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Effects of Promethazine and Midodrine on Orthostatic Tolerance
Abstract
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.
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.
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).
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.
... Appropriate monitoring of cardiovascular responses during sensorimotor challenges is required to differentiate the source of the symptoms. Astronauts often receive medication for motion sickness (Jennings, 1998;Shi et al., 2011), and in the 10 of 11 astronauts for whom we have at least partial reports from the flight surgeons, seven received at least one dosage of medication prophylactically before landing, six received medications soon before R+0A, five received medication in transit from Kazakhstan to the refueling stop, and three received medications between the refueling stop and arrival at JSC. ...
... Although these two individuals likely were suffering from more significant sensorimotor disturbances, even if they had started the test they may not have been able to complete it. Promethazine is a H1-receptor antagonist that induces presyncope during orthostasis, primarily through an inhibition of sympathetic responses to protect blood pressure with no effect on heart rate (Shi et al., 2011). However, the one astronaut who was unable to start testing at R+0A and R+0B received only Meclizine and Zofran prior to R+0A, and no antiemetic medications were recorded before R+0B. ...
The incidence of presyncopal events is high soon after a long-duration spaceflight;>60% of returning astronauts could not complete a 10-min 80° head-up tilt test on landing day (R+0) after ~6 months of spaceflight. The objective of this study was to demonstrate the ability of a lower body gradient compression garment (GCG) to protect against an excessive increase in heart rate and a decrease in blood pressure during standing after long-duration spaceflight. Methods: Eleven astronauts (9 M, 2 F) volunteered to participate. The stand test protocol consisted of 2 min of prone rest followed by 3.5 min of standing. Subjects completed one familiarization session, two preflight data collection sessions in standard clothing, and three tests on landing day while wearing GCG. Postflight tests were conducted 1–4 h (R+0A), ~12 h (R+0B), and ~28 h after landing (R+0C). Results: All astronauts completed the stand test preflight. Three astronauts were unable to attempt the stand test at R+0A, and one of these was unable to start the test at R+0B. One astronaut was unable to complete 3.5 min of standing at R+0B (test ended at 3.3 min). Review of the individual’s blood pressure data revealed no hypotension but the astronaut reported significant motion sickness. Of the astronauts who participated in testing on landing day, the heart rate and mean arterial pressure responses to standing (stand-prone) were not different than preflight at any of the postflight sessions. Conclusion: Wearing the GCG after spaceflight prevented the tachycardia that normally occurs while standing after spaceflight without compression garments and protected against a decrease in blood pressure during a short stand test.
... Midodrine and promethazine, which help combat dizziness, help to balance the body so that astronauts can carry out their research in space and safely return back to earth (Shi et al., 2011). ...
Objective: Astronauts deal with lots of health issues during space exploration. In this review article, we explore the health hazards of astronauts and possible therapeutic approaches or precautions they should take prior to or during space travel for relief from these health complications.
Background: The space environment is very different from our planet’s environment. The major differences include radiation from high-level hazardous radioactive particles, vacuum in space, and weightlessness in microgravity. In microgravity, gravitational force decreases with distance. Astronauts deal with anticipated as well as occasional incidents during space flight due to extreme temperatures (either hot or cold), high-energy radiation, vacuum, and atomic oxygen.
Method: A literature-based survey from different search engines is collected and reviewed.
Results: Possible therapeutic approaches can temporarily relieve astronauts of their specific health issues. Pranayama and Yoga heal both mind and body, and prepare the body to adjust and adapt to any kind of atmospheric situation as well as climatic conditions. Practicing these techniques during their training period can be beneficial for astronauts.
Conclusion: Researchers should work on alternative treatment approaches for health hazards during space flight. Effective treatment and care for astronauts, including proper nutrition and preparation of proper herbal or polyherbal formulations, should focus techniques that are beneficial for them and improve their outcomes in space exploration.
... The difference in OI between the control group (34%) and the countermeasures group (13%) was signifi cantly different ( 46 ). Pharmacological studies with midrodrine, an adrenergic agonist, have shown it counteracts some of the effects of OI in several studies, with rates of presyncope being 38% with placebo and 0% with midodrine alone ( 43 ). However, few studies document the small effect of midodrine on OI ( 19 ). ...
Objective:
To review the current state of knowledge with regards to clinical challenges related to women's health during spaceflight.
Methods:
Articles were reviewed relevant to "women", "sex," and "gender" in "microgravity," "weightlessness," and "spaceflight" in the English and Russian languages.
Results:
There were 50 papers identified. Studies have shown that crewmembers suffer from space motion sickness, but gender discrepancies have not been explored. Nearly all women experience orthostatic intolerance in space, which may be due to differences in female cardiovascular response. Immunosuppression in spaceflight results in susceptibility to opportunistic infections, but no studies have investigated gender differences. Finally, radiation exposure and germ cell viability influence the reproductive health of astronauts.
