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Dopaminergic Agonists and l -DOPA☆
Dopaminergic Agonists and L-DOPAq A Pisani, University of Rome Tor Vergata, Roma, Italy; and IRCSS Fondazione Santa Lucia, Roma, Italy C Liguori, University of Rome Tor Vergata, Roma, Italy NB Mercuri, University of Rome Tor Vergata, Roma, Italy; and IRCSS Fondazione Santa Lucia, Roma, Italy Ó 2017 Elsevier Inc. All rights reserved.
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Pharmacological Treatment of Parkinson’s Disease L-DOPA in PD L-DOPA and L-DOPA-Sensitive Dystonia Monoamine Oxidase Type-B Inhibitors Dopaminergic Agonists Ergoline Derivatives Non-Ergoline Derivatives Side Effects Conclusion Further Reading Relevant Websites
Pharmacological Treatment of Parkinson’s Disease Parkinson’s disease (PD) is the second most common chronic and progressive neurodegenerative disorder, affecting approximately 3% of people older than 65 years. Considerable advances have been made in identifying the etiopathogenesis of PD. In recent years, different genetic mutations have been identified as causing familial forms of PD, accounting for nearly 2% of cases. Despite this, the large majority of cases are “sporadic–idiopathic” and are thought to be the outcome of complex interactions between the environment and the genetic background. Cardinal features of PD are represented by resting tremor, rigidity, bradykinesia, and impaired balance, often complicated by autonomic, cognitive, and emotional disturbances. The main neuropathological characteristic of the disease is a loss of pigmented dopaminergic cells in the substantia nigra pars compacta that produces a massive depletion of dopamine in the basal ganglia (mainly striatum). Neurodegeneration is provoked by a toxic protein named “alpha-synuclein”, which aggregates and deposits in Lewy bodies. Neuropathological findings have also demonstrated degenerative processes in the serotoninergic, noradrenergic, cholinergic, and peptidergic pathways. Although there is currently no cure for PD, because no therapy has been definitely shown to halt its progression, there are medications available to treat the motor symptoms, which can certainly improve the quality of life of affected patients. These are mainly based on a dopamine replacement strategy.
L-DOPA
in PD
The dopamine precursor L-DOPA (L-3,4-dihydroxy-phenylalanine, also called levodopa) is still the “gold standard antiparkinsonian agent” because a drug superior to it has not been produced after more than four decades of use. Long-lasting observations in clinical practice have undoubtedly demonstrated that orally administered L-DOPA is a more “potent” symptomatic antiparkinsonian drug than any dopaminergic agonist thus far introduced in the therapeutic armamentaria. It has been also reported that it increases life expectancy in PD patients. The superiority of L-DOPA is very likely due to its special feature that allows de novo synthesis of dopamine mainly in the surviving dopamine-containing neurons, thus raising the level of this catecholamine in the striatum. L-DOPA is converted in dopamine by the enzyme aromatic L-amino acid decarboxylase (AADC) ie, present not only in the brain but also in many peripheral organs and vessels. It has been recognized that the peripheral transformation of L-DOPA by AADC only permits a small percentage of L-DOPA to reach the dopaminergic neurons in the brain. Therefore, in order to obtain valid therapeutic concentrations, a huge dose of L-DOPA was administered. This caused important side effects, including hypotension, nausea, and vomiting. Opportunely, the coadministration of L-DOPA with two compounds (benserazide and carbidopa), which block AADC but do not cross the blood–brain barrier, has increased the availability of this dopamine precursor to the brain, thus diminishing its dosage and reducing side effects.
q Change History: August 2015. Sections Pharmacological Treatment of Parkinson’s Disease, Monoamine Oxidase Type-B Inhibitors, Dopaminergic Agonists with Tables 1 and 2 have been updated.
Reference Module in Neuroscience and Biobehavioral Psychology
http://dx.doi.org/10.1016/B978-0-12-809324-5.02374-9
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Dopaminergic Agonists and L-DOPA
It has been suggested that the initial excellent therapeutic response to L-DOPA depends on the fact that newly synthesized dopamine can be released mainly at the synaptic contacts under a stimulus-dependent control. Thus, the newly formed catecholamine might be, at least initially, released respecting neurochemistry and the cytoarchitecture of the remaining dopaminergic neurons. As a result, despite a neuronal degeneration in PD, a phasic and a tonic release of dopamine could still be sustained by oral administrations of L-DOPA. Thus, this L-DOPA-induced dopamine release adequately stimulates dopaminergic receptors. At least six different dopamine receptor subtypes have been cloned. These receptors are divided in two classes: the D1 class comprises D1 and D5 receptor subtypes, whereas the D2 class includes D2 (D2S and D2L isoforms), D3, and D4 receptors. It has been demonstrated that the D2 receptors are mainly involved in the regulation of striatal motor functions. Interestingly, all dopaminergic receptors cloned from the brain are also present in tissues outside the central nervous system (CNS), mainly in the cardiovascular system, the kidney, as well as sympathetic ganglia and the adrenal glands. Whereas the phasic release of dopamine might control the transitory activation of the motor system during movement, the tonic release might prepare and set the motor programs. Therefore, both the phasic and the tonic release of dopamine induced by L-DOPA should correct the disturbances of muscle tone and the alterations of motor performances in Parkinsonian patients. Another important aspect, which might account for L-DOPA’s superiority with respect to other drugs, is the possibility that L-DOPA is not only the precursor of dopamine’s synthesis but also regulates the formation of noradrenaline and, eventually, the release of serotonin and trace amines in the extracellular space. Unfortunately, the “optimal” activation of different receptor systems obtained with L-DOPA in an early phase fades. Thus, the “honeymoon” with the use of the drug vanishes as more dopaminergic neurons degenerate. Therefore, despite L-DOPA administration, because the surviving dopaminergic cells cannot produce enough dopamine in advanced Parkinsonian patients, not only a phasic but also a tonic stimulation of dopaminergic receptors is no longer possible. Consequently, the Parkinsonian symptoms worsen. Important negative side effects also develop during long-term L-DOPA treatment of PD (3–5 years), including attenuation of drug efficacy, motor fluctuations, and psychoses. Along with disease progression, and the consequent loss of dopaminergic terminals, the duration of clinical benefit derived from each L-DOPA dose shortens and patients begin to experience motor fluctuations such as “end of dose deterioration” or the “wearing off” phenomena. The “off” periods do not necessarily respond to an increased frequency of L-DOPA intake. Indeed, the clinical response to L-DOPA becomes unpredictable and the patient may frequently switch from “on” condition to off states. Accordingly, the plasma levels of L-DOPA fluctuate as well and exceed the therapeutic range, producing excessive, involuntary movements (dyskinesias). With further progression of the disease, dyskinesias become even more complex in pattern, with the occurrence of “peak-dose dyskinesias,” and also “end-of-dose dyskinesias.” Currently, the pathogenesis of these motor fluctuations is elusive, although both pre- and postsynaptic mechanisms likely play a critical role. Similarly, psychoses are a common side effect of long-term use of L-DOPA, affecting nearly 20% of treated patients. Managing psychotic symptoms is a very difficult challenge in terms of pharmacological treatment and for daily nursing. For these reasons, some authors claim that it is preferable to avoid treating patients in the early phase of PD with L-DOPA and that, instead, it should be used later when the administration of dopaminergic agonists no longer controls symptoms. Nevertheless, there is not a consensus on this therapeutic approach because the optimal time for initiating L-DOPA therapy is still debated. Variations in the L-DOPA’s pharmacokinetic and alterations of the presynaptic and postsynaptic components in the dopaminergic system might account for the unpredictable responses to L-DOPA in individual patients. The unwanted effects of L-DOPA can be reduced by modifying the therapeutic schedule. For instance, it is important to avoid excessive fluctuations of L-DOPA concentrations in the blood and consequently in the brain. Thus, continuous stimulation of dopaminergic receptors should be obtained in order to attain an acceptable therapeutic outcome. Several attempts have been made to reduce the oscillations in the extracellular concentrations of L-DOPA: (1) the number of daily administrations of L-DOPA has been increased; (2) the dietary intake of proteins has been reduced to favor a better penetration in the brain (the amino acids and L-DOPA compete on the same carrier at the blood–brain barrier); (3) although not practical, a continuous duodenal or intravenous infusion of L-DOPA has been used to diminish “on–off” events; and (4) sustained-release preparations of L-DOPA have been used to avoid excessive plasmatic and cerebral peak concentrations of L-DOPA. This has been done to prolong the actions of each single dose of L-DOPA. However, there is no clear evidence that these formulations of LDOPA reduce side effects. It is also important to mention that established clinical studies have recognized that L-DOPA has a short-duration response (hours) and a long-duration response (days). It has been reported that the long-duration response is observed when consistent single doses of this drug are orally administered. Therefore, therapeutic regimens that use small and divided dosage during the day, as is currently done in clinical practice, might not achieve the beneficial long-duration response. Other strategies, via the use of different pharmacological agents, have also been used to enhance the availability of L-DOPA in the brain. All these approaches reduce the degradation of L-DOPA, thus prolonging its effects. It has been shown that inhibition of the catechol-O-methyltransferase enzyme potentiates L-DOPA efficacy. In fact, two inhibitors have been coadministered with L-DOPA to parkinsonian patients – tolcapone, which is centrally and peripherally acting, and entacapone, which does not cross the blood–brain barrier. These inhibitors prolong the effects of the drug, increasing on-time and reducing off-time. Of note, tolcapone has been associated with severe liver toxicity and hepatic failure, which represent a significant limitation to its clinical use. Thus, hepatic functions have to be carefully monitored during treatment. Some authors have also claimed that L-DOPA is toxic to the dopaminergic cells due to its oxidative metabolism. On the contrary, others have suggested that it might be neuroprotective. There is clear clinical evidence demonstrating that L-DOPA is not toxic and possibly increases the lifetime of Parkinsonian patients.
