Transcript Parkinson’s Disease
Drugs Used to Treat Parkinson’s Disease
By Jasmine and Morgan 11/13/03
Parkinson’s Disease subtypes
• Idiopathic Parkinson’s disease (unknown origin) – Primary • Parkinsonism – Secondary (known origin) – drugs, stroke, trauma • Familial – (genetic origin)
Subclinical hypodopaminergic state of 80-90% of DA neurons before symptoms present (roughly 20 years) - loss 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
Substantia Nigra, Normal. Pigment Loss Is Seen In Parkinson's Disease
Rodent Brain A9 System
• 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
Cardinal Symptoms
Bradykinesia - Slowness and poverty of movement Muscle “Cogwheel” rigidity Resting tremor Abates during voluntary movement Shuffling gait Impairment of postural balance
Secondary Symptoms
Dementia Visuospatial deficits, impaired attention and executive function Anxiety Sleep disturbances Sexual dysfunction Abnormal theromregulation
Therapy
see 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
Problems Associated with L-Dopa
Decrease high levels of DA in periphery that can cause nausea by inhibiting dopa decarboxylase which converts dopa to DA Carbidopa – Peripheral decarboxylase inhibitor Carbidopa/ levodopa combo reduces the amount necessary for therapeutic level of L-Dopa by 75%
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)
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
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)
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)
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
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
Dopaminergic substantia nigra neurons continue to die, until they’re all gone.