Orthostatic Hypotension in Adults With Hypertension: A Scientific Statement From the American Heart Association.

Although orthostatic hypotension (OH) has long been recognized as a manifestation of autonomic dysfunction, a growing body of literature has identified OH as a common comorbidity of hypertension. This connection is complex, related to pathophysiology in blood pressure regulation and the manner by which OH is derived as the difference between 2 blood pressure measurements. While traditional therapeutic approaches to OH among patients with neurodegenerative disorders focus on increasing upright blood pressure to prevent cerebral hypoperfusion, the management of OH among patients with hypertension is more nuanced; resting hypertension is itself associated with adverse outcomes among these patients. Although there is substantial evidence that intensive blood pressure treatment does not cause OH in the majority of patients with essential hypertension, some classes of antihypertensive agents may unmask OH in patients with an underlying autonomic impairment. Practical steps to manage OH among adults with hypertension start with (1) a thorough characterization of its patterns, triggers, and cause; (2) review and removal of aggravating factors (often pharmacological agents not related to hypertension treatment); (3) optimization of an antihypertensive regimen; and (4) adoption of a tailored treatment strategy that avoids exacerbating hypertension. These strategies include countermaneuvers and short-acting vasoactive agents (midodrine, droxidopa). Ultimately, further research is needed on the epidemiology of OH, the impact of hypertension treatment on OH, approaches to the screening and diagnosis of OH, and OH treatment among adults with hypertension to improve the care of these patients and their complex blood pressure pathophysiology.

Double-blinded, placebo-controlled crossover trial to determine the effects of midodrine on blood pressure during cognitive testing in persons with SCI.

STUDY DESIGN: Clinical trial. OBJECTIVES: Individuals with spinal cord injury (SCI) above T6 experience impaired descending cortical control of the autonomic nervous system, which predisposes them to hypotension. However, treatment of hypotension is uncommon in the SCI population because there are few safe and effective pharmacological options available. The primary aim of this investigation was to test the efficacy of a single dose of midodrine (10 mg), compared with placebo, to increase and normalize systolic blood pressure (SBP) between 110 and 120 mmHg during cognitive testing in hypotensive individuals with SCI. Secondary aims were to determine the effects of midodrine on cerebral blood flow velocity (CBFv) and global cognitive function. SETTING: United States clinical research laboratory. METHODS: Forty-one healthy hypotensive individuals with chronic (≥1-year post injury) SCI participated in this 2-day study. Seated SBP, CBFv, and cognitive performance were monitored before and after administration of identical encapsulated tablets, containing either midodrine or placebo. RESULTS: Compared with placebo, midodrine increased SBP (4 ± 13 vs. 18 ± 24 mmHg, respectively; p < 0.05); however, responses varied widely with midodrine (-15.7 to +68.6 mmHg). Further, the proportion of SBP recordings within the normotensive range did not improve during cognitive testing with midodrine compared with placebo. Although higher SBP was associated with higher CBFv (p = 0.02), global cognitive function was not improved with midodrine. CONCLUSIONS: The findings indicate that midodrine increases SBP and may be beneficial in some hypotensive patients with SCI; however, large heterogeneity of responses to midodrine suggests careful monitoring of patients following administration. CLINICAL TRIALS REGISTRATION: NCT02307565.

Efficacy of atomoxetine versus midodrine for neurogenic orthostatic hypotension.

OBJECTIVE: The efficacy and safety of 1-month atomoxetine and midodrine therapies were compared. Three-month atomoxetine and combination therapies were investigated for additional benefits. METHODS: This prospective open-label randomized trial included 50 patients with symptomatic neurogenic orthostatic hypotension (nOH). The patients received either atomoxetine 18 mg daily or midodrine 5 mg twice daily and were evaluated 1 and 3 months later. Those who still met the criteria for nOH at 1 month received both midodrine and atomoxetine for an additional 2 months, and if not, they continued their initial medication. The primary outcome was an improvement in orthostatic blood pressure (BP) drop (maximum BP change from supine to 3 min after standing) at 1 month. The secondary endpoints were symptom scores, percentage of patients with nOH at 1 and 3 months. RESULTS: Patients with midodrine or atomoxetine treatment showed comparative improvement in the orthostatic BP drop, and overall only 26.2% of the patients had nOH at 1 month, which was similar between the treatment groups. Only atomoxetine resulted in significant symptomatic improvements at 1 month. For those without nOH at 1 month, there was additional symptomatic improvement at 3 months with their initial medication. For those with nOH at 1 month, the combination treatment resulted in no additional improvement. Mild-to-moderate adverse events were reported by 11.6% of the patients. INTERPRETATION: One-month atomoxetine treatment was effective and safe in nOH patients. Atomoxetine improved orthostatic BP changes as much as midodrine and was better in terms of ameliorating nOH symptoms.

