Author Proof Epidemiology of OH in PD

Review CONTENTS Epidemiology of OH in PD Pharmacology is useful to understand the pathophysiology of OH in PD Clinical pharmacology of drugs for OH in PD Management of OH in PD Expert opinion & five-year view Key issues References Affiliations Author for correspondence Laboratoire de Pharmacologie Médicale et Clinique, INSERM U586, 37 allées Jules Guesde, 31073 Toulouse cedex, France Tel.: +33 5 61 14 59 61 Fax: +33 5 61 25 51 16 senard@cict.fr KEYWORDS: fludrocortisone, midodrine, nonpharmacological measures, orthostatic hypotension, peripheral autonomic failure, Pharmacology of orthostatic hypotension in Parkinson s disease: from pathophysiology to management Atul Pathak and Jean-Michel Senard Orthostatic hypotension is highly prevalent in the elderly, and affects up to 20% of patients with Parkinson s disease. Pharmacological approaches help to demonstrate that Parkinson s disease is a primary autonomic failure with involvement of the peripheral autonomic nervous system as shown by decreased [ 123 I] meta-iodobenzylguanidine cardiac uptake and preserved growth hormone response to clonidine. No specific clinical trial has evaluated efficacy of antihypotensive drugs in Parkinson s disease. End point of treatment should be a reduction in postural symptoms. Midodrine (Proamatin, Roberts Pharmaceutical), a vasoconstrictor and fludrocortisone (Florinef, Bristol Myers Squibb), a volume expander are first choice drugs. No data are available on their effects on orthostatic hypotension-related morbidity. The usefulness of other drugs remains to be demonstrated. This review will highlight the importance of nonpharmacological measures in the management of orthostatic hypotension in Parkinson s disease. Expert Rev. Cardiovasc. Ther. 2(3), (2004) Orthostatic hypotension (OH) is frequently encountered in the elderly [1,2]. In addition to falls and traumas, OH is now considered to be a risk factor for cognitive decline [3], cardiovascular morbidity [4,5] and increased mortality [6,7]. From a clinical point of view, OH is defined as a decrease of at least 20 mmhg in systolic and/or 10 mmhg in diastolic blood pressure during orthostatism or passive tilting with or without postural symptoms [8]. When associated with clinical symptoms it indicates a decrease in cardiac output and cerebral hypoperfusion. Prospective studies have shown that OH is highly variable and may be influenced by various factors, such as ambiental temperature, straining exertion, food ingestion and time of blood pressure measurement. Thus, OH diagnosis needs repeated blood pressure and symptom measurement in standardized conditions. Parkinson s disease (PD) is a primary cause of autonomic failure as well as many autonomic features including gastrointestinal, sudoromotor and bladder abnormalities [9]. Only limited attention has been paid to the prevalence and pathophysiological mechanisms of OH in this condition. This probably explains why the treatment of OH in PD remains dramatically empirical and often disappointing. This paper will discuss available data on epidemiology of OH related to PD and will focus on the importance of a pharmacological approach for a better understanding of its pathophysiology and the current limitation of its management. Epidemiology of OH in PD Despite the classification of PD as a cause of primary autonomic failure [10] there is still some controversy about the correct classification of Parkinsonian syndromes with OH. The main discrepancies come from the current criteria used for PD diagnosis. In fact, OH due to autonomic failure is considered as an important exclusion criteria for the diagnosis of PD and favors diagnosis of orientation through multiple system atrophy (MSA) [11]. However, OH and autonomic failure have been repeatedly www.future-drugs.com Future Drugs Ltd. All rights reserved. ISSN 1477-9072 89

Pathak & Senard reported in patients with typical clinical and pathological PD. Studies that investigated factors associated with autonomic dysfunction in PD all conclude that the occurrence of OH is directly related to disease duration and severity, age and medications being two other factors associated with poor autonomic responsiveness [12]. Furthermore, when considering differential diagnosis of extrapyramidal disorders associated with OH, it must be kept in mind that only early and severe autonomic symptoms unrelated to drugs have to be taken as atypical features for the diagnosis of PD. Since dopaminergic drugs may induce postural hypotension and because drug withdrawal in such patients is quite difficult to achieve, it may be sometimes difficult to differenciate idiopathic PD from MSA at least at the early stages of the diseases. A recent study, which used postmortem examination to histologically confirm the existence of Parkinsonian syndromes including idiopathic PD, found that OH does exist in 78% of patients with PD and in 87% of patients with MSA [13]. The same study reports that 20% of patients with MSA have OH within the first year of the disease whereas patients with PD developed it later. Thus, apart from the limitations due to cardiovascular side effects of anti-parkinsonian drugs, the presence of autonomic failure and of OH can no longer be considered as exclusion criteria for the diagnosis of PD, at least after some years of evolution. Due to these limitations, little is known about prevalence of OH in Parkinsonians. In a study from the authors group, 20% of Parkinsonian patients suffered from symptomatic OH during an active standing test [14]. The most frequent symptoms related to blood pressure fall were not different from those identified in other neurological conditions, such as MSA and pure autonomic failure (PAF). As previously reported by other authors, OH occurs late in the disease and concerns the most disabled patients. More recently, Bonuccelli and colleagues investigated autonomic cardiovascular function and OH during a 7 year follow-up through a survey of 51 patients with de novo PD, and found that 14% of these patients had manometric OH [15]. 