Pharmacist Consult: An Update on Parkinson's Disease Prevalence and Treatment

Parkinson’s disease (PD) is one of the most common neurodegenerative disorders, only second in frequency to Alzheimer’s disease¹. There are more than 10 million people living with PD worldwide, and approximately 60,000 Americans are diagnosed with PD yearly² (Figure 1). Majority of people diagnosed are over the age of 60 as the incidence of PD does increase with age, however, there is still approximately 4% of people diagnosed before the age of 50. The incidence of PD is increasing due to the aging population in the United States. Both men and women can be affect, but men are 1.5 times more likely to develop PD than women^2,3. PD is both a chronic, and progressive disease that affects the substantia nigra, where dopaminergic neurons start dying out. This results in a dopamine deficiency within the basal ganglia, and therefore leads to the characteristic movement disorders of PD³.

Figure 1: Overall Prevalence of PD in the United States. Adapted from the Parkinson’s Foundation².

PD is characterized by both motor or nonmotorized symptoms, but classic PD symptoms are all motor in nature and include bradykinesia, resting tremor (often referred to as a “pill-rolling” tremor), rigidity, and postural instability³. Common non-motor symptoms of PD include apathy, sleep disorders, depression, constipation, and loss of smell⁴. Typically, motor symptoms begin asymmetrically, being much more obvious on one side of the body. In time, motor symptoms often develop on both sides of the body, but typically the patient will still have one side of their body with more pronounced motor symptoms³.

Overall, PD symptoms develop slowly throughout the years and varies considerably from person to person. Physicians most commonly use the Hoehn and Yahr scale, which is a subjective scale to rate how advanced someone’s PD is. The Hoehn and Yahr scale is a five point scale that ranges from zero to five. At stage zero the patient shows minimal signs of PD and the diagnosis may still be up in the air, whereas stage five is the most advanced stage of PD and often characterized by patient confinement to bed or wheelchair. Over half of all PD patients, 51.03%, are categorized as being Hoehn and Yahr stage 3, or mid stage disease⁵. PD itself is not fatal, but complications from the disease can be serious in nature. In 2018, PD was listed as the 10th leading cause of death in all races and both sexes in the 65 + years age group⁶. The two major causes of death for PD patients are falls and pneumonia. PD patients tend to have weakened immune systems and difficulty swallowing, which increases the chance of aspiration pneumonias⁷.

Experts believe that PD is caused due to a combination of both environmental and genetic factors. One environmental fact that is thought to be a risk factor for the development of PD is the chronic exposure to pesticides, as most commonly seen in patients who live in rural areas^3,8,9. Genetics are thought to cause roughly 10 to 15% of all PD, as in some families certain genes are inherited and passed generation to generation. Although it is unknown why, certain ethnic groups, like Ashkenazi Jews and North African Arab Berbers, carry genes linked to PD more commonly than others⁹. Along with the several hypothesized risk factors, there are several hypothesized protective factors, such as smoking and drinking coffee^8-10. There is certainly not enough evidence to recommended patients pick up smoking or drinking excessive amounts of coffee to receive these protective effects though, as the risks do not outweigh the hypothesized benefits. Other suggested environmental risk factor and protective factors can be found in table 1.

Table 1: Potential Environmental Risk Factors and Protective Factors for the Development of PD. Adapted from Ascherio A⁸.

There are no specific blood or imaging tests to diagnosis PD. However, various diagnostic tests and symptoms are used in combination to make a diagnosis. In general, two of the four main PD symptoms (table 2) have to be present over an extended period of time for most neurologists to consider PD as a diagnosis¹¹. In the diagnostic period, it is recommended that a consult is made with a movement disorder specialist to help avoid misdiagnosing a patient. There are other neurologic disorders that can present similar to PD that should be ruled out before diagnosing a patient with PD. One way that other neurologic disorders can be ruled out is with the use of a DaTscan, an imaging test approved by the FDA in 2011 to help confirm an idiopathic PD diagnosis. A DaTscan detects the amount of dopamine function within the brain, after a radioactive tracer is injected into the blood¹². If a DaTscan is not done, it is also not uncommon to see physicians trial a PD medications in patients suspected to have PD. In typical idiopathic PD, there is often a predictable, positive response to the medications, whereas if a patient is experiencing a related Parkinsonian syndrome the medication response is typically minimal or completely absent^11,13.

Table 2: The Four Primary Symptoms of PD. Adapted from the National Institute of Neurological Disorders and Stroke¹.

