Small Animal Clinical
Pharmacology & Therapeutics
Second Edition
Dawn Merton Boothe, DVM, MS, PhD, DACVIM, DACVP
Professor, Department of Physiology and Pharmacology, College of
Veterinary Medicine
Director, Clinical Pharmacology Laboratory, Auburn University,
Auburn, Alabama
Copyright © 2012, 2001 by Elsevier Inc.
Saunders
drug metabolizing enzymes should be avoided. H2-receptor
antagonists also appear to be e ective in controlling upper GI
bleeding when hemorrhage is not due to erosion of major blood
vessels. H2-receptor antagonists have also been used in
gastroesophageal re ux disorders, esophagitis, and duodenal gastric
re ux. In exocrine pancreatic insu ciency, cimetidine or ranitidine
(and presumably famotidine), if given about 30 minutes before
feeding, may decrease enzymatic and acid hydrolysis of replacement
pancreatic enzymes added to food on their contact with gastric
secretions, thus improving the e cacy and decreasing the cost of
their use. Patients su ering from short bowel syndrome may bene t
from long-term H2-receptor therapy to decrease the hyperacidity
associated with this syndrome. The H2-receptor antagonists are
su ciently safe that high doses can be given to humans to maintain
pharmacologic e ects with once- to twice-daily dosing.48 A meta-
analysis in humans studied the impact of renal disease on the
disposition of H2-receptor blockers. Declining renal function is
associated with a concomitant reduction in the renal clearance of
those drugs renally eliminated. Appropriate dose reduction was
associated with decrease in cost, as well as decrease in adverse
events, with the major adversity being mentation disorders.78
KEY POINT 19-16
Proton pump inhibitors generally are more e ective than antihistaminergic
antisecretory drugs, but the lag time to e cacy may support initial therapy with both
classes of antisecretory drugs.
Proton Pump Inhibitors
The substituted benzimidazole proton pump inhibitors are the most
potent antisecretory drugs, reducing gastric acid secretion by 80%
to 95%.48 Each is a potent and irreversible antagonist of the H+,
K+-ATPase proton pump, the nal step in gastric acid secretion
stimulated by any secretagogue. No di erences in antisecretory
e cacy have been demonstrated among these drugs. Omeprazole
will be discussed as the model drug.
Mechanism of action
Omeprazole (Prilosec) (see Figures 19-4 and 19-5), was the rst of
the commercially available drugs. It is sold as a racemic mixture.
Other proton pump inhibitors currently approved for use in the
United States include esomeprazole (Nexium), the S-isomer of
omeprazole (cleared more slowly than the R isomer in some
species), lansoprazole (Prevacid), rabeprazole (Aciphex), and
pantoprazole (Protonix). Omeprazole is approximately 30 times
more potent as an antacid than is cimetidine.79 Secretory volume is
not as a ected as is acidity.79
Pharmacokinetics
As a weak base, omeprazole is unstable in an acid environment and
thus is formulated as encapsulated enteric-coated granules.79 Drug
dissolution occurs in the more alkaline environment of the small
intestine. Acidity degrades (inactivates) the drug. Consequently, the
drugs are generally prepared as enteric-coated products or combined
with antacids (e.g., sodium bicarbonate). Compounded products
must be made with attention to formulation, including pH, to ensure
pharmaceutical e cacy. Oral bioavailability increases with
environmental intestinal pH, and plasma drug concentrations tend
to increase the rst 4 to 5 days of therapy.79 The complicated nature
of proton pump inhibitors has limited the availability of parenteral
preparations; however, pantoprazole and lansoprazole (and, in
Europe, esomeprazole) are available for intravenous administration.
Once absorbed, the acidic environment (pH 0.8 to 1) of the GI
tract causes omeprazole to selectively partition into the secretory
canniculi of parietal cells compared with other cells (pH 5). In the
acidic environment, the drug is protonated, trapped, and
subsequently further transformed to the active inhibitor. As such,
proton pump inhibitors are prodrugs. Ideally, the drugs are
administered about 30 minutes before a meal; other antisecretory
drugs do not appear to a ect proton pump activity.80 Indeed,
antihistaminergic antisecretory drugs might be given in combination
with proton pump inhibitors for a rapid response because of the
slower onset of action of the proton pump inhibitors.81 Once in the
canniculi, omeprazole covalently and irreversibly binds to
sulfhydryl groups of potassium-adenosine triphosphate (H+, K+-
ATPase), thus inhibiting the energy source for the proton pump.48,79
Because the enzyme is permanently inhibited, secretion of HCl will
resume only after new molecules have been formed in the luminal
membrane, which generally requires 24 to 48 hours.48 Therefore the
duration of action of proton pump inhibitors is much longer than
their plasma half-life. Drug accumulation in parietal cells and
alternating activity of parietal cells or pumps result in a lag time of
up to 3 to 5 days before maximum e ect (generally 70% of pumps
are inhibited at steady state) is realized.79,82 Consequently,
alternative drugs may need to be considered if a rapid response is
desired. In addition, e cacy will be maintained at low plasma drug
concentrations and for some time after the drug is discontinued.
Because of these characteristics, omeprazole can be administered
once daily.82 In humans omeprazole is highly (96%) bound to serum
albumin and α1-acid glycoprotein. Its apparent volume of
distribution is 0.31 L/kg.79 Clearance is accomplished through
hepatic metabolism; in humans the major enzymes are CYP2C19, for
which genetic polymorphisms have been reported (decreased
activity in Asians), and CYP 3A4, an enzyme characterized by broad
substrate speci city. Also in humans drug elimination depends on
hepatic metabolism to inactive metabolites, and elimination half-life
is short (52 minutes).79 Omeprazole has been studied in dogs.83 Oral
bioavailability is reduced, although therapeutic concentrations can
be achieved.
