Susan R. Winkler, Pharm.D., BCPS
Spring 1998

Pharmacotherapy of Parkinson's Disease

  1. Parkinson's Disease
  2. Anatomy
  3. Pathophysiology
  4. Diagnosis
  5. Clinical Presentation
  6. Drug Therapy

Goals and Objectives:

1. Discuss the various etiologies of Parkinson’s disease.

2. Describe the major signs and symptoms associated with the disease.

3. Outline a rational therapeutic approach for the treatment of Parkinson’s disease.

4. Name the principle drugs and chemicals that may cause symptoms of the ailment.

5. List the major advantages and disadvantages of the drugs used to treat Parkinson’s disease.

6. Counsel patients regarding the appropriate administration, adverse effects and drug interactions associated with the medications used in the treatment of Parkinson’s disease.

Required Reading:

Nelson MV, Berchou RC, LeWitt, PA. Parkinson’s disease, in Dipiro JT, Talbert RL, Yee GC, Matzke GR, Wells BG, Posey LM (eds): Pharmacotherapy: A Pathophysiologic Approach. Third Edition. New York, Elsevier, 1997. Chapter 58, pp. 1243-1257.

I. Parkinson’s Disease

A. Parkinson’s Disease is a progressive, neurologic disorder caused by a degeneration of dopaminergic neurons. It is characterized clinically by four main features including resting tremor, rigidity, bradykinesia and postural instability.

B. Incidence:

Annual incidence rates are estimated at approximately 20 per 100,000 in North America.

C. Mortality:

Parkinson’s disease is a chronic, degenerative disease which progresses fairly slowly. With treatment, the life expectancy and death rates for Parkinson’s disease and non-Parkinson’s disease individuals are essentially equal.

D. Classification:

1. degenerative

2. infectious

3. drug and chemical-induced

  1. reversible
  2. non-reversible

II. Anatomy

A. Pyramidal System

B. Extrapyramidal System

1. Basal Ganglia

  1. substantia nigra
  2. neostriatum
  3. globus pallidus

2. Caudate Nucleus

III. Pathophysiology

A. Movement in the human body is produced by the motor cortex. The main motor pathway consists of the pyramidal system which extends from the motor cortex to the spinal cord. Lower motor neurons carry signals from the spinal cord to muscle to produce movement. The pyramidal system is modulated by the "extrapyramidal" circuit, which includes the substantia nigra, striatum, subthalamic nucleus, the external and internal segments of the globus pallidus, and the thalamus.

B. The extrapyramidal system can either promote or inhibit movement depending on tonic dopamine innervation of the striatum. Normal movement is dependent on appropriate dopamine production by substantia nigra neurons innervating the striatum.

C. Dopaminergic neurons originate in the substantia nigra and synapse with neurons in the caudate nucleus. Cholinergic neurons originate in the globus pallidus and also synapse with neurons in the caudate nucleus. Normal movement is a result of a balance between dopamine (inhibitory) and acetylcholine (excitatory) activity.

D. Pathologically, Parkinson’s disease is characterized by the massive degeneration of the presynaptic neurons of the substantia nigra, which results in a deficiency of DOPAMINE in the caudate nucleus. When approximately 60- 80% of the dopamine producing neurons of the substantia nigra are lost, the symptoms of Parkinson’s disease appear.

E. Deficiency of dopamine and relative excess of acetylcholine produces the characteristic symptoms of Parkinson’s disease. A relative excess of dopaminergic activity would result in abnormal involuntary movements or dyskinesia.

