Pharmacologic Safety Concerns in Parkinson's Disease: Facts and Insights

ABSTRACT

Knowledge and insight of pharmacologic safety issues and drug interactions are important for medical management of Parkinson's disease (PD). This review will discuss several topics, including apomorphine safety and interactions, impulsivity and excessive daytime somnolence associated with dopamine agonists (DAs), tolcapone hepatotoxicity, and monoamine oxidase type-B (MAO-B) inhibitor drug interactions. Initiation of apomorphine requires antiemetic prophylaxis to minimize nausea and orthostatic hypotension. Centrally acting antidopaminergic antiemetics will worsen parkinsonism and block the therapeutic effects of apomorphine and should be avoided. Additionally, serotonin 5-HT₃ receptor antagonist antiemetics should be avoided on the basis of limited clinical data suggesting lack of efficacy for apomorphine-induced nausea. Dopamine-agonist-induced impulsivity and daytime somnolence are not uncommon. When severe, these effects can be disabling and unsafe. Tolcapone-induced hepatotoxicity has been significantly minimized with routine monitoring of liver enzymes, especially during the initial 6 months of therapy. Early detection of abnormal results will allow tolcapone discontinuation before progression to fulminant hepatotoxicity. In patients treated with selective MAO-B inhibitors, the risk of serotonin toxicity (ST) due to a concomitant serotonergic agent (e.g., antidepressants, dextromethorphan, serotonergic analgesics) or hypertensive crisis due to dietary tyramine or sympathomimetic amines appears to be minimal and is based on isolated case reports and overgeneralizations from nonselective MAO inhibitor pharmacology. Concerns about ST or hypertensive crisis should not preclude or restrict clinicians from using MAO-B inhibitors in patients with PD.

KEYWORDS: :

• COMT inhibitors
• dopamine agonists
• drug interactions
• MAO-B inhibitors
• Parkinson's disease
• pharmacotherapy
• safety
• side effects

INTRODUCTION

Appropriate knowledge and understanding of pharmacologic safety issues and drug interactions can enable clinicians to better manage pharmacotherapy decisions for patients with Parkinson's disease (PD). The purpose of this article is to provide insight and facts regarding selected safety concerns and drug interactions associated with anti-Parkinson agents.

APOMORPHINE AND ANTIEMETICS

Apomorphine is a short-acting dopamine agonist (DA) that is effective for alleviation of “off” episodes in patients with PD [1]. Intermittent subcutaneous injection of apomorphine results in rapid onset of effect and significant improvement of motor features.

The initial administration of apomorphine is performed under medical supervision to enhance safety and establish efficacy. Clinicians should monitor for acute treatment emergent orthostasis. Supine and standing blood pressure are taken before administration of the initial test dose and at 20, 40, and 60 minutes after the dose. If significant orthostatic hypotension develops, the patient is not considered a candidate for apomorphine therapy. Patients with pre-existing neurogenic orthostatic hypotension may not be suitable candidates for apomorphine. Orthostasis may be exacerbated in patients taking concomitant antihypertensive agents or vasodilators.

Apomorphine is a potent emetic. Prior to initiation of apomorphine, 3 days of prophylactic antiemetic therapy with trimethobenzamide (300 mg three times a day [TID]) is recommended to minimize the risk of nausea and vomiting [1]. Many patients are able to discontinue concurrent antiemetic therapy within 2–4 months after initiation of apomorphine. Antiemetic prophylaxis with central dopamine receptor blockers (e.g., metoclopramide, prochlorperazine) should be avoided due to the likelihood of worsening the underlying parkinsonism as well as antagonizing the effect of apomorphine and other dopaminergic PD agents. The package insert for apomorphine provides a warning that antiemetics that block serotonin 5-HT₃ receptors (e.g., granisetron, ondansetron) should also be avoided due to reports of profound hypotension and loss of consciousness [2].

