Parkinson Disease ✔️ Flashcards
(127 cards)
1
Q
Parkinson’s disease is associated with insufficient levels of which neurotransmitter in the basal ganglia?
A
Dopamine (DA)
2
Q
Which other neurons are involved in Parkinson’s disease?
A
Intrinsic cholinergic neurons of the corpus striatum
3
Q
Why are cholinergic neurons involved in PD symptoms?
A
Because ACh release from the striatum is normally inhibited by DA
4
Q
What does the loss of dopamine lead to in the striatum?
A
Hyperactivity of ACh neurons, which causes PD symptoms
( loss of DA→ hyperactivity of Ach neurons→ PD symptoms)
5
Q
What is the significance of the pathway between the substantia nigra and corpus striatum in Parkinson’s disease?
A
It highlights how dopamine from the substantia nigra regulates the corpus striatum; its loss leads to disrupted motor signaling through the thalamus to the cortex and spinal cord, resulting in the motor symptoms of Parkinson’s disease.
6
Q
What type of neurotransmitter is dopamine?
A
Catecholamine
7
Q
Where is dopamine mostly distributed in the brain?
A
Mostly in the corpus striatum
8
Q
What is the role of dopamine in the corpus striatum?
A
It is part of the extrapyramidal motor system (EMS) concerned with coordination of movement
9
Q
Which brain region is associated with dopamine’s role in emotion and drug-induced reward?
A
Limbic system
10
Q
Which brain region is associated with dopamine’s role in regulating pituitary gland secretions?
A
Hypothalamus
11
Q
What are the main functions of dopamine?
A
• Motor system regulation
• Behavioral effects
• Neuroendocrine control
• Vomiting (at the chemoreceptor trigger zone – CTZ)
12
Q
What are the three main brain regions where dopamine is distributed?
A
• Corpus striatum
• Limbic system
• Hypothalamus
13
Q
How is dopamine removed from the synaptic cleft after release?
A
It is recaptured by a specific dopamine (DA) transporter.
(Reuptake)
14
Q
Which enzymes metabolize dopamine?
A
• Monoamine oxidase (MAO)
• Catechol-O-methyltransferase (COMT)
15
Q
What are the final breakdown products of dopamine and how are they excreted?
A
DOPAC and HVA
both excreted in the urine.
16
Q
What type of receptors are dopamine (DA) receptors?
A
G-protein coupled receptors
17
Q
What is the signaling pathway for D1-like receptors?
A
D1-like → AC activation → ↑ cAMP → ↑ PKA
18
Q
Which receptors are included in the D1-like group?
A
D1 and D5
19
Q
Where are D1-like receptors most abundant?
A
Striatum, limbic system, thalamus, and hypothalamus
20
Q
What is the signaling pathway for D2-like receptors?
A
D2-like → AC inhibition → no cAMP, no PKA
21
Q
Which receptors are included in the D2-like group?
A
D2S (short), D2L (long), D3, and D4
22
Q
Where are D2-like receptors found?
A
Same as D1-like (striatum, limbic system, thalamus, hypothalamus), plus the pituitary gland
23
Q
What affects dopamine’s affinity for D1-like vs D2-like receptors?
A
• Extracellular dopamine (DA) concentration
• Release pattern:
• Burst firing → D1
• Tonic activity → D2
• Timescale of engagement
• Receptor abundance in complex circuits
24
Q
Why is the classification of DA receptors not clear-cut?
A
Due to the complexity of heterocomplexes formed by DA receptors
25
What is the primary aim of drug treatment in Parkinson’s disease?
To re-establish the correct dopamine (DA)/acetylcholine (ACh) balance.
26
Do available drugs cure Parkinson’s disease or reverse neuronal degeneration?
No, they only provide symptomatic relief and do not cure the underlying cause or reverse degeneration.
27
Can dopamine itself cross the blood-brain barrier (BBB)?
No
dopamine does not cross the BBB
28
What are the main drug groups used to treat Parkinson’s disease?
1. Drugs that increase striatal dopamine (DA) activity
2. Antimuscarinic agents
29
How can striatal DA activity be increased pharmacologically?
a. By replacing DA
(e.g. Levodopa, a DA precursor that crosses the BBB)
b. By using levodopa optimisers
(Carbidopa, Benserazide, Domperidone, Selegiline, Entacapone, Tolcapone)
c. By using DA agonists
(e.g. Bromocriptine)
d. By using drugs that release DA
(e.g. Amantadine)
30
Which drug replaces dopamine as a precursor that crosses the blood-brain barrier?