Dopaminergic Agonists and L-DOPA
3
Very recently, according to the viewpoint that continuous administration of dopaminergic agents via a non-oral route may avoid fluctuations in absorption related to delayed gastric emptying and diet-related competition for intestinal uptake mechanisms, enteral L-DOPA/carbidopa (Duodopa) administration has been established. Duodopa treatment is allowed only when motor fluctuations and dyskinesias related to L-DOPA treatment, difficult to manage with conventional therapies, have appeared. Duodopa is currently a valid treatment option available in advanced PD patients, which constitutes a clinically significant therapy for those patients, continuing to ensure an adequate quality of life in the advanced stages of the disease.
L-DOPA
and L-DOPA-Sensitive Dystonia
It has been shown that L-DOPA has a dramatic therapeutic action in reducing the symptoms of a form of primary dystonia, the DOPA-responsive dystonia (DYT5). This disease is caused by a deficit in the synthesis of dopamine. This fact explains the remarkable positive response to L-DOPA therapy. Interestingly, the therapeutic response to L-DOPA is maintained for years with a low incidence of motor fluctuations, which instead are often observed after long-term treatment in Parkinsonian patients.
Monoamine Oxidase Type-B Inhibitors The enzyme monoamine oxidase (MAO) is a protein of the outer mitochondrial membrane metabolizing neurotrasmitters. The inhibition of this enzyme can potentially elevate levels of the main neurotrasmitters metabolized, such as dopamine and tyramine. MAO has been classified as MAO-A and MAO-B: (1) MAO-A enzymes are localized principally in the intestinal tract but also in some presynaptic neurons in the brain; (2) MAO-B enzymes are predominantly in the brain, situated in glial cells near to the dopaminergic synapsis, regulating both the releasable stores and free levels of intra-neuronal dopamine. The selective approved MAO-B inhibitors actually available are selegiline and rasagiline, which are irreversible MAO-B inhibitors. These drugs can be used alone or in conjunction with L-DOPA. Selegiline and rasagiline represent a well tolerated and safe therapeutic option improving motor symptoms and reducing motor complications in PD patients. These drugs are effective either in monotherapy or as an adjunct to L-DOPA therapy. In particular, selegiline and rasagiline have received significant attention since their use may significantly delay L-DOPA administration. Moreover, it has been extensively hypothesized that these drugs have neuroprotective and neurorestorative effects on brain neurons. In particular, in preclinical models it was demonstrated that they may prevent nigrostriatal damage and behavioral motor abnormalities. Moreover, rasagiline was demonstrated in in vivo models to be effective in reversing potentially toxic cellular metabolic changes preserving cells from oxydative damages which usually lead to apoptosis. In addition, rasaligiline seems to reduce glutamatergic excitotoxic processes preventing metabolic changes potentially detrimental for cells function and efficiency. Very recently, a new highly selective and reversible inhibitor of MAO-B enzyme with minimal effects on MAO-A enzyme has been submitted to the US FDA for its approval for routine use in clinical practice. As well as the aforementioned selegiline and rasaline, also safinamide seems to show dopamine reuptake inhibition, antiglutamate and neuroprotective effects. Safinamide can be used as add-on therapy to dopamine agonists and to L-DOPA and can improve motor and non-motor (cognitive) symptoms.
Dopaminergic Agonists Use of direct dopamine receptor agonists to treat PD has increased dramatically in the past two decades. These drugs can be used alone or in conjunction with L-DOPA. In the CNS, dopaminergic receptors are involved in a wide range of functions, including locomotion, cognition, emotion, and endocrine responses. Whereas the D1 receptors are mainly distributed in the medium spiny striatal cells, giving rise to the so-called direct pathway projecting to the globus pallidus interna and substantia nigra pars reticulata, the D2 receptors are preferentially localized in the striatal neurons, giving rise to the indirect pathway projecting to the globus pallidus externa. Experimental and clinical studies have provided evidence that activation of D2 receptors exerts a central role in mediating the beneficial effects of dopaminergic agonists, although stimulation of both classes (D1 and D2) of receptors has been shown to be necessary for optimization of the clinical response. The dopaminergic agonists introduced in PD therapy exert their pharmacologic effects by directly activating dopaminergic receptors with different affinities (Table 1). The use of dopamine receptor agonists has proven effective in the management of motor symptoms occurring in PD as adjunctive therapy to L-DOPA in advanced phases of disease. Moreover, compelling evidence supports the valuable role of dopaminergic agonists as a monotherapy in the early stages of PD. Although still a matter of debate, it is believed that early treatment with dopaminergic agonists could prevent or substantially reduce the neurochemical changes underlying the development of the disabling motor fluctuations commonly observed in the course of long-term L-DOPA therapy. Indeed, a significant advantage of dopaminergic agonists, compared to L-DOPA, is that they do not require metabolic conversion to an active compound to produce effects. Rather, they directly stimulate postsynaptic dopaminergic receptors, thus circumventing the synthetic processes of dopamine at degenerating nigrostriatal terminals. Moreover, these dopaminergic compounds have a significantly longer half-life compared to both standard and controlled-release formulations of L-DOPA, allowing a more continuous, rather than pulsatile, stimulation of target dopaminergic receptors. Another advantage compared to L-DOPA is that dopamine receptor agonists do not compete for
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Dopaminergic Agonists and L-DOPA
Table 1
Affinity of agonists for dopamine receptor subtypes D1-like
Bromocriptine Lisuride Pergolide Cabergoline Pramipexole Ropinirole Apomorphine Rotigotine
D2-like
D1
D5
D2
D3
D4
þ þþ 0 0 0 þþþ þþþ
þ ? þ ? 0 0 þþ þþþ
þþ þþþ þþþ þþþ þþþ þþþ þþþ þþþ
þþ þþþ þþþ þþþ þþþ þþþ þþþ þþþ
þ ? ? ? þþ þ þþ þþ
þ/þþþ, agonist; , antagonist; 0, no activity; ?, unknown activity.