A search of the literature reveals a double-blinded, randomized study that assessed the efficacy of ondansetron for prevention of apomorphine-induced nausea [3]. Eight patients with untreated PD were administered a single oral dose (8 mg) of ondansetron at least 2 hours prior to an apomorphine (2 or 3 mg) subcutaneous challenge. The comparator group consisted of eight patients with untreated PD who received oral domperidone (20 mg TID) starting 2 days prior to apomorphine challenge. In the ondansetron group, three (37.5%) patients had a decrease of systolic blood pressure (SBP) of more than 20 mmHg. This was not noted in domperidone pretreated patients. Seven patients taking ondansetron suffered from marked nausea and/or vomiting, whereas patients taking domperidone experienced mild or no nausea. In the ondansetron group, six patients experienced marked sedation (compared with three in the domperidone group) and one patient fell asleep. Additionally, marked diaphoresis was noticed in four ondansetron patients. Although ondansetron is generally considered an effective antiemetic, this is the only published controlled study to evaluate the efficacy of ondansetron in patients with PD. This study found ondansetron to be ineffective for apomorphine-induced side effects, and thus, a greater occurrence of hypotension, nausea, and somnolence would be expected. This suggests that the warning advising against the use of ondansetron is related to its lack of efficacy in preventing acute dopaminergic side effects, which can be severe.

COMT INHIBITORS: TOLCAPONE AND HEPATOTOXICITY

The catechol-O-methyltransferase (COMT) inhibitor tolcapone is an effective adjunctive agent for the management of motor fluctuations in levodopa-treated patients. In clinical trials, elevated liver enzymes were notable in tolcapone-treated patients and regulatory agencies required frequent liver enzyme testing as a condition for drug approval [4]. After approximately 1 year on the market, three cases of fatal hepatotoxicity and one case of reversible severe liver injury were attributed to tolcapone [5, 6].

It is noteworthy that in these four cases, the recommended guidelines for monitoring liver function were not followed, and in two cases, the drug was continued even after there was clear clinical evidence of hepatic dysfunction. As a consequence of these reports, the marketing of tolcapone underwent a 7-year suspension in Europe and Canada and, in the United States, a black box warning was issued. Currently, in all countries, tolcapone carries a black box warning on the risk of hepatotoxicity. In contrast, entacapone has not demonstrated any hepatotoxicity and carries no black box warning [7].

It has been over a decade since the initial cases were reported and there have been no further reports of tolcapone-induced hepatic fatality. However, there have been three reports of severe hepatocellular liver injury [4]. In one case, hepatocellular jaundice occurred after treatment with tolcapone (duration unknown). In another case, severe hepatocellular injury was reported in a patient receiving tolcapone for 3 years. The third case involved development of hepatotoxicity 17 months after starting treatment with tolcapone [8]. In addition, Olanow and Watkins reported less severe cases in which the serum glutamic-pyruvic transaminase (SGPT)/alanine transaminase (ALT) or serum glutamic-oxaloacetic transaminase (SGOT)/aspartate transaminase (AST) were three times greater than the upper limit of normal. The majority of elevations were transient, asymptomatic, and resolved spontaneously. The median time to elevated levels was 81 days, and the median duration of elevation was 22 days [4].

Prior to initiation of tolcapone, the presence of liver disease should be excluded. With initiation of therapy, ALT and AST levels should be determined at baseline and then periodically (i.e., every 2–4 weeks) for the first 6 months. After the first 6 months, periodic monitoring is recommended at intervals based on clinical judgment. If the tolcapone dose is increased, the liver enzyme monitoring schedule should be repeated (i.e., testing every 2–4 weeks for 6 months after dosage increase). Tolcapone should be discontinued if ALT or AST levels exceed two times the upper limit of normal or if clinical signs and symptoms suggest the onset of hepatic dysfunction. Additionally, because of the risk for hepatotoxicity, the drug should be discontinued if symptomatic anti-Parkinson benefit is not seen within 3 weeks of initiation.

