Anti-epilepsy Agents

1. Anti-epilepsy Agents Dr Andrew Mallon

2. Aims • To describe the pathophysiology of epilepsy • To determine the pharmacological agents used • Mechanism of action • Contra-indications • Adverse effects • Patient management

3. Introduction • 1 person in 20 will have an epileptic seizure at some time in their life • Epilepsy is diagnosed on the basis of two or more epileptic seizures. • Around 450,000 people in the UK have epilepsy (40 million people worldwide) • A seizure is triggered by a sudden interruption in the brain's highly complex electro-chemical activity (National Society for Epilepsy UK)

4. Age/Incidence

5. Brain • 100 billion neurons • Control centre: • temperature • sensory input • motor control • emotion • thought? • body functions Taken from OUP Illustration Resource, 2002

6. Gross anatomy Front part of the brain; involved in planning, organizing, problem solving, selective attention, personality and a variety of "higher cognitive functions" including behavior and emotions.

7. Gross anatomy The parietal lobes contain the primary sensory cortex which controls sensation (touch, pressure).

8. Gross anatomy Region in the back of the brain which processes visual information.

9. Gross anatomy These lobes allow a person to distinguish smells and are believed to be responsible for short-term memory.

11. Structure

12. Action Potential

13. Synapse Activity

14. Seizures are a symptom of an underlying CNS dysfunction • It is an abnormal, uncontrolled electrical discharge from neurons • Cell membrane disruptions (permeability) • Altered ion distributions (chemical balance) • Decreased neurotransmitters (Ach and GABA) • Everyone has seizure threshold

15. Classification of Seizures • Partial: • Simple partial seizures (no loss of consciousness) • With motor symptoms • With sensory symptoms • With autonomic symptoms • Only involve 1 hemisphere • Complex partial (loss of consciousness) • Simple followed by loss of consciousness • Impaired at the onset Dependant on which area of the brain

16. Unclassified: • Classification not possible to problems with diagnosis – suspected • Generalised (affect whole brain with loss of consciousness): • Clonic, tonic (1min) or tonic-clonic (2-4min): muscle spasm (extensors), respiration stops, defecation, salivation, violent jerks

17. Myoclonic: seizures of a muscle or group of muscles • Absence: Abrupt loss of awareness of surroundings, little motor disturbance, mostly children • Atonic: loss of muscle tone/strength

18. Pathological Basis • Abnormal electrical discharge in the brain • Coordinated activity among neurons depends on a controlled balance between excitation and inhibition • Any local imbalance will lead to a seizure • Imbalances occur between glutamate-mediated excitatory neurotransmission and gamma-aminobutyric acid (GABA) mediated inhibitory neurotransmission • Generalised epilepsy is characterised by disruption of large scale neuro-networks in the higher centres.

19. Normal Processes • Depolarising Na+ and Ca++ ionic current shifts are activated by glutamate receptors • Repolarising K+ currents are mediated by GABA receptors • Hyperpolarisation is mediated by GABAa receptors creating an influx of Cl- => inhibition of impulse generation.

20. Any defect causes the neuron to be closer to the all or none threshold for an AP = HYPEREXCITABLE STATE. • Leading to instability between excitation and inhibition => Epilepsy

21. Other possible causes • Inherited mutations of proteins involved in the ion channels • Reduction in the activity of homeostatic ATPase pumps within neuron cell membranes

22. Basis of Pharmacological Rx Most anti-epileptic agents act either by blockade of depolarisation channels (Na+ and Ca++) OR Enhancing the activity of GABA (neurotransmission inhibition)

23. 5 Categories of Anti-epileptic Drugs • All classifications are based upon chemistry: • Hydantoins • Succinimides • Benzodiazepines • Barbiturates • Miscellaneous

24. Hydantoins - Phenytoin (Dilantin) • Use for pts with Tonic-Clonic seizures • Acts to promote intracellular removal of sodium during the refractory period • Antagonism (blocking) of Na+ channels to reduce excitability • Antagonism of Ca++ channels • Potentiation (activation) of GABA receptors to promote the inhibitory role of GABA • Can be used in the Rx for neuropathic pain and cardiac arrhythmias

25. Pharmacokinetics: • Slowly absorbed from gut, use a slow IV if rapid action is required • Avoid IM – muscle damage • Eliminated by hepatic biotransformation • Can measure amount of free agent in the saliva