1. Tremor - shaking with a back and forth rhythmic motion
2. Rigidity - muscles that are stiff or resistant to movement
3. Bradykinesia - slowing of both automatic and spontaneous movement
4. Postural instability - increased risk of falls due to changes in balance or posture

 Unfortunately, there are still no known cures for PD, only therapies for symptom management. There is a tremendous healthcare cost related to PD treatment in the United States as the direct and indirect cost of treating PD is estimated to be close to $52 billion dollars per year.  Medications cost around $2,500 a year per person and surgery interventions can be around $100,000 per person². There is a wide variety of medications available in the United States that can provide significant relief from PD symptoms but as PD progresses, medications often bring significant and sometimes intolerable side-effects. It is critical to involve physical, occupational, and speech therapy into the overall treatment plan to provide the best possible quality of life for PD patients¹⁴. Treatment regimens are completely individualized and often change over time in correspondence to patient reported symptoms and side-effects as there are no objective measures to assess how well a treatment is working for a patient.

The medical management of an individual requires consideration of different factors including age, stage of disease, signs and symptoms, level of activity, degree if functional disability, and overall productivity. Initially, a newly diagnosed PD patient may not be started on any medication with hopes of preserving the benefits until worsening disease progression. When to initiate drug therapy must be determined with shared decision-making, with discussion of risks and benefits. Majority of symptomatic PD patients are started on carbidopa/levodopa, which is still considered the most effective PD therapy. The American Academy of Neurology recommends that carbidopa/levodopa or a dopamine agonist be initiated first-line^14,15. Other agents that can be used initially as a monotherapy agent includes monoamine oxidase type B (MAO B) inhibitors or amantadine. Initial therapy should be started at the lowest possible dose of to control symptoms. Following initially therapy, combination therapy is often used. Carbidopa/levodopa can most often be seen used in combination with dopamine agonists, catechol-o-methyl transferase (COMT) inhibitors, MAO B inhibitors, adenosine A2a antagonists and anticholinergic agents to help with worsening/progressive symptoms. A full list of PD medications can be found in table 3. Lastly, although never a first line strategy, a surgical options are available for a subgroup of PD patients. The most common surgical intervention is deep drain stimulation (DBS), which for over a decade has been approved by the FDA as a surgical therapy for progressive PD¹⁶. Figure 2 illustrates a PD treatment flow chart after initial diagnosis¹⁵.

Figure 2: Treatment flow diagram for PD. Adapted from American Family Physician¹⁵.

Table 3: PD Pharmacological Agents. Adapted from Parkinson’s Foundation¹⁷. 

Levodopa formulations

Carbidopa/levodopa is available in many different strengths and formulations for patient convenience. Although it is the most effective agent for PD, due to direct conversion to dopamine within the brain, around 50% of patients will develop levodopa related complications within 5-10 years of starting. Once such complication is known as the “wearing off” phenomenon. This phenomenon is more likely to occur the longer a patient has been treated with carbidopa/levodopa and the younger the age of PD onset. Overtime, the short half-life of carbidopa/levodopa (~90 minutes) becomes much more prominent and patients are described as being in their “off” state when carbidopa levodopa wears off throughout the day¹⁷.

Dopamine agonists

These agents work by mimicking the effects of dopamine and stimulating parts of the that are influenced by dopamine. Dopamine agonists are not as effective as carbidopa/levodopa but are often selected as one of the first line agents¹⁷.

COMT inhibitors

These agents are best used for “wearing-off” symptoms and have no direct effect on PD symptoms, rather they are used to increase effects of carbidopa-levodopa by preventing peripheral breakdown of levodopa. Opicapone is the newest COMT inhibitor, which was approved in April 2020 as the first once daily COMT inhibitor. There is a combination product available by the brand name Stalevo, which is carbidopa/levodopa/entacapone, to reduce pill burden¹⁷.

MAO B Inhibitors

These agents work by preventing the MAO B enzyme in our bodies from breaking down dopamine, allowing more dopamine to be present in the body. Taking MAO B inhibitors in combination with tyramine containing foods carries the risk of the patient developing dangerously high hypertension. Tyramine containing foods are typically fermented or aged and include cheeses, beer, sauerkraut, and cured or dried meats¹⁷.

Adenosine A2a antagonists

There is one agent in this class, istradefylline, which is only used as an adjunct therapy to carbidopa/levodopa. This medication is highly metabolized by the liver, and requires a higher dose in smokers due to increased metabolism¹⁷.

Anticholinergic Agents

These agents decrease the activity of acetylcholine and therefore can be helpful for tremor or dystonia. Anticholinergics are the oldest class of medications to treat PD, but have a long list of typical anticholinergic side-effects (dry mouth, blurred vision, urinary retention etc.). These agents may slow cognition and should always be avoided in people older than 70 years of age. The preferred patient to use this medication is young patients with the chief complaint of tremor¹⁷.