both absorption and transport across the blood–brain barrier with circulating plasma amino acids. Prolonged stimulation of the D3 receptors by a selective dopaminergic agonist has been reported to activate neurogenesis of the dopaminergic system in a rat model of PD. These experimental results may have very important clinical relevance if confirmed in PD patients. The concept of an initial monotherapy with a dopaminergic agonist, or an early combination of an agonist with L-DOPA, in an attempt to postpone disabling motor complications has been shown to be, at least to some extent, valid. Prospective long-term clinical trials have shown that early symptomatic treatment with a dopamine receptor agonist is associated with a significantly lower risk of developing motor complications compared to L-DOPA therapy. Despite these encouraging results, the clinical efficacy of dopaminergic agonists has been shown to decrease over time, along with disease progression, so that the number of patients receiving these agents as monotherapy rapidly decreases to 50% after 2–4 years of treatment and to less than 20% after 5 years. In such circumstances, it is mandatory to introduce L-DOPA. In some cases, switching dopaminergic agonists could be a strategy to maintain a clinical response or to avoid specific adverse events. Moreover, another aspect deserving consideration is the combination of two dopamine receptor agonists, which appears to be an attractive alternative to delay initiation of L-DOPA therapy. This dual agonist’s treatment has been shown to reduce the time spent in “off” conditions and to improve the motor scores by nearly 20%. However, only few controlled and well-designed trials have been conducted in an attempt to compare the efficacy of the different marketed dopaminergic agonists in clinical practice. Indeed, the way in which dopamine receptor agonists stimulate dopaminergic receptors appears to produce a tonic stimulation of the dopaminergic system (although this is an oversimplification); thus, a phasic stimulus is still necessary. Therefore, small amounts of L-DOPA (that might provide a phasic stimulus on dopaminergic receptors and, eventually, activation of other receptorial systems) are eventually required in patients treated with only direct dopaminergic agonists. This clinical observation highlights the importance of a phasic (neuronal-driven) stimulation of dopaminergic receptors that could be provided by L-DOPA, but it also suggests that the best way to activate striatal (and perhaps extrastriatal) dopaminergic receptors is by combining L-DOPA and dopaminergic agonists in the treatment of PD. It is worth mentioning that a central dopaminergic dysfunction has also been implicated in restless legs syndrome, a disorder characterized by periodic limb movements or abnormal sensations in the legs which are most prominent during sleep, that can lead to severe insomnia. Therefore, this syndrome has an excellent response to low doses of direct dopaminergic agonists.
Ergoline Derivatives Dopamine receptor agonists are classified into two major categories: ergolines, which are derivatives of ergot alkaloids that may be referred to as first-generation agents, and non-ergolines, more recently introduced in the pharmacotherapy of PD. Ergolines were introduced into clinical practice in the early 1970s. Bromocriptine, a bromo-substituted derivative of the natural peptide ergot alkaloid ergocryptine, was introduced for the treatment of hormonal disturbances, particularly for the treatment of prolactinomas, and was found to have anti-PD properties at higher dosages. It was first utilized as adjunctive therapy to L-DOPA in advanced PD patients experiencing motor fluctuations, and later it was proposed as monotherapy in the early stages of disease. The second agonist introduced, lisuride, had initially been employed in the prevention of migraine attacks and then was approved for the treatment of PD. Similar to bromocriptine, lisuride has been utilized both as adjunct to L-DOPA and as monotherapy. Notably, subcutaneous lisuride infusion by means of micropumps has been shown to provide benefit in advanced PD patients. The clavine derivative pergolide is a potent dopamine receptor agonist used as adjunct to L-DOPA therapy to retard the clinical progression of PD or to delay the occurrence of L-DOPA-induced motor complications. The efficacy of pergolide has also been shown as monotherapy in early stages of PD. Dihydroergocryptine is another ergoline derivative, showing affinity for D2 and partially for D1 receptors. The last marketed ergoline derivative was the lysergic acid amide derivative cabergoline, which shows a higher affinity for D2 receptors. The main feature of this drug is its longer half-life (nearly 65 h) compared to those of all other agonists, allowing a single
Dopaminergic Agonists and L-DOPA
5
daily intake. In adjunct to L-DOPA, cabergoline has been proven effective in ameliorating motor symptoms, compared to placebo, and in reducing the daily dosage of L-DOPA. However, ergot dopamine agonists use has been markedly reduced since their negative side-effect profile. In fact, it was demonstrated that they may be associated with severe multivalvular heart diseases and pulmonary fibrosis.
Non-Ergoline Derivatives Three dopaminergic agonists with no relation to ergot derivatives have been introduced in the pharmacotherapy of PD: the indole derivative ropinirole, the benzothiazol derivative pramipexole and the most recent non-ergot dopamine agonist, formulated in a transdermal delivery system, rotigotine. Ropinirole has high affinity for both D3 and D2 dopaminergic receptors, with little affinity for D1 receptors. Rapidly absorbed and well tolerated, it was reported to be as efficacious as bromocriptine in reducing motor fluctuations and decreasing L-DOPA daily dosage. As monotherapy, ropinirole was proven effective in treating tremor in PD patients. Several studies have demonstrated that ropinirole is effective both in the early and in the advanced phases of PD. A 5 year controlled clinical trial in newly diagnosed PD patients has been conducted comparing the effects of ropinirole to L-DOPA. After 5 years, the occurrence of dyskinesias was 20% in the group of patients receiving ropinirole compared to 45% in the L-DOPA group. Pramipexole, a non-ergoline derivative, features a preferential affinity for D3 over D2 dopamine receptor subtypes. Its efficacy and safety have been investigated in several clinical trials, which have demonstrated that pramipexole utilized both as adjunct to LDOPA and as monotherapy has beneficial effects on motor symptoms, significantly reduces the periods spent in “off” condition, and allows a reduction in the daily dosage of L-DOPA. In particular, patients with pronounced resting tremor derived a clear benefit from pramipexole use compared to L-DOPA. Among non-ergot derivatives, the most recent agent introduced in the pharmacotherapy of PD is the aminotetraline derivative rotigotine, considered as a D3/D2/D1-preferring dopamine receptor agonist. Indeed, rotigotine showed agonistic activity on dopaminergic receptors with higher affinity for D1, D2 and D3 receptors and a lower potency at D4 and D5 receptors. For this reason, rotigotine differs from conventional dopamine D2 agonists, such as ropinirole and pramipexole which not have effects at the D1 and D5 receptors. In consideration of this receptor–affinity profile rotigotine resembles apomorphine which is considered having greater efficacy in PD than other dopamine agonists. Despite the short duration of rotigotine efficacy on oral administration, the ability of the drug to act after transdermal application has provided a means of developing its clinical potential. Based on the pharmacologic profile of the agent and its effect in experimental models, subsequent clinical investigation has shown that transdermal rotigotine is an effective and long-acting treatment for the control of motor symptoms in PD. In two large clinical trials, early PD patients receiving rotigotine experienced a significant improvement in motor symptoms compared to placebo. Moreover, patients in more advanced disease stage, utilizing rotigotine as adjunctive therapy with L-DOPA resulted in a significant reduction in the time spent in “off” condition. Concerning the achievement of satisfactory results with dopaminergic agonists, the route of delivery is gaining importance more than their supposed receptor affinity. A “continuous dopaminergic stimulation” concept of the treatment of PD suggests that the use of long-acting dopaminergic agonists, such as transdermal patches or continuous subcutaneous infusion, may indeed produce effective control of motor symptoms, accompanied by a reduction of the motor fluctuations induced by L-DOPA. In the past decade, there has been renewed interest in apomorphine. The tetracyclic apomorphine is a morphine derivative but without opiate-like effects. It was introduced in the late 19th century for the treatment of intoxications because of its powerful emetic effects. It is a short-acting dopaminergic agonist with receptor affinity similar to that of dopamine, thereby representing the only agonist with a pharmacological profile comparable to that of dopamine. Apomorphine is commonly prescribed for subcutaneous use as bolus injection or continuous infusion by micropumps. The subcutaneous injection is commonly used in clinical practice as a confirmatory, diagnostic test for PD. Moreover, apomorphine is currently utilized for the management of severe, refractory “off” periods in fluctuating PD patients because of its rapid onset and good efficacy. Several studies have also demonstrated that continuous subcutaneous infusion of apomorphine results in reduced “off” periods, reduced occurrence of dyskinesias, and reduced daily L-DOPA dosage. Despite compelling evidence of both efficacy and safety, the validity of apomorphine as an important adjuvant in the advanced stages of PD is still underestimated.
