Medical Pharmacology: Clinical Presentation, Etiology and Treatment of Parkinson's Disease

Medical Pharmacology Chapter 18: Parkinson's Disease

Dopamine related Drugs in Parkinson's Disease

Dopamine Agonists

Overview^86,101
- While L-DOPA remains central to management of Parkinson's disease symptoms, other drugs which work by direct activation of striatal dopamine receptors are also effective.
- These agents do not depend on enzymatic conversion by aromatic acid decarboxylase (AADC), as is required for L-DOPA.
  - Not requiring enzymatic activation by AADC results in their effectiveness late in the course of Parkinson's disease.
- Dopamine receptor agonists are not competitive with L-DOPA or other neutral amino acids for transport into the brain across the blood brain barrier (BBB).
- Furthermore, contemporary dopamine receptor agonists exhibit half-lives longer than noted for L-DOPA.
  - Longer half-lives result in reduced dosing frequency and increase uniformity of response.
- Dopamine receptor agonists tend also to be helpful in management of dose-related motor state fluctuations.
Several dopamine agonists have been used in management of Parkinson's disease. ^101,108,128
- Of the two relatively older agents, bromocriptine (Parlodel) and pergolide (Permax), pergolide has been removed from the US market because of its association with an asymptomatic valvular heart disease in over 25% of chronically treated individuals.
- Bromocriptine is a strong agonist at the D₂ dopamine receptor subtype and a partial agonist at D₁ sites; furthermore, this agent has been used in management of endocrine disorders including hyperprolactinemia.
- Bromocriptine is absorbed from the gastrointestinal tract with peak plasma levels noted about 1-2 hours subsequent to oral dosing.
  - In order to minimize the development of adverse reactions to bromocriptine, dosing is usually initiated at lower levels and increased over period of a few months.
  - Bromocriptine (Parlodel)
Relatively newer agents include ropinerole (Requip), pramipexole (Mirapex) and rotigotine (Neupro). ^101,108,128
- Ropinerole exhibits receptor selectivity at D₂ while pramipexole is active mainly at D₃ sites; however, they exhibit extremely limited activity at D₁ receptors.
- Ropinerole (Requip) can be used as effective monotherapy in patients with mild disease and may also assist in "smoothing" L-DOPA response in patients who exhibit more advanced Parkinsonian symptoms as well as L-DOPA response fluctuations.
  - Ropinerole is metabolized by the liver microsomal enzyme CYP1A2; therefore, other drugs that are metabolized by the same cytochrome P450 enzyme can reduce ropinerole metabolism.
  - Ropinerole (Requip)
- Pramipexole (Mirapex) is also effective in monotherapy for patients exhibiting mild Parkinson's disease symptoms and, as was noted for ropinerole, can "smooth" L-DOPA response fluctuations. ^101,108,128
  - Pramipexole is readily absorbed following oral administration and reaches peak plasma concentrations about two hours following dosing.
  - Pramipexole is excreted unchanged in the urine and, similar to bromocriptine, dosing involves a slow buildup over a period of a few weeks.
    - Pramipexole (Mirapex)
- Ropinerole is available in a long-acting formulation with the intent of achieving more continuous dopaminergic agonist effects.
- Another long-acting agent rotigotine (Neupro) was promoted for transdermal patch delivery.
  - Although initially achieving FDA approval, rotigotine was removed from the market in 2008 due to crystal formation in the patch, a problem for delivery. At this time (2010), rotigotine has not been granted re-approval.
Another agent, apomorphine is available for subcutaneous injection. ^101,108,128
- Apomorphine is approved in the United States for the purpose of rescue therapy for dose failure, manifesting as motor fluctuations with extended "off" periods which affect patients with moderate to advanced Parkinson's disease.
  - Apomorphine
- Apomorphine exhibits highest affinity for D₄-type dopamine receptors and intermediate affinity for D₂, D₃, and D₅ receptor subtypes.¹⁰¹
  - Apomorphine binds to D₁dopamine receptors with low affinity.
  - Apomorphine is also an agonist at adrenergic α-receptors, specifically α_1D, α_2B, and α_2C subtypes.
- Apomorphine is a profound emetic and therefore requires pretreatment and post treatment with anti-emetic medications.¹⁰¹
  - Hypotention with loss of consciousness has been associated with concurrent administration of the anti-emetic (5-HT₃ antagonist type) ondansetron and apomorphine is the basis for contraindication of this class of anti-emetic drug use to manage apomorphine-associated emesis.
    - Ondanesetron (Zofran), a 5-HT₃-receptor antagonist antiemetic
  - Alternatively, oral trimethobenzamide (Tigan) may be used.
    - Trimethobenzamide (Tigan)
- Important side effects associated with apomorphine include injection-site effects, drug abuse, and the cardiac electrophysiological effect of QT prolongation.¹⁰¹
  - QT prolongation may predispose to ventricular arrhythmia.
    - ECG diagram of human normal sinus rhythm¹²⁹
  - Increased apomorphine use in the context of drug abuse can cause dyskinesia, hallucinations as well as unusual behavior.¹⁰¹
    - The range and character of these adverse effects suggest that apomorphine administration should be limited to those cases when dopamine agonists or COMT (catechol-O-methyltransferase) inhibitors have been shown insufficient to manage "off" periods.
Dopamine agonists have been approved for management of Parkinson's disease at every stage and in combination with other drugs; however, administration of two dopamine agonists concurrently is not recommended.
- Dopamine agonists are especially useful in managing bradykinesia, loss of fine motor dexterity, gait disturbances and tremor.
- At the higher doses, dose-dependent side effects are of increasing concern, particularly if the dopamine agonist is combined with L-DOPA/carbidopa and psychotropic medications.

