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movement disorders and dopaminergic drugs (levodopa (adverse effects (GI…
movement disorders and dopaminergic drugs
Parkinson's disease
2nd most common chroni neurodegenerative disorder and the 3rd most common movement disorder.
affects 1% of population >50 yrs
loss of dopaminergic neurons in the SN lead to DA depletion
causes lack of stimulation of D1 receptors in the direct pathway and loss of inhibition of D2a receptors in the indirect pathway
threshold for PD symptoms is with neuronal loss of >80%
cardinal features (TRAP)
tremor
rigidity
akinesia
postural instability
drugs
MAO-B inhibitors
selegiline, rasagiline
amantadine
dopamine agonists
pramipexole,ropinirole, apomorphine
catechol-0-methyltransferase inhibitors
tolcapone, entacapone
levodopa
anticholinergics
benztropine, trihexyphenidyl
dopamine in the CNS
dopaminergic and cholinergic striatal interneurons modulate GABA-ergic output to the substantia nigra
direct pathway
excitatory output to motor regions of cerebral cortex
indirect pathway
reduces excitatory output and acts to balance neuronal signals for smooth, purposeful movements
dopamine, ACh, GABA, glutamate, and serotonin play a role in the process
balance of DA and ACh is important
selegiline and rasagiline
MAO-I
segaline is a MAO-A metabolized NE, 5-HT, and DA
block breakdown of DA it prolongs its effects in the basal ganglia
adverse effects, nausea, dizziness, abdominal pain
rasagiline is a MAO-B metabolizes only DA
amantadine
antiviral agent found to posses antiparkinsonian activity, may influence the synthesis, release, and/or reuptake of dopamine
adverse effects include, restlessness, insomnia, dry mouth, vivid dreams
anticholinergics
restore balance between DA and ACh
trihexyphenidyl, benztropine, biperiden
most useful as monotherapy in younger patients with marked tremor
adverse effects: dry mouth, constipation, urinary retention, blurred vision, cognitive impairment
Dopamine agonist
directly stimulate D1,D2, and D3 receptors
drugs
ergot derived
bromocriptine (parlodel)
pergolide (permax)
non-ergot derived
pramipexole (mirapex)
ropinirole (requip)
effective as monotherapy in early PD, also used in restless leg syndrome
apomorphine (apokyn)
injectable, acute treatment of hypermobility episodes associated with advanced PD, lasts about an hour, pre treat with anti-emetic
ADR: nausea, postural hypotension, sudden onset of sleep, pathologic gambling and other compulsive behaviors, pleuropulmonary fibrosis and cardiac valvulopathy
levodopa
most effective drug for symptomatic treatment of PD
precursur of dopamine
kinetics
absorption in the GI tract depends on rate of gastric emptying, and Ph of gastric contents
food delays absorbtion and protein in meals may compete for absorption
high doses of L-dopa are required if administered alone, if given with dop-decarboxylase inhibitor may reduce by 75%
carbidopa improves facilitation of ll-dopa into the CNS
sinemet
dosage form
duopa intestinal gel
approved for motor fluctuations in late PD administered over 16 hours
levodopa metabolism
adverse effects
GI
nausea and vomiting
cardiovascular
postural hypotension,syncope,tachycardia,arrhythmias
behavioral
depression, anxiety, agitation, insomnia
fluctuations in response
"on-off" ,response wearing off effect, dyskinesias
malignant melanoma
levodopa is a precursor for skin melanin use caution if at all with patient with history
COMT inhibitors
MOA block conversion of L-dopa, extending its effects, and allows for a dose reduction tolcapone (tasmar), entacapone (comtan)
drug induced parkinsons
drugs that have dopamine antagonist activity may induce PD
agents
older antipsychotics
metoclopramide
dose dependent