US Pharm. 2006;12:HS32-HS41.
Orthostatic hypotension is defined by the Consensus Committee of the American Autonomic Society and the American Academy of Neurology as a reduction of systolic blood pressure of at least 20 mmHg or a reduction of diastolic blood pressure of at least 10 mmHg within three minutes of standing. For individuals who cannot stand, a drop in blood pressure within three minutes of tilting the head up to at least a 60° angle is indicative of orthostatic hypotension. The Consensus Committee describes orthostatic hypotension as a physical sign, rather than a disease, that may be symptomatic or asymptomatic.1 Common symptoms of orthostatic hypotension include light-headedness, dizziness, weakness, fatigue, cognitive impairment, nausea, palpitations, and tremulousness.1
The prevalence of orthostatic hypotension may increase with age, and studies report that as many as 13% to 30% of elderly people have orthostatic hypotension.2-5 Orthostatic hypotension as defined in these studies could be systolic or diastolic orthostatic hypotension, both systolic and diastolic orthostatic hypotension, or symptomatic orthostatic hypotension. Thus, depending on the definition of orthostatic hypotension in the cohort under study, the prevalence of orthostatic hypotension might vary.2-5 Food ingestion, time of day, state of hydration, hypertension medication, gender, and age can also affect the incidence of orthostatic hypotension.1 In a prospective study of 60 hypertensive individuals 65 or older, Vara-Gonzalez et al. determined the reproducibility (intra-individual variability) of postural changes in blood pressure in a primary care setting. Findings suggested that the reproducibility of orthostatic hypotension in the cohort was poor. The researchers recommended that orthostatic blood pressure be confirmed on at least two occasions in elderly individuals.6
Several studies have reported that orthostatic hypotension is a potential risk factor for vascular-related death, myocardial infarction, coronary heart disease, transient ischemic attack, falls, and fractures.7-11 Orthostatic hypotension has also been associated with increased mortality.12,13 Thus, orthostatic hypotension is associated with serious risks in the older population, adversely affecting patients' health and quality of life and increasing financial and social burdens.14
In healthy individuals, gravitational venous pooling in the legs and abdomen begins immediately when they change from supine to standing position.15 The subsequent transient decrease in venous return and cardiac output results in reduced blood pressure. Most of the venous pooling occurs within the first 10 seconds, and venous pooling is completed within three to five minutes of orthostatic stress.16 The initial reaction to orthostatic stress is mediated by the autonomic nervous system. During prolonged orthostatic stress (longer than three minutes), additional adjustments are mediated by the humoral limb of the autonomic nervous system. The main sensory receptors involved in orthostatic neural reflex adjustment are the arterial mechanoreceptors (baroreceptors) located in the aortic arch, and it is believed that the carotid sinuses and mechanoreceptors located in the heart and lungs (cardiopulmonary receptors) play a minor role.17 During orthostatic stress, these receptors activate autonomic reflexes that cause a sympathetic mediated increase in catecholamine levels and result in increased heart rate, myocardial contractility, and enhanced cardiac output. The increase in catecholamine levels also induce arterial and venous vasoconstriction that rapidly normalize blood pressure.18 During prolonged orthostatic stress, additional activation of the neurohumoral system reinforces the activation of the cardiovascular reflexes through additional constriction of blood vessels and minimization of water loss by activation of the renin-angiotensin-aldosterone system and vasopressin.15 When any of these responses to orthostatic stress is impaired, blood pressure and organ perfusion may be reduced upon standing, and the patient may display symptoms of orthostatic hypotension.
There are many causes for orthostatic hypotension, which can be categorized into neurogenic and nonneurogenic causes.19 Neurogenic causes can be subdivided into primary or secondary causes. Primary neurogenic causes include autonomic nervous system dysfunction and multiple system atrophy (formerly known as Shy-Drager syndrome). Patients with multiple-system atrophy have a loss of neurons in nuclei of the central nervous system and present with parkinsonian features, cerebellar dysfunction, or pyram idal symptoms. Secondary neurogenic causes include systemic diseases resulting in lesions of the central or peripheral nervous system (e.g., diabetes mellitus, Guillian-Barre syndrome, alcoholic polyneuropathy).
