Initiating and Monitoring Pharmacotherapy in Patients with Parkinson's Disease

FACULTY:

Michele A. Faulkner, PharmD
Associate Professor
Departments of Pharmacy Practice and Medicine
Creighton University

FACULTY DISCLOSURE STATEMENTS:

Michele A. Faulkner, PharmD, reported the following relationships to products or devices she has commercial interests related to the content of this CE activity: member of the Speaker’s Bureau of Teva Neuroscience.

U.S. Pharmacist does not view the existence of relationships as an implication of bias or that the value of the material is decreased. The content of the activity was planned to be balanced, objective, and scientifically rigorous. Occasionally, authors may express opinions that represent their own viewpoint. Conclusions drawn by participants should be derived from objective analysis of scientific data.

ACCREDITATION STATEMENT:

Pharmacists

Postgraduate Healthcare Education, LLC is accredited by the Accreditation Council for Pharmacy Education as a provider of continuing pharmacy education.
UAN: 430-000-09-003-H01-P; 430-000-09-003-H01-T
Credits: 2.0 hours (0.20 ceu)

Type of Activity: Knowledge

TARGET AUDIENCE:

This accredited activity is targeted to pharmacists and pharmacy technicians. Estimated time to complete this monograph and posttest is 120 minutes.

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DISCLAIMER:

Participants have an implied responsibility to use the newly acquired information to enhance patient outcomes and their own professional development. The information presented in this activity is not meant to serve as a guideline for patient management. Any procedures, medications, or other courses of diagnosis or treatment discussed or suggested in this activity should not be used by clinicians without evaluation of their patients’ conditions and possible contraindications or dangers in use, review of any applicable manufacturer’s product information, and comparison with recommendations of other authorities.

GOAL:

To provide direction to pharmacists regarding the initiation of therapy for Parkinson’s disease, treatment of comorbidities, and long-term medicaton management for optimization of patient outcomes

OBJECTIVES: 

After completing this activity, participants will be able to:

1. Review the pathophysiology of Parkinson's disease;*
2. Discuss the risks versus the benefits of early initiation of medication therapy;*
3. Describe available options for initial medication management of Parkinson's disease;*
4. Recognize common comorbidities associated with Parkinson’s disease and appropriate options for treatment;* and
5. Discuss strategies for enhancing patient outcomes.

Several advances in the management of Parkinson’s disease (PD) have been recently introduced. In addition to newer approaches to treatment initiation, there has been increasing emphasis placed on the control of comorbid conditions that exist in concert with PD. The pharmacist plays an integral role in ensuring that medications are initiated and monitored appropriately, leading to optimal patient outcomes.

ETIOLOGY AND PATHOPHYSIOLOGY

Degeneration of dopaminergic neurons in the substantia nigra pars compacta is the underlying pathology of PD. The overall result of neuronal loss is less inhibitory output from the basal ganglia secondary to dopamine deficiency.¹ At the time of diagnosis, as many as 80% of dopaminergic neurons are defunct. Acetylcholine, usually in balance with dopamine, faces less opposition, and relative overactivity ensues. To a lesser extent, serotonergic, noradrenergic, and cholinergic neurons play a role.²

Neurotransmitter imbalances, in particular dopamine imbalance, are primarily responsible for the cardinal features of PD (tremor, bradykinesia, rigidity, and postural instability) as well as for many comorbidities. Misfolded proteins called Lewy bodies are also characteristic of PD and are found in brain cells postmortem, as well as in other body tissues. Although the disease is progressive, the rate of advancement is patient specific.

The causes of PD are still under investigation, but it is likely that environmental factors and genetic factors play a role. Environmental toxins (pesticide and well-water exposure among them) have been linked to the disease. Additionally, a number of genetic mutations are believed to be linked to PD.³ Upon presentation, it is imperative that medication-induced disease be ruled out. Phenothiazines used for nausea, metoclopramide, and neuroleptic medications are implicated most often.⁴

PD is typically thought of as a disease of the aged, but young onset (before age 40) does occur.¹ Genetic predisposition accounts for up to 20% of young-onset PD.³ Tremor is the most likely initial cardinal feature seen in PD, but in younger patients the tremor may be inconsistent or may appear during times of fatigue.³ Significant bradykinesia and rigidity are less common early findings in the young.² Because PD in younger patients may be atypical, and because the disease is not common in this age group, a delayed or missed diagnosis may result.

