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

P - 20

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 .