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Editorial

What are the considerations for anti-hypertensive treatment in patients with Parkinson’s disease?

Pages 1127-1130 | Received 07 Jan 2020, Accepted 16 Mar 2020, Published online: 20 Mar 2020

1. Introduction

For a considerable length of time it was assumed that Parkinson’s disease (PD) is contingent on degeneration of the substantia nigra and that the lack of dopamine was the main cause of the symptoms. Seen in this light, a number of symptoms, including cardiovascular ones, were erroneously viewed as a consequence of the therapeutic interventions or as being independent of PD. Today we recognize that PD involves complex multisystem degeneration which affects several regions in both the peripheral and the central nervous system and does not begin or end in the substantia nigra [Citation1]. Cardiovascular symptoms occur frequently in PD and have high clinical relevance [Citation2Citation4], being an independent determinant of quality of life impairment, in particular in the advanced phases of the disease [Citation5]. The most frequent symptom concerns orthostatic hypotension (OH), which could occur prior to the occurrence of motor symptoms and their pharmaceutical therapy [Citation3,Citation6Citation8], and in the course of the disease affects over half the patients [Citation2,Citation3].

2. Cardiovascular symptoms in PD

The causes of cardiovascular symptoms in PD have not yet been conclusively identified, the central neurodegenerative process may play a role, but the peripheral (sympathetic efferent, postganglionic) dysfunction is even more important [Citation9,Citation10]. Disturbances in hormonal regulation are likewise of relevance, in both central and peripheral symptomatology. Thus in active orthostasis patients present with a distinct reduction in norepinephrine rise in the serum [Citation11]. Disturbed functioning in the post-ganglionic sympathetic efferences, though to date not yet sufficiently described, is of significance here as well [Citation8]. In the meantime, one tentative explanation involves systemic sympathetic denervation, although varying in degree of expression and distribution. In view of the fact that PD is predominantly a disease that affects the elderly, there are of course frequent comorbidities to be expected. We also have to take interaction between medications and contraindications into consideration. The most frequent cardiological comorbidity involves arterial hypertension.

3. Diagnostics in arterial hypertension

The association between arterial hypertension (AH) and PD remains controversial [Citation12]. AH is even discussed as a risk factor for PD [Citation12].

Adjusting blood pressure in PD patients always requires checking for possible disturbances in their circadian blood pressure regulation and for OH. Many PD patients, and in particular those affected by cardiovascular dysautonomia, are so-called non-dippers [Citation13Citation15], meaning that they lack nocturnal blood pressure reduction. Once again this state has not yet been sufficiently explained. Tentatively we assume a disturbance in the circadian rhythm, which thus makes 24-hour blood pressure (BP) measurements necessary before initiating therapy. Unfortunately, there is too little ambulatory BP measurement and accordingly the non-dipper behavior is overlooked, which also has prognostic consequences.

For checking on possible OH, the so-called Schellong-test (lying-to-standing orthostatic test, after sufficient time of lying down, at least 10 minutes) can be well recommended: it easily reveals any frequent significant decreases in blood pressure and also whether the blood pressure fails to recover within the first ten minutes after tilt up [Citation3]. The tilt table examination is easier to standardize, but is not available everywhere. The Schellong test is sufficient for the clinical question, especially since it also reflects the conditions in everyday life.

At present there is controversy as to the association with type and duration of the disease. An OH can occur simultaneously with or prior to motor symptoms [Citation6,Citation8,Citation13]. The pharmaceutical therapy of PD itself is viewed as an essential factor in OH. While these factors contribute essentially to the problem, there continue to be underestimated in many cases. Our studies have found no difference in the patients before and after levodopa therapy [Citation16]. If there is a hypotensive effect, for example of dopamine agonists, the first step toward effective BP control is to review antiparkinsonian treatment In apomorphine for example the effect can be attenuated by pre-administering a peripheral dopamine receptor antagonist (e.g. domperidone).

