Page 306 - Basic _ Clinical Pharmacology ( PDFDrive )

292 SECTION IV Drugs with Important Actions on Smooth Muscle

no effect on the gastric secretion stimulated by histamine. It also acetylcholine, tyramine, and other biologically active products in
has significant antimuscarinic effects and causes sedation. addition to a score or more of unique ergot alkaloids. These alka-
The major clinical applications of cyproheptadine are in the loids affect α adrenoceptors, dopamine receptors, 5-HT receptors,
treatment of the smooth muscle manifestations of carcinoid and perhaps other receptor types. Similar alkaloids are produced
tumor and in cold-induced urticaria. The usual dosage in adults by fungi parasitic to a number of other grass-like plants.
is 12–16 mg/d orally in three or four divided doses. It is of some The accidental ingestion of ergot alkaloids in contaminated
value in serotonin syndrome, but because it is available only in grain can be traced back more than 2000 years from descriptions
tablet form, cyproheptadine must be crushed and administered by of epidemics of ergot poisoning (ergotism). The most dramatic
stomach tube in unconscious patients. The drug also appears to effects of poisoning are dementia with florid hallucinations;
reduce muscle spasms following spinal cord injury, in which con- prolonged vasospasm, which may result in gangrene; and stimu-
stitutive activity of 5-HT receptors is associated with increases lation of uterine smooth muscle, which in pregnancy may result
2C
2+
in Ca currents leading to spasms. Anecdotal evidence suggests in abortion. In medieval times, ergot poisoning was called
some efficacy as an appetite stimulant in cancer patients, but St. Anthony’s fire after the saint whose help was sought in
controlled trials have yielded mixed results. relieving the burning pain of vasospastic ischemia. Identifiable
Ketanserin blocks 5-HT receptors on smooth muscle and epidemics have occurred sporadically up to modern times (see
2
other tissues and has little or no reported antagonist activity at Box: Ergot Poisoning: Not Just an Ancient Disease) and mandate
other 5-HT or H receptors. However, this drug potently blocks continuous surveillance of all grains used for food. Poisoning of
1
vascular α adrenoceptors. The drug blocks 5-HT receptors on grazing animals is common in many areas because the fungus
1
2
platelets and antagonizes platelet aggregation promoted by may grow on pasture grasses.
serotonin. The mechanism involved in ketanserin’s hypotensive In addition to the effects noted above, the ergot alkaloids
action probably involves α adrenoceptor blockade more than produce a variety of other central nervous system and peripheral
1
5-HT receptor blockade. Ketanserin is available in Europe for effects. Detailed structure-activity analysis and appropriate semi-
2
the treatment of hypertension and vasospastic conditions but synthetic modifications have yielded a large number of agents of
has not been approved in the USA. Ritanserin, another 5-HT experimental and clinical interest.
2
antagonist, has little or no α-blocking action. It has been reported
to alter bleeding time and to reduce thromboxane formation,
presumably by altering platelet function. BASIC PHARMACOLOGY OF ERGOT
Ondansetron is the prototypical 5-HT antagonist. This drug ALKALOIDS
3
and its analogs are very important in the prevention of nausea and
vomiting associated with surgery and cancer chemotherapy. They Chemistry & Pharmacokinetics
are discussed in Chapter 62.
Considering the diverse effects attributed to serotonin and the Two major families of compounds that incorporate the tetracyclic
heterogeneous nature of 5-HT receptors, other selective 5-HT ergoline nucleus may be identified; the amine alkaloids and the
antagonists may prove to be clinically useful. peptide alkaloids (Table 16–7). Drugs of therapeutic and toxico-
logic importance are found in both groups.
The ergot alkaloids are variably absorbed from the gastro-
■ THE ERGOT ALKALOIDS intestinal tract. The oral dose of ergotamine is about 10 times
larger than the intramuscular dose, but the speed of absorption
Ergot alkaloids are produced by Claviceps purpurea, a fungus that and peak blood levels after oral administration can be improved
infects grasses and grains—especially rye—under damp growing by administration with caffeine (see below). The amine alkaloids
or storage conditions. This fungus synthesizes histamine, are also absorbed from the rectum and the buccal cavity and after

Ergot Poisoning: Not Just an Ancient Disease

As noted in the text, epidemics of ergotism, or poisoning by ergotism occurred in the small French village of Pont-Saint-Esprit
ergot-contaminated grain, are known to have occurred sporadi- in 1951. It was vividly described in the British Medical Journal in
cally in ancient times and through the Middle Ages. It is easy to 1951 (Gabbai et al, 1951) and in a later book-length narrative
imagine the social chaos that might result if fiery pain, gangrene, account (Fuller, 1968). Several hundred individuals suffered symp-
hallucinations, convulsions, and abortions occurred simultane- toms of hallucinations, convulsions, and ischemia—and several
ously throughout a community in which all or most of the people died—after eating bread made from contaminated flour. Similar
believed in witchcraft, demonic possession, and the visitation events have occurred even more recently when poverty, famine,
of supernatural punishments upon humans for their misdeeds. or incompetence resulted in the consumption of contaminated
Fortunately, such beliefs are uncommon today. However, ergot- grain. Ergot toxicity caused by excessive self-medication with
ism has not disappeared. A most convincing demonstration of pharmaceutical ergot preparations is still occasionally reported.