Side Effects Despite a significantly different affinity for the distinct classes of dopamine receptor subtypes, the beneficial clinical and side effects of dopaminergic receptor agonists are remarkably similar, independent of their chemical structure (Table 2). Indeed, expectations of clinical improvements claimed on the basis of their biochemical and pharmacological profile have not been met. Experimental and clinical evidence indicates a central role for the pharmacokinetics of dopaminergic agonists in the development of side effects. The commonly observed undesired effects, such as nausea, dizziness, somnolence, emesis, and orthostatic hypotension, are not in fact directly related to the effective plasma levels but, rather, seem to be triggered by the rapid increase in drug level in the blood, probably related to drug bioavailability and individual susceptibility. Although in some PD patients the occurrence of these side effects requires the discontinuation of the drugs, in a much larger number of patients ongoing treatment with slowly increasing dosages of agonists permits the development of tolerance for the undesired effects
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Dopaminergic Agonists and L-DOPA
Table 2
Side effects of dopamine receptor agonists utilized in the therapy of Parkinson’s disease
Gastrointestinal Nausea Emesis Hypotension Dyskinesia Psychiatric Hallucinations Confusion Sleepiness Sleep attacks Edema
Bromocriptine
Lisuride
Pergolide
Cabergoline
Pramipexole
Ropinirole
Rotigotine
Apomorphine
þ þþþ þ þþ þþ þ þþþ þþ n.r.
þ þþ þ þ þ þ þ þþ þ þ
þ þþ þ þþ þþþ þ þþþ n.r.
þþþ þ þþþ þþþ n.r. þþþ þþþ þþ þ
þþþ þþþ þþþ n.r. þþþ þþþ þþ þ
n.r. þþþþ þþ þþ þþþ þþ þ þ þ
þ þþþ þ n.r. n.r. þ þþþ þ þþ þþ þ
þþ þþþ þþþ þþ þþ þ þþ þ
Reported incidence: , 0–1%; þ, 1–5%; þþ, 5–10%; þþþ, 10–25%; þþþþ, >25%; n.r., no specific reports of effect.
while preserving the beneficial actions. To some extent, the use of antagonists of peripheral dopamine D2 receptors, such as domperidone, is helpful in preventing some of the side effects caused by the dopaminergic agonists and enables a more rapid titration of the drugs within a few weeks. However, despite these therapeutic precautions, serious side effects may occur, and they may be comparable to those observed with L-DOPA therapy. These also include psychiatric symptoms, such as hallucinations, paranoia, vivid dreams, mood alterations, compulsive gambling, and compulsive sexual behavior, and they appear to be more frequent in elderly patients or in patients with preexisting cognitive impairment. Similarly, excessive daytime somnolence is very common and often complicated by sudden sleep attacks. Sleep attacks have been shown to occur with virtually all of the dopaminergic agonists. Ergoline derivatives have also been associated with pleuropulmonary and retroperitoneal fibrosis, so careful patient selection is required. Thus, during treatment patients should be monitored for persistent cough, dyspnea, chest and abdominal pain, and cardiac failure. Pergolide and cabergoline have been associated with a significantly higher incidence of valvular heart disease, which will certainly limit their use in clinical practice. Thus, in the course of ergot-derived agonist treatment, an annual screening with chest X-rays, blood tests, and echocardiographic examination should be warranted.
Conclusion There are a range of drugs that target the dopaminergic system and are used most often to treat patients with Parkinson’s disease. Considering all the points discussed in this article, the dosage of these medications should be customized to the needs of the individual patient on the basis of the clinical response and the profile of adverse events.
Further Reading Bonuccelli, U., Pavese, N., 2006. Dopamine agonists in the treatment of Parkinson’s disease. Expert Rev. Neurother. 6, 81–89. Calne, D.B., 1993. Treatment of Parkinson’s disease. N. Engl. J. Med. 329, 1021–1027. Colosimo, C., Merello, M., Albanese, A., 1994. Clinical usefulness of apomorphine in movement disorders. Clin. Neuropharmacol. 17, 243–259. Colzi, A., Turner, K., Lees, A.J., 1998. Continuous subcutaneous waking day apomorphine in the long term treatment of levodopa induced interdose dyskinesias in Parkinson’s disease. J. Neurol. Neurosurg. Psychiatry 64, 573–576. Dezsi, L., Vecsei, L., May 2014. Safinamide for the treatment of Parkinson’s disease. Expert Opin. Investig. Drugs 23 (2), 729–742. Fahn, S., Shoulson, I., Kieburtz, K., The Parkinson Study Group, et al., 2004. Levodopa and the progression of Parkinson’s disease. N. Engl. J. Med. 351, 2498–2508. Hutton, J.T., Metman, L.V., Chase, T.N., et al., 2001. Transdermal dopaminergic D(2) receptor agonist therapy in Parkinson’s disease with N-0923 TDS: a double-blind, placebocontrolled study. Mov. Disord. 16, 459–463. Jankovic, J.J., 2002. Therapeutic strategies in Parkinson’s disease. In: Jankovic, J.J., Tolosa, E. (Eds.), Parkinson’s Disease and Movement Disorders, 4th ed. Lippincott Williams & Wilkins Philadelphia, pp. 116–151. LeWitt, P.A., Boroojerdi, B., Surmann, E., Poewe, W., 2013. Rotigotine transdermal system for long-term treatment of patients with advanced Parkinson’s disease: results of two open-label extension studies, CLEOPATRA-PE and PREFER. J. Neural Transm. 120, 1069–1081. Mercuri, N.B., Bernardi, G., 2005. The ‘magic’ of L-DOPA: Why is it the gold standard Parkinson’s disease therapy? Trends Pharmacol. Sci. 26, 341–344. Olanow, C.W., Agid, Y., Mizuno, Y., et al., 2004. Levodopa in the treatment of Parkinson’s disease: current controversies. Mov. Disord. 19, 997–1005. Parkinson’s disease research group in the United Kingdom comparisons of therapeutic effects of levodopa, levodopa and selegiline, and bromocriptine in patients with early, mild Parkinson’s disease: three year interim report. Br. Med. J. 307, 1993, 469–472. Parkinson Study Group, 2000. Pramipexole vs levodopa as initial treatment for Parkinson disease: a randomized controlled trial. J. Am. Med. Assoc. 284, 1931–1938. Poewe, W., Wenning, G., 2002. Levodopa in Parkinson’s disease: mechanisms of action and pathophysiology of late failure. In: Jankovic, J.J., Tolosa, E. (Eds.), Parkinson’s Disease and Movement Disorders, 4th ed. Lippincott Williams & Wilkins Philadelphia, pp. 104–115. Rascol, O., Payoux, P., Ory, F., et al., 2003. Limitations of current Parkinson’s disease therapy. Ann. Neurol. 53, S3–S15.
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Stocchi, F., Ruggieri, S., Vacca, L., et al., 2002. Prospective randomized trial of lisuride infusion versus oral levodopa in patients with Parkinson’s disease. Brain 125, 2058–2066. Wood, M., Dubois, V., Scheller, D., Gillard, M., February 2015. Rotigotine is a potent agonist at dopamine D1 receptors as well as at dopamine D2 and D3 receptors. Br. J. Pharmacol. 172 (4), 1124–1135. Zanettini, R., Antonini, A., Gatto, G., et al., 2007. Valvular heart disease and the use of dopamine agonists for Parkinson’s disease. N. Engl. J. Med. 356, 39–46.
