Which class of drugs is administered to treat on off fluctuations in a patient with Parkinson disease?

Selected Agents Associated with Parkinsonism and Other Acute Extrapyramidal Reactions

Psychosis and/or Hallucinations Induced by Antiparkinsonian Medications

Antiparkinsonian medications such as bromocriptine, amantadine, and levodopa may induce hallucinations, delusions, and agitation and precipitate a manic episode. Treatment consists of reducing the dose of the dopamine agonists and adding an antipsychotic such as quetiapine, which has low extrapyramidal syndrome [EPS] side effects. The addition of clozapine or olanzapine are other options for patients who require dopaminergic medications and control of iatrogenic psychosis. If the symptoms suggest a more manic presentation, it may be helpful to add mood stabilizers such as divalproic acid or carbamazepine. Anticholinergics such as benztropine and trihexiphenidyl used to treat parkinsonism may also lead to a toxic confusional state as well.

Drugs for Parkinson Disease

Selected pharmacokinetic parameters for drugs used for Parkinson disease are listed inTable 15.1.

l-DOPA is always administered with carbidopa to increase plasma levels and the half-life ofl-DOPA and to ensure that sufficientl-DOPA is available to cross the BBB.l-DOPA/carbidopa is rapidly absorbed by the gastrointestinal tract but competes with dietary protein for both intestinal absorption and transport across the BBB.l-DOPA/carbidopa is available in an immediate-release form, which has a half-life of only 60–90 minutes. Controlled-release formulations are available to minimize the number of daily doses required and prolong therapeutic plasma concentrations. A rapidly dissolving formulation ofl-DOPA/carbidopa that dissolves on the tongue is available for Parkinson patients who have difficulty swallowing. This preparation dissolves immediately and releases the active drugs within 30 minutes, with other pharmacokinetic parameters similar to the oral preparations.

The COMT inhibitorsentacapone andtolcapone are rapidly absorbed, highly bound to plasma proteins, and almost completely inactivated before excretion. Like carbidopa, the COMT inhibitors also prolong the half-life ofl-DOPA approximately twofold; entacapone is available in combination withl-DOPA/carbidopa.

Selegiline is rapidly absorbed and metabolized toN-desmethylselegiline, amphetamine, and methamphetamine with half-lives of 2, 18, and 20 hours, respectively.Rasagiline is also rapidly absorbed, but if taken with a meal containing high fat, absorption decreases substantially. Rasagiline is almost totally metabolized in the liver by CYP1A2, followed by glucuronidation and urinary excretion. Although both selegiline and rasagiline have short to intermediate half-lives, because they are irreversible MAO inhibitors, their effects will be manifest until new enzyme is synthesized.Safinamide is also rapidly absorbed, with peak plasma levels reached at 2–4 hours and a half-life of approximately 22 hours. Safinamide is metabolized primarily by nonmicrosomal enzymes to inactive products. Steady-state levels are achieved within 5–6 days of dosing.

Ropinirole andpramipexole differ markedly in their plasma protein binding but have similar half-lives and must be taken orally several times per day. Ropinirole is metabolized extensively by CYP1A2 to inactive metabolites that are excreted in the urine, whereas pramipexole does not appear to be metabolized, with 90% of an administered dose excreted unchanged in the urine. The transdermalrotigotine patch releases drug continuously over 24 hours and, in contrast to the other DA agonists, appears to maintain fairly constant plasma levels throughout the day. Rotigotine is rapidly and extensively metabolized by several P450s in the liver, and glucuronidated and sulfated metabolites are excreted in the urine [71%] and feces [23%].

2.1 Treatment of PD With Natural Antimuscarinic Alkaloids

Antiparkinsonian effects of anticholinergics were first described by Ordenstein [1868], a student of Jean-Martin Charcot, who discovered the beneficial effect of the belladonna alkaloids [mainly containing atropine as active component] on tremor and other PD symptoms, when fortuitously administering tinctures of deadly nightshade [Atropa belladonna] and henbane [Hyoscyamus niger] to patients to control the excessive salivation and drooling [Lang & Blair, 1989]. When Ordenstein wrote a thesis on PD and multiple sclerosis to obtain his medical degree, he mentions “Monsieur Charcot has begun to prescribe 2 or 3 granules of hyoscyamine daily, approximately 1 mg each. This medication was able to provide several hours of rest for some patients” [Fahn, 2015]. At the end of the 19th century, subsequent investigators such as Erb, Mendel, and Gowers began using antimuscarinic substances, such as scopolamine [hyoscine], hyoscyamine [duboisine] and Indian hemp [containing Cannabis sativa] [Erb, 1887; Gowers, 1893; Mendel, 1893]. Hyoscine was the preferred treatment for PD by the end of the 19th century [Oppenheim, 1905], and these natural antimuscarinic alkaloids were widely prescribed in the early 20th century [Fahn, 2015]. In the early 1940s, stramonium, particularly the Bulgarian variety, was thought to be the most potent of the belladonna alkaloids and was often administered in the form of cigarettes, and in the form of wine extracts [Lang & Blair, 1989].

