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CNS > Parkinson's Disease Lecture > Flashcards

Parkinson's Disease Lecture Flashcards

1
Q

Risk Factors of PD

A
  • Age: the most important risk factor
  • Gender:
    male gender (M/F = 1.5/1) ??
  • Genetic:
    several genetic form of the disease have been
    identified positive family history
  • Environmental exposure:
    herbicide and pesticide exposure, metals (manganese, iron), well water, farming, rural residence, wood pulp mills; and steel alloy industries;
  • Life experiences:
    trauma, emotional stress, personality traits such as shyness and depressiveness
  • Smoking Caffeine:
    an inverse correlation between cigarette smoking and caffeine intake in case-control
    studies.
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2
Q

Clinical features of PD

A
  • Resting tremor (Most common first symptom) Usually asymmetric, most evident in one hand with the arm at rest;
  • Hypokinesia (suppression of voluntary movements):
    Difficulty with daily activities; decreased blinking, masked
    facies, slowed chewing and swallowing;
  • Rigidity Muscle tone increased in both flexor and extensor muscles providing a constant resistance to passive movements of the joints;
  • Posture stooped posture, instability
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3
Q

Additional clinical features of PD

A

 Dysfunction of ANS: impaired GI motility, bladder dysfunction, sialorrhea, excessive head and neck sweating, orthostatic hypotension.
 Depression: mild to moderate depression in 50% of patients.
 Cognitive impairment: mild cognitive decline including impaired visualspatial perception and attention, slowness in execution of motor tasks, impaired concentration in most patients; at least 1/3 become demented during the course of the disease.

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4
Q

Motor symptoms

A
  • Tremor at rest
  • Hypokinesia
  • Rigidity
  • Postural instability
  • Other (eg, dysarthria, shuffling gait, dystonia)
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5
Q

Nonmotor symptoms

A
  • Neuropsychiatric (e.g., dementia, cognitive decline, depression, anxiety, psychosis, apathy)
  • Sensory (e.g., hyposmia, pain, paresthesias)
  • Sleep disturbances (e.g., insomnia, sleep apnea, sleep attacks, daytime somnolence)
  • Autonomic dysfunction
  • Other (e.g., fatigue, weight loss)
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6
Q

Pathophysiology – Lewy bodies

A

Lewy bodies: eosinophilic, round cytoplasmic inclusions;

caused by alpha-synuclein accumulation in neurons particularly numerous in the substantia nigra.

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7
Q

Dopamine and PD

A

• Carlsson found DA was a NT in the brain and not just a precursor for NA; (in the 1950s)
• Ehringer & Hornykiewicz: The levels of DA severely
reduced in the striatum of PD patients; (in 1960)
• L-Dopa (a precursor to DA), alleviates some of the
symptoms in the early stages of Parkinson’s;

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8
Q

Treatment of Parkinson’s Disease

A
  • Since PD is related to a deficiency of dopamine, it would be appropriate to administer dopamine
  • Problem: Dopamine does not cross BBB, since it is too polar
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9
Q

L-DOPA

A
  • L-DOPA is transported across the BBB by an amino acid transport system (same one used for tyrosine and phenylalanine);
  • Once across, L-DOPA is decarboxylated to dopamine by Dopa Decarboxylase;
  • This is an example of a “prodrug”, that is, a molecule that is a precursor to the drug and is converted to the actual drug at an appropriate place in the body;
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10
Q

Levodopa

A

• Most effective drug for PD symptoms;
• Still the cornerstone of Parkinson therapy;
• Large neutral amino acid; requires active transport
across the gut-blood and blood-brain barriers;
• Short half time (1.5hr);
• 95% is rapidly decarboxylated in to dopamine;
• Peripheral dopamine is metabolized in the liver, and then excreted in urine;

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11
Q

Levodopa alone a problem

A

 L-DOPA is decarboxylated to dopamine in peripheral tissues
 Large oral doses of L-DOPA are requested
 A high rate of ADR of L-DOPA & dopamine

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12
Q

Levodopa with Carbidopa (Sinemet)

A

 Carbidopa: an inhibitor of AA decarboxylase
 Sinemet : carbidopa/levodopa – 25/100 form (1:4),
(containing 25 mg carbidopa and 100 mg levodopa);

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13
Q

Levodopa ADR

A
  • CNS: Depression, anxiety, agitation, insomnia, delusions, hallucinations, euphoria anorexia, nausea, vomiting (likely due to dopamine’s stimulation of the chemoreceptor trigger zone in the medulla oblongata).
  • Peripheral:
    (1) Motor complications: see next slide
    (2) . Cardiovascular side effects in the form of orthostatic hypotension and cardiac arrhythmias
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14
Q

Levodopa - drug interactions

A
  1. pyridoxine (vitamin B6) enhance metabolism of levodopa;.
  2. monoamine oxidase A inhibitors lead to hypertensive crises;
  3. phenothiazines, reserpine, and butyrophenones antagonize the effects of levodopa;
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15
Q

Levodopa - CI

A

Psychotic patients; Angle-closure glaucoma; Cardiac disease; Peptic ulcer; Melanoma

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16
Q

Motor Complications

A

• Motor fluctuations:
“wearing off”, the duration of clinical response shortens;
“on-off fluctuation”, patients fluctuate between being “off,” having no beneficial effects from their medications
(immobility), and being “on” but with dyskinesias
• PD is progressive and degenerative fewer neurons are making and storing dopamine require more dopamine supplies the effects of the drug lasts for shorter periods of time

