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Gastrointestinal Drugs
Antacids
Drugs used to neutralize gastric acid
(Diarrhea)(Constipation)
Adverse Effects
Sodium Bicarbonate: Distension, belching, systemic alkalosis, fluid retention
Calcium Carbonate: Distension, belching, systemic alkalosis, hypercalcemia
Al hydroxide and Mg hydroxide: Long acting, constipation/diarrhea (respectively)
Caution in renal insuffiency
Drug interaction:
All antacids reduce absorption of other medications by binding and altering pH
Should be taken 2 hrs before or after other drugs
Therapeutic uses
Peptic ulcers
GERD (relived symptoms, no healing)
Endoscopic view of a gastric ulcer of a 82 year-old female patient
Normal Gastric Mucosa
The pathogenesis of peptic ulcer diseaseis not fully understood
Three major factors are recognized:
1. infection with gram-negative Helicobacter pylori
2. increased hydrochloric acid secretion
3. inadequate mucosal defenseagainst gastric acid
Treatment approaches include
(1) eradicating H. pylori infection
(2) reducing secretion of gastric acid or neutralizing the acid after it is released, and/or
(3) Providing agents that protectthe gastric mucosa from damage.
Acid secretion inhibitors
Drugs used to lower
gastric acid production
Activation of Proton Pump Inhibitor (PPI) in Parietal Cell
Basal Membrane
12
3
4
INHIBITORS OFPROTON PUMP
Lansoprazole
Omeprazole
Rabeprazole
Pantoprasole
Esomeprosole
Adverse Effects• These drugs have a good adverse effects profile, and are generally well-tolerated.
• The most common adverse effect is diarrhea, particularly with long-term use.
• Other rare adverse effects include rash, liver enzyme abnormalities, and interstitial nephritis.
• Long-term treatment with these drugs causes carcinoid tumors in the stomachs of laboratory animals, but has not been observed in clinical practice. Always consider whether maintenance treatment is required.• What about the bones?
Interactions• The potential for drug interactions with these drugs is low.
• Lansoprazole, omeprazole, and esomeprazole inhibit hepatic cytochrome P450 enzymes to some degree. This effect is not great, but may enhance the actions of warfarin and phenytoin
Safety• Beware of prolonged treatment with these drugs without a diagnosis; they can mask the symptoms of gastric malignancy.
• Patients with Barrett's esophagus require regular endoscopic follow-up.
Drugs used to lower
gastric acid production
P - 15
H2 – HISTAMINE RECEPTOR BLOCKERS
Cimetidine
Famotidine
Nizatidine
Ranitidine
Pharmacokinetics- Oral bioavailability: 50%- Distributed in all organs, including brain.-A large fraction of these drugs is eliminated as such in the urine, mainly by tubular secretion.
Therapeutic Uses• When suppression of gastric acid is required.• Healing of gastric and duodenal ulcers.• Reflux esophagitis.• May be used in prophylaxis against gastric ulceration in an ICU.• Use famotidine, nizatidine, or ranitidine in preference to cimetidine, because of drug interactions with cimetidine.
Contraindications and Cautions• Rule out other upper GI diseases e.g. malignancy• H2 receptor antagonists are less effective than proton pump inhibitors.• Halve the dose in severe renal or hepatic insufficiency.• There is no information on the safety of these drugs in pregnancy. Avoid using them.
Mechanism of Action: Competitive blockade of H2 receptors
Remember H2 receptor blockers are more effective for nocturnal acid secretion as opposed to food stimulated acid secretion
Adverse effects
The most common are: diarrhea, altered liver function, rash, headache and dizziness
Cimetidine blocks androgen receptors and may cause gynecomastia, loss of libido and impotence.
P - 16
Drugs metabolized by CYP1A2, CYP2C9 and CYP3A4
Drug-drug Interactions
Nizatidine, famotidine, and ranitidine do not do this.