Dosing at 0.17 mg/kg orally once a day for ve years was well
tolereated in Beagles (n = 10). Changes in disposition were not
detected across time. The AUC was similar to that measured in
humans receiving 20 mg (approximately 0.28 mg/kg) daily.
omeprazole daily. Mean inhibition of acid secretion by omeprazole
4-7 hours after dosing approximalted 50%.
Drug interactions
Partial inhibition of drugs eliminated by selected cytochrome P450
enzymes have been reported for omeprazole.84 However, compared
with cimetidine, omeprazole may be less likely to be involved in
drug interactions. All proton pump inhibitors appear to inhibit a
variety of CYPS (including CYP3A4), with clinically relevant drug
interactions described for warfarin, cyclosporine, and diazepam.
Omeprazole (more so than other proton pump inhibitors) appears to
inhibit CYP2C19 and induce CYP1A2 (metabolism of several
trycyclic or other behavior-modifying drugs); its S isomer is
characterized by less in hibition. Other interactions are likely to
exist, indicating caution when combining proton pump inhibitors
with other drugs metabolized by the liver. Lansoprazole may be
involved with fewer cytochrome P450–based drug interactions.
Drug interactions appear to occur at the level of P-glycoprotein;
omeprazole, lansoprazole, and pantoprazole appear to be
substrates.85 Because of the delay in onset of action, the use of more
rapidly acting antihistaminergic drugs might be considered as
proton pump therapy has begun. That the latter does not appear to
have the e cacy of the former has been demonstrated.80,81
KEY POINT 19-19
The potential for inhibition of drug metabolism because of drugs or disease may result
in longer drug half-lives of other drugs.
Adverse reactions
Adverse reactions caused by omeprazole are limited because the
drug is selective for the H+, K+-ATPase pump. An exception is the
sequelae of achlorhydria. Diarrhea and transient uctuations in liver
enzymes have been reported. Hypergastrinemia has been
documented in human patients79 after therapy with omeprazole,
and is more severe compared with that associated with use of
antihistaminergic antisecretory drugs and may be associated with
gastric hyperplasia or an increase in gastric tumors. Rebound
hypersecretion of gastric acid as described for antihistaminergic
drugs should be anticipated, and discontinuation of proton pump
inhibitors should occur gradually, with tapering or substitution of
alternative drugs in at-risk patients.48 Hypertrophy of gastric
mucosa has been reported. A marked increase in gastric acid
secretory capacity has been detected after omeprazole treatment,
presumably owing to proliferation of an enterochroma n-like cell
mass.86 However, in contrast to H2-receptor blockers, proton pump
inhibitors may not cause tolerance because their inhibition is distal
to histamine-mediated secretion targeted by increased gastrin.
Chronic use may decrease absorption of vitamin B12, although
clinical relevance is not clear.48
Clinical use
Proton pump inhibitors are indicated to support gastroduodenal
healing, prevention or treatment of gastroesophogeal re ux,
treatment of hypersecretory conditions, and other conditions that
bene t from reduced hydrochloric acid secretion (e.g., IBDs).
Omeprazole is the drug of choice for the treatment of the Zollinger–
Ellison syndrome. Omeprazole has been used to control gastric acid
secretion that has not responded to H2-receptor antagonists,
although its superiority to these and other antacid drugs has not
been rmly established. Generally, however, studies support the
superiority of omeprazole over cimetidine for treatment of GI
ulceration, including response of pain.79 Lansoprazole is often
preferred in humans for prevention of NSAID-induced ulceration but
does not appear to o er an bene t in terms of long-term e cacy.
Bersenas and coworkers87 studied normal fasting and postprandial
intragastric pH and its response to a variety of antisecretory drugs in
Beagles (n = 12). Antisecretory drugs included ranitidine (2 mg/kg
intravenously every 12 hours), famotidine (0.5 mg/kg intravenously
every 12 hours), pantoprazole (1 mg/kg intravenously every 24
hours), and omeprazole (1 mg/kg orally every 24 hours), or saline
placebo. Intragastric pH was recorded on days 0, 2, and 6. Outcome
measures included median 24-hour intragastric pH, percentage of
time pH was at or above 3, and percentage of time pH was at or
above 4. All outcome measures were better (pH higher for longer) in
the fasting compared with the postprandial state. Only famotidine,
pantoprazole, and omeprazole suppressed gastric acid secretion,
compared with placebo. The investigators also found that a
suspension of omeprazole (1 mg/kg orally every 12 hours; n = 6)
but not famotidine (0.5 mg/kg intravenously every 8 hours; n = 6)
suppressed gastric acid secretion; information was not available
regarding quality assurance of the suspensions. The authors
concluded that only famotidine (at the doses and intervals studied),
pantoprazole, and omeprazole signi cantly suppressed gastric acid
secretion and the only suspension that was anticipated to be
e ective in treating gastric acid-related diseases (in normal dogs),
based on outcome measures targeted in humans, was omeprazole;
the power of the study may have impacted interpretation. This
study suggests that ranitidine at 2 mg/kg, administered
intravenously, is not an e ective antisecretory drug in dogs, and
famotidine is indicated at 12-hour intervals.
KEY POINT 19-20
Studies in the dog suggest that famotidine and omeprazole provide the most e ective
control of gastric acid secretion.
Prostaglandin Analogs