Levodopa
31
What are examples of drugs that optimize levodopa’s effectiveness?
• Carbidopa
• Benserazide
• Domperidone
• Selegiline
• Entacapone
• Tolcapone
32
What is an example of a dopamine agonist used to treat Parkinson’s disease?
Bromocriptine
33
Which drug works by releasing dopamine from neurons?
Amantadine
34
What is an example of an antimuscarinic agent used in Parkinson’s treatment?
Benztropine
35
What is the major effect of Levodopa in Parkinson’s disease?
It decreases rigidity and tremors
36
What is Levodopa a precursor to?
Dopamine (DA)
37
Does Levodopa cross the blood-brain barrier (BBB)?
Yes
38
What happens to Levodopa after it crosses the BBB?
It is converted to dopamine (DA) in the brain
39
LDOPA half-life
Short half life
1–2 hours
40
What is the clinical significance of Levodopa’s short half-life?
It causes plasma concentration fluctuations
41
Where is Levodopa extensively metabolized?
In the intestinal wall and other peripheral sites
42
Why are large doses of Levodopa required, and how much of it actually enters the brain?
Only 1% of Levodopa enters the brain because it is extensively metabolized in peripheral sites, requiring large doses for effectiveness.
43
When is Levodopa most effective in Parkinson’s treatment, and when does it start losing efficacy?
It is most effective in the first few years of treatment
and typically begins to lose efficacy from the 3rd to 5th year.
44
What is the major peripheral product of Levodopa responsible for most peripheral side effects?
Dopamine (DA)
45
What is dyskinesia, and when does it typically develop in Parkinson’s patients on Levodopa therapy?
Involuntary writhing movements, develops in most patients within 2 years of starting L-dopa therapy.
Cause: Due to dopamine overactivity at receptors in the basal ganglia.
46
True or False:
Dyskinesia from Levodopa is caused by dopamine overactivity at receptors in the basal ganglia.
True
47
What is the ‘on-off effect’ in L-dopa treatment?
Rapid fluctuations in clinical state where hypokinesia and rigidity suddenly worsen within minutes to hours and then improve.
Cause: Due to fluctuating plasma concentrations of Levodopa.
48
True or False:
The ‘on-off effect’ in Levodopa therapy is caused by fluctuating plasma concentrations of the drug.
True
49
What are the gastrointestinal side effects of Levodopa?
Nausea, vomiting, and anorexia.
Cause: CTZ stimulation at the medulla.
50
True or False:
Levodopa-induced nausea and vomiting occur due to stimulation of the chemoreceptor trigger zone (CTZ) in the medulla.
True
51
What cardiovascular adverse effects are associated with Levodopa?
Tachycardia and arrhythmia.
Cause: Due to the action of dopamine on the heart.
52
True or False:
Cardiovascular side effects like tachycardia and arrhythmia in Levodopa therapy are caused by dopamine’s action on the heart.
True
53
What behavioral changes can occur with Levodopa therapy?
Confusion, hallucinations, and schizophrenia-like effects.
Cause: Due to increased dopamine activity in the brain.
54
True or False:
Behavioral changes such as confusion and hallucinations in Levodopa-treated patients are due to increased dopamine activity in the brain.
True
55
What are the major adverse effects associated with Levodopa therapy?
• Dyskinesia
• ‘On-off’ effect
• Nausea, vomiting, and anorexia
• Tachycardia and arrhythmia
• Confusion, hallucinations, and schizophrenia-like effects
56
What can happen if a patient on Levodopa is also taking MAO inhibitors?
Hypertensive crisis
57
What is the risk of giving Levodopa to a patient with psychosis?
Exacerbation of psychotic symptoms
58
What complication can occur in patients with cardiac problems taking Levodopa?
Cardiac arrhythmias
59
What is the effect of vitamin B6 on Levodopa?
It increases the breakdown of Levodopa in the periphery
60
What effect does Levodopa have in patients with glaucoma?
Increases intraocular pressure (I.O.P)
61
Why is Levodopa contraindicated in patients taking antipsychotic drugs?
Because antipsychotics themselves can produce Parkinson’s-like symptoms.
62
What is the goal of Levodopa combination therapy?