The behaviour of some antihypertension drugs on human serum paraoxonase-1: an important protector enzyme against atherosclerosis.

OBJECTIVES: Paraoxonase-1 (PON1) enzyme is related to high-density lipoprotein (HDL), which is calcium dependent. It has essential roles such as protecting LDL against oxidation and detoxification of highly toxic substances. It is a significant risk to reduce the levels of this enzyme in patients with diabetes mellitus, cardiovascular diseases, hyperthyroidism and chronic renal failure. METHODS: Here, it was reported that the purification of human serum PON1 using straightforward methods and determination of the interactions between some antihypertension drugs and the enzyme. KEY FINDING: It was found that these drugs exhibit potential inhibitor properties for human serum PON1 with IC50 values in the range of 131.40-369.40 µm and Ki values in the range of 56.24 ± 6.75-286.74 ± 28.28 µm. These drugs showed different inhibition mechanisms. It was determined that midodrine and nadolol were exhibited competitive inhibition, but atenolol and pindolol were exhibited non-competitive inhibition. CONCLUSION: Usage of these drugs would be hazardous in some cases.

The effect of single oral doses of duloxetine, reboxetine, and midodrine on the urethral pressure in healthy female subjects, using urethral pressure reflectometry.

AIMS: To evaluate the effect on urethral pressure of reference drugs known to reduce stress urinary incontinence symptoms by different effect size and mechanisms of action on urethral musculature under four test conditions in healthy female subjects using urethral pressure reflectometry. METHODS: Healthy females aged 18-55 years were recruited by advertising for this phase 1, single site, placebo-controlled, randomized, four-period, crossover study. The interventions were single oral doses of 10 mg Midodrine, 80 mg Duloxetine, 12 mg Reboxetine, and placebo. The endpoints were the opening urethral pressure measured in each period at four time points (predose and 2, 5.5, and 9 h after dosing). RESULTS: Twenty-nine females were enrolled; 25 randomized and 24 completed the study. The opening urethral pressure was higher in all measurements with filled bladder compared with empty bladder, and during squeezing compared to the resting condition. All three drugs increased the opening urethral pressure during all four conditions with a ranking of their effect on urethral pressure matching their reported clinical effect (difference vs. placebo at their reported time of peak plasma concentrations [Tmax ] during resting with filled bladder: Midodrine 9.3 cmH2 O [95%CI 3.0, 15.5], Duloxetine 24.2 cmH2 O [95%CI 17.9, 30.5], and Reboxetine 44.9 cmH2 O [95% CI 40.2, 52.8] cmH2 O). CONCLUSIONS: Urethral pressure reflectometry is capable of detecting drug-induced changes in urethral tone in various conditions. The magnitude of drug-induced changes by the test drugs seems to match their clinical profile and differences in mode of action.

Emerging hepatic syndromes: pathophysiology, diagnosis and treatment.

Liver cirrhosis is a major cause of morbidity and mortality worldwide, mainly due to complications of portal hypertension. In this article, we review the current understanding on the pathophysiology, the diagnostic criteria and the available therapeutic options for patients with emerging hepatic syndromes in cirrhosis, namely the hepatorenal, hepato-adrenal and hepatopulmonary syndrome. The hepatorenal syndrome is a well-recognized complication of advanced cirrhosis and is usually associated with an accelerated course to death unless liver transplantation is performed. The hepatopulmonary syndrome is often missed in the evaluation of patients with cirrhosis; however, early recognition is essential for the efficient management of individual patients. The hepato-adrenal syndrome, although not fully characterized, offers an exciting field for research and potential therapeutic interventions.

Effects of midodrine and L-NAME on systemic and cerebral hemodynamics during cognitive activation in spinal cord injury and intact controls.

