A 68-year-old man presents with a complaint of light-headedness on standing that is worse after meals and in hot environments. Symptoms started about 4 years ago and have slowly progressed to the point that he is disabled. He has fainted several times but always recovers consciousness almost as soon as he falls. Other symptoms include slight worsening of constipation, urinary retention out of proportion to prostate size, and decreased sweating. He is otherwise healthy with no history of hypertension, diabetes, or Parkinson disease. Because of urinary retention, he was placed on the α1A antagonist tamsulosin, but the fainting spells got worse. Physical examination is unremarkable except for a blood pressure of 167/84 mm Hg supine and 106/55 mm Hg standing. There was an inadequate compensatory increase in heart rate (from 84 to 88 bpm), considering the magnitude of orthostatic hypotension. There is no evidence of peripheral neuropathy or parkinsonian features. Laboratory examinations are negative except for a low plasma norepinephrine (98 pg/mL; normal for his age 250–400 pg/mL). A diagnosis of pure autonomic failure is made, based on the clinical picture and the absence of drugs that could induce orthostatic hypotension and diseases commonly associated with autonomic neuropathy (eg, diabetes, Parkinson disease). What precautions should this patient observe in using sympathomimetic drugs? Can such drugs be used in his treatment?
The sympathetic nervous system is an important regulator of virtually all organ systems.* This is particularly evident in the regulation of blood pressure. As illustrated in the case study, the sympathetic nervous system is required to maintain blood pressure stable even under relatively minor situations of stress. For example, during standing, the gravitational pooling of blood in the lower body triggers sympathetic stimulation that causes the release of norepinephrine from nerve terminals, which then activates adrenoceptors on postsynaptic sites (see Chapter 6) to restore blood pressure. Also, in response to more stressful situations (eg, hypoglycemia), sympathetic activation causes the adrenal medulla to release epinephrine, which is then transported in the blood to target tissues. In other words, epinephrine acts as a hormone, whereas norepinephrine acts as a neurotransmitter. Both have a role in the “fight or flight” response that characterizes sympathetic activation.
Drugs that mimic the actions of epinephrine or norepinephrine have traditionally been termed sympathomimetic drugs. The sympathomimetics can be grouped by mode of action and by the spectrum of receptors that they activate. Some of these drugs (e.g., norepinephrine and epinephrine) are direct agonists; they directly interact with and activate adrenoceptors. Others are indirect agonists because their actions are dependent on their ability to enhance the actions of endogenous catecholamines by (1) inducing the release of catecholamines by displacing them from adrenergic nerve endings (e.g., the mechanism of action of tyramine), (2) decreasing the clearance of catecholamines by inhibiting their neuronal reuptake (e.g., the mechanism of action of cocaine and certain antidepressants), or (3) preventing the ...