The diagnosis should also take into account that there are differences between normal ambulatory and office BP levels. Another problem in outpatient diagnostics occurs whenever resting blood pressure is taken after insufficient duration of resting, which leads to an inappropriately lower blood pressure measurement due precisely to the OH. For this reason, many PD patients with AH report having normal blood pressure. A topic that could well be discussed involves whether or not supine hypertension is a distinct type of reaction and not a typical type of AH [Citation14]. Nevertheless supine hypertension is linked to OH in chronic autonomic failure, and probably also in PD [Citation17].

4. Therapy of arterial hypertension (AH)

Because AH is frequent in higher age groups, many PD patients are implicated. Pharmaceutical treatment thus has to select a substance which does not aggravate the symptoms of PD or those of OH. If antihypertense drugs are given in the morning, for example, this will aggravate OH while at night blood pressure will increase. Adjusting for blood pressure must take both aspects into consideration. Medications that can induce OH (such as alpha-blockers, molsidomine, nitroglycerin or naftidrofuryl) should only be given with special attention and with the appropriate controls for blood pressure [Citation14,Citation18]. Use of beta-blockers as anti-hypertensives should principally be given critical review due to the fact that the preexisting adrenergic deficit is reinforced [Citation3,Citation14]. If the prescription of beta-blockers is indispensable, e.g. for atrial fibrillation, the substance should be given at night. Restrictions also exist for diuretics, which are indicated only for cardiac insufficiency. Otherwise, they should be avoided as they aggravate OH [Citation3,Citation14]. It would clearly be counterproductive to increase liquid intake in the hopes of treating OH while at the same time prescribing diuretics as antihypertensives.

The joint occurrence of AH or supine hypertension and OH is a dilemma, because they are hemodynamic opposites: improvement of one is accomplished only at the expense of the other [Citation14,Citation19]. One argument to treat hypertension is that prevention of the long-term consequences of hypertension, which might be similar to those seen in people without PD, should be a priority [Citation14]. On the other hand, untreated AH can cause pressure natriuresis and nocturia, which ultimately result in volume depletion and worsening of neurogenic OH [Citation14].

For treating OH fludrocortisone or the alpha-receptor agonist midodrine are recommended [Citation20]. Both substances only raise blood pressure and are thus symptomatic interventions, without substantially treating OH. A preexisting AH is thereby increased. Alternatively, the use of pyridostigmine can be discussed [Citation21,Citation22], but controlled studies are to date lacking. Nonpharmacologic measures for the treatment of OH is very helpful, but even for supine hypertension it is helpful and can be recommended [Citation22].

In the treatment of AH in PD antihypertensives containing moxonidine, alpha-methyldopa or reserpine [Citation2,Citation18,Citation23] are contraindicated. Verapamil, diltiazem, amlodipine and nifedipine should not be combined with levodopa. Amlodipine was reported to induce Parkinson symptoms [Citation24], not confirmed in several studies [Citation25,Citation26]. On the other hand some molecules used as antihypertensives are discussed as disease-modifying drugs [Citation25,Citation26] Negative influence on the PD results from preparations containing reserpine [Citation2,Citation18]. Combinations of guanethidine with dopaminergic agents often results in arrhythmias [Citation18]. The effect of molsidomine is reinforced in combination with levodopa [Citation18,Citation23].

5. Edema of the lower leg and PD

Edema of the lower leg can have numerous causes in patients at advanced ages, among them right heart insufficiency and lymphedema. But for PD patients the side effects of dopamine agonists are probably the most frequent causes. Exclusion diagnostics have to be performed in all cases, whereby therapy must not be oriented purely symptomatically, that is, by prescribing diuretics, which would not only be less effective but in fact counterproductive, as, for example, OH would be reinforced. All medications which induce edema should be substituted, even fludrocortisone may induce leg edema.

6. Consequences for medical therapy

In patients with AH, the first step toward effective BP control is to review antiparkinsonian treatment. General recommendations for treating AH [Citation27] do not apply to PD patients, because we have to differentiate between hypertension that appears only when supine, in contrast to essential hypertension. In PD patients with essential hypertension monotherapy should initially be preferred because of their polypharmacy and because of possible interactions. Preference should be given to either isradipine (from the group of calcium antagonists) or sartans (Angiotensin II receptor blocker). Subsequently, ACE blockers can be applied. Calcium blockers are complicated because of inducing edema of the leg and constipation and are thus not recommended medication alternatives. Beta-blockers and diuretics can only be used with particular caution and then only with additional indications such as auricular fibrillation and cardiac insufficiency. Recommend drugs for supine hypertension associated with neurogenic orthostatic hypotension are e.g. captopril, losartan, or nitroglycerin [Citation22].

