Drugs Acting on the GI Tract: Peptic Ulcer and Motility & Secretions

Peptic Ulcer (PU)• Peptic ulcer – any ulcer in which the mucosa is

bathed in HCl and gastric juice (i.e., stomach and upper duodenum).

• Drugs treating these ulcers either decr gastic acid secretion or incr mucosal resistance.

• Parietal cells’ secretion of HCl is decr by H2-histamine antagonists or by H+ pump inhibitors (inhibit the pump that transports H+ ions out of the parietal cell).

• H+ inhibitors are very effective in promoting ulcer healing, even in patients who are resistant to H2-antagonists.

• The mucosal strengtheners incr ulcer healing by binding to the ulcer base. This is physically protective and allows HCO3

- to re-establish the pH gradient normally present in the mucus layer.

• Misoprostol – PG analogue that promotes ulcer healing by stim protective mechanisms in the gastric mucosa and decr acid secretion. Used to prevent ulcers in patients taking NSAIDS.

• Even after healed, PUs will often recur w/o cont drug administration – bec chronic infection of the stomach by H. pylori is an important etiological factor in ulcer formation (assoc with ~ 90% of duodenal ulcers and ~ 75% of gastric ulcers).

• Infection chronic hypergastrinemia acid production ulcers.

• Uncomplicated PUs assoc with H. pylori infection are treated by eradicating the bacteria with a combination of a H+ inhibitor (e.g. omeprazole and antibiotics (later)).

• Before treatment, infection with H. pylori confirmed with a urea breath test in which some 14C-urea is ingested.

• This test can also be used to confirm that H. pylori has been eradicated.

• Antacids (bases) incr the gastric luminal pH by neutralizing gastric acid – effective treatment for many dyspepsias and symptomatic relief in Pus and esophageal reflux.

• Many proprietary mixtures are available either prescription or OTCs

Acid Secretion – How it works at the Receptor Level

H/KP

H/KP

histamine-secreting cell

Acetylcholine neural input neurocrine

Gastrin hormonal input

endocrine

PARIETAL cell

paracrine release of histamine

histamine receptor

ACh receptor

gastrin receptor

transduction-activation events

HCl

secretion

Combined neurocrine, endocrine and paracrine events in the activation of gastric HCl secretion

ECL cell

G cellcirculation

ECL cell = enterochromaffin-like cell

G cell = gastrin-secreting cell

HOW IT WORKS AT THE RECEPTOR LEVEL

neural input

chemical input

H/KP

H/KP

histamine-secreting cell

Acetylcholine neural input neurocrine

Gastrin hormonal input

endocrine

PARIETAL cell

paracrine release of histamine

histamine receptor

ACh receptor

gastrin receptor

transduction-activation events

HCl

secretion

Combined neurocrine, endocrine and paracrine events in the activation of gastric HCl secretion

ECL cell

G cellcirculation

ECL cell = enterochromaffin-like cell

G cell = gastrin-secreting cell

HOW IT WORKS AT THE RECEPTOR LEVEL

H-2 receptor blockers

H/K ATPase pump inhibitors

Tagamet ZantacPepcid

Prilosec Nexium Aciphex

neural input

chemical input

NSAIDS

Protective FactorsMucus Layer

• Physical Barrier ~ 0.5 mm thick on the surface of the stomach and proximal duodenum.

• Consists of a mucus gel into which HCO3- is secreted.

• Here, HCO3- neutralizes the acid diffusing into the

lumen pH gradient, even when the stomach contents are at pH 2.

• PGs E2 and I2 synthesized by the gastric mucosa cytoprotective action by stim the secretion of mucus and HCO3

- and by incr mucus blood flow.

Ulcer-Healing Drugs

Acid Secretion Reducers• Histamine H2-receptor antagonists:• Cimetidine and rantidine – orally rapidly absorbed.• Block the action of hist on parietal cells and decr

acid secretion.• Relieve the pain of PU and incr rate of healing.• Cimetidine binds cyt P-450 and may decr the

hepatic metabolism of other drugs (e.g., warfarin, phenytoin, theophylline).

