describe the levadopa part in harrison

LEVODOPA Since its introduction in the late 1960s, levodopa has been the mainstay of therapy for PD. Experiments in the late 1950s by Carlsson and colleagues demonstrated that blocking dopamine uptake with reserpine caused rabbits to become parkinsonian; this could be reversed with the dopamine precursor, levodopa. Subsequently, Hornykiewicz demonstrated a dopamine deficiency in the striatum of PD patients and suggested the potential benefit of dopamine replacement therapy. Dopamine does not cross the blood-brain barrier (BBB), so clinical trials were initiated with levodopa, the precursor of dopamine. Studies over the course of the next decade confirmed the value of levodopa and revolutionized the treatment of PD. Levodopa is routinely administered in combination with a peripheral decarboxylase inhibitor to prevent its peripheral metabolism to dopamine and the development of nausea, vomiting, and orthostatic hypotension due to activation of dopamine receptors in the area postrema (the nausea and vomiting center) that are not protected by the BBB. In the United States, levodopa is combined with the decarboxylase inhibitor carbidopa (Sinemet), whereas in many other countries it is combined with benserazide (Madopar). Levodopa plus a decarboxylase inhibitor is also available in a methylated formulation, a controlled-release formulation (Sinemet CR or Madopar HP) and in combination with a catechol-Omethyltransferase (COMT) inhibitor (Stalevo). A long-acting formulation of levodopa (Rytary) and a levodopa carbidopa intestinal gel that is administered by continuous intraintestinal infusion via an implanted jejunal tube are also now available. An inhaled form of levodopa that is rapidly and reliably absorbed through the pulmonary alveoli has recently been approved as an on-demand therapy for the treatment of individual “off ” episodes (see below). Levodopa remains the most effective symptomatic treatment for PD and the gold standard against which new therapies are compared. No current medical or surgical treatment provides antiparkinsonian benefits superior to what can be achieved with levodopa. Levodopa benefits the classic motor features of PD, prolongs independence and employability, improves quality of life, and increases life span. Indeed, levodopa also benefits some “nondopaminergic” features such as anxiety, depression, and sweating. Almost all PD patients experience improvement, and failure to respond to an adequate trial of levodopa should cause the diagnosis to be questioned. There are important limitations of levodopa therapy. Acute dopaminergic side effects include nausea, vomiting, and orthostatic hypotension. These are usually transient and can generally be avoided by starting with low doses and gradual titration. If they persist, they can be treated with additional doses of a peripheral decarboxylase inhibitor (e.g., carbidopa), administering with food, or adding a peripheral dopamine-blocking agent such as domperidone (not available in the United States). As the disease continues to progress, features such as falling, freezing, autonomic dysfunction, sleep disorders, and dementia may emerge that are not adequately controlled by levodopa. Indeed, these nondopaminergic features (especially falls and dementia) are the primary source of disability and the main reason for hospitalization and nursing home placement for patients with advanced PD in the levodopa era. The major concern with levodopa is that chronic levodopa treatment is associated with the development of motor complications in the large majority of patients. These consist of fluctuations in motor response (“on” episodes when the drug is working and “off ” episodes when parkinsonian features return as drug wears off) and involuntary movements known as dyskinesias, which typically complicate “on” periods (Fig. 435-6). When patients initially take levodopa, benefits are long-lasting (many hours) even though the drug has a relatively short half-life (60–90 min). With continued treatment, however, the duration of benefit following an individual dose becomes progressively shorter until it approaches the half-life of the drug. This loss of benefit is known as the wearing-off effect. Some patients may also experience a rapid and unpredictable switch from the “on” to the “off ” state known as the on-off phenomenon. In advanced cases, because of variability in the bioavailability of standard oral levodopa, the response to a dose of levodopa may be variable and unpredictable with a given dose leading to a full-on response, a partial on-on response, a delay in turning on (delayed-on), or no response at all (no-on). Peak-dose dyskinesias can occur at the time of levodopa peak plasma concentration and maximal clinical benefit. They are usually choreiform but can manifest as dystonic movements, myoclonus, or other movement disorders. They are not troublesome when mild but can be disabling when severe, and can limit the ability to use higher doses of levodopa to better control PD motor features. In more advanced states, patients may cycle between “on” periods complicated by disabling dyskinesias and “off ” periods in which they suffer from severe parkinsonism and painful dystonic postures. Patients may also experience “diphasic dyskinesias,” which occur with lower plasma levodopa levels, and manifest as the levodopa dose begins to take effect and again as it wears off. These dyskinesias typically consist of transient, stereotypic, rhythmic movements that predominantly involve the lower