parkinsons Flashcards
what are some anti-parkinson drugs?
Levodopa (w/Carbidopa) Entacapone Tolcapone Bromocriptine Selegiline (Deprenyl) Rasagiline Benztropine Trihexyphenidyl Pramipexole Ropinirole Rotigotine Amantadine Apomorphine Biperiden Procyclidine M30 (under development)
what are the extrapyramidal tracts for and where are they found?
The extrapyramidal tracts are chiefly found in thereticular formationof theponsandmedulla, and target neurons in the spinal cord involved in reflexes, locomotion, complex movements, and postural control. These tracts are in turn modulated by various parts of the central nervous system, including thenigrostriatal pathway, thebasal ganglia, thecerebellum, thevestibular nuclei, and different sensory areas of thecerebral cortex. All of these regulatory components can be considered part of the extrapyramidal system, in that they modulate motor activity without directly innervating motor neurons.
From Wikipedia
what is the extra-pyramideal motor system?
involved in regulation of fine motor activity
directs the stimulation and inhibition of antagonistic muscle groups allowing smooth and coordinated movement
EPS output reflects a balance between dopamine-mediated inhibition and acetylcholine-mediated excitation of GABA output neurons
when dopamine inhibition becomes deficient, due to the death of SN neurons (or presence of dopamine antagonists) acetylcholine excitation is unchecked and GABA output becomes excessive
the dopamine / acetylcholine balance can be restored by augmenting dopamine inhibition or by reducing acetylcholine excitation
what is the pathway for the parkinson stuff?
glutamatergic input from cortex goes to the putamen and dopaminergic input from the SNc goes to the putamen. In the putamen there are D1 and D2 pathways. The D1 pathways is the direct pathway that enables movement. The D2 is the indirect pathway that inhibits movement.
In Parkinsons disease, the direct pathway is inhibited because of loss of D1 stimulation and the indirect pathway is activated both of which lead to reduced movement.
what is parkinsons disease?
a neurodegenerative disorder of the central nervous system in the elderly
what are the symptoms of parkinsons disease?
Symptoms motor Akinesia - can’t initiate movement Bradykinesia - slow movement, shuffle muscle rigidity - stiff limbs, trunk tremor at rest - pill rolling mask-like faces - face is expressionless cogwheel locomotion (cogwheel rigidity - an abnormal rigor in muscle tissue characterized by jerky movements when the muscle is passively stretched. The condition is often found in cases of Parkinson's disease.)
Other
many patients have cognitive (dementia) and mood (depression) symptoms as well in later stages
what is the neuropathology of parkinsons disease?
death of dopamine cell bodies in the substantia nigra
loss of dopamine nerve terminals in the neostriatum, i.e., caudate nucleus, globus pallidus, and putamen (basal ganglia)
when about 80% of original number of dopamine neurons in the substantia nigra have died, the symptoms appear (may take decades)
dopamine neurons continue to die and symptoms progressively worsen
what is about dopamine for treatment of parkinson disease?
Dopamine replacement therapy
dopamine cannot cross the BBB (5 times more mitochondria)
levodopa (l-dopa), the immediate precursor of dopamine, is actively transported across the BBB and taken up by surviving dopamine neurons
restores the dopamine / acetylcholine balance and normal output of the extrapyramidal motor system (i.e., smooth coordinated movement)
what are adverse effects of levodopa?
Adverse effects of levodopa
levodopa is metabolized by aromatic amino acid decarboxylase into dopamine which is metabolized by dopamine beta hydroxylase into noradrenaline which is metabolized by phenylethanolamine-N- methyltransferase into adrenaline.
taking levodopa increases the levels of dopamine, noradrenaline and adrenaline in the periphery as well as in the brain.
Peripheral effects
stimulation of noradrenaline and adrenaline receptors increases SNS activity leading to hypertension, tachycardia and arrhythmias
stimulation of dopamine receptors in chemoreceptive trigger zone produces nausea and vomiting (CTZ outside the blood brain barrier)
Central effects
over-stimulation of dopamine receptors in meso-limbic areas produces psychosis
stimulating dopamine receptors in the pituitary inhibits prolactin release (not big problem for elderly Parkinson’s patients)
over-stimulation of dopamine receptors in motor control areas produces abnormal motor movements (dyskinesias)
stimulating noradrenaline receptors in the reticular activating system and limbic system produces insomnia and anxiety
what are the limiting adverse effects of l-dopa?
peripheral side effects reduced/prevented by l-dopa with peripheral decarboxylase inhibitor such as carbidopa (Sinemet®) or benserazide (Prolopa®)
carbidopa and benserazide inhibit aromatic amino acid decarboxylase, but do not cross the BBB
entacapone (Comtan®) inhibits peripheral COMT
given with l-dopa and carbidopa (Stalevo®) or with Prolopa® to prevent metabolism of l-dopa by COMT
This reduces fluctuations in plasma l-dopa levels and improves overall control of Parkinson disease
selegiline, an MAO-B inhibitor, inhibits the breakdown of dopamine (lowers dose necessary for l-dopa)
You need to give dopamine with the MAO-B inhibitor to slow the breakdown of dopamine into the toxic byproducts.
(look at the diagram in notes)
what are dopamine receptor agonists?
bromocriptine, T1/2 about 5 hours, is an agonist at dopamine receptors that improves symptoms of Parkinson’s disease when added to l-dopa plus carbidopa or benserazide
pramipexole (Mirapex®), ropinirole (ReQuip®) and rotigotine (Neupro) are newer DA agonists with fewer side effects than bromocriptine
what is anti-cholinergic therapy about?
the imbalance can also be restored by muscarinic acetylcholine antagonists such as benztropine (Cogentin®) or trihexyphenidyl.
what does anti-oxidant therapy have to do with anything?
oxidative stress seems to be responsible for the death of dopamine neurons in the substantia nigra, but so far, there is no evidence that anti-oxidants help
At diagnosis, the patient has already lost over 80% of the dopamine neurons and the dopamine neurons continue to die. Eventually, levodopa stops working.
To prevent Parkinson’s disease, “pre-symptomatic” diagnosis is crucial
In addition to being an MAO-B inhibitor, selegiline also has some neuroprotective actions. Numerous neuroprotective drugs are under development.
Rasagiline, MAO-B inhibitor, is new and improved propargylamine that has been shown to increase free radical scavengers and inhibit apoptosis with less side effects associated with breakdown products (opposed to selegiline- neurotoxic methamphetamine metabolite)
