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

1314 within 1-3 hours. Absorption may be enhanced by food or
decreased by antacids, but these effects probably are unimportant
clinically. Therapeutic levels are achieved rapidly after intravenous
dosing and are maintained for 4-5 hours (cimetidine), 6-8 hours
(ranitidine), or 10-12 hours (famotidine). Unlike proton pump
inhibitors, only a small percentage of H 2
receptor antagonists are
protein bound. Small amounts (from <10% to ~35%) of these drugs
undergo metabolism in the liver, but liver disease per se is not an
indication for dose adjustment. The kidneys excrete these drugs
and their metabolites by filtration and renal tubular secretion, and
it is important to reduce doses of H 2
receptor antagonists in patients
with decreased creatinine clearance. Neither hemodialysis nor peritoneal
dialysis clears significant amounts of the drugs.
SECTION VI
DRUGS AFFECTING GASTROINTESTINAL FUNCTION
Adverse Reactions and Drug Interactions. Like the proton pump
inhibitors, the H 2
receptor antagonists generally are well tolerated,
with a low (<3%) incidence of adverse effects. Side effects usually are
minor and include diarrhea, headache, drowsiness, fatigue, muscular
pain, and constipation. Less common side effects include those affecting
the CNS (confusion, delirium, hallucinations, slurred speech, and
headaches), which occur primarily with intravenous administration of
the drugs or in elderly subjects. Long-term use of cimetidine at high
doses—seldom used clinically today—decreases testosterone binding
to the androgen receptor and inhibits a CYP that hydroxylates estradiol.
Clinically, these effects can cause galactorrhea in women and
gynecomastia, reduced sperm count, and impotence in men. Several
reports have associated H 2
receptor antagonists with various blood
dyscrasias, including thrombocytopenia. H 2
receptor antagonists cross
the placenta and are excreted in breast milk. Although no major teratogenic
risk has been associated with these agents, caution nevertheless
is warranted when they are used in pregnancy.
All agents that inhibit gastric acid secretion may alter the rate
of absorption and subsequent bioavailability of the H 2
receptor
antagonists (see “Antacids” section). Drug interactions with H 2
receptor antagonists occur mainly with cimetidine, and its use has
decreased markedly. Cimetidine inhibits CYPs (e.g., CYP1A2,
CYP2C9, and CYP2D6), and thereby can increase the levels of a
variety of drugs that are substrates for these enzymes. Ranitidine
also interacts with hepatic CYPs, but with an affinity of only 10% of
that of cimetidine; thus, ranitidine interferes only minimally with
hepatic metabolism of other drugs. Famotidine and nizatidine are
even safer in this regard, with no significant drug interactions mediated
by inhibiting hepatic CYPs. Slight increases in blood-alcohol
concentration may result from concomitant use of H 2
receptor antagonists,
but this is unlikely to be clinically significant.
Therapeutic Uses. The major therapeutic indications for H 2
-receptor
antagonists are to promote healing of gastric and duodenal ulcers, to
treat uncomplicated GERD, and to prevent the occurrence of stress
ulcers. More information about the therapeutic applications of H 2
receptor antagonists is provided in the section “Specific Acid-Peptic
Disorders and Therapeutic Strategies.”
TOLERANCE AND REBOUND WITH
ACID-SUPPRESSING MEDICATIONS
Tolerance to the acid-suppressing effects of H 2
receptor
antagonists is well described and may account for a
diminished therapeutic effect with continued drug
administration (Sandevik et al., 1997). Tolerance can
develop within 3 days of starting treatment and may be
resistant to increased doses of the medications.
Diminished sensitivity to these drugs may result from
the effect of the secondary hypergastrinemia to stimulate
histamine release from ECL cells. Proton pump
inhibitors, despite even greater elevations of endogenous
gastrin, do not cause this phenomenon, probably
because their site of action is distal to the action of histamine
on acid release. However, rebound increases in
gastric acidity can occur when either of these drug
classes is discontinued, possibly reflecting changes in
function and justifying a gradual drug taper or the
substitution of alternatives (e.g., antacids) in at-risk
patients.
AGENTS THAT ENHANCE
MUCOSAL DEFENSE
Prostaglandin Analogs: Misoprostol
Chemistry; Mechanism of Action; Pharmacology.
Prostaglandin E 2
(PGE 2
) and prostacyclin (PGI 2
) are the
major prostaglandins synthesized by the gastric mucosa.
Contrary to their cyclic AMP-elevating effects on many
cells via EP 2
and EP 4
receptors, these prostanoids bind
to the EP 3
receptor on parietal cells (Chapters 33 and
34) and stimulate the G i
pathway, thereby decreasing
intracellular cyclic AMP and gastric acid secretion.
PGE 2
also can prevent gastric injury by cytoprotective
effects that include stimulation of mucin and bicarbonate
secretion and increased mucosal blood flow.
Although smaller doses than those required for acid suppression
can protect the gastric mucosa in laboratory
animals, this has not been convincingly demonstrated in
humans; acid suppression appears to be the most important
effect clinically (Wolfe and Sachs, 2000).
Because NSAIDs diminish prostaglandin formation by
inhibiting cyclooxygenase, synthetic prostaglandin analogs offer a
logical approach to reducing NSAID-induced mucosal damage.
Misoprostol (15-deoxy-16-hydroxy-16-methyl-PGE 1
; CYTOTEC, others)
is a synthetic analog of PGE 1
. Structural modifications include
an additional methyl ester group at C1 that increases potency and
duration of antisecretory effect, and transfer of a hydroxyl group
from C15 to C16 and addition of a methyl group that increases oral
bioactivity, duration of antisecretory action, and safety. The degree
of inhibition of gastric acid secretion by misoprostol is directly
related to dose; oral doses of 100-200 μg significantly inhibit basal
acid secretion (up to 85-95% inhibition) or food-stimulated acid
secretion (up to 75-85% inhibition). The usual recommended dose
for ulcer prophylaxis is 200 μg four times a day.