INITIATION OF THERAPY

Clinicians often disagree about the optimal time to initiate medication therapy in patients with PD. Some opt for a conservative approach and initiate therapy only when the patient’s functional ability becomes compromised out of concern for side effects and to delay medication-induced motor complications. Others prefer a more aggressive approach, initiating therapy immediately, since there is evidence suggesting disease progression may be more rapid around initial presentation and the possibility of slowing that progression is viewed as worth risking drug exposure.^5,6 Furthermore, quality-of-life (QOL) studies clearly favor early intervention.^7-9

In addition to concerns over side effects and waning efficacy, barriers to treatment include the potential for drug toxicity. The ELLDOPA trial compared active levodopa with placebo to determine whether the former was toxic to neurons.¹⁰ The imaging portion of the study revealed a decrease in uptake of beta-CIT, suggesting that levodopa may in fact be toxic to neurons. However, the Unified Parkinson Disease Rating Scale (UPDRS) scores were significantly improved in patients taking levodopa, which suggested disease modification rather than destruction. Families, caregivers, and patients can also pose barriers to treatment, particularly if there is denial over the diagnosis, a common finding even more prevalent in young-onset patients. In an effort to self-educate, patients may obtain erroneous information leading to fear of treatment exposure.

THERAPEUTIC OPTIONS FOR TREATMENT INITIATION

More medications are available for PD than for any other neurological disease. Even so, complete symptom control over the duration of the disease has remained elusive. There are no available treatments to stop disease progression, but recent evidence indicates some medications may have a role in preserving function through neuroprotection or disease modification. Typical dosing of agents used in treatment initiation is presented in Table 1.

The mainstay of PD treatment is levodopa, which provides direct replacement of dopamine through conversion of the parent compound in the brain. To ensure this conversion takes place centrally rather than peripherally, the drug is given with a dopa decarboxylase inhibitor (carbidopa in the US). The addition of carbidopa prevents peripheral conversion to dopamine, allowing for higher brain levels and less nausea and hypotension. No other medication works as well to control the symptoms of PD.¹¹ However, dyskinesias, abnormal movements that have been linked to pulsatile receptor stimulation, occur in approximately half of late-onset patients and up to 80% of early-onset patients within the first five years of levodopa exposure.¹²

Levodopa has a short plasma half-life, allowing for peaks and troughs in drug level and less continuous receptor stimulation, which is believed to contribute to these issues. Additionally, levodopa efficacy begins to wane after several years, resulting in breakthrough symptoms at the end of a dosing interval (wearing-off) or unpredictable return of symptoms (on-off phenomena).⁵ Because of this, many practitioners feel it is prudent to delay use in younger patients since virtually all will be given levodopa at some point.¹¹

Levodopa should be taken on an empty stomach if possible or should be given with a low-protein meal if food is necessary to offset nausea, thus avoiding competition for transport into the brain. Common side effects include confusion, changes in bowel habits, dizziness, drowsiness, and nausea. This agent should be tapered to avoid neuroleptic malignant syndrome, which is characterized by delirium, rigid muscles, fever, and autonomic nervous system instability. Levodopa with carbidopa is usually dosed three times daily at initiation of therapy, but may be dosed more often as disability progresses.

Dopamine agonists are first-line alternatives to dopamine replacement and are often employed in younger patients. The older dopamine agonists, bromocriptine primary among them, are ergot derivatives with affinity for inhibitory D2 receptors, but also for excitatory D1 receptors.¹³ The newer non-ergot dopamine agonists, pramipexole, ropinirole, and rotigotine, bind to D3 (inhibitory) and D2 receptors in varying degrees. Few head-to-head trial data are available to suggest that one dopamine agonist is better than another, although the newer drugs have a more favorable side-effect profile. Dopamine agonists have shown efficacy throughout the spectrum of disease for both symptoms and QOL.^2,14 As monotherapy, they usually provide adequate control for three to five years and used alone produce fewer dyskinesias than levodopa. Both the transdermal rotigotine patch (currently unavailable in the US due to manufacturing issues) and the new extended-release formulation of ropinirole should, in theory, limit pulsatile receptor stimulation associated with dyskinesias, but this remains to be confirmed.³ When a dopamine agonist is added to levodopa, the dose of the latter can often be adjusted downward, thus limiting exposure. Both the CALM-PD-CIT (pramipexole) and REAL-PET (ropinirole) trials suggested possible neuroprotection with dopamine agonists, but due to the trial designs it was not possible to draw that conclusion with certainty.^15,16