We previously showed that increases in mean arterial pressure (MAP) following administration of midodrine hydrochloride (MH) and nitro-L-arginine methyl ester (L-NAME) resulted in increased mean cerebral blood flow velocity (MFV) during head-up tilt in hypotensive individuals with spinal cord injury (SCI) and question if this same association was evident during cognitive activation. Herein, we report MAP and MFV during two serial subtraction tasks (SSt) given before (predrug) and after (postdrug) administration of MH; (10 mg), L-NAME (1 mg/kg) or no drug (ND) in 15 subjects with SCI compared to nine able-bodied (AB) controls. Three-way factorial analysis of variance (ANOVA) models were used to determine significant main and interaction effects for group (SCI, AB), visit (MH, L-NAME, ND), and time (predrug, postdrug) for MAP and MFV during the two SSt. The three-way interaction was significant for MAP (F = 4.262; P = 0.020); both MH (30 ± 26 mmHg; P < 0.05) and L-NAME (27 ± 22 mmHg; P < 0.01) significantly increased MAP in the SCI group, but not in the AB group. There was a significant visit by time interaction for MFV suggesting an increase from predrug to postdrug following L-NAME (6 ± 8 cm/sec; P < 0.05) and MH (4 ± 7 cm/sec; P < 0.05), regardless of study group, with little change following ND (3 ± 3 cm/sec). The relationship between change in MAP and MFV was significant in the SCI group following administration of MH (r(2) = 0.38; P < 0.05) and L-NAME (r(2) = 0.32; P < 0.05). These antihypotensive agents, at the doses tested, raised MAP, which was associated with an increase MFV during cognitive activation in hypotensive subjects with SCI.

Diagnosing and treating neurogenic orthostatic hypotension in primary care.

In response to a change in posture from supine or sitting to standing, autonomic reflexes normally maintain blood pressure (BP) by selective increases in arteriovenous resistance and by increased cardiac output, ensuring continued perfusion of the central nervous system. In neurogenic orthostatic hypotension (NOH), inadequate vasoconstriction and cardiac output cause BP to drop excessively, resulting in inadequate perfusion, with predictable symptoms such as dizziness, lightheadedness and falls. The condition may represent a central failure of baroreceptor signals to modulate cardiovascular function, a peripheral failure of norepinephrine release from cardiovascular sympathetic nerve endings, or both. Symptomatic patients may benefit from both non-pharmacologic and pharmacologic interventions. Among the latter, two pressor agents have been approved by the US Food and Drug Administration: the sympathomimetic prodrug midodrine, approved in 1996 for symptomatic orthostatic hypotension, and the norepinephrine prodrug droxidopa, approved in 2014, which is indicated for the treatment of symptomatic neurogenic orthostatic hypotension caused by primary autonomic failure (Parkinson's disease, multiple system atrophy and pure autonomic failure). A wide variety of off-label options also have been described (e.g. the synthetic mineralocorticoid fludrocortisone). Because pressor agents may promote supine hypertension, NOH management requires monitoring of supine BP and also lifestyle measures to minimize supine BP increases (e.g. head-of-bed elevation). However, NOH has been associated with cognitive impairment and increases a patient's risk of syncope and falls, with the potential for serious consequences. Hence, concerns about supine hypertension - for which the long-term prognosis in patients with NOH is yet to be established - must sometimes be balanced by the need to address a patient's immediate risks.

Midodrine in patients with spinal cord injury and anejaculation: A double-blind randomized placebo-controlled pilot study.

OBJECTIVE: The objective of this study is to evaluate the efficacy of midodrine in the treatment of anejaculation in men with spinal cord injury (SCI). STUDY DESIGN: Prospective, double-blind, randomized, placebo-controlled pilot study. METHOD: Men with anejaculation associated with SCI (level of injury above T10) of more than 1 year in duration were approached. Those with no ejaculatory response to one penile vibratory stimulation (PVS) trial were assigned in a double-blind manner to one of the two following interventions once a week for a maximum of 3 weeks or until ejaculation occurred: oral administration of flexible midodrine (7.5-22.5 mg max) followed by PVS (group M), or oral administration of flexible sham-midodrine (placebo) followed by PVS (group P). Sociodemographic data, medical characteristics, and plasma desglymidodrine concentration were collected for all participants. OUTCOME MEASURE: Ejaculation success rate in each group. RESULTS: Among the 78 men approached, 23 participants (level of SCI: C4-T9) were randomized. Three participants abandoned the study and 20 completed the study; 10 were assigned to group M, 10 to group P. Ejaculation was reached for one participant of group M and for two participants of group P. Autonomic dysreflexia associated to PVS occurred in three patients. CONCLUSION: In this small sample study, treatment of anejaculation after SCI with midodrine and PVS did not result in a better rate of antegrade ejaculation in 10 men than in 10 men treated with a placebo and PVS.

