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Chapter: Basic & Clinical Pharmacology : Adrenoceptor Agonists & Sympathomimetic Drugs

Adrenoceptor Agonists & Sympathomimetic Drugs

The sympathetic nervous system is an important regulator of virtually all organ systems.

Adrenoceptor Agonists & Sympathomimetic Drugs


The sympathetic nervous system is an important regulator of virtually all organ systems. This is particularly evident in the regula-tion of blood pressure. As illustrated in the case study, the autonomic nervous system is crucial for the maintenance of blood pressure even under relatively minor situations of stress (eg, the gravitational stress of standing).The ultimate effects of sympathetic stimulation are mediated by release of norepinephrine from nerve terminals, which then activates adrenoceptors on postsynaptic sites . Also, in response to a variety of stimuli such as stress, the adrenal medulla releases epinephrine, which is transported in the blood to target tissues. In other words, epinephrine acts as a hormone, whereas norepinephrine acts as a neurotransmitter. Drugs that mimic the actions of epinephrine or norepineph-rine 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 (eg, norepinephrine and epinephrine) are direct agonists; that is, they directly interact with and activate adrenoceptors. Others are indirect agonists because their actions are dependent on their abil-ity to enhance the actions of endogenous catecholamines. These indirect agents may have either of two different mechanisms: (1) they may displace stored catecholamines from the adrenergic nerve ending (eg, the mechanism of action of tyramine), or they may decrease the clearance of released norepinephrine either by (2a) inhibiting reuptake of catecholamines already released (eg, the mechanism of action of cocaine and tricyclic antidepressants) or (2b) preventing the enzymatic metabolism of norepinephrine (monoamine oxidase and catechol-O-methyltransferase inhibi-tors). Some drugs have both direct and indirect actions. Bothtypes of sympathomimetics, direct and indirect, ultimately cause activation of adrenoceptors, leading to some or all of the charac-teristic effects of endogenous catecholamines.

The pharmacologic effects of direct agonists depend on the route of administration, their relative affinity for adrenoreceptor subtypes, and the relative expression of these receptor subtypes in target tissues. The pharmacologic effects of indirect sympathomi-metics are greater under conditions of increased sympathetic activ-ity and norepinephrine storage and release.


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 pro-gressed to the point that he is disabled. He has fainted several times, but always recovers consciousness almost as soon as he falls. Review of symptoms reveals slight worsening of constipa-tion, urinary retention out of proportion to prostate size, and decreased sweating. He is otherwise healthy with no history of hypertension, diabetes, or Parkinson’s disease. Because of his urinary retention, he was placed on the α1 antagonist tamsu-losin but he could not tolerate it because of worsening of orthostatic hypotension. Physical examination revealed 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 degree of orthostatic hypotension. Physical examination is otherwise unremarkable with no evidence of peripheral neuropathy or parkinsonian features. Laboratory examinations are negative except for plasma norepinephrine, which is low at 98 pg/mL (normal is 250–400 pg/mL for his age). A diagnosis of pure autonomic failure is made, based on the clinical picture and the absence of drugs that could induce orthostatic hypoten-sion and diseases commonly associated with autonomic neu-ropathy (eg, diabetes, Parkinson’s disease). What precautions should this patient observe in using sympathomimetic drugs? Can such drugs be used in his treatment?


The clinical picture is that of autonomic failure. The best indicator of this is the profound drop in orthostatic blood pressure without an adequate compensatory increase in heart rate. Pure autonomic failure is a neurodegenerative disorder selectively affecting peripheral autonomic fibers. Patients’ blood pressure is critically dependent on whatever residual sympathetic tone they have, hence the symptomatic worsening of orthostatic hypotension that occurred when this patient was given the α blocker tamsulosin. Conversely, these patients are hypersensitive to the pressor effects ofagonists and other sympathomimetics. For example, the agonist midodrine can increase blood pressure signifi-cantly at doses that have no effect in normal subjects and can be used to treat their orthostatic hypotension. Caution should be observed in the use of sympathomimetics (includ-ing over-the-counter agents) and sympatholytic drugs.

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