Relevant Websites http://www.movementdisorders.org – The Movement Disorder Society (last accessed on 26.04.16.). http://www.wemove.org – We Move (last accessed on 26.04.16.).
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Pharmacological Treatment of Parkinson’s Disease L-DOPA in PD L-DOPA and L-DOPA-Sensitive Dystonia Monoamine Oxidase Type-B Inhibitors Dopaminergic Agonists Ergoline Derivatives Non-Ergoline Derivatives Side Effects Conclusion Further Reading Relevant Websites
Pharmacological Treatment of Parkinson’s Disease Parkinson’s disease (PD) is the second most common chronic and progressive neurodegenerative disorder, affecting approximately 3% of people older than 65 years. Considerable advances have been made in identifying the etiopathogenesis of PD. In recent years, different genetic mutations have been identified as causing familial forms of PD, accounting for nearly 2% of cases. Despite this, the large majority of cases are “sporadic–idiopathic” and are thought to be the outcome of complex interactions between the environment and the genetic background. Cardinal features of PD are represented by resting tremor, rigidity, bradykinesia, and impaired balance, often complicated by autonomic, cognitive, and emotional disturbances. The main neuropathological characteristic of the disease is a loss of pigmented dopaminergic cells in the substantia nigra pars compacta that produces a massive depletion of dopamine in the basal ganglia (mainly striatum). Neurodegeneration is provoked by a toxic protein named “alpha-synuclein”, which aggregates and deposits in Lewy bodies. Neuropathological findings have also demonstrated degenerative processes in the serotoninergic, noradrenergic, cholinergic, and peptidergic pathways. Although there is currently no cure for PD, because no therapy has been definitely shown to halt its progression, there are medications available to treat the motor symptoms, which can certainly improve the quality of life of affected patients. These are mainly based on a dopamine replacement strategy.
L-DOPA
in PD
The dopamine precursor L-DOPA (L-3,4-dihydroxy-phenylalanine, also called levodopa) is still the “gold standard antiparkinsonian agent” because a drug superior to it has not been produced after more than four decades of use. Long-lasting observations in clinical practice have undoubtedly demonstrated that orally administered L-DOPA is a more “potent” symptomatic antiparkinsonian drug than any dopaminergic agonist thus far introduced in the therapeutic armamentaria. It has been also reported that it increases life expectancy in PD patients. The superiority of L-DOPA is very likely due to its special feature that allows de novo synthesis of dopamine mainly in the surviving dopamine-containing neurons, thus raising the level of this catecholamine in the striatum. L-DOPA is converted in dopamine by the enzyme aromatic L-amino acid decarboxylase (AADC) ie, present not only in the brain but also in many peripheral organs and vessels. It has been recognized that the peripheral transformation of L-DOPA by AADC only permits a small percentage of L-DOPA to reach the dopaminergic neurons in the brain. Therefore, in order to obtain valid therapeutic concentrations, a huge dose of L-DOPA was administered. This caused important side effects, including hypotension, nausea, and vomiting. Opportunely, the coadministration of L-DOPA with two compounds (benserazide and carbidopa), which block AADC but do not cross the blood–brain barrier, has increased the availability of this dopamine precursor to the brain, thus diminishing its dosage and reducing side effects.
q Change History: August 2015. Sections Pharmacological Treatment of Parkinson’s Disease, Monoamine Oxidase Type-B Inhibitors, Dopaminergic Agonists with Tables 1 and 2 have been updated.
Reference Module in Neuroscience and Biobehavioral Psychology
http://dx.doi.org/10.1016/B978-0-12-809324-5.02374-9
1
2
Dopaminergic Agonists and L-DOPA
It has been suggested that the initial excellent therapeutic response to L-DOPA depends on the fact that newly synthesized dopamine can be released mainly at the synaptic contacts under a stimulus-dependent control. Thus, the newly formed catecholamine might be, at least initially, released respecting neurochemistry and the cytoarchitecture of the remaining dopaminergic neurons. As a result, despite a neuronal degeneration in PD, a phasic and a tonic release of dopamine could still be sustained by oral administrations of L-DOPA. Thus, this L-DOPA-induced dopamine release adequately stimulates dopaminergic receptors. At least six different dopamine receptor subtypes have been cloned. These receptors are divided in two classes: the D1 class comprises D1 and D5 receptor subtypes, whereas the D2 class includes D2 (D2S and D2L isoforms), D3, and D4 receptors. It has been demonstrated that the D2 receptors are mainly involved in the regulation of striatal motor functions. Interestingly, all dopaminergic receptors cloned from the brain are also present in tissues outside the central nervous system (CNS), mainly in the cardiovascular system, the kidney, as well as sympathetic ganglia and the adrenal glands. Whereas the phasic release of dopamine might control the transitory activation of the motor system during movement, the tonic release might prepare and set the motor programs. Therefore, both the phasic and the tonic release of dopamine induced by L-DOPA should correct the disturbances of muscle tone and the alterations of motor performances in Parkinsonian patients. Another important aspect, which might account for L-DOPA’s superiority with respect to other drugs, is the possibility that L-DOPA is not only the precursor of dopamine’s synthesis but also regulates the formation of noradrenaline and, eventually, the release of serotonin and trace amines in the extracellular space. Unfortunately, the “optimal” activation of different receptor systems obtained with L-DOPA in an early phase fades. Thus, the “honeymoon” with the use of the drug vanishes as more dopaminergic neurons degenerate. Therefore, despite L-DOPA administration, because the surviving dopaminergic cells cannot produce enough dopamine in advanced Parkinsonian patients, not only a phasic but also a tonic stimulation of dopaminergic receptors is no longer possible. Consequently, the Parkinsonian symptoms worsen. Important negative side effects also develop during long-term L-DOPA treatment of PD (3–5 years), including attenuation of drug efficacy, motor fluctuations, and psychoses. Along with disease progression, and the consequent loss of dopaminergic terminals, the duration of clinical benefit derived from each L-DOPA dose shortens and patients begin to experience motor fluctuations such as “end of dose deterioration” or the “wearing off” phenomena. The “off” periods do not necessarily respond to an increased frequency of L-DOPA intake. Indeed, the clinical response to L-DOPA becomes unpredictable and the patient may frequently switch from “on” condition to off states. Accordingly, the plasma levels of L-DOPA fluctuate as well and exceed the therapeutic range, producing excessive, involuntary movements (dyskinesias). With further progression of the disease, dyskinesias become even more complex in pattern, with the occurrence of “peak-dose dyskinesias,” and also “end-of-dose dyskinesias.” Currently, the pathogenesis of these motor fluctuations is elusive, although both pre- and postsynaptic mechanisms likely play a critical role. Similarly, psychoses are a common side effect of long-term use of L-DOPA, affecting nearly 20% of treated patients. Managing psychotic symptoms is a very difficult challenge in terms of pharmacological treatment and for daily nursing. For these reasons, some authors claim that it is preferable to avoid treating patients in the early phase of PD with L-DOPA and that, instead, it should be used later when the administration of dopaminergic agonists no longer controls symptoms. Nevertheless, there is not a consensus on this therapeutic approach because the optimal time for initiating L-DOPA therapy is still debated. Variations in the L-DOPA’s pharmacokinetic and alterations of the presynaptic and postsynaptic components in the dopaminergic system might account for the unpredictable responses to L-DOPA in individual patients. The unwanted effects of L-DOPA can be reduced by modifying the therapeutic schedule. For instance, it is important to avoid excessive fluctuations of L-DOPA concentrations in the blood and consequently in the brain. Thus, continuous stimulation of dopaminergic receptors should be obtained in order to attain an acceptable therapeutic outcome. Several attempts have been made to reduce the oscillations in the extracellular concentrations of L-DOPA: (1) the number of daily administrations of L-DOPA has been increased; (2) the dietary intake of proteins has been reduced to favor a better penetration in the brain (the amino acids and L-DOPA compete on the same carrier at the blood–brain barrier); (3) although not practical, a continuous duodenal or intravenous infusion of L-DOPA has been used to diminish “on–off” events; and (4) sustained-release preparations of L-DOPA have been used to avoid excessive plasmatic and cerebral peak concentrations of L-DOPA. This has been done to prolong the actions of each single dose of L-DOPA. However, there is no clear evidence that these formulations of LDOPA reduce side effects. It is also important to mention that established clinical studies have recognized that L-DOPA has a short-duration response (hours) and a long-duration response (days). It has been reported that the long-duration response is observed when consistent single doses of this drug are orally administered. Therefore, therapeutic regimens that use small and divided dosage during the day, as is currently done in clinical practice, might not achieve the beneficial long-duration response. Other strategies, via the use of different pharmacological agents, have also been used to enhance the availability of L-DOPA in the brain. All these approaches reduce the degradation of L-DOPA, thus prolonging its effects. It has been shown that inhibition of the catechol-O-methyltransferase enzyme potentiates L-DOPA efficacy. In fact, two inhibitors have been coadministered with L-DOPA to parkinsonian patients – tolcapone, which is centrally and peripherally acting, and entacapone, which does not cross the blood–brain barrier. These inhibitors prolong the effects of the drug, increasing on-time and reducing off-time. Of note, tolcapone has been associated with severe liver toxicity and hepatic failure, which represent a significant limitation to its clinical use. Thus, hepatic functions have to be carefully monitored during treatment. Some authors have also claimed that L-DOPA is toxic to the dopaminergic cells due to its oxidative metabolism. On the contrary, others have suggested that it might be neuroprotective. There is clear clinical evidence demonstrating that L-DOPA is not toxic and possibly increases the lifetime of Parkinsonian patients.
