Treatment of Parkinson disease (J.W. Choi M.D., Ph.D.

2011-10-14

Pharmacologic management of Parkinsonism & Other movement disorders

Treatment of Parkinson disease (J.W. Choi M.D., Ph.D.)

2011-10-14

1. 2. 3. 4. 5. 6. 7. Parkinson ? Parkinson l-dopa L-dopa on-off L-doap L-dopa aromatic l-amino acid decarboxylase Parkinson Bromocriptine

Treatment of Parkinson disease (J.W. Choi M.D., Ph.D.)

2011-10-14

Parkinson's Disease
Chronic, progressive Equal gender distribution Frequency:
General Population: 1-2 per 1000 people Population > 65 years: 1 per 100 persons

Treatment of Parkinson disease (J.W. Choi M.D., Ph.D.)

2011-10-14

Symptoms of Parkinson's disease

Tremor Rigidity Bradykinesia Postural instability

Characteristic gait/postural abnormality

Treatment of Parkinson disease (J.W. Choi M.D., Ph.D.)

2011-10-14

dopamine (caudate nucleus) (Putamen) (substantia nigra) (g/g) 3.55 3.46 0.76 Parkinson (g/g) 1.10 1.80 0.07

Treatment of Parkinson disease (J.W. Choi M.D., Ph.D.)

2011-10-14

Treatment of Parkinson disease (J.W. Choi M.D., Ph.D.)

2011-10-14

Dopamine receptors

Treatment of Parkinson disease (J.W. Choi M.D., Ph.D.)

2011-10-14

Treatment of Parkinson disease (J.W. Choi M.D., Ph.D.)

2011-10-14

Treatment of Parkinson disease (J.W. Choi M.D., Ph.D.)

2011-10-14

Parkinson's disease
Cause
Possibilities include: Environmental toxin : MPTP, MPP+ Endogenous toxins

Genetic Aspect:
Possibilities include: -Synuclein, parkin, UCHL1

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Treatment of Parkinson disease (J.W. Choi M.D., Ph.D.)

2011-10-14

Pharmacokinetics: L-DOPA
Dopamine

does not cross blood-brain barrier crosses the blood-brain barrier (LAT, L-amino acid transporter) decarboxylation to dopamine

Levodopa

Rapid absorption from small intestine, influenced by:

Gastric emptying rate, food

Plasma levels
Peak at 1~2 hrs after oral dose t1/2, 1~3 hrs

Peripheral aromatic amino acid decarboxylase

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Treatment of Parkinson disease (J.W. Choi M.D., Ph.D.)

2011-10-14

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Treatment of Parkinson disease (J.W. Choi M.D., Ph.D.)

2011-10-14

Levodopa & aromatic a.a. decarboxylase inhibitor

Carbidopa
Peripheral dopa decarboxylase inhibitor Prolong plasma half-life of levodopa more levodopa available for brain entry
~75% reduction in daily levodopa

Benserazide

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Treatment of Parkinson disease (J.W. Choi M.D., Ph.D.)

2011-10-14

Clinical use: levodopa

Usage: levodopa plus carbidopa Clinical Efficacy:
most effective in diminishing bradykinesia improves all Parkinson's disease symptoms

Efficacy to L-DOPA diminishes with time (~ 3-4 yrs) Does not stop disease progression

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Treatment of Parkinson disease (J.W. Choi M.D., Ph.D.)

2011-10-14

Gastrointestinal Effects: levodopa

20%: when administered with carbidopa 80%: monotherapy Anorexia, nausea & vomiting:
brain stem emetic center tolerance do not use phenothiazines (reduced efficacy of levodopa/disease exacerbation)

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Treatment of Parkinson disease (J.W. Choi M.D., Ph.D.)

2011-10-14

Cardiovascular Effects: levodopa

Arrhythmias:
low incidence possibly due to increased catecholamine synthesis in peripheral tissues

Orthostatic hypotension:
common side effect less frequent a problem with continuing therapy

Hypertension
very large doses of levodopa, sympathomimetics, or nonselective MAO inhibitors

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Treatment of Parkinson disease (J.W. Choi M.D., Ph.D.)

2011-10-14

Dyskinesias: levodopa
80%: with long-term treatment Dose-related Dyskinesias:
chorea, ballismus, athetosis, dystonia, myoclonus, tics, tremor the particular dyskinesia tends to remain constant most common: choreoathetosis of the face and distal extremities

Management:
dosage reduction drug holidays

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Treatment of Parkinson disease (J.W. Choi M.D., Ph.D.)

2011-10-14

Behavioral Effects: levodopa

Adverse mental effects:
depression, agitation, insomnia, somnolence, anxiety, confusion, delusions, hallucinations, euphoria, nightmares, mood changes, personality changes

More common: L-DOPA + carbidopa Management:

Drug holiday Atypical antipsychotics: clozapine, olanzapine, quetiapine, risperidone

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Treatment of Parkinson disease (J.W. Choi M.D., Ph.D.)

2011-10-14

Response Fluctuations: levodopa

Wearing-off reractions; end-of-dose akinesia
related to L-DOPA intake timing

On-off phenomenon
unrelated to L-DOPA intake timing unknown mechanism alternating intervals of marked akinesia with intervals of control (or marked dyskinesia) management: dopamine agonists (e.g.,apomorphine SQ)

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Treatment of Parkinson disease (J.W. Choi M.D., Ph.D.)

2011-10-14

Miscellaneous Adverse Reactions: levodopa Mydriasis acute glaucoma Blood dyscrasias: rare Precipitation/worsening: gout Others

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Treatment of Parkinson disease (J.W. Choi M.D., Ph.D.)

