drugs in epilepsy-PATEL

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Drug treatment in Epilepsy:

Drug treatment in Epilepsy P.MEGARAJ PATEL

Treatment Goals:

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

What actually happens:

3 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

Principals of pharmacological treatment 1:

4 Principals of pharmacological 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

Principals of pharmacological treatment 2:

5 Principals of pharmacological 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:

6 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

Why don’t patients comply?:

7 Why don’t 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

When should levels be monitored?:

8 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

But:

9 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

Modes of action:

10 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

Sodium channels:

11 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

Potassium channels:

12 Potassium channels Very diverse group of ion channels Responsible for resting potential Influences excitability of neurones Determine potential width

GABA A and GABA B:

13 GABA A and GABA B Inhibitory neurotransmitter GABA A post synaptic; 7 classes Dependent upon chloride and bicarbonate ions GABA B pre and post synaptic

GABA A Transmission:

14 GABA A Transmission Barbiturates primidone Benzodiazepines Clobazam, clonazepam, diazapam Tiagabine Vigabatrin

Calcium channels:

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

Calcium channels:

16 Calcium channels T type Ethosuximide, zonisamide L type Barbiturates, felbamate N type Lamotrigine, barbiturates , oxcarbazepine P/Q type Lamotrigine, oxcarbazepine

Glutamate:

17 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

Other Mechanisms:

18 Other Mechanisms Valproic acid Gabapentin Piracetam Levetiracetam

BUT:

19 BUT Why do persistent alterations in neuronal circuits or excitability result in a paroxysmal disorder like epilepsy?

Sites of action 1:

20 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 :

22 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

Choice of antiepileptic 1:

23 Choice of antiepileptic 1 Seizure type Drug of choice Alternatives Partial simple & Partial complex Carbamazepine Phenytoin Valproate Lamotrigine Gabapentin Levetiracetam Topiramate Tiagabine Oxcarbazepine Phenobarbital

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Choice of antiepileptic 2:

25 Choice of antiepileptic 2 Seizure type Drug of choice Alternatives Generalised tonic clonic Carbamazepine Phenytoin Valproate Lamotrigine Topiramate Phenobarbital Absence Ethosuximide Valproate Lamotrigine Clonazepam Atypical absence Atonic, myoclonic Valproate Clonazepam

Carbamazepine 1:

26 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

Carbamazepine 2:

27 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

Oxcarbazepine :

28 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

Clonazepam 1:

29 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

Clonazepam 2:

30 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%

Clobazam:

31 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

Ethosuximide 1:

32 Ethosuximide 1 Dose 500mg to 1500 mg daily Therapeutic plasma concentration 300 -700 micromoles/L 50 -100 micrograms/L Indicated for Simple absence seizures

Ethosuximide 2:

33 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

Gabapentin 1:

34 Gabapentin 1 Dose 300mg to 2400mg daily (needs tds dose) Therapeutic plasma concentration Not established Indicated for Adjunctive treatment for refractory partial seizures

Gabapentin 2:

35 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

Lamotrigine 1:

36 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

Lamotrigine 2:

37 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)

Levetiracetam:

38 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

Phenobarbital 1:

39 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

Phenobarbital 2:

40 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

Primidone :

41 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)

Phenytoin 1:

42 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

Phenytoin 2:

43 Phenytoin 2 Comments Zero order kinetics small increase in dose can cause large increase in levels Plasma levels (TDM) mandatory Many drug interactions including other AEDs Enzyme inducer Metabolised in the liver Half life 22 hours

Sodium valproate/valproic acid 1:

44 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

Valproic acid/sodium valproate 2:

45 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

Tiagabine 1:

46 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.

Tiagabine 2:

47 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

Topiramate 1:

48 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)

Topiramate 2:

49 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

Vigabatrin 1:

50 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

Vigabatrin 2:

51 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

Zonisamide 1:

52 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

Zonisamide 2:

53 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

Zonisamide 3:

54 Zonisamide 3 Serious but rare effects: Blood dyscrasias, panreatitis Hallucinations, psychosis Comment: - New drug - monitor

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Drug history:

56 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

others:

57 others Felbamate Aplastic anaemia Liver failure Remacemide Piracetam

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Drugs to be used with care:

59 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

Web sites:

60 Web sites www.BNF.org www.e-epilepsy.org.uk/ www.medicines.org.uk

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