Drugs Used in Digestive System

Drugs Used for:

-PUD& GERD
-
 Peptic Ulcer Disease (PUD)
 Localized defect in the mucosa of any part of the GIT.
 The most important symptom is abdominal pain and discomfort.
 Epigastric pain, which comes 90 min to 3 h after eating

 Atypical symptoms are abdomen distention, inappetence, belching,

reflux of gastric acid.

 The severe complications are hemorrhage, perforation, obstruction

and canceration.
 [Pathogenesis of peptic ulcer]

 The imbalance between mucosal defense and aggressive factors.

1. Aggressive factors….↑ ulcer formation

 H. Pylori, NSAIDs, gastric acid, pepsin and stress

2. Defensive factors…↓ ulcer formation

 Mucus, bicarbonate barrier, prostaglandins

 1. Mucosal ulcer aggravating factors

Helicobacter Pylori ( H. Pylori)

In 1983, H. pylori was found by two Australians, Marshall and
Warren.
And the two men won the noble prize for the important findings
in 2005.
It is believed that H. pylori is the most important pathogenic
factor to peptic ulcer.
 H.pylori is a pathogenic bacteria which can directly damage
mucosal layer
 Aggravating factors cont’d…
Gastric acid (HCl)
 Is the key-factor of the formation of peptic ulcer.
 Like H.pylori, HCl directly damage mucosal layer

Pepsin
 GI enzyme which can decompose mucosal protein molecule.
 But its activity is depended on the pH value.
 When local pH value elevates to 4, pepsin can’t work well.

NSAIDs (Diclofenac, Aspirin, ibuprofen)

 They Inhibits the synthesis of prostaglandins.
2. Mucosal ulcer Defensive factors
Mucus-bicarbonate barrier
The epithelial layer of the mucosa is composed of tightly
adjoined cells
Their tight junctions, synthesis of PGs and secretion of mucus
and bicarbonate all contribute to maintenance of the epithelial
barrier.
Mucous forms film layer to protect physical damage
Bicarbonate neutralizes HCl

 Mucosal ulcer Defensive factors

Prostaglandins(PGs)
Prostaglandins are thought to enhance resistance to injury by:

 Maintaining blood flow to the mucosa.

 Facilitates mucous and bicarbonate production

 Inhibits HCl secretion

 Mechanism of HCl, HCO3- and mucous production
ACh Cl-, K+
Gastrin transport
M1
+ Ca2+-dependent
G pathway
K+
Histamine H2 + H+, K +
_ ATPase
cAMP-dependent
ECL cells PG pathway H+
Parietal cells
Prostag Mucous
landin + +
PG HCO3-
+
Superficial epithelial cells Gastric
Mucous
lumen PH=2
lumen PH=7
Classification of drugs

Ⅰ. Antacids (neutralizes the acid )

Ⅱ. Agents decreasing secretion of gastric acid

Ⅲ. Agents protecting mucosal barrier (Cytoprotective

agents)

Ⅳ. Agents eradicating H.pylori (Antimicrobials)

 Antacids
 Are weak alkalis that bring about neutralization of the acidic
pH in the stomach.
 They provide symptomatic relief in peptic ulceration and
gastro-esophageal reflux.
 Have been used for centuries in the treatment of patients with
acid-peptic disorders.
 Were the mainstay of treatment for PUD until the advent of
agents that decreases secretion of gastric acid
 Antacids Cont.…

Weak bases : Mg(OH)2, Al(OH)3, CaCO3, NaHCO3

Actions: neutralization that enables to:

1) prevent injury from gastric acid

2) Reduce pepsin activity

Reactions

NaHCO3+HCl → Nacl+H2O+CO2↑

Al(OH)3+3HCl → AlCl3+3H2O

Mg(OH)2+HCl → MgCl2+2H2O

CaCO3+2HCl → CaCl2+H2O+CO2 ↑
 Antacids Cont.…

Systemic antacids : Sodium bicarbonate

After oral administration it is absorbed and may cause alkalosis.

It is usually present in compound indigestion remedies.

It should be used with care in patients on salt restricted intake

(e.g. patients with hypertension).

To be used for short-term periods.

