Parkinson’s disease

Parkinson’s disease is a progressive neurologic disorder affecting the brain centers that are responsible for control and regulation of movement. It is characterized by bradykinesia (slowness of movement), tremor, and muscle stiffness or rigidity (Katzung, Mastes, & Trevor, 2012).

The major lesion appears to result in a loss of pigmented neurons, particularly those in the substantia nigra of the brain. The substantia nigra is a collection of midbrain nuclei that project fibers to the corpus striatum. One of the major neurotransmitters in this area of the brain, and in other parts of the central nervous system, is dopamine, which has an important inhibiting function in the central control of movement (Brunton, Chabner, & Knollman, 2011). Although dopamine normally exists in high concentration in certain parts of the brain, in Parkinson’s disease it is depleted in the substania nigra and the corpus striatum. Depletion of dopamine levels in the basal ganglia is associated with bradykinesia, rigidity, and tremors (Brunton, Chabner, & Knollman, 2011).

Regional cerebral blood flow is reduced in patients with Parkinson’s disease, and there is a high prevalence of dementia. Biochemical and pathologic data suggest that demented patients with Parkinson’s disease may have coexistent Alzheimer’s disease (Connelly & Fox, 2012).

In the majority of patients, the cause of the disease is unknown. Arteriosclerotic Parkinsonism is seen more frequently in older age groups. It may follow encephalitis, poisoning, or toxicity (manganese, carbon monoxide), or hypoxia, or may be drug induced. The disease most frequently attacks persons in their fifties and sixties and is the second most common neurologic disorder of the elderly (Brunton, Chabner, & Knollman, 2011).

The clinical manifestations of Parkinson’s disease are impaired movement, muscle rigidity, tremor, muscle weakness, and loss of postural reflexes. Early signs include a stiffening of the extremities and a wax-like rigidity in the performance of all movements. The patient has difficulty in initiating, maintaining, and performing motor activities, and experiences some delay in carrying out normal activity (Kofman).

As the disease progresses, the tremor begins, frequently in one hand and arm, then the other, and later in the head, although the tremor may remain unilateral. The tremor is characteristic: it is a slow, turning motion (pronation-supination) of the forearm and the hand, and motion of the thumb against the fingers as if rolling a pill between the fingers. It increases when the patient is concentrating or feels anxious (Connelly & Fox, 2012).

Other characteristics of the disease affect the face, stature, and gait. There is loss of normal arm swing. Eventually, the rigid extremities become weaker. Since there is limited movement in the muscles, the face has so little expression that it is said to be masklike (with infrequency of blinking), a feature that can be recognized at a glance (Connelly & Fox, 2012).

There is a loss of postural reflexes, and the patient stands with head bent forward and walks as if in danger of falling forward. Difficulty in pivoting and loss of balance may lead to frequent falls (Katzung, Mastes, & Trevor, 2012).

Frequently, these patients show signs of depression, and it has not been established whether the depression is a reaction to the disorder or related to a biochemical abnormality. Mental manifestations may appear in the form of cognitive, perceptual, and memory deficits. A number of psychiatric manifestations (personality changes, psychosis, dementia, confusion) are particularly common among the elderly (Kofman). Complications from immobility (pneumonia, urinary tract infection) and the consequences of falls and accidents are major causes of death (Kofman).

Early diagnosis of Parkinson’s disease can be difficult, as the patient can rarely pinpoint when symptoms started. Often someone close to the patient notices a change such as stooped posture, stiff arm, a slight limp, or tremor. Handwriting changes may be an early diagnostic clue. The diagnosis of Parkinson’s disease can usually be made with certainty when there is evidence of tremor, rigidity, and bradykinesia (Brunton, Chabner, & Knollman, 2011). The results of the patient’s history and neurological examination are carefully evaluated. Without treatment Parkinson’s disease progresses over ten to fifteen years to a rigid, akinetic state in which patients are incapable of caring for themselves (Brunton, Chabner, & Knollman, 2011). The availability of effective pharmacological treatment has altered the prognosis of Parkinson’s disease; in most cases, functional mobility can be maintained for many years. Life expectancy of adequately treated patients is increased substantially (Brunton, Chabner, & Knollman, 2011). The presence of dysphagia is associated with shorter survival times. Motor impairment of the muscles in the throat impairs swallowing and poses a risk for aspiration pneumonia. Other complications of Parkinson’s disease include sleep disorders, sexual dysfunction, bowel and bladder complications, and sensory problems, such as the loss of smell (Kofman).

