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

PROTON PUMP INHIBITORS
Chemistry; Mechanism of Action; Pharmacology. The
most potent suppressors of gastric acid secretion are
inhibitors of the gastric H + , K + -ATPase (proton pump)
(Figure 45–2). In typical doses, these drugs diminish the
daily production of acid (basal and stimulated) by 80-95%.
Six proton pump inhibitors are available for clinical
use: omeprazole (PRILOSEC, others) and its S-isomer,
esomeprazole (NEXIUM), lansoprazole (PREVACID) and its
R-enantiomer, dexlansoprazole (KAPIDEX), rabeprazole
(ACIPHEX), and pantoprazole (PROTONIX, others). These
drugs have different substitutions on their pyridine and/or
benzimidazole groups but are remarkably similar in their
pharmacological properties (Appendix II). Omeprazole
is a racemic mixture of R- and S-isomers; the S-isomer,
esomeprazole (S-omeprazole), is eliminated less rapidly
than R-omeprazole, which theoretically provides a therapeutic
advantage because of the increased t 1/2
. Despite
claims to the contrary, all proton pump inhibitors have
equivalent efficacy at comparable doses.
Proton pump inhibitors (PPIs) are prodrugs that
require activation in an acid environment. After absorption
A
B
into the systemic circulation, the prodrug diffuses into
the parietal cells of the stomach and accumulates in the
acidic secretory canaliculi. Here, it is activated by
proton-catalyzed formation of a tetracyclic sulfenamide
(Figure 45–2), trapping the drug so that it cannot diffuse
back across the canalicular membrane. The activated
form then binds covalently with sulfhydryl groups of
cysteines in the H + , K + -ATPase, irreversibly inactivating
the pump molecule. Acid secretion resumes only
after new pump molecules are synthesized and inserted
into the luminal membrane, providing a prolonged (up
to 24- to 48-hour) suppression of acid secretion, despite
the much shorter plasma half-lives (0.5-2 hours) of the
parent compounds. Because they block the final step in
acid production, the proton pump inhibitors are effective
in acid suppression regardless of other stimulating
factors.
To prevent degradation of proton pump inhibitors by acid in
the gastric lumen, oral dosage forms are supplied in different formulations:
• enteric-coated drugs contained inside gelatin capsules (omeprazole,
dexlansoprazole, esomeprazole, and lansoprazole)
OCH 3 OCH 3
CH 3
OCH 2 CF 3
O (CH 2 ) 3 OCH 3
H +
H 3 C CH 3
CH 3
OCH 3
N
N
N
N
N S
N S
N S
N S
O
O
O
O
F 2 HCO
NH
NH
NH
N
OCH 3
LANSOPRAZOLE OMEPRAZOLE
RABERPRAZOLE PANTOPRAZOLE
OCH 3
CYCLIC SULFENAMIDE SULFENIC ACID
H 3 C CH 3
OCH 3 OCH 3
H 3 C CH 3 H 3 C CH 3
+
Enzyme SH
N
+ +
N N
S S Enzyme
N NH
S
S
N N H 2 O N NH OH
OCH 3
ENZYME-INHIBITOR COMPLEX
Figure 45–2. Proton pump inhibitors. A. Inhibitors of gastric H + , K + -ATPase (proton pump). B. Conversion of omeprazole to a sulfenamide
in the acidic secretory canaliculi of the parietal cell. The sulfenamide interacts covalently with sulfhydryl groups in the proton
pump, thereby irreversibly inhibiting its activity. The other three proton pump inhibitors undergo analogous conversions.
OCH 3
OCH 3
1311
CHAPTER 45
PHARMACOTHERAPY OF ACIDITY, ULCERS, AND REFLUX DISEASE