Conclusions:
With changes in space access offered by commercial space activities, research areas devoted to women's health in microgravity should become one of the priorities for safe space exploratory efforts.
... Their anti-a-adrenergic effects include dizziness and orthostatic hypotension. 1,18,92,93 They have also been implicated in impairing the innate immune response to bacterial infection 94 ; however, this is more likely attributable to coadministered H 2 -antihistamines. 95 For 70 years, H 1 -antihistamines have been marketed to the medical profession and the general public as safe medications, despite the voluminous medical literature documenting their CNS adverse effects and toxicity (Table IV). ...
In this review we celebrate a century of progress since the initial description of the physiologic and pathologic roles of histamine and 70 years of progress since the introduction of H(1)-antihistamines for clinical use. We discuss histamine and clinically relevant information about the molecular mechanisms of action of H(1)-antihistamines as inverse agonists (not antagonists or blockers) with immunoregulatory effects. Unlike first (old)-generation H(1)-antihistamines introduced from 1942 to the mid-1980s, most of the second (new)-generation H(1)-antihistamines introduced subsequently have been investigated extensively with regard to clinical pharmacology, efficacy, and safety; moreover, they are relatively free from adverse effects and not causally linked with fatalities after overdose. Important advances include improved nasal and ophthalmic H(1)-antihistamines with rapid onset of action (in minutes) for allergic rhinitis and allergic conjunctivitis treatment, respectively, and effective and safe use of high (up to 4-fold) doses of oral second-generation H(1)-antihistamines for chronic urticaria treatment. New H(1)-antihistamines introduced for clinical use include oral formulations (bilastine and rupatadine), and ophthalmic formulations (alcaftadine and bepotastine). Clinical studies of H(3)-antihistamines with enhanced decongestant effects have been conducted in patients with allergic rhinitis. Additional novel compounds being studied include H(4)-antihistamines with anti-inflammatory effects in allergic rhinitis, atopic dermatitis, and other diseases. Antihistamines have a storied past and a promising future.
Background: Orthostatic hypotension(OH) is a sustained reduction of systolic blood pressure of at least 20mmHg or diastolic blood pressure of at least 10mmHg within three minutes of standing from supine position. Increase in the elderly population has been accompanied by a rising number of injuries and accidents due to physical disabilities associated with ageing and also the problem of orthostatic hypotension which until recently has been almost exclusively associated with cerebrovascular diseases. Methods: This cross-sectional analysis of a community-based cohort evaluated the risk factors associated with orthostatic hypotension in community-dwelling elderly in Anambra State, Nigeria. The study population was 400 persons aged 60 years and older selected by multistage sampling method. Results: There was no statistically significant difference in the mean ages of participants with and without OH. There was no statistically significant differences in BMI between participants having OH and those not having OH. There was statistically significant difference between hypertensives (χ 2 = 4.758,p= 0.027) , diabetics (χ 2 = 6.034 ,p= 0.012) and hypertensive diabetics(χ 2 = 4.982,p=0.030) participants having OH and those not having OH. There was no statistically significant difference in the use and non use of antihypertensives between participants having OH and those not having OH. Conclusion: Factors associated with orthostatic hypotension in the elderly in Anambra State were found to be diabetes and hypertension.
Background: Orthostatic hypotension(OH) is a sustained reduction of systolic blood pressure of at least 20mmHg or diastolic blood pressure of at least 10mmHg within three minutes of standing from supine position. Increase in the elderly population has been accompanied by a rising number of injuries and accidents due to physical disabilities associated with ageing and also the problem of orthostatic hypotension which until recently has been almost exclusively associated with cerebrovascular diseases. Methods: This cross-sectional analysis of a community-based cohort evaluated the risk factors associated with orthostatic hypotension in community-dwelling elderly in Anambra State, Nigeria. The study population was 400 persons aged 60 years and older selected by multistage sampling method. Results: There was no statistically significant difference in the mean ages of participants with and without OH. There was no statistically significant differences in BMI between participants having OH and those not having OH. There was statistically significant difference between hypertensives (χ 2 = 4.758,p= 0.027) , diabetics (χ 2 = 6.034 ,p= 0.012) and hypertensive diabetics(χ 2 = 4.982,p=0.030) participants having OH and those not having OH. There was no statistically significant difference in the use and non use of antihypertensives between participants having OH and those not having OH. Conclusion: Factors associated with orthostatic hypotension in the elderly in Anambra State were found to be diabetes and hypertension.
CV3: Is orthostatic intolerance a potential hazard?
Postflight orthostatic intolerance, the inability to maintain blood pressure while in an
upright position, is an established, spaceflight related medical problem. Risk definition work was largely accomplished prior to establishment of HRP risks/gaps. Current gaps are heavily focused on mitigation.