New developments in the management of neurogenic orthostatic hypotension.

Orthostatic hypotension (OH) is defined as a sustained reduction of ≥ 20 mmHg systolic blood pressure or ≥ 10 mmHg diastolic blood pressure upon standing for ≤ 3 min. Orthostatic hypotension is commonly associated with hypertension, and its prevalence is highest in those with uncontrolled hypertension compared to those with controlled hypertension or normotensive community elderly subjects. Orthostatic hypotension can cause significant disability, with patients experiencing dizziness, lightheadedness or syncope, and other problems that potentially have a profound negative impact on activities of daily living that require standing or walking. Furthermore, OH increases the risk of falls and, importantly, is an independent risk factor of mortality. Despite its importance, there is a paucity of treatment options for this condition. Most of the advances in treatment options have relied on small studies of repurposed drugs done in patients with severe OH due to rare neurodegenerative conditions. Midodrine, an oral prodrug converted to the selective α1-adrenoceptor agonist desglymidodrine, was approved by the FDA for the treatment of OH in 1996. For almost two decades, no other pharmacotherapy was developed specifically for the treatment of OH until 2014, when droxidopa was approved by the FDA for the treatment of neurogenic OH associated with primary autonomic neuropathies including Parkinson disease, multiple system atrophy, and pure autonomic failure. These are neurodegenerative diseases ultimately characterized by failure of the autonomic nervous system to generate norepinephrine responses appropriate to postural challenge. Droxidopa is a synthetic amino acid that is converted to norepinephrine by dopa-decarboxylase, the same enzyme that converts levodopa into dopamine in the treatment of Parkinson disease. We will review this and other advances in the treatment of OH in an attempt to provide a practical guide to its management.

Increased central arterial stiffness explains baroreflex dysfunction in spinal cord injury.

After cervical spinal cord injury (SCI), orthostatic hypotension and intolerance commonly ensue. The cardiovagal baroreflex plays an important role in the acute regulation of blood pressure (BP) and is associated with the onset of presyncope. The cardiovagal baroreflex is dysfunctional after SCI; however, this may be influenced by either increased stiffening of the arteries containing the stretch-receptors (which has been shown in SCI) or a more downstream neural mechanism (i.e., solitary nucleus, sinoatrial node). Identifying where along this pathway baroreflex dysfunction occurs may highlight a potential therapeutic target. This study examined the relationship between spontaneous cardiovagal baroreflex sensitivity (BRS) and common carotid artery (CCA) stiffness in those with high level SCI before and after midodrine (alpha1-agonist) administration, as well as in able-bodied controls, to evaluate: (1) the role arterial stiffening plays mediating baroreflex function after SCI and (2) the effect of normalizing BP on these parameters. Three to five min recordings of beat-by-beat BP and heart rate, as well as 30 sec duration recordings of CCA diameter were used for analysis. All participants were tested supine and during upright-tilt. Arterial stiffness (ß-stiffness index) was elevated in those with SCI when upright (+12%; p<0.05). Further, ß-stiffness index was negatively related to reduced BRS in those with SCI when upright (R2=0.55; p<0.05), but not in able-bodied persons. Normalizing BP did not improve BRS or CCA stiffness. This study clearly shows that reduced BRS is closely related to increased arterial stiffness in the population with SCI.

MicroRNA changes in rat mesentery and serum associated with drug-induced vascular injury.

