Atomoxetine is a selective inhibitor of the norepinephrine reuptake transporter. Its actions, therefore, are mediated by potentiation of norepinephrine levels in noradrenergic synapses. It is used in the treatment of attention deficit disorders (see below). Reboxetine (investigational in the USA) has similar characteristics to atomoxetine but is used mainly for major depression disorder. Because reuptake inhibitors potentiate norepinephrine actions, there is concern about their cardiovascular safety. Atomoxetine has surprisingly little cardiovascular effect because it has a clonidine-like effect in the CNS to decrease sympathetic outflow while at the same time potentiating the effects of norepinephrine in the periphery. However, it may increase blood pressure in some patients. Norepinephrine reuptake is particularly important in the heart, especially during sympathetic stimulation, and this explains why atomoxetine and other norepinephrine reuptake inhibitors can cause orthostatic tachycardia. Pharmacoepidemiologic studies have not found significant adverse cardiovascular events associated with the use of norepinephrine reuptake inhibitors. However, sibutramine, a serotonin and norepinephrine reuptake inhibitor used as an appetite suppressant, was taken off the market because it was associated with a small increase in cardiovascular events, including strokes, in patients with a history of cardiovascular disease. Duloxetine is a widely used antidepressant with balanced serotonin and norepinephrine reuptake inhibitory effects (see Chapter 30). Increased cardiovascular risk has not been reported with duloxetine. Duloxetine and milnacipran, another serotonin and norepinephrine transporter blocker, are approved for the treatment of pain in fibromyalgia (see Chapter 30).
Cocaine is a local anesthetic with a peripheral sympathomimetic action that results from inhibition of transmitter reuptake at noradrenergic synapses (Figure 9–3). It readily enters the CNS and produces an amphetamine-like psychological effect that is shorter lasting and more intense than amphetamine. The major action of cocaine in the CNS is to inhibit dopamine reuptake into neurons in the “pleasure centers” of the brain. These properties and the fact that a rapid onset of action can be obtained when smoked, snorted, or injected have made cocaine a heavily abused drug (see Chapter 32). It is interesting that dopamine-transporter knockout mice still self-administer cocaine, suggesting that cocaine may have additional pharmacologic targets.
Levodopa, which is converted to dopamine in the body, and dopamine agonists with central actions are of considerable value in the treatment of Parkinson’s disease and prolactinemia. These agents are discussed in Chapters 28 and 37.
Fenoldopam is a D1-receptor agonist that selectively leads to peripheral vasodilation in some vascular beds. The primary indication for fenoldopam is in the intravenous treatment of severe hypertension (see Chapter 11).
In keeping with the critical role of the sympathetic nervous system in the control of blood pressure, a major area of application of the sympathomimetics is in cardiovascular conditions.
A. Treatment of Acute Hypotension