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Gastrointestinal Agents & Antiulcer Drugs

Dr.Datten Bangun MSc,SpFK

Dept.Farmakologi& Terapeutik

Fakultas Kedokteran
Universitas HKBP Nommensen
MEDAN
Drugs for the Gastrointestinal Tract

Gastrointestinal disorders
Vomiting
Toxic substance ingestion
Diarrhea
Constipation
Peptic ulcer
Cerebral Centers Affecting Vomiting
Vomiting (contd)
Nonpharmacologic measure
Nonprescription antiemetics
Antihistamines
Bismuth subsalicylate
Phosphorylated carbohydrate solution
Prescription Antiemetics
Prescriptive antihistamines
Anticholinergic
Dopamine antagonists
Phenothiazines
Butyrophenones
Metoclopramide
Emetics
Ipecac is an OTC drug
Administration
Take with a glass of water or fluid, not with milk or
carbonated beverage
Vomiting occurs in 20 to 30 minutes and if not,
repeat dose
Gastric lavage may be needed if vomiting does
not occur
Caution: avoid vomiting if substance is caustic
or petroleum
Diarrhea
Causes of diarrhea
Nonpharmacologic measures
Travelers diarrhea
Frequent cause: Escherichia coli
Preventive measures
Antidiarrheals
Purpose of antidiarrheals
Types of antidiarrheals
Opiates and opiate-related agents
Diphenoxylate with atropine
Somatostatin analog, octreotide
(Sandostatin) for severe diarrhea
Adsorbents; Kaopectate
Antidiarrheal combinations
Constipation
Causes
Nonpharmacologic measures
Laxatives
Laxatives vs. cathartics vs. purgatives
Types of laxatives
Osmotic (saline)
Stimulant (contact)
Bulk-forming
Emollient (stool softeners)
Osmotic (Saline) Laxatives
Types and action
Side effect: electrolyte imbalances,
hypotension, weakness, etc.
Stimulants ( contact) laxatives
Types and action
Side effects: abdominal cramps,
electrolyte imbalances
Bulk-Forming Laxatives
Type and action

Administration of bulk-forming
laxatives
Adverse effects: intestinal obstruction
without sufficient amount of water
Stool softeners
Types and action
Bulk-Forming Laxatives (contd)

Contraindications
Inflammatory disorders of the GI tract
Appendicitis
Diverticulitis
Ulcerative colitis
Spastic colon
Bowel obstruction
Pregnancy
Case Study
A client who is taking chemotherapy for
cancer of the right kidney is extremely
nauseated and vomiting.

Critical Thinking
Which type of antiemetic are appropriate for
cancer chemotherapy?
Practice Question
Ondansetron (Zofran) has been ordered for the
client who is taking cancer chemotherapy to control
the severe nausea and vomiting. What side effects
are possible?
A. Headache, dizziness, and fatigue
B. Constipation, anxiety, and fever
C. Abdominal cramping, and irritability
D. Psychosis and middle ear disturbances
Practice Question (contd)
Answer: A
Rationale: Side effects of Zofran include
headache, dizziness, and fatigue.
Constipation, anxiety, fever, abdominal
cramping, irritability, psychosis, and
middle ear disturbances are not side
effects/adverse effects of Zofran
Antiulcer Drugs

Peptic Unclers
Peptic Ulcers
Gastric secretions
Gastric mucosal barrier (GMB)
Peptic ulcers
Esophageal ulcer
Duodenal ulcer
Stress ulcer
Predisposing factors in peptic ulcers disease;
Helicobacter pylori (H. pylori)
Gastroesophageal reflux disease (GERD)
Nonpharmacologic Measures
Avoid tobacco
Avoid alcohol
Weight loss
Avoid hot, spicy, and greasy foods
Take any NSAIDs including aspirin and oral
glucocorticoids with food or in deceased dosage
Sit upright
Do not eat before bed
Ware loose-fitting clothing
Pharmacologic Measures
Antiulcer drugs
Tranquilizers
Anticholinergic drugs
Antacids
Histamine2 (H2)-blockers
Proton Pump Inhibitors
Pepsin inhibitors
Prostaglandin E1 analog
Gastric Secretory Cells
Chief cells
Secrete pepsinogen
Parietal cells
Secrete 1-3 L of Hydrochloric Acid daily
Intrinsic factor

