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Parkinsons Disease
- 21. Additional information to read later Parkinson-plus syndromes:
Editor's Notes
- VCP3042; 1st August 2008 [email_address] Slightly more Caucasians and males Like Alzheimer’s disease, the incidence of PD is lower in smokers Death – medical complications 12-15 years or 1-3 years… variable Mutations in Alpha synuclein and Parkin genes May be induced by drugs or toxins (e.g. MPTP), and major tranquillizers cause extrapyramidal side effects, e.g. neuroleptics; manganese and CO produce extrapyramidal effects Exposure to pesticides increased risk for developing PD by 70% (Ascherio et al., 2006). Neuromelanin; oxidation of DA Increased Fe2+ in SN, decreased transferrin = increased oxidation Increased lipid peroxidation
- VCP3042; 1st August 2008 [email_address] Start low and go slow! Education, physical and speech therapy, dietary modifications In Australia, l-dopa is not available without peripheral DDC inhibitors Anti-cholinergics will worsen dementia M receptor antagonists, e.g. benzatropine; modest effect, only used at the beginning to delay l-dopa; better for tremor D-dopa not converted to dopamine in vivo, and causes granulocytopaenia
- VCP3042; 1st August 2008 [email_address] L-dopa effectiveness gradually declines as time progresses (2-5 years) (may rely on presence of functional dopaminergic neurones) Converted and metabolised in gut and in plasma by DDC, MAO, COMT Carbidopa and benserazide inhibit aromatic L-amino acid decarboxylase , which converts L-DOPA into , which cannot cross the BBB. Awakenings. It tells the true story of British neurologist Oliver Sacks, fictionalized as American Malcolm Sayer and portrayed by Robin Williams who, in 1969, discovers beneficial effects of the then-new drug L-Dopa. He administered it to catatonic patients who survived the 1917-1928 epidemic of encephalitis lethargica. Encephalitis lethargica or von Economo disease is an atypical form of encephalitis. Also known as "sleepy sickness" or as "sleeping sickness" (though different from the sleeping sickness transmitted by the tsetse fly), it was first described by the neurologist Constantin von Economo in 1917.[1][2] The disease attacks the brain, leaving some victims in a statue-like condition, speechless and motionless.[3] Between 1915 and 1926,[4] an epidemic of encephalitis lethargica spread around the world; no recurrence of the epidemic has since been reported, though isolated cases continue to occur.[5][6]
- VCP3042; 1st August 2008 [email_address] Diminished window between wanted effect – reduced rigidity – and unwanted effect – dyskinesia (involuntary writhing) On-off effect – fluctuat es from being symptom free to having full blown symptoms Implementation of drug holidays is controversial
- VCP3042; 1st August 2008 [email_address] Peripheral dopa decarboxylase inhibitors p enetrate only weakly into CNS, therefore stop conversion in periphery only; reduce dose by ¼ or a 1/5 th , reduce dopamine-induced emesis Inhibitors of dopamine degradation in the CNS by MAO, s elective for MAO B (CNS – lacks peripheral side effects); may retard progression of disease (protecting against free-radical induced neurotoxicity and apoptosis) Inhibitors of dopamine degradation in the periphery by COMT, e.g. entacepone (peripheral only); tolcapone is able to penetrate the CNS When you have a peripheral decarboxylase inhibitor this shifts the metabolism of L-dopa to the COMT pathway; COMT converts L-dopa to 3-O-methyldopa, compete with L-dopa to cross the BBB (may also contribute to the development of motor dysfunctions) Increase the amount of L-dopa available to cross the blood brain barrier Antagonists of peripheral dopamine receptors (reduce side effects)
- VCP3042; 1st August 2008 [email_address] Redressing the balance between dopaminergic and cholinergic neurons appears to be some compensation for the overall deficit in dopamine function
- Amantadine – less effective; better for bradykinesia and rigidity; some patients develop tachyphylaxis – drug holiday
- Bromocriptine: D2 receptor agonist, mild D1 receptor antagonist Pergolide: D1/D2 receptor agonist, more potent and longer acting