Dopamine agonists share many side effects with levodopa including nausea, somnolence, and hypotension. However, the incidence of psychiatric side effects, particularly delusions and hallucinations, occurs more often with dopamine agonists. In fact, up to 17% of patients on a dopamine agonist experience hallucinations compared with less than 5% taking levodopa.² Other side effects unique to the class include edema (usually isolated to the ankles, but in severe cases it may extend to the thighs), and impulsivity leading to excessive gambling or buying and hypersexuality.^6,17 This impulsivity is thought to be related to the role dopamine plays in reward processing. Excessive sedation leading to “sleep attacks” has also been noted, primarily with the newer agents. There is not complete agreement as to whether these are true narcoleptic-like attacks or merely excessive sleepiness with amnesia prior to sleep onset.¹⁷ Dosing of the oral agents can be complicated due to recommended titration schedules.

Anticholinergic medications were the sole agents used to treat PD for nearly a century.¹⁸ Efficacy is believed to stem from their ability to narrow the gap between dopamine underactivity and acetylcholine overactivity. The medications used most often for the treatment of PD from this class are the muscarinic receptor agonists benztropine and trihexyphenidyl. Efficacy for PD symptom control is moderate at best and is primarily limited to tremor. Rarely are these agents used in older patients due to their propensity to cause dry mucous membranes, urinary retention, constipation, tachycardia, memory impairment, and orthostatic hypotension.¹⁸ Furthermore, they are contraindicated in closed-angle glaucoma and benign prostatic hypertrophy and may increase cognitive impairment in patients with dementia.¹⁹ However, in younger patients, anticholinergics may play an early role. Rebound symptoms can occur with abrupt discontinuation.⁷

Amantadine may also be useful early. Evidence of efficacy of this antiviral agent comes primarily from trials that were not adequately controlled, were done in patients with parkinsonian syndromes rather than true idiopathic PD, or had small sample sizes.²⁰ Amantadine has anticholinergic properties, making its primary role the control of tremor; however, the effects are mild to moderate and are temporary.⁸ Hallucinations and leg edema are frequent problems, and doses must be adjusted in patients with renal dysfunction.²¹ As with the anticholinergics, rebound symptoms may occur, necessitating tapering of amantadine dosing.

The monoamine oxidase (MAO) inhibitors used in the treatment of PD are selective for MAO type B (MAO-B), which accounts for 80% of MAO activity in the basal ganglia.²² Through irreversible MAO-B inhibition, dopamine concentrations increase. The two available agents are selegiline and the newer drug, rasagiline.

Selegiline is approved only for adjunctive PD therapy. Traditional dosing is twice daily, but single daily doses have been employed. The drug should be given no later than early afternoon due to its metabolism to amphetamine derivatives that may contribute to sleeplessness. A rapidly dissolving tablet is now available, and since it is directly absorbed through the oral mucosa, it avoids significant first-pass metabolism, resulting in fewer stimulant metabolites and a faster onset of activity.²¹

Rasagiline is approved for both initiation of therapy as a single agent in the early stages of PD or as an add-on to levodopa in mild to advanced patients with PD. Rasagiline, which is dosed once daily (1 mg alone or 0.5 mg when added to levodopa), has no amphetamine metabolites.

