PARKINSON DISEASE

Question 1

Clinically, PD is characterized

by:

Answer 1

• Clinically, PD is characterized by:
• Resting tremor
• Muscular rigidity
• Bradykinesia
• Gait impairment
• These are known as the
“cardinal features” of the
disease.

Question 2

Etiology of Parkinson’s disease?

Answer 2

• The cause is unknown.

* There is a loss of the neurons of the dopaminergic nigrostriatal pathway.

Question 3

Dopamine synthesis pathway?

Answer 3

• Dopamine synthesis originates from the amino
acid precursor tyrosine.
• Tyrosine must be transported across the blood-brain barrier into the dopamine neuron.
• Tyrosine is transported by system L across the blood
brain barrier in a Na+ -independent manner.
DOPA is converted to
dopamine by aromatic Lamino acid decarboxylase
(DOPA decarboxylase)
DOPA decarboxylase turns over so rapidly that DOPA levels in the brain are negligible under normal
conditions
• It is therefore possible to enhance the formation of dopamine by providing this
enzyme with increased amounts of substrate.

Question 4

DOPAMINE RECEPTORS in regards to Parkinson’s disease?

Answer 4

• D1 and D2 receptors are the most important
receptor sites with regard to the causes and
treatment of Parkinson’s disease.
• D1 receptors: increase adenylyl cyclase
• D2 receptors: decrease adenylyl cyclase
increase K+ conductance
decrease Ca2+ conductance.
• The benefits of dopaminergic antiparkinsonism drugs appear to depend
mostly on stimulation of the D2 receptors.
• But D1 stimulation may also be required for maximal benefit

Question 5

PATHOPHYSIOLOGY OF PARKINSON DISEASE?

Answer 5

• Dopaminergic neurons from the substantia
nigra normally inhibit the GABAergic output
from the striatum, whereas cholinergic neurons stimulate it.
• In Parkinson disease, there is destruction of
the neurons of the nigrostriatal pathway
responsible for secreting dopamine in the striatum.
• This results in loss of the control of muscle
movement.
• At least 70% of the neurons are destroyed at
the time symptoms first appear.
• Often, 95% of the neurons are missing at
autopsy.

Question 6

STRATEGY OF TREATMENT FOR PD?

Answer 6

• Symptoms of PD reflect an imbalance between the excitatory cholinergic neurons and the diminished number of inhibitory
dopaminergic neurons.
• Therapy is aimed at restoring dopamine in
the basal ganglia and antagonizing the
excitatory effect of cholinergic neurons,
thus reestablishing the correct dopamine/ACh
balance.

Question 7

Types of drugs in Parkinsons disease?

Answer 7

DRUGS THAT RESTORE
DOPAMINE ACTIONS:
DOPAMINE
PRECURSORS
DOPAMINE RECEPTOR
AGONISTS
INHIBITORS OF
DOPAMINE METABOLISM
AMANTADINE

ANTAGONISTS OF
ACETYLCHOLINE:
ANTIMUSCARINICS

Question 8

What is dopamine precursor used clincally?

Answer 8

LEVODOPA
• Levorotatory stereoisomer of dopa.
• Metabolic precursor of dopamine (and
norepinephrine).
• Restores dopamine levels in the extrapyramidal centers.

Question 9

Scope of Levodopa?

Answer 9

• In patients with early disease, the number of residual dopaminergic neurons in the substantia nigra is enough for conversion of levodopa to dopamine.
• With time, the number of neurons decrease and there
are fewer cells capable of taking up levodopa
and converting it to dopamine.
• Consequently, motor control fluctuation develops.
• Relief provided by levodopa is only symptomatic and lasts only while the drug is present in the body.

Question 10

MOA of Levodopa?

Answer 10

• Dopamine does not cross the blood-brain barrier.
• Levodopa is transported into the CNS and converted to dopamine in the brain.
• Much of the drug is decarboxylated to
dopamine in the periphery.
• This results in peripheral side effects
(nausea, vomiting, cardiac arrhythmias, hypotension)

Question 11

What is CARBIDOPA and its purpose?

