Download H2-receptor antagonists proton pump inhibitors

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Peptic ulcer
Gastric and duodenal mucosa are eroded
by acid , pepsin or HP,which cause
mucosa injure.
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When does peptic ulcer
happen?
aggressive factors
>
defensive factors
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Defensive factors
①mucus
②bicarbonate
③blood
④prostaglandins
Aggressive
factors
①acid（Ach
gastin、
histamin）
②pepsin
③HP.
④smoking,drugs
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Anti-Peptic Ulcer Drugs
1. Antacids
2. Gastric acid secretion inhibitors
• H2-receptor antagonists proton pump
inhibitors
• M1 muscarinic receptor antagonists
• Cholecystokinin receptor 2 (CCK2) antagonist
3. Agents that enhance mucosal defense
4. anti- H. pylori drugs：
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1. Drugs that
Reduce intragastric acidity
Include two classes:
Antacids and inhibiting secretary drugs
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Antacids
Principle
Base + acid
(-OH)
salt + water
(HCl)
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Tipycal drugs
Magnesium Hydroxide
and Aluminum Hydroxide
+ Hcl
Al(OH)3 + Hcl
Mg(OH)2
Mgcl2 + H2O
Alcl3 + H2O
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Adverse effects
Mgcl2 cannot be absorbed ,it produces
osmotic diarrhea.
Alcl3 can produce constipation.
So these drugs are commonly
administered together to minimize the
impact upon bowel function.
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Calcium carbonate
CaCO3 + Hcl
Cacl2 + H2O+ CO2
Adverse effects
Metabolic alkalosis
hypercalcemia
belching
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Sodium Bicarbonate
NaHCO3 + Hcl
Nacl + H2O+ CO2
Adverse effects
Metabolic alkalosis
distention
belching
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comparison of some commonly used antacid preparations).
NaHCO3 MgSiO3 Al（OH）3 Mg(OH)2 CaCO3
Strengh
Onset time
strong
fastest
weak
faster
moderate strong
slower
longer longer
moderate
faster
faster
duration
short
longer
astringency
－
－
CO2
alkalemia
＋
＋
－
－
－
－
－
－
＋
－
protection
－
＋
＋
±
－
diachoresis
－
diarrhea
＋
constipation
－
longer
＋
dia.
Cons.
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Acid secretion inhibitor
H2-receptor antagonists
Proton pump inhibitors (PPI)
Antimuscarinic drugs(M-R inhibitors)
Antagonist of gastrin receptor
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Proton pump
CCK2
CCK2
(-)
Drug
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H2-receptor antagonists
• Mechanism
It can exhibit competitive inhibition at
the parietal cell H2 receptor,and
suppress acid secretion.
• Typical drugs
• cimetidine (TAGAMET), ranitidine
(ZANTAC), famotidine (PEPCID), and
nizatidine (AXID).
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• The H2-receptor antagonists inhibit acid production by
reversibly competing with histamine for binding to H2 receptors
on the basolateral membrane of parietal cells.
• These drugs are less potent than proton pump inhibitors but still
suppress 24-hour gastric acid secretion by about 70%. The H2receptor 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 H2receptor antagonists is adequate therapy in most instances.
• Ranitidine and nizatidine also may stimulate GI motility, but the
clinical importance of this effect is unknown.
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Adverse Reactions
• with a low (3%) incidence of adverse effects.
• are minor and include diarrhea, headache,
drowsiness, fatigue, muscular pain, and constipation.
• cause galactorrhea in women and gynecomastia,
reduced sperm count, and impotence in men.
• Famotidine and nizatidine are even safer in this
regard, with no significant drug interactions mediated
by inhibiting hepatic CYPs.
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Proton pump inhibitors
(PPI)
It is the main drug for the treatment of acidpeptic disorders.
Five proton pump inhibitors are available for
clinical use: omeprazole (PRILOSEC,
RAPINEX, ZEGERID) and its S-isomer,
esomeprazole (NEXIUM), lansoprazole
(PREVACID), rabeprazole (ACIPHEX), and
pantoprazole (PROTONIX).
