Therapeutic strategies for orthostatic intolerance: mechanisms, observations, and making patients feel better.

Abnormalities in orthostatic tolerance result from a number of disease processes and are often disabling and difficult to treat. Conditions resulting in orthostatic intolerance include primary autonomic failure, multiple system atrophy, autonomic neuropathy due to systemic conditions such as diabetes and amyloidosis, and idiopathic orthostatic intolerance (also known as chronic orthostatic intolerance or postural orthostatic tachycardia syndrome, among other names). Whereas the former conditions are due to well-defined, identifiable, autonomic neuropathic states, the pathophysiology of idiopathic orthostatic intolerance is less clear. There are also other disorders of orthostatic tolerance that are associated with drug therapy, whether because of hypovolemia due to diuretics or due to impaired vasoconstriction resulting from drugs such as prazosin. Aging and prolonged bed rest may also induce varying degrees of orthostatic intolerance in healthy persons. In patients with orthostatic intolerance due to hypotension, the inability to maintain blood pressure while standing can be consequent upon decreased blood volume, impaired arterial and venous constriction, or inappropriate cardiac chronotropic responses to standing. By contrast, in patients with idiopathic orthostatic intolerance, blood pressure does not fall, heart rate is fast, and symptoms of palpitations, lightheadedness, fainting, dizziness, and even syncope develop (1,2). Although it is important to differentiate between hypotensive orthostatic intolerance and idiopathic orthostatic intolerance, both conditions may benefit from treatment with the same agents. Therapeutic strategies based on pathophysiologic mechanisms are typically directed at increasing blood volume, enhancing venous return (by crossing legs [3] or with compression stockings), inducing systemic arterial vasoconstriction or venoconstriction, and improving the heart rate response to standing. The paradoxes that characterize hypoadrenergic orthostatic hypotension may modify treatment approaches. First, the supine hypertension that is typical of these conditions is often exacerbated by some of the therapeutic options, thus enhancing the likelihood of developing hypertensive end organ disease (4). Second, adrenergic receptor sensitivity may increase because of low levels of norepinephrine (5,6). Alpha-2 (2) adrenergic agonists such as clonidine, which normally lower blood pressure (7), instead induce arterial constriction, increase forearm vascular resistance, and increase supine blood pressure (8). Third, these patients demonstrate excellent autoregulation of the cerebral circulation and are often able to tolerate systemic blood pressures70 mm Hg while standing, with only minimal symptoms (9). This issue of the Journal includes two papers related to the treatment of patients with orthostatic syndromes. The paper by Victor and Talman (8) concerns a mechanism in search of a therapeutic effect, whereas Shannon et al. (10) describe a therapeutic effect in search of a mechanism. These different investigative strategies offer promising approaches with the potential to affect patient management. Victor and Talman note that postjunctional -adrenergic receptors are located mainly on venous capacitance rather than arterial resistance vessels. They hypothesize that the -adrenergic agonist clonidine, which raises blood pressure in patients with hypoadrenergic orthostatic hypotension, may maintain standing blood pressure in these patients through venoconstriction. Their data show that both clonidine and dihydroergotamine increased supine blood pressure and forearm vascular resistance. Dihydroergotamine, a known venoconstrictor agent, increased venous tone, whereas clonidine had no significant effect. This differential physiologic effect may have important implications for predicting the therapeutic response since dihydroergotamine improved orthostatic tolerance far more than did clonidine. Clonidine was also associated with stupor and central apnea that