Page 164 - Basic _ Clinical Pharmacology ( PDFDrive )

150 SECTION II Autonomic Drugs

Mixed-Acting Sympathomimetics known. It inhibits both norepinephrine and dopamine transport-
ers, and it increases synaptic concentrations not only of norepi-
Ephedrine occurs in various plants and has been used in China nephrine and dopamine, but also of serotonin and glutamate,
for over 2000 years; it was introduced into Western medicine in while decreasing γ-aminobutyric acid (GABA) levels. It is used
1924 as the first orally active sympathomimetic drug. It is found primarily to improve wakefulness in narcolepsy and some other
in ma huang, a popular herbal medication (see Chapter 64). Ma conditions. It is often associated with increases in blood pressure
huang contains multiple ephedrine-like alkaloids in addition to and heart rate, although these are usually mild (see Therapeutic
ephedrine. Because ephedrine is a noncatechol phenylisopropyl- Uses of Sympathomimetic Drugs).
amine (Figure 9–5), it has high bioavailability and a relatively long Tyramine (see Figure 6–5) is a normal byproduct of tyrosine
duration of action—hours rather than minutes. As with many metabolism in the body. It is an indirect sympathomimetic, induc-
other phenylisopropylamines, a significant fraction of the drug is ing the release of catecholamines from noradrenergic neurons.
excreted unchanged in the urine. Since it is a weak base, its excre- Tyramine can be produced in high concentrations in protein-
tion can be accelerated by acidification of the urine. rich foods by decarboxylation of tyrosine during fermentation
Ephedrine has not been extensively studied in humans despite (Table 9–5) but is normally inactive when taken orally because
its long history of use. Its ability to activate β receptors probably it is readily metabolized by MAO in the liver (ie, low bioavail-
accounted for its earlier use in asthma. Because it gains access to ability because of a very high first-pass effect). In patients treated
the CNS, it is a mild stimulant. The US Food and Drug Admin- with MAO inhibitors—particularly inhibitors of the MAO-A
istration (FDA) has banned the sale of ephedra-containing dietary isoform—the sympathomimetic effect of tyramine may be greatly
supplements because of safety concerns. Pseudoephedrine, one of intensified, leading to marked increases in blood pressure. This
four ephedrine enantiomers, has been available over the counter occurs because of increased bioavailability of tyramine and
as a component of many decongestant mixtures. However, the use increased neuronal stores of catecholamines. Patients taking
of pseudoephedrine as a precursor in the illicit manufacture of MAO inhibitors should avoid tyramine-containing foods (aged
methamphetamine has led to restrictions on its sale.
cheese, cured meats, and pickled food). There are differences in
the effects of various MAO inhibitors on tyramine bioavailability,
INDIRECT-ACTING and isoform-specific or reversible enzyme antagonists may be safer
(see Chapters 28 and 30).
SYMPATHOMIMETICS

As noted previously, indirect-acting sympathomimetics can have
one of two different mechanisms (Figure 9–3). First, they may TABLE 9–5 Foods reputed to have a high content
enter the sympathetic nerve ending and displace stored catechol- of tyramine or other sympathomimetic
amine transmitter. Such drugs have been called amphetamine-like agents.
or “displacers.” Second, they may inhibit the reuptake of released
transmitter by interfering with the action of the norepinephrine Food Tyramine Content of an
Average Serving
transporter, NET.
Beer 4–45 mg
A. Amphetamine-Like Broad beans, fava beans Negligible (but contains
Amphetamine is a racemic mixture of phenylisopropylamine dopamine)
(Figure 9–5) that is important chiefly because of its use and Cheese, natural or aged Nil to 130 mg (cheddar, Gruyère,
and Stilton especially high)
misuse as a CNS stimulant (see Chapter 32). Pharmacokinetically,
it is similar to ephedrine; however, amphetamine enters the CNS Chicken liver Nil to 9 mg
even more readily, where it has marked stimulant effects on mood Chocolate Negligible (but contains
and alertness and a depressant effect on appetite. Its d-isomer is phenylethylamine)
more potent than the l-isomer. Amphetamine’s actions are medi- Sausage, fermented (eg, salami, Nil to 74 mg
ated through the release of norepinephrine and, to some extent, pepperoni, summer sausage)
dopamine. Smoked or pickled fish Nil to 198 mg
(eg, pickled herring)
Methamphetamine (N-methylamphetamine) is very similar
to amphetamine, with an even higher ratio of central to periph- Wine (red) Nil to 3 mg
eral actions. Methylphenidate is an amphetamine variant whose Yeast (eg, dietary brewer’s 2–68 mg
major pharmacologic effects and abuse potential are similar to yeast supplements)
those of amphetamine. Methylphenidate may be effective in chil- Note: In a patient taking an irreversible monoamine oxidase (MAO) inhibitor drug,
dren with attention deficit hyperactivity disorder (see Therapeutic 20–50 mg of tyramine in a meal may increase the blood pressure significantly (see
also Chapter 30: Antidepressant Agents). Note that only cheese, sausage, pickled fish,
Uses of Sympathomimetic Drugs). Modafinil is a psychostimu- and yeast supplements contain sufficient tyramine to be consistently dangerous. This
lant that differs from amphetamine in structure, neurochemical does not rule out the possibility that some preparations of other foods might contain
significantly greater than average amounts of tyramine. Amounts in mg as per regu-
profile, and behavioral effects. Its mechanism of action is not fully lar food portion.