Both of these agents have been evaluated for potential neuroprotective or disease-modifying properties. In the DATATOP trial, selegiline was found to delay the need for levodopa therapy compared with placebo.²³ However, after 35 months, no difference was noted between the two treatment groups, supporting a symptomatic effect of selegiline as opposed to a neuroprotective one. Two other trials, TEMPO and the recently completed ADAGIO trial, suggest the potential for disease modification with rasagiline.⁹ Both trials were performed using a delayed-start design to minimize the possibility that improvement in disease progression could be attributed solely to a symptomatic effect. With this type of trial, one group is placed on placebo at first and then switched to the active drug, whereas the comparison group is exposed to the active drug for the entire trial. TEMPO demonstrated better UPDRS scores in the group receiving rasagiline throughout the study.²⁴ Similarly, the results of ADAGIO favored early-start rasagiline in terms of symptoms at 72 weeks and UPDRS progression.²⁵

Common side effects associated with the MAO-B inhibitors include nausea, headache, and dizziness. Non-selective MAO inhibitors have been associated with interactions involving tyramine, which may lead to potentiation of sympathomimetic effects such as hypertension and tachycardia due to sustained elevated levels of norepinephrine. This phenomenon is sometimes called the “cheese effect,” as tyramine is found in certain dietary choices including some cheeses and other aged, pickled, or fermented foods and drinks. There are rare reports of this interaction occurring with selegiline. To date, the interaction has not been identified with rasagiline, and a group of persons using rasagiline and ingesting supraphysiologic doses of tyramine did not develop the reaction.²⁶ At normal doses, neither drug is likely to induce the cheese effect. However, it should be noted that drug selectivity may be lost at higher doses, and tyramine sensitivity may vary from person to person.

Another concern associated with MAO-B inhibitors is the potential for the development of serotonin syndrome, a compilation of symptoms associated with elevated serotonin concentrations in the body leading to toxicity and causing mental status changes, myoclonus, hyperreflexia, diaphoresis, shivering, tremor, or any combination thereof. This too is more of a concern with the non-selective agents when given with another drug that potentiates serotonin activity. Interacting drugs include, but are not limited to, selective serotonin and norepinephrine reuptake inhibiting antidepressants (SSRIs and SNRIs); sympathomimetics such as pseudoephedrine; dextromethorphan; meperidine; and tramadol.^22,26 Studies of rasagiline have allowed several of these drugs without incident, and many, such as the antidepressants, are used routinely in patients with PD taking an MAO-B inhibitor.²² However, caution is warranted, and alternate agents should be used when possible.

MANAGEMENT OF COMORBIDITIES

Several comorbidities associated with PD have been identified and many require drug therapy (Table 2).

Depression

Depression is a frequent complication associated with PD, and no definitive correlation has been found with age or severity of disease.²⁷ Estimates are that anywhere from 30% to 60% of patients are affected.²⁸ PD and depression are likely linked pathologically, as evidenced by the higher rate of incidence in the PD population, but it remains to be determined whether they are part of one disease, are caused by the same underlying abnormalities, or one leads to the other. Depression as a component of PD may be the first sign, even before motor symptoms appear.

The diagnostic criteria used for depression are not specific to patients with PD.²⁹ This can pose a challenge with regard to diagnosis, since symptoms often overlap. Restriction of movement can be related to both.²⁹ Similarly, lack of facial expression, low-voice volume, fatigue, stooped posture, sleep disturbances, and impaired concentration may lead to a missed diagnosis of depression in a patient with PD.

Depression in the absence of PD is often associated with guilt, shame, and suicidal ideation. Patients with PD rarely exhibit these symptoms, making the diagnosis of comorbid depression that much more difficult.³⁰ There is a lack of robust data available to drive antidepressant therapy choice. In clinical practice, the SSRIs, SNRIs, and tricyclic antidepressants (TCAs) have all been used with success.³¹ At this time, the choice of antidepressant should be based on the physical needs of the patient, concomitant drugs, and potential side effects. Younger patients are more likely to tolerate the anticholinergic side effects associated with the TCAs and may benefit from their propensity to be successfully treated for common symptoms associated with PD, such as insomnia and drooling. If a TCA is chosen, patients should be monitored for orthostasis, confusion, and constipation. Caution should be exercised, as with the anticholinergics discussed previously, noting that use with MAO inhibitors is not recommended. Of this drug class, nortriptyline and desipramine are likely to be easiest to tolerate.³¹ Some of the SSRI antidepressants may be more sedating or have a greater risk of sexual side effects than the others, and both issues can be a problem in patients with PD. When this drug class is used, individual agents should be chosen carefully.¹⁰ Additionally, there are isolated reports of the SSRIs causing movement derangements.³¹ As previously stated, serotonin syndrome may be a consequence of interacting drugs, although rarely are the SSRIs bypassed as treatment options secondary to concomitant PD therapy.³¹ Due to the belief that D3 receptors are involved in mood regulation, a dopamine agonist with high affinity for these binding sites may be beneficial in depression. Data exist to support the use of pramipexole for this purpose.^11,27,31

