Antiparkinson Drugs



Antiparkinson Drugs


Objectives


When you reach the end of this chapter, you will be able to do the following:



Drug Profiles



Key Terms


Adjunctive drugs Drugs that are added as a second drug for combined therapy with a primary drug and may have additive or independent properties. (p. 241)


Akinesia Classically defined as “without movement.” Absence or poverty of movement that results in a masklike facial expression and impaired postural reflexes. (p. 239)


Bradykinesia Slowness of movement; a classic symptom of Parkinson’s disease. (p. 239)


Chorea A condition characterized by involuntary, purposeless, rapid motions such as flexing and extending the fingers, raising and lowering the shoulders, or grimacing. (p. 239)


Dyskinesia Term for abnormal and distressing involuntary movements; inability to control movements, which often occurs as a side effect of levodopa therapy. (p. 239)


Dystonia Impaired or distorted voluntary movement, often involving the head, neck, or feet. (p. 239)


Exogenous A term describing any substance produced outside of the body that may be taken into the body (e.g., a medication, food, or environmental toxin). (p. 245)


On-off phenomenon A common experience of patients taking medication for Parkinson’s disease in which they experience periods of greater symptomatic control (“on” time) alternating with periods of lesser symptomatic control (“off” time). (p. 239)


Parkinson’s disease A slowly progressive, degenerative neurologic disorder characterized by resting tremor, pill-rolling of the fingers, masklike facies, shuffling gait, forward flexion of the trunk, loss of postural reflexes, and muscle rigidity and weakness. (p. 238)


Postural instability A decrease or change in motor and muscle movements that leads to unsteadiness and hesitation in movement and gait when the individual starts or stops walking, or causes leaning to the left or right when sitting; occurs in Parkinson’s disease. (p. 239)


Presynaptic Drugs that exert their antiparkinson effects before the nerve synapse. (p. 243)


Rigidity Resistance of the muscles to passive movement; leads to the “cogwheel” rigidity seen in Parkinson’s disease. (p. 239)


TRAP (Tremor, rigidity, akinesia, postural instability); an acronym for symptoms of Parkinson’s disease. (p. 239)


Tremor In Parkinson’s disease, shakiness of the extremities seen mostly at rest. (p. 239)


Wearing-off phenomenon A gradual worsening of parkinsonian symptoms as a patient’s medications begin to lose their effectiveness, despite maximal dosing with a variety of medications. (p. 239)


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http://evolve.elsevier.com/Lilley



Anatomy, Physiology, and Pathophysiology Overview


Pathophysiology Of Parkinson’s Disease


Parkinson’s disease is a chronic, progressive, neurodegenerative disorder affecting the dopamine-producing neurons in the brain. Other chronic central nervous system (CNS) neuromuscular disorders are myasthenia gravis and Alzheimer’s disease. Parkinson’s disease was initially recognized in 1817, at which time it was called shaking palsy. James Parkinson later described in more detail the symptoms of both the early and advanced stages of the disease. The underlying pathologic defect was not discovered until the1960s. It was then recognized that Parkinson’s disease involves a dopamine deficit in the area of the cerebral cortex called the substantia nigra, which is contained within another brain structure known as the basal ganglia. Also relevant is the adjacent structure called the globus pallidus. All three structures are parts of the brain that make up the extrapyramidal system, which is involved in motor function, including posture, muscle tone, and smooth muscle activity. In addition, the thalamus serves as a relay station for brain impulses, whereas the cerebellum regulates muscle coordination (Figure 15-1).



Dopamine is an inhibitory neurotransmitter and acetylcholine is an excitatory neurotransmitter in this area of the brain. A correct balance between these two neurotransmitters is needed for the proper regulation of posture, muscle tone, and voluntary movement. Parkinson’s disease results from an imbalance in these two neurotransmitters in the basal ganglia. This imbalance is caused by failure of the nerve terminals in the substantia nigra to produce dopamine. Dopamine acts in the basal ganglia to control movements. Destruction of the substantia nigra by Parkinson’s disease leads to dopamine depletion. This often results in excessive, unopposed acetylcholine (cholinergic) activity due to the lack of a normal dopaminergic balancing effect. Figure 15-2 illustrates the difference in neurotransmitter concentrations in persons with normal balance and in patients with Parkinson’s disease.



Some theorize that Parkinson’s disease is the result of an earlier head injury or of excess iron in the substantia nigra, which undergoes oxidation and causes the generation of toxic free radicals. Another theory postulates that, because dopamine levels naturally decrease with age, Parkinson’s disease represents a premature aging of the nigrostriatal cells of the substantia nigra resulting from environmental or intrinsic biochemical factors, or both. Evidence from animal studies suggests that environmental toxins, such as pesticides and metals, also may contribute to the development of Parkinson’s disease.