Dopaminergic Agonists and L-DOPA
3
Very recently, according to the viewpoint that continuous administration of dopaminergic agents via a non-oral route may avoid fluctuations in absorption related to delayed gastric emptying and diet-related competition for intestinal uptake mechanisms, enteral L-DOPA/carbidopa (Duodopa) administration has been established. Duodopa treatment is allowed only when motor fluctuations and dyskinesias related to L-DOPA treatment, difficult to manage with conventional therapies, have appeared. Duodopa is currently a valid treatment option available in advanced PD patients, which constitutes a clinically significant therapy for those patients, continuing to ensure an adequate quality of life in the advanced stages of the disease.
L-DOPA
and L-DOPA-Sensitive Dystonia
It has been shown that L-DOPA has a dramatic therapeutic action in reducing the symptoms of a form of primary dystonia, the DOPA-responsive dystonia (DYT5). This disease is caused by a deficit in the synthesis of dopamine. This fact explains the remarkable positive response to L-DOPA therapy. Interestingly, the therapeutic response to L-DOPA is maintained for years with a low incidence of motor fluctuations, which instead are often observed after long-term treatment in Parkinsonian patients.
Monoamine Oxidase Type-B Inhibitors The enzyme monoamine oxidase (MAO) is a protein of the outer mitochondrial membrane metabolizing neurotrasmitters. The inhibition of this enzyme can potentially elevate levels of the main neurotrasmitters metabolized, such as dopamine and tyramine. MAO has been classified as MAO-A and MAO-B: (1) MAO-A enzymes are localized principally in the intestinal tract but also in some presynaptic neurons in the brain; (2) MAO-B enzymes are predominantly in the brain, situated in glial cells near to the dopaminergic synapsis, regulating both the releasable stores and free levels of intra-neuronal dopamine. The selective approved MAO-B inhibitors actually available are selegiline and rasagiline, which are irreversible MAO-B inhibitors. These drugs can be used alone or in conjunction with L-DOPA. Selegiline and rasagiline represent a well tolerated and safe therapeutic option improving motor symptoms and reducing motor complications in PD patients. These drugs are effective either in monotherapy or as an adjunct to L-DOPA therapy. In particular, selegiline and rasagiline have received significant attention since their use may significantly delay L-DOPA administration. Moreover, it has been extensively hypothesized that these drugs have neuroprotective and neurorestorative effects on brain neurons. In particular, in preclinical models it was demonstrated that they may prevent nigrostriatal damage and behavioral motor abnormalities. Moreover, rasagiline was demonstrated in in vivo models to be effective in reversing potentially toxic cellular metabolic changes preserving cells from oxydative damages which usually lead to apoptosis. In addition, rasaligiline seems to reduce glutamatergic excitotoxic processes preventing metabolic changes potentially detrimental for cells function and efficiency. Very recently, a new highly selective and reversible inhibitor of MAO-B enzyme with minimal effects on MAO-A enzyme has been submitted to the US FDA for its approval for routine use in clinical practice. As well as the aforementioned selegiline and rasaline, also safinamide seems to show dopamine reuptake inhibition, antiglutamate and neuroprotective effects. Safinamide can be used as add-on therapy to dopamine agonists and to L-DOPA and can improve motor and non-motor (cognitive) symptoms.
Dopaminergic Agonists Use of direct dopamine receptor agonists to treat PD has increased dramatically in the past two decades. These drugs can be used alone or in conjunction with L-DOPA. In the CNS, dopaminergic receptors are involved in a wide range of functions, including locomotion, cognition, emotion, and endocrine responses. Whereas the D1 receptors are mainly distributed in the medium spiny striatal cells, giving rise to the so-called direct pathway projecting to the globus pallidus interna and substantia nigra pars reticulata, the D2 receptors are preferentially localized in the striatal neurons, giving rise to the indirect pathway projecting to the globus pallidus externa. Experimental and clinical studies have provided evidence that activation of D2 receptors exerts a central role in mediating the beneficial effects of dopaminergic agonists, although stimulation of both classes (D1 and D2) of receptors has been shown to be necessary for optimization of the clinical response. The dopaminergic agonists introduced in PD therapy exert their pharmacologic effects by directly activating dopaminergic receptors with different affinities (Table 1). The use of dopamine receptor agonists has proven effective in the management of motor symptoms occurring in PD as adjunctive therapy to L-DOPA in advanced phases of disease. Moreover, compelling evidence supports the valuable role of dopaminergic agonists as a monotherapy in the early stages of PD. Although still a matter of debate, it is believed that early treatment with dopaminergic agonists could prevent or substantially reduce the neurochemical changes underlying the development of the disabling motor fluctuations commonly observed in the course of long-term L-DOPA therapy. Indeed, a significant advantage of dopaminergic agonists, compared to L-DOPA, is that they do not require metabolic conversion to an active compound to produce effects. Rather, they directly stimulate postsynaptic dopaminergic receptors, thus circumventing the synthetic processes of dopamine at degenerating nigrostriatal terminals. Moreover, these dopaminergic compounds have a significantly longer half-life compared to both standard and controlled-release formulations of L-DOPA, allowing a more continuous, rather than pulsatile, stimulation of target dopaminergic receptors. Another advantage compared to L-DOPA is that dopamine receptor agonists do not compete for
4
Dopaminergic Agonists and L-DOPA
Table 1
Affinity of agonists for dopamine receptor subtypes D1-like
Bromocriptine Lisuride Pergolide Cabergoline Pramipexole Ropinirole Apomorphine Rotigotine
D2-like
D1
D5
D2
D3
D4
þ þþ 0 0 0 þþþ þþþ
þ ? þ ? 0 0 þþ þþþ
þþ þþþ þþþ þþþ þþþ þþþ þþþ þþþ
þþ þþþ þþþ þþþ þþþ þþþ þþþ þþþ
þ ? ? ? þþ þ þþ þþ
þ/þþþ, agonist; , antagonist; 0, no activity; ?, unknown activity.
