Drugs for parkinson’s disease

CHAPTER 21


Drugs for parkinson’s disease


Parkinson’s disease (PD) is a slowly progressive neurodegenerative disorder first described in 1817 by Dr. James Parkinson, a London physician. The disease afflicts over 1 million Americans, making it second only to Alzheimer’s disease as the most common degenerative disease of neurons. Cardinal symptoms are tremor, rigidity, postural instability, and slowed movement. In addition to these motor symptoms, most patients also experience nonmotor symptoms, especially autonomic disturbances, sleep disturbances, depression, psychosis, and dementia. Years before functional impairment develops, patients may experience early symptoms of PD, including loss of smell, excessive salivation, clumsiness of the hands, worsening of handwriting, bothersome tremor, slower gait, and reduced voice volume. As a rule, symptoms first appear in middle age and progress relentlessly. The underlying cause of motor symptoms is loss of dopaminergic neurons in the substantia nigra. Although there is no cure for motor symptoms, drug therapy can maintain functional mobility for years, and can thereby substantially prolong quality of life and life expectancy. The most effective drug for PD is levodopa, given in combination with carbidopa. Unfortunately, as neurodegeneration progresses, levodopa eventually becomes ineffective.




Pathophysiology that underlies motor symptoms


Motor symptoms result from damage to the extrapyramidal system, a complex neuronal network that helps regulate movement. When extrapyramidal function is disrupted, dyskinesias (disorders of movement) result. The dyskinesias that characterize PD are tremor at rest, rigidity, postural instability, and bradykinesia (slowed movement). In severe PD, bradykinesia may progress to akinesia—complete absence of movement.


In people with PD, neurotransmission is disrupted primarily in the striatum, an important component of the extrapyramidal system. A simplified model of striatal neurotransmission is depicted in Figure 21–1A. As indicated, proper function of the striatum requires a balance between two neurotransmitters: dopamine and acetylcholine (ACh). Dopamine is an inhibitory transmitter; ACh is excitatory. According to the model, the neurons that release dopamine inhibit neurons that release gamma-aminobutyric acid (GABA, another inhibitory transmitter). In contrast, the neurons that release ACh excite the neurons that release GABA. Movement is normal when the inhibitory influence of dopamine and the excitatory influence of ACh are in balance. Note that the neurons that supply dopamine to the striatum originate in the substantia nigra. Between 70% and 80% of these neurons must be lost before PD becomes clinically recognizable. This loss takes place over 5 to 20 years. Put another way, neuronal degeneration begins long before overt motor symptoms appear.


image
Figure 21–1  A model of neurotransmission in the healthy striatum and parkinsonian striatum.
A, In the healthy striatum, dopamine (DA) released from neurons originating in the substantia nigra inhibits the firing of neurons in the striatum that release gamma-aminobutyric acid (GABA). Conversely, neurons located within the striatum, which release acetylcholine (ACh), excite the GABAergic neurons. Hence, under normal conditions, the inhibitory actions of DA are balanced by the excitatory actions of ACh, and controlled movement results. B, In Parkinson’s disease, the neurons that supply DA to the striatum degenerate. In the absence of sufficient DA, the excitatory effects of ACh go unopposed, and disturbed movement results.

In PD, there is an imbalance between dopamine and ACh in the striatum (Fig. 21–1B). As noted, the imbalance results from degeneration of the neurons that supply dopamine to the striatum. In the absence of dopamine, the excitatory influence of ACh goes unopposed, causing excessive stimulation of the neurons that release GABA. Overactivity of these GABAergic neurons contributes to the motor symptoms that characterize PD.