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Omeprazole
Parmacodynamics
It blocks the final common pathway of
acid secretion,the proton pump.
In standard doses,it inhibit 90%-98% of
24-hours acid secretion.
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Pharmacokinetics
Serum half-life : 1 hour
Duration of acid inhibition : 24 hours
Metabolism : hepar
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Adverse effects
It is extremely safe.
Diarrhea
headache
abdominal pain
15%
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Clinical use
Gastroesophafeal Reflux Disease
Peptic Ulcer Disease
Prevention of stress gastritis
In children, omeprazole is safe and
effective for treatment of erosive
esophagitis and (gastroesophageal
reflux disease) GERD.
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Antimuscarinic drugs
(M-R inhibitors)
Typical drug : Pirenzepine
It has dramatic inhibition on motility and some of the secretory
functions of the gut.
The ACh receptor on the parietal cell itself is of the M3 subtype,
and these drugs are believed to suppress neural stimulation of
acid production via actions on M1 receptors of intramural
ganglia.
Because of their relatively poor efficacy, significant and
undesirable anticholinergic side effects, and risk of blood
disorders (pirenzepine), they rarely are used today.
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Antagonist of gastrin
receptor
Typical drug : Proglumide
Mechanism
It can exhibit
competitive inhibition at
the parietal cell gastrinreceptor ,and suppress
acid secretion.
CCK2
CCK2
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2. Mucosal protective
agents
• Typical drugs : misoprostol
•
sucralfate
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Cavity
Cl-
H+
H+
Gastric juice
Cl- pepsin
pH2
NaCl H2O+CO2
NaHCO3mucous layer
PGE2R
PGI2R
pH7
PG
mucosa
parietal cells
The protection of mucous layer
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misoprostol
A methyl analog of PGE1
Administration : oral
Serum half-life : less than 30 min
Pharmacological action:
acid inhibitory
stimulating mucus and bicarbonate secretion
enhance mucosal blood flow
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Adverse effects
Diarrhea, with or without abdominal pain and cramps,
occurs in up to 30% of patients who take misoprostol.
Apparently dose-related, it typically begins within the
first 2 weeks after therapy is initiated and often
resolves spontaneously within a week; more severe
or protracted cases may necessitate drug
discontinuation. Misoprostol can cause clinical
exacerbations of inflammatory bowel disease and
should be avoided in patients with this disorder.
Misoprostol is contraindicated during pregnancy
because it can increase uterine contractility.
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Therapeutic Use.
• Misoprostol is FDA approved to prevent
NSAID-induced mucosal injury. However, it
rarely is used because of its adverse effects
and the inconvenience of four-times-daily
dosing. The proton pump inhibitors and H2receptor antagonists also are used to
diminish the gastrointestinal side effects of
NSAIDs, but only lansoprazole holds an FDA
approved indication for this purpose.
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sucralfate
It is a salt of sucrose complexed to sulfated aluminum
hydroxide.
Mechanism
In water or acidic(ph<4) solution it form a paste that
bind to ulcer.
It stimulates mucosal prostaglandin and bicarbonate
secretion.
It binds epithelial growth factor and fibroblast growth
factor ,enhence mucosal repair.
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Adverse
The most common side effect of sucralfate is
constipation (about 2%).
renal failure---should be avoided
Sucralfate forms a viscous layer in the stomach that
may inhibit absorption of other drugs, including
phenytoin, digoxin, cimetidine, ketoconazole, and
fluoroquinolone antibiotics. Sucralfate therefore
should be taken at least 2 hours after the
administration of other drugs.
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Drugs against H pylori
Treatment regimen
“Triple therapy”------10-14days
Proton pump inhibitors(omeprazole) +
clarithromycin + amoxicillin(metronidazole)
They are all twice daily,and then omeprazole
should be continued once daily for 4-6 weeks
to ensure complete ulcer healing.
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3. Hp
Also called helicobacter pylori
It is a kind of bacterium ,living in the
mucosa and it can induce mucosa
injure ,which discovered by scientists
recently.
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