When antihypertensive drugs are prescribed, patients should be warned about the increased risk of hypotension and falls [Citation22].

7. Expert opinion

To date, many non-motor symptoms in PD have been insufficiently studied. Rather, the standard explanations developed for viewing the corresponding symptoms in other patient groups have simply been transferred to PD patients without considering the specific nature of this disease. This holds true for arterial hypertension (AH) when it occurs comorbid with PD. The diagnostic key opinion in this field so far is that in PD patients orthostatic hypertension (OH) and non-dipper reactions are concurrent. In that view it would be insufficient to take single measures of blood pressure, and only 24-hour long-term blood pressure measurements (ambulatory if possible) and the Schellong-test are called for. These alone would quarantee a reliable analysis. The weakness of all the studies and recommendions here is that larger studies on blood pressure behavior in PD populations and sub-groups are completely lacking.

One additional requirement would entail considering all medications which the patient is taking and which can have influence on his or her blood pressure. After that, a recommendation should ensue as to just which antihypertensive is opportune. And in this case the guidelines for treating AH should not be given precedence, first and foremost it is the basic underlying disease that has to have prior consideration. Thus OH has to be treated, and beta-blockers and diuretics should be avoided and likewise of course any medications that could aggravate the PD symptoms or that are contraindicated due to possible unwanted interactions with PD specific medications. However, on just this point it has to be reminded that there are no studies on the interactions between taking several different medications and patients with PD plus AH, and PD patients with such hypertension already take a large spectrum of pharmaceuticals.

Studies are clearly needed which examine on the one hand AH (supine and/or essential) in PD and on the other specific therapeutic possibilities. We have to remind ourselves that PD involves a multi-system degeneration. Because in PD a degenerative process affects the autonomic nervous system the results of studies on other classifications of hypertension cannot be transferred automatically to PD patients, especially when adrenegic/noradrenergic transmission is involved. The ultimate goal in this field would entail establishing an individual „PD-specific“ antihypertensive therapy. Successful approaches have been taken with novel therapies like baroreflex stimulation or inhibition.

The biggest challenge, however, is the fact that PD patients do not constitute a homogenous disease entity. There are clearly different clinical courses, both for the motor and the non motor symptoms, and in addition a plethora of possible drug combinations. Controlling for the different subgroups would be an impossible undertaking. If we finally succeed in classifying the different groups of patients with PD we will reach our goal. This will necessitate working on genetically determined subgroups as well as on, for example, patients with different results in MIBG scintigraphy. The corresponding patient collectives, however, can only be collected through large-scale networks and this fact already indicates that the high cost of such a study will be a considerable problem. In a second step financing the corresponding therapy will then have to be clarified. A high-graded individual antihypertensive therapy is definitely more costly than the prescription of the hypertensive medications already available on the market today. But it is apparent that the future belongs to just this individualized therapy.

A considerable number of basic and as yet unsolved questions is still prevalent in the pathophysiology of PD, and this is particularly the case for cardiovascular symptoms: What is the ultimate cause of the disease, where does it essentially begin, what role do the catecholamines and the central and peripheral autonomic nervous systems play here? Quite possibly we will attain new insights into the pathophysiology of PD by precisely studying its cardiovascular symptoms and vice versa. I appreciate full well the fact that work on the gastrointestinal symptoms of PD has led to a variety of new approaches for studying its pathophysiology and developing reliable diagnostics and therapies and I am just as convinced that this will also hold for intensive investigation of the cardiovascular symptoms. The ultimate goal will always be the optimal therapy for our patients.

Declaration of Interest

W Jost has served as an advisor and speakear for AbbVie, Allergan, Bial, Ipsen, UCB Pharma, Zambon, Desitin, and Merz. He has no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Reviewer Disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This manuscript was not funded.

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