Parkinson's Disease Flashcards
etiology of PD?
unknown.
Loss of neurons in the substantia nigra which provide dopaminergic innervation to the striatum.
describe dopamine synthesis…
originates from tyrosine -> transport across BBB into the dopamine neuron via system L in a Na-independent manner.
tyrosine -[tyrosine hydroxylase]-> DOPA -[DOPA decarboxylase]-> dopamine.
what is the rate-limiting step in dopamine synthesis?
tyrosine hydroxylase
what receptors are abundant in the striatum?
D1 receptors: increase adenylyl cyclase
D2 receptors: decrease adenylyl cyclase, increase K conductance, decrease Ca conductance.
what is the pathophysiology of PD?
Dopa neurons from the substantia nigra normally inhibit the GABAergic output from the striatum, whereas cholinergic neurons stimulate it.
in PD, there is destruction of the neurons of the nigrostriatal pathway responsible for secreting dopa in the striatum -> loss of control of muscle movement.
what are the strategy of tx for PD?
restoring dopa in the basal ganglia and antagonizing the excitatory effect of cholinergic neurons; reestablishing the correct dopa/Ach balance.
what are the drug categories that restore dopa actions?
- dopamine precursors
- dopamine receptor agonists
- inhibitors of dopamine metabolism
- amantadine
what is the drug category for antagonists of Ach?
- antimuscarinics
what is the dopamine precursors?
levodopa
- levodopa
chemistry?
steroisomer of dopa.
metabolic precursor of dopa (and NE).
restores dopa levels in extrapyramidal centers.
what happens in early stage of DP with levodopa?
late stage?
number of residual dopaminergic neurons in the substantia nigra is enough for conversion of levodopa to dopa.
late stage, number of neurons decreased and there are few cells capable of taking up levodopa and converting it to dopa -> motor control fluctuation develops -> relief by levodopa is only symptomatic and lasts only while the drug is present in body.
Levodopa
MOA?
- dopa does not cross BBB, much is decarboxylated to dopa int he periphery.
- transported into the CNS and converted to dopa in the brain
levodopa
peripheral s.e?
nausea
vomiting
cardiac arrythmias
hypotension
Carbidopa
MOA?
- dopa decarboxylase inhibitor that does not cross BBB.
- given in combo c levodopa to decrease metabolism of levodopa in the GI and peripheral tissues -> increase availability to the CNS.
what is sinemet?
dopa prep containing carbidopa and levodopa (1:10 or 1:4).
Levodopa
PK?
absorbed rapidly from the small intestine.
food delays appearance in plasma.
certain a.a can compete c the drug for absorption from the gut and for transport from the blood to brain.
levodopa
metabolism?
levodopa -[COMT]–> 3-o-methyl dopa
dopamine -[COMT]–> 3-methoxytyramine -[MAO, aldehyde DH]–> 3-methoxy 4-hydroxyphenylacetate (HVA)
dopamine -[MAO, aldehyde DH]–> 3,4-dihydroxyphenylacetate (DOPAC) -[COMT]–> HVA
levodopa/carbidopa
clinical uses?
- efficacious drug regimen for PD
- decline in response during the 3rd to 5th yr of therapy.
- levodopa does not stop progression, but early initation of levodopa therapy lowers mortality d/t the disease.
What is Wearing-Off rxns (end-of-dose akineasia)?
fluctuations related to the timing of levodopa intake.
What is the on-off phenomenon?
- fluctuations in response unrelated to the timing of doses.
- mechanism is unknown
- pts c severe off-periods who are unresponsive to other measures, apomorphine SC may provide benefit.
levodopa
interactions?
- vit b6 is a cofactor of Dopa decarboxylase: increases periph metabolism of levodopa
- concomitant adm of nonspecific MAO inhibotrs = precipitate htn crisis.
- should not give to psychotic pts = exacerbate the mental disturbance.
levodopa
contraindications?
