Parkinson's Disease Flashcards
Which part of the brain is affected by Parkinson’s Diease?
_________
Which neurotransmitters are involved in Parkinson’s Disease?
Nigrostriatal Projection
_______
- Dopamine
- Acetylcholine
- GABA
What is often the earliest sign of Parkinson’s disease?
Tremor (Pill Rolling)
What type of Rigidity is expressed in Parkinson’s Disease?
Cogwheel type; increased muscle tone
________
Definition:
- When a limb is bent, it seems to catch at regular points throughout its range of motion, much as a second hand jerks from interval to interval instead of smoothly traversing the face of a clock.
- muscular rigidity in which passive movement of the limbs (as during a physical examination) elicits ratchet-like start-and stop movements through the range of motion of a joint
What symptoms make up the clinical syndrome of Parkinson’s disease?
- Bradykinesia/akinesia
- Tremor (“pill rolling”)
- Rigidity (“Cogwheel type”)
- Impairment of postural balance (shuffling gait; disturbances in gait; falling)
What are the autonomic symptoms of Parkinson’s disease?
- sweating
- constipation
- hypersalivation
- urinary retention
What is the total symptom profile of Parkinson’s Disease?
Clinical Syndrome
- Bradykinesia/akinesia
- Tremor (“pill rolling”)
- Rigidity (“Cogwheel type”)
- Impairment of postural balance (shuffling gait;disturbances in gait; falling)
Autonomic symptoms
- sweating
- constipation
- hypersalivation
- urinary retention
Other symptoms
- mask-like face
- weight loss
- anorexia
- depression
What does the clinical severity of Parkinson’s Disease correspond to?
Loss of dopamine neurons in the substantia nigra pars compacta
Approximately what level of cell loss of the dopamine neurons in substantia nigra pars compacta results in symptoms?
Symptoms appear after >50% cell loss
Which age group is most common for Parkinson’s Disease?
Age 65 and older
What is the basic pathology of Parkinson’s Disease?
- Progressive degeneration of dopamine neurons in substantia nigra pars compacta
- Disease is progressive, ultimately fatal
What is a significant comorbidity with Parkinson’s Disease?
depression
Describe, in detail, the pathophysiology of Parkinson’s Disease in the Nigrostriatal Projection?
Nigrostriatal Projection
- Nigrostriatal Neuron and Cholinergic Interneuron act on striatal GABAergic efferent neuron
- DA from nigrostriatal neuron is inhibitory; ACh from cholinergic interneuron is excitatory
- Nigrostriatal neurons die, thus they do not produce DA and Cholinergic interneuron does not die; thus balance is altered toward ACh excitatory
What are the 6 Pharmacological strategies for treating Parkinson’s Disease?
- DA replacement (L-DOPA)
- Enzyme inhibitors to enhance CNS delivery
- MAO-B inhibition to prolong CNS effects
- Enhance DA release, block re-uptake
- Directly stimulate DA receptors
- Anticholinergics (antimuscarinics)
Broadly speaking, what does Pharmacotherapy for Parkinson’s Disease aim to accomplish?
Treat the imabalance between striatal cholinergic and dopaminergic activity
You are seeking to treat Parkinson’s Disease using the pharmacological strategy of DA replacement. What do you use? How does it work?
L-DOPA; L-DOPA is a precursor for DA synthesis
What is the fate of orally administered L-DOPA?
~70% metabolism in GI tract
~27-29% Peripheral Tissues (toxicity)
1-3% Brain
What is L-DOPA utilized instead of DA?
L-DOPA is able to traverse the blood/brain barrier; DA is not able to
How much of L-DOPA is decarboxylated in the periphery? What side effects does this lead to?
~95% of L-DOPA is decarboxylated in the periphery
Peripheral Side Effects
- Nausea
- Cardiac palpitations and arrythmias
- Postural hypotension
What are the CNS toxicities and side effects of L-DOPA?
- Psychotic symptoms
- Dyskinesias
- On-Off Phenomenon
The motor CNS toxicities of L-DOPA are due to what? Where?