Urinary incontinence is a common problem among women worldwide, resulting in a substantial economic burden and decreased quality of life. The Women's Preventive Services Initiative is the only major organization that recommends annual screening for urinary incontinence in all women despite low to insufficient evidence regarding effectiveness and accuracy of methods. No other major organization endorses screening. Initial evaluation should include determining whether incontinence is transient or chronic; the subtype of incontinence; and identifying any red flag findings that warrant subspecialist referral such as significant pelvic organ prolapse or suspected fistula. Helpful tools during initial evaluation include incontinence screening questionnaires, a three-day voiding diary, the cough stress test, and measurement of postvoid residual. Urinalysis should be ordered for all patients. A step-wise approach to treatment is directed at the urinary incontinence subtype, starting with conservative management, escalating to physical devices and medications, and ultimately referring for surgical intervention. Pelvic floor strengthening and lifestyle modifications, including appropriate fluid intake, smoking cessation, and weight loss, are first-line recommendations for all urinary incontinence subtypes. No medications are approved by the U.S. Food and Drug Administration for treatment of stress incontinence. Pharmacologic therapy for urge incontinence includes antimuscarinic medications and mirabegron. Patients with refractory symptoms should be referred for more invasive management such as mechanical devices, injections of bulking agents, onabotulinumtoxinA injections, neuromodulation, sling procedures, or urethropexy. [Am Fam Physician. 2019;100[6]:339-348. Copyright © 2019 American Academy of Family Physicians.]

Postoperative Management

Postoperative antiparkinsonian treatment should be restarted as soon as possible to relieve discomfort and limit the risk of acute dopaminergic withdrawal and malignant hyperthermia. The postoperative levodopa equivalent dose [LED] should be the same as the presurgical dose and composed primarily of levodopa to facilitate simple titration during the process of programming the stimulation. A confusional state may be present in some patients, but it generally lasts a few days and can be managed easily with atypical antipsychotics such as clozapine or quetiapine. Neuroimaging to confirm the electrode location and to rule out intracranial adverse events is recommended.

Programming can be initiated at any time after the whole device has been implanted depending on the center and the situation of the patient. When a lesionlike effect is present, the programming can be delayed until the parkinsonian symptoms reappear. Programming should be started in the off-medication state to select and set up the parameters with the highest antiparkinsonian efficacy. Parameters inducing permanent adverse events should be ruled out. Stimulation with the greatest efficacy and fewest side effects is selected for therapy. Once programming has been selected, gradual reduction of drug doses has to be initiated to adjust the medication to the new motor state. Levodopa and STN stimulation have similar and additive effects in the antiparkinsonian and dyskinetic states. Thus, in PD patients treated with DBS of the STN, medication titration is needed for fine adjustment of the motor situation in the majority of patients. In cases with DBS of the GPi, this additive effect of stimulation and medication is not as strong, and LED cannot be reduced.

Treatment should be maintained with levodopa to allow the programming to be adjusted adequately to both off- and on-medication motor conditions. Once programming is stable, dopaminergic agonists can help to achieve a more stable motor benefit than levodopa.

After this first adjustment of stimulation and medication, the frequency of visits to the neurologist depends on the patient’s needs and on the available resources of each center. In any case, follow-up visits are recommended.

D Re-Positioning of Existing Drugs for the Ttreatment of Dyskinesia

Drug Class:

Antiparkinsonian

Amantadine

The antiparkinson effects of amantadine, an antiviral agent, were discovered when the drug was used to treat a viral infection in a patient who had PD. The mechanism of action of amantadine is unknown. It has been proposed that the drug [1] prevents dopamine reuptake and facilitates the release of dopamine; [2] has weak anticholinergic properties; and [3] blocks the glutamate N-methyl-d-aspartate [NMDA] receptor, which could contribute to reducing excitation-induced neurotoxicity and dyskinesias. Amantadine offers mild benefit in treating motor symptoms associated with PD in early course of the illness; however, these effects do not last long, and often patients will require more advanced treatment. Amantadine is often used later in the disease course to reduce the severity and extent of dyskinesias induced by levodopa.

Approximately 80% to 90% of amantadine is excreted unchanged in the urine, and accumulation occurs in patients with impaired renal function. This accumulation may lead to the toxic manifestations of confusion, hallucinations, toxic psychosis, and convulsions. Geriatric populations tend to be more sensitive to these adverse effects. Amantadine may cause livedo reticularis of the lower extremities. More common side effects include anorexia, insomnia, nausea, vomiting, dizziness, dry mouth, lightheadedness, lower-extremity edema, and sweating. These side effects are not severe and are limited further by the development of tolerance.

Drug Class:

Antiparkinsonian