One feature that distinguishes a nonneurogenic cause from a neurogenic cause is that the postural drop in blood pressure that is associated with nonneurogenic etiologies is accompanied by a compensatory increase in heart rate. This increase in heart rate does not occur in individuals with neurogenic causes of orthostatic hypotension.19,20 Nonneurogenic causes of orthostatic hypotension include cardiac pump failure, reduced intravascular volume, venous pooling, or causative medications.
It is estimated that about 50% of orthostatic hypotension cases involve causative medications (see table 1 for a list of select causative medications).21 Antihypertensives that impair autonomic reflex mechanisms are frequent causes of orthostatic hypotension. Drugs that induce diuresis can reduce intravascular volume and cause orthostatic hypotension. Peripheral vasodilation resulting from the use of non-selective alpha-blocking agents is associated with first-dose syncope, and therefore, dose should be started low and slowly titrated upwards.18 In a retrospective study of veterans 75 and older, Poon and Braun reported that the incidence of orthostatic hypotension increased with increasing numbers of concurrent medications used that are known to cause orthostatic hypotension.21 Therefore, the use of potentially causative medications for orthostatic hypotension should be carefully evaluated in older patients, particularly those who have concurrent illnesses that can cause orthostatic hypotension, such as cardiac impairment, low intravascular volume, or vasodilation.
Comorbidities and Consequences
There are a number of associated comorbidities of orthostatic hypotension. Stroke, isolated systolic hypertension, and dementia have all been associated with orthostatic hypotension. In a study by Eigenbrodt et al., 11,707 patients who were initially stroke-free were followed for a period of 7.9 years.11 Orthostatic hypotension was found to be statistically predictive of ischemic stroke, even after adjustment for numerous other stroke risk factors (hazard ratio, 2.0; 95% CI, 1.2 to 3.2). In another study by Rutan et al., 5,201 men and women who were 65 or older at initial examination were studied to determine the prevalence of orthostatic hypotension and its associations with various cardiovascular risk factors and symptomatology.8 In this study, orthostatic hypotension was significantly associated with isolated systolic hypertension (odds ratio, 1.35; CI, 1.09 to 1.68). Studies have also been conducted to determine the effect of orthostatic hypotension on cognition and dementia. In a study by Elmstahl and Rosen, 33 healthy women ages 75 to 95 with no signs of cerebrovascular disease or dementia at baseline examination were enrolled into a longitudinal five-year follow-up study.22 Seven women had documented cognitive decline at the five-year follow-up and a greater decrease in orthostatic blood pressure during tilting at baseline (16 mmHg) than did controls (1 mmHg; P<.01).
There are also a number of consequences of orthostatic hypotension that can lead to decreased quality of life, such as headaches, blurred vision, syncope, falls, fractures, and dyspnea. These consequences can lead to significant debilitation necessitating long-term care and are especially concerning and problematic to the caregivers of these patients.
History and Physical Examination: The initial step in evaluating patients with orthostatic hypotension is the identification of causative medications that induce orthostatic hypotension. 19,23 The history should also include a review of stimuli that increase the incidence of orthostatic hypotension. Such stimuli include meals, hot environments (after showers), alcohol consumption, hyperventilation, and time of the day. Once the stimuli are identified, safety precautions should be practiced to prevent any falls secondary to orthostatic hypotension. For example, orthostatic hypotension occurs more commonly in the early morning; therefore, patients should schedule activities in the afternoon.24 A comprehensive review of the patient's medical history should be performed to identify neurogenic and nonneurogenic causes of orthostatic hypotension. The physical examination should include measurement of supine and standing pulse and blood pressure, with an interval of three minutes between measurements in each position. A thorough neurologic evaluation--including a mental status examination to identify cognitive impairment, a cranial nerve assessment to evaluate down gaze, a motor examination to identify parkinsonian features such as tremor, rigidity, and bradykinesia, and a sensory evaluation to identify polyneuropathies--should be completed.19
Diagnostic Tests: There are many autonomic function tests available to assist the practitioner in identifying the cause of orthostatic hypotension, especially when history and physical examination are inconclusive.21 A commonly used test is Valsalva's maneuver, which assesses the functional integrity of the baroreceptor reflex. During the test, the patient exerts a constant expiratory pressure for 15 seconds while blood pressure and heart rate changes are recorded.19 Other autonomic function tests such as the tilt table test, the quantitative sudomotor axon reflex test, and the cold pressor test can be used to assess orthostatic hypotension.