Psychosis

Patients with psychosis and PD in general have worse outcomes than those without psychosis.³¹ Psychosis has sometimes been attributed to the use of dopaminergic drug therapy such as that used for PD treatment.³¹ However, there is a clear association with the disease itself, with the approximate incidence being 17%.³²

Psychosis is associated with alterations in thought or perception and is often accompanied by hallucinations in the patient with PD. Usually the hallucinations are visual and are perceived by the patient as non-threatening. Less often, patients experience delusions and paranoia.³³ Anti-parkinson drugs should be dosed downward or discontinued if they are suspected to be contributing and if the patient can tolerate the change. The generally accepted order of consideration is anticholinergics/amantadine, MAO-B inhibitors, dopamine agonists, and levodopa, although the order should be patient specific according to the robustness of the individual effects of a drug.

If hallucinations are not a concern to the patient and occur without dementia, it is often not necessary to treat with drug therapy. However, if the patient is disturbed by the hallucinations and drug-associated side effects (ie, hallucinations induced by dopaminergic medications) and medical conditions (eg, infection, lesions, or bleeding) have been ruled out, drug therapy may be employed.³²

The older antipsychotic drugs have a high affinity for D2 receptors and frequently induce extrapyramidal symptoms. Of the atypical agents, olanzapine and risperidone are associated with worsening motor symptoms.^32,33 The most widely studied drug, and the one that has shown the most efficacy in PD, is clozapine.³³ Clozapine does not worsen motor function. However, its association with cardiomyopathy and agranulocytosis has limited its use. Quetiapine is structurally similar to clozapine and has become the antipsychotic of choice despite few robust studies using the drug in patients with PD.^12,33 Similar to clozapine, quetiapine does not cause motor deterioration. There are few data evaluating the use of aripiprazole.

Of note, the FDA has recently required manufacturers of antipsychotic medications to place a warning on their labeling indicating that the use of these agents has been linked to increased mortality in elderly patients with dementia, a common diagnosis in patients with PD.

Dementia

The dementia seen in patients with PD has been associated with a higher mortality rate.³⁴ Risk factors for development include advanced age, advanced disease, and cognitive dysfunction preceding a PD diagnosis.¹³ In comparison to dementia seen in patients with Alzheimer’s disease, the dementia in patients with PD tends to be characterized by fluctuating attention, and patients with PD have more trouble with recognition than with recall in early disease.³⁴ Language is usually preserved.

Treatment of dementia in patients with PD is most often accomplished by employment of a cholinesterase inhibitor, typically rivastigmine (the drug is now FDA approved for this purpose). There is a paucity of evidence regarding other agents.

Patients should be monitored for motor deterioration, as cholinergic side effects may occur prior to achieving therapeutic doses.³³

Hypotension

Hypotension occurs in some patients with PD and may be due to drug therapy or autonomic dysfunction. Lewy bodies have been found in the part of the brain that is responsible for control of blood pressure via the baroreflex arch.³⁵ Dopaminergic drugs may contribute by causing dilation of the vessels in the splanchnic and renal vascular beds as well as decreasing catecholamine release. Selegiline has also been implicated.³⁵

Orthostatic hypotension is defined as a drop of 20 mm Hg systolic or 10 mm Hg diastolic. Symptomatic pressure changes early in the disease are suggestive of multiple system atrophy and should call the diagnosis of PD into question. Patients not experiencing symptoms related to their blood pressure fluctuations need not be treated.