Motor effects due to increased DA in the striatum
The psychotic CNS toxicities of L-DOPA are due to what? Where?
Psychotic effects due to increased DA in the accumbens
What causes on-off phenomenon? Describe the “on” phase? Describe the “off” phase? Which enzymes, if inhibited, reduce on-off phenomenon?
Cause: Variable CNS metabolism of DA by COMT and MAO-B
______
On-phase: PD symptoms are controlled (but dyskinesias)
_____
Off-phase: PD symptoms are not controlled (may have dystonias/sustained muscle contractions)
______
If COMT and MAO-B are inhibited, on-off phenomenon is reduced
3 contraindications of L-DOPA
- Psychosis (already have too much DA activity)
- Melanoma (L-DOPA is precursor for melanin in skin)
- Narrow angle glaucoma (due to alpha1 agonist activity at high concentrations of DA which causes an inability of vitreous humor to drain from canal of Schlemm)
Name 3 interactions with other drugs of L-DOPA
- Nonselective MAO inhibitors (antidepressants)
- risk of hypertensive crisis (alpha a1 agonism)
- Exception: Selegeline
- Pyridoxine (Vitamin B6)
- Enhances peripheral metabolism of L-DOPA via L-AAD (more peripheral side effects)
- Anti-psychotics
- Will block effects at DA receptors
How long after prescription is L-DOPA most effective for a Parkinson’s Patient? What happens longer term?
Most effective first 3-4 years of use. Longer term:
- Increasing intolerance to side effects (result in need to decrease dose)
- Decreased effectiveness as more neurons die and thus, less neurons to convert L-DOPA to DA
What is L-DOPA’s effectiveness?
- Effective 1/3 pts
- Somewhat effective 1/3 pts
- Ineffective 1/3 pts
L-DOPA is particularly good at treating which PD symptoms?
- Bradykinesia
- Akinesia
In a younger Parkinson patient, would you recommend L-DOPA as first line therapy?
No; most physicians prefer to start young PD patients with something other than L-DOPA
If you would like to treat Parkinson’s Disease by employing the strategy of inhibiting the enzyme L-AAD in the periphery to increase delivery of the DA precursor and slow metabolism of CNS DA, what pharmacological agent would you use?
Carbidopa
What is the mechanism of action of carbidopa?
- Inhibit L-AAD in the periphery
- BUT; this causes a shunt to an alternate metabolic pathway such that COMT upregulates in the periphery
___________
In order to inhibit COMT use tolcapone or entacapone
If you would like to treat Parkinson’s Disease by employing the strategy of inhibiting the enzyme COMT in the periphery to increase delivery of the DA precursor and slow metabolism of CNS DA, what pharmacological agent would you use?
Tolcapone or Entacapone
_____
****Tolcapone also inhibits central L-DOPA metabolism by COMT as well
What pharmacological agent inhibits BOTH peripheral L-DOPA metabolism AND central L-DOPA metabolism
Tolcapone
What are the advantages and disadvantages of Enzyme Inhibitors? (Carbidopa, Tolcapone, or Entacapone)
Advantages
- >75% reduction in the amount of L-DOPA administered
- Peripheral side effects are diminished
- On-Off phenomenon diminished
Disadvantages
- CNS toxicity of L-DOPA (ex. psychosis) can be increased
If you would like to treat PD by inhibiting metabolism of MAO-B of CNS dopamine, which pharmacologic agents would you use? What is the mechanism of action?
selegeline or rasagiline
_____
Act by inhibiting MAO-B, a precursor to 3,4-dihydroxy Phenylactic acid which is converted by COMT to homovanillic acid, a neurotoxic metabolite
How is smoking neuroprotective with regard to Parkinsons?
