Page 1110 - Basic _ Clinical Pharmacology ( PDFDrive )

1096 SECTION X Special Topics

PROSTAGLANDIN ANALOGS Bismuth compounds are used in four-drug regimens for the
eradication of H pylori infection (see earlier discussion of H pylori-
Chemistry & Pharmacokinetics associated ulcers). One regimen consists of a PPI twice daily
combined with bismuth subsalicylate (two tablets; 262 mg each),
The human gastrointestinal mucosa synthesizes a number of pros- tetracycline (250–500 mg), and metronidazole (500 mg) four
taglandins (see Chapter 18); the primary ones are prostaglandins E times daily for 10–14 days. Another regimen consists of a PPI
and F. Misoprostol, a methyl analog of PGE , has been approved twice daily combined with three capsules of a combination pre-
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for gastrointestinal conditions. After oral administration, it is scription formulation (each capsule containing bismuth subcitrate
rapidly absorbed and metabolized to a metabolically active free 140 mg, metronidazole 125 mg, and tetracycline 125 mg) taken
acid. The serum half-life is less than 30 minutes; hence, it must be four times daily for 10–14 days.
administered 3–4 times daily. It is excreted in the urine; however,
dose reduction is not needed in patients with renal insufficiency.
Misoprostol has both acid inhibitory and mucosal protective Adverse Effects
properties. It is believed to stimulate mucus and bicarbonate secre- All bismuth formulations have excellent safety profiles. Bismuth
tion and enhance mucosal blood flow. Misoprostol can reduce causes harmless blackening of the stool, which may be confused
the incidence of NSAID-induced ulcers to less than 3% and the with gastrointestinal bleeding. Liquid formulations may cause
incidence of ulcer complications by 50%. It is approved for pre- harmless darkening of the tongue. Bismuth agents should be
vention of NSAID-induced ulcers in high-risk patients; however, used for short periods only and should be avoided in patients
misoprostol has never achieved widespread use owing to its high with renal insufficiency. Prolonged usage of some bismuth
adverse-effect profile and need for multiple daily dosing. compounds may rarely lead to bismuth toxicity, resulting in
encephalopathy (ataxia, headaches, confusion, seizures). How-
BISMUTH COMPOUNDS ever, such toxicity is not reported with bismuth subsalicylate or
bismuth citrate. High dosages of bismuth subsalicylate may lead
to salicylate toxicity.
Chemistry & Pharmacokinetics
Two bismuth compounds are available: bismuth subsalicylate, a
nonprescription formulation containing bismuth and salicylate, ■ DRUGS STIMULATING
and bismuth subcitrate potassium. In the USA, bismuth subci- GASTROINTESTINAL MOTILITY
trate is available only as a combination prescription product that
also contains metronidazole and tetracycline for the treatment Drugs that can selectively stimulate gut motor function
of H pylori. Bismuth subsalicylate undergoes rapid dissociation (prokinetic agents) have significant potential clinical useful-
within the stomach, allowing absorption of salicylate. Over 99% ness. Agents that increase lower esophageal sphincter pressures
of the bismuth appears in the stool. Although minimal (<1%), may be useful for GERD. Drugs that improve gastric emptying
bismuth is absorbed; it is stored in many tissues and has slow renal may be helpful for gastroparesis and postsurgical gastric emp-
excretion. Salicylate (like aspirin) is readily absorbed and excreted tying delay. Agents that stimulate the small intestine may be
in the urine.
beneficial for postoperative ileus or chronic intestinal pseudo-
obstruction. Finally, agents that enhance colonic transit may be
Pharmacodynamics useful in the treatment of constipation. Unfortunately, only a

The precise mechanisms of action of bismuth are unknown. limited number of agents in this group are available for clinical
Bismuth coats ulcers and erosions, creating a protective layer use at this time.
against acid and pepsin. It may also stimulate prostaglandin,
mucus, and bicarbonate secretion. Bismuth subsalicylate reduces Physiology of the Enteric Nervous System
stool frequency and liquidity in acute infectious diarrhea, due
to salicylate inhibition of intestinal prostaglandin and chloride The enteric nervous system (see also Chapter 6) is composed of
secretion. Bismuth has direct antimicrobial effects and binds interconnected networks of ganglion cells and nerve fibers mainly
enterotoxins, accounting for its benefit in preventing and treating located in the submucosa (submucosal plexus) and between the
traveler’s diarrhea. Bismuth compounds have direct antimicrobial circular and longitudinal muscle layers (myenteric plexus). These
activity against H pylori. networks give rise to nerve fibers that connect with the mucosa
and muscle. Although extrinsic sympathetic and parasympathetic
nerves project onto the submucosal and myenteric plexuses, the
Clinical Uses enteric nervous system can independently regulate gastrointestinal
Despite the lack of comparative trials, nonprescription bismuth motility and secretion. Extrinsic primary afferent neurons project
compounds (eg, Pepto-Bismol, Kaopectate) are widely used by via the dorsal root ganglia or vagus nerve to the central nervous
patients for the nonspecific treatment of dyspepsia and acute system (Figure 62–4). Release of serotonin (5-HT) from intestinal
diarrhea. Bismuth subsalicylate also is used for the prevention of mucosa enterochromaffin (EC) cells stimulates 5-HT receptors
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traveler’s diarrhea (30 mL or two tablets four times daily). on the extrinsic afferent nerves, stimulating nausea, vomiting, or