Parkinson’s disease affects at least 1 million Americans and 4 million people worldwide. It is the second most common neurodegenerative disease after Alzheimer’s disease. Some patients may have symptoms of both conditions. In most patients, the disease becomes apparent between 45 and 65 years of age, with a mean age of onset of 56 years. The number of patients with Parkinson’s disease is expected to continue to increase as our elderly population grows. The disease occasionally occurs in younger people, especially after acute encephalitis, or carbon monoxide or metallic poisoning. However, it is usually idiopathic (of no known cause). Overall, there is a 2% chance of developing the disease in one’s lifetime. Men are affected more often than women in a ratio of up to 3:2. Evidence now suggests a possible genetic link, with up to 20% of patients having a family history of the disease.


There are no readily available laboratory tests that can detect or confirm Parkinson’s disease. The diagnosis is usually made on the basis of the classic symptoms and physical findings. The classic symptoms of Parkinson’s disease include bradykinesia, postural instability, rigidity, and tremors (TRAP [Tremor, rigidity, akinesia, postural instability] with akinesia really manifesting as bradykinesia) (see Table 15-1). Computed tomography (CT), magnetic resonance imaging (MRI), cerebrospinal fluid analysis, and electroencephalography (EEG) are usually normal and of little diagnostic value. Positron emission tomography (PET) may offer some additional information. CT, MRI, and PET may be useful tools for ruling out other possible diseases as causes of the symptoms, as well as for follow-up imaging after drug and surgical treatments.



Unfortunately, Parkinson’s disease is a progressive condition. Over time, there is substantial reduction in the number of surviving dopaminergic terminals that can take up pharmacologically administered levodopa and convert it into dopamine. Rapid swings in the response to levodopa, called the on-off phenomenon, also occur. The result is worsening of the disease when too little dopamine is present, or dyskinesias when too much is present. In contrast, the wearing-off phenomenon occurs when anti–Parkinson’s disease medications begin to lose their effectiveness, despite maximal dosing, as the disease progresses. Dyskinesia is the difficulty in performing voluntary movements and is commonly seen in the disease. The two dyskinesias most frequently associated with antiparkinson therapy are chorea (irregular, spasmodic, involuntary movements of the limbs or facial muscles) and dystonia (abnormal muscle tone leading to impaired or abnormal movements). Dystonia commonly involves the head, neck, or feet and is a symptom common to patients with Parkinson’s disease. These motor complications make Parkinson’s disease a prominent cause of disability. Dementia may also be a result of the disease and is referred to as Parkinson’s disease–associated dementia.


Symptoms of Parkinson’s disease do not appear until approximately 80% of the dopamine store in the substantia nigra has been depleted. This means that by the time the disease is diagnosed, only approximately 20% of the patient’s original dopaminergic terminals are functioning normally.


Treatment of Parkinson’s Disease


The first step in the treatment of Parkinson’s disease is to provide a full explanation of the disease to the patient and his or her family members or significant others. Physical therapy, speech therapy, and occupational therapy are almost always needed when the patient is in the later stages of the disease.


Treatment of the disease centers around drug therapy. However, physical activity is a must for these patients. Many experts believe that physical activity is as important as any drug therapy, and together they greatly improve mobility. For severe cases, the surgical technique of deep brain stimulation may be used. This involves electrical stimulation of dopamine-deficient brain tissues in a way that helps to reduce Parkinson-associated dyskinesias. Surgical treatments are for the more severe cases, and the patient must still respond well to drug therapy.


Pharmacology Overview


Because Parkinson’s disease is thought to be due to an imbalance of dopamine and acetylcholine, drug therapy is aimed at increasing the levels of dopamine and/or antagonizing the effects of acetylcholine. Unfortunately, current drug therapy does not slow the progression of the disease, but rather is used to slow the progression of symptoms. The drugs available for the treatment of Parkinson’s disease are listed in Table 15-2.



TABLE 15-2


REVIEW OF PHARMACOLOGIC THERAPY FOR PARKINSON’S DISEASE




















































































GENERIC NAME TRADE NAME ROUTE INDICATIONS
Indirect-Acting Dopamine Receptor Agonists (MAO-B Inhibitors)
selegiline Eldepryl, Zelapar∗ PO Used in conjunction with carbidopa-levodopa in early stages of disease; helpful with symptom fluctuations
rasagiline Azilect PO
Dopamine Modulator
amantadine Symmetrel PO Used in early stages; can be effective in moderate or advanced stages; reduces tremor or muscle rigidity
COMT Inhibitors
tolcapone Tasmar PO Usually added to carbidopa-levodopa to treat symptom fluctuations; delays “off” periods; has levodopa dose-sparing effect
entacapone Comtan PO  
Direct-Acting Dopamine Receptor Agonists
Ergot
bromocriptine Parlodel PO Usually used as drug of choice for young patients; first- or second-line therapy of choice for elderly; can be used as adjunct to levodopa for “off” periods; can be used to reduce dyskinesia associated with later stages
Nonergot
pramipexole Mirapex PO
ropinirole Requip PO
Dopamine Replacement Drugs
carbidopa-levodopa Sinemet, Parcopa∗ PO Usually started as soon as patient becomes functionally impaired; drug of choice for most elderly patients
Anticholinergic Drugs†
benztropine Cogentin PO, IV Used as secondary drug for tremor/muscle rigidity
trihexyphenidyl Generic only (formerly Artane) PO
Antihistamines‡
diphenhydramine Benadryl PO, IV Used as secondary drug for tremor/muscle rigidity


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COMT, Catechol ortho-methyltransferase; IV, intravenous; MAO-B, monoamine oxidase type B; PO, oral.


