
Oxcarb (Cipla)
Selzic (Solus Pharma)
Zenoxa (Intas)
Trioptal (Novartis)
OXCARBAZEPINE
9. What are the advantages ?
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Better than Carbamazepine
Milder side effects
Fewer idiosyncratic reactions
Fewer interactions with other drugs
OXCARBAZEPINE
10. What are the disadvantages ?
• Moderately high cost
• May render hormonal contraceptive
ineffective
• May increase plasma level of Phenytoin and
Phenobarbitone and these drugs may
decrease oxcarbazepine level
CLONAZEPAM
CLONAZEPAM
1. What is the mechanism of action ?
• It is a benzodiazepine
• GABA – A receptor agonist
CLONAZEPAM
2. What is the pharmacokinetics ?
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Oral bioavailability – 80 %
Time to peak levels – 1 – 8 hours
Time to steady state – 4 – 10 days
Biotransformation
• Reduction, Hydroxylation, Acetylation, Nitration in liver
• Elimination half life – 20 – 80 hours
• Protein binding – 86 %
• Active metabolite - none
CLONAZEPAM
3. What are the indications ?
• Partial seizures, simple
and complex
• GTCS
• Atonic seizures
• Absence seizures
• Myoclonic seizures
• Lennox Gastaut Syndrome
• Infantile spasms
• Neonatal seizures
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Drug induced dyskinesia
Anxiety
Panic attacks
Bipolar affective disorder
Multifocal tics
Neuralgias
Hypokinetic Dysarthria in
Parkinsonism
CLONAZEPAM
4. What are the contraindications ?
• Pregnancy
• Lactation
• Hepatic dysfunction
• Pulmonary
insufficiency
• Sleep apnea
• Respiratory depression
Renal dysfunction (can be used with caution)
CLONAZEPAM
5. What are the side effects ?
Sedation
Dizziness
Forgetfulness
Drowsiness
Short attention span Hypersalivation
Hyperactivity
Unsteadiness
Restlessness
Aggressiveness
LEUCOPENIA
Personality changes
Behavioral changes
Psychosis
CLONAZEPAM
6. What are the drug interactions ?
Nil significant
CLONAZEPAM
7. What is the dose, available formulations and cost ?
• Start with 0.25 mg hs. Can go upto 2 mg bd
• 0.5 mg Rs 1.5/• 1 mg
Rs 2/• 2 mg
Rs 3/-
CLONAZEPAM
8. What are the available market preparations ?
Clonotril
Epitril
Lona
Lonazep
Melzap
Petril
Rivotril
Sezolep
Zee
(Torrent)
(Novartis)
(Triton)
(Sun)
(Pentacare)
(Micro Labs)
(Nicholas)
(Merind)
(Sali – Mano)
CLONAZEPAM
9. What are the main advantages ?
Wide spectrum of activity including many
childhood epilepsy syndromes
CLONAZEPAM
10. What are the main disadvantages ?
• Sedation
• Probable teratogenecity
• Withdrawal symptoms
– Sudden withdrawal – may even lead to status
– Moderately slow withdrawal
• Increased seizure frequency
• Anxiety, Insomnia, Restlessness, Confusion
– Withdrawal rate should not exceed 0.5 mg per month
LAMOTRIGINE
LAMOTRIGINE
1. What is the mechanism of action ?
• Inhibits release of excitatory aminoacids
especially glutamate
• Blocks voltage dependant sodium channel
conductance
LAMOTRIGINE
2. What is the pharmacokinetics ?
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Bioavailability 98 %
Oral dose rapidly and completely absorbed
Peak serum level 1 – 3 hours (adults) and 1 – 6 hours (children)
Plasma half life 12 – 60 hours
Time to steady state 3 – 15 days
Protein binding 55 %
85 % metabolised by conjugation in liver and excreted as glucuronide
Active metabiolite – none
10 % excreted by kidneys unchanged
Eliminated more rapidly in patients on hepatic enzyme inducing drugs
like phenytoin, phenobarbitone and carbamazepine
LAMOTRIGINE
3. What is the dosage ?
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Starting dose 12.5 to 25 mg / day
Increase dose by 50 mg every 1 – 2 weeks
Maintenance dose 200 – 500 mg / day in 2 divided doses
Clearance of lamotrigine is reduced by 50 % in presence of
valproate – so dose in patient already getting valproate
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25 mg on alternate days for 2 weeks
Then 25 mg / day for 2 weeks
Increase by 25 mg / day every 1 – 2 weeks
Maximum dose 75 mg bd
• Dose reduction should be 50 % per week over 2 – 3 weeks
unless safety concerns require rapid withdrawal
LAMOTRIGINE
4. What are the indications ?
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Preferably II line drug, rarely I line drug
Partial seizures
} adults
Secondary generalised seizures
}
Absences
Atonic seizures
Lennox Gastaut Syndrome
Drug may increase frequency of myoclonic
seizures
LAMOTRIGINE
5. What are the side effects ?
• Rash especially if valproate is also given, if starting dose is high or
if dose escalation is rapid (Rash may disappear despite continued
medication)