The hepatotoxicty seen with tolcapone appears to be dose related and onset appears to be time dependent. Elevations of liver enzymes are greater in patients treated with 200 mg compared with 100 mg and occur within the first 6 months of therapy. Therefore, proper monitoring will identify onset of liver enzyme elevations and allow discontinuation of tolcapone. Overall, if liver enzymes remain normal during the first 6 months of continuous tolcapone therapy, the risk of hepatotoxicity appears to be very small. Nevertheless, continued monitoring at 3–6 months intervals would be clinically reasonable.

DOPAMINERGICS AND EXCESSIVE DAYTIME SLEEPINESS

The initial report of “sleep attacks” with DAs resulted in a heighten awareness of excessive daytime sleepiness (EDS) in PD [9]. Since this report, sleepiness in PD has been critically reappraised and EDS is common [10, 11].

EDS is complex, multifaceted, and unique to each patient. Factors contributing to EDS in PD include PD-related sleep–wake pathophysiology, nighttime sleep disruptions and intrusions (e.g., due to dementia, depression, motor fluctuations, nocturia, obstructive sleep apnea, “off” symptoms, pain, rapid eye movement [REM] sleep behavior disorder, restless legs syndrome), and concurrent use of dopamimetic drugs as well as sedative hypnotics. Pathologic EDS is characterized by inappropriate and undesirable sleepiness during waking hours and affects up to 50% of patients with PD [10]. EDS adversely affects patients’ quality of life and also has a significant impact on caregivers and patient safety. DAs are known to be associated with a greater risk of causing or exacerbating EDS compared with levodopa. The severity of EDS also appears to be dose related. It is believed that the sedating effect of DAs is related to stimulation of inhibitory D₂-like autoreceptors within the ventral tegmental area (VTA) [12]. Sudden daytime sleep episodes that occur without warning (“sleep attacks”) are also associated with DAs [9–13]. The cumulative knowledge to date suggests that EDS in PD is predominantly accounted for by underlying PD-related pathophysiology, but dopamimetics play a pivotal role.

Concerns regarding EDS should not generally prevent clinicians from using DAs; however, in a patient with pathologic EDS or history of sudden onset sleep, DAs should be avoided or used with caution.

DOPAMINERGICS AND IMPULSIVITY

Impulsivity and impulse control disorders (ICDs) have become increasingly recognized in PD [14–17]. Impulsivity in PD patients likely involves interaction between cognitive, social, and pharmacologic influences. Although untreated patients with PD can display impulsive behaviors, it is clear that dopaminergic therapies can exacerbate, trigger, or unmask impulsivity. A pattern of impulsivity that results in harm is considered pathologic and can be defined as “a failure to resist an impulse, drive or temptation to perform an act that is harmful to the person or others” [18]. It is important to note that not all DA-associated impulsivity is problematic or harmful; however, ICDs with potentially harmful sequelae must be addressed. It is important for clinicians to educate and ask patients and caregivers about the presence of impulsive behavior. Often times, the clinician may not become aware of the impulsivity problem until substantial financial and social disruption has already occurred.

Harmful ICD phenotypes are wide ranging and include compulsive eating, compulsive shopping, hypersexuality, or pathological gambling. Patients experiencing compulsive eating will consume greater amounts of food than necessary, often resulting in harmful weight gain. Patients may also binge eat. Examples of hypersexuality include an increased preoccupation with sexual thoughts, excessive demands for sex from spouses, increased use of pornography, seeking out prostitutes, and engaging in paraphilia-like behavior (e.g., exhibitionism, excessive masturbation, transvestic fetishism, voyeurism). Pathologic gambling is the preoccupation with gambling and the persistence of gambling behavior despite negative impacts upon financial, social, and work relationships. Compulsive shopping is uncontrollable excessive purchasing of goods that can lead to substantial financial debt. Patients can experience a single or multiple types of ICDs.