Treatment of Orthostatic Hypotension
Nonpharmacologic Treatment: Nonpharmacologic measures are the mainstay of treatment in the management of orthostatic hypotension. The predominant cause of the signs and symptoms of orthostatic hypotension is the inability of the body to compensate the normal gravitational pooling of the blood in the lower extremities and abdomen. Therefore, nonpharmacologic approaches should focus on decreasing venous pooling, avoiding volume depletion, and increasing plasma volume.
Patients should be encouraged to change position slowly. When rising from a supine position, patients should be encouraged to sit on the side of the bed for a few minutes before standing up. If getting up after a period of prolonged sitting, patients should cross their legs a couple of times prior to standing. Lift chairs may also be useful for these situations. Use of compression stocking and abdominal binders are encouraged; however, they must be worn all day to be useful, and many patients find them uncomfortable to wear, especially during hot weather.25 Physical adjustments and use of restrictive agents raise cardiac output and mean blood pressure.26
Additionally, adequate fluid intake should be maintained to prevent dehydration and to improve the symptoms of orthostatic hypotension. The usual recommendation is to drink 2.0 to 2.5 L (66 to 83 ounces) of fluids during the day, while avoiding drinking one hour prior to bedtime to minimize nighttime trips to the bathroom. In a study by Shannon et al., 11 patients with severe orthostatic hypotension due to autonomic failure ingested 480 mL (16 ounces) of tap water over a period of five minutes.27 Mean (± standard deviation) blood pressure after one minute of standing was 83 ± 6/53 ± 3.4 mmHg at baseline, which increased to 114 ± 30/66 ± 18 mmHg ( P <.01) 35 minutes after drinking water (P<.01).
Individuals experiencing postprandial orthostatic hypotension due to gastrointestinal and hepatic pooling should be counseled to eat more frequent, smaller meals and to plan on a 60-minute postprandial resting period.28 Shannon et al. tested the effect of drinking water on postprandial hypotension in seven patients who had autonomic failure. After they had eaten a meal, blood pressure decreased by 43 ± 36/20 ± 13 mmHg without patients drinking water, compared with 22 ± 10/12 ± 5 mmHg with drinking (P<.001).27 Sodium intake should also be increased, as long as there are no contraindications.
Patients should be advised to avoid hot showers or exercising in warm environments. Patients with orthostatic hypotension often have an inability to sweat, which causes a rise in core body temperature that may lead to compensatory vasodilation and subsequent fall in blood pressure. 26 While patients are in bed, the head should be elevated 10° to 20°. This elevation reduces renal arterial pressure and causes release of rennin, resulting in aldosterone release, retention of sodium and water, and thereby, increasing blood pressure.28 Coffee drinking is encouraged to enhance peripheral resistance and reduce postprandial exacerbations. In addition, eating black licorice has been documented to exhibit mineralocorticoid effects.28,29 Straining during micturition and defecation should be minimized; therefore, these patients should be advised to increase fiber consumption, especially in the form of wheat and oat bran. All of these nonpharmacologic treatment strategies minimize the impact of postural orthostatic hypotension on activities of daily living.
Pharmacologic Treatment: Pharmacologic treatment is aimed at increasing central plasma volume and preventing plasma pooling. A number of agents have been studied for this purpose.