extremities asymmetrically and are frequently associated with parkinsonism in other body regions. They can be relieved by increasing the dose of levodopa, although higher doses may induce more severe peak-dose dyskinesia and disappear as the concentration declines. Long-term double-blind studies show that the risk of developing motor complications can be minimized by using the lowest dose of levodopa that provides satisfactory benefit and through the use of polypharmacy to avoid the need for raising the dose of levodopa. The cause of levodopa-induced motor complications is not precisely known. They are more likely to occur in younger individuals, with the use of higher doses of levodopa, in women, and in those with more severe disease. The classic model of the basal ganglia has been useful for understanding the origin of motor features in PD but has proved less valuable for understanding levodopainduced dyskinesias (Fig. 435-5). The model predicts that dopamine replacement might excessively inhibit the pallidal output system, thereby leading to increased thalamocortical activity, enhanced stimulation of cortical motor regions, and the development of dyskinesia. However, lesions of the pallidum that dramatically reduce its output are associated with amelioration rather than induction of dyskinesia as would be suggested by the classic model. It is now thought that dyskinesia results from alterations in the GPi/SNr neuronal firing pattern (pauses, bursts, synchrony, etc.) and not simply the firing frequency alone. This leads to the transmission of “misinformation” from pallidum to thalamus/cortex that, along with firing frequency, contributes to the development of dyskinesia. Surgical lesions or high-frequency stimulation targeted at the GPi or STN presumably ameliorate dyskinesia by interfering with (blocking or masking) this abnormal neuronal activity and preventing the transfer of misinformation to motor systems. A number of studies suggest that motor complications develop in response to nonphysiologic levodopa replacement. Striatal dopamine levels are normally maintained at a relatively constant level. In PD, where dopamine neurons and terminals have degenerated, striatal dopamine levels are dependent on the peripheral availability of levodopa. Intermittent oral doses of levodopa result in fluctuating plasma levels because of variability in the transit of the drug from the stomach to the duodenum where it is absorbed and the short half-life of the drug. This variability is translated to the brain and results in exposure of striatal dopamine receptors to alternating high and low concentrations of dopamine. This in turn has been shown to induce molecular alterations in striatal neurons, neurophysiologic changes in pallidal output neurons, and ultimately the development of motor complications. It has been hypothesized that more continuous delivery of levodopa might be more physiologic and prevent the development of motor complications. Indeed, double-blind studies have demonstrated that continuous intraintestinal infusion of levodopa/carbidopa or subcutaneous infusion of apomorphine is associated with significant improvement in “off ” time and in “on” time without dyskinesia in advanced PD patients compared with optimized standard oral levodopa. These benefits are superior to what has been observed in double-blind placebocontrolled studies with other dopaminergic agents. Intestinal infusion of levodopa is approved in the United States (Duopa) and Europe (Duodopa). The treatment is, however, complicated by potentially serious adverse events related to the surgical procedure, problems related to the tubing, and the inconvenience of having to wear an infusion system. SC apomorphine infusion is approved in Europe but not yet in the United States (see below). New approaches are currently being tested in which levodopa is continuously administered by a subcutaneous route, an intraoral infusion system, or by long-acting oral levodopa formulations in an effort to avoid the need for a surgical procedure. Behavioral complications can also be associated with levodopa treatment. A dopamine dysregulation syndrome has been described where patients have a craving for levodopa and take frequent and unnecessary doses of the drug in an addictive manner. (In this regard, it is noteworthy that cocaine binds to the dopamine uptake receptor.) PD patients taking high doses of levodopa can also develop purposeless, stereotyped behaviors such as the assembly and disassembly or collection and sorting of objects. This is known as punding, a term taken from the Swedish description of the meaningless behaviors seen in chronic amphetamine users. Hypersexuality and other impulse-control disorders are occasionally encountered with levodopa, although these are more commonly seen with dopamine agonists. Finally, because levodopa undergoes oxidative metabolism and has the potential to generate toxic free radicals, there has been long-standing concern that, independent of the drug’s ability to provide symptomatic benefits, it might accelerate neuronal degeneration. Alternatively, as levodopa improves long-term outcomes in comparison to the pre-levodopa era, it has been suggested that by restoring striatal dopamine, levodopa has the potential to have a disease-modifying or neuroprotective effect. Neither of these hypotheses has been established. A recent delayed-start study showed neither beneficial nor deleterious effects of levodopa on disease progression. Thus, it is generally recommended that levodopa be used solely based on its potential to provide symptomatic benefits balanced by the risk of inducing motor complications and other side effects. explain the text