Regulatory miRNAs play a role in vascular biology and are involved in biochemical and molecular pathways dysregulated during vascular injury. Collection and integration of functional miRNA data into these pathways can provide insight into pathogenesis at the site of injury; the same technologies applied to biofluids may provide diagnostic or surrogate biomarkers. miRNA was analyzed from mesentery and serum from rats given vasculotoxic compounds for 4 days. Fenoldopam, dopamine and midodrine each alter hemodynamics and are associated with histologic evidence of vascular injury, while yohimbine is vasoactive but does not cause histologic evidence of vascular injury in rat. There were 38 and 35 miRNAs altered in a statistically significant manner with a fold change of 2 or greater in mesenteries of fenoldopam- and dopamine-dosed rats, respectively, with 9 of these miRNAs shared. 10 miRNAs were altered in rats given midodrine; 6 were shared with either fenoldopam or dopamine. In situ hybridization demonstrated strong expression and co-localization of miR-134 in affected but not in adjacent unaffected vessels. Mesenteric miRNA expression may provide clarity or avenues of research into mechanisms involved in vascular injury once the functional role of specific miRNAs becomes better characterized. 102 miRNAs were altered in serum from rats with drug-induced vascular injury. 10 miRNAs were commonly altered in serum from dopamine and either fenoldopam or midodrine dosed rats; 18 of these 102 were also altered in mesenteries from rats with drug-induced vascular injury, suggesting their possible utility as peripheral biomarkers.

Orthostatic effects of midodrine versus L-NAME on cerebral blood flow and the renin-angiotensin-aldosterone system in tetraplegia.

OBJECTIVE: To compare responses to head-up tilt (HUT) in individuals with chronic tetraplegia after midodrine hydrochloride (10 mg) versus nitro-L-arginine methyl ester (L-NAME, 1 mg/kg) administration. DESIGN: Prospective comparative drug trial. SETTING: Veterans Affairs medical center. PARTICIPANTS: Participants (N=7) were studied during 3 laboratory visits: no drug, midodrine (administered orally 30 min before HUT), and L-NAME (infused over a 60-min period). INTERVENTIONS: Anti-hypotensive agents, midodrine, and L-NAME. MAIN OUTCOME MEASURES: Mean arterial pressure (MAP), cerebral blood flow (CBF), and markers of the renin-angiotensin-aldosterone system (RAAS, plasma renin and serum aldosterone) were measured in the supine position at baseline (BL) and during a 45° HUT maneuver. Data were compared between BL and the average of 3 assessments collected during HUT. RESULTS: Orthostatic MAP and CBF were increased with the midodrine and L-NAME groups compared with the no drug trial and the relationship between the change in MAP and CBF was significant (r=0.770; P<0.001). Both L-NAME and midodrine appeared to suppress the post-HUT RAAS response compared with no drug. CONCLUSIONS: Increasing orthostatic blood pressure with L-NAME or midodrine appears to increase CBF and suppress the RAAS during HUT in persons with tetraplegia, although more data are needed to confirm these preliminary findings.

Effects of promethazine and midodrine on orthostatic tolerance.

INTRODUCTION: Astronauts experience both orthostatic hypotension and space motion sickness during re-entry. Midodrine, an alpha1-adrenergic agonist, is used to treat orthostatic hypotension. Promethazine, a histamine H1-receptor antagonist, is prescribed for space motion sickness. Many astronauts need both midodrine and promethazine. This study evaluated the interactive effects of midodrine and promethazine on hemodynamic responses to upright tilt. METHODS: Subjects (5 men; 3 women) were studied four times: control (no drug); midodrine only; promethazine only; or midodrine plus promethazine. Hemodynamic parameters, plasma norepinephrine, renin activity, and aldosterone were measured supine and upright. RESULTS: Rates of presyncope were 38% with no drug; 0% with midodrine alone; 100% with promethazine alone; and 63% with both drugs. Supine to upright decreases in systolic pressure were greater with promethazine alone than control (P < 0.01); midodrine (P < 0.05) or both drugs (P < 0.05). Supine to upright increases in plasma norepinephrine, renin activity, and aldosterone all were significantly reduced with promethazine alone compared to control (P < 0.05, P < 0.05, P < 0.05) and midodrine alone (P < 0.05, P < 0.01, P < 0.01). Cardiac output fell more with promethazine alone than with no drug (P < 0.05) or with midodrine plus promethazine (P < 0.05). DISCUSSION: Promethazine significantly increased the incidence of orthostatic hypotension in subjects, even when combined with midodrine. Inhibition of sympathetic responses, likely via enhancement of the inhibitive effects of GABA, by promethazine may underlie the increased orthostatic hypotension. Promethazine also appears to inhibit responses of the renin angiotensisn system during orthostatic challenge.