Amantadine formulations

Amantadine is a weak, noncompetitive antagonists of the NMDA receptor, which increases dopamine release and prevents dopamine reuptake. Immediate release amantadine can be used as monotherapy or combination therapy for PD, whereas extend-release amantadine is just used as combination therapy with carbidopa/levodopa¹⁷.

As mentioned previously, medication regimens are highly individualized to each PD patient, and often require dosing every 1 to 2 hours for appropriate symptom management. A delay in dosing time my cause an immediate increase in patient symptoms and an overall substantial impact on patient quality of life. A patient should never abruptly discontinue his/her PD medications as this can lead to serious reactions such as neuroleptic malignant-like syndrome. Abrupt discontinuation may result in unstable blood pressure, muscle rigidity, sweating, stupor, high fever, and autonomic dysfunctions that can be life-threatening¹⁸. Non-adherence and inappropriate administration is attributable to 8-11% of hospitalizations in PD, and a very costly to the healthcare system¹⁹.

Appropriate administration of PD medications is not just important in the outpatient setting, but also the inpatient setting. The Institute for Safe Medication Practices (ISMP) reports that 3 out of 4 hospitalized PD patients do not receive their medications on time, or completely miss a dose while inpatient, resulting in exacerbated PD symptoms and lengthening hospitalizations^18,20. The ISMP also mentions that surgical procedures are quite risky for PD patients when it comes to appropriate administration as often time medications are held due to NPO requirements leading to omitted doses. In regards to surgery, not only are missed doses of the PD medications concerning, but it is also estimated that 1 in 3 PD patients receive a contraindicated drug pre- or post-operatively resulting in a neuropsychiatric complications in more than half of these patients¹⁸. Agents that should be avoided during and after surgery can be found in table 4²¹.

Table 4: Medications That May Be Contraindicated in PD. Adapted from Parkinson’s Foundation²¹.

As mentioned previously, using inappropriate agents in PD diagnosed patients can lead to exacerbated symptoms and neuropsychiatric complications. This should not be confused with the term drug-induced parkinsonism (DIP), an underdiagnosed entity, which presents similar to idiopathic PD. DIP refers to reversable Parkinson’s like side-effects initiated from the use of certain medications and is the term used in patients without an idiopathic PD diagnosis. DIP occurs due to a postsynaptic blockade of dopamine receptors, especially when D2 receptors are blocked. DIP is seen most often occurring with first-generation (typical) antipsychotics, several second-generation (atypical) antipsychotics, different gastrointestinal prokinetic agents, and others³ (Table 5).  Roughly 90% of DIP cases occur within three months after the medication is initiated. The most common parkinsonism symptoms are reported to be bradykinesia, masked face, tremor, and rigidity. In comparison to idiopathic PD, these symptoms tend to be only motor and symmetric in nature, which is a distinguishing feature since idiopathic Unlike the uncurable nature of idiopathic PD, DIP is resolved by weaning the patient off the offending agent and eventually discontinuing it³.

Table 5: Agents That Can Cause Parkinsonism. Adapted from Hayes MT³.

Drugs frequently causing parkinsonism:

• First-generation antipsychotics (typicals)
  • Chlorpromazine, prochlorperazine, perphenazine, fluphenazine, promethazine, haloperidol, pimozide, sulpiride
• Second-generation antipsychotics (atypicals)
  • Risperidone, olanzapine, ziprasidone, aripiprazole
• Dopamine depleters
  • Reserpine, tetrabenazine
• Antiemetics/Prokinetics
  • Metoclopramide, levosulpiride, clebopride
• Calcium channel blockers 
  • Flunarizine, cinnarizine

Drugs infrequently causing parkinsonism: 
Clozapine, quetiapine, lithium, SSRIs, Valproic acid, phenytoin, Domperidone, itopride

Due to the current COVID-19 pandemic, it should be noted that having PD does not increase the chance of contracting COVID-19. However, if a PD patient develops COVID-19 the recovery process is often lengthier than it is for a non-PD patient due to slight differences in immune systems.  PD patients with COVID-19 often appear and feel as though their daily medications are not working as well, which results from motor and non-motor symptoms being exacerbated, which also occurs with any other medical illness²².

The prevalence of PD is continuing to rise around the world due to the ageing population and appropriate care can have a substantial impact on a patient’s quality of life. There are several risk factors associated with the development of PD, but genetics may also play an uncontrollable role in the development in this incurable disease. Throughout the years, several pharmacological agents have been developed to be used in the tool box of physicians to tailor treatment regimens to specific patients in order to achieve maximal symptom management. Different treatment regimens can help manage patients’ disease appropriately only when taken correctly. Appropriate administration, both outpatient and inpatient, is key when living with PD.