Answer 11

• Carbidopa is a dopa decarboxylase inhibitor that does not cross the bloodbrain barrier.
• Levodopa is given in combination with carbidopa.
• Carbidopa decreases the metabolism of levodopa in the GI tract and peripheral tissues, thus increasing the availability of levodopa to the CNS.
• Sinemet is a dopa preparation containing
carbidopa and levodopa in fixed proportion
(1:10 or 1:4).

Question 12

PK of levodopa?

Answer 12

• Levodopa is absorbed rapidly from the small
intestine.
• Food delays the appearance of levodopa in
the plasma.
• Certain amino acids can compete with the
drug for absorption from the gut and for transport from the blood to the brain.

Question 13

Clinical uses of levodopa/carbidopa?

Answer 13

• Levodopa/carbidopa is an efficacious drug
regimen for PD.
• There is a decline in response during the 3rd
to 5th year of therapy.
• Responsiveness to levodopa may ultimately
be lost completely, because of the disappearance of dopaminergic nigrostriatal
neurons.
• Levodopa does not stop progression of PD

Question 14

ADVERSE EFFECTS of levodopa?

Answer 14

GI effects
• Anorexia, nausea and vomiting.
CV effects
• Tachycardia and ventricular extrasystoles.
• Hypotension.
CNS Effects
• Visual and auditory hallucinations.
• Dyskinesias.
• Mood changes, depression, anxiety, agitation,
insomnia.

Question 15

discuss FLUCTUATIONS IN RESPONSE with levodopa wearing off reaction?

Answer 15

Wearing-Off Reactions (End-Of-Dose Akinesia)
• Fluctuations related to the timing of levodopa
intake.

Question 16

Discuss On-off phenomenon with levodopa?

Answer 16

The On-Off Phenomenon
• Fluctuations in response unrelated to the
timing of doses.
• The exact mechanism is unknown.
• For patients with severe off-periods who are
unresponsive to other measures, apomorphine SC may provide benefit

Question 17

LEVODOPA: INTERACTIONS &

CONTRAINDICATIONS

Answer 17

• Vitamin B6 is a cofactor for Dopa decarboxylase: it increases peripheral
metabolism of levodopa
• Concomitant administration of nonspecific MAO inhibitors, may precipitate hypertensive crisis.
• Levodopa should not be given to psychotic
patients, as it may exacerbate the mental
disturbance.
• Levodopa is contraindicated in angle-closure glaucoma.
• Cardiac patients should be carefully
monitored because of possible arrhythmias.
• Antipsychotic drugs are contraindicated in
PD: they may produce a parkinsonian syndrome.

Question 18

Types DOPAMINE RECEPTOR AGONISTS and unique features?

Answer 18

• ERGOT DOPAMINE AGONISTS
• NONERGOT DOPAMINE AGONISTS
• Dopamine agonists don’t require enzymatic
conversion for activity
• Therefore they do not depend on the
functional capacities of the nigrostriatal neurons.

Question 19

Name a ERGOT DOPAMINE AGONISTS?

Answer 19

Bromocriptine

• D2 agonist.

Question 20

NONERGOT DOPAMINE AGONISTS

Answer 20

Pramipexole & ropinirole
• Used increasingly as initial treatment for PD rather than as adjuncts to levodopa.
• Particularly for younger patients.
• Older patients are more vulnerable to the adverse cognitive effects of the dopamine agonists.
Rotigotine
• Available in a transdermal formulation.
• Once-daily use.

Question 21

DOPAMINE AGONISTS: ADVERSE EFFECTS?

Answer 21

GI Effects
• Anorexia, nausea and vomiting, constipation,
dyspepsia.
• Bleeding from peptic ulceration.
Cardiovascular Effects
• Postural hypotension.
• Cardiac arrhythmias.
• Peripheral edema.
• Ergot derivatives may cause painless digital
vasospasm. 
Dyskinesias
• Abnormal movements.
Mental Disturbances
• Confusion, hallucinations, delusions

Question 22

Miscellaneous Adverse Effects of Dopamine Agonists?