The combination of promethazine and opioids is known to have an opioid-sparing effect, thereby facilitating a reduction in total patient opioid consumption. In recent years, this practice has fallen out of favor in many healthcare facilities, except primarily in the post anesthesia care unit (PACU). The goal of this study was to highlight the potential of promethazine as a direct or indirect adjuvant medication in acute pain management. The present investigation was undertaken with a case series of adult female patients who underwent open total abdominal hysterectomies. Data from the PACU was reviewed with patients being separated into two groups. Group 1 received only intravenous opioids for acute pain management. Group 2 received a combination of intravenous opioids for acute pain management and intravenous promethazine for nausea and/or vomiting. Patients were discharged from the PACU with a modified Aldrete score of 9 or 10. The study showed that patients who received promethazine in addition to opioids were discharged from the PACU an average of 19.2 minutes earlier than those patients who received only opioids (p=0.003). The time to achieve modified Aldrete score of 9 or higher was more quickly achieved when open abdominal hysterectomy patients received promethazine in addition to opioids in the PACU. The study concluded that promethazine, in combination with opioids, could potentially decrease PACU stay postoperatively. Based on the present investigation, the prospect of using promethazine in other facets of pain management are intriguing and warrant future studies. Specifically, it may be worth investigating whether promethazine is truly an adjunct in combination with opioids and to determine if there are any other antihistamines or neuroleptics which may have similar clinical effects to promethazine.
Objective: To investigate aviator demands for drug supply and pharmaceutical care, and find out factors associated with medication safety among aviators. Methods: From July 2009 to June 2011, sub-regional clusters of 300 aviators from 38 units were investigated with questionnaire on drug supply, self-medication, medication compliance, demands for drug knowledge and pharmaceutical care. Results: Forty percent of the aviators thought that poor drug supply was due to many reasons. The number of people on self-medication accounted for 77.5%, among whom the percentage of self-medication in the junior-age group was significantly higher than that of the senior-age group (P<0.05). Total medication compliance accounted for 85.6%, with medication compliance for those on jobs in flight units and those on convalescence being 80% and 79.6% respectively, which were significantly lower than that of the hospitalized (100%) (P<0.01). Ninety-four percent of the aviators would like to know adverse drug reactions. They hoped to get more knowledge on the drugs for those commonly occurred illnesses or injuries, such as injuries from falls, fractures and strains, or painkillers and drugs for relieving sore throat. Conclusion: Pharmaceutical care to aviators is beneficial to enhanced supervision of rational medication, better understanding of the changes in drug supply, better improvement of safe medication, and more importantly, is beneficial to the guarantee of flight safety and increase in the fighting capacity of aviators.
Countermeasures are defined as solutions to prevent the undesirable physiologic outcomes associated with spaceflight. Spaceflight analogs provide a valuable opportunity for the evaluation of countermeasures because that they allow for the evaluation of more subjects, more experimental control and are considerably less expensive than actual spaceflight. The various human analogs have differing strengths and weaknesses with respect to the development and evaluation of countermeasures. The human analogs are briefly reviewed with a focus on their suitability for countermeasure evaluation. Bed rest is the most commonly used analog for evaluating countermeasures. While countermeasures are typically developed to target one or maybe two particular physiologic issues, it is increasingly important to evaluate all of the organ systems to discern whether they might be unintended consequences on non-targeted tissues. In preparation for Mars exploration it will be necessary to fully integrate countermeasures to protect all organ systems. The synergistic and antagonistic effects of multiple countermeasures needs to be the focus of future work.
This chapter discusses space physiology, describing space motion sickness as a special form of motion sickness. It include such symptoms as depressed appetite, a nonspecific malaise, gastrointestinal discomfort, nausea, and vomiting. Many astronauts returning to Earth after long-duration stays on board the International Space Station now experience symptom recurrence at landing. The severity of the symptoms and the functional recovery after the flight seem to be directly proportional to the time on orbit. A sensory conflict theory of motion sickness postulates that motion sickness occurs when patterns of sensory inputs to the brain are markedly re-arranged, at variance with each other, or differ substantially from expectations of the stimulus relationships in a given environment. The extent of orthostatic intolerance postflight is variable and depends on the duration of the flight, individual differences in cardiovascular function among the astronauts, and the elapsed time after landing and method of postflight testing. Astronauts in orbit experience a headward shift of fluid at the onset of weightlessness resulting in facial puffiness and distended neck veins.