240 OH is rarely isolated in PD patients 200 with autonomic failure (FIGURE 1). Postprandial hypotension [16] and supine arte- 160 rial hypertension (mainly during the 120 night) are frequently found, thus indicating the usefulness of ambulatory monitoring of blood pressure to detect patients with probable autonomic failure [17]. Detection of supine hypertension may also modulate the choice of drugs when pharmacological treatment is required. However, the prognosis value of supine hypertension is still not known as the need or not to treat elevated blood pressure during the night. Ambulatory monitoring of blood pressure may also sometimes be used to assess efficacy and safety of OH pharmacological treatment. Blood pressure (mmhg) 80 40 200 160 120 80 40 0 Pharmacology is useful to understand the pathophysiology of OH in PD The loss of dopaminergic neurons and the presence of Lewy bodies in the zona compacta of the substantia nigra remain the main hallmark of PD. However, cell loss and Lewy bodies can also be observed in the hypothalamus, cerebellum, nucleus vagus dorsalis and intermediolateral column of the spinal cord and also in sympathetic ganglia which are involved in the control of blood pressure via the baroreflex arch [18]. These pathological changes in peripheral autonomic nervous system are very similar to those found in patients with PAF and clearly distinguish these two conditions from the autonomic failure observed in MSA. Furthermore, it has been shown that patients with defined symptomatic OH and PD exhibit low plasma levels of noradrenaline whereas this parameter is usually normal in MSA patients [19]. The consequences of these pathological changes can be determined by pharmacological investigation of the autonomic nervous system and through the study of cardiovascular reflexes. These can also change the cardiovascular responses to drugs and explain the high prevalence of drug-induced OH in patients with impaired baroreflex arch. Pharmacological characteristics of autonomic failure & OH Parkinsonians with OH and autonomic failure exhibit both a denervation supersensitivity of vascular adrenergic receptors and an upregulation of platelet α2-adrenoceptors. These changes are not specific to PD but are considered as secondary to the decreased activity of the orthosympathetic efferent pathway and the low plasma levels of norepinephrine. Central α 2 - adrenergic receptors seem to be intact in PD. In fact, acute pharmacological challenge with clonidine leads to a normal and expected increase in growth hormone (GH) plasma levels in idiopathic PD whereas it remains without effect in MSA [20]. As Heart rate (beats/min) 10 12 14 16 18 20 22 0 2 4 6 8 10 Time (h) Figure 1. Ambulatory blood pressure monitoring in a patient with idiopathic Parkinson's disease and autonomic failure marked by severe orthostatic hypotension. Blood pressure is highly variable during the day, with marked postprandial hypotension. Nocturnal period is associated with significant supine hypertension (personal data). 90 Expert Rev. Cardiovasc. Ther 2(3), (2004)

Orthostatic hypotension in Parkinson s disease normal GH increase is also observed during clonidine stimulation in patients with PAF, it has been suggested that OH during the course of PD is mainly related to a peripheral dysfunction of the autonomic nervous system and not only to a central nervous system disorder. Additional pharmacological arguments favor this hypothesis. Acute challenge with yohimbine, an α 2 -adrenergic antagonist which increases norepinephrine spill-over from sympathetic nerve endings, leads to a normal increase in plasma norepinephrine levels in control subjects and in patients with MSA but not in Parkinsonian patients with OH and autonomic failure [21]. Various authors have demonstrated, using [ 123 I]metaiodobenzylguanidine (MIBG), a radiopharmaceutical analog of guanethidine, an impairement of the capacity of neuronal uptake at the level of the heart (FIGURE 2) in Parkinsonian patients with autonomic failure [22,23]. This abnormality is present from the first stages of the disease, and therefore strongly suggests that autonomic dysfunction is an early event in the course of the disease [24]. Similar results have been obtained using positron emission tomography (PET) scan and [ 18 F]fluorodopa [25]. Taken as a whole, pharmacological studies corroborate pathological studies suggesting the involvement of peripheral autonomic nervous system in autonomic failure and OH during PD. Both cardiac scintigraphy [24] and clonidine challenge [26] can be useful for the diagnosis of Parkinsonian syndromes sometimes difficult to distinguish clinically overall in the early stages of the diseases. Clinical pharmacology of drugs for OH in PD When considering pharmacological treatment of OH, one important point to kept in mind is that patients with autonomic failure have a large variability in blood pressure, explaining why so many patients suffer both from OH and supine arterial hypertension. As most drugs used in the treatment of OH act as vasoconstrictors or volume expanders, they may worsen supine hypertension with consequences on mor- Autonomic failure & drug-induced OH Many drugs have been reported as able to induce or aggravate OH [27]. Excepting anti-parkinsonian medications, the drugs most frequently prescribed to patients with PD are diuretics, most antihypertensive medications and tricyclic antidepressants. It is clear that all dopaminomimetic drugs can impair blood pressure and heart rate adaptation to standing position. Levodopa and dopaminergic agonists can lower supine and standing blood pressure through both peripheral and central mechanisms. At a peripheral level they may induce vasodilation in splanchnic and renal vascular beds. They can also decrease the activity of vasopressor areas within the brainstem and a decrease the catecholamine release from nerve endings through specific dopaminergic receptors. The effects of levodopa plus dopa-decarboxylase inhibitors are probably mild and clinical consequences are restricted to the days or weeks following the introduction of the drug. Monoamine oxidase inhibitors such as selegiline (Eldepryl, Orion Pharma) also diminish cardiovascular autonomic responses in PD and increase the risk of OH [28]. By contrast, catechol-o-methyltransferase (COMT) inhibition seems not to alter cardiovascular autonomic responses in Parkinsonian