Page 165 - Basic _ Clinical Pharmacology ( PDFDrive )

CHAPTER 9 Adrenoceptor Agonists & Sympathomimetic Drugs 151

B. Catecholamine Reuptake Inhibitors in the treatment of Parkinson’s disease and prolactinemia. These
Many inhibitors of the amine transporters for norepinephrine, agents are discussed in Chapters 28 and 37.
dopamine, and serotonin are used clinically. Although specificity Fenoldopam is a D -receptor agonist that selectively leads to
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is not absolute, some are highly selective for one of the transport- peripheral vasodilation in some vascular beds. The primary indi-
ers. Many antidepressants, particularly the older tricyclic antide- cation for fenoldopam is in the intravenous treatment of severe
pressants, can inhibit norepinephrine and serotonin reuptake to hypertension (see Chapter 11).
different degrees. Some antidepressants of this class, particularly
imipramine, can induce orthostatic hypotension presumably by
their clonidine-like effect or by blocking α receptors, but the THERAPEUTIC USES OF
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mechanism remains unclear. SYMPATHOMIMETIC DRUGS
Atomoxetine is a selective inhibitor of the norepinephrine
reuptake transporter. Its actions, therefore, are mediated by poten-
tiation of norepinephrine levels in noradrenergic synapses. It is Cardiovascular Applications
used in the treatment of attention deficit disorders (see below). In keeping with the critical role of the sympathetic nervous system
Reboxetine (investigational in the USA) has similar character- in the control of blood pressure, a major area of application of the
istics to atomoxetine but is used mainly for major depression sympathomimetics is in cardiovascular conditions.
disorder. Because reuptake inhibitors potentiate norepinephrine
actions, there is concern about their cardiovascular safety. Atom- A. Treatment of Acute Hypotension
oxetine has surprisingly little cardiovascular effect because it has a
clonidine-like effect in the CNS to decrease sympathetic outflow Acute hypotension may occur in a variety of settings such as
while at the same time potentiating the effects of norepinephrine severe hemorrhage, decreased blood volume, cardiac arrhythmias,
in the periphery. However, it may increase blood pressure in some neurologic disease or accidents, adverse reactions or overdose of
patients. Norepinephrine reuptake is particularly important in the medications such as antihypertensive drugs, and infection. If cere-
heart, especially during sympathetic stimulation, and this explains bral, renal, and cardiac perfusion is maintained, hypotension itself
why atomoxetine and other norepinephrine reuptake inhibitors does not usually require vigorous direct treatment. Rather, placing
can cause orthostatic tachycardia. Pharmacoepidemiologic studies the patient in the recumbent position and ensuring adequate fluid
have not found significant adverse cardiovascular events associated volume while the primary problem is determined and treated is
with the use of norepinephrine reuptake inhibitors. However, usually the correct course of action. The use of sympathomimetic
sibutramine, a serotonin and norepinephrine reuptake inhibitor drugs merely to elevate a blood pressure that is not an immediate
used as an appetite suppressant, was taken off the market because threat to the patient may increase morbidity. However, sympatho-
it was associated with a small increase in cardiovascular events, mimetics may be required in cases of sustained hypotension with
including strokes, in patients with a history of cardiovascular evidence of tissue hypoperfusion.
disease. Duloxetine is a widely used antidepressant with balanced Shock is a complex acute cardiovascular syndrome that results
serotonin and norepinephrine reuptake inhibitory effects (see in a critical reduction in perfusion of vital tissues and a wide
Chapter 30). Increased cardiovascular risk has not been reported range of systemic effects. Shock is usually associated with hypo-
with duloxetine. Duloxetine and milnacipran, another serotonin tension, an altered mental state, oliguria, and metabolic acidosis.
and norepinephrine transporter blocker, are approved for the If untreated, shock usually progresses to a refractory deteriorating
treatment of pain in fibromyalgia (see Chapter 30). state and death. The three major forms of shock are septic, car-
Cocaine is a local anesthetic with a peripheral sympathomi- diogenic, and hypovolemic. Volume replacement and treatment of
metic action that results from inhibition of transmitter reuptake the underlying disease are the mainstays of the treatment of shock.
at noradrenergic synapses (Figure 9–3). It readily enters the CNS If vasopressors are needed, adrenergic agonists with both α and
and produces an amphetamine-like psychological effect that is β activity are preferred. Pure β-adrenergic stimulation increases
shorter lasting and more intense than amphetamine. The major blood flow but also increases the risk of myocardial ischemia.
action of cocaine in the CNS is to inhibit dopamine reuptake into Pure α-adrenergic stimulation increases vascular tone and blood
neurons in the “pleasure centers” of the brain. These properties pressure but can also decrease cardiac output and impair tissue
and the fact that a rapid onset of action can be obtained when blood flow. Norepinephrine provides an acceptable balance and
smoked, snorted, or injected have made cocaine a heavily abused is considered the vasopressor of first choice: it has predominantly
drug (see Chapter 32). It is interesting that dopamine-transporter α-adrenergic properties, but its modest β-adrenergic effects help
knockout mice still self-administer cocaine, suggesting that to maintain cardiac output. Administration generally results in a
cocaine may have additional pharmacologic targets. clinically significant increase in mean arterial pressure, with little
change in heart rate or cardiac output. Dopamine has no advan-
Dopamine Agonists tage over norepinephrine because it is associated with a higher
incidence of arrhythmias and mortality. However, dobutamine
Levodopa, which is converted to dopamine in the body, and is arguably the inotropic agent of choice when increased cardiac
dopamine agonists with central actions are of considerable value output is needed.