Pakinson's Disease and Movement Disorders Flashcards
(38 cards)
What are the hallmark signs of Parkinson’s Disease?
Repetitive pin-rolling; persistent tremor; shuffling gait; rigidity; bradykinesia; slowed speech; personality changes; sleep disorder; and cognitive decline.
Describe the basic pathophysiology behind Parkinson’s Disease:
Parkinson’s Disease is characterized by a state of low dopamine; this is caused by loss of dopaminergic neurons in the nigro-striatal pathway.
How do ACh and dopamine influence GABA release in the brain?
ACh promotes GABA release; whereas dopamine inhibits GABA release.
How does dopamine deficiency in Parkinson’s Disease have an impact on GABA levels?
Less dopamine in Parkinson’s disease means that there is an increase in GABA levels.
Why must exogenous supplementation involve dopamine’s immediate precursor (levodopa)?
Dopamine itself cannot cross the blood-brain-barrier.
What are some other barriers to the optimization of dopamine therapy?
There are a seres of enzymes that affect the use of dopamine and levodopa: DOPA decarboxylase; MAO; and COMT.
Describe the three peripheral pathways of levodopa:
(1) Cross the blood-brain-barrier via an amino-acid transporter, and enter the brain; (2) conversion to peripheral dopamine via DOPA decarbxylase; and (3) conversion to 3-OMD by COMT.
Why is it bad for levodopa to be converted to dopamine in the periphery by DOPA decarboxylase?
Dopamine in the periphery is bad – (1) this means less levodopa will make it into the brain to have a therapeutic effect; and (2) dopamine in the periphery is the source of many ADRs.
Why is is bad for levodopa to be converted to 3-OMD in the periphery by COMT?
This makes less levodopa available to cross the blood-brain-barrier and exert a therapeutic effect.
Why must high-protein meals be avoided within 30-60 minutes of taking levodopa?
Because levodopa crosses the blood-brain-barrier via an amino acid transporter; consumption of a high protein meal would create competition at this transporter and lessen the therapeutic effect of levodopa.
What are the possible pathways of levodopa once it crosses into the brain?
(1) Conversion to dopamine by DOPA-decarboxylase (desired); (2) or conversion to other metabolites by COMT or MAO-B (limits the therapeutic effect).
How does dopamine exert its therapeutic effect in the brain?
Dopamine acts on D2-receptors in the basal ganglia in order to control movement and posture; activation of other dopamine receptors can cause ADRs.
What are the therapeutic modalities fr treating Parkinson’s Disease?
(1) L-DOPA; (2) D2-agonists; (3) COMT/MAO-B inhibitors; and (4) muscarinic agonists.
What is Sinemet (levodopa/carbidopa)?
Levodopa plus a DOPA decarboxylase inhibitor (carbidopa), whch helps to limit ADRs by preventing the conversion of levodopa to peripheral dopamine.
What are the two types of D2-agonists?
(1) Ergo-derivative (bromocriptine); and (2) the non-ergot derivatives (pramipexole and ropinerole).
How do D2-agonists compare to L-DOPA?
They have fewer metabolic conversion concerns; better blood-brain-barrier penetration; more selective receptor activation; and less response fluctuation.
What is the most common use for D2-agonsts?
They are often used in combination with Sinemet to help reduce the required dose and limit ADRs; the non-ergot D2-agonsts may be used as monotherapy in mild PD, or for the treatment of restless leg syndrome.
Why is bromocriptine not commonly used in Parkinson’s Disease anymore?
It is an older drug, is not D2 selective, and has CYP3A4 interactions.
What are the current uses of bromocriptine?
Hyperprolactinemia; pituitary adenomas; cocaine withdrawal; and alcohol dependence.
What are the ADRs of D2-agonists?
GI upset, cardiovascular concerns, dyskinesias, and mental disturbances; use caution in those with psychotic tendencies, recent MI, or uncontrolled hypertension.
What percent of L-DOPA makes it into the brain?
Only 1-3%; this is why an enzyme inhibitor is necessary.
How is Sinemet typically dosed?
3-4 times a day; 30-60 minutes before meals; and with minimal protein intake – this creates compliance concerns.
What are the ADRs of Sinemet?
N/V (common; take with small meal); cardiovascular concerns due to the conversion of dopamine to norepinephrine (tachycardia/hypertension); depression, anxiety, and dyskinesia (very common).
What are the two types of response fluctuation seen with Sinemet?
(1) End-of-dose akinesia (doe wears off more quickly); and (2) on/off phenomenon (unrelated to dose-timing).