patients [29]. The cardiovascular effects of dopaminergic agonists are still a matter of controversy. It has been shown that impaired cardiovascular adaptation during standing or OH can be observed with all dopamine agonists available, independently of their selectivity for the different isoforms of dopaminergic receptors overall, shortly after drug introduction or increases in dosage [30]. However, both human and experimental data strongly suggest that hypotensive effects of dopamine agonists are only observed after acute challenge and would be of short duration due to baroreflex adaptation and cardiovascular tolerance [31,32]. Since autonomic adaptation is impaired in patients with autonomic failure it can be expected that, in such patients, pharmacological tolerance to the cardiovascular effects of these drugs would be absent. However, there are no data available describing the time course of the pharmacological cardiovascular effects of dopamine agonists in humans with autonomic failure. From a clinical point of view, OH that is associated with a significant increase in heart rate will suggest that postural hypotension is related to the anti-parkinsonian drug. Dose reduction or dopamine agonist withdrawal sometimes also help to assess drug imputability when it is followed by a reduction or suppression of blood pressure fall when standing. By contrast, OH associated with fixed heart rate, which is not influenced by drug reduction favors autonomic failure which can be confirmed using classical clinical tests not described in this review. This step is of prime importance in order to avoid the introduction of drugs to manage OH in patients with drug-induced postural hypotension. Figure 2. [ 123 I] MIBG cardiac scintigraphy. a) In a patient with Parkinson's disease and autonomic failure-related orthostatic hypotension. b) In a patient with multiple system atrophy (MSA). The cardiac uptake on the radiopharmaceutical is almost absent in the Parkinsonian, whereas it is normal in the MSA patient (personal data). [ 123 I] MIBG: [ 123 I]meta-iodobenzylguanidine. b www.future-drugs.com 91

Pathak & Senard bidity and mortality still not clarified. The primary endpoint is to improve the incidence and severity of postural symptoms and not only to limit blood pressure fall during standing. This is of particular importance since there is no clear correlation between blood pressure fall and postural symptoms. Whatever the drug or the combination of drugs used, the control of OH is very frequently incomplete. Thus, because of these different factors, pharmacological treatment should be reserved to symptomatic patients not improved by educational and nonpharmacological measures. As there is no scientific evidence demonstrating specific efficacy of any antihypotensive drug in PD, the choice of medication to be introduced when necessary mainly depends on concomittant medical conditions and patient life style. Many drugs have been proposed for the treatment of OH (TABLE 1). According to their major pharmacological properties, they could be classified into: Drugs acting on postsynaptic adrenoceptors Drugs inhibiting vasodilating factors Drugs acting on volemia The aim of this section is not to make an exhaustive presentation of antihypotensive agents but only to discuss the properties and evidence for the efficacy of drugs frequently used and overall of those which seem of major interest in PD. More information on specific drugs may be found in the recent review from Bannister and Mathias [33]. A further section will focus on data available for postprandial hypotension very often associated with OH in patients with autonomic failure. Drugs acting on efferent sympathetic pathways Yohimbine hydrochloride is an α 2 -adrenergic antagonist which interacts with both central and peripheral α 2 -adrenergic receptors and increases norepinephrine release from sympathetic nerve endings in humans. Despite its the fact that its potential as an antihypotensive medication has been repeatedly discussed, the benefits of using yohimbine in OH related to PD would probably be limited. Acute challenge with large doses of yohimbine can be useful to study the capacity of activation of efferent orthosympathetic pathways [21]. Since yohimbine has only weak selectivity for α 2 -adrenergic receptors, it will also behave as an α1-adrenergic antagonist and when used at large Table 1. Drugs proposed for the treatment of orthostatic hypotension: main side effects, potential interactions with anti- Parkinsonian drugs and contraindications. Adverse reactions Interactions with anti- Parkinsonian drugs Contraindications Drugs acting on sympathetic pathways L-DOPS Malignant neuroleptic syndrome, hypertension, headache Yohimbine Domperidone, metoclopramide Pyridostigmine Anxiety, hypertension, tachycardia, OH worsening Worsening of PD motor status, hyperprolactinemia Worsening of PD motor status, sialorrhea, diarrhea, abdominal pain Drugs acting on blood vessels Midodrine Piloerection, dysesthesia, supine hypertension, bradycardia, dysuria Carbidopa, benserazide, (MAO and COMT inhibitors?) Not reported May be used to prevent peripheral adverse reactions Anticholinergics Bromocriptine Investigational drug Renal and hepatic failure Tardive dyskinesias Asthma, occlusion Author P roof Glaucoma, arteriopathy, urinary retention, renal failure Ergot alkaloids Peripheral vasoconstriction, fibrosis Ergot-derivated dopamine agonists Arteriopathies, macrolides Drugs acting on blood volume Fludrocortisone Edema, cardiac failure, hypokaliemia Not reported Same as glucorticoids Erythropoietin Hypertension, thrombosis Not reported Stroke, myocardial infarction Desmopressin Hyponatremia Not reported Drugs for postprandial hypotension Caffeine Diarrhea, nausea, tremor, sleep disorders, tachycardia, polyuria Not reported Octreotide Diarrhea, nausea, galbladder, alopecia Not reported Pregancy COMT: Catechol O-methyltransferase; L-DOPS: L-Threo-3,4-dihydroxyphenylserine; MAO: Monoamine oxidase; OH: Orthostatic hypotension; PD: Parkinson s disease. 92 Expert Rev. Cardiovasc. Ther 2(3), (2004)

