Peripheral dopaminergic blockade for the treatment of diabetic orthostatic hypotension

This study was designed to evaluate the effects of domperidone, a peripheral dopaminergic antagonist, in diabetic patients with symptomatic orthostatic hypotension. Nine patients were admitted to the hospital, placed on a diet containing 150 mEq sodium, and studied for periods of 4 hours, on different days, in the following conditions: (1) supine position, (2) upright posture (UP), (3) UP after 10 mg domperidone, intravenously in bolus, and (4) UP after 3 days of domperidone, 30 mg orally. Before domperidone the mean blood pressure observed in supine position of 132 +/- 37/75 +/- 6 mm Hg fell to 75 +/- 22/57 +/- 13 mm Hg after 2 hours in UP. Acute domperidone did not change the blood pressure response to UP. After 3 days of oral domperidone and in UP for 2 hours, the mean blood pressure value of 89 +/- 21/61 +/- 8 mm Hg was higher than that before domperidone (p less than 0.05), with relief of symptoms in all patients. This blood pressure response to UP has been maintained in six patients who completed 6 months of therapy. No differences were observed in plasma renin activity, aldosterone, sodium, and potassium and in 4-hour urinary excretion of aldosterone, epinephrine, norepinephrine, and dopamine, determined during the UP tests. Administration of domperidone for 3 days reduced the falls in creatinine clearance and the urinary excretion of sodium and potassium induced by UP but did not alter the blood pressure and aldosterone dose-response curves to angiotensin II. Although the mechanism of action is not defined, it is concluded that domperidone is effective for the treatment of orthostatic hypotension in patients with diabetes.     

Severe orthostatic hypotension in a diabetic patient may not be due to diabetic autonomic neuropathy

This lesson describes an unusual case of a man who was recently diagnosed with type 1 diabetes and who presented with severe orthostatic hypotension. As his diabetes was recent in onset, well controlled, and he had no other signs of microvascular disease, other causes of orthostatic hypotension were sought. His serum and cerebrospinal fluid were strongly positive for Borrelia burgdorferi IgG, suggesting a diagnosis of Lyme neuroborreliosis. Autonomic instability in Lyme, while rare, has been previously reported.     

Droxidopa in neurogenic orthostatic hypotension

Neurogenic orthostatic hypotension (nOH) is a fall in blood pressure (BP) on standing due to reduced norepinephrine release from sympathetic nerve terminals. nOH is a feature of several neurological disorders that affect the autonomic nervous system, most notably Parkinson disease (PD), multiple system atrophy (MSA), pure autonomic failure (PAF), and other autonomic neuropathies. Droxidopa, an orally active synthetic amino acid that is converted to norepinephrine by the enzyme aromatic L-amino acid decarboxylase (dopa-decarboxylase), was recently approved by the FDA for the short-term treatment of nOH. It is presumed to raise BP by acting at the neurovascular junction to increase vascular tone. This article summarizes the pharmacological properties of droxidopa, its mechanism of action, and the efficacy and safety results of clinical trials.     

Idiopathic orthostatic hypotension (IOH) and sympathotonic orthostatic hypotension (SOH)]

IOH occurs as progressive autonomic failure (PAF) without any neurologic symptoms indicating multiple system atrophy or Parkinson's disease. The responsible lesion for IOH is yet obscure but has been suggested to be in the peripheral sympathetic nerves, since postganglionic sympathetic neurons in IOH fail to release norepinephrine and there present extensive supersensitivities to exogenous pressors. SOH is characterized as marked tachycardia induced by hypotensive stress like standing, and is less sensitive to the administered catecholamines. Careful examinations by some pharmacological studies are essential to diagnose IOH and SOH in patients with orthostatic hypotension.     

Severe orthostatic hypotension in carcinoma of the pancreas.

Autonomic dysfunction has been described in patients with advanced forms of cancer. We report a case of severe orthostatic hypotension in a patient with carcinoma of the pancreas in whom there was no clinical evidence of autonomic failure to account for the severity of the hypotension. Despite normal circulating levels of nor-adrenalin and an appropriate rise in the erect position, the vascular system appeared unresponsive. We suggest that in this patient the orthostatic hypotension was due to a paraneoplastic complication of the pancreatic tumour.     