In addition to the traditional renin-angiotensin system, a great deal of evidence favors the existence of numerous independent tissue-specific renin-angiotensin systems. We report that mast cells are an additional source of renin and constitute a unique extrarenal renin-angiotensin system. We use renin-specific antibodies to demonstrate that cardiac mast cells contain renin. Extending this observation to the human mast cell line HMC-1, we show that these mast cells also express renin. The HMC-1 renin RT-PCR product is 100% homologous to Homo sapiens renin. HMC-1 cells also contain renin protein, as demonstrated both by immunoblot and immunocytochemical analyses. Renin released from HMC-1 cells is active; furthermore, HMC-1 cells are able to synthesize renin. It is known that, in the heart, mast cells are found in the interstitium in close proximity to nerves and myocytes, which both express angiotensin II receptors. Inasmuch as myocardial interstitium contains angiotensinogen and angiotensin-converting enzyme, and because we were able to detect renin only in mast cells, we postulate that the release of renin from cardiac mast cells is the pivotal event triggering local formation of angiotensin II. Because of the ubiquity of mast cells, our results represent a unique paradigm for understanding local renin-angiotensin systems, not just in the heart, but in all tissues. Our findings provide a rationale for targeting mast cells in conjunction with renin-angiotensin system inhibitors in the management of angiotensin II-related dysfunctions.
Synopsis
Midodrine is a prodrug which undergoes enzymatic hydrolysis to the selective α1-adrenoceptor agonist desglymidodrine after oral administration.
Oral midodrine significantly increases 1- minute standing systolic blood pressure compared with placebo. The drug also improves standing time and energy level and clinical symptoms of orthostatic hypotension including dizziness, light- headedness and syncope.
Comparative studies have shown midodrine to have similar efficacy to dihydroergotamine mesylate, norfenefrine, fludrocortisone and etilefrine, and to be more effective than dimetofrine and ephedrine in patients with orthostatic hypotension.
Midodrine is well tolerated, with the most commonly reported adverse events being piloerection, pruritus, paraesthesias, urinary retention and chills. The risk of supine hypertension, which is associated with midodrine therapy in up to 25% of patients, can be reduced by taking the final daily dose at least 4 hours before bedtime.
Thus, oral midodrine is an effective therapeutic option for the management of various forms of orthostatic hypotension. This well- tolerated agent is likely to be useful in conjunction with standard nonpharmacological care.
Pharmacological Overview
The sympathomimetic agent midodrine is a prodrug which is converted to its pharmacologically active metabolite desglymidodrine after oral administration. Desglymidodrine, a selective α1-adrenoceptor agonist, increases blood pressure via arterial and venous vasoconstriction.
Single oral doses of midodrine (2.5, 10 and 20mg) dose-dependently increased standing systolic blood pressure 1 hour postdose in patients with orthostatic hypotension; the duration of action of midodrine 10mg was approximately 4 hours. Midodrine also increased the time patients were able to stand motionless compared with placebo (4 vs 2 minutes). In diabetic patients with severe orthostatic hypotension, midodrine 10mg significantly improved standing blood pressure, cerebral blood flow and cognitive function.
Desglymidodrine reached peak plasma concentrations (0.027 mg/L) about 1 hour after a 5 to 10mg oral dose of midodrine in fasted patients with orthostatic hypotension. The absolute bioavailability of midodrine (as desglymidodrine) is 93% after oral administration. The elimination half-life of desglymidodrine is about 2 to 3 hours (0.49 hours for midodrine). Although the distribution of midodrine in humans has not been established, it does not appear to cross the blood-brain barrier after oral administration. Desglymidodrine is excreted primarily in the urine; faecal elimination of midodrine or desglymidodrine is insignificant.
Therapeutic Use
Recently published results of 2 placebo-controlled studies (involving a total of 268 patients) which used 1-minute standing blood pressure 1 hour postdose as a surrogate end-point for clinical efficacy showed that midodrine (10mg 3 times daily for 3 or 4 weeks) significantly increased standing systolic blood pressure by up to 22mm Hg in patients with orthostatic hypotension. In addition, a higher proportion of patients receiving midodrine versus placebo had a ≥10mm Hg increase in 1-minute standing systolic blood pressure (47 vs 28%). Midodrine significantly improved clinical symptoms of orthostatic hypotension, including dizziness, lightheadedness, syncope and depression. The drug also significantly improved the global evaluation score (incorporating lightheadedness, standing time and orthostatic energy level) compared with placebo when assessed by patient or investigator.
Small, predominantly crossover and short term comparative studies have shown midodrine to have an efficacy at least similar to that of dihydroergotamine mesylate, norfenefrine, fludrocortisone and etilefrine, and to be more effective than dimetofrine and ephedrine in patients with orthostatic hypotension.
Tolerability
Midodrine is well tolerated in most patients with orthostatic hypotension. The most common adverse events associated with the use of midodrine 10mg 3 times daily in a 3-week placebo-controlled trial in 171 patients included piloerection (13%), scalp or general pruritus (10 and 2%), scalp or general paraesthesia (9% each), urinary retention (6%) and chills (5%). 18% of 82 midodrine recipients withdrew because of adverse events. The use of midodrine 10mg 3 times daily has been associated with supine hypertension in up to 25% of patients enrolled in clinical trials.