Orthostatic hypotension in Parkinson s disease doses it may worsen OH. The effects of low daily dose of yohimbine in the treatment of OH in PD have been investigated in a 1 month yohimbine (6 mg daily) double-blind, cross-over trial in 17 Parkinsonians with OH [34]. The primary end point of this study was an effect on blood pressure load, measured using ambulatory blood pressure monitoring. Yohimbine treatment was not associated with any change in blood pressure parameters. Even though the design of this study did not include measurement of postural symptoms, the results are in accordance with those for acute challenge and strongly suggest that there is no place for yohimbine in the management of postural hypotension in PD. Domperidone (Motilium, Sanofi Synthelabo) is a peripheral dopaminergic antagonist which does not enter the brain. Due to its pharmacology, domperidone is often used in combination with anti-parkinsonian medications in order to prevent the adverse effects on the digestive system. As presynaptic dopamine receptors to sympathetic nerve endings also participate to the regulation of norepinephrine release, metoclopramide (Maxolon, Shire Pharmaceuticals Ltd) or domperidone have been proposed for the treatment of OH [35,36]. However, there is no evidence that domperidone can be useful in correcting OH related to autonomic failure in Parkinsonians. In contrast, some data suggest that domperidone can, at least sometimes, prevent blood pressure fall and the occurrence of OH induced by dopamine agonists [37]. L-Threo-3,4-dihydroxyphenylserine (L-DOPS) is a prodrug which is converted to norepinephrine by DOPA-decarboxylase. Its exact mechanism of action remains undetermined. L-DOPS increases plasma norepinephrine levels through a peripheral mechanism (FIGURE 3). It also increases sympathetic nerve activity, probably through a central mechanism. The corrective effect of L-DOPS has been reported in various conditions, such as dopamine β-hydroxylase deficiency [38] and PAF or MSA [39,40]. As far as PD is concerned, an unpublished European multicentric, placebo-controlled study which investigated the efficacy of three different doses of L-DOPS in the treatment of OH in PD and MSA found a marginal decrease in blood pressure fall during orthostatism without any change in postural symptoms (UNPUBLISHED DATA). There are various possible explanations for this disappointing result, but a pharmacokinetic interaction between L-DOPS and anti-parkinsonian medications seems most likely. In fact, conversion of L-DOPS into norepinephrine is dependent on DOPA-decarboxylase, the activity of which is blocked by carbidopa or benserazide used in combination with levodopa (Sinemet [Bristol Myers Squibb] and Madopar [Roche], respectively). In a recent paper, Kaufmann and colleagues demonstrated that carbidopa prevents both the pressor effects and the increase in noradrenaline plasma levels induced by L-DOPS in patients with MSA [41]. Many reports have been published indicating that central muscarinic receptors have pressor effects and stimulate activity in sympathetic efferent pathways. The description of these results is beyond the scope of this review but it is clear that centrally acting cholinergic agonists or cholinesterase inhibitors may have potential interest in OH related to autonomic failure. This hypothesis was investigated in drug-induced OH including dopamine agonists and it was shown that physostigmine and neostigmine reverse OH in rats [42]. Very recently, an uncontrolled trial in a small survey of patients with neurogenic OH, some, suffering from PD, suggested that pyridostigmine (Mestinon, ICN Pharmaceuticals Ltd) at a low dose is able to reduce blood pressure fall and postural symptoms during a head-up tilt test without significant modifications of supine blood pressure or cholinergic side effects [43]. Despite their potential, these data remain preliminary and need to be confirmed in a controlled trial. Drugs acting on postsynaptic α 1 -adrenoceptors Both α 1 - and α 2 -adrenoceptors are found in vascular smooth muscle and mediate vasoconstrictor responses which have been shown to be enhanced in autonomic failure because of receptor supersensitivity or vagal activity withdrawal. From a therapeutic point of view, even though α 2 -adrenoceptor agonists, such as clonidine have sometimes been proposed, only α 1 -adrenoceptor agonists, such as dihydroergotamine (Migranal, Xcel Pharmaceuticals, Inc.), etilefrine (Effortil, Boehringer Ingelheim) and midodrine are used in the management of OH. Due to the complex pharmacology and poor bioavaibility, there is no clear evidence of beneficial effects of dihydroergotamine or ergotamine. Etilefrine has agonist activity on both α- and β-adrenergic receptors. This latter property may limit its vasoconstrictor action. The effect of etilefrine (15 mg/day) on blood pressure fall and postural symptoms was investigated in a single-blind study versus placebo in 20 Parkinsonians with OH [44]. After 6 days of treatment, standing blood pressure drop was reduced in the etilefrine but not in the placebo group. Phenylpropanolamine was shown to induce potent pressor effects in a small double-blind trial versus placebo, but not in patients suffering from PD [45]. Adverse events related to both etilefrine and phenylpropanolamine are similar to those of midodrine and special attention has to be paid to the risk of supine arterial hypertension. Obviously, adverse events will limit their use particularly in patients with autonomic failure who present hypersensitivity to pressor stimuli. The cardiovascular events associated with phenylpropanolamine and other ephedra alkaloids have been highlighted [46,47]. HO OH L-Threo-DOPS H OH H NH 2 aacd COOH HO OH Norepinephrine H OH H NH 2 H Figure 3. Biochemical conversion of L-Threo-DOPS into norepinephrine is achieved by amino acid decarboxylase at the peripheral level. aacd: Amino acid ecarboxylase; L-Threo-DOPS: L-Threo-3,4- dihydroxyphenylserine. www.future-drugs.com 93