What causes degeneration of dopaminergic neurons? No one knows for sure. However, some evidence strongly implicates alpha-synuclein—a potentially toxic protein synthesized by dopaminergic neurons. Under normal conditions, alpha-synuclein is rapidly degraded. As a result, it doesn’t accumulate and no harm occurs. Degradation of alpha-synuclein requires two other proteins: parkin and ubiquitin. (Parkin is an enzyme that catalyzes the binding of alpha-synuclein to ubiquitin. Once bound to ubiquitin, alpha-synuclein can be degraded.) If any of these proteins—alpha-synuclein, parkin, or ubiquitin—is defective, degradation of alpha-synuclein cannot take place. When this occurs, alpha-synuclein accumulates inside the cell, forming neurotoxic fibrils. At autopsy, these fibrils are visible as so-called Lewy bodies, which are characteristic of PD pathology. Failure to degrade alpha-synuclein appears to result from two causes: genetic vulnerability and toxins in the environment. Defective genes coding for all three proteins have been found in families with inherited forms of PD. In people with PD that is not inherited, environmental toxins may explain the inability to degrade alpha-synuclein.


As discussed in Chapter 31, movement disorders similar to those of PD can occur as side effects of antipsychotic drugs. These dyskinesias, which are referred to as extrapyramidal side effects, result from blockade of dopamine receptors in the striatum. This drug-induced parkinsonism can be managed with some of the drugs used to treat PD.



Overview of motor symptom management




Therapeutic goal

Ideally, treatment would reverse neuronal degeneration, or at least prevent further degeneration, and control symptoms. Unfortunately, the ideal treatment doesn’t exist: We have no drugs that can prevent neuronal damage or reverse damage that has already occurred. Hence, the goal with current drugs is simply to improve the patient’s ability to carry out activities of daily life. Drug selection and dosage are determined by the extent to which PD interferes with work, walking, dressing, eating, bathing, and other activities. Drugs benefit the patient primarily by improving bradykinesia, gait disturbance, and postural instability. Tremor and rigidity, although disturbing, are less disabling. It is important to note that drugs only provide symptomatic relief; they do not cure PD. Furthermore, there is no convincing proof that any current drug can delay disease progression.



Drugs employed

Given the neurochemical basis of parkinsonism—too little striatal dopamine and too much ACh—the approach to treatment is obvious: Give drugs that can restore the functional balance between dopamine and ACh. To accomplish this, two types of drugs are used: (1) dopaminergic agents (ie, drugs that directly or indirectly cause activation of dopamine receptors); and (2) anticholinergic agents (ie, drugs that block receptors for ACh). Of the two groups, dopaminergic agents are by far the more widely employed.


As shown in Table 21–1, dopaminergic drugs act by several mechanisms: levodopa promotes dopamine synthesis; the dopamine agonists activate dopamine receptors directly; inhibitors of monoamine oxidase-B (MAO-B) prevent dopamine breakdown; amantadine promotes dopamine release (and may also block dopamine reuptake); and the inhibitors of catechol-O-methyltransferase (COMT) enhance the effects of levodopa by blocking its degradation.



In contrast to the dopaminergic drugs, which act by multiple mechanisms, all of the anticholinergic agents share the same mechanism: blockade of muscarinic receptors in the striatum.



Clinical guidelines

The American Academy of Neurology (AAN) has developed evidence-based guidelines for the treatment of Parkinson’s disease. These guidelines were published in Neurology as six separate articles, released in 2002, 2006, and 2010. Their titles and release years are as follows:



The entire set is available free online at www.neurology.org. The recommendations below are based on these guidelines.



Drug selection





Pharmacology of the drugs used for motor symptoms


Levodopa


Levodopa was introduced in the 1960s, and has been a cornerstone of PD treatment ever since. Unfortunately, although the drug is highly effective, beneficial effects diminish over time. The most troubling adverse effects are dyskinesias. To enhance effects, levodopa is always combined with carbidopa as discussed in the following section.



Use in parkinson’s disease


Beneficial effects.

Levodopa is the most effective drug for PD. At the beginning of treatment, about 75% of patients experience a 50% reduction in symptom severity. Levodopa is so effective, in fact, that a diagnosis of PD should be questioned if the patient fails to respond.


Full therapeutic responses may take several months to develop. Consequently, although the effects of levodopa can be significant, patients should not expect immediate improvement. Rather, they should be informed that beneficial effects are likely to increase steadily over the first few months.