Midodrine, a peripheral selective direct alpha-1 adrenoreceptor agonist, is the only FDA-approved agent that is specifically indicated for treatment of orthostatic hypotension. It works by inducing both arterial and venous constriction. Midodrine is enzymatically hydrolyzed to the pharmacologically active metabolite, desglymidodrine. Desglymidodrine works by binding to alpha-1 receptors on arteries and veins, producing an increase in vascular tone and elevating blood pressure. 30 Dosing should start at 2.5 mg three times per day, while gradually increasing to a target dose of 10 mg three times per day. Midodrine should be dosed in three- to four-hour intervals and should not be administered within four hours of bedtime or in the evening, because the drug can increase the incidence of supine hypertension.28 In a randomized, double-blind, placebo-controlled study by Low et al., 171 patients with orthostatic hypotension were randomized to receive either placebo or midodrine 10 mg three times per day for a period of six weeks.31 On day 15 of the treatment period, midodrine improved systolic blood pressure while standing by 22.4 mmHg (24%) versus 6 mmHg (6%) with placebo (P <.01). Midodrine improved diastolic blood pressure during standing by 13.3 mmHg (21%) versus 4.3 mmHg (7%) with placebo (P <.01). Reports of light-headedness by the end of the second week of treatment was lower (P = .001) and the global symptom relief score rated by both the patient (P = 0.03) and the investigator (P <.001) was higher in the midodrine group. The most common adverse effects were piloerection, urinary retention, and supine hypertension.
Fludrocortisone, a synthetic mineralocorticoid, is used as a first-line agent. Small oral doses produce marked sodium retention and increased urinary potassium excretion with a resultant rise in blood pressure which is apparently due to increased angiotensin activity and fluid retention.32,33 Treatment is started at 0.1 mg daily, and maintenance doses usually range from 0.1 to 0.4 mg daily, with titration of 0.1 mg occurring at about one- to two-week intervals.28 Side effects include hypokalemia, which may necessitate potassium supplementation, as well as edema, dizziness, headaches, and supine hypertension. Electrolytes should be checked one week following initiation of therapy and approximately each week following a dose increase.
Dihydroergotamine (DHE) causes vasoconstriction by stimulating alpha-adrenergic receptors and by inhibiting reuptake of norepinephrine, leading to increases in venous return and decreases in venous stasis and pooling.34 Dosing should start at 1.0 mg intramuscularly (IM) once daily or at 0.0065 to 0.013 mg/kg subcutaneously (SC) once daily in the morning. Maximum dosage is 3.0 mg IM or SC in a 24-hour period and 6.0 mg IM or SC on a weekly basis. Side effects include myalgia, numbness and tingling in extremities, edema, pruritus, dizziness, and hypertension.
Erythropoietin has also been utilized for management of orthostatic hypotension. Anemia is now considered to be an important cause of orthostatic hypotension, and treatment with erythropoietin increases intravascular volume, leading to improvements in orthostatic tolerance.35 The recommended dose is 25 to 50 U/kg SC three times per week. In a small clinical study by Perera et al., treatment with erythropoietin (4,000 U SC biweekly for six weeks) increased hematocrit and blood pressure in all patients.36 Hematocrit increased from 33.9% ± 0.7% to 44.3% ± 1.4%, blood pressure in supine position increased from 150 ± 8 mmHg/87 ± 8 mmHg to 166 ± 25 mmHg/92 ± 12 mmHg (P <.05), and after three minutes in the head-up tilt position, from 86 ± 21 mmHg/47 ± 15 mmHg to 102 ± 23 mmHg/63 ± 12 mmHg, (P <.05). Side effects include headache, seizures, edema, and hypertension.