Pathak & Senard Midodrine (and more precisely its active metabolite, desglymidodrine) is the sole α 1 -adrenoceptor agonist available today for OH treatment. Its efficacy was investigated several times in different kinds of neurogenic OH [48]. Midodrine consistently improves symptoms and blood pressure fall related to orthostatism. The most frequently reported side effects are pilomotor reactions, paresthesia, pruritus, dysuria and chills, as expected from an α 1 -agonist. Moreover, midodrine can induce or aggravate supine hypertension which is frequently found in patients with autonomic failure. This effect can be attenuated by taking the last daily dose of midodrine at least 4 h before bedtime. Due to renal excretion, midodrine has to be used with caution in patients with renal failure, and in the case of concomitant administration with other vasoconstrictors. From a theorical point of view, simultaneous administration of dopamine agonists with ergot structure may be responsible for an increase in the prevalence of adverse events, thus justifying special caution in these patients. No study has specifically investigated the efficacy of midodrine in OH of PD. However, in two large placebo-controlled studies, Parkinsonian patients with OH were included. In the first study [49], the efficacy of three different doses midodrine of was tested on both blood pressure drop and symptoms related to orthostatism. Of the 19 Parkinsonians evaluated, 16 received midodrine and 11 were considered as responders (increase in standing systolic blood pressure 10 mmhg). In the second study [50], 171 patients with autonomic failure and OH, 19 of them with PD, received midodrine (30 mg/day) or placebo for 4 weeks. According to primary end points (improvement in blood pressure fall and in postural symptoms) midodrine was shown to be efficacious. No specific subgroup evaluation was performed in the Parkinsonian patients, but statistical analysis suggested that the etiology of autonomic failure did not influence drug effect. Midodrine is marketed in various countries for the treatment of severe neurogenic OH with large variation in recommended doses. Recently, the authors investigated characteristics of the prescription of midodrine in 97 consecutive medical reports from patients with autonomic failure [51]. In this survey, PD accounted for 54% of the population. The mean daily dose (12 ± 6 mg), was rather low when compared with doses used in clinical trials. Of the patients included in the survey, 52 (53.6%) had at least one contraindication to midodrine including hypertension, cardiopathy, severe renal dysfunction and glaucoma. This inappropriate prescription was associated with an increase in adverse drug reactions. Drugs acting on blood volume A decrease in total blood volume is one of the possible causes of OH. In patients with autonomic failure, total blood volume is considered normal but a significant decrease in total erythrocyte volume is frequently found, and correlates with a decrease in hemoglobin levels. Various drugs acting on blood volume have been proposed to treat OH including mineralocorticoids, vasopressin analogs and erythropoietin. Fludrocortisone, a synthetic mineralocorticoid almost devoid of glucocorticoid acitvity, is proposed as the first choice treatment for OH. The rationale for its use is the reduction in a defective plasma renin and aldosterone secretion during standing, together with a reduced blood volume. Apart from replacing aldosterone levels, fludrocortisone is also known to increase norepinephrine release and to sensitize vacular adrenergic receptors. The combination of low doses of fludrocortisone (0.1 mg/day) with head-up tilt at night and high salt diet was shown to improve postural hypotension [52]. The efficacy of fludrocortisone has scarcely been reported in patients with PD. Hoehn reported six Parkinsonians in whom OH-induced by levodopa was improved by fludrocortisone (0.05 0.20 mg/day) [53]. Hakamaki and colleagues compared ambulatory blood pressure recordings in eight Parkinsonians with (0.1 0.2 mg/day) and in 12 Parkinsonians without fludrocortisone conclude that Parkinsonians are nondippers and that fludrocortisone is associated with higher blood pressure levels during the night [54]. Finally, despite its frequent use in OH related to PD, the efficacy of fludrocortisone has never been specifically evaluated in this condition. Available data suggest that dosage and adverse events are similar to those observed in other causes of primary autonomic failure. During fludrocortisone treatment, supine blood pressure, body weight (a gain of 2 3 kg is often observed), pedal edema, cardiac function and kalemia must to be monitored. The dose should be progressively increased starting from a low dose of 0.01 mg per day. Repeated observations of both decreased erythropoietin levels and total erythrocyte volume support the hypothesis that the sympathetic nervous system participates in stimulation of erythropoiesis in humans. An increase in red cell volume by erythropoietin treatment has been reported to be able to correct OH in autonomic failure related to diabetes mellitus and pure autonomic failure [55 57]. Only one case of dramatic improvement of postural hypotension in PD has been reported [58]. Vasopressin analogs, such as desmopressin, which interact with V2 renal receptors prevent nocturnal polyuria responsible for overnight weight loss and severe morning postural symptoms [59]. The effect of intranasal desmopressin has never been reported in Parkinsonians with OH. With desmopressin, careful monitoring of serum sodium has to be carried out in order to detect hyponatremia. Drugs for postprandial hypotension As discussed above, a particular aspect of postural hypotension in Parkinsonians is postprandial hypotension. Chaudhuri and colleagues showed that in Parkinsonian patients, a standard meal induces a larger decrease in blood pressure than in controls and may result in postural hypotension in 60% of the patients [16]. Postprandial hypotension may explain exacerbation of Parkinsonian symptoms after meals [16]. If postprandial hypotension is not suspected in such patients, any intempestive increase in anti-parkinsonian medication may lead to a worsening of postprandial symptoms. It has been shown that 94 Expert Rev. Cardiovasc. Ther 2(3), (2004)