26. Cautions: hepatic impairment, pregnancy, breast-feeding; • avoid sudden withdrawal; • Blood or skin disorders • Adverse effects:  nausea, vomiting, mental confusion, dizziness, headache, tremor, transient nervousness, insomnia occur commonly; rarely dyskinesias, peripheral neuropathy; ataxia, slurred speech, nystagmus and blurred vision are signs of overdosage; rashes (discontinue; if mild re-introduce cautiously but discontinue immediately if recurrence), gingival hypertrophy and tenderness, coarse facies, acne and hirsutism, fever and hepatitis; lupus erythematosus, Stevens-Johnson syndrome, toxic epidermal necrolysis, polyarteritis nodosa; lymphadenopathy; rarely haematological effects, including megaloblastic anaemia (may be treated with folic acid), leucopenia, thrombocytopenia, agranulocytosis, and aplastic anaemia; plasma-calcium concentration may be lowered (rickets and osteomalacia) • Dose: • By mouth, initially 3–4 mg/kg daily or 150–300 mg daily (as a single dose or in 2 divided doses) increased gradually as necessary (with plasma-phenytoin concentration monitoring); usual dose 200–500 mg daily (exceptionally, higher doses may be used); child initially 5 mg/kg daily in 2 divided doses, usual dose range 4–8 mg/kg daily (max. 300 mg) • Contraindications: increases metabolism of the contraceptive pill, anti-coagulants, and pethidine

27. Succinimides – Ethosuximide (Zarontin) • Use for pts with Absence seizures • Acts by antagonising Ca++ channels in the thalamocortical relay neurons => prevention of synchronised neuronal firing => raising AP threshold

28. Pharmacokinetics: • Almost complete absorption from the gut • Extensive metabolism in the liver with a long half-life (2-3 days) • Plasma and salivary concentrations correlate well for monitoring purposes

29. Cautions: hepatic and renal impairment; pregnancy and breast-feeding; • avoid sudden withdrawal • Blood disorders (review) • Adverse effects:  gastro-intestinal disturbances, weight loss, drowsiness, dizziness, ataxia, dyskinesia, hiccup, photophobia, headache, depression, and mild euphoria. Psychotic states, rashes, hepatic and renal changes (see Cautions), and haematological disorders such as agranulocytosis and aplastic anaemia occur rarely (blood counts required if signs or symptoms of infection); systemic lupus erythematosus and erythema multiforme (Stevens-Johnson syndrome) reported; other side-effects reported include gum hypertrophy, swelling of tongue, irritability, hyperactivity, sleep disturbances, night terrors, inability to concentrate, aggressiveness, increased libido, myopia, vaginal bleeding • Dose: • adult and child over 6 years initially, 500 mg daily, increased by 250 mg at intervals of 4–7 days to usual dose of 1–1.5 g daily; occasionally up to 2 g daily may be needed; child up to 6 years initially 250 mg daily, increased gradually to usual dose of 20 mg/kg daily • Contraindications: may make tonic-clonic seizures worse

30. Bensodiazepines – Clorazepam (Klonopin), Diazepam (Valium) • Act by potentiating the actions of GABA causing neurotransmission inhibition (primarily in the CNS) • Can be used to induce sleep (high dose), anticonvulsant therapy and reduction in muscle tone.

31. Pharmacokinetics: • Well absorbed from the gut • Lipid soluble to ensure ready prentration of the blood brain barrier • Metabolised in the liver to create active agents (prolonged therapeutic action) • Slow elimination from body

32. Eg Clonazepam • Cautions: elderly and debilitated, respiratory disease, spinal or cerebellar ataxia; history of alcohol or drug abuse, depression or suicidal ideation; myasthenia gravis; porphyria; hepatic impairment; renal impairment; pregnancy; breast-feeding • Contra-indications:  respiratory depression; acute pulmonary insufficiency; sleep apnoea syndrome; marked neuromuscular respiratory weakness including unstable myasthenia gravis • Adverse effects:  drowsiness, fatigue, dizziness, muscle hypotonia, co-ordination disturbances; also poor concentration, restlessness, confusion, amnesia, dependence, and withdrawal; salivary or bronchial hypersecretion in infants and small children; rarely gastro-intestinal symptoms, respiratory depression, headache, paradoxical effects including aggression and anxiety, sexual dysfunction, urinary incontinence, urticaria, pruritus, reversible hair loss, skin pigmentation changes; dysarthria, and visual disturbances on long-term treatment; blood disorders reported; overdosage: • Dose: • 1 mg (elderly 500 micrograms) initially at night for 4 nights, increased according to response over 2–4 weeks to usual maintenance dose of 4–8 mg daily in 3–4 divided doses; may be given as a single daily dose in the evening once maintenance dose established; max. 20 mg daily; child up to 1 year, initially 250 micrograms increased as above to usual maintenance dose of 0.5–1 mg, 1–5 years, initially 250 micrograms increased as above to 1–3 mg, 5–12 years, initially 500 micrograms increased as above to 3–6 mg

33. Barbiturates – Phenobarbital (Luminal) • Used for tonic-clonic seziures. • Act by increasing the duration of Cl- ion channel opening by activating neuronal GABAa receptors • Causing hyperpolarisation of the AP, making it less likely to fire again • Essentially, acts like GABA and can even potentiate the effects of GABA when present.

