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Pharmacotherapy of Cardiovascular Autonomic Dysfunction in Parkinson Disease.

ABSTRACT: Cardiovascular autonomic dysfunctions, including neurogenic orthostatic hypotension, supine hypertension and post-prandial hypotension, are relatively common in patients with Parkinson disease. Recent evidence suggests that early autonomic impairment such as cardiac autonomic denervation and even neurogenic orthostatic hypotension occur prior to the appearance of the typical motor deficits associated with the disease. When neurogenic orthostatic hypotension develops, patients with Parkinson disease have an increased risk of mortality, falls, and trauma-related to falls. Neurogenic orthostatic hypotension reduces quality of life and contributes to cognitive decline and physical deconditioning. The co-existence of supine hypertension complicates the treatment of neurogenic orthostatic hypotension because it involves the use of drugs with opposing effects. Furthermore, treatment of neurogenic orthostatic hypotension is challenging because of few therapeutic options; in the past 20 years, the US Food and Drug Administration approved only two drugs for the treatment of this condition. Small, open-label or randomized studies using acute doses of different pharmacologic probes suggest benefit of other drugs as well, which could be used in individual patients under close monitoring. This review describes the pathophysiology of neurogenic orthostatic hypotension and supine hypertension in Parkinson disease. We discuss the mode of action and therapeutic efficacy of different pharmacologic agents used in the treatment of patients with cardiovascular autonomic failure.

SUBMITTER: Shibao CA

PROVIDER: S-EPMC5809001 | biostudies-literature | 2017 Nov

REPOSITORIES: biostudies-literature

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Pharmacotherapy of Cardiovascular Autonomic Dysfunction in Parkinson Disease.

Shibao Cyndya A CA Kaufmann Horacio H

CNS drugs 20171101 11

Cardiovascular autonomic dysfunctions, including neurogenic orthostatic hypotension, supine hypertension and post-prandial hypotension, are relatively common in patients with Parkinson disease. Recent evidence suggests that early autonomic impairment such as cardiac autonomic denervation and even neurogenic orthostatic hypotension occur prior to the appearance of the typical motor deficits associated with the disease. When neurogenic orthostatic hypotension develops, patients with Parkinson dise ...[more]

PMID: 29076058

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Project description:Importance:Evidence suggests that development of autonomic dysfunction (AutD) may negatively affect disease course and survival in patients with synucleinopathies. However, the few available studies on Parkinson disease (PD) have conflicting results, comprise a small number of patients, have short follow-up periods, and lack pathologic confirmation of the diagnosis. Objective:To examine the association of time of onset of AutD with disease progression and survival in PD. Design, Setting, and Participants:This retrospective review of clinical data from 100 consecutive patients with an autopsy-confirmed diagnosis of PD from the archives of the Queen Square Brain Bank in London, United Kingdom, from January 1, 2006, to June 3, 2016, included patients with PD regularly seen by hospital specialists (neurologists or geriatricians) in the United Kingdom throughout their disease until death. Patients with dementia before or within 1 year after onset of motor symptoms, monogenic forms of PD, comorbidities that affect autonomic function, a coexisting neuropathologic diagnosis, or insufficient clinical information were excluded. Main Outcomes and Measures:Survival and time from diagnosis to specific disease milestones were calculated to assess disease progression. Autonomic dysfunction was defined as autonomic failure at autonomic function testing or 2 of the following symptoms: urinary symptoms, constipation, upper gastrointestinal tract dysfunction, orthostatic hypotension, sweating abnormalities, or erectile dysfunction. Multivariable Cox proportional hazards regression models on the risk of a disease milestone and death were used. Results:A total of 100 patients (60 [60.0%] male; mean [SD] age at diagnosis, 63.9?[10.3] years; mean [SD] disease duration, 14.6?[7.7] years) were studied. Autonomic dysfunction developed in 85 patients (mean [SD] time from diagnosis, 6.7?[7.7] years) and was associated with older age at diagnosis, male sex, poor initial levodopa treatment response, and postural instability and gait difficulty motor PD subtype in linear regression analysis, but staging of ?-synuclein pathologic changes was unrelated. Earlier AutD increased the risk of reaching the first milestone (hazard ratio, 0.86; 95% CI, 0.83-0.89; P?<?.001) and shortened survival (hazard ratio, 0.92; 95% CI, 0.88-0.96; P?<?.001). Older age at diagnosis and poorer levodopa treatment response were the other factors associated with shorter survival in adjusted multivariate analysis. Conclusions and Relevance:Earlier AutD is associated with a more rapid development of disease milestones and shorter survival in patients with PD.