- Tobacco smoke inhibits MAO-B
- Nicotine is neuroprotective and releases DA
What are the advantages and disadvantages of using MAO-B inhibitors for PD? (Selegiline, Rasagiline)
Advantages
- Allows reduction in L-DOPA use
- Reduces “on-off”
Disadvantages
- Can worsen L-DOPA CNS side effects
- Oral administration causes metabolism to amphetamines
- Cannot give in combo with non-selective MAO inhibitors
If you wanted to treat Parkinsons Disease by stimulating CNS D2 receptors directly with an agonist, which pharmacological agents would you use?
- Ropinirole
- Pramipexole
What are the advantages of D2 agonists (Ropinirole and Pramipexole)?
- Allows L-DOPA use to be reduced
- Alleviates on-off phenomenon
- Can be used in patients becoming refractory to L-DOPA
Which drugs are sometimes used in younger patients with Parkinson’s Disease prior to L-DOPA?
- Ropinirole
- Pramipexole
What are the side effects of CNS D2 receptor agonists?
Peripheral
- Nausea
- Hypotension
CNS
- Dyskinesias (lower incidence than L-DOPA)
- Psychosis (higher incidence than L-DOPA)
Which has a higher incidence of dyskinesias: L-DOPA or Ropinirole/Pramipexole?
L-DOPA
Which has a higher incidence of psychosis: L-DOPA or Ropinirole/Pramipexole?
Ropinirole/Pramipexole
What are the contraindications for D2 agonists (Ropinirole/Pramipexole)?
- Psychosis
- Recent MI, peripheral vascular disease (ex. at risk for orthostatic hypotension)
- Peptic ulcers (nausea and vomiting will exacerbate these)
If you wanted to treat Parkinson’s Diease by enhancing DA release from remaining terminals and inhibit its reuptake, which pharmacological agent would you use?
Amatadine
What are the therapeutic benefits of enhancing DA release from remaining terminals and inhibiting its reuptake (Amantadine)?
- Sometimes used as initial therapy
- Can reduce bradykinesia, rigidity, and tremor in early stages
- Can be used for L-DOPA/Carbidopa fluctuations and dyskinesias
- May improve cognition through actions at NMDA receptors
__________
Notes: Benefits may be short-lived
What are the side effects of enhancing DA release from remaining terminals and inhibiting its reuptake (Amantadine)?
- Generally mild
- Overdose can produce acute toxic psychosis
If you wanted to treat Parkinson’s Disease by creating a rebalance using mascarinic antagonishts, which pharmacological agent would you use?
Antimuscarinic (benztropine)
Which pharmacological agent can be used in very MILD parkinson’s disaease, especially if TREMOR is the only symptom?
antimuscarinic (benztropine)
Which pharmacological agent in Parkinson’s Disease works better on tremor and rigidity than on bradykinesia?
antimuscarinic (benztropine)
True or false: Antimuscarinics like benztropine may be useful in combo with L-DOPA.
True
What are the side effects of anticholinergics?
Peripheral
- Dry mouth
- Blurred vision
- Mydriasis
- Urinary retention
- Nausea
Central
- Drowsiness
- Mental slowness, confusion
- Inattention
- Restlessness
OVERALL, for patients with mild symptoms in Parkinson’s Disease, which pharmacological agents would you consider?
- MAO-B inhibitors (Selegiline/Rasagiline)
- amantadine
- (in younger patients) anticholinergics
OVERALL, in patients with Parkinsons disease, treatment with which parmacological agents will eventually be required?
Treatment with a dopaminergic drug, either levodopa or a DA agonist (Ropinirole/Pramipexole)
True or false? Treatment of PD should be tailored to the individual patient
true
True or false? Drug therapy is not obligatory in early PD; many patients can be managed for a time with exercise and lifestyle interventions
True
Large controlled clinical trials provide convincing evidence for a reduced rate of motor fluctuation in patients in which ___________ are used as initial treatment.
This benefit was, however, accompanied by an increased rate of adverse effects, especially somnolence and hallucinations
DA agonists
Practitioners prefer _______ as initial therapy in younger patients in order to reduce the occurence of motor complications.
DA agoinst
Practitioners prefer _________ in older patients or those with substantial comorbidity
levodopa/carbidopa