There is no cure for Parkinson’s disease. Treatment mainly relies on replacing dopamine with focus on controlling symptoms and improving quality of life (Katzung, Mastes, & Trevor, 2012). Because Parkinson’s disease symptoms are due to a deficiency of the brain chemical dopamine, the brain drug treatment help increase dopamine levels in the brain. Levodopa, usually in combination with carbidopa, is the standard drug treatment (Katzung, Mastes, & Trevor, 2012). For patients who do not respond to levodopa, dopamine agonists may be prescribed. Physical therapy is an important part of Parkinson’s disease treatment. Rehabilitation can help improve balance, mobility, speech and functional abilities. No treatment method has been proven to change the course of the disease. For early disease, with little or no impairment, drug therapy may not be necessary (Kofman).

There is no cure for Parkinson’s disease, but medications, physical therapy, and surgical interventions can help control symptoms and improve the quality of life (Connelly & Fox, 2012). The goals of treatment are to relieve disabilities and balance the problems of the disease with the side effects of the medications. A number of issues must be considered in choosing a medication for treatment. These include the effectiveness of the medication, the side effects of the medication, and the loss of effectiveness over time (Brunton, Chabner, & Knollman, 2011).

Levodopa (L-dopa) has been used for years and is the gold standard for treatment. L-dopa increases brain levels of dopamine. It is probably the most effective drug for controlling symptoms and is used in all phases of the disease. The standard preparations, Sinemet and Atamet, combine levodopa with carbidopa, a drug that slows the breakdown of levodopa. Levodopa is better at improving motor problems than dopamine agonists but increases the risk of involuntary movements. Effectiveness tends to decrease after four to five years of use (Brunton, Chabner, & Knollman, 2011).

Dopamine agonists’ drugs mimic dopamine to stimulate the dopamine system in the brain. The drugs included are pramipexole (Mirapex), ropinirole (Requip), bromocriptine (Parlodel), and rotigotine (Neupro) (Katzung, Mastes, & Trevor, 2012).

Monoamine oxidase B inhibitors may have some mild benefits in initial therapy; they include selegiline (Eldepryl) and rasagiline (Azilect), and they slow the breakdown of dopamine that occurs naturally in the brain and dopamine produced by levodopa (Katzung, Mastes, & Trevor, 2012).

Entacapone (comtan) is a catechol-o-methyl transferase (COMT) inhibitor that helps to prolong the effects of levodopa by blocking an enzyme that breaks down dopamine (Brunton, Chabner, & Knollman, 2011).

Medications to treat other symptoms associated with Parkinson’s disease include antidepressants. Tricyclic’s, particularly Amitriptyline (Elavil), studies indicate that the use of SSRIs may worsen symptoms. Anti-psychotics include clozapine and quetiapine help with psychotic symptoms seen with Parkinson’s disease (Brunton, Chabner, & Knollman, 2011). The cholinesterase inhibitor drugs donepezil (Aricept) and rivastigmine (Exelon) are used to treat Alzheimer’s disease and are sometimes used for Parkinson’s disease. The benefits are small and may not be noticed. Daytime sleepiness and fatigue may be treated with modafinil (Provigil) a drug used to treat narcolepsy or methylphenidate (Ritalin) may be considered for fatigue. Glycopyrrolate, scopolamine, and injections of botulinum toxin may be used to relieve drooling symptoms (Brunton, Chabner, & Knollman, 2011).

Advanced Parkinson’s disease poses challenges for the patient and caregivers. Eventually, symptoms such as stooped posture, freezing, and speech difficulties may no longer respond to drug therapy. Surgery (deep brain stimulation) may be considered. Patients become increasingly dependent on others for care and require assistance with daily tasks. The goal of treatment for advanced Parkinson’s disease should be on providing safety, comfort, and quality of life (Brunton, Chabner, & Knollman, 2011).

The toxic effects of Levodopa with carbidopa are considerable. Dyskinesia, the ability to control muscles, can take many forms, most often uncontrolled flailing of the arms and legs or chorea, rapid and repetitive motions that can affect the limbs, face, tongue, mouth, and neck (Brunton, Chabner, & Knollman, 2011). Hypotension is a common problem during the first few weeks of therapy. Cardiac arrhythmias and gastrointestinal difficulties are common, with the potential of gastric bleeding. Levodopa can cause disturbances in breathing function, but may benefit patients with upper airway obstructions. Hair loss and mental and psychiatric side effects including confusion, extreme emotional states, especially anxiety, vivid dreams, visual and auditory hallucinations, sleepiness, and effects on learning are other side effects of levodopa (Connelly & Fox, 2012). Levodopa causes fewer psychiatric side effects than other drugs including anticholinergics, selegiline, amantadine, and dopamine agonists. Psychiatric side effects often occur at night, therefore, some doctors recommend reducing the evening dose (Connelly & Fox, 2012).