In a review of studies, subtle changes in impulsivity occurred in 14%–28% of patients and problematic ICD in approximately 14% [14]. Although impulsivity has been associated with levodopa and amantadine use, DA use has been found to be the strongest predictor. In a study of 3,090 PD patients, 17.1% of patients receiving DA therapy displayed problematic ICD behavior and DA use was a predictor of impulsivity (Table 1) [15]. In another study, DA use was strongly associated (adjusted odds ratio 10.47) with ICDs [19]. Dopamine-agonist-induced impulsivity appears to be a class effect, and its development cannot be predicted on the basis of dosage, as patients with restless legs syndrome receiving low-dose DA have experienced problematic ICDs [20–21].

TABLE 1.  Risk of impulse control disorder in patients with PD. Multivariate predictors

Variable	Odds ratio	95% confidence interval
Dopamine agonist	2.7	(2.1, 3.6)
Age under 65 years	2.5	(2.0, 3.2)
Family history of gambling	2.1	(1.3, 3.3)
Smoker	1.7	(1.1, 2.7)
Living in USA	1.6	(1.3, 2.1)
Levodopa	1.5	(1.1, 2.1)
Not married	1.5	(1.2, 1.9)

Source: Adapted from Weintraub et al. [15].

Treatment of dopaminergic-induced ICDs involves reducing the dose, discontinuation, or switching to another agent. The adjunctive use of atypical antipsychotics, selective serotonin reuptake inhibitors (SSRIs), topiramate, and zonisamide have also been attempted with mixed results [21–24].

Concerns regarding impulsivity should not preclude clinicians from using DAs; however, patient and caregiver education should be provided. Routine monitoring for safety and side effects should include steps to detect treatment emergent impulsivity.

SELECTIVE MONOAMINE OXIDASE TYPE-B INHIBITORS AND SEROTONERGIC AGENTS

Rasagiline and selegiline are irreversible selective monoamine oxidase type-B (MAO-B) inhibitors and concerns exist regarding pharmacologic interactions and the associated risk for serotonin toxicity (ST). ST or serotonin syndrome is a potentially life-threatening drug-induced toxidrome consisting of neuromuscular hyperactivity, autonomic hyperactivity, and altered mental status [25, 26]. The primary pharmacologic mechanism underlying ST is excessive stimulation of serotonergic receptors in the central and autonomic nervous system, with agonism of serotonin2A (5HT2A) receptors playing a major role. Diagnositic features of ST are outlined in Table 2.

TABLE 2.  Outline of diagnostic features of serotonin toxicity

Administration of serotonergic agent (within past 5 weeks)^a and presence of one of the following:

• Spontaneous clonus

• Ocular clonus and either agitation or diaphoresis

• Inducible clonus and either agitation or diaphoresis

• Muscle rigidity, temperature >38°C, and either ocular clonus or inducible clonus^b

• Tremor and hyperreflexia

^aSome serotonergic agents such as fluoxetine and metabolites have long half-lives.

^bMuscle rigidity can mask clonus.

Source: Adapted from Dunkley et al. [26].

Historically, nonselective monoamine oxidase inhibitors (MAOIs), such as linezolid, phenelzine, and tranylcypromine, in combination with serotonergic agents or precursors have been associated with severe, and sometimes fatal, cases of ST [25, 27, 28]. These reports have led to the contraindicated use of nonselective MAOIs with serotonergic agents (e.g., antidepressants). Although the selective MAO-B inhibitors, rasagiline and selegiline, are not contraindicated with serotonergic antidepressants, regulatory agencies have mandated such warnings.

At therapeutic doses for PD, selegiline (10 mg/day) is selective for MAO-B. However, cases of ST have been reported with tricyclic antidepressants (TCAs), SSRIs, and serotonin norepinephrine reuptake inhibitors (SNRIs) [29–33]. Some cases involved selegiline dosages greater than 10 mg/day [33]. To assess the occurrence of ST with selegiline–antidepressant combination, Richard et al. conducted a survey of 63 neurologists [29]. From the 47 respondents, a total of 4,568 patients were reported to have received selegiline with an antidepressant. Eleven patients (0.24%) experienced symptoms possibly consistent with ST; however, none fulfilled criteria for ST. Further, a review of the literature (six published cases) found one case (selegiline–fluoxetine) meeting the criteria for ST. An analysis of adverse events occurring with selegiline–antidepressant combination obtained from the manufacturer and reported to the Food and Drug Administration (FDA) between 1989 and 1996 found that 4 of 57 met the criteria for ST (2 PD patients and 2 non-PD patients) [29].