Although the metabolic effects of midodrine have not been fully investigated, the drug does not appear to affect blood glucose or insulin levels, glucose tolerance, serum lipid profiles, or uric acid or urea levels. In addition, it does not appear to affect pulmonary or renal function, bone marrow, blood coagulation or fibrinolysis.
Dosage and Administration
The recommended initial dosage of midodrine in patients with orthostatic hypotension is 2.5mg administered orally 2 to 3 times daily. This dosage is gradually increased to the recommended maintenance dosage of 10mg 3 times daily if needed. The dose interval is 3 to 4 hours, with the final dose given at least 4 hours before bedtime to reduce the risk of supine hypertension. To maximise the therapeutic efficacy of midodrine, the dosage should be individualised for each patient.
Blood pressure should be monitored regularly during treatment and the use of midodrine should be stopped if supine blood pressure increases excessively. Treatment should be continued only in patients with symptomatic improvement during initial treatment. Midodrine should be used with caution in patients with renal or hepatic dysfunction, and is contraindicated in patients with severe heart disease, acute renal disease, urinary retention, phaeochromocytoma or thyrotoxicosis.
In hypophysectomized-nephrectomized dogs after intravenous injection of histamine, a marked increase was observed in the rate of secretion of aldosterone, although it was smaller than that in intact dogs. Hypophysectomy plus bilateral nephrectomy greatly impaired the secretion of corticosterone and cortisol in the dog in response to histamine. However, a small yet significant increase in corticosterone and cortisol secretion was observed in hypophysectomized-nephrectomized dogs after intravenous injection of histamine. Additional experiments showed that plasma concentrations of potassium and sodium in hypophysectomized-nephrectomized dogs remained unchanged after intravenous injection of histamine. These results suggest that histamine stimulates aldosterone secretion in the dog partly by a direct effect on the adrenal cortical cells, whereas the effect of histamine on corticosterone and cortisol secretion is mediated mainly, but not totally, by pituitary release of ACTH.
Effects of the histamine H1- or H2-receptor antagonists mepyramine (Mep) and cimetidine (Cim) on neuroendocrine and cardiovascular responses to 50 degrees head-up tilt were evaluated in seven human males. Central hypovolemia was characterized by two phases. The first is a normotensive phase with increases in heart rate (HR), total peripheral resistance (TPR), and decrease in cardiac output. Plasma adrenocorticotropic hormone, beta-endorphin, cortisol, catecholamines, and renin activity increased moderately. Normotension lasted 39 +/- 7 min during infusion of saline but was reduced by Mep [18 +/- 3 min, F(2,12) = 9.60, P less than 0.01] and was unaffected by Cim (44 +/- 4 min). The second is a hypotensive phase associated with presyncopal symptoms (hypovolemic shock) and decreases in HR and TPR and a further increase in pituitary-adrenal and sympathoadrenal activity. Decreases in mean arterial pressure and TPR were augmented by Mep, which inhibited release of norepinephrine. Cim inhibited epinephrine release without affecting the development of hypovolemic shock. It is concluded that histaminergic mechanisms are involved in activation of the sympathoadrenal system but not in the pituitary-adrenal axis during central hypovolemia in humans.
Brain histamine (HA) was depleted in conscious Sprague-Dawley rats by central administration of alpha-fluoromethyl-histidine (alpha-FMH), an irreversible inhibitor of the HA synthesizing enzyme. Isotonic or hypertonic saline was infused intravenously at 10 microliters.100 g-1.min-1 for 30 min and mean arterial pressure (MAP) and heart rate (HR) were monitored. In addition, plasma vasopressin (AVP) and norepinephrine (NE) were measured pre- and postinfusion. Animals pretreated with alpha-FMH showed a delayed and attenuated pressor response and bradycardia during hypertonic saline (HTS) infusion and a significant reduction in plasma NE levels (-29 +/- 8% below control values). However, plasma concentrations of AVP were similar in both groups. Central pretreatment with the H1-antagonist pyrilamine (PYR) also delayed the onset and significantly attenuated the pressor response to HTS infusion, and caused dose-related decreases in plasma NE concentrations (-34 +/- 8, -47 +/- 5, and -52 +/- 7% after 60, 100, and 600 nmol PYR, respectively). These data indicate a role for central HA in peripheral sympathetic activation but not as a mediator of AVP release to a peripheral hyperosmotic stimulus.
