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Drugs Used to Treat Parkinson’s Disease

By Jasmine and Morgan 11/13/03 . Drugs Used to Treat Parkinson’s Disease . Parkinson’s Disease subtypes. Idiopathic Parkinson’s disease – Primary (unknown origin) Parkinsonism – Secondary (known origin) – drugs, stroke, trauma Familial – (genetic origin).

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Drugs Used to Treat Parkinson’s Disease

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  1. By Jasmine and Morgan 11/13/03 Drugs Used to Treat Parkinson’s Disease

  2. Parkinson’s Disease subtypes Idiopathic Parkinson’s disease – Primary (unknown origin) Parkinsonism – Secondary (known origin) – drugs, stroke, trauma Familial – (genetic origin)

  3. Subclinical hypodopaminergic state - loss of 80-90% of DA neurons before symptoms present (roughly 20 years) • DA neuronal loss not from Basal Ganglia - loss of dopaminergic input to Striatum • Neuronal death observed in Substantia Nigra (Pars Compacta) and the Nigrastriatal bundle • A9 DA System • DA content decrease in extra pyramidal motor areas of basal ganglia • Caudate and putamen

  4. Substantia Nigra, Normal. Pigment Loss Is Seen In Parkinson's Disease

  5. Rodent Brain A9 System

  6. 1 % Prevalence in Adult Population- Age 65 and Older • As many as 10% aged 60 and older may have undiagnosed early stages of the disease • Increased onset due to • Transitory Ischemic Attacks (TIA) • Brain Damage • Drug Abuse • 1 ½ times more prevalent in women

  7. Cardinal Symptoms • Bradykinesia - Slowness and poverty of movement • Muscle “Cogwheel” rigidity • Resting tremor • Abates during voluntary movement • Shuffling gait • Impairment of postural balance

  8. Secondary Symptoms • Dementia • Visuospatial deficits, impaired attention and executive function • Anxiety • Sleep disturbances • Sexual dysfunction • Abnormal theromregulation

  9. Therapysee table18.2 pg534 • Levodopa (L-dopa) • Rapid oral absorption – 95% converted to DA in plasma • DA doesn’t cross BBB from plasma into CNS • Precursor L-dopa does cross BBB via active transport system (about 5%) • Most effective current treatment

  10. Problems Associated with L-Dopa • Decrease high levels of DA in periphery that can cause nausea • by inhibiting dopadecarboxylasewhich converts dopa to DA • Carbidopa – Peripheral decarboxylase inhibitor • Carbidopa/ levodopa combo reduces the amount necessary for therapeutic level of L-Dopa by 75%

  11. Problems Associated with L-Dopa • Even with carbidopa, much of L-Dopa converted by COMT (in GI tract and Liver) to inactive metabolic by-product • Recent addition of peripheral COMT inhibitors to standard treatment – Talcapone and Entacapone • Increase the half-life and prolong the effects of L-Dopa • A few cases of serious liver toxicity attributed to Talcapone (1998) – Entacapone too new to say (2000)

  12. Limitations to L-dopa Therapy • Becomes less effective as time goes on • “on-off”/ “wearing off” effect • between 1-5 yrs patients on L-dopa therapy gradually become less responsive • Results in hypermovement, then hypomovement, then no movement (akinesia) • Taking doses more often, or taking large doses results in dyskinesias (uncontrolled movements) and may result in psychiatric complications. • On-off effect possibly related to DA neurons inability to synthesize and store DA

  13. DA Receptor Agonists • Bind to postsynaptic striatal neurons • Possible use for early and late stages • Four currently available • Bromocriptine (1978) and Pergolide (1989) • Derived from lysergic acid, structurally similar to DA • Marginally effective with numerous side effects • Affinity for D2 receptors (Inhibitory)

  14. DA Receptor Agonists • Pramipexole and Ropinirole (1997) • Affinity for D3 receptors (Inhibitory) • Indicated for use in early onset • Increased safety and efficacy over older agonists (although risk of sleep attacks) • Long half lives may partially explain reduction in on-off effect • Side effects: hallucinations, insomnia, nausea, somnolence and dizziness. • Long term use of DA agonists results in increased sensitivity of DA receptors (sensitization)

  15. Additional Therapies • Selegiline • Selectively inhibits MAO-B (preferential affinity for DA neurons) • Used in newly diagnosed, younger patients • Appears to slow disease progression and delay need for L-Dopa • Metabolized to several by-products, including amphetamine and methamphetamine • In combo with L-Dopa, may result in increased morbidity after 5 years

  16. Additional Therapies • Muscarinic Receptor Antagonists • Widely used before L-Dopa • Still used as an adjunct to L-Dopa for severe tremors • Cognitive dysfunction limits their use • Experimental Brain Surgery • Lesions (thalamus and GPi) • Neural tissue implants (fetal substantia nigra neurons) • Transplantation of carotid body glomus cells (secrete DA) to the putamen

  17. Dopaminergic substantia nigra neurons continue to die, until they’re all gone.

  18. Thank You ……now it’s your turn Q&A!!!

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