IV. Diagnosis

A. Neurological Examination

B. History

C. R/O other diseases (cerebrovascular disease, medications, toxins, infection, normal pressure hydrocephalus, metabolic abnormalities, and other degenerative diseases)

D. Response to levodopa therapy

V. Clinical Presentation

A. Resting Tremor

B. Rigidity

C. Bradykinesia

D. Postural Disturbances (develops late in the disease process)

E. Other Symptoms

  1. difficulty with fine coordinated movements
  2. daily tasks may be more difficult to perform
  3. family members may notice a flattened facial expression (masked facies)
  4. voice may become soft (hypophonia) and monotonal
  5. first affected arm may not swing fully when walking and the foot on that side may scuff the floor (shuffling gait)
  6. handwriting may be small and cramped (micrographia)
  7. patient may eventually notice drooling and have difficulty swallowing foods
  8. pain may occur in an affected limb
  9. depression or dementia may emerge
  10. symptoms of autonomic dysfunction are common (constipation, urinary frequency, sweating abnormalities, dermatitis, and sexual dysfunction)

F. Staging

1. Stage I: Unilateral involvement

2. Stage II: Bilateral or axial involvement without balance impairment

3. Stage III:

4. Stage IV:

5. Stage V:

VI. Drug Therapy

It is important to remember that there is no cure for Parkinson’s disease. Treatment is only symptomatic. No drug therapy is proven to prevent or stop the progression of the disease.

Each treatment plan must be individualized for each patient and usually requires frequent changes. It is important to include in the treatment plan other modalities of treatment such as exercise, physical therapy, speech therapy and psychological support.

A. Anticholinergics

1. Dosing

Benztropine (Cogentin)-------- 0.5-6 mg/day --------available in 0.5, 1, 2 mg

Biperiden (Akineton) -----------2-16 mg/day --------available in 2 mg

Diphenhydramine (Benadryl)--- 25-100 mg/day ------available in 25, 50 mg

Procyclidine (Kemadrin) --------2.5-20 mg/day ------available in 5 mg

Trihexyphenidyl (Artane) ---------1-15 mg/day -------available in 2, 5 mg, 2/5 mL, 5 LA

2. Contraindications

  1. BPH
  2. narrow angle glaucoma
  3. GI obstruction

3. Side Effects

  1. dry mouth, dry eyes
  2. urinary retention
  3. blurred vision
  4. constipation
  5. tachycardia
  6. mental confusion, forgetfulness
  7. hallucinations
  8. sedation
  9. depression
  10. anxiety

4. Use in Therapy

  1. The anticholinergics are most effective for reducing tremor and usually provide minimal benefit with regard to bradykinesia and rigidity. Their use is often limited by side effects and they are less well tolerated by older patients and those with dementia.
  2. May be considered for the treatment of tremor that causes functional disability. Some patients with early disease have tremor without bradykinesia or rigidity and these patients may also benefit from anticholinergic therapy.

B. Amantadine

1. Dosing

Amantadine (Symmetrel) 200-300 mg/day (100 mg PO BID or TID) available in 100 mg & 50/5 mL

2. Contraindications

  1. hypersensitivity to amantadine
  2. CHF ?
  3. seizure disorder ?

3. Side Effects

  1. dry mouth
  2. ankle edema
  3. livedo reticularis
  4. sedation (may decrease with time)
  5. vivid dreams ( may decrease with time)
  6. depression, hallucinations, dizziness
  7. confusion, psychosis, anxiety

4. Use in Therapy

  1. The exact mechanism of action is unknown; however, it appears to augment dopamine release, may inhibit dopamine reuptake and may stimulate dopamine receptors.
  2. Well absorbed with a long half-life of 24 hours.
  3. Renally eliminated, use with caution in patients with renal dysfunction and adjust dose based on creatinine clearance.

C. Levodopa (Larodopa) and Carbidopa/Levodopa (Sinemet)

1. DOPAMINE does not cross the blood-brain-barrier; therefore, levodopa, a precursor of dopamine, is administered instead. Levodopa is capable of crossing the blood-brain-barrier. When given alone, large oral doses are required since levodopa undergoes metabolism by the enzyme dopa-decarboxylase in the periphery as well as centrally.

2. Modern therapy now combines levodopa with carbidopa, a dopa- decarboxylase inhibitor. This prevents the conversion of levodopa to dopamine in the periphery, while allowing its conversion in the CNS. This leads to a decrease in peripheral side effects such as nausea, vomiting, cardiac arrhythmias and postural hypotension and an increase in the amount of levodopa that is transported into the brain.