 Antacids Cont.…
Systemic antacids : calcium-containing salts
These can induce rebound acid secretion and so should not be used
for prolonged periods.
Prolonged high doses may cause hypercalcemia and alkalosis.

Non-systemic antacids
These are antacids that are not absorbed.
They include aluminum salts, magnesium salts and aluminum-
magnesium compound preparations (mixture).
 Antacids Cont.…

Mixtures of Magnesium trisilicate and Aluminium hydroxide

First line for non-H.pylori associated PUD along with H2-

receptor blockers.

Dosage forms: chewable tablet, 400mg + 400 mg, suspension,

195mg + 220mg in 5 ml.

 Antacids Cont.…

 Side-effects
 Aluminum: constipation, phosphate depletion
 Magnesium: diarrhea

 Mixed compound is free of constipation and diarrhea

 Calcium carbonate: acid rebound, hypercalcaemia
 Sodium bicarbonate: hypernatremia, bicarbonate alkalosis,
increases BP
Ⅱ Agents reducing secretion of gastric acid

1.H2-receptor antagonists

2.Antimuscarinic agents

3.Inhibitors of the proton pump

4.Gastrin-receptor antagonists
 H2-R antagonists

Cimetidine, Ranitidine, Famotidine , Nizatidine

MOA:

 Competitively block the binding of histamine to H2 receptor. (Fig1)

 Completely inhibit gastric acid secretion induced by histamine.

characteristics: more effective than M-R antagonists; long duration;

high rate of healing up; rebound acid secretion

Cimetidine
[ Pharmacokinetics]

 Absorption: p.o F=70%

 Distribution: widely

 Elimination: kidney

 Heptic microsomal enzyme inhibitor

 Inhibit all kinds of gastric acid secretion due to histamine

[Clinical uses]

① peptic ulcers :
 Effective in promoting healing of peptic ulcers.
 First line therapy for non-H. pylori PUD
 400 mg p.o. twice daily, with breakfast and at night, or
800 mg at night for 4 - 6 weeks.
 GU may require 6 weeks of 400 mg bid treatment.
 After treatment is stopped, recurrence is common. This
can be effectively prevented by eradication of H. Pylori.
② Zollinger-Ellison syndrome :

A fatal disorder in which a gastrin-producing tumor on

pancreas causes hypersecretion of gastric acid.

In many patients, H2 receptor antagonists can effectively

keep the acid secretion to safe levels so as to control

symptoms related to excess acid secretion.

③ Gastro esophageal reflux disorder (GERD):

Because they act through stopping acid secretion, they may

not relieve symptoms of heartburn for at least 45 minutes

after administration.

Antacid will be more efficient to neutralize secreted acid

already in the stomach.

[Adverse reactions]

1.The common side effects are:

Headache, dizziness, diarrhea and muscular pain, skin rash
2.CNS effects:
Confusion, disorientation and hallucination
3. Endocrine system effects:
Gynecomastia, impotency, galactorrhea

4. Inhibits hepatic microsomal metabolism system

Ranitidine
 Antisecretive effect is 10 times that of Cimetidine
150 mg p.o. bid or 300 mg at bedtime for 4 - 6 weeks
Less effect on hepatic microsomal metabolism system
Longer duration and less antiandrogenic effect

Famotidine
Antisecretive effect is 40 times that of Cimetidine
40 mg, p.o. at night for 4 - 6 weeks
Have no effect on hepatic microsomal metabolism system

Nizatidine

Stimulate proliferation of epithelium and increase mucus secretion

 Inhibitors of the proton pump

Omeprazole, lansoprazole, pantoprazole, esomeprazole

[pharmacological effects]
 Inhibit irreversibly at the final step in gastric acid secretion
 Inhibits H+ being transported to gastric lumen through inhibiting the
proton pump. (Fig 2)
 Potent and efficacious: Can inhibit over 95% of gastric acid secretion.
 Proton pump inhibitors are prodrugs
 These drugs ideally should be given about 30 min before meals.
[Clinical uses]

① Peptic ulcer: was judged to be superior to H2-R antagonists

② Zollinger-Ellison syndrome: superior to H2-R antagonists (fig3)