A large proportion of the cases involved selegiline–fluoxetine combination. Selegiline is believed to be predominantly metabolized by the polymorphic isoenzymes, CYP450 2B6, and 2C19. Individuals who are 2C19 poor metabolizers may accumulate selegiline and then the addition of a potent CYP450 2C19 inhibitor, such as fluoxetine, would further enhance selegiline plasma concentration and thus conversion to MAO nonselectivity and greater risk of ST [34–36].

At therapeutic doses, rasagiline (1 mg/day) is selective for MAO-B and no cases of ST have been published. One published case described ST-like symptoms in a patient who received an unintentional overdose of rasagiline (4 mg/day) for 4 days [37]. However, exposure to a serotonergic agent (criteria for ST) was not reported.

In clinical trials, rasagiline-treated patients were allowed to receive antidepressants and no cases of ST were reported [38]. Additionally, a retrospective analysis of pooled adverse event data from clinical trials did not reveal ST [39]. In that analysis, 316 patients received a concomitant antidepressant for a median of 367 days. No cases suggestive of ST were observed in patients receiving rasagiline plus antidepressants. A confirmatory risk analysis of the same cohort indicated that rasagiline–antidepressant combination was associated with a theoretical population incidence of ST of 0 to 1.16% [40]. In a different approach, the tolerability of the combination of rasagiline and SSRIs was evaluated in a clinical practice population [41, 42]. Of 475 patients included in this retrospective analysis, 97 received a combination of rasagiline and SSRI. The drug combination was well tolerated by a majority of patients and no patients exhibited ST. In the largest study to date [43], of 1,507 patients with PD, 471 patients were receiving concomitant rasagiline–antidepressant. All hospital and emergency room records were reviewed, and on the basis of Hunter Serotonin Toxicity Criteria, no cases of ST were found.

Rasagiline is metabolized primarily via CYP450 1A2, and administration of the potent CYP450 1A2 inhibitor ciprofloxacin can significantly increase plasma levels of rasagiline. However, concurrent use is not contraindicated. The SSRI fluvoxamine is also a potent inhibitor of CYP450 1A2 and could increase plasma rasagiline levels and should be avoided.

In summary, there have been rare cases of ST associated with selegiline–antidepressant combination and no cases of ST associated with rasagiline–antidepressant combination. The potential for a rasagiline or selegiline and antidepressant combination to induce ST has been studied systematically and the data support the safety of the drug combination [43, 44].

The package labels for rasagiline and selegiline contain contraindications regarding concurrent use of dextromethorphan, meperidine, methadone, propoxyphene, St. John's wort, and tramadol. Additionally, rasagiline is contraindicated with cyclobenzaprine. These warnings are generalized and derived from experience and literature with the nonselective MAOIs.

Cyclobenzaprine is a centrally acting muscle relaxant, and its concomitant use with rasagiline is contraindicated. However, this warning appears to be based on generalizations rather than actual reports. Cyclobenzaprine shares pharmacophore homology with the TCAs and has been associated with ST in one isolated case of a patient taking concomitant phenelzine (nonselective MAOI) and oxycodone [45]. There are no reports of ST due to combination of rasagiline or selegiline with cyclobenzaprine.

Dextromethorphan is the d-isomer of levorphanol (a codeine analog) and is widely available as an antitussive in over-the-counter pharmaceutical preparations. Additionally, dextromethorphan/quinidine is FDA approved for treatment of pseudobulbar affect. Dextromethorphan blocks glutamate receptors, stimulates opioid sigma-1 receptors, inhibits reuptake of serotonin, and promotes serotonin release in a dose-dependent manner. There are no published cases of ST due to concomitant dextromethorphan with rasagiline or selegiline. However, ST associated with dextromethorphan in combination with nonselective MAOIs (as well as other serotinergic agents) has been reported. Many of these cases involved supratherapeutic doses of dextromethorphan obtained from over-the-counter sources [46–49].