both absorption and transport across the blood–brain barrier with circulating plasma amino acids. Prolonged stimulation of the D3 receptors by a selective dopaminergic agonist has been reported to activate neurogenesis of the dopaminergic system in a rat model of PD. These experimental results may have very important clinical relevance if confirmed in PD patients. The concept of an initial monotherapy with a dopaminergic agonist, or an early combination of an agonist with L-DOPA, in an attempt to postpone disabling motor complications has been shown to be, at least to some extent, valid. Prospective long-term clinical trials have shown that early symptomatic treatment with a dopamine receptor agonist is associated with a significantly lower risk of developing motor complications compared to L-DOPA therapy. Despite these encouraging results, the clinical efficacy of dopaminergic agonists has been shown to decrease over time, along with disease progression, so that the number of patients receiving these agents as monotherapy rapidly decreases to 50% after 2–4 years of treatment and to less than 20% after 5 years. In such circumstances, it is mandatory to introduce L-DOPA. In some cases, switching dopaminergic agonists could be a strategy to maintain a clinical response or to avoid specific adverse events. Moreover, another aspect deserving consideration is the combination of two dopamine receptor agonists, which appears to be an attractive alternative to delay initiation of L-DOPA therapy. This dual agonist’s treatment has been shown to reduce the time spent in “off” conditions and to improve the motor scores by nearly 20%. However, only few controlled and well-designed trials have been conducted in an attempt to compare the efficacy of the different marketed dopaminergic agonists in clinical practice. Indeed, the way in which dopamine receptor agonists stimulate dopaminergic receptors appears to produce a tonic stimulation of the dopaminergic system (although this is an oversimplification); thus, a phasic stimulus is still necessary. Therefore, small amounts of L-DOPA (that might provide a phasic stimulus on dopaminergic receptors and, eventually, activation of other receptorial systems) are eventually required in patients treated with only direct dopaminergic agonists. This clinical observation highlights the importance of a phasic (neuronal-driven) stimulation of dopaminergic receptors that could be provided by L-DOPA, but it also suggests that the best way to activate striatal (and perhaps extrastriatal) dopaminergic receptors is by combining L-DOPA and dopaminergic agonists in the treatment of PD. It is worth mentioning that a central dopaminergic dysfunction has also been implicated in restless legs syndrome, a disorder characterized by periodic limb movements or abnormal sensations in the legs which are most prominent during sleep, that can lead to severe insomnia. Therefore, this syndrome has an excellent response to low doses of direct dopaminergic agonists.
Ergoline Derivatives Dopamine receptor agonists are classified into two major categories: ergolines, which are derivatives of ergot alkaloids that may be referred to as first-generation agents, and non-ergolines, more recently introduced in the pharmacotherapy of PD. Ergolines were introduced into clinical practice in the early 1970s. Bromocriptine, a bromo-substituted derivative of the natural peptide ergot alkaloid ergocryptine, was introduced for the treatment of hormonal disturbances, particularly for the treatment of prolactinomas, and was found to have anti-PD properties at higher dosages. It was first utilized as adjunctive therapy to L-DOPA in advanced PD patients experiencing motor fluctuations, and later it was proposed as monotherapy in the early stages of disease. The second agonist introduced, lisuride, had initially been employed in the prevention of migraine attacks and then was approved for the treatment of PD. Similar to bromocriptine, lisuride has been utilized both as adjunct to L-DOPA and as monotherapy. Notably, subcutaneous lisuride infusion by means of micropumps has been shown to provide benefit in advanced PD patients. The clavine derivative pergolide is a potent dopamine receptor agonist used as adjunct to L-DOPA therapy to retard the clinical progression of PD or to delay the occurrence of L-DOPA-induced motor complications. The efficacy of pergolide has also been shown as monotherapy in early stages of PD. Dihydroergocryptine is another ergoline derivative, showing affinity for D2 and partially for D1 receptors. The last marketed ergoline derivative was the lysergic acid amide derivative cabergoline, which shows a higher affinity for D2 receptors. The main feature of this drug is its longer half-life (nearly 65 h) compared to those of all other agonists, allowing a single
Dopaminergic Agonists and L-DOPA
5
daily intake. In adjunct to L-DOPA, cabergoline has been proven effective in ameliorating motor symptoms, compared to placebo, and in reducing the daily dosage of L-DOPA. However, ergot dopamine agonists use has been markedly reduced since their negative side-effect profile. In fact, it was demonstrated that they may be associated with severe multivalvular heart diseases and pulmonary fibrosis.
Non-Ergoline Derivatives Three dopaminergic agonists with no relation to ergot derivatives have been introduced in the pharmacotherapy of PD: the indole derivative ropinirole, the benzothiazol derivative pramipexole and the most recent non-ergot dopamine agonist, formulated in a transdermal delivery system, rotigotine. Ropinirole has high affinity for both D3 and D2 dopaminergic receptors, with little affinity for D1 receptors. Rapidly absorbed and well tolerated, it was reported to be as efficacious as bromocriptine in reducing motor fluctuations and decreasing L-DOPA daily dosage. As monotherapy, ropinirole was proven effective in treating tremor in PD patients. Several studies have demonstrated that ropinirole is effective both in the early and in the advanced phases of PD. A 5 year controlled clinical trial in newly diagnosed PD patients has been conducted comparing the effects of ropinirole to L-DOPA. After 5 years, the occurrence of dyskinesias was 20% in the group of patients receiving ropinirole compared to 45% in the L-DOPA group. Pramipexole, a non-ergoline derivative, features a preferential affinity for D3 over D2 dopamine receptor subtypes. Its efficacy and safety have been investigated in several clinical trials, which have demonstrated that pramipexole utilized both as adjunct to LDOPA and as monotherapy has beneficial effects on motor symptoms, significantly reduces the periods spent in “off” condition, and allows a reduction in the daily dosage of L-DOPA. In particular, patients with pronounced resting tremor derived a clear benefit from pramipexole use compared to L-DOPA. Among non-ergot derivatives, the most recent agent introduced in the pharmacotherapy of PD is the aminotetraline derivative rotigotine, considered as a D3/D2/D1-preferring dopamine receptor agonist. Indeed, rotigotine showed agonistic activity on dopaminergic receptors with higher affinity for D1, D2 and D3 receptors and a lower potency at D4 and D5 receptors. For this reason, rotigotine differs from conventional dopamine D2 agonists, such as ropinirole and pramipexole which not have effects at the D1 and D5 receptors. In consideration of this receptor–affinity profile rotigotine resembles apomorphine which is considered having greater efficacy in PD than other dopamine agonists. Despite the short duration of rotigotine efficacy on oral administration, the ability of the drug to act after transdermal application has provided a means of developing its clinical potential. Based on the pharmacologic profile of the agent and its effect in experimental models, subsequent clinical investigation has shown that transdermal rotigotine is an effective and long-acting treatment for the control of motor symptoms in PD. In two large clinical trials, early PD patients receiving rotigotine experienced a significant improvement in motor symptoms compared to placebo. Moreover, patients in more advanced disease stage, utilizing rotigotine as adjunctive therapy with L-DOPA resulted in a significant reduction in the time spent in “off” condition. Concerning the achievement of satisfactory results with dopaminergic agonists, the route of delivery is gaining importance more than their supposed receptor affinity. A “continuous dopaminergic stimulation” concept of the treatment of PD suggests that the use of long-acting dopaminergic agonists, such as transdermal patches or continuous subcutaneous infusion, may indeed produce effective control of motor symptoms, accompanied by a reduction of the motor fluctuations induced by L-DOPA. In the past decade, there has been renewed interest in apomorphine. The tetracyclic apomorphine is a morphine derivative but without opiate-like effects. It was introduced in the late 19th century for the treatment of intoxications because of its powerful emetic effects. It is a short-acting dopaminergic agonist with receptor affinity similar to that of dopamine, thereby representing the only agonist with a pharmacological profile comparable to that of dopamine. Apomorphine is commonly prescribed for subcutaneous use as bolus injection or continuous infusion by micropumps. The subcutaneous injection is commonly used in clinical practice as a confirmatory, diagnostic test for PD. Moreover, apomorphine is currently utilized for the management of severe, refractory “off” periods in fluctuating PD patients because of its rapid onset and good efficacy. Several studies have also demonstrated that continuous subcutaneous infusion of apomorphine results in reduced “off” periods, reduced occurrence of dyskinesias, and reduced daily L-DOPA dosage. Despite compelling evidence of both efficacy and safety, the validity of apomorphine as an important adjuvant in the advanced stages of PD is still underestimated.