2011-10-14

Drug Holidays: levodopa

D/C of the drug for 3~21 days Helpful:
neurological adverse effects behavioral adverse effects little advantage in managing the on-off phenomenon

Risks:
aspiration pneumonia, pulmonary embolism, venous thrombosis, depression from the immobility accompanying severe parkinsonism

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Treatment of Parkinson disease (J.W. Choi M.D., Ph.D.)

2011-10-14

Drug Interactions: levodopa

Pyridoxine (vitamine B6)
increases metabolism of levodopa in peripheral tissues (in the absence of carbidopa)

MAO-A inhibitors + levodopa

risk for hypertensive crisis

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Treatment of Parkinson disease (J.W. Choi M.D., Ph.D.)

2011-10-14

Contraindications: levodopa
1. Psychotic patients 2. Angle-closure glaucoma 3. Melanoma
levodopa is a precursor of melanin

4. Careful management is required in cases of:

cardiac disease peptic ulcer disease (bleeding may be precipitated)

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Treatment of Parkinson disease (J.W. Choi M.D., Ph.D.)

2011-10-14

Dopamine Agonists
Ergot alkaloids
Bromocriptine
D2 agonist, D1 partial antagonist

Pergolide
D1 and D2 agonist

Non-ergoline derivatives
Pramipexole, PO Ropinirole, PO Rotigotine, patch

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Treatment of Parkinson disease (J.W. Choi M.D., Ph.D.)

2011-10-14

Gastrointestinal effects: Dopamine agonists

Common side effect:
anorexia, nausea, vomiting

Others:
constipation, dyspepsia, symptoms of reflux esophagitis peptic ulceration with bleeding

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Treatment of Parkinson disease (J.W. Choi M.D., Ph.D.)

2011-10-14

Cardiovascular effects: Dopamine agonists

Common
postural/orthostatic hypotension -- early in therapy

Digital vasospasm
ergot alkaloids occurs with long-term treatment reversible by decreasing dosage

Cardiac arrhythmias
indication for drug discontinuation

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Treatment of Parkinson disease (J.W. Choi M.D., Ph.D.)

2011-10-14

Other adverse effects: Dopamine agonists

Dyskinesias
similar to levodopa dyskinesias reduction in total dopaminergic agents indicated

Mental Disturbances
more common/severe with bromocriptine than with levodopa confusion, hallucinations, delusions, etc.

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Treatment of Parkinson disease (J.W. Choi M.D., Ph.D.)

2011-10-14

Contraindications: Dopamine agonists

Psychosis Recent myocardial infarction Relative contraindications:
peripheral vascular disease peptic ulcer

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Treatment of Parkinson disease (J.W. Choi M.D., Ph.D.)

2011-10-14

Monoamine Oxidase
Monoamine oxidase A (MAO-A)
norepinephrine, serotonin, dopamine

Monoamine oxidase B (MAO-B)

dopamine predominant form in striatum

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Treatment of Parkinson disease (J.W. Choi M.D., Ph.D.)

2011-10-14

Selegiline (deprenyl)
Selective irreversible inhibitor of MAO-B Prolongs levodopa effect (inhibits metabolism)
may allow levodopa dose reduction may reduce mild on-off syndrome may reduce wearing-off phenomenon

Adjunctive treatment to L-DOPA

dose not inhibit peripheral metabolism of catecholamines

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Treatment of Parkinson disease (J.W. Choi M.D., Ph.D.)

2011-10-14

Adverse/toxic Effects:selegiline
Should not be used if patients are taking:
tricyclic antidepressants serotonin reuptake inhibitors meperidine (Demerol)

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Treatment of Parkinson disease (J.W. Choi M.D., Ph.D.)

2011-10-14

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Treatment of Parkinson disease (J.W. Choi M.D., Ph.D.)

2011-10-14

Levodopa & COMT inhibitors

Tolcapone
Liver function test

Entacapone Helpful in patients who developed response fluctuation

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Treatment of Parkinson disease (J.W. Choi M.D., Ph.D.)

2011-10-14

Apomorphine
Potent dopamine agonist Temporary relief of off-periods of akinesia Apomorphine hydrochlorde S.Q.
effect begins within ~10 min, lasts ~2 hrs

Nausea, dyskinesia, drowsiness, hypotension etc.

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Treatment of Parkinson disease (J.W. Choi M.D., Ph.D.)

2011-10-14

Amantadine
Antiviral drug Mechanism of action
Unclear may influence dopamine release /reuptake/ synthesis

Pharmacokinetics
peak plasma levels: 1-4 hours half-life: 2-4 hours urinary excretion: mainly unchanged

Clinical Use
short-term benefits improves rigidity, tremor, bradykinesia

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Treatment of Parkinson disease (J.W. Choi M.D., Ph.D.)

2011-10-14

Anticholinergics
Improvement: rigidity, tremor Minor effect: bradykinesia
Drug Benztropine mesylate Biperiden Orphenadrine Procyclidine Trihexyphenidyl Usual daily dose (mg) 1-6 2-12 150-400 7.5-30 6-20

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Treatment of Parkinson disease (J.W. Choi M.D., Ph.D.)

2011-10-14

Contraindications: antimuscarinics
Prostatic hyperplasia Obstructive gastrointestinal disease:
pyloric stenosis paralytic ileus

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Treatment of Parkinson disease (J.W. Choi M.D., Ph.D.)

2011-10-14

Questions ?
jwchoiphar@yonsei.ac.kr HP: 010-8786-9174 pharmacology2011_2@yahoo.co.kr

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