The effects of midodrine on the natriuretic response to furosemide in cirrhotics with ascites.

BACKGROUND: Resistance to loop diuretics is common in patients with ascites. Diminished glomerular filtration rate (GFR) is thought to mediate resistance to loop diuretics. Midodrine, a commonly used alpha-1 agonist, has been shown to improve GFR in non-azotemic patients with cirrhosis. AIM: To conduct a randomized, double-blind, placebo-controlled, cross-over study to test the hypothesis that midodrine significantly increases natriuretic response of IV furosemide in non-azotemic cirrhotics with ascites. METHODS: All subjects participated in both phases, which were (i) furosemide IV infusion + oral midodrine 15 mg administered 30 min before furosemide (ii) furosemide IV infusion + oral placebo administered 30 min before furosemide. Primary outcomes were 6-h urine sodium excretion and 6-h total urine volume. RESULTS: A total of 15 patients (men: 8; age: 52.7 ± 7.6 years; serum creatinine: 1.06 ± 0.2 mg/dL) were studied. Total 6-h urine sodium excretion was 109 ± 42 mmol in the furosemide + midodrine treatment phase and was not significantly different from that in the furosemide + placebo treatment phase (126 ± 69 mmol, P = 0.6). Similarly, mean 6-h total urine volume was not significantly different between two groups (1770 ± 262 mL vs. 1962 ± 170 mL, P = 0.25). CONCLUSIONS: Oral midodrine does not increase the natriuretic response to furosemide in non-azotemic cirrhotic patients with ascites. Orally administered midodrine does not increase natriuretic response to furosemide in non-azotemic cirrhotic patients with ascites.

Effects of midodrine hydrochloride on blood pressure and cerebral blood flow during orthostasis in persons with chronic tetraplegia.

OBJECTIVE: To determine the mean arterial pressure (MAP) and middle cerebral artery mean blood flow velocity (MFV) responses to 5 and 10mg midodrine during head-up tilt (HUT) in persons with tetraplegia. DESIGN: Prospective dose-response trial. SETTING: James J. Peters Veterans Administration Medical Center. PARTICIPANTS: Persons (N=10) with chronic tetraplegia (duration of injury=23+/-11 y). INTERVENTION: A dose titration study was performed over 3 testing days: control (no drug), 5mg midodrine (5mg), or 10mg midodrine (10mg) during 30 minutes of baseline (predrug/no drug), 30 minutes of supine rest postdrug/no drug, 15 minutes of progressive HUT (5 minutes at 15 degrees , 25 degrees , 35 degrees ), and 45 minutes of 45 degrees HUT. MAIN OUTCOME MEASURES: MAP and MFV response to midodrine supine and during HUT. RESULTS: Ten milligrams of midodrine significantly increased MAP while supine and during the HUT maneuver. Of note, the mean increase in MAP during HUT with 10mg was a result of a robust effect in 2 persons, with minimal change in the remaining 8 study subjects. The reduction in cerebral MFV during HUT was attenuated with 10mg. CONCLUSIONS: These findings suggest that midodrine 10mg may be efficacious for treatment of hypotension and orthostatic hypotension in select persons with tetraplegia. Although midodrine is routinely prescribed to treat orthostatic hypotension, the results of our work suggests limited efficacy of this agent, but additional studies in a larger sample of subjects with spinal cord injury should be performed.

Hemodynamic determinants of chronic hypotension and their modification through vasopressor application.