One clue as to whether hypotension is drug induced is the compensatory heart rate with positional change. In the face of a heart rate that does not increase as compensation for a pressure drop, the problem is less likely drug induced, since normal physiologic responses are obviously impaired.

Treatment of hypotension in patients with PD should include non-drug therapy first. Strategies include increasing sodium and fluid intake and avoiding alcohol, heat, and strenuous exercise (moderate exercise may actually help). Furthermore, since orthostatic hypotension in patients with PD is often exaggerated postprandially, smaller meals at an increased frequency and comprising low-carbohydrate and low-fat foods have been recommended.^14,35

If drug therapy is employed, it is done empirically. The two agents used most often are the alpha-1 adrenoceptor agonist midodrine (a vasoconstrictor) and fludrocortisone, which increases aldosterone and noradrenaline release (a volume expander). A possible consequence of the use of these drugs is supine hypertension.³⁵ Because of the prolonged effect of fludrocortisone, if hypertension is a problem, midodrine is recommended.¹⁵ The final daily dose of the drug should be given no later than four hours before bedtime.

Sleep Disorders

Sleep problems are frequently experienced in patients with PD. They include insomnia (difficulty falling or staying asleep and early morning awakening), vivid dreams, rapid eye movement sleep behavior disorder (RBD), restless leg syndrome (RLS), and daytime somnolence.³⁶

Insomnia is by far the most common complaint and there are several contributing factors.¹⁶ Approximately 40% of patients with PD have sleep apnea requiring positive airway pressure for control.³⁷ Additionally, one half of patients complain of RLS. Avoidance of SSRI and TCA antidepressants and antihistamines is recommended for patients with RLS, although this may present a challenge, since depression is the most common cause of insomnia in the elderly.³⁸ Additionally, serum iron levels should be checked and corrected with supplementation.³⁷ The success seen with dopamine agonists in patients with RLS, which is believed to be linked to dopamine deficiency, makes them a logical choice for treating PD symptoms in patients with RLS.

In patients experiencing insomnia, behavioral changes should be employed before drug therapy. Strategies include routine sleep and wake times, making sure that exposure to bright light during the day is of adequate duration, and engaging patients in daytime activities to keep them stimulated and decrease the desire for naps that might interfere with the ability to sleep overnight.^36,37 The presence of PD symptoms may lead patients to premature work retirement and avoidance of social situations, further decreasing daytime stimulation and increasing the incidence of daytime napping.³⁸

Adequate control of nocturnal PD symptoms is a necessity, since inability to switch positions due to bradykinesia, dystonic pain, and off-time may lead to less sleep or fragmented sleep. Long-acting preparations may be employed, and sometimes a scheduled middle-of-the-night dose of medication is necessary. If response is inadequate, consideration should be given to using a soporific. There is no preferred agent in the PD population, and all agents approved for this purpose are potentially helpful. If antidepressant therapy is necessary and there are no contraindications, choosing a sedating drug and dosing at night may be sufficient. TCAs are often used as soporifics, but, if not tolerated, a sedative SSRI might be beneficial, since serotonin is involved in the induction of sleep and derangements of this neurotransmitter are common in patients with PD.³⁸

Second in prevalence to insomnia is excessive daytime sleepiness (EDS).³⁷ The condition tends to worsen with the duration of disease. Medications should be evaluated as causes, and doses should be decreased or suspected drugs should be discontinued when possible. Since many of the drugs used for PD are known to cause drowsiness during the day, this is not always practical.

Some stimulant medications have been used to treat EDS in patients with PD. The most studied drug is modafinil, an agent used for narcolepsy.³⁷ Dosing should begin with 100 mg daily, although doses as high as 400 mg have been employed. Another drug that has been used is methylphenidate, although it has not been systematically studied in patients with PD.³⁷ It should be noted that if patients are sleeping well at night and functioning well during the day, limited scheduled daytime naps should not be discouraged.

RBD is typically medication-related and has a link to antidepressants.³⁶ However, it may occur in the absence of a causative medication. It is known that most people are paralyzed while dreaming. With RBD, however, patients are able to act out their dreams, often violently, and patients and bedmates can sustain injury. If patients are on an antidepressant or another drug suspected to be a cause, the dose should be decreased or another agent tried. When drug therapy for RBD becomes necessary, clonazepam is usually used.³⁶ Dosing should be initiated at 0.25 mg and slowly titrated as necessary and tolerated.