Gastric juice = combined secretions of chief


and parietal cells. Most acid fluid in the
body
Pharmacotherapy for
Peptic Ulcer Disease
Four primary classes
H2-receptor antagonists
Proton pump inhibitors
Antacids
antibiotics
Miscellaneous drugs
I. Agents that inhibit Gastric Acid Production
& Antiulcer Drugs
Sites/Location of Various Anti-Ulcer Agents
Brief Pharmacology of Antiulcer agents

1) Agents that Neutralize acid: Antacids: (NaHCO3,


Al(OH)2, Ca(CO)3).
These are weak bases that form salts with HCl
causing Chemical NEUTRALIZATION to buffer acid in
the stomach. Antacids are thought to heal ulcer by
protective effect particularly aluminum compounds.
Advantages:Immediate Pain Relief & Less expensive.
Disadvantages: i) Short Duration of Effect
ii) Rebound Gastric Acid Secretion.
Antacids: Mechanism of Action
Promote gastric mucosal defense mechanisms
Secretion of:
Mucus: protective barrier against HCl
Bicarbonate: helps buffer acidic properties of
HCl
Prostaglandins: prevent activation of proton
pump which results in HCl production

Antacids DO NOT prevent the over-production of


acid
Antacids DO neutralize the acid once its in the
stomach
ANTACIDS
Pharmacokinetics:
Work locally in the stomach by
neutralizing gastric acid.
Distributed throughout the GI tract;
eliminated primarily in the feces.
Pharmacodynamics:
Reduces the total amount of acid in the
GI tract.
ANTACIDS
Pharmacotherapeutics:
Prescribed to relieve pain and promote
healing in peptic ulcer disease.
Also used to relieve symptoms of acid
indigestion, heart-burn, dyspepsia, or
GERD.
Also used to prevent stress ulcers, GI
bleeding, and hyperphosphatemia in
kidney failure.
ANTACIDS
Drug interactions:
All antacids can interfere with the
absorption of oral drugs given at the
same time.
Adverse reactions:
Diarrhea, constipation, electrolyte
imbalances
Major Constituents of some Antacids
Antacids: Drug Effects
Reduction of pain associated with acid-
related disorders
Raising gastric pH from 1.3 to 1.6 neutralizes
50% of the gastric acid
Raising gastric pH 1 point (1.3 to 2.3) neutralizes
90% of the gastric acid
Reducing acidity reduces pain

Used alone or in combination


Histamine H2 Receptor Antagonist
Reversible competitive inhibitors of H2
receptor
Highly selective, No action on H1 or H3
receptors
Very effective in inhibiting nocturnal acid
secretion ( as it depends largely on
Histamine )
Modest impact on meal stimulated acid
secretion (As it depends on gastrin, acetyl
choline and histamine)
H2-RECEPTOR ANTAGONIST
Pharmacokinetics:
Absorbed rapidly and completely except for
famotidine;
food and antiacids may reduce absorption;
distributed widely throughout the body;
metabolized by the liver;
excreted primarily in the urine.
Pharmacodynamics:
Block histamine from stimulating the
acid-secreting parietal cells of the
stomach.
H2-RECEPTOR ANTAGONISTS

Pharmacotherapeutics:
Used therapeutically to:
Promote healing of duodenal and
gastric ulcers.
Provide long-term treatment of
pathological GI hypersecretory
conditions.
Reduce gastric acid production and
prevent stress ulcers.
H2-RECEPTOR ANTAGONISTS

Drug interactions:
Cimetidine inhibits metabolism of ethyl
alcohol in the stomach resulting in
higher blood alcohol levels.
Adverse reactions:
Headache, diarrhea, and rash
Cimetidine Ranitidine Famotidine Nizatidine

Bioavailability 80 50 40 >90
Relative Potency 1 5 -10 32 5 -10
Half life (hrs) 1.5 - 2.3 1.6 - 2.4 2.5 - 4 1.1 -1.6
Duration of 6 8 12 8
action (hrs)
Inhibition of 1 0.1 0 0
CYP 450
Dose mg(bd) 400 150 20 150
H2 BlockersSide effects & Interactions

Extremely safe drugs


Cimetidine causes gynecomastia, galactorrhea
(as it is antiandrogenic & increases prolactin level)
Cimetidine inhibits CYP450:
-- increases conc. of :
Warfarin,
Theophylline,
Phenytoin,

