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As noted previously, indirect-acting sympathomimetics can have one of two different mechanisms (Figure 9–3). First, they may enter the sympathetic nerve ending and displace stored cate-cholamine transmitter. Such drugs have been called amphetamine-like or “displacers.” Second, they may inhibit the reuptake of released transmitter by interfering with the action of the norepi-nephrine transporter, NET
Amphetamine is a racemic mixture of phenylisopropylamine(Figure 9–5) that is important chiefly because of its use and misuse as a central nervous system stimulant . Pharmacokinetically, it is similar to ephedrine; however, amphet-amine even more readily enters the central nervous system, where it has marked stimulant effects on mood and alertness and a depressant effect on appetite. Its D-isomer is more potent than the L-isomer. Amphetamine’s actions are mediated through the release of norepinephrine and, to some extent, dopamine.
Methamphetamine (N-methylamphetamine) is very similar toamphetamine with an even higher ratio of central to peripheral actions. Phenmetrazine is a variant phenylisopropylamine with amphetamine-like effects. It has been promoted as an anorexiant and is also a popular drug of abuse. Methylphenidate is an amphetamine variant whose major pharmacologic effects and abuse potential are similar to those of amphetamine. Methylphenidate may be effective in some children with attention deficit hyperactivity disorder (see Therapeutic Uses of Sympathomimetic Drugs). Modafinil is a psychostimulant that differs from amphetamine in structure, neurochemical profile, and behavioral effects. Its mechanism of action is not fully known. It inhibits both norepinephrine and dopamine transporters, and it increases synaptic concentrations not only of norepinephrine and dopamine, but also of serotonin and glutamate, while decreasing GABA levels. It is used primarily to improve wakefulness in nar-colepsy and some other conditions. It is often associated with increases in blood pressure and heart rate, though these are usually mild (see Therapeutic Uses of Sympathomimetic Drugs).
Tyramine (see Figure 6–5) is a normal by product of tyrosinemetabolism in the body and can be produced in high concentra-tions in protein-rich foods by decarboxylation of tyrosine during fermentation (Table 9–5). It is readily metabolized by MAO in the liver and is normally inactive when taken orally because of a very high first-pass effect, ie, low bioavailability. If administered paren-terally, it has an indirect sympathomimetic action caused by the release of stored catecholamines. Consequently, tyramine’s spec-trum of action is similar to that of norepinephrine. In patients treated with MAO inhibitors—particularly inhibitors of the MAO-A isoform—this effect of tyramine may be greatly intensi-fied, leading to marked increases in blood pressure. This occurs because of increased bioavailability of tyramine and increased neuronal stores of catecholamines. Patients taking MAO inhibi-tors must be very careful to avoid tyramine-containing foods. There are differences in the effects of various MAO inhibitors on tyramine bioavailability, and isoform-specific or reversible enzyme antagonists may be safer.
Many inhibitors of the amine transporters for norepinephrine, dop-amine, and serotonin are used clinically. Although specificity is not absolute, some are highly selective for one of the transporters. Many antidepressants, particularly the older tricyclic antidepressants, can inhibit norepinephrine and serotonin reuptake to different degrees. This may lead to orthostatic tachycardia as a side effect. Some anti-depressants of this class, particularly imipramine, can induce ortho-static hypotension presumably by their clonidine-like effect or by blocking α1 receptors, but the mechanism remains unclear.
Atomoxetine is a selective inhibitor of the norepinephrinereuptake transporter. Its actions, therefore, are mediated by poten-tiation of norepinephrine levels in noradrenergic synapses. It is used in the treatment of attention deficit disorders . Atomoxetine has surprisingly little cardiovascular effect because it has a clonidine-like effect in the central nervous system 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 sympa-thetic stimulation, and this explains why atomoxetine and other norepinephrine reuptake inhibitors frequently cause orthostatic tachycardia. Reboxetine has similar characteristics as atomox-etine. Sibutramine is a serotonin and norepinephrine reuptake inhibitor and was initially approved by the FDA as an appetite suppressant for long-term treatment of obesity. It has been taken off the market in the United States and several other countries because it has been associated with a small increase in cardiovascu-lar events including strokes in patients with a history of cardiovas-cular disease, which outweighed the benefits gained by modest weight reduction. Duloxetine is a widely used antidepressant with balanced serotonin and norepinephrine reuptake inhibitory effects . 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 .
Cocaine is a local anesthetic with a peripheral sympathomi-metic action that results from inhibition of transmitter reuptake at noradrenergic synapses (Figure 9-3). It readily enters the central nervous system and produces an amphetamine-like psychological effect that is shorter lasting and more intense than amphetamine. The major action of cocaine in the central nervous system 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 into the nose, or injected, has made cocaine a heavily abused drug . It is interesting that dopamine-transporter knockout mice still self-administer cocaine, suggesting that cocaine may have addi-tional pharmacologic targets.
Levodopa, which is converted to dopamine in the body, and dop-amine agonists with central actions are of considerable value inthe treatment of Parkinson’s disease and prolactinemia. Fenoldopam is a D1-receptor agonist that selectively leads toperipheral vasodilation in some vascular beds. The primary indica-tion for fenoldopam is in the intravenous treatment of severe hypertension .
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