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Anti-epileptics

Anti-epileptics. Charley Bruce. So… Epilepsy. “The Tendency to have recurrent seizures” A seizure is caused by abnormal electrical activity. Normal electrical activity is controlled by a balance between excitatory and inhibitory influences.

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Anti-epileptics

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  1. Anti-epileptics Charley Bruce

  2. So… Epilepsy • “The Tendency to have recurrent seizures” • A seizure is caused by abnormal electrical activity. • Normal electrical activity is controlled by a balance between excitatory and inhibitory influences. • In the brain these influences are mainly controlled by: • Glutamate - excitatory • GABA - Inhibitory • What does GABA stand for?... • Gamma-aminobutynic acid.

  3. Why is there abnormal activity?? • Structural changes • Increased number of excitatory axons • Loss of excitatory neurones whose specific action is to control inhibitory neurones. • Loss of inhibitory neurones • Ion channel dysfunction • Neurones left in a hyperexcitable state due to the membrane potential being closer to the threshold level. • This may be due to a reduction in activity of membrane-bound ATPases. MAINLY FOR GENERALISED SEIZURES - CAUSE OF PARTIAL SEIZURES UNKOWN

  4. Membrane potential

  5. Ok so we have the background.. Now the Meds. • They are prescribed according to the type of seizure… • Partial (focal) • Simple, complex, or secondary generalised • Generalised • Clonic, tonic, tonic-clonic, myoclonic, absence, atonic and unclassified. • Go through handout answers….

  6. Secondary generalised seizure Vs Primary generalised seizure. • Secondary generalised seizure (SGS) will present as a simple partial or complex partial seizure and then become generalised. • Primary generalised seizure will be generalised from the start. • Continue to next slides for details.

  7. The Drugs • Three first line drugs depending on type of seizure: • Carbamazepine • Sodium Valproate • Ethosuximide • Three main mechanisms • Blockade of Na+ channels • GABA receptor • Blockade of T-type Ca2+ channel

  8. Carbamazepine • Prodrug • Main indication – Partial seizures • Can be used for most types of epilepsy but NOT myoclonic or absences as it may exacerbate them. • Mechanism: • Blockade of Na+channels - Inhibits repetitive neuronal firing. • Reducesaction of glutamate at NMDA receptors, and reduces glutamate release - Reduced excitatory influence from glutamate. • Unwanted effects: • N&V, constipation, diarrhoea, anorexia, rashes (from generalised erythema to stevens-johnson), CNS toxicity (double vision, dizziness, drowsiness, confusion, ataxia), transient leucopenia. • Hyponatraemia– Potentiation of ADH. • Teratogenicity (neural tube defects) • Induction of hepatic CYP3A4 (therefore can reduce effectiveness of COCP, warfarin and ciclosporin)

  9. Sodium Valproate • Main indication – Primary GTCS or Myoclonic. • Suitable for all forms of epilepsy. • Mechanisms: • Potentiation of GABA, possibly by enhanced synthesis or release, and reduced degradation. • Blockade of Na+channels – most important mechanism • Attenuation of excitatory action of glutamate a NMDA receptors. • Inhibition of voltage-gated T-type Ca2+ channels • Activation of neuroprotective/neurotrophic intracellular proteins such as brain derived neurotrophic factor • Unwanted Effects: • GI upset • Weight gain – increased appetite • Transient hair loss – with regrowth of curly hair. • Ataxia, tremor, confusion and, rarely, encephalopathy and coma – minimise by slow dosage titration. • Rarely hepatotoxicity • Teratogenicity – neural tube defects. • Inhibition of cytochrome P450

  10. Ethosuximide • Main indication: Absence seizures • Can also be used for tonic or atonic seizures. • Mechanism: • Blocks T-type Ca2+ channels – prevents synchronised neuronal firing by reducing thalamocortical relay neuron activity. • Unwanted effects: • N&V, anorexia. • Drowsiness, dizziness, ataxia, dyskinesis, photophobia, headache and depression. • Rashes • Agranulocytosis and aplastic anaemia are rare. • Teratogenicity.

  11. Topiramate • Partial or generalised seizures • Mechanism: • Enhancement of GABA receptors – unknown mechanism • Blockade of Na+channels • Unwanted Effects: • CNS: Impaired concentration, cognative impairment, confusion, dizziness, ataxia, headache, agitation, emotional labilityor depression. • GI upset: N&V, abdo pain, anorexia, dry mouth, weight loss. • Acute angle-closure glaucoma (esp. 1st month)

  12. Lamotrigine • Partial and generalised seizures. • Mechanism: • Inhibits neuronal voltage-gated Na+ channels. • Selectively targets dendrites of pyramidal neurones and reduces glutamate release. • Unwanted effects: • Hypersensitivity syndrome – fever, rash, etc. • Rashes – mild to stevens-johnson. • N&V, diarrhoea. • CNS – drowsiness, headache, fatigue, dizziness, diplopia, ataxia; tremor at high doses. • Bone marrow suppression.

