Drugs in Epilepsy Modified 03.11.2010

8/6/2019 Drugs in Epilepsy Modified 03.11.2010

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New Formulations of

Antiepileptic Drugs for

the Management of Epilepsy

Prepared By: Dr. Rahul Arora

Under Guidance ofProf. Dr. G.G. Mansharamani


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Earlier studies suggested that manypatients respond to monotherapy but

fewer and fewer patients respond tocombination therapy.

AED Response Established AEDs

Monotherapy

70%controlled*

30% poorly

managed

30% controlled* on

2 drugs

Combinations of two ormore drugs provide littlemore benefit

1. Mattson, 1992

* Controlled was defined as adequately managed but not

necessarily seizure-free


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AED Response

Newer is Not Always Better 525 untreated patients (470 drug-native)

1st Monotherapy

2nd Monotherapy

60% controlled*

40%

difficult to

control

3rd

Monotherapy

1% controlled*

99% not

controlled

Only 3% were controlled with two AEDs, and

none with three.1. Brodie & Kwan, 2002

*Controlled was defined as seizure-free


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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 andsafety

Most used as adjunctive therapy21. Yoon & Jagoda, 20002. Brodie & French, 2000


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Treatment Goals

No seizures

No side effects

Monotherapy Once daily dosing

No blood tests


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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 toxicityappears (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


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Compliance

For a drug to be effective it has to be

taken

Non compliance is an important issue inpoor 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 opener2 Enhance GABA transmission

GABA uptake inhibitor

GABA mimetics3 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 inexcitable cells and membranes

Examples:

PhenytoinCarbamazepine

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 A and GABA B

Inhibitory neurotransmitter

GABA A post synaptic; 7 classes

Dependent upon chloride and bicarbonateions

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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4

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

Partial simple &Partial complex

Carbamazepine

PhenytoinValproate

Lamotrigine

GabapentinLevetiracetam

Topiramate

Tiagabine

Oxcarbazepine

Phenobarbital


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Choice of antiepileptic 2

Seizure type Drug of choice Alternatives

Generalised

tonic clonic

Carbamazepine

PhenytoinValproate

Lamotrigine

TopiramatePhenobarbital

Absence Ethosuximide

Valproate

Lamotrigine

Clonazepam

Atypical absence

Atonic,

myoclonic

Valproate Clonazepam


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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 breastmilk (40% plasma level)

t MAX 4 to 8 hours Indicated for

All forms of seizures except absence and myoclonicseizures


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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 secondarygeneralised tonic-clonic seizures

Auto induces own metabolism slow escalation

V

ariable half life25

-65

initially8

-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


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


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)


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


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 secondarilygeneralised 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


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


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


Therapeutic plasma concentration 40 to 40micromoles/L


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


300 to 600 micromoles/L


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




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 givenwith enzyme inducing drugs


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Vigabatrin 1

Dose




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 after2-6hours

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 1989

Lamotrigine 1991

Gabapentin 1993

Tiagabine Topiramate 1995

Levetiracetam 2000

Fosphenytoin 2001

Zonisamide 2005


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others

Felbamate

Aplastic anaemia

Liver failure

Remacemide

Piracetam


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Documents

Drugs in Epilepsy Modified 03.11.2010