Aging and susceptibility to drug-induced orthostatic hypotension.

OBJECTIVE: To test the hypothesis that the short-term effect of transbuccal nitroglycerin (glyceryl trinitrate, 0.0625 to 1.5 mg) on orthostatic cardiovascular responses would predict the effect of a diuretic (5 mg bendroflumethiazide daily for 1 week), particularly in elderly subjects who may be at higher risk for orthostatic hypotension. METHODS: This was a randomized crossover study. Participants were 17 elderly (age range, 63 to 84 years) and 15 younger (age range, 19 to 35 years) healthy ambulant volunteers. Interventions and measures of outcome included blood pressure (BP; in millimeters of mercury) and heart rate (HR; in beats per minute) changes with standing, which were measured before administration of medication and after each drug treatment. RESULTS: Subjects in the elderly and younger groups had different BP and HR changes (mean percentage change) at 1 minute after standing in all three study phases (unmedicated, elderly: BP, -4%/+1%; HR, +12%; young: BP, +2%/+12%; HR, +27%; p = 0.06 for BP, p less than 0.01 for HR; bendroflumethiazide, elderly: BP, -9%/-3%; HR, +17%; young: BP, +1%/+11%; HR, +33%; p less than 0.05 for all; nitroglycerin (0.25 mg), elderly: BP, -15%/-12%; HR, +21%; young: BP, -6%/+7%; HR, +38%; p less than 0.05 for all). The incremental orthostatic effects of the two drugs were similar in the two age groups and were positively correlated (r = 0.65, p less than 0.001) in individual subjects. CONCLUSIONS: Individual susceptibility to drug-induced orthostatic hypotension depends on a combination of the age-related unmedicated orthostatic response and the additional drug effect, which is independent of age. The BP response to standing after administration of nitroglycerin may be useful in predicting the effect of other drugs known to influence orthostatic BP control.     

Afferent baroreflex dysfunction and age-related orthostatic hypotension.

1. To test the hypothesis that in apparently healthy elderly subjects with orthostatic hypotension there is afferent baroreflex dysfunction, cardiovascular and neurohumoral responses were measured after separate stimuli which activated baroreceptor (head-up tilt) and non-baroreceptor (cold stress, isometric exercise) afferent pathways. 2. In 15 healthy elderly control subjects blood pressure did not change with 60 degrees head-up tilting and there was a moderate increase in heart rate, whereas in 13 subjects with age-related orthostatic hypotension head-up tilting was associated with a marked fall in blood pressure but a similar heart rate response to that in the elderly control group. In contrast, both groups of subjects had similar blood pressure and heart rate responses to cold stress and sustained isometric exercise. 3. Nine subjects with autonomic neuropathy also showed a marked hypotensive response to head-up tilt, but produced no pressor response to cold stress or isometric exercise. 4. The plasma concentrations of noradrenaline, adrenaline and neuropeptide-Y-like immunoreactivity rose and that of atrial natriuretic peptide fell after head-up tilt in the study population as a whole. There were no significant differences between groups despite the much greater blood pressure drops in the subjects with autonomic neuropathy and in those with age-associated orthostatic hypotension. 5. The aorto-iliac pulse wave velocity index was significantly higher in subjects with age-associated orthostatic hypotension compared with that in control subjects. 6. The pattern of responses to the separate stresses observed in the group with age-associated orthostatic hypotension is characteristic and different from that in the elderly control subjects and the subjects with autonomic neuropathy.(ABSTRACT TRUNCATED AT 250 WORDS)     