∗Orally disintegrating tablet (see Chapter 2).


†See Chapter 21.


‡See Chapter 36.


Antiparkinson drug therapy is based upon the fact that nerve terminals can take up substances, store them, and release them for use when needed. As long as there are functioning nerve terminals that can take up dopamine, the symptoms of Parkinson’s disease can be at least partially controlled. Since Parkinson’s disease is essentially a deficiency of dopamine in certain areas of the brain, it seems logical that drug therapies focus primarily on restoring and enhancing dopaminergic activity in these neurons. A variety of both indirect- and direct-acting drugs are available for this purpose. The indirect-acting drugs are often administered first in the disease process.


Indirect-Acting Dopaminergic Drugs


Monoamine Oxidase Inhibitors


The enzyme monoamine oxidase (MAO) causes the breakdown of catecholamines in the body, which include dopamine, norepinephrine, and epinephrine. There are two subclasses of MAO in the body: MAO-A and MAO-B. As early as 1965, nonselective monoamine oxidase inhibitors (MAOIs), which inhibit both MAO-A and MAO-B, were being used to improve the therapeutic effect of levodopa by preventing its metabolic breakdown. They were also among the first medications used to treat depression but have been replaced by newer drug categories (see Chapter 16). A major adverse effect of the nonselective MAOIs is that they interact with tyramine-containing foods (cheese, red wine, beer, and yogurt) because of their inhibitory activity against MAO-A. This has been called the cheese effect, and can result in severe hypertension. Selegiline is a selective MAO-B inhibitor and is much less likely to elicit the classic cheese effect. It is approved for use in conjunction with levodopa therapy in the treatment of Parkinson’s disease. There was earlier speculation that selegiline, as well as possibly vitamins E and C, might have antiparkinson effects due to “neuroprotective” activity at the neuronal (nerve cell) level. However, no studies to date have demonstrated this to be true. Nonetheless, this theoretical neuroprotective effect is still debated in the literature.


Rasagiline is the newest antiparkinson drug and received FDA approval in 2008. Like selegiline, rasagiline is a selective MAO-B inhibitor. It is approved to be given once a day as monotherapy in the early stages of the disease, as well as in combination with other drugs in advanced cases. Drug interactions and adverse effects are similar to those of selegiline.


Mechanism of Action and Drug Effects


The MAO enzymes are widely distributed throughout the body, with the highest concentrations found in the liver, kidney, stomach, intestinal wall, and brain. Most MAO-B occurs in the CNS, primarily in the brain. The primary role of MAO enzymes is the breakdown of catecholamines, such as dopamine, norepinephrine, and epinephrine, as well as serotonin. Giving an MAO-B inhibitor such as selegiline or rasagiline causes an increase in the levels of dopaminergic stimulation in the CNS. This helps to counter the dopaminergic deficiency seen in Parkinson’s disease. Administration of selegiline can also allow the dose of levodopa (discussed later in this chapter) to be reduced. Improvement in functional ability and decreased severity of symptoms can occur; however, only approximately 50% to 60% of patients show a positive response.


Indications


Selegiline and rasagiline are currently approved for use in combination with carbidopa-levodopa. They are adjunctive drugs used when a patient’s response to levodopa is fluctuating. They may also be somewhat beneficial as a prophylactic drug to delay reduction in a patient’s response to levodopa. Studies have shown that selegiline-treated patients required levodopa therapy approximately 1.8 times later than control patients. As Parkinson’s disease progresses, it becomes more difficult to manage it with levodopa. Ultimately, levodopa no longer controls the disease, and the patient is seriously debilitated. This generally occurs between 5 and 10 years after the start of levodopa therapy.


Contraindications


Selegiline and rasagiline are contraindicated in cases of known drug allergy. Concurrent use with the opioid analgesic meperidine (see Chapter 10) is also contraindicated due to well-documented drug interactions between MAOIs and meperidine.


Adverse Effects


The most common adverse effects associated with selegiline use are mild and are listed in Table 15-3. At recommended dosages of 10 mg/day, the drug maintains its selective MAO-B inhibition. However, at dosages that exceed 10 mg/day, selegiline becomes a nonselective MAOI, which contributes to the development of the cheese effect described earlier.



Interactions


Selegiline interacts with meperidine and has been associated with delirium, muscle rigidity, hyperpyrexia (high fever), and hyperirritability. Other reported reactions are listed in Table 15-4. Selegiline may safely be taken concurrently with catechol ortho-methyltransferase (COMT) inhibitors (see later drug section). Patients taking higher doses of selegiline need to avoid tyramine-containing foods such as aged cheese, sausages, and draft beer.



Dosages


For dosage information, see the table on p. 242. Also see the Safety and Quality Improvement: Preventing Medication Errors box on p. 243.


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May 9, 2017 | Posted by in NURSING | Comments Off on Antiparkinson Drugs

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