DƯỢC LÍ Goodman & Gilman's The Pharmacological Basis of Therapeutics 12th, 2010

mainstay in the treatment of pathological hypersecretory conditions,
including the Zollinger-Ellison syndrome. Lansoprazole and
esomeprazole are FDA approved for treatment and prevention of
recurrence of nonsteroidal anti-inflammatory drug (NSAID)-associated
gastric ulcers in patients who continue NSAID use. It is not clear
if proton pump inhibitors affect the susceptibility to NSAID-induced
damage and bleeding in the small and large intestine. In addition, all
proton pump inhibitors are approved for reducing the risk of duodenal
ulcer recurrence associated with H. pylori infections. Therapeutic
applications of proton pump inhibitors are further discussed later under
“Specific Acid-Peptic Disorders and Therapeutic Strategies.”
Use in Children. In children, omeprazole is safe and effective for
treatment of erosive esophagitis and GERD. Younger patients generally
have increased metabolic capacity, which may explain the
need for higher dosages of omeprazole per kilogram in children
compared with adults.
H 2 RECEPTOR ANTAGONISTS
The description of selective histamine H 2
receptor
blockade was a landmark in the treatment of acid-peptic
disease (Black, 1993). Before the availability of the
H 2
receptor antagonists, the standard of care was simply
acid neutralization in the stomach lumen, generally
with inadequate results. The long history of safety and
efficacy with the H 2
receptor antagonists eventually led
to their availability without a prescription. Increasingly,
however, proton pump inhibitors are replacing the H 2
receptor antagonists in clinical practice.
Chemistry; Mechanism of Action; Pharmacology. The H 2
receptor
antagonists inhibit acid production by reversibly competing with histamine
for binding to H 2
receptors on the basolateral membrane of
parietal cells. Four different H 2
receptor antagonists, which differ
mainly in their pharmacokinetics (Appendix II) and propensity to
cause drug interactions, are available in the U.S. (Figure 45–3):
cimetidine (TAGAMET, others), ranitidine (ZANTAC, others), famotidine
(PEPCID, others), and nizatidine (AXID, others). These drugs are
less potent than proton pump inhibitors but still suppress 24-hour
gastric acid secretion by ~70%. The H 2
receptor antagonists predominantly
inhibit basal acid secretion, which accounts for their efficacy
in suppressing nocturnal acid secretion. Because the most important
determinant of duodenal ulcer healing is the level of nocturnal acidity,
evening dosing of H 2
-receptor antagonists is adequate therapy in
most instances. Ranitidine and nizatidine also may stimulate GI
motility, but the clinical importance of this effect is unknown.
H 3 C
HN
S
S
NH
CH 2 CH 2 NH 2
CH 2 N(CH 3 ) 2
NIZATIDINE
Figure 45–3. Histamine and H 2
receptor antagonists.
N
HISTAMINE
CH 2 SCH 2 CH 2 N CNHCH 3
HN C N
CIMETIDINE
CH 2 SCH 2 CH 2 NHCNHCH 3
O
CHNO 2
N
N
N
RANITIDINE
CH 2 SCH 2 CH 2 CNH 2
C(NH 2 ) 2
FAMOTIDINE
NSO 2 NH 2
CH 2 SCH 2 CH 2 NHCNHCH 3
CHNO 2
All four H 2
receptor antagonists are available as prescription
and over-the-counter formulations for oral administration. Intravenous
and intramuscular preparations of cimetidine, ranitidine, and famotidine
also are available. When the oral or nasogastric routes are not an
option, these drugs can be given in intermittent intravenous boluses
or by continuous intravenous infusion (Table 45–1). The latter provides
better control of gastric pH but is not proven to be more effective
in preventing significant bleeding in critically ill patients.
Pharmacokinetics. The H 2
receptor antagonists are rapidly
absorbed after oral administration, with peak serum concentrations
Table 45–1
Intravenous Doses of H 2
Receptor Antagonists
CIMETIDINE RANITIDINE FAMOTIDINE
Intermittent bolus 300 mg every 6-8 hours 50 mg every 6-8 hours 20 mg every 12 hours
Continuous infusion 37.5-100 mg/hour 6.25-12.5 mg/hour 1.7-2.1 mg/hour