Management of orthostatic hypotension in the elderly

Orthostatic hypotension (OH) is a common health problem that affects 6% to 30% of the community-dwelling elderly. OH prevalence has been found to increase with age, influence the individual's quality of life, and be associated with increased rates of morbidity and mortality. Referencing evidence-based reports, the aim of the present article was to construct an OH management protocol for the elderly with OH. Causes of OH can be generally divided into recoverable and unrecoverable types. Recoverable types refer to OH conditions in which the patient's original health status can be restored following treatment. If such cannot be achieved, medical staffs must consider the possibility of an underlying unrecoverable factor. To treat unrecoverable OH, non-pharmacological intervention should be applied first. If such fails, then pharmacological interventions should be considered. Whether recoverable or unrecoverable, OH treatment should control acute health problems and follow general prevention principles. Nursing staffs play a crucial role in OH treatment. This proposed protocol may assist clinical nursing staffs to provide more appropriate elderly care.     

Adrenergic supersensitivity in Parkinsonians with orthostatic hypotension

The adrenergic status was studied through evaluation of platelet alpha 2-adrenoceptor number [( 3H]yohimbine binding sites), plasma catecholamine levels and blood pressure response to noradrenaline infusion in three groups of subjects (1) Parkinsonians with orthostatic hypotension; (2) Parkinsonians without orthostatic hypotension; and (3) control subjects. In Parkinsonians with orthostatic hypotension, systolic and diastolic blood pressures significantly (P less than 0.05) decreased from 144 +/- 9 and 76 +/- 6 mmHg in the lying position to 95 +/- 12 and 60 +/- 7 mmHg after 5 min standing. In these patients, noradrenaline plasma levels were significantly low (62 +/- 11 pg ml-1, (P less than 0.05) when compared with controls (219 +/- 13 pg ml-1) whereas no difference was noticed in Parkinsonians without orthostatic hypotension (195 +/- 14 pg ml-1). The noradrenaline dose required for a 25 mmHg increase in systolic blood pressure was significantly (P less than 0.01) lower in Parkinsonians with orthostatic hypotension (0.19 +/- 0.03 microgram kg-1) when compared with Parkinsonians without orthostatic hypotension (0.86 +/- 0.11 microgram kg-1) or with controls (0.68 +/- 0.1 microgram kg-1). Platelet alpha 2-adrenoceptor number was higher in Parkinsonians with orthostatic hypotension (313 +/- 52 fmol mg-1 protein) than in Parkinsonians without orthostatic hypotension (168 +/- 9 fmol mg-1 protein) or in controls (175 +/- 4 fmol mg-1 protein) with no change in Kd. This study demonstrates that in patients with Parkinson's disease, orthostatic hypotension is associated with an increase in both vascular sensitivity to noradrenaline and platelet alpha 2-adrenoceptor number.(ABSTRACT TRUNCATED AT 250 WORDS)     

Evaluation and management of orthostatic hypotension

Orthostatic hypotension is defined as a decrease in systolic blood pressure of 20 mm Hg or a decrease in diastolic blood pressure of 10 mm Hg within three minutes of standing when compared with blood pressure from the sitting or supine position. It results from an inadequate physiologic response to postural changes in blood pressure. Orthostatic hypotension may be acute or chronic, as well as symptomatic or asymptomatic. Common symptoms include dizziness, lightheadedness, blurred vision, weakness, fatigue, nausea, palpitations, and headache. Less common symptoms include syncope, dyspnea, chest pain, and neck and shoulder pain. Causes include dehydration or blood loss; disorders of the neurologic, cardiovascular, or endocrine systems; and several classes of medications. Evaluation of suspected orthostatic hypotension begins by identifying reversible causes and underlying associated medical conditions. Head-up tilt-table testing can aid in confirming a diagnosis of suspected orthostatic hypotension when standard orthostatic vital signs are nondiagnostic; it also can aid in assessing treatment response in patients with an autonomic disorder. Goals of treatment involve improving hypotension without excessive supine hypertension, relieving orthostatic symptoms, and improving standing time. Treatment includes correcting reversible causes and discontinuing responsible medications, when possible. Nonpharmacologic treatment should be offered to all patients. For patients who do not respond adequately to nonpharmacologic treatment, fludrocortisone, midodrine, and pyridostigmine are pharmacologic therapies proven to be beneficial.