Orthostatic hypotension in Parkinson s disease pancreatic and gut peptides released after food ingestion are partly responsible for splanchnic vasodilation, and may explain how meal intake may worsen or induce OH. When nonpharmacological methods, such as reduction in meal size or restriction of carbohydrate intake remain without effect, the use of drugs may be discussed. Caffeine is an antagonist at adenosine receptors and, at high doses, a phosphodiesterase inhibitor. Due to its pharmacological properties, caffeine has sometimes been proposed for the treatment of postprandial hypotension but with controversial results. An uncontrolled study suggested that 250 mg of caffeine given 30 min before a meal could prevent a decline in blood pressure [60] but this effect was never verified during controlled studies. In contrast, caffeine is ineffective when given during meals [61]. There is no information on caffeine in the treatment of postprandial hypotension in patients with PD. Octreotide, a somatostatin analog, inhibits peptide release and has been reported to prevent food and glucose-induced hypotension but also nonmeal-related postural hypotension in patients with autonomic failure [62,63]. Management of OH in PD After OH is diagnosed, the first step of management should include eludication of the pathophysiological mechanisms, particularly searching for evidence of drug-induced OH. The whole drug prescription should be re-evaluated, including dopamine agonists. Persistence of OH and the lack of tachycardia during standing lead the diagnosis toward neurogenic OH although clinical investigation of the autonomic nervous system is needed to confirm autonomic failure. Evaluation of severity and frequency of postural symptoms must be undertaken even if clinical manifestations of OH are sometimes difficult to distinguish from symptoms related to PD (postural instability, asthenia, falls). Before treatment, it is also useful to screen for supine hypertension with ambulatory blood pressure monitoring, as well as for other risk factors for cardiovascular diseases. Nonpharmacological measures Nonpharmacological treatment has to be proposed as first-line management [64]. Various methods have been described as being useful to reduce OH. Patients have to be told to avoid situations which can lower blood pressure, such as sudden postural changes, prolonged recumbency, high environmental temperatures, large meals and alcohol. Sustained education efforts have to be made to obtain gradual stand-up, sleeping in the head-up position, fragmentation of meals and avoidance of carbohydrates in order to limit severity of postprandial hypotension. Low sodium diets have to be avoided and adequate fluid intake assured. The use of elastic stockings has not been extensivey studied even though very frequently proposed. It was shown that compression tights appropriate to the patient s morphology was able to reduce blood pressure fall and symptoms during an acute 90 head-up tilt in 45 elderly patients with OH [65]. However, long-term efficacy has never been studied and correct fitting of elastic stockings is sometimes difficult to achieve in patients with neurological handicap and they are not well-tolerated overall during summertime. Some simple physical countermaneuvers have been described, such as squatting or leg crossing which can sometimes increase standing blood pressure or delay syncope [66,67]. Pharmacological treatment Pharmacological treatment should be reserved to patients in whom other measures were unsuccessful and in combination with nonpharmacological methods. The choice for a drug depends on the presence or not of supine arterial hypertension and the results of cardiological examination and analysis of risk factors. For instance, in a patient with nocturnal supine hypertension, fludrocortisone may not be the first choice drug because of its prolonged effects on blood pressure which can lead to augmentation of night blood pressure load. By contrast, a patient with medical history of coronary ischemia or multiple risk factors for coronary disease, midodrine should be considered a risk. Whatever the case, the choice has to be based on the benefit/risk ratio of each drug for the individual patient and the drug introduced at a low dose. As shown for midodrine, strict respect of contraindication is needed to reduce the occurence of side effects [51]. Management of OH in patients with cardiovascular diseases Prescription of drugs for OH in patients with cardiovascular diseases remains a critical management problem. In fact, OH itself is associated with increased risk of coronary heart or cerebrovascular morbidity. Morevover, because of sympathomimetic action or increase in blood volume, drugs used in OH may also increase resting blood pressure, precipitating heart failure or provoking arrhythmias or vascular ischemia. Thus, systematic assessment of cardiovascular status of PD patients with is advisable before starting drugs for OH. Another important management difficulty concerns patients already receiving drugs for OH, who present with an ischemic event. Two mechansims may explain this situation. First, the treatment is ineffective and persistent blood pressure fall during standing is caused by a fall in cerebral or coronary blood flow. In this case, if appropriate explorations confirm normality of coronary or cerebral vessels, treatment must be maintained and adapted until control of OH is achieved. In the second case, explorations reveal vascular disease at heart or cerebral levels irrespective of the efficacy of treatment for OH. In this situation, secondary prevention treatment should be introduced and rechallenge of antihypotensive drug using low doses and avoiding potent vasoconstrictors should be started. The problem of supine hypertension is crucial and frequent. The question of usefulnes of antihypertensive therapy for nocturnal supine hypertension remains an unanswered question. It is clear that long-acting drugs, such as fludrocortisone have an impact on nocturnal pressure load. In such patients, the use of drugs with short half-life, like midodrine and avoiding late afternoon intake will limit impact on night blood pressure. Even if the use of antihypertensive drugs with short action in www.future-drugs.com 95