Gastrointestinal Dysfunction

Gastrointestinal (GI) dysfunction in patients with PD occurs secondary to discoordination of musculature and dysfunctional autonomic regulation.³⁹ Lewy bodies have been found in the GI tract.⁴⁰ The most common complaint is constipation. Contributing factors include lack of exercise and decreased fluid and food intake. Medications may also contribute, especially those with anticholinergic properties.³⁹

Increasing fiber intake may be tried, but the osmotic laxatives, particularly polyethylene glycol, are the agents with the most data supporting efficacy in PD.^17,39 Stimulant laxatives may be used for rescue therapy. The new chloride receptor agonist, lubiprostone, has not been extensively studied in PD but may be an option if chronic therapy is needed. In extreme cases, botulism toxin has been injected into the external anal sphincter to promote relaxation, allowing for defecation.³⁹

Besides constipation, dysphagia can arise secondary to discoordination of the oral, pharyngeal, and esophageal musculature.⁴⁰ Safe swallowing of food and medications is essential to avoid choking and aspiration. Alterations in medications or dosage forms may help to overcome these problems.

Bladder Dysfunction

Dopaminergic mechanisms play a role in the control of bladder function as well.⁴¹ The most common complaint of patients with PD is nocturia. This is not surprising, since PD usually occurs in men who are in the age group most often affected with benign prostatic hypertrophy. However, women also complain of urgency, irritation, and obstructive symptoms.⁴¹

The hypothesis for the underlying pathology of bladder dysfunction is insufficient stimulation of D1 receptors that are involved in maintaining tone. Uncontrolled nocturia can contribute to the risk of falls and negatively affect QOL. The most frequently employed medications for treatment are the anticholinergics. When choosing an agent and in order to minimize side effects, it is important to consider the drug’s selectivity for urinary receptors. The choice of agent is empiric due to the paucity of information about these drugs in the PD population.

Sexual Dysfunction

Both men and women with PD may suffer from sexual dysfunction. Motor impairment may interfere with mobility and sexual activity, and patients may be concerned about their attractiveness as their appearance changes due to onset of symptoms.⁴² Women often have difficulty with arousal and orgasm, and men frequently complain of erectile dysfunction.^42,43 Sildenafil has shown promise in treating erectile dysfunction in patients with PD and has also shown improvement in desire and ability to achieve orgasm.⁴³ It is likely that other phosphodiesterase inhibitors may have similar effects.

Falls

One of the primary comorbidities associated with PD is falling. A prospective survey of patients with PD demonstrated a 70% risk of at least one annual fall.^18,44 Postural instability, a common cardinal feature in later disease, is a major contributor and is poorly responsive to medications. Cognitive side effects associated with some drugs may add to the risk.

Patients with PD who experience fractures are unlikely to recover as quickly or as completely as those without mobility issues. Furthermore, as patients experience falls, they may become fearful and self-limit their activities, ultimately leading to additional functional decline.⁴⁵

From a medication standpoint, optimizing treatment of motor dysfunction is most important. Adding calcium and vitamin D supplementation and other medications for the prevention or treatment of osteoporosis is one strategy to avoid the sequelae of falls in both men and women with PD.

THE ROLE OF THE PHARMACIST

The pharmacist’s role in helping patients manage PD includes education and therapy optimization. It is imperative that pharmacists see their patients face to face and on a regular basis in order to monitor changes in functional ability and to monitor for motor side effects such as dyskinesia. When medications are added or doses changed, scheduling a follow-up appointment, either in person or by phone, should be considered. Ideally, there should be a private space in the pharmacy for a limited physical examination.⁴⁶

Monitoring the use of over-the-counter medications is essential as well, since many are associated with anticholinergic side effects or may be potentially dangerous depending on which PD medication the patient is taking. A number of websites promote neutraceutical products for PD, so it is necessary for the pharmacist to inquire about such agents and offer practical advice about their efficacy.

