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 ?

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 300 mg Rs 3 / Rs 5 / -

600 mg

Rs 10 / -

OXCARBAZEPINE

8. Name some proprietary preparations.

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 ?

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 ?

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 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 ?

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 ?

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
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 ?

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
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 ?

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

Partial seizures Secondary generalised seizures GTCS Atonic seizures Lennox Gastaut syndrome

Second line drug for

Migraine Trigeminal neuralgia

TOPIRAMATE

6. What are the contraindications ?

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
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 AEDs 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
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 ?

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 ?

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 Renal calculi Abdominal pain

Drowsiness Fatigue Irritability depression

Skin rashes Itching Oligohydrosis

Ataxia Dizziness Diplopia

Nausea Vomiting Anorexia Weight loss

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