Pathak & Senard order to avoid remanent effect during daytime and potential worsening of OH seems logical, this strategy has never been validated. Expert opinion & five-year view This section will discuss some important points for better management of OH in PD from both clinical and pharmacological points of view. Since OH is highly prevalent in PD, the search for OH should be systematic during the clinical follow-up of these patients. For most neurologists, following the widely used rating scale for PD (the Unified Parkinson s Disease Rating Scale [UPDRS]), OH is still often considered a complication of anti- Parkinsonian treatments [68] despite the large amount of evidence demonstrating that autonomic dysfunction is part of the disease, as are motor features. A revision of UPDRS taking into account items not already covered [69], as well as a better training of physicians, students and nurses to autonomic testing, too often limited to specialized laboratories, are the main measures to consider to change current thinking. In the same way, the various specialists in charge of Parkinsonian patients should collaborate to improve evaluation of risk factors and thus the choice of the right drug for the right patient. This will also limit the frequency of potentially dangerous prescriptions (such as antihypertensives and α-blockers) by physicians not always aware of the autonomic status of the patient. Anti-Parkinsonian drugs are usually developped for their ability to improve motor Parkinsonian symptoms or to reduce fluctuations and dyskinesias. Their effects on the autonomic nervous system are not extensively studied, at least in humans, and most of the time safety data do not use the current definition of OH, thus leading to unprecise results. For obvious reasons, the impact of anti-parkinsonian drugs on blood pressure regulation should also be undertaken in patients with defined autonomic failure as well as the interactions of antiparkinonian medications with antihypotensive drugs. The same is true for drugs used in PD autonomic disorders other than OH such as drugs for urinary disorders or impotence. Sildenafil (Viagra, Pfizer) is a good example of incorrect evaluation of drugs in References Papers of special note have been highlighted as: of interest of considerable interest 1 Rutan GH, Hermanson B, Bild DE, Kittner SJ, LaBaw F, Tell GS. Orthostatic hypotension in the older adults. The cardiovascular health study. Hypertension 19, 508 519 (1992). One of the largest epidemioloigcal studies on orthostatic hypotension (OH). Discusses the importance of diagnosis criteria for calculation of prevalence. 2 Raïha I, Luutonen S, Piha J, Seppanen A, Toikka T, Sourander L. Prevalence predisposing factors and prognosis importance of postural hypotension. Arch. Intern. Med. 155, 930 935 (1995). 3 Elmstahl S, Rosen I. Postural hypotension and EEG variables predict cognitive decline: results from a 5-year follow-up of healthy elderly women. Dement. Geriatr. Cogn. Disord. 8, 180 187 (1997). 4 Eigenbrodt ML, Rose KM, Couper DJ, Arnett DK, Smith R, Jones D. Orthostatic hypotension as a risk factor for stroke. The Atherosclerosis Risk in Communities (ARIC) study, 1987 1996. Stroke 31, 2307 2313 (2000). Clearly indicates that OH is associated with a significant increased risk of stroke PD. In fact, if cardiovascular side effects of sildenafil have sometimes been investigated in patients with PD leading to the conclusion that sildenafil is safe and does not induce OH in these patients, these studies excluded patients with neurogenic impotence [70] or OH [7,71]! Finally, as recently underlined in an evidence based assessment of therapeutic interventions for PD, no clinical trial has focused on OH treatment in PD [72]. This is the reason why recommendation of fludrocortisone or midodrine as first-line drugs, based on clinical experience in other conditions, remains totally empirical in PD. Due to the high frequency of OH and specific pathophysiological mechanisms, there is a clear need for specific clinical trials in OH of PD. These trials should start with already available drugs and be carried out using correct efficacy criteria: postural symptoms frequency and severity, quality of life, cardiovascular safety and morbimortality. Key issues Parkinson's disease (PD) is a frequent cause of autonomic failure and of orthostatic hypotension (OH). OH is often associated with other disorders of blood pressure control including postprandial hypotension and supine hypertension. The pathophysiological mechanisms relevant to OH in PD clearly differ from those observed in other causes of primary autonomic failure and include a disorder of peripheral autonomic nervous system as shown by decreased cardiac uptake of [ 123 I] meta-iodobenzylguanidine. The objective of OH treatment is to reduce postural symptoms and morbidity related to blood pressure fall. The treatment of OH during PD must start using non pharmacological methods including patient education. Drugs are to be reserved as second line intervention. No trial demonstrating efficacy on OH in PD patients is available for any of the drugs proposed including those considered as first line drugs, midodrine and fludrocortisone. Author P roof 5 Rose KM, Tyroler HA, Nardo CJ et al. Orthostatic hypotension and the incidence of coronary heart disease: the Atherosclerosis Risk in Communities Study. Am. J. Hypertens. 13, 571 578 (2000). Clearly indicates that OH is associated with a significant increased risk of coronary events. Discusses other risk factors such as smoking, blood pressure and dylipidemia. 6 Masaki KH, Schatz IJ, Burchfiel CM et al. Orthostatic hypotension predicts mortality in elderly men. The Honolulu heart program. Circulation 98, 2290 2295 (1998). Very interesting study demonstrating that the presence of OH is associated with a 60% increase in mortality 4 four years after diagnosis. 96 Expert Rev. Cardiovasc. Ther 2(3), (2004)