DOPAMINE AGONISTS Dopamine agonists are a diverse group of drugs that act directly on dopamine receptors. Unlike levodopa, they do not require metabolic conversion to an active product and do not undergo oxidative metabolism. Initial dopamine agonists were ergot derivatives (e.g., bromocriptine, pergolide, cabergoline) and were associated with potentially serious ergot-related side effects such as cardiac valvular damage and pulmonary fibrosis. They have largely been replaced by a second generation of non-ergot dopamine agonists (e.g., pramipexole, ropinirole, rotigotine). In general, dopamine agonists do not have comparable efficacy to levodopa. They were initially introduced as adjuncts to levodopa to enhance motor function and reduce “off ” time in fluctuating patients. Subsequently, it was shown that dopamine agonists are less prone than levodopa to induce dyskinesia, possibly because they are relatively longacting in comparison to levodopa. For this reason, many physicians initiate therapy with a dopamine agonist particularly in younger patients who are more prone to develop motor complications, although supplemental levodopa is eventually required in virtually all patients. This view has been tempered by the recognition that dopamine agonists are associated with potentially serious adverse effects such as unwanted sleep episodes and impulse-control disorders (see below). Both ropinirole and pramipexole are available as orally administered immediate (tid) and extended-release (qd) formulations. Rotigotine is administered as a once-daily transdermal patch and may be useful in managing surgical patients who are not able to be treated with an oral therapy. Apomorphine is the one dopamine agonist with efficacy thought to be comparable to levodopa, but it must be administered parenterally as it is rapidly and extensively metabolized if taken orally. It has a short half-life and duration of activity (45 min). It can be administered by subcutaneous injection as a rescue agent for the treatment of severe “off ” episodes but can also be administered by continuous subcutaneous infusion where it has been demonstrated to reduce both “off ” time and dyskinesia in advanced patients. This latter approach has been approved in Europe but not yet in the United States. A sublingual bilayer formulation of apomorphine has recently been approved as a rapid and reliable therapy for individual “off ” periods that avoids the need for a subcutaneous (SC) injection (see below). Dopamine agonist use is associated with a variety of side effects. Acute side effects are primarily dopaminergic and include nausea, vomiting, and orthostatic hypotension. These can usually be avoided or minimized by starting with low doses and using slow titration over weeks. Side effects associated with chronic use include hallucinations, cognitive impairment, and leg edema. Sedation with sudden unintended episodes of falling asleep that can occur in dangerous situations such as while driving a motor vehicle has been reported. Patients should be informed about this potential problem and should not drive when tired. Dopamine agonists can also be associated with impulse-control disorders, including pathologic gambling, hypersexuality, and compulsive eating and shopping. Patients should be advised of these risks and specifically questioned for their occurrence at follow-up examinations. The precise cause of these problems, and why they appear to occur more frequently with dopamine agonists than levodopa, remains to be resolved, but reward systems associated with dopamine and alterations in the ventral striatum and orbitofrontal regions have been implicated. In general, chronic side effects are dose-related and can be avoided or minimized with lower doses. Injections of apomorphine can be complicated by skin lesions at sites of administration, which can be minimized by proper cleaning and alteration of the injection site. The sublingual bilayer formulation of apomorphine is associated with a relatively high frequency of oropharyngeal side effects, which are generally mild and resolve either spontaneously or with treatment withdrawal explain the text

NEUROPROTECTION Despite the many therapeutic agents available for the treatment of PD, patients continue to progress and to develop intolerable disability. A neuroprotective or disease-modifying therapy that slows or stops disease progression remains the major unmet therapeutic need. Some trials have shown positive results (e.g., selegiline, rasagiline, pramipexole, ropinirole) consistent with a diseasemodifying effect. However, it has not been possible to determine with certainty if the positive results were due to neuroprotection with slowing of disease progression or confounding symptomatic or pharmacologic effects that mask disease progression. Based on genetic and laboratory findings described above, several novel targets for a putative neuroprotective therapy have been discovered and multiple candidate therapies are currently being investigated. The most exciting targets among these etiopathogenic factors include agents that interfere with SNCA accumulation, LRRK2 inhibitors, GBA and GCase enhancers and anti-inflammatory agents that inhibit activation of microglia and cytokine production. Many of these agents have already shown promise in relevant animal models of PD and are currently in clinical trials in PD patients. explain the text