Pharmacological Management

Drug treatment is an important part of the overall therapeutic regimen and, if used well, greatly enhances BP control (44). The main drugs are midodrine, pyridostigmine, and possibly fludrocortisone.


The optimal approach, with the availability of midodrine, is to expand plasma volume modestly with increased salt and fluid intake without aggravating supine hypertension and to add midodrine during the waking period to reduce OH. The safest approach to volume expansion is oral salt supplementation. The best guide to adequate salt intake is the 24-hour urinary sodium. The patient has a normal plasma volume and adequate salt intake if the 24-hour urine sodium is at or slightly exceeds 170 mequivalents per 24 hours. Patients who achieve this excretion have normal measured plasma volumes (39). To ensure adequate fluid intake, it is optimal to aim for a volume of 1500-2500 mL in 24 hours.

Midodrine is a directly acting a-agonist (45). The minimal effective dose of mido-drine is 5 mg. Most patients respond best to 10 mg. The duration of action is between 2 and 4 hours, corresponding to the blood levels of midodrine and its active metabolite desglymidodrine (46). The onset of action is between 30 minutes and 1 hour. In some patients, the duration of action of midodrine is short, less than 4 hours. Because one of the mechanisms of hypertensive swings is severe hypotension, it is best to increase the frequency of dosing to every 3 hours during the period of maximal orthostatic stress. Patients should generally avoid midodrine after 6 PM so as not to aggravate supine nocturnal hypertension. The main limiting factor is the worsening of supine BP. The drug dose-dependently increases both supine and standing BP (46).


As baroreflex activity is modest with the patient supine and increases proportional to orthostatic stress, a novel approach in treatment is to enhance ganglionic transmission (through autonomic ganglia) by acetylcholinesterase inhibition (47). Pyridostigmine has minimal effect on supine BP, but improves standing BP (by enhancing standing baroreflex-mediated vasoconstriction). It functions as a smart drug, improving OH without aggravating supine hypertension (Fig. 1). The preferred dose is 180 mg per day as the time span. To minimize cholinergic side effect, the drug can be started as 30 mg morning and noon and slowly increased.


For patients who cannot take enough salt or who do not have an adequate response to midodrine, fludrocortisone, 0.1 mg once or twice daily, can be added to provide volume expansion and to sensitize vascular smooth muscle. This approach of reducing dependence on fludrocortisone and avoiding nocturnal midodrine substantially reduces supine hypertension. Uncommonly, the dose of fludrocortisone may be increased to 0.4 or 0.6 mg daily for patients with refractory OH. Because the regulatory reflexes are greatly impaired, it is necessary to overexpand the plasma volume slightly in these patients. A reasonable clue for adequate volume expansion is a weight gain of 3-5 pounds. Mild dependent edema is to be expected. The potential risks are congestive heart failure and excessive supine hypertension. Two weeks after starting treatment with fludrocortisone, patients should have their BP checked while supine and standing.

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