To reduce peripheral effects and enhance central effects.
63
What are examples of drugs used to optimize Levodopa treatment?
• Carbidopa
• Benserazide
• Domperidone
• Selegiline
• Entacapone
• Tolcapone
64
What is the mechanism of action of Carbidopa and Benserazide?
They are peripheral dopa decarboxylase inhibitors.
65
How are Carbidopa and Benserazide administered with Levodopa?
Orally, in combination with Levodopa.
66
What effect do Carbidopa and Benserazide have on Levodopa dosage?
They reduce the required dose of Levodopa to reach the CNS by up to 80%.
67
How do Carbidopa and Benserazide affect Levodopa metabolism?
They decrease Levodopa metabolism in the GI tract and peripheral tissues.
68
What type of adverse effects do Carbidopa and Benserazide help minimize?
Peripheral adverse effects like arrhythmia and nausea.
69
Do Carbidopa and Benserazide reduce central side effects like dyskinesia?
No, they do not minimize central side effects.
70
What are the benefits of combining Carbidopa or Benserazide with Levodopa?
• Reduce the required dose of Levodopa to reach the CNS (by up to 80%)
• Decrease Levodopa metabolism in the GI tract and peripheral tissues
• Minimize peripheral adverse effects like arrhythmia and nausea
71
What is the mechanism of action of Domperidone?
It is a peripheral acting dopamine (D2) receptor antagonist.
72
Where does Domperidone act, and does it cross the blood-brain barrier (BBB)?
Domperidone does not cross the BBB; thus, it does not access the basal ganglia. Instead, it works at the chemoreceptor trigger zone (CTZ).
73
What are the antiemetic benefits of Domperidone in Levodopa therapy?
It prevents nausea and anorexia
74
What peripheral adverse effects can Domperidone reduce?
Headache, dizziness, and dry mouth.
75
How is Selegiline administered in Parkinson’s therapy?
Taken orally with Levodopa and Carbidopa
76
What is the mechanism of action of Selegiline?
It selectively inhibits MAO-B, the enzyme that metabolizes dopamine, decreasing dopamine breakdown and increasing its levels in the brain.
77
What is the purpose of using Selegiline with Levodopa?
To enhance Levodopa’s actions, reduce the required dose, and minimize motor complications.
78
According to long-term trials, what is the benefit of combining Levodopa with Selegiline?
Levodopa + Selegiline is more effective than Levodopa alone in relieving symptoms.
79
What are the active metabolites of Selegiline?
Amphetamine and Methamphetamine
80
What side effect may occur if Selegiline is administered later than midafternoon?
Insomnia
81
What serious adverse effect can occur at high doses of Selegiline?
Severe hypertension, due to loss of MAO-B selectivity.
82
What is the mechanism of action of Entacapone and Tolcapone?
They inhibit COMT (catechol-O-methyltransferase)
83
True or False:
Entacapone and Tolcapone are among the newest drugs used to optimize Levodopa therapy.
True
84
How do Entacapone and Tolcapone affect Levodopa metabolism?
They prevent Levodopa’s metabolism to 3-O-methyldopa, increasing central Levodopa levels.
85
How are Entacapone and Tolcapone administered in Parkinson’s therapy?
Orally with Levodopa-Carbidopa, and can also be taken with Selegiline.
86
What Levodopa-Carbidopa complication is reduced by COMT inhibitors like Entacapone and Tolcapone?
The ‘wearing off’ phenomenon
87
What are the adverse effects of Entacapone and Tolcapone?
• Hallucinations
• Sleep disorders
• Nausea
• Postural hypotension
• Anorexia
• Dyskinesia (similar to Levodopa-Carbidopa)
88
How does the duration of action of dopamine receptor agonists compare to Levodopa?
Their duration of action is much longer than that of Levodopa.
89
How are dopamine agonists used in early and later stages of Parkinson’s disease?
• In early stages: used as single agents
• In later stages: used in combination with Levodopa-Carbidopa
90
In which patients are dopamine agonists particularly useful?
In patients who exhibit Levodopa-associated fluctuations.
91
What is the benefit of starting Parkinson’s therapy with dopamine agonists instead of Levodopa?
There is less risk of developing dyskinesias and motor fluctuations.
92
What is the mechanism of action of Bromocriptine?
It is a dopamine receptor agonist at the D₂ receptor and a weak partial agonist at the D₁ receptor.