Side Effects Despite a significantly different affinity for the distinct classes of dopamine receptor subtypes, the beneficial clinical and side effects of dopaminergic receptor agonists are remarkably similar, independent of their chemical structure (Table 2). Indeed, expectations of clinical improvements claimed on the basis of their biochemical and pharmacological profile have not been met. Experimental and clinical evidence indicates a central role for the pharmacokinetics of dopaminergic agonists in the development of side effects. The commonly observed undesired effects, such as nausea, dizziness, somnolence, emesis, and orthostatic hypotension, are not in fact directly related to the effective plasma levels but, rather, seem to be triggered by the rapid increase in drug level in the blood, probably related to drug bioavailability and individual susceptibility. Although in some PD patients the occurrence of these side effects requires the discontinuation of the drugs, in a much larger number of patients ongoing treatment with slowly increasing dosages of agonists permits the development of tolerance for the undesired effects
6
Dopaminergic Agonists and L-DOPA
Table 2
Side effects of dopamine receptor agonists utilized in the therapy of Parkinson’s disease
Gastrointestinal Nausea Emesis Hypotension Dyskinesia Psychiatric Hallucinations Confusion Sleepiness Sleep attacks Edema
Bromocriptine
Lisuride
Pergolide
Cabergoline
Pramipexole
Ropinirole
Rotigotine
Apomorphine
þ þþþ þ þþ þþ þ þþþ þþ n.r.
þ þþ þ þ þ þ þ þþ þ þ
þ þþ þ þþ þþþ þ þþþ n.r.
þþþ þ þþþ þþþ n.r. þþþ þþþ þþ þ
þþþ þþþ þþþ n.r. þþþ þþþ þþ þ
n.r. þþþþ þþ þþ þþþ þþ þ þ þ
þ þþþ þ n.r. n.r. þ þþþ þ þþ þþ þ
þþ þþþ þþþ þþ þþ þ þþ þ
Reported incidence: , 0–1%; þ, 1–5%; þþ, 5–10%; þþþ, 10–25%; þþþþ, >25%; n.r., no specific reports of effect.
while preserving the beneficial actions. To some extent, the use of antagonists of peripheral dopamine D2 receptors, such as domperidone, is helpful in preventing some of the side effects caused by the dopaminergic agonists and enables a more rapid titration of the drugs within a few weeks. However, despite these therapeutic precautions, serious side effects may occur, and they may be comparable to those observed with L-DOPA therapy. These also include psychiatric symptoms, such as hallucinations, paranoia, vivid dreams, mood alterations, compulsive gambling, and compulsive sexual behavior, and they appear to be more frequent in elderly patients or in patients with preexisting cognitive impairment. Similarly, excessive daytime somnolence is very common and often complicated by sudden sleep attacks. Sleep attacks have been shown to occur with virtually all of the dopaminergic agonists. Ergoline derivatives have also been associated with pleuropulmonary and retroperitoneal fibrosis, so careful patient selection is required. Thus, during treatment patients should be monitored for persistent cough, dyspnea, chest and abdominal pain, and cardiac failure. Pergolide and cabergoline have been associated with a significantly higher incidence of valvular heart disease, which will certainly limit their use in clinical practice. Thus, in the course of ergot-derived agonist treatment, an annual screening with chest X-rays, blood tests, and echocardiographic examination should be warranted.
Conclusion There are a range of drugs that target the dopaminergic system and are used most often to treat patients with Parkinson’s disease. Considering all the points discussed in this article, the dosage of these medications should be customized to the needs of the individual patient on the basis of the clinical response and the profile of adverse events.
Further Reading Bonuccelli, U., Pavese, N., 2006. Dopamine agonists in the treatment of Parkinson’s disease. Expert Rev. Neurother. 6, 81–89. Calne, D.B., 1993. Treatment of Parkinson’s disease. N. Engl. J. Med. 329, 1021–1027. Colosimo, C., Merello, M., Albanese, A., 1994. Clinical usefulness of apomorphine in movement disorders. Clin. Neuropharmacol. 17, 243–259. Colzi, A., Turner, K., Lees, A.J., 1998. Continuous subcutaneous waking day apomorphine in the long term treatment of levodopa induced interdose dyskinesias in Parkinson’s disease. J. Neurol. Neurosurg. Psychiatry 64, 573–576. Dezsi, L., Vecsei, L., May 2014. Safinamide for the treatment of Parkinson’s disease. Expert Opin. Investig. Drugs 23 (2), 729–742. Fahn, S., Shoulson, I., Kieburtz, K., The Parkinson Study Group, et al., 2004. Levodopa and the progression of Parkinson’s disease. N. Engl. J. Med. 351, 2498–2508. Hutton, J.T., Metman, L.V., Chase, T.N., et al., 2001. Transdermal dopaminergic D(2) receptor agonist therapy in Parkinson’s disease with N-0923 TDS: a double-blind, placebocontrolled study. Mov. Disord. 16, 459–463. Jankovic, J.J., 2002. Therapeutic strategies in Parkinson’s disease. In: Jankovic, J.J., Tolosa, E. (Eds.), Parkinson’s Disease and Movement Disorders, 4th ed. Lippincott Williams & Wilkins Philadelphia, pp. 116–151. LeWitt, P.A., Boroojerdi, B., Surmann, E., Poewe, W., 2013. Rotigotine transdermal system for long-term treatment of patients with advanced Parkinson’s disease: results of two open-label extension studies, CLEOPATRA-PE and PREFER. J. Neural Transm. 120, 1069–1081. Mercuri, N.B., Bernardi, G., 2005. The ‘magic’ of L-DOPA: Why is it the gold standard Parkinson’s disease therapy? Trends Pharmacol. Sci. 26, 341–344. Olanow, C.W., Agid, Y., Mizuno, Y., et al., 2004. Levodopa in the treatment of Parkinson’s disease: current controversies. Mov. Disord. 19, 997–1005. Parkinson’s disease research group in the United Kingdom comparisons of therapeutic effects of levodopa, levodopa and selegiline, and bromocriptine in patients with early, mild Parkinson’s disease: three year interim report. Br. Med. J. 307, 1993, 469–472. Parkinson Study Group, 2000. Pramipexole vs levodopa as initial treatment for Parkinson disease: a randomized controlled trial. J. Am. Med. Assoc. 284, 1931–1938. Poewe, W., Wenning, G., 2002. Levodopa in Parkinson’s disease: mechanisms of action and pathophysiology of late failure. In: Jankovic, J.J., Tolosa, E. (Eds.), Parkinson’s Disease and Movement Disorders, 4th ed. Lippincott Williams & Wilkins Philadelphia, pp. 104–115. Rascol, O., Payoux, P., Ory, F., et al., 2003. Limitations of current Parkinson’s disease therapy. Ann. Neurol. 53, S3–S15.
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Stocchi, F., Ruggieri, S., Vacca, L., et al., 2002. Prospective randomized trial of lisuride infusion versus oral levodopa in patients with Parkinson’s disease. Brain 125, 2058–2066. Wood, M., Dubois, V., Scheller, D., Gillard, M., February 2015. Rotigotine is a potent agonist at dopamine D1 receptors as well as at dopamine D2 and D3 receptors. Br. J. Pharmacol. 172 (4), 1124–1135. Zanettini, R., Antonini, A., Gatto, G., et al., 2007. Valvular heart disease and the use of dopamine agonists for Parkinson’s disease. N. Engl. J. Med. 356, 39–46.
Relevant Websites http://www.movementdisorders.org – The Movement Disorder Society (last accessed on 26.04.16.). http://www.wemove.org – We Move (last accessed on 26.04.16.).