③ GERD : the most effective agents

④ Hemorrhage of upper digestive tract

⑤ H.pylori infection (as part of triple therapy)

Omeprazole
 Easily absorbed, but affected by food
 Is also hepatic enzyme inhibitor (the only PPI)
 PUD only
 2nd line therapy
 20 mg p.o. once daily for 4 weeks (DU) or 8 weeks (GU).
 PUD associated with H. pylori
 1st line as part of triple therapy
 20mg p.o. BID (or 40mg OD ) x 7 -14 days
[Adverse reactions]
 Extremely safe
 1)G.I reactions: N,V,D, abdominal pain etc.
 2)NS: headache, insomnia, peripheral neuritis, etc.
 3) Overgrowth of bacteria: Increases in gastric bacterial

concentrations.
 4) Canceration (long term use)
 5) Rebound acid
Antimuscarinic agents

 Muscarinic receptor stimulation increase gastrointestinal

motility and secretion.(Fig4)

 So cholinergic antagonists can be used as adjuncts in the

management of PUD and ZES, particularly in patients

refractory to standard therapies.

Antimuscarinic agents

 In contrast to the classic anticholinergic, the relatively specific

M1-receptor antagonist, Pirenzepine is a good choice as an

anti-secretory agent.

 Because it suppresses cholinergic receptor stimulated gastric

acid secretion at doses having a minimal effect on other organs

(salivary glands, the heart and eye)

Ⅲ Agents protecting mucosal barrier

(1) Prostaglandins

(2) Other mucosal protective agents

1. Prostaglandins

MOA:
 Inhibit secretion of gastric acid
 stimulate secretion of mucus and bicarbonate
(cytoprotective effect) .
 Increases blood flow to the site
 So, deficiency of prostaglandins is thought to be involved
in the pathogenesis of peptic ulcers.
 Synthetic prostaglandin are unstable so they are not
indicated clinically
2. Others mucosal protective agents

 AKA cytoprotective agents

 Enhance mucosal protection mechanisms, thereby

preventing mucosal injury and healing existing ulcers.

Clinical uses: NSAID-induced ulcer

Adverse reactions:

 Dose-dependent diarrhea

 Stimulate uterus contraction

a. Misoprostol: Stable analog of PG

 Inhibits secretion of gastric acid and stimulate secretion of

mucus and bicarbonate. (Fig 5)
 Dilate blood vessel of mucous membrane.
 Currently the only agent approved for prevention of gastric
ulcers induced by NSAIDs.
 Less effective than H2-receptor antagonists for acute treatment
of peptic ulcers.
 Produces uterine contractions and is C/I during pregnancy.
b. Sucralfate

 MOA
 In water or acidic solutions it forms a viscous that binds
selectively to ulcers or erosions
 Also stimulates prostaglandin release and mucus and
bicarbonate output
 Inhibit H. Pylori
 Needs acidic environment
 Affects absorption of other drugs
Sucralfate Cont.…
 1 g four times a day, 1h before each meal and at
bedtime
ADR

 Constipation or diarrhea,

 Backache, dizziness, nausea, stomach cramps, allergic

reaction
Colloidal bismuth subcitrate

 MOA

 Binds to an ulcer crater, coating it and protecting it from acid

and pepsin

 Increases mucous secretion

 Increase prostaglandin synthesis

 Helps to eradicate H. pylori

 Ⅳ. Agents eradicating H. pylori

 Peptic ulcer disease associated with H.Pylori requires

antimicrobial treatment.

 Eradication of H.Pylori results in rapid healing of active peptic

ulcers and low recurrence rates.

 Triple therapy (2 Antimicrobials +1 Antisecretory)

 Duration: 7-14 days (mostly 10 days)

Agents eradicating H. pylori Cont.…

First line
Amoxicillin, 1g, p.o. BID + Clarithromycin, 500mg p.o. BID +
Omeprazole, 20mg p.o. BID(or 40mg once daily) X 7-14 days

Alternatives
Amoxicillin, 1g, p.o. BID + Metronidazole, 500mg, p.o. BID +
Omeprazole, 20mg p.o. twice daily (or 40mg once daily) X 7-4
days