Side effects: dopamine agonists^128,108

Side effects/adverse effects associated with dopamine agonist administration are described in several different organ systems.

Initiation of dopamine agonist treatment may be associated with nausea and vomiting and anorexia.
Nausea may be managed by use of peripheral dopamine antagonists including domperidone (not available in the United States) or by trimethobenzamide or dronabinol.
Other gastrointestinal complications include:
- Reflux esophagitis
- Dyspepsia and
- Constipation.
Prominent cardiovascular effects include orthostatic hypotension, again noted usually at the beginning of treatment.
- Vasospasm affecting the digits has also been reported associated with prolonged administration of bromocriptine (an ergot derivative).
- Dopamine agonist-induced cardiac arrhythmias represent a serious adverse reaction and constitute a basis for discontinuing management with these agents.
With respect to CNS effects both dyskinesias and mental abnormalities have been reported.
- Dyskinesias appear comparable to those noted with L-DOPA administration and maybe managed by dosage reduction.
- Compared to L-DOPA, CNS effects including confusion, delusions, hallucinations as well as other psychiatric sequelae are more likely with dopamine receptor agonists.
  - Impulse control abnormalities, such as gambling, sexual activity, shopping and other related activities, are associated with dopamine agonists.
  - Another CNS effect of dopamine agonists, which is seen to a lessened extent with L-DOPA/carbidopa administration, is "sleep attacks", which can appear without warning.
    - Such reactions have been associated with traffic accidents and represent the complication that requires discontinuation of the causative drug. "Sleep attacks" appear most likely associated with ropinerole and pramipexole administration.

Some miscellaneous effects include: headache, pulmonary infiltrates, pleural and retroperitoneal fibrosis, and erythromelalgia (Mitchell's disease).

Retroperitoneal fibrosis (Ormond's disease) is characterized by fibrous tissue proliferation in the retroperitoneum, a body compartment containing many anatomical structures including kidneys, renal tract, and aorta.¹³²
- Idiopathic retroperitoneal fibrosis (RPF) is thought to be autoimmune in nature; however, many cases are associated with medications, malignancy or aortic aneurysm.

Erythromelalgia is a peripheral neurovascular pain disorder characterized by intermittent blood vessel constriction.

This disorder is associated with significant burning pain and skin redness.

"Erythromelalgia: This 77-year-old woman with longstanding polycythemia vera had a six-month history of increasingly prolonged bouts of redness, swelling, and burning pain in her extremities. The severity and sites of involvement varied with each episode. At presentation, she was unable to ambulate without assistance."¹³⁰
"

Primary erythromelalgia is associated with an abnormal voltage-gated sodium channel α-subunit due to mutation.^131,130
- This disorder represented the first association between chronic neuropathic pain and ion channel mutation.
- Secondary erythromelalgia may occur due to small fiber peripheral neuropathy of a variety of causes, including medications (bromocriptine, verapamil and nifedipine, for example).

Dopamine agonists are contraindicated in those patients with pre-existing psychotic illness or active peptic ulceration or recent myocardial infarction.
Ergot-derived agents, such as bromocriptine, probably should not be used in individuals with peripheral vascular disease.

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