This modification of the catechol-O-methyltransferase (COMT) based radioenzymatic assay for norepinephrine (NE) and epinephrine (E) improves sensitivity, selectivity and eliminates many inhibitors of COMT. Prior to assay, samples are extracted into heptane with diphenylborate, then into dilute acetic acid. This extraction procedure has an efficiency of 78% for NE but less than 2% for S-adenosylmethionine (SAM). The extraction procedure also excludes calcium and other COMT inhibitors present in urine, plasma and every tissue tested. This eliminates the requirement for individual standardization of tissue and urine samples. Sensitivity of the assay for NE and E is 10 and 6 pg/ml respectively in 1 ml of plasma. The intraassay coefficients of variation for NE and E are 4 and 13% and the interassay coefficients of variation for NE and E are 10 and 16% in a human plasma sample containing low catecholamine levels. The assay permits quantitation of plasma E levels that were undetectable in prior assays.
Orthostatic cardiovascular reflexes were evaluated in conscious cynomolgus monkeys during interruption of the renin-angiotensin system with the renin inhibitor: RIP (Pro-His-Pro-Phe-His-Phe-Phe-Val-Tyr-Lys-OH). RIP was synthesized via solid phase techniques and purified to homogeneity. In vitro studies indicated that it exhibited classical competitive inhibition of renin with a KI of 2.3 microM. In vivo, RIP at 2 mg/kg per min inhibited renin and angiotensin I pressor responses indicating that it was not a specific renin inhibitor at this dose. However, in spite of the nonspecificity, RIP did not affect the supine blood pressure of sodium-replete monkeys, but did evoke hypotension in supine sodium depleted monkeys. RIP did not elicit significant orthostatic hypotension in either sodium-replete or sodium depleted monkeys. The cardiovascular effects of RIP described in this study appear to be due to inhibition of the renin-angiotensin system.
The left adrenal of hypophysectomized-nephrectomized dogs was perfused in situ with artificial medium equilibrated with 95% O2-5% CO2. Repeated secretory responses of aldosterone to ACTH and histamine were almost reproducible during 2 h of perfusion, but those of cortisol and corticosterone gradually reduced. The secretion of aldosterone in response to histamine markedly increased at 1 microM and those of cortisol and corticosterone significantly increased at 1 and 10 microM, respectively. The secretory response of aldosterone to 10 microM histamine was comparable with that to 300 microU/ml ACTH, but the secretory responses of cortisol and corticosterone to 10 microM histamine were very much lower than those to 1 microU/ml ACTH. The secretory responses of these three steroids to 10 microM histamine were almost completely depressed by continuous administration of 10 microM pyrilamine maleate, but not abolished by that of 100 microM metiamide. The secretory responses of these three steroids to 10 microM histamine were slightly depressed by continuous infusion of 10 microM methysergide maleate. These results suggest that histamine at pathophysiological concentrations stimulates the secretion of aldosterone markedly, and those of cortisol and corticosterone slightly, via an H1 receptor of adrenocortical cells in the dog.
Intraventricular administration of histamine (HA; 2.5 and 5 μg) caused a significant increase of plasma adrenaline and noradrenaline levels in conscious freelymoving male rats.
The increase of adrenaline was more rapid (5 min after injection) and greater than that of noradrenaline. The plasma adrenaline increase observed 15 min after HA administration was dose-dependent. In contrast, plasma noradrenaline increased maximally in response to the low dose and reached similar values after the largest dose studied. Receptor mediation was examined by means of selective HA antagonists. Pretreatment with mepyramine blunted the adrenaline response at 15 min which suggests mediation at H1 receptors. In contrast, it was ineffective on plasma adrenaline at 5 min and plasma noradrenaline increase. Ranitidine, an H2-receptor antagonist, did not modify adrenaline response but enhanced the HA-induced increase of plasma noradrenaline.
These findings suggest that HA activates the central drive to the adrenal medulla and to the peripheral sympathetic system. A participation of peripheral catecholamine secretion in the acute cardiovascular changes induced in rats by centrally injected HA is postulated.
The renal effects of histamine, histamine receptor agonists and antagonists were studied in the isolated rat kidney, which was perfused with a synthetic medium at constant perfusion pressure in a single pass system.
Histamine induced a concentration-dependent increase of renin release ranging from a two-fold increase at 0.5 μM to a four-fold increase at 10 μM. No change in renal vascular resistance, glomerular filtration rate and sodium excretion occurred. Histamine-H2-antagonists (ranitidine and cimetidine) were more effective to block the response to histamine than was the histamine H1-antagonist diphenhydramine.
Histamine-H2-agonists (impromidine and dimaprit, 2.5 μM each) were potent stimulators of renin release, their effect was blunted by H2-antagonists.
The histamine-H1-agonist pyridyl-2-ethylamine had a low stimulatory activity at 10 μM final concentration, which may reflect partial H2-agonistic effects.
It is concluded that histamine stimulates renin release via H2-receptor activation.