In contrast to the dramatic improvements seen during initial therapy, long-term therapy with levodopa has been disappointing. Although symptoms may be well controlled during the first 2 years of treatment, by the end of year 5 ability to function may deteriorate to pretreatment levels. This probably reflects disease progression and not development of tolerance to levodopa.



Acute loss of effect.

Acute loss of effect occurs in two patterns: gradual loss and abrupt loss. Gradual loss—“wearing off”—develops near the end of the dosing interval, and simply indicates that drug levels have declined to a subtherapeutic value. Wearing off can be minimized in three ways: (1) shortening the dosing interval, (2) giving a drug that prolongs levodopa’s plasma half-life (eg, entacapone), and (3) giving a direct-acting dopamine agonist.


Abrupt loss of effect, often referred to as the “on-off” phenomenon, can occur at any time during the dosing interval—even while drug levels are high. “Off” times may last from minutes to hours. Over the course of treatment, “off” periods are likely to increase in both intensity and frequency. Drugs that can help reduce “off” times are listed in Table 21–2. As discussed below, avoiding high-protein meals may also help.




Mechanism of action

Levodopa reduces symptoms by increasing synthesis of dopamine in the striatum (Fig. 21–2). Levodopa enters the brain via an active transport system that carries it across the blood-brain barrier. Once in the brain, the drug undergoes uptake into the few dopaminergic nerve terminals that remain in the striatum. Following uptake, levodopa, which has no direct effects of its own, is converted to dopamine, its active form. As dopamine, levodopa helps restore a proper balance between dopamine and ACh.


image
Figure 21–2  Steps leading to alteration of CNS function by levodopa.
To produce its beneficial effects in PD, levodopa must be (1) transported across the blood-brain barrier; (2) taken up by dopaminergic nerve terminals in the striatum; (3) converted into dopamine; (4) released into the synaptic space; and (5) bound to dopamine receptors on striatal GABAergic neurons, causing them to fire at a slower rate. Note that dopamine itself is unable to cross the blood-brain barrier, and hence cannot be used to treat PD.

Conversion of levodopa to dopamine is depicted in Figure 21–3. As indicated, the enzyme that catalyzes the reaction is called a decarboxylase (because it removes a carboxyl group from levodopa). The activity of decarboxylases is enhanced by pyridoxine (vitamin B6).


image
Figure 21–3  Conversion of levodopa to dopamine.
Decarboxylases present in the brain, liver, and intestine convert levodopa into dopamine. Pyridoxine (vitamin B6) accelerates the reaction.

Why is PD treated with levodopa and not with dopamine itself? There are two reasons. First, dopamine cannot cross the blood-brain barrier (see Fig. 21–2). As noted, levodopa crosses the barrier by means of an active transport system, a system that does not transport dopamine itself. Second, dopamine has such a short half-life in the blood that it would be impractical to use even if it could cross the blood-brain barrier.



Pharmacokinetics

Levodopa is administered orally and undergoes rapid absorption from the small intestine. Food delays absorption by slowing gastric emptying. Furthermore, since neutral amino acids compete with levodopa for intestinal absorption (and for transport across the blood-brain barrier as well), high-protein foods will reduce therapeutic effects.


Only a small fraction of each dose reaches the brain. The majority is metabolized in the periphery, primarily by decarboxylase enzymes and to a lesser extent by COMT. Peripheral decarboxylases convert levodopa into dopamine, an active metabolite. In contrast, COMT converts levodopa into an inactive metabolite. Like the enzymes that decarboxylate levodopa within the brain, peripheral decarboxylases work faster in the presence of pyridoxine. Because of peripheral metabolism, less than 2% of each dose enters the brain.



Adverse effects

Most side effects of levodopa are dose dependent. The elderly, who are the primary users of levodopa, are especially sensitive to adverse effects.




Dyskinesias.