Monoamine Oxidase B (MAO-B) inhibitors block monoamine oxidase B, an enzyme that degrades dopamine. Selegiline was commonly used in early onset disease in combination with L-dopa for maintenance (Brunton, Chabner, & Knollman, 2011). Concerns of the significant side effects have been raised. Azilect, a newer MAO-B Inhibitor, is used alone during early stage Parkinson’s disease and in combination with L-dopa for moderate to advanced Parkinson’s disease. Side effects of MAO-B inhibitors include orthostatic hypotension, hypertension if combined with drugs that increase serotonin levels, such as many antidepressants (Brunton, Chabner, & Knollman, 2011). A dangerous increase in blood pressure may occur if patients eat foods rich in the amino acid tyramine, while taking selegiline or rasagiline, and for two weeks after stopping the medications. Patients should avoid foods such as aged cheeses, processed lunch meats, pickled herring, yeast extracts, aged red wine, draft beers, sauerkraut, and soy sauce (Connelly & Fox, 2012).

Dopamine agonists stimulate dopamine receptors in the substantia nigra. Dopamine agonists are effective in delaying motor complications during the first years of treatment (Katzung, Mastes, & Trevor, 2012). Newer dopamine agonists, Mirapex (pramipexole) and Requip (ropinirol) are the most commonly prescribed. Mirapex appears to work better and have fewer side effects than requip. Side effects include nausea, vomiting, constipation, headache, nasal congestion, nightmares, hallucinations, and psychosis. Bromocriptine is the only ergot dopamine agonist approved for treatment in the US (Connelly & Fox, 2012). Apomorphine is a dopamine agonist used as a rescue drug in people having on-off effects severe enough to require going off L-dopa for a few days. Because it causes severe nausea and vomiting, it must be taken with an anti-emetic. Rotigotine (Neupro) is a once daily transdermal patch to treat early and advanced stage Parkinson’s disease (Connelly & Fox, 2012).

Catechol-O- Methyl Transferase Inhibitors (COMT Inhibitors) increase concentrations of existing dopamine in the brain. Entacapone (Comtan, Stalevo) is the current standard COMT inhibitor. It improves motor fluctuations related to weaning off effects. The side effects include involuntary muscle movement, confusion, hallucinations, nausea, vomiting, insomnia, headache, urinary retention, cramps, diarrhea, less common constipation, susceptibility to respiratory infection, sweating and dry mouth (Brunton, Chabner, & Knollman, 2011). A major concern is reports of death from liver damage in patients taking tolcapone (Tasmar) and is recommended only for patients unable to tolerate other drugs. Entacapone does not appear to have the same effects on the liver and does not require the same monitoring (Katzung, Mastes, & Trevor, 2012).

Anticholinergic drugs were the first used in the treatment for Parkinson’s disease. They are used only for control of tremors in early stages (Brunton, Chabner, & Knollman, 2011). Side effects are dry mouth, nausea, urinary retention, blurred vision, and constipation. They can increase heart rate and constipation. They may cause mental problems including memory loss, confusion, and hallucinations (Brunton, Chabner, & Knollman, 2011).

Amantadine stimulates the release of dopamine and may be used with early mild symptoms. Side effects include swollen ankles, and mottled skin, visual hallucinations. Overdose can cause serious and life-threatening toxicity (Brunton, Chabner, & Knollman, 2011).

References

Brunton, L., Chabner, B., & Knollman, B. (2011). Goodman & Gilman’s: The pharmacological basis of therapeutics (12 ed.). McGraw-Hill.

Connelly, B., & Fox, S. (2012, December). Drug treatments for the neuropsychiatric complications of Parkinson’s disease. Retrieved from Medscape.com: http://www.medscape.com/viewarticles/777166

Katzung, B., Mastes, S., & Trevor, A. (2012). Basic & clinical pharmacology (12 ed.). McGraw-Hill.

Kofman, O. (n.d.). Complications of therapy in Parkinson’s disease. CKP-MFC, 12, 87-91. Retrieved from http://www.ncbi.nih.gov/pmc/articles/pmc2153537