Page 513 - Basic _ Clinical Pharmacology ( PDFDrive )

CHAPTER 28 Pharmacologic Management of Parkinsonism & Other Movement Disorders 499

Ropinirole complications of dopaminergic treatment and are more common
and severe with dopamine receptor agonists than with levodopa.
Another nonergoline derivative, ropinirole (now available in a generic They tend to occur earlier in older patients and become more
preparation) is a relatively pure D receptor agonist that is effective as common as the disease advances. There appears to be no dif-
2
monotherapy in patients with mild disease and as a means of smooth- ference between the various dopamine agonists in their ability
ing the response to levodopa in patients with more advanced disease to induce these disorders. They may respond to atypical anti-
and response fluctuations. It is introduced at 0.25 mg three times psychotic agents such as clozapine, olanzapine, quetiapine, and
daily, and the total daily dose is then increased by 0.75 mg at weekly risperidone or to pimavanserin.
intervals until the fourth week and by 1.5 mg thereafter. In most Disorders of impulse control may occur either as an exaggeration
instances, a dosage between 2 and 8 mg three times daily is necessary. of a previous tendency or as a new phenomenon and may lead to
Ropinirole is metabolized by CYP1A2; other drugs metabolized by compulsive gambling, shopping, betting, sexual activity, and other
this isoform may significantly reduce its clearance. A prolonged- behaviors (see Chapter 32). Their prevalence varies in different
release preparation taken once daily is available.
reports but may be as high as 15–25% in parkinsonian patients
CH 3 CH 2 CH 2 treated with dopamine agonists. They relate to activation of D or
2
N CH 2 CH 2 D dopamine receptors in the mesocorticolimbic system, may occur
CH 3 CH 2 CH 2 3
with one dopamine agonist and not another, and may occur at any
time after the initiation of treatment. They are not dose-dependent,
O
but in some patients, a dose reduction may ameliorate them; they
N
resolve on withdrawal of the offending medication. Impulse control
Ropinirole disorders are generally under-reported by patients and their families
and often unrecognized by health care professionals. Risk factors
Rotigotine include an impulsive personality, a history of drug use or other
addictive behaviors, and a family history of gambling disorders.
The dopamine agonist rotigotine, delivered daily through a skin
patch, is approved for treatment of early Parkinson’s disease. It E. Miscellaneous
supposedly provides more continuous dopaminergic stimulation Headache, nasal congestion, increased arousal, pulmonary infiltrates,
than oral medication in early parkinsonism; its efficacy in more pleural and retroperitoneal fibrosis, and erythromelalgia are other
advanced disease is less clear. Benefits and side effects are similar reported adverse effects of the ergot-derived dopamine agonists.
to those of other dopamine agonists but reactions may also occur Erythromelalgia consists of red, tender, painful, swollen feet and,
at the application site and are sometimes serious. occasionally, hands, at times associated with arthralgia; symptoms and
signs clear within a few days of withdrawal of the causal drug. In rare
Adverse Effects of Dopamine Agonists instances, an uncontrollable tendency to fall asleep at inappropriate
A. Gastrointestinal Effects times has occurred, particularly in patients receiving pramipexole or
Anorexia and nausea and vomiting may occur when a dopamine ropinirole; this requires discontinuation of the medication.
agonist is introduced and can be minimized by taking the medica- Contraindications
tion with meals. Constipation, dyspepsia, and symptoms of reflux
esophagitis may also occur. Bleeding from peptic ulceration has Dopamine agonists are contraindicated in patients with a history
been reported. of psychotic illness or recent myocardial infarction, or with active
peptic ulceration. The ergot-derived agonists are best avoided in
B. Cardiovascular Effects patients with peripheral vascular disease.
Postural hypotension may occur, particularly at the initiation of
therapy. Painless digital vasospasm is a dose-related complication MONOAMINE OXIDASE INHIBITORS
of long-term treatment with the ergot derivatives (bromocriptine
or pergolide). When cardiac arrhythmias occur, they are an indica- Two types of monoamine oxidase have been distinguished in the
tion for discontinuing treatment. Peripheral edema is sometimes nervous system. Monoamine oxidase A metabolizes norepineph-
problematic. Cardiac valvulopathy may occur with pergolide. rine, serotonin, and dopamine; monoamine oxidase B metabolizes
dopamine selectively. Selegiline (deprenyl) (Figure 28–3), a selec-
C. Dyskinesias tive irreversible inhibitor of monoamine oxidase B at normal doses
Abnormal movements similar to those introduced by levodopa (at higher doses it inhibits monoamine oxidase A as well), retards
may occur and are reversed by reducing the total dose of dopami- the breakdown of dopamine (Figure 28–5); in consequence, it
nergic drugs being taken. enhances and prolongs the antiparkinsonism effect of levodopa
(thereby allowing the dose of levodopa to be reduced) and may
D. Mental Disturbances reduce mild on-off or wearing-off phenomena. It is therefore used
Confusion, hallucinations, delusions, and other psychiatric reac- as adjunctive therapy for patients with a declining or fluctuating
tions may develop as a feature of Parkinson’s disease or as response to levodopa. The standard dose of selegiline is 5 mg with