  13. Summary of Mechanisms • Blockade of Na+channels • Carbamazepine • Sodium Valproate • Lamotrigine • Phenytoin and Fosphenytoin • Blockade of T-type Ca2+ channels • Ethosuximide • GABA receptor enhancer • Topiramate

  14. Summary of Side Effects • Nearly all epileptic meds are/cause… • GI upset • Teratogenic • Have an effect on P450 • Affect metabolism of folic acid and vitamin D. • Cause problems with CNS – at least with toxicity or overdose.

  15. Name some AED’s that block Sodium Channels… • Carbamezepine • Sodium Valproate • Lamotrigine • Phenytoin

  16. Which AED would you use for absence seizures? • Ethosuximide

  17. Fill in the table… Carbamazepine Sodium Valproate Ethosuximide Sodium Valproate

  18. What would be the most appropriate medication for each case?... • A 24-year-old man with complex partial seizures. • First-line anti-epileptic in a 17-year-old girl with tonic-clonic seizures. She has the Depo-Provera injection for contraception. • Useful in patients with absence seizures who are intolerant of sodium valproate Carbamazepine Sodium Valproate – if pregnancy could be an issue lamotrigine would be better. Ethosuximide – silly passmedicine trying to trick you…(Davidson’s and Medical Pharmacology and Therapeutics have Ethosuximide 1st line and Sodium Valproate 2nd line.

  19. Name some common side effects of AED’s in general… • GI upset • CNS upset • Rashes • Teratogenicity • P450 issues

  20. Specific Side Effects.. • Which drug can cause hyponatraemia and how? • Which AED’s cause weight gain? • Which drug can cause bone marrow suppression? Carbamazepine – Potentiation of ADH in the kidney. Sodium Valproate (+Gabapentin) Lamotrigine

  21. The End

  22. Phenytoin and Fosphenytoin(Prodrug of Phenytoin) • Effective for most types (except absences) • Mechanisms: • Blockade of Na+channels • blockade of voltage-gated L-type Ca2+ channels –also reduces repetitive neuronal firing. • Potentiation of GABA and GABAA receptors – increases inhibitory influence. • Unwanted effects: • N&V, constipation, anorexia • CNS effects – impaired brainstem and cerebellar function (confusion, dizziness, tremor, nervousness, insomnia. Nystagmus, blurred vision, ataxia & dysarthria = overdose) • Chronic connective tissue effects: gum hypertrophy, coarse facial features, hirsutism, acne. (Avoid in young women and adolescents) • Rashes • Increased folic acid metabolism – megaloblastichaemopoiesis (anaemia rare) • Increased Vit D metabolism • Teratogenicity – Facial and digital malformations. • Induction of hepatic cytochrome P450 – warfarin, ciclosporin.

  23. Gabapentin and pregabalin • For partial seizures (with or without 2nd generalisation) • Mechanism: • Gabapentin is a structural analogue of GABA but it does NOT mimic GABA in the brain. • Mechanism is unclear but may involve a blockade of P/Q-type voltage-gated Ca2+ channels in the neocortex and hippocampus. - This may reduce the Ca2+ entry into neurones and inhibit release of excitatory neurotransmitters such as glutamate. • Unwanted effects: • N&V, dry mouth, diarrhoea, constipation, abdo pain. • CNS – drowsiness, dizziness, ataxia, fatigue, headache, tremor, diplopia, confusion, mood swings. • Weight gain – appetite stimulant. • Rhinitis, cough, dyspnoea. • Myalgia and Arthralgia. • Rashes.

  24. Phenobarbital and Primidone • Mechanism: • Acitates the postsynaptic neuronal GABAA receptors – increases duration of opening for Cl- channel, therefore hyperpolarising the membrane potential. • Unwanted effects: • CNS: sedation, fatigue and memory impairment for adults; paradoxical excitement, confusion and restlessness for elderly; and hyperactivity in children. • Increased folic acid metabolism – megaloblastichaemopoiesis. • Increased Vit D metabolism – osteomalacia (rare) • Tolerance • Dependence – with physical withdrawal symptoms • Induction of hepatic cytochrome P450 – increased metabolism of COCP, warfarin, ciclosporin. • Primidone – less well tolerated.

  25. http://jw1.nwnu.edu.cn/jpkc/jwc/2009jpkc/rtkx/jp.htm

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