Octreotide is a long-acting somatostatin analogue that inhibits the secretion of hormones involved in vasodilation, including vasoactive intestinal peptide. Octreotide increases splanchnic arteriolar resistance and decreases gastrointestinal blood flow, resulting in increases in both semirecumbent and standing blood pressure, and is most useful in patients with autonomic orthostatic hypotension.37,38 The recommended doses range from 0.2 to 0.4 mcg/kg SC, with a maximum dose of up to 1.6 mcg/kg. The effectiveness of octreotide was studied in a small uncontrolled study by Hoeldtke and Israel.38 Doses ranging from 0.2 to 0.4 mcg/kg resulted in an average increase in semirecumbent mean blood pressure of 15 to 20 mmHg in patients with autonomic failure and diabetic autonomic neuropathy. Its use is limited by the fact that gastrointestinal symptoms worsen in patients who initially have these symptoms. Other side effects include nausea, vomiting, diarrhea, and hyperglycemia.
Clonidine, an alpha-2 receptor agonist, is used to treat orthostatic hypotension in patients with severe autonomic dysfunction. Clonidine stimulates alpha-1 receptors in peripheral vascular smooth muscle, resulting in acute vasoconstriction and an increase in blood pressure.39 The central hypotensive effect of this drug is reduced in this patient population.26The doses of clonidine that have been studied for this indication include 0.4 and 0.8 mg daily, in twice-daily dosing. Side effects include sedation, dry mouth, altered mental status, and excessive hypertension. 39
Pyridostigmine, an acetylcholinesterase inhibitor, may be utilized for the treatment of orthostatic hypotension. This drug works by enhancing sympathetic ganglion transmission, thereby leading to increased systemic resistance. In a study by Singer et al., 15 patients with neurogenic orthostatic hypotension who were treated with pyridostigmine 60 mg showed increases in their orthostatic pressure and improvements in their orthostatic symptoms (P >.05).40 Side effects include abdominal cramps, blurred vision, diaphoresis, diarrhea, and miosis.
Other agents that have been utilized in a small number of patients include desmopressin acetate, yohimbine, indomethacin, ephedrine, pseudoephedrine, ergotamine, vitamin B12, fluoxetine, and nonselective beta-blockers such as pindolol.28 Combination therapy consisting of midodrine and fludrocortisone, midodrine and pyridostigmine, or midodrine and octreotide has demonstrated increases in blood pressure compared with monotherapy.28,37,41 Studies evaluating these combination therapies have been of short duration; therefore, the impact of combination therapy on adverse events has been minimal. Another treatment option for patients with severe orthostatic hypotension is placement of dual-chamber pacemakers.25
The Pharmacist's Role
Education and prevention are important components of caring for patients with orthostatic hypotension, and that is where pharmacists should and must play a major role. Pharmacists can educate patients and caregivers about the appropriateness of following nonpharmacologic treatment strategies. Patients and caregivers must be educated about following preventive strategies, including proper diet and physical activity.
In addition, pharmacists must take an active role in educating, identifying, and assisting in the selection and modification of appropriate medication for hypertension. Pharmacists should take a complete medical history to determine if the cause of orthostatic hypotension is drug induced and contact a physician to assist in the selection of alternative treatments, with the goal of minimizing the number of medications that may induce orthostatic hypotension and its complications.
If a patient is taking a potentially causative medication, the primary treatment of choice is discontinuation of the drug. In fact, simply stopping antihypertensive therapy can successfully treat orthostatic hypotension in half the patients with these symptoms.42,43 Ending treatment with certain classes of antihypertensives, such as diuretics, vasodilators, nondihydropyridine calcium channel antagonists, and alpha-blockers has shown greater promise in treating orthostatic hypotension, compared with others such as angiotensin-converting enzyme inhibitors, beta-antagonists with intrinsic sympathomimetic activity, and angiotensin-receptor antagonists.
Orthostatic hypotension is a common cause of increased morbidity and mortality, especially in the elderly population. There are many reversible and nonreversible causes of orthostatic hypotension, both neurogenic and nonneurogenic. Pharmacists have a role in educating patients about both pharmacologic and nonpharmacologic modalities for controling and preventing the incidence and consequences of orthostatic hypotension.
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