3. Levodopa therapy is the cornerstone of symptomatic treatment. It is most effective in relieving bradykinesia and rigidity, while its effect on tremor is highly variable.

4. Dosing

  1. Dosage Forms
  1. Sinemet 10/100 and 25/250 (1:10 ratio)
  2. Sinemet 25/100 (1:4 ratio)
  3. Sinemet CR 25/100, 50/200
  4. Larodopa, Dopar 100, 250, 500 mg
  1. Dose of levodopa is decreased by 75-80% when used with carbidopa and the effective dose can be achieved more rapidly. Does not eliminate all side effects and may cause additional ones.
  2. Approximately 75-100 mg of carbidopa are required to saturate peripheral decarboxylase.
  3. Administer on an empty stomach; one-half hour before meals or one to two hours after meals to achieve consistent absorption.
  4. The dose must be tailored to the individual patient. Start with a low dose and titrate slowly to the desired effect.

5. Contraindications

  1. patients with a history of melanoma
  2. patients currently on MAOI’s (not MAOI type B)

6. Side Effects

  1. nausea
  2. orthostatic hypotension
  3. confusion, hallucinations, delusions, hypersexuality
  4. cardiac arrhythmias
  5. abnormal involuntary movements (AIMS)
  6. end-of-dose failure
  7. on-off phenomenon

D. Dopamine Agonists

1. Place in Therapy

  1. Dopamine agonists do not depend on functioning presynaptic neurons for their pharmacologic activity. They directly stimulate post-synaptic dopamine receptors.
  2. They provide symptomatic benefit as adjuncts to levodopa, and as monotherapy in early disease.
  3. Monotherapy with dopamine agonists is generally as effective as levodopa when a patient first requires symptomatic therapy.
  4. After one to three years of disease progression, monotherapy often becomes inadequate and levodopa therapy must be added.
  5. In moderate and advanced disease, patients with motor fluctuations on levodopa may benefit from the addition of a dopamine agonist to smooth motor fluctuations and improve symptom control.

2. Bromocriptine (Parlodel)

  1. Bromocriptine is an ergot alkaloid dopamine receptor agonist. It is a strong D2 receptor agonist and a weak D1 receptor antagonist. It stimulates both pre- and post-synaptic receptors.
  2. Dose
  1. Begin with 1.25 mg per day.
  2. Increase slowly to 10-40 mg per day.
  1. Contraindications
  1. history of psychosis
  2. severe angina
  3. recent MI
  4. peptic ulcer disease
  1. Side Effects
  1. nausea, vomiting
  2. orthostatic hypotension (first dose should be taken lying down)
  3. nightmares, hallucinations, confusion
  4. leg edema
  5. constipation
  6. erythromelalgia (painful, reddish skin discoloration)

3. Pergolide (Permax)

  1. Strong D1 receptor agonist and a weak D2 receptor agonist.
  2. More potent and longer duration of action than bromocriptine.
  3. Dose
  1. Begin with 0.025 mg per day.
  2. Titrate to 0.25 mg TID over one month.
  3. Daily doses of up to 3.0 mg per day are usually well tolerated.
  1. Side Effects
  1. similar to those of bromocriptine

4. Ropinirole (Requip)

  1. Highly selective D2 agonist with little affinity for D1, 5HT, muscarinic or adrenergic receptors.
  2. Dose
  1. Begin with 0.25 mg TID.
  2. Titrate to 1.0 mg TID over one month.
  3. Patients may respond to dose of 1-3 mg TID.
  1. Side Effects
  1. similar to the other dopamine agonists

5. Pramipexole (Mirapex)

  1. non-ergot D2/D3 agonist
  2. Binds to D3 receptors with a 7-fold greater affinity than to D2 or D4 receptors and has little affinity for D1, 5HT, muscarinic, or adrenergic receptors.
  3. Dose
  1. Begin at 0.25 mg per day.
  2. Increase to 1.5 mg per day over one month.
  3. The usual maximum dose is 3-4.5 mg per day.
  1. Side Effects
  1. similar to the other dopamine agonists
  2. Somnolence may be more common than with the other agents and may necessitate a dose reduction or discontinuation.

