Page 166 - Basic _ Clinical Pharmacology ( PDFDrive )

152 SECTION II Autonomic Drugs

B. Chronic Orthostatic Hypotension Epinephrine, 1:200,000, is the favored agent for this application.
On standing, gravitational forces induce venous pooling, resulting Systemic effects on the heart and peripheral vasculature may occur
in decreased venous return. Normally, a decrease in blood pressure is even with local drug administration but are usually minimal. Use
prevented by reflex sympathetic activation with increased heart rate, of epinephrine with local anesthesia of acral vascular beds (digits,
and peripheral arterial and venous vasoconstriction. Impairment of nose, and ears) has not been advised because of fear of ischemic
autonomic reflexes that regulate blood pressure can lead to chronic necrosis. Recent studies suggest that it can be used (with caution)
orthostatic hypotension. This is more often due to medications for this indication.
that can interfere with autonomic function (eg, imipramine and Alpha agonists can be used topically as mucous membrane
other tricyclic antidepressants, α blockers for the treatment of uri- decongestants to reduce the discomfort of allergic rhinitis or the
nary retention, and diuretics), diabetes, and other diseases causing common cold by decreasing the volume of the nasal mucosa.
peripheral autonomic neuropathies, and less commonly, primary These effects are probably mediated by α 1 receptors. Unfortu-
degenerative disorders of the autonomic nervous system, as in the nately, rebound hyperemia may follow the use of these agents,
case study described at the beginning of the chapter. and repeated topical use of high drug concentrations may result in
Increasing peripheral resistance is one of the strategies to treat ischemic changes in the mucous membranes, probably as a result
chronic orthostatic hypotension, and drugs activating α recep- of vasoconstriction of nutrient arteries. Constriction of the latter
tors can be used for this purpose. Midodrine, an orally active α vessels may involve activation of α receptors, and phenylephrine or
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agonist, is frequently used for this indication. Other sympathomi- the longer-acting oxymetazoline are often used in over-the-counter
metics, such as oral ephedrine or phenylephrine, can be tried. A nasal decongestants. A longer duration of action—at the cost of
novel approach to treat orthostatic hypotension is droxidopa, a much lower local concentrations and greater potential for cardiac
synthetic (L-threo-dihydrophenylserine, L-DOPS) molecule that and CNS effects—can be achieved by the oral administration of
has been approved by the FDA to treat neurogenic orthostatic agents such as ephedrine or one of its isomers, pseudoephedrine.
hypotension. It is a prodrug that is converted to norepinephrine
by the aromatic L-amino acid decarboxylase (dopa-decarboxylase), Pulmonary Applications
the enzyme that converts L-dopa to dopamine. One of the most important uses of sympathomimetic drugs is in
the therapy of asthma and chronic obstructive pulmonary disease
C. Cardiac Applications (COPD; discussed in more detail in Chapter 20). Beta -selective
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Epinephrine is used during resuscitation from cardiac arrest. drugs (albuterol, metaproterenol, terbutaline) are used for this
Current evidence indicates that it improves the chance of return- purpose to reduce the adverse effects that would be associated
ing to spontaneous circulation, but it is less clear that it improves with β stimulation. Short-acting preparations can be used only
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survival or long-term neurologic outcomes and this is an area of transiently for acute treatment of asthma symptoms. For chronic
active investigation. asthma treatment in adults, long-acting β agonists should only
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Dobutamine is used as a pharmacologic cardiac stress be used in combination with steroids because their use in mono-
test. Dobutamine augments myocardial contractility and pro- therapy has been associated with increased mortality. Long-acting
motes coronary and systemic vasodilation. These actions lead to β agonists are also used in patients with COPD. Indacaterol,
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increased heart rate and increased myocardial work and can reveal olodaterol, and vilanterol, new ultralong β agonists, have been
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areas of ischemia in the myocardium that are detected by echocar- approved by the FDA for once-a-day use in COPD. Nonselective
diogram or nuclear medicine techniques. Dobutamine can thus be drugs are now rarely used because they are likely to have more
used in patients unable to exercise during the stress test. adverse effects than the selective drugs.
D. Inducing Local Vasoconstriction Anaphylaxis
Reduction of local or regional blood flow is desirable for achiev-
ing hemostasis during surgery, for reducing diffusion of local Anaphylactic shock and related immediate (type I) IgE-mediated
anesthetics away from the site of administration, and for reducing reactions affect both the respiratory and the cardiovascular systems.
mucous membrane congestion. In each instance, α-receptor acti- The syndrome of bronchospasm, mucous membrane congestion,
vation is desired, and the choice of agent depends on the maximal angioedema, and severe hypotension usually responds rapidly
efficacy required, the desired duration of action, and the route of to the parenteral administration of epinephrine, 0.3–0.5 mg
administration. (0.3–0.5 mL of a 1:1000 epinephrine solution). Intramuscular
Effective pharmacologic hemostasis is often necessary for facial, injection may be the preferred route of administration, since
oral, and nasopharyngeal surgery. Epinephrine is usually applied skin blood flow (and hence systemic drug absorption from sub-
topically in nasal packs (for epistaxis) or in a gingival string (for cutaneous injection) is unpredictable in hypotensive patients. In
gingivectomy). Cocaine is still sometimes used for nasopharyn- some patients with impaired cardiovascular function, intravenous
geal surgery because it combines a hemostatic effect with local injection of epinephrine may be required. The use of epinephrine
anesthesia. for anaphylaxis precedes the era of controlled clinical trials, but
Combining α agonists with some local anesthetics greatly extensive experimental and clinical experience supports its use as
prolongs their duration of action; the total dose of local anesthetic the agent of choice. Epinephrine activates α, β 1 , and β receptors,
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(and the probability of systemic toxicity) can therefore be reduced. all of which may be important in reversing the pathophysiologic