93
When is Bromocriptine often used with Levodopa?
When Levodopa does not adequately control symptoms or when severe ‘on-off’ fluctuations are experienced.
94
What type of receptor is the D₂ receptor and what is its effect?
It is G-protein linked and inhibits adenylate cyclase (AC).
95
What are the major side effects of Bromocriptine?
• Hallucinations, confusion, and delirium
• Nausea
• Postural hypotension
• Dyskinesia (less than with Levodopa)
• Cardiac problems in patients with a history of myocardial infarction
• Worsening of mental condition in psychiatric illness
96
How does Bromocriptine compare to Levodopa in terms of causing dyskinesia?
Bromocriptine causes less dyskinesia than Levodopa.
97
True or False:
Bromocriptine can cause cardiac problems in patients with a history of myocardial infarction.
True
98
True or False:
Bromocriptine worsens the mental condition of patients with psychiatric illness.
True
99
How is Rotigotine administered?
As a once-daily transdermal skin patch (every 24 hours).
100
How does Rotigotine compare to oral DA agonists like pramipexole and ropinirole in clinical trials?
It is just as effective
101
What is the most common adverse effect of Rotigotine?
Skin irritation
102
How can the risk of skin irritation from Rotigotine patches be minimized?
By rotating the patch adherence sites
103
Why did the use of Apomorphine decline after its introduction in 1950?
Due to numerous adverse effects, especially nausea and vomiting.
104
What advancement in Apomorphine administration occurred in 1990?
A self-injectable form was introduced.
105
How is Apomorphine currently used in Parkinson’s disease management?
As a ‘rescue drug’, up to 5 times a day, for patients with advanced disease and severe off episodes.
106
What type of drug is Amantadine?
It is an antiviral drug for influenza
107
What is the proposed mechanism of action of Amantadine in Parkinson’s disease?
It may enhance dopamine release from surviving neurons and block cholinergic neurons.
108
When is Amantadine ineffective?
If dopamine release is already maximal.
109
How does Amantadine compare to Levodopa or Bromocriptine?
It is less efficacious, tolerance develops faster, but it has fewer side effects.
110
What is the short-term benefit of Amantadine?
It provides mild relief.
111
True or False:
Amantadine has little effect on tremor.
True
112
What symptoms does Amantadine help more effectively than antimuscarinic agents?
Rigidity and bradykinesia.
113
What are the side effects of Amantadine?
• Restlessness, agitation, confusion, hallucinations
• Acute toxic psychosis at high doses
114
Where is acetylcholine synthesized?
In the nerve terminal
115
What enzyme synthesizes acetylcholine and where is it found?
Choline acetyl transferase (CAT), found in cholinergic neurons.
116
What are the two main types of acetylcholine receptors?
Nicotinic (nAChR) and Muscarinic (mAChR) receptors.
117
What is the function of nicotinic ACh receptors?
• Directly coupled to ion channels
• Mediate FAST excitatory synaptic transmission
118
What is the function of muscarinic ACh receptors?
• G-protein coupled recs
• → activation of phospholipase C (and thus IP3 and DAG)
• → AC inhibition
• → activation of K channels / inhibition of Ca channels
• mediates SLOW excitatory synaptic transmission
119
True or False:
Benztropine is one of the oldest drugs, used since the 1900s (e.g. atropine).
True
120
What is the mechanism of action of Benztropine?
Blocks muscarinic receptors in the nigro-striatal region in the brain to re-establish the correct DA/ACh balance.
121
How is Benztropine used in Parkinson’s disease therapy, and how does its effectiveness compare to Levodopa?
It is used as an adjunct in PD therapy, providing modest improvement in the early stages, but it is less effective than Levodopa.
122
Which Parkinson’s symptom is most improved by Benztropine?
Tremor (more than rigidity and dyskinesia)
123
What are the adverse effects of Benztropine?
• Dry mouth
• Urinary retention
• Blurred vision
• Constipation
• Confusion
• Hallucination
(especially in elderly/demented patients)
124
What are the contraindications for Benztropine use?
Glaucoma, prostatic hypertrophy, pyloric stenosis.
125
True or False:
Benztropine use has become limited due to its troublesome adverse effects.
True
126
In which patients is Benztropine particularly useful?
In patients on antipsychotics with Parkinson’s symptoms (since antipsychotics are DA antagonists that nullify Levodopa effects).
127
Review
Done