6. Cabergoline

  1. Long-acting ergot derivative agonist with a high affinity for D2 receptors. The biological half-life is 65 hours; therefore, it is administered once daily.
  2. Dose
  1. Begin at a dose of 0.05 mg per day.
  2. Titrate to a maximum dose of 5.0 mg per day.

7. Lisuride

  1. Hydrophilic semisynthetic ergot alkaloid dopamine agonist that stimulates D2 and 5HT receptors.
  2. available in Europe

8. Apomorphine

  1. D2 and D1 receptor agonist that is highly lipophilic and is administered SC.
  2. available in Europe

E. Selegiline (Eldepryl, L-Deprenyl)

1. irreversible MAO B Inhibitor

2. Blocks the breakdown of dopamine in the brain and may also interfere with the uptake of dopamine at the synapse.

3. Selegiline might protect the substantia nigra cells and slow the progression of Parkinson’s disease; however, this effect has only been demonstrated to last for about one year.

4. Metabolized in liver to L-amphetamine and L-methamphetamine

5. Dose

  1. most commonly used dose is 10 mg/day

6. Side Effects

  1. vivid dreams, nightmares
  2. insomnia
  3. dizziness
  4. jitteriness

7. Drug Interactions

  1. meperidine
  2. fluoxetine

8. Role in Therapy

  1. May boost the symptomatic effect and extend the duration of action of levodopa by slowing the breakdown of dopamine. May allow a decrease in the dose of levodopa needed for an optimal effect.
  2. It is beneficial as an adjunct to levodopa for patients who are experiencing a deterioration in the quality of their response. For patients with motor fluctuations, selegiline reduces "off" time and extends the short duration of response to levodopa.
  3. The use of selegiline in early Parkinson’s disease delays the need for levodopa therapy (15 vs. 24 months in the DATATOP Study).
  4. Increases the peak concentration of levodopa and may increase or enhance the adverse effects of levodopa such as dyskinesia and psychiatric symptoms.

F. COMT (Catechol-O-methyltransferase) Inhibitors

1. Role in Therapy

  1. COMT is one of the main enzymes responsible for the metabolism of levodopa, dopamine, adrenaline, noradrenaline and their metabolites. COMT is widely distributed throughout the body, but not in the nigrostriatal dopamine neurons.
  2. When levodopa is administered with a peripheral dopa- decarboxylase inhibitor, COMT metabolism of levodopa predominates.
  3. Peripherally acting COMT inhibitors block COMT in the gut and periphery. By making more levodopa available for transport across the blood-brain-barrier. When COMT inhibitors are added to levodopa therapy, striatal dopamine concentrations increase.

2. Tolcapone

  1. reversible COMT inhibitor both centrally and peripherally
  2. Dose
  1. 100-200 mg TID
  1. Side Effects
  1. mostly those relating to increased dopaminergic stimulation
  2. dyskinesia
  3. nausea, vomiting
  4. hallucinations
  5. hypotension

3. Entacapone

  1. reversible peripheral COMT inhibitor
  2. Side Effects
  1. similar to tolcapone

G. Surgical Treatments

1. transplantation of autologous adrenal medulla tissue into the caudate nucleus(results disappointing)

2. implantation of dopamine-rich dissociated mesencephalic fetal tissue into the caudate nucleus (still investigational due to ethical issues)

3. ventrolateral thalamotomy for tremor reduction

4. ventroposterior pallidotomy for reduction of akinesia and rigidity

  1. involves destroying a section of nerve tissue in the globus pallidus

H. Other Treatments

1. Chronic Thalamic Stimulation

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