Project description:Background: Clozapine is the antipsychotic of choice for treatment-resistant schizophrenia and has minimal risk for extrapyramidal symptoms. Therapeutic benefits, however, are accompanied by a myriad of cardiometabolic side-effects. The specific reasons for clozapine's high propensity to cause adverse cardiometabolic events remain unknown, but it is believed that autonomic dysfunction may play a role in many of these. Objective: This systematic review summarizes the literature on autonomic dysfunction and related cardiovascular side effects associated with clozapine treatment. Method: A search of the EMBASE, MEDLINE, and EBM Cochrane databases was conducted using the search terms antipsychotic agents, antipsychotic drug*, antipsychotic*, schizophrenia, schizophren*, psychos*, psychotic*, mental ill*, mental disorder*, neuroleptic*, cardiovascular*, cardiovascular diseases, clozapine*, clozaril*, autonomic*, sympathetic*, catecholamine*, norepinephrine, noradrenaline, epinephrine, adrenaline. Results: The search yielded 37 studies that were reviewed, of which only 16 studies have used interventions to manage cardiovascular side effects. Side effects reported in the studies include myocarditis, orthostatic hypotension and tachycardia. These were attributed to sympathetic hyperactivity, decreased vagal contribution, blockade of cholinergic and adrenergic receptors, reduced heart rate variability and elevated catecholamines with clozapine use. Autonomic neuropathy was identified by monitoring blood pressure and heart rate changes in response to stimuli and by spectral analysis of heart rate variability. Metoprolol, lorazepam, atenolol, propranolol, amlodipine, vasopressin and norepinephrine infusion were used to treat tachycardia and fluctuations in blood pressure, yet results were limited to case reports. Conclusion: The results indicate there is a lack of clinical studies investigating autonomic dysfunction and a limited use of interventions to manage cardiovascular side effects associated with clozapine. As there is often no alternative treatment for refractory schizophrenia, the current review highlights the need for better designed studies, use of autonomic tests for prevention of cardiovascular disease and development of novel interventions for clozapine-induced side effects.

Project description:Cardiovascular autonomic dysfunctions (CAD) are prevalent in Parkinson's disease (PD). It contributes to the development of cognitive dysfunction, falls and even mortality. Significant progress has been achieved in the last decade. However, the underlying mechanisms and effective treatments for CAD have not been established yet. This review aims to help clinicians to better understand the pathogenesis and therapeutic strategies. The literatures about CAD in patients with PD were reviewed. References for this review were identified by searches of PubMed between 1972 and March 2021, with the search term "cardiovascular autonomic dysfunctions, postural hypotension, orthostatic hypotension (OH), supine hypertension (SH), postprandial hypotension, and nondipping". The pathogenesis, including the neurogenic and non-neurogenic mechanisms, and the current pharmaceutical and non-pharmaceutical treatment for CAD, were analyzed. CAD mainly includes four aspects, which are OH, SH, postprandial hypotension and nondipping, among them, OH is the main component. Both non-neurogenic and neurogenic mechanisms are involved in CAD. Failure of the baroreflex circulate, which includes the lesions at the afferent, efferent or central components, is an important pathogenesis of CAD. Both non-pharmacological and pharmacological treatment alleviate CAD-related symptoms by acting on the baroreflex reflex circulate. However, pharmacological strategy has the limitation of failing to enhance baroreflex sensitivity and life quality. Novel OH treatment drugs, such as pyridostigmine and atomoxetine, can effectively improve OH-related symptoms via enhancing residual sympathetic tone, without adverse reactions of supine hypertension. Baroreflex impairment is a crucial pathological mechanism associated with CAD in PD. Currently, non-pharmacological strategy was the preferred option for its advantage of enhancing baroreflex sensitivity. Pharmacological treatment is a second-line option. Therefore, to find drugs that can enhance baroreflex sensitivity, especially via acting on its central components, is urgently needed in the scientific research and clinical practice.

Dataset Information

Pharmacotherapy of Cardiovascular Autonomic Dysfunction in Parkinson Disease.

Publications

Pharmacotherapy of Cardiovascular Autonomic Dysfunction in Parkinson Disease.

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