• Headache, fever, arthralgia, asthenia
• Tremor, eosinophilia, blood dyscrasias, Steven Johnson syndrome
• Nausea, dyspepsia, vomiting
• Confusion, agitation, hallucination, psychosis
• Insomnia, drowsiness
• Blurred vision, diplopia
• Rhinitis, pharyngitis, bronchitis, cough
• Hepatic dysfunction
• Unsteadiness especially if carbamazepine is also given
LAMOTRIGINE
6. What are the contraindications ?
• Lactation – as considerable amount is excreted in
milk and elimination in infants is slow
• Special caution in
• Renal dysfunction
• Hepatic dysfunction
• Concomitant valproate therapy
(a few cases have been reported when patients who had
sexual dysfunction while on AED improved with
Lamotrigine)
LAMOTRIGINE
7. Formulations, Cost, Brand names ?
25, 50, 100 mg
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Lamitor (Torrent)
Lamepil (Innova)
Lamidus (Zydus)
Lametec (Cipla)
Lamez (Intaz)
Lamosyn (Sun)
100 mg
Rs 10 / -
TOPIRAMATE
TOPIRAMATE
1. What is the mechanism of action ?
• Multiple actions contributing to its antiepileptic
potential
• Actions on sodium conductance, GABA - A
receptor activity, glutamate receptor activity,
calcium channel activity and carbonic anhydrase
TOPIRAMATE
2. What is the pharmacokinetics ?
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Bioavailability 100 %
Plasma elimination half life 18 – 30 hours
Time to steady state 4 – 5 days
Protein binding 15 %
80 % drug eliminated unchanged in urine
Rest metabolised to inactive compounds in
liver
TOPIRAMATE
3. Any interactions with other drugs ?
• Topiramate levels decreased by concomitant
administration of carbamazepine, phenytoin and
phenobarbital
• Phenytoin level increased by topiramate
TOPIRAMATE
4. What is the dosage ?
• Start with 25 mg / day
• Increase dose by 25 – 50 mg every fortnight
• Maximum dose 200 mg bd (rarely 300 mg bd)
TOPIRAMATE
5. What are the indications ?
• Second line drug for
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Partial seizures
Secondary generalised seizures
GTCS
Atonic seizures
Lennox Gastaut syndrome
• Second line drug for
– Migraine
– Trigeminal neuralgia
TOPIRAMATE
6. What are the contraindications ?
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Renal dysfunction
History of presence of renal calculi
Pregnancy
Glaucoma
(ensure adequate fluid intake to decrease risk
of renal calculi)
TOPIRAMATE
7. What are the side effects ?
• Confusion, impaired concentration, memory difficulty,
mental slowing, word finding difficulty
• Fatigue, somnolence, headache
• Agitation, emotional lability, depression, paresthesiae
• Anorexia, nausea, diarrhea, weight loss
• Leucopenia
• Nystagmus, ataxia, diplopia, tremor
• Renal stones
• Adverse effects reduced by slow titration of drug
TOPIRAMATE
8. Formulations, Cost, Brands ?
25, 50, 100 mg
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Epitome (Triton)
Topiram (Zydus)
Topaz (Intaz)
Topiral (Symbiosis)
Topirate (Stimulus)
Topamate (Cipla)
Nextop (Torrent)
100 mg
Rs 14 / -
TOPIRAMATE
9. What are the main advantages ?
• Weight loss (especially when valproate
causes weight gain)
• Powerful antiepileptic effect, sometimes
effective when all other AED’s are
ineffective
TOPIRAMATE
10. What are the main disadvantages ?
• Cost
• Weight loss
• Side effects
ZONISAMIDE
ZONISAMIDE
1. How is it different from other AEDs ?
It is a sulfonamide derivative chemically
distinct from others
ZONISAMIDE
2. What is the mechanism of action ?
Multiple
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Inhibits voltage gated sodium channel
Affects T type calcium currents
Affects excitatory glutaminergic transmission
Binds to benzodiazepine GABA – A receptor
ZONISAMIDE
3. What are the indications ?
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Partial seizures
Generalised seizures
Lennox Gastaut Syndrome
Infantile spasm
Atypical absences
Progressive myoclonic epilepsy
(Licenced for monotherapy and adjunct therapy in Japan
Licenced for adjunct therapy in refractory partial epilepsy
only in USA, UK and Europe)
ZONISAMIDE
4. What are the formulations and brands ?
25, 50 and 100 mg capsules
Zonisep (Synergy)
Zonimide
ZONISAMIDE
5. What is the pharmacokinetics ?
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Oral bioavailability < 100 %
Time to peak levels 2 – 4 hours
Elimination half life 50 – 70 hours
Protein binding 30 – 60 %
Biotransformation: Acetylation, Reduction,
Glucuronidation
• Active metabolite - none
ZONISAMIDE
6. What are the drug interactions ?
Half life of zonisamide reduced by
phenytoin to
45 %
carbamazepine to
65 %
phenobarbitone to
65 %
valproate to
75 %
ZONISAMIDE
7. What is the dosage ?
• Adults:
– Initial 25 mg bd
– Maintenance 100 – 400 / day
– Maximum 600 mg / day
• Children:
– Initial 2 – 4 mg / kg / day
– Maintenance 4 – 8 mg / kg / day
• Dosing interval:
– 1 – 2 times / day
• Half life is long on monotherapy but considerably reduced in
adjunctive therapy
ZONISAMIDE
8. What are the side effects ?
Impaired
concentration
Mental slowing
Insomnia
Drowsiness
Fatigue
Irritability
depression
Ataxia
Dizziness
Diplopia
Nausea
Vomiting
Anorexia
Weight loss
Renal calculi
Abdominal
pain
Skin rashes
Itching
Oligohydrosis
Risk of heat stroke
especially in infants and
young children
ZONISAMIDE
9. What are the contraindications ?
• Renal failure
• Pregnancy
• Lactation
ZONISAMIDE
10. What are the main advantages ?
• Broad spectrum of action
• Specially useful in Lennox Gastaut syndrome,
infantile spasms, progressive myoclonic
epilepsy
ZONISAMIDE
11. What are the main disadvantages ?
• Side effects