The role of adrenoreceptor stimulation and the peripheral mechanism mediating the increase in mean arterial blood pressure (MAP) and heart rate (HR) during administration of histamine (HA) in the paraventricular nucleus/anterior hypothalamus (PVN/AH) was evaluated in conscious rats. HA administered through microdialysis probes in the PVN/AH region increased MAP (18 +/- 1 mmHg) and HR (81 +/- 10 beats/min). The pressor response was abolished by simultaneous administration of phentolamine (alpha 1- and alpha 2-antagonist) or prazosin (alpha 1-antagonist) but not altered by yohimbine (alpha 2-antagonist). The tachycardia was not effected by any adrenergic antagonist. Furthermore, ganglionic blockade did not reduce the increase in MAP (21 +/- 2 mmHg) during PVN/AH perfusion with HA, while V1-vasopressin receptor blockade abolished the pressor response (4 +/- 2 mmHg). These data suggest that HA administered to the PVN/AH increases blood pressure by local release of norepinephrine and alpha 1-adrenoreceptor stimulation of vasopressin secretion, while the tachycardia is not mediated by alpha-adrenoreceptors.
We report the first case of a patient in a promethazine-induced coma responding to treatment with flumazenil. A literature search conducted to determine the mechanism behind the antagonism of this overdose showed that promethazine interacts with receptors in the central nervous system. Sedative effects may, in fact, be mediated through the benzodiazepine receptor. We concluded that flumazenil can antagonize the sedative effects of promethazine at these receptors to return the patient to a wakeful state.
Space motion sickness is a well-recognized problem for space flight and affects 73% of crewmembers on the first 2 or 3 days of their initial flight. Illness severity is variable, but over half of cases are categorized as moderate to severe. Management has included elimination of provocative activities and delay of critical performance-related procedures such as extra-vehicular activity (EVA) or Shuttle landing during the first three days of missions. Pharmacological treatment strategies have had variable results, but intramuscular promethazine has been the most effective to date with a 90% initial response rate and important reduction in residual symptoms the next flight day. Oral prophylactic treatment of crewmembers with difficulty on prior flights has had mixed results. In order to accommodate more aggressive pharmacologic management, crew medical officers receive additional training in parenteral administration of medications. Preflight medication testing is accomplished to reduce the risk of unexpected performance decrements or idiosyncratic reactions. When possible, treatment is offered in the presleep period to mask potential treatment-related drowsiness. Another phenomenon noted by crewmembers and physicians as flights have lengthened is readaptation difficulty or motion sickness on return to Earth. These problems have included nausea, vomiting, and difficulty with locomotion or coordination upon early exposure to gravity. Since landing and egress are principal concerns during this portion of the flight, these deficits are of operational concern. Postflight therapy has been directed at nausea and vomiting, and meclizine and promethazine are the principal agents used. There has been no official attempt at prophylactic treatment prior to entry. Since there is considerable individual variation in postflight deficit and since adaptation from prior flights seems to persist, it has been recommended that commanders with prior shuttle landing experience be named to flights of extended duration.
We evaluated in-flight use of medications from astronaut debriefings after 79 U.S. Space Shuttle missions. From the 219 records obtained (each representing one person-flight), 94% included some medication being taken during flight; of that number, 47% were for space motion sickness, 45% for sleep disturbances, and smaller percentages for headache, backache, and sinus congestion. Drugs were taken most often orally, followed in decreasing order of frequency by intranasal, intramuscular, and rectal routes. Drugs for space motion sickness were taken mostly during the first 2 d of flight, drugs for pain during the first 4 d, and drugs for sleeplessness and sinus congestion were taken consistently for 9 flight days. About 85% of all doses had no reported side effects, and most of the side effects that were reported happened during the first mission day. About 80% of the drug-dose events were perceived effective by the recipients; most of the reports of ineffectiveness occurred during the first mission day. Promethazine, the only drug given by three different routes (orally, intramuscularly, and rectally), was most effective and had minimal side effects when taken intramuscularly. This information, although useful, should be expanded to include objective measures of effectiveness so that therapeutic efficacy can be assessed during flight.
Many astronauts after being weightless in space become hypotensive and presyncopal when they assume an upright position. This phenomenon, known as orthostatic intolerance, may interfere with astronaut function during reentry and after spaceflight and may limit the ability of an astronaut to exit a landed spacecraft unaided during an emergency. Orthostatic intolerance is more pronounced after long-term spaceflight and is a major concern with respect to the extended flights expected aboard the International Space Station and for interplanetary exploration class missions, such as a human mission to Mars. Fully effective countermeasures to this problem have not yet been developed. To test the hypothesis that alpha-adrenergic stimulation might provide an effective countermeasure, we conducted a 16-day head-down-tilt bed-rest study (an analog of weightlessness) using normal human volunteers and administered the alpha(1)-agonist drug midodrine at the end of the bed-rest period. Midodrine was found to significantly ameliorate excessive decreases in blood pressure and presyncope during a provocative tilt test. We conclude that midodrine may be an effective countermeasure for the prevention of orthostatic intolerance following spaceflight.
