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Drugs for parkinsonism and dementia

Drugs for parkinsonism and dementia. Parkinsonism: summary. Diverse causes. Variable natural history. Main features: Bradykinesia Rigidity Coarse tremor Festinating gait. Aims of treatment. Prolong life Parkinsonism ultimately kills (often through respiratory infection).

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Drugs for parkinsonism and dementia

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  1. Drugs for parkinsonism and dementia

  2. Parkinsonism: summary • Diverse causes. • Variable natural history. • Main features: • Bradykinesia • Rigidity • Coarse tremor • Festinating gait

  3. Aims of treatment • Prolong life • Parkinsonism ultimately kills (often through respiratory infection). • No drug has yet been shown to affect mortality. • Restore function for as long as possible

  4. Dopaminergic neurone Receptors

  5. Idiopathic Parkinsonism: too little dopamine

  6. Drug-induced Parkinsonism: presence of antagonist (e.g. neuroleptic drugs)

  7. Promote dopamine D’amine precursor Direct agonists  metabolism Commonly used for idiopathic P Oppose acetyl choline Direct antagonists Mainly for drug-induced disease Strategies, in a nutshell

  8. Dopaminergic drugs • Direct agonists: ropinirole etc. • Levodopa • Enzyme inhibitors: • MAO-B inhibitors: selegiline. • COMT inhibitors: entacopone • Other drugs

  9. Dopamine agonists • Ropinirole • Pergolide • Cabergoline • Bromocryptine • Lisuride Ergot derivatives Ergot is a fungus that makes several vasoactive amines like ergotamine

  10. Dopamine agonists: adverse effects • GI upset • Neuropsychiatric – confusion and hallucinations • ERGOT DERIVATIVES: Fibrotic reactions: pulomonary, pericardial and retroperitoneal fibrosis. Uncommon.

  11. Dopamine agonists: clinical use • Ropinirole may be treatment of choice for younger patients. • Small starting dose, small dose increments, withdraw slowly. • May be used with levodopa in advanced cases.

  12. Levodopa • Dopamine does not cross the BBB • L-dihydroxy-phenyl-alanine (Levodopa; L-DOPA) is a precursor. • Levodopa does cross the BBB. • BUT…….

  13. Metabolised to dopamine: GOOD L-DOPA Metabolised to dopamine: BAD

  14. Enzyme inhibitor X Dopamine: GOOD Dopamine: BAD

  15. Levodopa + carbidopa • Levodopa crosses BBB and  dopamine • Carbidopa does not cross BBB. • Carbidopa inhibits peripheral production of dopamine.

  16. Levodopa pharmacokinetics • Absorbed by a ‘facilitated carrier’ mechanism. • Amino acids compete for transport. • Bioavailability reduced after meals. • Extensive first pass. • Short half life.

  17. Levodopa adverse effects • GI upset • Dyskinesias (choreo-athetosis, facial tics, dystonia and others). • Erratic response – probably related to rapid changes in dopamine delivery. ‘On-off phenomenon’. • Cardiovascular: postural hpyotension is common. (Paradoxically) levodopa may worsen hypertension.

  18. Levodopa: clinical use. • Probably still among first-line choices, especially for older patients. • May be added to dopamine agonists for advanced disease. • More adverse effects than dopamine agonists. • Small starting dose and small dose increments. • Intervals between doses may need to be short in some patients.

  19. Monoamine-oxidase inhibitors • MAO-A inhibitors – relevant to depression. • MAO-B inhibitors – e.g. selegiline. • MAO-B metabolises dopamine. • Selegiline is used with levodopa to reduce ‘end-of-dose’ problems. • GREAT CAUTION if there is postural hypotension

  20. Catechol-o-methyltransferase inhibitors • COMT metabolises levodopa. • Entacapone and tolcapone inhibit COMT. • COMT inhibition peripherally increases available Levodopa for the brain. • COMT inhibition in the brain ‘diverts’ levodopa towards dopamine. • Used as an adjunct to levodopa. • GI upset; rarely hepatitis.

  21. Drugs for dementia

  22. NICE guidelines • Alzheimers should be diagnosed by a specialist unit. • Treatment should be started by specialists. • Assessment 2-4 months after maintenance dose established. • Reassessment every 6-months in specialist unit.

  23. Basic pharmacodynamics. • Loss of neuronal function. • All the drugs are cholinesterase inhibitors, and merely potentiate this one transmitter. • This is a pretty CRUDE approach to treatment. • But it can achieve modest improvement in cognition

  24. Acetylcholinesterase • An enzyme of the synaptic cleft. • Terminates acetyl-choline. • Anticholinesterases are traditionally used for: • Reversal of depolarising muscle relaxants in GA. • Management of myasthenia gravis. • E.g. Neostigmine, pyridostigmine etc.

  25. Anticholinesterases for Alzheimers • Donepezil, galantamine, memantine, rivastigmine. • The ‘traditional’ drugs gain negligible entry to the CNS (they are mainly needed peripherally). • Anticholinesterases potentiate acetylcholine in the periphery, e.g.: • Bradycardia • Increased gastric secretion - ulcer

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