New Formulations of Antiepileptic Drugs for the Management of Epilepsy

Prepared By: Dr. Rahul Arora Under Guidance of Prof. Dr. G.G. Mansharamani

AED Response Established AEDs

Earlier studies suggested that many patients respond to monotherapy but fewer and fewer patients respond to combination therapy.
70% controlled* Monotherapy 30% poorly managed 30% controlled* on 2 drugs Combinations of two or more drugs provide little more benefit

* Controlled was defined as adequately managed but not necessarily seizure-free

1. Mattson, 1992

AED Response Newer is Not Always Better

525 untreated patients (470 drug-native)
60% controlled*
1st Monotherapy 2nd Monotherapy 3rd

1% controlled* 40% difficult to control

Monotherapy

99% not controlled

*Controlled was defined as seizure-free

Only 3% were controlled with two AEDs, and none with three.
1. Brodie & Kwan, 2002

Newer AEDs
Similar effectiveness to established AEDs in the treatment of partial seizures All AEDs have adverse effects1 Not appropriate for all seizure types1 Possible teratogenicity2 Limited data available for efficacy and safety Most used as adjunctive therapy2
1. Yoon & Jagoda, 2000 2. Brodie & French, 2000

Treatment Goals
No seizures No side effects Monotherapy Once daily dosing No blood tests

What actually happens

70% seizure free with one drug
With careful monitoring and adjustment

5% to 10% seizure free with two or more drugs 20% still have seizures
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Principles of pharm. treatment 1

Use the right drug for the seizure type Use one drug and increase the dose until a therapeutic effect is gained or toxicity appears (maximum tolerated dose) Monitor treatment including blood levels If required add a second drug.
If a response consider slowly removing the first drug
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Principals of pharm.treatment 2
If monotherapy fails use two drugs
Review and replace the combinations used

Add in a third drug if necessary Be prepared to accept that a significant reduction in seizure frequency maybe as good as it gets

Compliance
For a drug to be effective it has to be taken Non compliance is an important issue in poor control Patients must be fully involved in decisions Patients views must be respected Better knowledge and respect leads to better compliance
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Why dont patients comply?

Poor communication Poor memory Poor understanding of instructions Mis-information Side effects Poor dose regimes Difficult to swallow/nasty taste medication

Good information makes medicines work

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When should levels be monitored?

Uncontrolled seizures Recurrence of seizures Side effects Assessment of compliance Confirmation of desired results Assessment of therapy when seizures infrequent Minor dose adjustments Concurrent illness
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But
Blood concentrations are a guide only Timing of sample important Never look at the blood level in isolation Always consider blood level with respect to:
Side effects Seizure frequency

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Modes of action
1 Suppress action potential Sodium channel blocker or modulator Potassium channel opener 2 Enhance GABA transmission GABA uptake inhibitor GABA mimetics 3 Suppression of excitatory transmission
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Sodium channels
Main target for many drugs Sodium channels are responsible for the rising phase of the action potential in excitable cells and membranes Examples:
Phenytoin Carbamazepine Oxcarbazepine Lamotrigine
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Potassium channels
Very diverse group of ion channels Responsible for resting potential Influences excitability of neurones Determine potential width

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GABA and GABA

Inhibitory neurotransmitter GABA A post synaptic; 7 classes

Dependent upon chloride and bicarbonate ions

GABA B pre and post synaptic

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GABA A Transmission
Barbiturates
primidone

Benzodiazepines
Clobazam, clonazepam, diazapam

Tiagabine Vigabatrin

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Calcium channels
Four main types
L, P/G, N; high voltage T; low voltage Mono amines modulate the circuit Nifedipine blocks L

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Calcium channels
T type
Ethosuximide, zonisamide

L type
Barbiturates, felbamate

N type
Lamotrigine, barbiturates , oxcarbazepine

P/Q type
Lamotrigine, oxcarbazepine
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Glutamate
Major excitatory transmitter
Mainly intracellular

Three receptor types

NMDA
Associated with sodium and calcium ions Magnesium ions block Other messengers act at NMDA site

AMPA and kainate receptors metabotropic

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Other Mechanisms
Valproic acid Gabapentin Piracetam Levetiracetam

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Sites of action 1
Valproate, vigabatrin, tiagabine increase GABA by inhibiting reuptake (2) and preventing breakdown within the cell (3) Benzodiazepines bind to GABA receptors (4) Phenobarbital opens chloride channels (4) Topiramate blocks sodium channels and is a GABA agonist at some sites (4)
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Other modes of action