Ironically, levodopa, which is given to alleviate movement disorders, actually causes movement disorders in many patients. About 80% develop involuntary movements within the first year. Some dyskinesias are just annoying (eg, head bobbing, tics, grimacing), whereas others can be disabling (eg, ballismus, choreoathetosis). These dyskinesias develop just before or soon after optimal levodopa dosage has been achieved. Dyskinesias can be managed in three ways. First, the dosage of levodopa can be reduced. However, dosage reduction may allow PD symptoms to re-emerge. Second, we can give amantadine (see below), which can reduce dyskinesias in some patients. If these measures fail, the only remaining options are surgery and electrical stimulation (see Box 21–1).



imageBOX 21–1    SPECIAL INTEREST TOPIC


SURGICAL AND ELECTRICAL TREATMENTS FOR PARKINSON’S DISEASE


For patients with advanced Parkinson’s disease (PD), levodopa therapy is far from ideal. Over time, the drug becomes less and less effective. Patients typically experience “off” times as well as drug-induced dyskinesias. For these patients, nondrug therapies may help. Potential options are deep brain stimulation, pallidotomy, and cell implants. Brain stimulation and pallidotomy have been very successful; cell implants have not.


Deep brain stimulation (DBS)


Electrical stimulation of specific brain areas can improve motor symptoms in patients with PD. Three areas have been targeted: the subthalamic nucleus (STN), the globus pallidus internus (GPI), and the ventralis intermedius nucleus of the thalamus. Stimulation of the STN and GPI have produced the best results. Compared with pallidotomy, electrical stimulation has several advantages: it’s reversible and adjustable, and, because brain tissue is not permanently damaged, it can be done bilaterally with low risk. On the other hand, electrical stimulation is very expensive. Several studies on electrical stimulation have been conducted. A study on STN stimulation is described below.


In 1998, researchers reported that continuous, long-term electrical stimulation of the STN can improve symptoms in patients with advanced PD. This work was based on animal models of PD in which (1) motor symptoms were associated with abnormal neuronal activity in the STN and (2) electrical stimulation of the STN improved the symptoms. In patients with PD, electrodes were implanted bilaterally in the STN and then connected by a subcutaneous lead to a pulse generator implanted in the subclavicular region, much like a cardiac pacemaker. The pulse generator was then programmed by telemetry to adjust stimulation parameters (eg, voltage, frequency). All patients in the study had advanced PD and all were experiencing “off” periods with levodopa.


Electrical stimulation produced substantial benefits during “off” times but only modest benefits during “on” times. During “off” times, there was a 60% improvement in motor function (bradykinesia, rigidity, tremor, and gait). During “on” times, improvement was only 10%. Stimulation allowed all patients to become independent in most activities of daily living. On average, stimulation permitted a 50% reduction in levodopa dosage. Subsequent studies have confirmed these results.


Adverse effects were generally mild, but serious sequelae of the neurosurgery are possible. Of the 20 patients in this study, 8 experienced transient CNS effects, including confusion, hallucinations, temporospatial disorientation, and abulia (lack of will; inability to make decisions). All symptoms resolved within 2 weeks of the surgery. Of much greater concern, the procedure carries a 2% to 8% risk of cerebral hemorrhage. Surgical site infection and pain may also occur. Device-related complications include electrode migration, electrode failure, and pulse generator failure. Stimulation also carries an increased risk of falls, gait disturbance, balance disorder, depression, and dystonia (muscle contraction and spasm). Because of these risks, DBS should be reserved for patients with advanced PD who are otherwise good candidates for surgery.


How does STN stimulation improve PD symptoms? The answer is unclear. One theory, based on animal studies, suggests that electrical stimulation may inhibit overactivity of neurons in the STN. The net result would be to increase excitatory input to the cerebral cortex.


Electrical stimulation is expensive. The cost of surgery and the stimulation device may be $50,000 or more. And every 3 to 5 years, additional costs arise when the batteries in the pulse generator must be replaced.