- angle-closure glaucoma
- cardiac pts should be carefully monitored b/c of possible arrythmias
- antipsychotic drugs = produce a parkinsonian syndrome.
what is the benefit of dopamine receptor agonists?
don’t require enzymatic conversion for activity, therefore they do not depend on the functional capacities of the nigrostriatal neurons.
what are the two dopamine receptor agonist categories?
- ergot dopamine agonists
2. nonergot dopamine agonists
what is an ergot dopamine agonist?
bromocriptine: D2 agonist
what are some nonergot dopamine agonists?
- pramipexole
- ropinirole
- rotigotine
dopamine agonists
GI A.E?
anorexia nausea and vomiting constipation dyspepsia bleeding from peptic ulceration
dopamine agonists
Cardiovascular A.E?
postural hypotension
cardiac arrythmias
peripheral edema
ergot derivatives may cause painless digital vasospasm.
dopamine agonists
CNS A.E?
dyskinesias
mental disturbances: confusion, hallucination, delusion.
dopamine agonists
miscellaneous A.E?
ergot dopamine agonists:
- pulmonary infiltrates
- pleural and retroperitoneal fibrosis
- erythromelalgia
Pramipexole, ropinirole, rotigotine:
-uncontrolled somnolence
dopamine agonists
contraindications?
- psychotic illness
- recent MI
- peripheral vascular disease
- peptic ulceration
what is a nonergot dopamine agonists rescue therapy?
apomorphine
apomorphine
uses?
tx of “off” episodes of akinesia in pts on dopaminergic therapy.
apomorphine
A.E?
emetogenic; pretx c an antiemetic is rec’d.
QT prolongation dyskinesias drowsiness sweating hypotension bruising at injxn site
what are the two inhibitors of dopamine metabolism?
- Monoamine oxidase inhibitors
2. Catechol-o-methyltransferase inhibitors
what are the monoamine oxidase inhibitors?
- deprenyl (selegiline)
2. Rasagiline
deprenyl (selegiline)
MOA?
selective/irreversible inhibits MAO-B -> retards breakdown of dopamine in brain.
enhances effect of levodopa (can reduce dosage c combo)
used adjunct to levodopa.
deprenyl (selegiline)
A.E?
metabolized to methamphetamine and amphetamine: may cause insomnia if taken late in the day.
rasagiline
MOA?
MAO-B inhibitor
what happens to COMT when given carbidopa to inhibit Dopa decarboxylase?
compensation activation of COMT pathway -> increases plasma levels of 3-o-methydopa -> competes c levodopa for an active carrier that transports levodopa across the intestinal mucosa and BBB.
what are the two COMT inhibitors?
- tolcapone
2. entacapone
- tolcapone
- entacapone
effects?
- decreased metabolism of levodopa
- decreased plasma levels of 3-o-methyldopa
- increased uptake of levodopa
- higher dopamine levels in brain.
- tolcapone
- entacapone
A.E?
tocapone: fulminating hepatic necrosis
entacapone: not hepatotoxic (preferred).
Amantadine
what is it?
antiviral drug c antiparkinsonian actions.
Amantadine
MOA?
increases synthesis, release or re-uptake of dopamine from the surviving neurons.
less efficacious than levodopa and tolerance develops more readily, but few s.e’s.
Amantadine
A.E?
restlessness
agitation
confusion
hallucinations
high dose: acute toxic psychosis
peripheral edema - response to diuretics
livedo reticularis
Amantadine
contraindications?
pts c a hx of seizures or HF.
What is the use of antimuscarinics in PD?
- adjuvant therapy.
- improve tremor and rigidity, little on bradykinesia
antimuscarinics
A.E?
mood changes xerostomia pupillary dilation confusion hallucinations urinary retention
antimuscarinics
contraindications?
pts c glaucoma, prostatic hypertrophy or pyloric stenosis
what is PD choice of tx?
best: levodopa + carbidopa
next best: dopamine agonists
addition of a COMT inhibitor or a MAO-B inhibitor to levodopa can reduce motor fluctuations in pts c advanced disease
antimusc can be useful addition to levodopa for control of tremor and drooling
parkinson characteristics?
resting tremor
muscular rigidity
bradykinesia
gait impairment
