Page 162 - Basic _ Clinical Pharmacology ( PDFDrive )

148 SECTION II Autonomic Drugs

In the eye, the radial pupillary dilator muscle of the iris other hand, epinephrine has been used to treat hyperkalemia in
contains α receptors; activation by drugs such as phenyleph- certain conditions, but alternatives are more commonly used.
rine causes mydriasis (see Figure 6–9). Alpha agonists increase Beta receptors and α receptors that are expressed in pancreatic
2
2
the outflow of aqueous humor from the eye and can be used islets tend to increase and decrease insulin secretion, respectively,
clinically to reduce intraocular pressure. In contrast, β agonists although the major regulator of insulin release is the plasma con-
have little effect, but β antagonists decrease the production of centration of glucose.
aqueous humor and are used in the treatment of glaucoma (see Catecholamines are important endogenous regulators of hor-
Chapter 10). mone secretion from a number of glands. As mentioned above,
In genitourinary organs, the bladder base, urethral sphinc- insulin secretion is stimulated by β receptors and inhibited by
ter, and prostate contain α receptors that mediate contrac- α receptors. Similarly, renin secretion is stimulated by β and
2
1A
1
tion and therefore promote urinary continence. This effect inhibited by α receptors; indeed, β-receptor antagonist drugs
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explains why urinary retention is a potential adverse effect may lower blood pressure in patients with hypertension at least
of administration of the α agonist midodrine, and why α in part by lowering plasma renin. Adrenoceptors also modulate
1A
1
antagonists are used in the management of symptoms of urinary the secretion of parathyroid hormone, calcitonin, thyroxine, and
flow obstruction. gastrin; however, the physiologic significance of these control
Alpha-receptor activation in the ductus deferens, seminal mechanisms is probably limited. In high concentrations, epineph-
vesicles, and prostate plays a role in normal ejaculation and rine and related agents cause leukocytosis, in part by promoting
in the detumescence of erectile tissue that normally follows demargination of sequestered white blood cells back into the
ejaculation. general circulation.
The salivary glands contain adrenoceptors that regulate the The action of sympathomimetics on the CNS varies dramati-
secretion of amylase and water. However, centrally acting sym- cally, depending on their ability to cross the blood-brain barrier.
pathomimetic drugs, eg, clonidine, produce symptoms of dry The catecholamines are almost completely excluded by this bar-
mouth. It is likely that CNS effects are responsible for this side rier, and subjective CNS effects are noted only at the highest rates
effect, although peripheral effects may contribute. of infusion. These effects have been described as ranging from
The apocrine sweat glands, located on the palms of the “nervousness” to “an adrenaline rush” or “a feeling of impend-
hands and a few other areas, are nonthermoregulatory glands that ing disaster.” Furthermore, peripheral effects of β-adrenoceptor
respond to psychological stress and adrenoceptor stimulation with agonists such as tachycardia and tremor are similar to the somatic
increased sweat production. (The diffusely distributed thermo- manifestations of anxiety. In contrast, noncatecholamines with
regulatory eccrine sweat glands are regulated by sympathetic cho- indirect actions, such as amphetamines, which readily enter the
linergic postganglionic nerves that activate muscarinic cholinergic CNS from the circulation, produce qualitatively very different
receptors; see Chapter 6.) effects on the nervous system. These actions vary from mild alert-
Sympathomimetic drugs have important effects on intermedi- ing, with improved attention to boring tasks; through elevation of
ary metabolism. Activation of β adrenoceptors in fat cells leads mood, insomnia, euphoria, and anorexia; to full-blown psychotic
to increased lipolysis with enhanced release of free fatty acids and behavior. These effects are not readily assigned to either α- or
glycerol into the blood. Beta adrenoceptors play a role in mediat- β-mediated actions and may represent enhancement of dopamine-
3
ing this response in animals, but their role in humans is not clear. mediated processes or other effects of these drugs in the CNS.
Experimentally, the β agonist mirabegron stimulates brown
3
adipose tissue in humans. The potential importance of this find-
ing is that brown fat cells (“good fat”) are thermogenic and thus SPECIFIC SYMPATHOMIMETIC DRUGS
have a positive metabolic function. Brown adipose tissue is present
in neonates, but only remnant amounts are normally found in Endogenous Catecholamines
adult humans. Therefore, it is not clear whether β 3 agonists can Epinephrine (adrenaline) is an agonist at both α and β recep-
be used therapeutically for the treatment of obesity. Human fat tors. It is therefore a very potent vasoconstrictor and cardiac
cells also contain α receptors that inhibit lipolysis by decreasing stimulant. The rise in systolic blood pressure that occurs after
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intracellular cAMP. Sympathomimetic drugs enhance glycogenol- epinephrine release or administration is caused by its positive
ysis in the liver, which leads to increased glucose release into the inotropic and chronotropic actions on the heart (predominantly
circulation. In the human liver, the effects of catecholamines are β receptors) and the vasoconstriction induced in many vascular
receptors 1
probably mediated mainly by β receptors, although α 1 beds (α receptors). Epinephrine also activates β receptors in
2
may also play a role. Catecholamines in high concentration may some vessels (eg, skeletal muscle blood vessels), leading to their
also cause metabolic acidosis. Activation of β adrenoceptors by dilation. Consequently, total peripheral resistance may actually
2
endogenous epinephrine or by sympathomimetic drugs promotes fall, explaining the fall in diastolic pressure that is sometimes seen
the uptake of potassium into cells, leading to a fall in extracellular with epinephrine injection (Figure 9–6; Table 9–4). Activation of
potassium. This may result in a fall in the plasma potassium con- β receptors in skeletal muscle contributes to increased blood flow
2
centration during stress or protect against a rise in plasma potas- during exercise. Under physiologic conditions, epinephrine func-
sium during exercise. Blockade of these receptors may accentuate tions largely as a hormone; it is released from the adrenal medulla
the rise in plasma potassium that occurs during exercise. On the and carried in the blood to distant sites of action.