Medication adherence may be an issue for patients with PD, and the importance of adherence and its relationship to improved outcomes should be emphasized (eg, there may be motor complications if patients are not adherent.) Routine screening for possible nonadherence and identification of the reasons behind it should be a regular part of patient assessment. Patients and caregivers alike must be given honest and clear information about what to expect. It is important that patients understand that the disease is progressive and that symptom control is the primary goal but that it may remain incomplete, especially with advancing disease. Potential side effects should be discussed at the outset, and patients should be told which ones are transient in the hope that they will maintain use of the drug (Table 3).

Some side effects are unlikely to be recognized as related to drug therapy by laypersons. For instance, a patient who becomes a compulsive gambler after initiation of a dopamine agonist will not likely connect the two, so including this information when counseling a patient is essential. However, it is necessary to make sure that in being thorough the approach is tailored so as not to frighten patients away from using a drug that might make a substantial difference in their QOL and functional ability.¹⁹

Dosing must be addressed with physicians to assure adherence as well. Titration of medication that is too rapid or dosing that is insufficient (eg, too little carbidopa to prevent nausea) should be discussed before patients start a drug, since once patients experience untoward effects, they are less likely to give that agent another chance. Patients should be warned against abrupt discontinuation of a medication should side effects appear. Regimen complexity is also a concern, especially for those with cognitive impairment or depression.⁴⁷ Longer-acting agents and those that can be dosed once daily are more likely to advance adherence.

Pharmacists should not wait for patients or caregivers to mention that they are having problems with known comorbid conditions. Some problems, such as constipation or urinary dysfunction, may be thought of as part of the normal aging process, so patients may not bring them up in the context of their PD. Patients are also less likely to volunteer information about sexual dysfunction. Additionally, those that have fallen may deny it for fear that they might lose their autonomy through intervention and potential placement outside the home. Swallowing difficulties may lead to nonadherence or choking, but patients may not mention this or may take it upon themselves to alter the dosage form to make taking the drug easier at the expense of efficacy or safety. Changes to liquids from solids (or vice versa) or using rapidly dissolving products or transdermal products may result in better outcomes. Depression should also be a subject of inquiry, since overlap of symptoms may prevent recognition, and failure to treat contributes to nonadherence and worse outcomes.^20,21

Communication among all health care professionals involved in the care of patients with PD is the best way to ensure optimal outcomes. Many community physicians who treat patients with early PD are not movement disorder specialists and may not be as familiar with the subtle differences among medications or dosage forms or the evidence supporting earlier use of some drugs over others. To be effective, pharmacists should communicate with the patients’ prescribing physician, both before a drug is dispensed and if a problem is identified, and during therapy if negative functional changes or comorbid conditions that cannot be treated with nonprescription medications become apparent.

The involvement of other health care professionals for both the treatment of PD symptoms and comorbidities is often necessary as well, and pharmacists should refer patients to other health care professionals as necessary. For instance, speech therapists may often help with safe swallowing and improving vocal volume. Social workers, support groups, and therapists can be adjunctive for helping patients control depression and sexual dysfunction or to help obtain medications that patients might otherwise not be able to afford. Physical therapists can help with muscle strength and balance, and occupational therapists can intervene with assistive aids that help patients to maintain a level of autonomy they might otherwise lose. Pharmacists can help therapists in developing a dosing schedule that maximizes patients’ ability to participate in therapy. Dietitians and pharmacists can work together to ensure that patients are receiving adequate nutrition while eating appropriately so as not to interfere with drug efficacy.

CONCLUSION

The management of patients with PD goes well beyond treatment of the cardinal features. Which drugs are employed early in therapy can have a significant effect on functional outcome later in the disease. The potential for disease modification and delay of waning drug efficacy should be factored in to the decision about which agents to employ first. Failure to treat comorbid conditions can ultimately lead to unsatisfactory patient outcomes. Counseling patients and caregivers about what to expect avoids unrealistic expectations and should help to optimize adherence. Finally, recognition of the roles of other health care professionals in the treatment of PD and its comorbidities and a commitment to communication are the best way to ensure optimal outcomes for patients with PD.

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