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Drug treatment in Epilepsy

Drug treatment in Epilepsy. Martin Reed Pharmacy QEPH Miriam Wilcher. 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

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Drug treatment in Epilepsy

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  1. Drug treatment in Epilepsy Martin Reed Pharmacy QEPH Miriam Wilcher

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

  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

  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

  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

  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

  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

  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

  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

  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

  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

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

  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

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

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

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

  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

  18. Other Mechanisms • Valproic acid • Gabapentin • Piracetam • Levetiracetam

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

  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)

  21. 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 hasweak carbonic anhydrase activity

  22. Choice of antiepileptic 1

  23. Choice of antiepileptic 2

  24. 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

  25. 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

  26. 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

  27. 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

  28. 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%

  29. 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

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

  31. 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

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

  33. 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

  34. 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

  35. 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)

  36. 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

  37. 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

  38. 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

  39. 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)

  40. 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

  41. 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

  42. 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

  43. 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

  44. 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.

  45. 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

  46. 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)

  47. 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

  48. 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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