Pallidotomy


Posteroventral medial pallidotomy, or simply pallidotomy, is a neurosurgical procedure for destroying a region of the globus pallidus. As indicated in Figure 21–1, the globus pallidus, which helps regulate movement, receives input from the striatum. In patients with PD, striatal input to the globus pallidus is disrupted, causing the globus pallidus itself to malfunction. It has been argued that altered output from the globus pallidus underlies many of the symptoms of PD, including tremor, rigidity, and bradykinesia. The results of pallidotomy support this argument: For many patients with PD, unilateral destruction of the posteroventral medial region of the globus pallidus produces a substantial improvement in symptoms. The most consistent benefit is a reduction in levodopa-induced dyskinesias. Motor control during levodopa “off” times also improves. In contrast, very little improvement is seen during levodopa “on” times. Following pallidotomy, about 50% of patients who previously needed help with activities of daily living are able to live independently. Pallidotomy may also permit a temporary reduction in levodopa dosage. Although complications of the procedure are generally mild, intracerebral hemorrhage is a potential and serious risk.


Because pallidotomy is irreversible, and because complications can be serious, the procedure should be limited to patients with intractable levodopa-induced dyskinesias and to patients who are disabled by levodopa “off” times. Furthermore, because brain tissue is permanently destroyed, pallidotomy is usually performed unilaterally—thereby leaving the other side of the brain intact, just in case something goes wrong.



Cell implants


The objective with cell implants is to replace degenerated dopaminergic neurons. Implants have been tried with human adrenal cells and with fetal brain cells from humans and pigs. Human brain cells work best, and even then benefits are modest.


In 1995, researchers finally obtained definitive proof that transplanting fetal dopaminergic neurons into the brain can benefit a patient with PD. In this case study, the patient had severe parkinsonism that would no longer respond to drug therapy. Following the transplant, symptoms steadily improved over 3 months, eventually allowing the patient to perform all activities of daily living without assistance. The improvements were sustained for 15 months, at which time the patient died of a massive pulmonary embolism unrelated to the transplant. Autopsy revealed that the grafts not only took but had become seamlessly integrated into the surrounding tissue. This was the first clear demonstration of a correlation between graft survival and improvement of symptoms.


In 1999, a study done with 40 patients showed that fetal tissue transplants are only moderately effective, and then only in patients who are relatively young. In this study, 20 patients received bilateral implants of dopamine-producing cells and 20 control patients received sham implants. Twelve months later, brain scans indicated cell survival in 60% of the treated patients, regardless of age. However, functional improvement was modest (30%) and occurred only in patients under 60 years old. In patients over 60, there was no motor improvement despite survival of the implants. Furthermore, although motor function improved in some younger patients, it was not enough to permit a reduction in levodopa dosage.




Psychosis.

Psychosis develops in about 20% of patients. Prominent symptoms are visual hallucinations, vivid dreams or nightmares, and paranoid ideation (fears of personal endangerment, sense of persecution, feelings of being followed or spied on). Activation of dopamine receptors is in some way involved. Symptoms can be reduced by lowering levodopa dosage, but this will reduce beneficial effects too.


Treatment of levodopa-induced psychosis with first-generation antipsychotics is problematic. Yes, these agents can decrease psychologic symptoms. However, they will also intensify symptoms of PD. Why? Because they block receptors for dopamine in the striatum. In fact, when first-generation antipsychotic agents are used for schizophrenia, the biggest problem is parkinsonian side effects, referred to as extrapyramidal symptoms (EPS).


Two second-generation antipsychotics—clozapine and quetiapine—have been used successfully to manage levodopa-induced psychosis. Unlike the first-generation antipsychotic drugs, clozapine and quetiapine cause little or no blockade of dopamine receptors in the striatum, and hence do not cause EPS. In patients taking levodopa, these drugs can reduce psychotic symptoms without intensifying symptoms of PD. Interestingly, the dosage of clozapine is only 25 mg/day, about 20 times lower than the dosage used for schizophrenia. Clozapine and quetiapine are discussed at length in Chapter 31.




Drug interactions

Interactions between levodopa and other drugs can (1) increase beneficial effects of levodopa, (2) decrease beneficial effects of levodopa, and (3) increase toxicity from levodopa. Major interactions are summarized in Table 21–3. Several interactions are discussed immediately below; others are discussed later on.


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Jul 24, 2016 | Posted by in NURSING | Comments Off on Drugs for parkinson’s disease

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