Gabapentin, has similar structure to GABA Phenytoin,carbamazepine,oxcarbazepine, lamotrigine, act on sodium channels Ethosuximide, reduces calcium currents Levetiracetam, has neuroprotective effect Topiramate, acetazolamide, are carbonic anhydrase inhibitors Zonisamide has weak carbonic anhydrase activity
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Choice of antiepileptic 1
Seizure type Drug of choice Alternatives Carbamazepine Lamotrigine Partial simple & Phenytoin Gabapentin Partial complex Valproate Levetiracetam Topiramate Tiagabine Oxcarbazepine Phenobarbital
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Choice of antiepileptic 2
Seizure type Generalised tonic clonic Absence Drug of choice Carbamazepine Phenytoin Valproate Ethosuximide Valproate Alternatives Lamotrigine Topiramate Phenobarbital Lamotrigine Clonazepam Clonazepam

Atypical absence Valproate Atonic, myoclonic

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Carbamazepine 1
Dose
200mg to 1600mg a day in divided doses

Therapeutic plasma concentration

4 to 12 micrograms per ml 20 to 50 micromoles/L Poor correlation between dose and plasma level in children Widely distributed in tissues, found in placenta and breast milk (40% plasma level) t MAX 4 to 8 hours

Indicated for
All forms of seizures except absence and myoclonic seizures
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Carbamazepine 2
Common side effects
Headache, drowsiness, dizziness, ataxia, double vision,

Serious effects
Osteomalacea, folate deficency, peripheral neuropathy, water retention, hyponatraemia, rash, blood dyscrasias-leucopaenia

Comments
Drug of choice for partial seizures, primary or secondary generalised tonic-clonic seizures Auto induces own metabolism slow escalation Variable half life 25-65 initially 8-18 chronically Active metabolite Many drug interactions as enzyme inducer Can make myoclonus worse or appear to cause it
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Oxcarbazepine
Dose
600mg to 2400mg daily

Therapeutic plasma concentration Indicated for

Partial seizures with or without secondarily generalised tonic clonic seizures

Common side effects

As for carbamazepine less severe

Comments
Fewer drug interactions than carbamazepine
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Clonazepam 1
Dose
4 to 8 mg a day

Therapeutic plasma concentration

0.63 to 2.2 mmol/litre

Indicated for
Refractory absence and myoclonic seizures

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Clonazepam 2
Common side effects
Sedation, ataxia, behaviour problems, hyperactivity

Comments
Used for partial seizures Half life 18 to 50 hours Tolerance develops in 30%

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Clobazam
Dose
20 to 60mg a day

Indicated for
Refractory partial seizures Cluster seizures Seizures connected with periods

Common side effects

As for clonazepam

Comments
As for clonazepam
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Ethosuximide 1
Dose
500mg to 1500 mg daily

Therapeutic plasma concentration

300 -700 micromoles/L 50 -100 micrograms/L

Indicated for
Simple absence seizures

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Ethosuximide 2
Common side effects
Gastro intestinal upset, nausea, drowsiness, headache, behavioural changes, hiccups, skin rashes

Comments
Half life 50 to 60 hours in adults 30 to 40 hours in children Administered tds to reduce gastric upset
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Gabapentin 1
Dose
300mg to 2400mg daily (needs tds dose)

Therapeutic plasma concentration

Not established

Indicated for
Adjunctive treatment for refractory partial seizures

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Gabapentin 2
Common side effects
Drowsiness, dizziness, fatigue, ataxia, tremor, diplopia, nausea and vomiting

Comments
Excreted unchanged; 95% in urine Only 60% of dose absorbed Unaffected by food Seizure frequency may increase No common drug interactions Comparatively safe in overdose
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Lamotrigine 1
Dose
100 to 200mg monotherapy or with valproate 200mg to 400mg with enzyme inducers

Therapeutic plasma concentration

Not clinically relevant

Indicated for
All forms of seizures

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Lamotrigine 2
Common side effects
Dizziness, ataxia, double vision, nausea, somnolence Rash (worse in children) less if slow escalation

Comments
Complex interaction with valproate very slow escalation needed Indicated for partial seizures and secondarily generalised tonic clonic seizures Half life 25 hours shorter with enzyme inducers Excreted in breast milk Reasonably safe in overdose (10x)
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Levetiracetam
Dose
500mg to 3000mg

Therapeutic plasma concentration

Not relevant

Indicated for
Partial seizures, Generalised absences

Common side effects

Nausea, drowsiness, anorexia, headache, rash, Very rarely leucopenia

Comments
No drug interactions described
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Phenobarbital 1
Dose
90 to 600mg daily

Therapeutic plasma concentration

60 to 160 micromoles /L 20 to 40 micrograms/ml

Indicated for
All forms of seizures except absence seizures

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Phenobarbital 2
Common side effects
Sedation (tolerance develops), headache, hyperkinesia (old & young) slurred speech, skin reactions, cognitive impairment

Comments
Dependency; needs very, very slow withdrawal Interactions - increases valproate effect; -enzyme inducer, reduces effects of many other drugs - Half life 2 to 7 days - Can cause folate deficiency
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Primidone
Dose
50mg to 1500mg daily