Some analgesic opioid receptor agonists modestly inhibit serotonin reuptake, in particular, meperidine, methadone, propoxyphene, and tramadol. Each of these agents is contraindicated with rasagiline and selegiline. There are no published reports of ST due to the use of rasagiline and analgesic opioids. However, several cases of ST have occurred with the combination of these analgesic agents and nonselective MAOIs [50, 51]. There is one published case of ST with selegiline and meperidine, although the patient was also on TCAs [52].

The opioid analgesics codeine, hydrocodone, hydromorphone, and morphine do not possess serotonergic properties and do not precipitate ST. These opioids can be used safely in patients on rasagiline or selegiline. The opioids fentanyl and oxycodone are generally not considered to possess serotoninergic properties, however this remains unclear [53–57].

St. John's wort has been studied as an antidepressant and is available as an over-the-counter herbal product and is contraindicated with rasagiline. The active major constituents of St. John's wort are believed to be hypericin and hyperforin. These compounds have been shown to inhibit MAO and also reuptake of serotonin, as well as dopamine and norepinephrine [58]. This is a generalized statement based on pharmacology as there are no literature reports of ST associated with combination of St. John's wort and rasagiline or selegiline.

SELECTIVE MONOAMINE OXIDASE TYPE-B INHIBITORS AND FOOD INTERACTIONS

Selegiline at therapeutic doses for PD has not been associated with tyramine reactions or hypertensive crisis. There is a single case report of hypertensive reaction due to tyramine (cheese) ingestion in a non-PD patient receiving concomitant selegiline 20 mg/day (as a part of a clinical study for atypical depression) [59]. However, until recently, the rasagiline package insert had recommended limiting intake of tyramine-containing foods and beverages due to risk of hypertensive crisis or cheese reaction. As of December 2009, rasagiline use no longer requires avoidance of tyramine.

This section focuses on the currently available data regarding the potential for rasagiline to induce a tyramine-provoked hypertensive response (i.e., tyramine sensitivity), with particular focus on the results of tyramine challenge studies. Tyramine is an indirect sympathomimetic amine with known pressor effects and is found in high concentrations within certain foods including hard, aged cheeses, concentrated yeast extract (e.g., Marmite), and tap beers, all of which are historically implicated in the provocation of hypertensive crisis in patients receiving nonselective MAOIs, such as phenelzine or tranylcypromine. Investigations have demonstrated that as little as 8 mg of tyramine is sufficient to elicit a significant hypertensive response in tranylcypromine-treated patients.

In addition to tyramine, various sympathomimetic vasopressor amines are also substrates for monoamine oxidase type-A (MAO-A). These drugs have a molecular scaffold similar to norepinephrine and include ephedrine, phenylephrine, and phenylpropanolamine. Therapeutic doses of these sympathomimetic amines have also been reported to induce a hypertensive crisis in patients treated concurrently with nonselective MAOIs.