34. Pharmacokinetics: • Almost complete absorption • Elimination is by heptic and renal (25% excreted unchanged) • Biotransformed in the liver into 2 active metabolites • Plasma concentrations relate poorly to seizure control, use only for monitoring of patient compliance.

35. Adverse effects: • CNS effects (sedation and fatigue) • Restlessness/Hyperactivity • Folate deficiency • Tolerance • Dependence with physical withdrawal reactions • Adverse drug-drug reactions (contraception and warfarin). • Contraindications: Do not use with patients with respiratory depression, children or elderly. • NOTE: low therapeutic index means more toxic and overdose can have serious consequences

36. Miscellaneous Agents – Carbamazepine (Tegretol) • Used in most epilepsy types. • MoA not fully understood but believed to be related to: • Antagonist action of Na+ channels to inhibit repetitive neuronal firing • Decreasing the production (or release) of glutamate (excitatory chemical) • Can also be used in the Rx of neuropathic pain

37. Pharmacokinetics: • Slow and incomplete absorption • Metabolised in the liver – creates an expoxide metabolite that can have a weak therapeutic effect • Relatively long half-life (1-2 days) • Potency decreases overtime therefore need to increase dose to ensure adequate control of seizures • Plasma and salivary concentrations correlate well to clinical effectiveness

38. Adverse effects: • Nausea & vomiting (especially early Rx), constipation, diarrhoea and anorexia • Skin irritation • CNS toxcity – dizzy, drowsy, confusion • Bone marrow depression (rare) • Drug-drug reactions (contraception, warfarin) • Contraindications: see drug-drug reactions.

39. Sodium Valproate • Use in all forms of epilepsy, as it suppresses the initial seizure discharge and its spread. • Clinical actions are: • Antagonism of Na+ and Ca++ channels • Potentiation of GABA • Attenuation of Glutamate • Can be fast acting due to Na+ MoA, although the full Rx effect usually takes weeks.

40. Pharmacokinetics: • Well absorbed from gut (should be taken with food to counteract gastric irritation) • Extensively metabolised in the liver • Rapidly transported across the blood brain barrier • Monitor plasma concentration for patient compliance only

41. Adverse effects: • GI upset (Nausea, vomiting, anorexia, abdominal pain and diarrhoea) • Weight gain (appetite stimulation) • Transient hair loss • Tremor • Coma (rare) • Thrombocyptopenia (platelets) • Oedema • Severe hepatotoxicity (liver damage) • Contraindications: People with liver damage or a history hepatic dysfunction

42. Vigabatrin • Only used in conjunction with other agents when pt becomes resistant (due to tolerance) or poorly tolerates • Effective in partial epilepsy but with restricted used due to severe adverse effects (vision) • MoA: completely different to other agents as it is a structural analogue of GABA that the enzyme that normally inactivates GABA will degrade instead of GABA. • More GABA available to inhibit neuron transmission

43. Pharmacokinetics: • Rapidly absorbed from the gut • Unchanged by renal processes • Intermediate half-life (hrs) • Blood concentrations are of no value.

44. Adverse effects: • Sedation, fatigue, dizziness, nervousness, irritability, depression, impaired concentration. tremor (CNS effects) • Psychotic reactions (check pt history) • Visual defects after prolonged use • Weight gain and oedema

45. Lamotrigine (Lamictal) • Used for partial seizures in adults only • Acts by the inhibition (antagonism) of neuronal Na+ channels but is highly selective (onlu neurons that synthesise glutamate and aspartate) • Additionally, decrease glutamate release • Pharmacokinetics: well absorbed, extensively metabolised in the liver and has a long half-life.

46. Adverse effects: • Fever, influenza-like symptoms • Skin irritation • GI disturbances (vomiting, diarrhoea) • CNS effects (drowsiness, headache, dizziness, double vision) • Contraindications: Pts with hepatic impairment

47. Gabapentin (Neuronitin) • Used for partial seizures in adults • Designed to be a structural analogue of GABA but it does not mimic GABA in the brain. • Acts via: • Increased synthesis and release of GABA • Decrease degradation of GABA • Inhibition of Ca++ channels

48. Pharmacokinetics: • Incompletely absorbed in the gut • Excreted unchanged via kidney processes • Short half-life • Adverse effects: • CNS effects (dizzy, drowsy, fatigue, headache, double visions) • Nausea and vomiting • Contraindication: be careful with sudden withdrawal in the elderly due to kidney effects and alterations in acid-base balance.

49. Anti-Parkinson Drugs Dr Andrew Mallon

50. Aims • To review pathogenesis of Parkinson's • To review clinical presentation • To identify treatment drugs