Parkinson's Disease Lecture Flashcards
Risk Factors of PD
- 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.
Clinical features of PD
- 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
Additional clinical features of PD
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.
Motor symptoms
- Tremor at rest
- Hypokinesia
- Rigidity
- Postural instability
- Other (eg, dysarthria, shuffling gait, dystonia)
Nonmotor symptoms
- 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)
Pathophysiology – Lewy bodies
Lewy bodies: eosinophilic, round cytoplasmic inclusions;
caused by alpha-synuclein accumulation in neurons particularly numerous in the substantia nigra.
Dopamine and PD
• 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;
Treatment of Parkinson’s Disease
- 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
L-DOPA
- 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;
Levodopa
• 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;
Levodopa alone a problem
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
Levodopa with Carbidopa (Sinemet)
Carbidopa: an inhibitor of AA decarboxylase
Sinemet : carbidopa/levodopa – 25/100 form (1:4),
(containing 25 mg carbidopa and 100 mg levodopa);
Levodopa ADR
- 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
Levodopa - drug interactions
- pyridoxine (vitamin B6) enhance metabolism of levodopa;.
- monoamine oxidase A inhibitors lead to hypertensive crises;
- phenothiazines, reserpine, and butyrophenones antagonize the effects of levodopa;
Levodopa - CI
Psychotic patients; Angle-closure glaucoma; Cardiac disease; Peptic ulcer; Melanoma
Motor Complications
• 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
Dyskinesia
the inability to control muscle excessive and abnormal involuntary movements (chorea and tremor) usually occurs when the drug level peaks
Dopamine Agonists adv
- 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)
Dopamine Agonists disadv
- Not as effective as levodopa
- A higher rate of confusion and psychosis in the elderly
Ergot derivatives
• 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
Non ergot derivatives
• 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
Apomorphine
- 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))
Catechol O-methyl Transferase (COMT) Inhibitors
- 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
MAO (B) inhibitors
• 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
MAO (B) inhibitors - ADR
- insomnia
- hallucinations
- nausea (rarely)
MAO (B) inhibitors - Drug interaction
It should not be taken by patients receiving TCA, or serotonin reuptake inhibitors because of the risk of acute ADR
Amantadine
• 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.
Amantadine - ADR
- CNS effects: headache
- Peripheral edema, heart failure, postural hypotension, urinary retention, GI disturbances (e.g., anorexia, nausea, constipation, and dry mouth).
Amantadine - CI
• Patients with a history of seizures or heart failure.
Anticholinergics
• 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
Anticholinergics - ADR
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
Anticholinergics - CI
Prostatic hyperplasia; Obstructive gastrointestinal disease (eg, paralytic ileus); Angle-closure glaucoma
Other therapies
- 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
Principles of drug treatment
i. to enhance dopaminergic transmission
ii. to inhibit cholinergic pathway;
the motor symptoms of PD result from
the motor symptoms of PD result from the death of dopamine-generating cells in the substantia nigra, a region of the midbrain