Chronic low blood pressure is typically accompanied by symptoms such as fatigue, reduced drive, dizziness, headaches and cold limbs. Reduced cognitive performance, diminished cerebral blood flow and autonomic dysregulation have been furthermore documented in this condition. The present contribution reports two studies exploring systemic hemodynamics in chronic hypotension and their modification through vasopressor application. In study I, effects of the alpha-sympathomimetic midodrine were examined in 54 hypotensive individuals using a placebo-controlled double-blind design. Hemodynamic parameters were assessed at rest and during mental stress. They were derived from continuous blood pressure recordings using Modelflow analysis. The drug led to marked increases in blood pressure, total peripheral resistance and stroke volume. However, due to strong heart rate deceleration, cardiac output remained virtually unchanged. In study II, 40 hypotensive and 40 normotensive control persons were compared with respect to hemodynamics. While groups did not differ in total peripheral resistance, hypotensives exhibited markedly diminished stroke volume and heart rate, resulting in a reduction in cardiac output of 25% at rest and of 33% during mental stress. The data provide relevant knowledge about the hemodynamic mediation of chronic hypotension. In contrast to elevated blood pressure, which is mainly determined by increased peripheral resistance, reduced cardiac output may be the cardinal hemodynamic aberration in chronic hypotension. Midodrine proved to be effective in elevating blood pressure. However, given the cardiac origin of chronic hypotension and the lack of drug effect on cardiac output, alpha-sympathomimetic treatment may be suboptimal.

Pharmacokinetic and pharmacodynamic effects of midodrine on blood pressure, the autonomic nervous system, and plasma natriuretic peptides: a prospective, randomized, single-blind, two-period, crossover, placebo-controlled study.

BACKGROUND: Midodrine is an alpha-agonist prodrug of desglymidodrine (DGM) that has been reported to be of clinical benefit in patients with neurocardiogenic syncope. Its effects may be mediated not only by its hypertensive properties but also by its neurohumoral influences independent of blood pressure (BP). OBJECTIVE: The present study aimed to simultaneously characterize the effects of midodrine on BP, plasma catecholamines, plasma atrial natriuretic peptide (ANP), and power spectral analysis of heart rate (HR) in healthy volunteers. METHODS: This was a prospective, randomized, single-blind, 2-period, crossover study in which a single, oral, 5-mg dose of midodrine was compared with placebo. The washout period between midodrine and placebo was 1 week. The study parameters included plasma DGM (as measured by high-performance liquid chromatography [HPLC]); systolic and diastolic BP (as measured with an oscillometric monitor); HR; plasma catecholamines (measured by HPLC); plasma ANP, also known as venous return (measured by a radio-immunoassay); and low- and high-frequency HR variation (calculated from computerized 5-minute electrocardiographic recordings). All study parameters were measured simultaneously 12 times just before and over a period of 8 hours after drug administration. RESULTS: Fifteen healthy nonsmoking male subjects (14 white, 1 black; mean [SD] age, 28.6 [4.7] years; weight, 74.5 [16.4] kg; seated BP, 109.9 [9.0]/73.6 [9.5] mm Hg; seated HR, 63.8 [8.4] bpm) were randomized. No significant effects of midodrine on BP were observed. At Cmax, midodrine decreased norepinephrine from 188.4 (30.6) to 162.5 (29.8) pg/mL (P = 0.011) and HR from 57.2 (7.3) to 54.9 (6.6) bpm (P = 0.022). A significant correlation was found between DGM concentration and HR ( varphi -0.61; P = 0.014). A DGM-related increase in plasma ANP (+29.6 [90.0] fmoL/mL) was observed. CONCLUSION: This study in healthy male volunteers found that midodrine has sympatholytic influences that are independent of BP but related to augmented venous return.

Midodrine hydrochloride and L-threo-3,4-dihydroxy-phenylserine preserve cerebral blood flow in hemodialysis patients with orthostatic hypotension.

Orthostatic hypotension (OH) after hemodialysis (HD) is a serious complication, as it causes various neurological symptoms and even ischemic brain damage. The aim of the present study was to evaluate the effects of antihypotensive agents, midodrine hydrochloride (MID) and L-threo-3,4-dihydroxyphenylserine (L-DOPS), on OH after HD. We measured systolic blood pressure (SBP) and cerebral blood flow velocity in the middle cerebral artery (MCVm, by transcranial Doppler sonography), in patients with OH during a 5-min 60-degree head-up tilt test at both before and after 4-week treatment with MID at 4 mg/day (N = 6) or L-DOPS at 400 mg/day (N = 7). Both MID and L-DOPS did not significantly protect against falls in systolic BP (SBP) after passive head-up tilt. However, a significant improvement was achieved in MCVm-decrement in the MID group at 3 min and the L-DOPS group at 0, 1 and 3 min during head-up tilt. Although MID and L-DOPS did not prevent OH after HD in HD patients, both agents preserved cerebral blood flow during orthostasis in HD patients with OH.