Answer 22

• Ergot dopamine agonists: Headache, nasal
congestion, increased arousal, pulmonary
infiltrates, pleural and retroperitoneal
fibrosis, and erythromelalgia.
• Pramipexole, ropinirole and rotigotine:
Uncontrollable somnolence. This requires discontinuation of the medication.

Question 23

DOPAMINE AGONISTS:

CONTRAINDICATIONS?

Answer 23

• Dopamine agonists are contraindicated in patients with a history of psychotic illness or recent MI.
• Best avoided in patients with peripheral vascular disease or peptic ulceration.

Question 24

NONERGOT DOPAMINE AGONISTS:

RESCUE THERAPY use?

Answer 24

APOMORPHINE
• Rescue therapy for treatment of “off” episodes of akinesia in patients on dopaminergic therapy.
• Emetogenic; pretreatment with the antiemetic
trimethobenzamide is recommended.
• Other adverse effects: QT prolongation, dyskinesias, drowsiness, sweating, hypotension.

Question 25

INHIBITORS OF

DOPAMINE METABOLISM

Answer 25

• MAO INHIBITORS

* COMT INHIBITORS

Question 26

Two MAO inhibitiors used for PD?

Answer 26

Deprenyl (Selegiline)
• Selectively and irreversibly inhibits MAO-B (which selectively metabolizes dopamine),
• Retards breakdown of dopamine in the brain.
• Enhances effect of levodopa.
• Allows dose of levodopa to be reduced.
• Mainly used as adjunct to levodopa.
• Metabolized to methamphetamine and amphetamine: may cause insomnia if taken late in the day.
Rasagiline
• Second MAO-B inhibitor approved for
treatment of PD.

Question 27

Name 2 COMT inhibitors and what their effects?

Answer 27

• Inhibition of COMT by tolcapone and entacapone leads to:
• Decreased metabolism of levodopa
• Decreased plasma levels of 3-Omethyldopa
• Increased uptake of levodopa
• Higher dopamine levels in the brain

Question 28

COMT INHIBITORS: ADVERSE EFFECTS?

Answer 28

• Fulminating hepatic necrosis is associated with the use of tolcapone
• Entacapone is not hepatotoxic and is therefore preferred.
• Entacapone is also available as fixed dose combinations with levodopa/carbidopa.

Question 29

Role of Amantadine in regards to PD?

Answer 29

• Antiviral drug with antiparkinsonian actions.
• Its effects in PD are modest.
• Its MOA in PD unclear.
• Increases release of dopamine.
• Antagonist at cholinergic receptors.
• Antagonist at the NMDA receptor

Question 30

AMANTADINE: ADVERSE EFFECTS?

Answer 30

• May cause restlesness, agitation, confusion,
hallucinations.
• At high doses: acute toxic psychosis.
• Peripheral edema: responds to diuretics.
• Should be used with caution in patients with a history of seizures or heart failure.
• Livedo reticularis sometimes occurs in patients taking amantadine. Usually clears within a month of withdrawing the drug

Question 31

Antimuscaric role in PD?

Answer 31

• Adjuvant therapy.
• May improve tremor and rigidity.
• Little effect on bradykinesia.
• Can produce mood changes, xerostomia, pupillary dilation, confusion, hallucinations, and urinary retention.
• Cannot be used in patients with glaucoma,
prostatic hypertrophy or pyloric stenosis.

Question 32

CHOICE OF TREATMENT

in PD?

Answer 32

• Levodopa + carbidopa is the best treatment.
• Dopamine agonists are the next most effective drugs.
• Addition of a COMT inhibitor or a MAO-B inhibitor to levodopa can reduce motor fluctuations in patients with advanced disease.
• Antimuscarinics can be useful addition to levodopa for control of tremor and drooling.