Tyramine challenge studies are a standard method to evaluate tyramine sensitivity. Blood pressure is measured after each tyramine administration to determine whether there is a pressor effect with a specified tyramine dose or to establish the dose of tyramine that induces a predetermined increase in blood pressure (a pressor endpoint of ≥30 mmHg increase in SBP, also known as TYR30, is commonly used). To allow for comparisons between drugs and to account for variations in individual study participants, the ratio of the TYR30 before study drug administration and TYR30 during treatment is calculated. This ratio of before and after TYR30 is referred to as the tyramine sensitivity factor (TSF). A TSF of 1 indicates no risk of enhanced tyramine sensitivity. In other words, there is no difference in the before and after TYR30 values. In contrast, a higher TSF indicates an elevated risk of the study drug to induce tyramine sensitivity. Examples of TSFs are 3.8 for high dose selegiline (20 mg/day) and 14–17 for phenelzine (45 mg/day) and 31–55 for tranylcypromine (20 mg/day) [60]. A recently published oral tyramine challenge study in healthy volunteers compared the geometric mean TSFs after 2 weeks of treatment with various daily doses of rasagiline (1–6 mg/day), placebo, phenelzine (a nonselective MAOI), and selegiline [61]. Rasagiline 1 and 2 mg/day did not increase tyramine sensitivity (i.e., TSF = 2.03 and 3.33, respectively) compared with the positive control, the nonselective MAOI phenelzine (TSF = 17.32). There was, however, a slight increase in the mean TSFs for rasagiline 4 and 6 mg/day (TSF = 4.50 and 5.10, respectively), suggesting that higher doses (e.g., ≥ 4 mg/day) of rasagiline increase the risk of tyramine sensitivity. In addition, the study assessed the difference in TSFs after 2 and 4 weeks of rasagiline (2 mg/day) treatment; the results did not demonstrate any trend for loss of selectivity over time (i.e., TSF = 3.3 and 2.4 for 2 and 4 weeks of treatment, respectively). Changes in plasma levels of dihydroxyphenylethylene glycol (DHPG; a product of the MAO-A-mediated metabolism of norepinephrine) following treatment with rasagiline 1 or 2 mg/day compared with baseline indicated little to no inhibition of MAO-A. In contrast, rasagiline 4 or 6 mg/day resulted in reductions in mean plasma DHPG compared with baseline. These results support the findings that higher doses (e.g.,) of rasagiline are associated with increased TSFs likely due to the loss of MAO selectivity and spillover inhibition of MAO-A. The results of this study demonstrated that rasagiline at the recommended therapeutic dose of 1 mg/day is selective for MAO-B inhibition and was not associated with clinically significant inhibition of MAO-A. The selectivity and safety results are consistent with other tyramine challenge studies that were conducted in patients with PD treated with rasagiline [62, 63].

In summary, data from controlled studies demonstrate that the risk of dietary-tyramine-induced hypertensive crisis in patients receiving the indicated dose of rasagiline, in the context of normal food intake, is extremely low or nonexistent. In line with these findings, previous contraindications regarding concomitant use of rasagiline with sympathomimetic amines are no longer valid and have been removed. Rasagiline-treated patients can be advised that therapeutic use of sympathomimetic amines found in the over-the-counter pharmaceutical preparations is permissible. The same can be applied to the use of sympathomimetic vasopressors during perioperative procedures.

CONCLUSION

Knowledge and insight of pharmacologic safety issues and drug interactions is important for clinical decision making and medical management of PD. Initiation of apomorphine requires antiemetic prophylaxis and direct medical supervision to minimize nausea and orthostatic hypotension. Additionally, the serotonin 5-HT₃ receptor antagonists should be avoided on the basis of limited clinical data suggesting lack of efficacy for apomorphine-induced dopaminergic side effects.

Impulsivity and daytime somnolence are associated with DAs and when severe, these effects can be disabling and unsafe. Education and interviewing DA-treated patients and caregivers for impulsivity and somnolence should be a routine.

Tolcapone hepatotoxicity has been significantly minimized with routine monitoring of liver enzymes, especially during the initial 6 months of therapy. Early detection of abnormal results will allow tolcapone discontinuation before progression to fulminant hepatotoxicity.

In patients treated with selective MAO-B inhibitors, the risk of ST due to concomitant serotonergic therapy (e.g., antidepressants, dextromethorphan, serotonergic analgesics) or hypertensive crisis due to dietary tyramine or sympathomimetic amines appears to be minimal and below the threshold for detection. Concerns about ST or hypertensive crisis should not preclude or restrict clinicians from using MAO-B inhibitors in patients with PD.

Declaration of Interest: The author has served as a consultant and on the speaker bureau for Teva Neuroscience.