Absorption of cimetidine is reduced by antacids
P - 16
Lumen of Stomach
PARIETAL CELL
Pirenzepine blocks cholinergic receptor
Cimetidine blocks H2 histamine receptor
Misoprostol stimulates prostaglandin receptor
Omeprazole blocks proton pump
Acetylcholine Histamine Prostaglandin I2 and E2 Gastrin
No activation of protein kinase
Treatment of H. pylori Infection
Urease
Urease
UreaseUrease
UreaseUrease
Urease
UreaseUrease
Urease
Urease Urease Urease
UreaseUreaseUrease
UreaseUrease
Urease
Urease
Urea H2O
2CO2
Type IV secretion system
Ammonia cloud
NH3
Helicobacter eradication
Use of multiple drugs prevents development of drug resistance
Quadruple TherapyBismuth SubsalicylateMetronidazoleTetracyclineH2 receptor antagonist or PPI
More commonly given for 2 weeks
Gastric acid suppressors for 6-8 weeks
Eradication rate = 90%
P - 20
Mucosal Protective Agents
P - 21
PROSTAGLANDINS (Mucosal
protective)
Misoprostol
DRUGS USED TO TREAT PEPTIC ULCER DISEASE
MUCOSAL PROTECTIVE
AGENTS
COLLOIDAL BISMUTH
SUCRALFATE
Structure and protective effect of Misoprostol
Low acid secretion
MucusMucusMucusMucusMucus
MucusMucusMucusMucusMucus
+ -
Chemical structure and protective effect of Sucralfate
Also stimulates
Prostaglandin Mucus and Bicarbonate release
Sucrose
Aluminum Hydroxide
Sulfate
Ulcer crater
Antiemetics
CTZ5-HT3, D2, M1
Solitary Tract Nucleus5-HT3, D2, M1, H1, NK1
Stomach5-HT3
Solitary Tract Nucleus5-HT3, D2, M1, H1, NK1
CTZ5-HT3, D2, M1
Solitary Tract Nucleus5-HT3, D2, M1, H1, NK1
CTZ5-HT3, D2, M1
Solitary Tract Nucleus5-HT3, D2, M1, H1, NK1
CerebellumM1, H1
CTZ5-HT3, D2, M1
Solitary Tract Nucleus5-HT3, D2, M1, H1, NK1
CerebellumM1, H1
Cannabinoids
ANTIEMETIC ACTIVITY
Low High
Serotonin antagonist
Substituted benzamide
Phenothiazine
Butyrophenone
Corticosteroid
Cannabinoid
Antihistamine
Anticholinergic
Benzodiazepine
91%
76%
63%
58%
0% 100%
% RESPONSE
AGAINST CISPLATIN CHEMOTHERAPY
DrugCombinations
DexamethasoneOndansetron
DexamethasoneDiphenhydramineMetoclopramideDroperidol
LorazepamDexamethasoneMetoclopramide
DiphenhydramineDexamethasoneMetoclopramide
Anti-diarrheal / Laxative drugs
Antidiarrheals
• Antimotility Agents– Diphenoxylate, loperamide
• Both are meperidine derivatives• Activate presynaptic opioid receptors, inhibit Ach
release (see next slide)• Adsorbents
– Kaolin, pectin• Agents that modify fluid/electrolyte transport
– NSAIDS– Bismuth subsalicylate (Pepto Bismol)
Lomotil
• Diphenoxylate and atropine• Atropine is added to discourage
deliberate overdosage and may also contribute to anti-diarrheal effect
methscopolamine atropine, scopolamine
CONSTIPATION
Bulk Laxatives
Stimulation of persistalsis by an intraluminal bolus
Epsom salt (MgSO4) and Glauber’s salt (Na2SO4), the SO4 2- anion is not absorbable so causes osmotic laxative effect
Osmotically active laxatives
Mannitol is also an osmotic laxative
Fe ca l s oft e n e r s ( o r Em o l l i e nt l a xa ti v e )
Docusate SodiumA s u r fa ce - a cti v e com p ou n d t ha t a ct s i n t h e G I T i n a m a n n e r s i m i l a r to a d ete r g e nt a n d p ro d uce s s o ft e r fe ce s .I t i s a l s o a w e a k sti m u l a nt l a xa ti v e .