Ethanol.
Proton Pump Inhibitors

Most effective drugs in antiulcer therapy

Irreversible inhibitor of H+ K+ ATPase


Prodrugs requiring activation in acid
environment
Weakly basic drugs & so accumulate in
canaliculi of parietal cell
Activated in canaliculi & binds covalently to
extracellular domain of H+ K+ ATPase
Acid secretion resumes only after synthesis
of new molecules
PROTON PUMP INHIBITORS
Pharmacokinetics:
Given orally in enteric-coated form to bypass the
stomach and are dissolved and absorbed in the
small intestine.
Highly protein-bound and are extensively
metabolized by the liver; eliminated in the urine.
Half life 1.5 hrs
Since it requires acid for activation - given 1 hr
before meals
Other acid suppressing agents not coadministered
Pharmacodynamics of PPI
Block the last step in the secretion of gastric
acid by combining;
with hydrogen, potassium, and adenosine
triphosphate in the parietal cells of the
stomach

Irreversibly bind to H+/K+ ATPase enzyme


Result: achlorhydriaALL gastric acid
secretion is blocked
PROTON PUMP INHIBITORS
Indicated for:
Short term treatment of gastric ulcers
Active duodenal ulcers and peptic ulcers (H.
pylori)
Erosive esophagitis
GERD
Hypersecretory states
PROTON PUMP INHIBITORS
Drug interactions:
May interfere with the metabolism of
diazepam, phenytoin, and warfarin.
May also interfere with drugs that
depend on gastric pH for absorption.
Adverse reactions:
Abdominal pain, diarrhea, nausea, and
vomiting
Proton Pump Inhibitors

Omeprazole 20 mg o.d.
Esomeprazole 20 - 40 mg o.d.
Lansoprazole 30 mg o.d.
Pantoprazole 40 mg o.d.
Rabeprazole 20 mg o.d.
P.P.I. Side effects & Interactions

Extremely safe drugs

Causes hypergastrinemia which leads to


carcinod tumor in rats
But no evidence of such tumors in man
Inhibit CYP 450 & hence metabolism of
warfarin, phenytoin, etc
Pantoprazole & Rabeprazole have no
significant interactions
Mucosal Protective Agents
Sucralfate

Misoprostol
Colloidal Bismuth compounds
Sucralfate

Salt of sucrose complexed to sulfated


aluminium hydroxide
In acidic pH polymerises to viscous gel that
adheres to ulcer crater
Taken on empty stomach 1 hr. before meals

Concurrent antacids, H2 antagonist avoided


( as it needs acid for activation )
Misoprostol
PGE1 analogue

Modest acid inhibition


Stimulate mucus & bicarbonate secretion

Enhance mucusal blood flow

Approved for prevention of NSAID induced


ulcer
Diarrhoea & cramping abd. pain 20 %

Not so popular as P.P.I are more effective &


better tolerated
= Contra-indication: Pregnancy
Colloidal Bismuth Compounds
Coats ulcer, stimulates mucus & bicarbonate
secretion
Direct antimicrobial activity against H.pylori

May cause blackening of stools & tongue


Not used for long periods bismuth toxicity

Available compounds :
Bismuth subsalicylate in USA
Bismuth sobcitrate in Europe
Bismuth dinitrate
Helicobacter Pylori Treatment
Infections must be treated properly to
eradicate bacterium
Multiple antibiotic therapy
Antibiotic therapy combined with
antiulcer medication
Bismuth compounds may be added to
regimen
Triple Therapy

The BEST among all the Triple therapy regimen


is
Omeprazole / Lansoprazole - 20 / 30 mg bd
Clarithromycin - 500 mg bd
Amoxycillin / Metronidazole - 1gm / 500 mg td

Given for 14 days followed by P.P.I for 4 6


weeks
Short regimens for 7 10 days not very effective
Triple Therapy cont

Some other Triple Therapy Regimens are


Bismuth subsalicylate 2 tab qid
Metronidazole - 250 mg qid
Tetracycline - 500 mg qid

Ranitidine Bismuth citrate - 400 mg bd


Tetracycline - 500 mg qd
Clarithromycin / Metronidazole - 500 mg bd
Quadruple Therapy

Given when Triple Therapy fails

Omeprazole / Lansoprazole - 20 / 30 mg bd
Bismuth subsalycilate - 2 tabs qid
Metronidazole - 250 mg qid
Tetracycline - 500 mg qid
Now you have learnt about drugs used for treating peptic
ulcer ? Are there any drugs that can cause peptic ulcer ?

Drugs causing peptic ulcer


Non Steroidal Anti Inflammatory Drugs
(NSAIDs)
Glucocorticoids

Cytotoxic agents