Previous echocardiographic studies of astronauts before and after short-duration (4-17 d) missions have demonstrated a decrease in resting left ventricular stroke volume, but maintained ejection fraction (EF) and cardiac output. Similar studies before and after long-duration (129-144 d) spaceflight have been rare and their overall results equivocal.
Echocardiographic measurements (M-mode, 2-D, and Doppler) were obtained from short-duration (n = 13) and long-duration (n = 4) crewmembers to evaluate cardiac chamber sizes and function.
Compared with short-duration astronauts, long-duration crewmembers had decreases in EF (+6+/-0.02 vs. -10.5+/-0.03%, p = 0.005) and percent fractional shortening (+7+/-0.03 vs. -11+/-0.07%, p = 0.015), and an increase in left ventricular end systolic volume (-12+/-0.06 vs. +39+/-0.24%, p = 0.011).
These data suggest a reduction in cardiac function that relates to mission duration. As the changes in BP and circulating blood volume are reported to be similar after short- and long-duration flights, the smaller EF after longer spaceflights may be due to a decrease in cardiac function rather than altered blood volume.
Insomnia is a common symptom, not only in the adult population but also in many astronauts. Hypnotics, such as temazepam (a benzodiazepine) and zolpidem (an imidazopyridine), are often taken to relieve insomnia. Temazepam has been shown clinically to have hemodynamic side effects, particularly in the elderly; however, the mechanism is not clear. Zolpidem does not cause hemodynamic side effects. The purpose of this study was to determine whether the use of different hypnotics during spaceflight might contribute significantly to the high incidence of postflight orthostatic hypotension, and to compare the findings in astronauts with clinical research. Astronauts were separated into three groups: control (n = 40), temazepam (15 or 30 mg; n = 9), and zolpidem (5 or 10 mg; n = 8). In this study, temazepam and zolpidem were only taken the night before landing. The systolic and diastolic blood pressures and heart rates of the astronauts were measured during stand tests before spaceflight and on landing day. On landing day, systolic pressure decreased significantly and heart rate increased significantly in the temazepam group, but not in the control group or in the zolpidem group. Temazepam may aggravate orthostatic hypotension after spaceflight when astronauts are hemodynamically compromised. Temazepam should not be the initial choice as a sleeping aid for astronauts. These results in astronauts may help to explain the hemodynamic side effects in the elderly who are also compromised. Zolpidem may be a better choice as a sleeping aid in these populations.
Many astronauts exhibit post-spaceflight orthostatic hypotension due to inadequate norepinephrine release when in an upright posture. We hypothesized that an alpha1-adrenergic agonist, midodrine, would be an effective countermeasure. A female astronaut, who had problems with postflight orthostatic hypotension after a previous flight, consumed 10 mg midodrine after a subsequent flight, prior to her tilt test. Hemodynamic variables were compared between the two flights. Midodrine prevented severe falls in stroke volume, cardiac output and systolic pressure, and severe increases in heart rate without increasing vascular resistance, thus preventing orthostatic hypotension. This is the first report showing that midodrine has the potential to improve post-spaceflight orthostatic hypotension and suggesting that reduced venous return contributes to the etiology.
The purpose of this study is to evaluate the relationship between aldosterone and blood pressure in a total of 220 normotensive and 293 essential hypertensive subjects in 2 genetically distinct populations-blacks and white French Canadians. The 24-hour blood pressure monitoring was performed under standardized conditions after discontinuing antihypertensive medications. Plasma renin activity and plasma aldosterone were measured in the supine position and after standing for 10 minutes. Plasma atrial natriuretic factor was also measured. Supine and standing plasma renin activities were lower (P< or =0.01), plasma aldosterone was higher (P<0.0001), and the aldosterone/renin ratios were higher (P<0.0001) in the hypertensive subjects. Atrial natriuretic factor was also higher in the hypertensive subjects (P<0.0001). Among blacks, blood pressures did not correlate with plasma renin activity. However, both average daytime and nighttime systolic and diastolic blood pressures were correlated with supine and standing plasma aldosterone and with the aldosterone/renin ratio (P<0.005 or less). In French Canadians, blood pressures tended to be positively correlated with standing plasma renin activity and aldosterone, but not with the aldosterone/renin ratio. Correlations of blood pressure with aldosterone were more consistent and more striking in blacks than in French Canadians. In both ethnic groups, there were inconsistent correlations of blood pressure with atrial natriuretic factor. These observations are consistent with the hypothesis that aldosterone-induced volume expansion is an important contributor to hypertension, especially in blacks.