Orthostatic hypotension in Parkinson s disease 7 Luukinen H, Koski K, Laippala P, Kivela SL. Prognosis of diastolic and systolic orthostatic hypotension in older persons. Arch. Intern. Med. 159, 273 280 (1999). 8 The Consensus Committee of the American Autonomic Society and the American Academy of Neurology. Consensus statement on the definition of orthostatic hypotension, pure autonomic failure and multiple system atrophy. Neurology 46, 1470 (1996). Describes the current diagnosis criteria of OH to be used in clinical practice and clinical pharmacology. 9 Korczyn AD. Autonomic nervous system disturbances in Parkinson s disease. In: Advances in Neurology: Parkinson s Disease: Anatomy, Pathology and Therapy. Streifler MB, Korczyn AD, Melamed E, Youdim MBH (Eds). Raven Press, NY, USA,53, 463 468 (1990). An updated classification of autonomic disorders very useful to interested readers. 10 Bannister R, Mathias CJ. Introduction and classification of autonomic disorders. In: A textbook of Clinical Disorders of the Autonomic Nervous System. Mathias CJ, Bannister R (Eds). Oxford University Press, Oxford, UK 17 22 (1999). 11 Gilman S, Low PA, Quinn N et al. Consensus statement on the diagnosis of multiple system atrophy. J. Auton. Nerv. Syst. 74, 189 192 (1998). 12 van Dijk JG, Haan J, Zwinderman K, Kremer B, van Hilten BJ, Roos RA. Autonomic nervous system dysfunction in Parkinson s disease: relationship with age, medication, duration and severity. J. Neurol. Neurosurg. Psychiatry 56, 1090 1095 (1993). 13 Wenning GK, Scherfler C, Granata R et al. Time course of symptomatic orthostatic hypotension and urinary incontinence in patients with postmortem confirmed Parkinsonian syndromes: a clinicopathological study. J. Neurol. Neurosurg. Psychiatry 67, 620 623 (1999). Confirms that OH may exist in Parkinson's disease and gives some indication for the differential diagnosis with multiple system atrophy (MSA) during the early stages. 14 Senard JM, Raï S, Lapeyre-Mestre M. Prevalence of orthostatic hypotension in Parkinson s disease. J. Neurol. Neurosurg. Psychiatry 63, 584 589 (1997). Largest study on the prevalence of OH in clinical practice. 15 Bonuccelli U, Lucetti C, Del Dotto P et al. Orthostatic hypotension in de novo Parkinson s disease. Arch. Neurol. 60, 1400 1404 (2003). 16 Chaudhuri KR, Ellis C, Love-Jones S et al. Postprandial hypotension and Parkinsonian state in Parkinson s disease. Mov. Disord.12, 877 884 (1997). 17 Senard JM, Chamontin B, Rascol A, Montastruc JL. Ambulatory blood pressure in patients with Parkinson s disease without and with orthostatic hypotension. Clin. Auton. Res. 2, 99 104 (1992). 18 Wakabayashi K, Takahashi H, Ohama E, Takeda S, Ikuta F. Lewy bodies in the visceral autonomic nervous system in Parkinson s disease. In: Advances in Neurology. Narabayashi H, Nagatsu T, Yanagisawa N, Mizuno Y (Eds). Raven Press, NY, USA, 609 612 (1993). 19 Golstein DS, Holmes C, Sharabi Y, Brentzel S, Eisenhofer G. Plasma levels of catechols and metanephrines in neurogenic orthostatic hypotension. Neurology 60, 1327 1332 (2003). Describes in details the levels of catecholamines and metabolites seen in plasma in MSA, pure autonomic failure (PAF) and Parkinson's disease with consideration of the patophysiological mechanisms of autonomic failure. 20 Kimber JR, Watson L, Mathias CJ. Distinction of Parkinson s disease from multiple system atrophy by stimulation of growth-hormone release with clonidine. Lancet 349, 1877 1881 (1997). Strongly suggests that autonomic pharmacology may be useful to differenciate MSA from Parkinson's disease with OH 21 Senard JM, Rascol O, Durrieu G et al. Effects of yohimbine on plasma catecholamine levels in orthostatic hypotension related to Parkinson s disease or multiple system atrophy. Clin. Neuropharmacol. 16, 70 76 (1993). 22 Braune S, Reinhardt M, Schnitzer R, Riedel A, Lucking CH. Cardiac uptake of [ 123 I]MIBG separates Parkinson s disease from multiple system atrophy. Neurology 53, 1020 1025 (1999). Strongly suggests that autonomic pharmacology may be useful to differenciate MSA from Parkinson's disease with OH. 23 Takatsu H, Nishida H, Matsuo H et al. Cardiac sympathetic denervation from the early stage of Parkinson s disease: clinical and experimental studies with radiolabeled MIBG. J. Nucl. Med. 41, 71 77 (2000). 24 Courbon F, Brefel-Courbon C, Thalamas C et al. Cardiac MIBG scintigraphy is a sensitive tool for detecting cardiac sympathetic denervation in Parkinson s disease. Mov. Disord. 18, 890 897 (2003). Strongly suggests that [ 123 I] metaiodobenzylguanidine (MIBG) cardiac scintigraphy in Parkinson's disease plus OH is a very sensitive method. It also shows that in patients without severe clinical autonomic failure, there is heterogeneity in regional MIBG captation. 25 Goldstein DS. Dysautonomia in Parkinson s disease: neurocardiogical abnormalities. Lancet Neurol. 2, 669 676 (2003). An exhaustive and comprehensive review of the pathophysiology of autonomic failure and OH in Parkinson's disease. 26 Lee EA, Kim BJ, Lee WY. Diagnosing multiple system atrophy with greater accuracy: combined analysis of the clonidinegrowth hormone test and external anal sphincter electromyography. Mov. Disord. 6, 1242 1247 (2002). 27 Verhaeverbeke I, Mets T. Drug-induced orthostatic hypotension in the elderly. Avoiding its onset. Drug Safety 17, 105 118 (1997). 28 Turkka J, Suominen K, Tolonen U, Sotaniemi K, Myllyla VV. Selegiline disminishes cardiovascular autonomic responses in Parkinson s disease. Neurology 48, 662 667 (1997). 29 Lyytinen J, Sovijärvi A, Kaakkola S, Gordin A, Teräväinen H. The effect of catechol-omethyltransferase inhibition with entacapone on cardiovascular autonomic responses in L- Dopa-treated patients with Parkinson s disease. Clin. Neuropharmacol. 24, 50 57 (2001). 30 Kujawa K, Leurgans S, Raman R, Blasucci L, Goetz CG. Acute orthostatic hypotension when starting dopamine agonists in Parkinson s disease. Arch. Neurol. 57, 1461 1463 (2000). Strongly suggests that there is a pharmacological tolerance to the cardiovascular effects of dopamine agonists. 31 Parker SG, Raval P, Yeulet S, Eden RJ. Tolerance to peripheral but not central, effects of ropinirole, a selective dopamine D2-like receptor agonist. Eur. J. Pharmacol. 265, 17 26 (1991). Further evidence that pharmacological tolerance to the cardiovascular effects of dopamine agonists can be developped. 32 Montastruc JL, Llau ME, Senard JM, Tran MA, Rascol O, Montastruc P. A study of tolerance to apomorphine. Br. J. Pharmacol.117, 781 786 (1996). 33 Bannister R, Mathias CJ. Management of postural hypotension. In: A Text Book of Clinical Disorders of the Autonomic Nervous System. Mathias CJ, Bannister R (Eds). Oxford University Press,Oxford, UK, 342 356 (1999). Author P roof www.future-drugs.com 97