Parkinson's Disease Flashcards
What is Parkinson’s Disease?
PD is a progressive neurological disorder principally of muscle movement, but also has non-motor symptoms
No cure for motor symptoms, but drug therapy can maintain functional mobility for years. (Prolong and improve QOL)
“Lewy Body” aggregates are a hallmark pathological finding
Loss of Substantia Nigra Neurons
How does Dopamine play a role in Parkinson’s Disease?
Normally: Dopamine inhibits the indirect pathway and stimulates the direct pathway, yielding a net bias that allows purposeful movement.
Parkinson’s Disease: Degeneration of dopaminergic neurons in the substantia nigra results in under stimulation of the direct (movement-enabling) pathway and under inhibition of the indirect (movement-inhibiting) pathway.
Etiology of Parkinson’s Disease
10-15% of cases have a specific genetic correlate
The majority are considered “sporadic”
- Oxidation
- Malfunctioning protein degradation pathways
- Mitochondrial Dysfunction
Cardinal Features of PD
- Tremor at rest
- Rigidity
- Bradykinesia / Akinesia
- Postural instability
In addition:
• Autonomic disturbances
• Depression & sleep disturbances
• Psychosis and dementia
MOTOR SIGNS & SYMPTOMS OF PD
- Bradykinesia
- Rigidity
- Rest tremor
- Postural instability: Balance impairment affecting a person’s ability to change
or maintain postures such as walking or standing; typically a late Parkinson disease feature
PD Drug Treatment Goals
Therapeutic goals:
The ideal treatment (i.e. to reverse neuronal degeneration or prevent further degeneration) does not yet exist.
The goal now is to improve patient’s ability to carry out activities of daily life.
Drug selection and dosages are determined by the extent to which PD interferes with work, dressing, eating, bathing, etc. AND by the appearance of adverse drug effects.
TWO MAIN APPROACHES FOR DRUG THERAPY
Dopamine enhancing agents
• By far the most commonly used drugs for PD
• Promote activation of dopamine receptors
• Major drug is Levodopa (l-dopa)
Anticholinergic agents
• Inhibition of Ach action in the striatum
• Benztropine (Cogentin®)
Other agents (e.g. amantadine)
Levodopa (L-dopa)
MOA:
Steps leading to alteration of CNS function by L-dopa.
To produce its beneficial effects in PD, levodopa must be:
(1) absorbed from the GI tract in blood, then to BBB
(2) taken up by dopaminergic nerve terminals in the striatum;
(3) converted into dopamine;
(4) released into the synaptic space; and
(5) bind to dopamine receptors on striatal GABAergic neurons, causing them to alter their firing rate.
Dopamine cannot cross the blood brain barrier so it is not used to treat PD
PK: orally, food delay absorption
AE: N/V and Dyskinesias
L-dopa Induced Dyskinesias
• Overall occurrence in about 2/3
- Head bobbing
- Tics
- Grimacing
- Ballismus
- Choreoform-like
- Hand wringing
ENTACAPONE
- Selective & reversible inhibitor of COMT
- Inhibits metabolism of levodopa in the intestines and peripheral tissues (not CNS)
- Prolongs time that levodopa is available to the brain
- Decreases production of levodopa metabolites that compete with levodopa for BBB transport
- Adverse effects arise mainly from increasing the levodopa levels
SELEGILINE
- Causes selective, irreversible inhibition of CNS type B monoamine oxidase (MAO-B)
- Monotherapy or used with levodopa
- Can suppress destruction of dopamine and prolong the effects of levodopa
- Combination with levodopa – can reduce the wearing off effect
- Alone - only modest improvement in motor function
Pramipexole
NON-ERGOT DOPAMINE AGONISTS
- Used alone in milder PD and with l-dopa in advancing PD
- May reduce the wearing off phenomena w/l-dopa
- Less likely to cause dyskinesias
- Still active when DA neuron loss is extensive
AE:
- mono-therapy: nausea, daytime somnolence, constipation, and hallucinations
- In Combination – orthostatic hypotension and increase in dyskinesias and hallucinations
- Dopamine dysregulation syndrome *
DOPAMINE AGONISTS - ADR
Dopamine dysregulation syndrome
- Impaired impulse control
- Rare but, instances of pathologic gambling and other compulsive self-rewarding behaviors
• e.g. Compulsive eating, shopping, sex
Punding – obsessive, repetitive behaviors
RAPID-ACTING DOPAMINE AGONIST
- Apomorphine
- used SubQ or SubLingual for rapid reversal of akinesia (freezing episodes),
- transient action (5-10 min)
- ADR - Emetic. Hypotension in advanced PD
A rescue drug
ANTI-CHOLINERGICS: Muscarinic
Benztropine & Trihexiphenidyl
- Can suppress cholinergic interneuron actions in the striatum to restore Ach:DA balance.
- Reduces tremor more so than rigidity & bradykinesia.
- Has typical atropine-like side effects: impaired memory, confusion, hallucinations, constipation, dry mouth and impaired urination.