Therapeutic plasma concentration

No clinical relevance

Indicated for
All form of seizures except absence seizures

Common side effects

As for phenobarbital

Comments
Metabolised to phenobarbital and phenyethylmalonamide (PEMA)
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Phenytoin 1
Dose
150mg to 600mg daily

Therapeutic plasma concentration

40 to 40micromoles/L 10 to 20 micrograms/ml t MAX 4 to 12 hours

Indicated for
All forms of seizures except absence seizures

Common side effects

Dizziness, nausea, skin rashes, gum tenderness, hirsutism in females, peripheral neuropathy, tremor, ataxia, osteomalacia, folate deficiency
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Phenytoin 2
Comments
Zero order kinetics small increase in dose can cause large increase in levels Plasma levels mandatory Many drug interactions including other AEDs Enzyme inducer Metabolised in the liver Half life 22 hours
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Sodium valproate/valproic acid 1

Dose
600mg to 2400mg daily

Therapeutic plasma concentration

300 to 600 micromoles/L 50 to 100 micrograms/ml But of little clinical value

Indicated for
All forms of epilepsy
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Valproic acid/sodium valproate 2

Common side effects
Nausea, gastrointestinal irritation, drowsiness, ataxia, weight gain & also anorexia, alopecia. Rare but serious impaired liver function thrombocytopenia

Comments
Half life 10 to 20 hours, reduced with polytherapy GI upset reduced by enteric coating Interacts with lamotrigine and phenobarbital
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Tiagabine 1
Dose
30 to 45 mg daily with enzyme inducers 15 to 30mg daily without enzyme inducers

Therapeutic plasma concentration

Not relevant

Indicated for
Adjunctive treatment for refractory partial seizures

Common side effects

Diarrhoea, dizziness, tiredness, concentration difficulties, emotional changes, speech impairment.
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Tiagabine 2
Comments
Short half life (4 to 10 hours) Used when add on therapy is required Efficacy reduced by enzyme inducing AEDs Reduces plasma concentration of sodium valproate

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Topiramate 1
Dose
200mg to 800mg daily

Therapeutic plasma concentration

Not clinically relevant

Indicated for
Adjunctive treatment for refractory partial seizures

Common side effects

Nausea, abdominal pain, anorexia, cog. impairment, mood disorders (can be aggressive in LD)
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Topiramate 2
Comments
Watch for weight loss and depressive psychosis Ensure adequate hydration; increased risk of kidney stones. Avoid carbonic anhydrase inhibitors e.g. acetazolamide Half life 18 to 30 hours reduced where given with enzyme inducing drugs

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Vigabatrin 1
Dose
2000mg to 3000mg daily

Therapeutic plasma concentration

Not clinically relevant

Indicated for
Adjunctive treatment for refractory generalised tonic clonic and partial seizures

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Vigabatrin 2
Common side effects
Drowsiness, confusion, irritability, fatigue Visual field defects Psychotic experiences

Comments
Irreversible inhibitor of GABA transaminase Short half life irrelevant to dosing regime

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Zonisamide 1
Dose
100mg/day increased every 2 weeks to max of 400mg higher doses in presence of enzyme inducers Peak plasma after 2-6hours delayed by food but total absorbed not affected. Steady state 14days Low plasma protein binding but bound to erythrocytes

Indicated for partial seizures

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Zonisamide 2
Contra indications : sulfonamide hypersensitvity Cautions:
Renal impairment - excreted in urine Tendancy to kidney stones - advise plenty of fluids Co-administration with enzyme inducers Avoid in pregnancy possibly teratogenic

Very Common Side effects - Agitation, confusion, dizziness, somnolence,

double vision

Common side effects - Diarrhoea, nausea, anorexia, rash

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Zonisamide 3
Serious but rare effects:
Blood dyscrasias, panreatitis Hallucinations, psychosis

Comment:
- New drug - monitor

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Drugs to be used with care

Aminophylline Amphetamines Analgesics Antibiotics Antidepressants Antimuscarinics Antipsychotics Baclofen Bupropion Donepezil etc Cyclosporin Cocaine Isoniazid Lignocaine Mefloquine NSAIDs Opioids Oral contraceptives Vincristine

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Drug history
Phenobarbitone 1912 Phenytoin 1938 Primidone 1952 Ethosuximide 1955 Carbamazepine 1965 Sod. Valproate 1973 Valproic acid 1993 Clonazepam 1974 Clobazam 1979 Vigabatrin Lamotrigine Gabapentin Tiagabine Topiramate Levetiracetam Fosphenytoin Zonisamide 1989 1991 1993 1995 2000 2001 2005

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others
Felbamate
Aplastic anaemia Liver failure

Remacemide Piracetam

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