17
Q

Dyskinesia

A

the inability to control muscle excessive and abnormal involuntary movements (chorea and tremor) usually occurs when the drug level peaks

18
Q

Dopamine Agonists adv

A
  • Directly stimulate dopamine receptors
  • No metabolic conversion;
  • No absorption delay from competition with dietary AA
  • Longer half-life than levodopa
  • May delay or reduce motor fluctuations & dyskinesias (associated with levodopa)
19
Q

Dopamine Agonists disadv

A
  • Not as effective as levodopa

- A higher rate of confusion and psychosis in the elderly

20
Q

Ergot derivatives

A

• These first-generation dopamine agonists are now not
preferred because of their high rate of ADR;
• Cabergoline, pergolide, lisuride, bromocriptine;
• Cabergoline has the advantage of being very long acting, a t1/2 of more than 80h, allowing a once daily administration;
• The t1/2 of pergolide is 6h, longer than that of levodopa;
• ADR: cause heart valve disease

21
Q

Non ergot derivatives

A

• These drugs are currently preferred as first-line therapy in newly diagnosed patients under the age of 70 years old;
• Ropinirole, pramipexole, rotigotine;
• Both ropinirole and pramipexole are relatively selective D2 receptor agonists, generally more effective against tremor;
• The t1/2 of both drugs is short, thus thrice daily administration;
• ADR: psychosis in elderly patients, postural hypotension, ankle edema, daytime somnolence;
• Rotigotine can be used daily as a transdermal patch,
particularly convenient in patients with dysphagia

22
Q

Apomorphine

A
  • A derivative of morphine with structure similar to dopamine;
  • A full agonist at D1 and D2 receptors;
  • Main use: in patients with advanced disease under 70 years old, with severe motor fluctuations; sometimes used to control the “off effect” with levodopa.
  • ADR: follow from the fact that it is both a dopamine agonist and a morphine derivative. e.g. overdose leads to respiratory depression
  • Because of its powerful emetic action, it must be combined with as oral antiemetic drug (e.g. domperidone (Motilium))
23
Q

Catechol O-methyl Transferase (COMT) Inhibitors

A
  • Prevent degradation by inhibiting COMT;
  • Drugs: entacapone, tolcapone;
  • Helpful for both early and fluctuating PD;
  • May be particularly useful for patients with only shortlived “on” period with levodopa;
  • Reduces LD dose necessary for a given clinical effect
24
Q

MAO (B) inhibitors

A

• Enhance and prolong the antiparkinsonism effect of LD;
• Given alone, it has a weak action. It is therefore used as
adjunctive therapy for patients with a declining response to LD;
• Reduce mild on-off or wearing-off phenomena;
• Drugs: selegiline, rasagiline

25
Q

MAO (B) inhibitors - ADR

A
  • insomnia
  • hallucinations
  • nausea (rarely)
26
Q

MAO (B) inhibitors - Drug interaction

A

It should not be taken by patients receiving TCA, or serotonin reuptake inhibitors because of the risk of acute ADR

27
Q

Amantadine

A

• Amantadine is an antiviral agent used in the prophylaxis of influenza A2. It was found to improve parkinsonian symptoms accidently in 1969;
• Exact mechanism unknown; possibly:
– enhancing release of stored dopamine
– inhibiting presynaptic reuptake of catecholamines
– dopamine receptor agonism
– NMDA receptor blockade
• It has been used alone to treat early PD and as an adjunct in later stages.

28
Q

Amantadine - ADR

A
  1. CNS effects: headache
  2. Peripheral edema, heart failure, postural hypotension, urinary retention, GI disturbances (e.g., anorexia, nausea, constipation, and dry mouth).
29
Q

Amantadine - CI

A

• Patients with a history of seizures or heart failure.

30
Q

Anticholinergics

A

• Dopaminergic depletion  cholinergic over-activity
• Initially used in the 1950s
• Effective mainly for tremor and rigidity
• Common agents (Start low, go slow):
– Trihexyphenidyl; Benztropine; Ethopropazine

31
Q

Anticholinergics - ADR

A

1) CNS effects, including drowsiness, restlessness, confusion, agitation, hallucinations, and mood changes;
2) Atropine – like actions: dryness of the mouth, blurring of vision, urinary retention, nausea and vomiting, etc

withdrawal should be gradual to prevent acute PD exacerbation

32
Q

Anticholinergics - CI

A

Prostatic hyperplasia; Obstructive gastrointestinal disease (eg, paralytic ileus); Angle-closure glaucoma

33
Q

Other therapies

A
  • Deep brain stimulation:
    Deep brain stimulation of the globus pallidus or subthalamic nucleus may help all the cardinal features of the disease and reduces the time spent in the off-state in patients with response fluctuations. High-frequency thalamic stimulation is effective for the relief of Parkinsonian tremor
  • Surgery Thalamotomy or Pallidotomy:
    For patients become unresponsive to pharmacologic measures or intolerable ADR to antiparkinsonian medication.
  • Stem Cell Transplantation:
    Rationale: Limited nerve cell birth in the adult brain
    Challenge: Brain is the most complex tissue
34
Q

Principles of drug treatment

A

i. to enhance dopaminergic transmission

ii. to inhibit cholinergic pathway;

35
Q

the motor symptoms of PD result from

A

the motor symptoms of PD result from the death of dopamine-generating cells in the substantia nigra, a region of the midbrain

CNS (7 decks)

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