Ulcer-Healing DrugsAcid Secretion ReducersH+-Pump Inhibitors:• Omeprazole and lansoprazole – inactive at

neutral pH.• But in acid, they rearrange into 2 types of

reactive molecule react with sulphydral groups in the H+/K+-ATPase (H+ pump) responsible for transporting H+ ions out of parietal cells.

• This enzyme is irreversibly inhibited: So, when would acid secretion resume?

• Particularly useful in patients with severe gastric acid hypersecretion caused by Zollinger-Ellison syndrome and Cushing’s ulcers:

• Zollinger-Ellison Syndrome: gastrin-secreting tumour of the non-β cells (pancreas) incr acid secretion.

• Cushing’s Ulcers: in patients with severe head injuries, increased vagal (Ach) tone gastric hyperacidity.

Ulcer-Healing DrugsMucosal StrengthenersSucralfate polymerizes below pH 4 a very sticky gel that

adheres strongly to the base of ulcer craters.Bismuth chelate (tripotassium dicitratobismuthate) acts

similarly to sucralfate.Strong affinity for mucosal glycoproteins, esp in the

necrotic tissue of the ulcer craters, which become coated in a protective layer of polymer-glycoprotein complex.

Bismuth may blacken the teeth and stools.Bismuth and sucralfate must be given on an empty

stomach or they will complex with food proteins.

Antacids

• The incr in rate of incr the luminal pH incr the rate of gastric emptying effect is short.

• Gastrin release is incr and, because this acid release, larger amts of antacids are needed than would be predicted (acid rebound).

• Frequent high doses of antacids promote ulcer bleeding, but not practical.

Antacids (cont’d)

• NaHCO3-: the only useful H2O-soluble antacid. Acts rapidly,

but has a transient action. High doses may systemic alkalosis.

• Mg(OH)2 and Mg trisilicate are H2O-insoluble and have a fairly rapid action. Mg has a laxative effect and may diarrhea.

• Al(OH)3: relatively slower action. Al3+ ions form complexes with certain drugs (e.g., tetracyclines) and tend to cause constipation.

• Mixtures of Mg and Al may be used to minimize the effects on motility.

Motility and Secretions: Motility Stimulants

• Metoclopramide and domperidone: DA antagonists blockade of central DA receptors in the chemoreceptor trigger zone antinausea/antiemetic action.

• Enhance contractions in stomach.• Enhance tone of lower esophageal sphincter.• Both actions speed the transit of contents from the

stomach• This action is blocked by atropine => these actions arise

from an incr in Ach release from the myenteric plexus.

Motility and Secretions: Motility Stimulants

• This effect on Ach release may be caused by the activation of 5-HT4 receptors on cholinergic neurons.

• Tegaserod, a 5-HT4 partial agonist, modest improvement in some patients with IBS-with-predominant constipation.

• Alosetron – 5-HT3 receptor antagonist on enteric afferents blocking reflex contraction of the intestine. But, unlike tegaserod, which is very safe, alosetron may fatal ischemic colitis.

Motility and Secretions: Laxatives

• Constipation: abdominal discomfort, loss of appetite, and malaise from insufficient bowel movements.

• Freq and vol of defecation best regulated by diet, but drugs may be needed for specific purposes (e.g., before surgery, colonoscopy).

• Bulk laxatives: incr the vol of the intestinal contents, stim peristalsis. Include indigestible polysaccharides (e.g., cellulose (bran) and ispaghula.

Motility and Secretions: Laxatives• Osmotic laxatives incr bulk in the bowel by retaining H2O by an

osmotic effect. Include salts containing poorly absorbed ions (e.g., MgSO4, Epsom salts) and lactulose (takes 48 hr to act and must be given regularly).

• Stimulant laxatives incr motility by acting on the mucosa or nerve plexus, which may be damaged by prolonged drug use. Abdominal cramp is common.Antraquinones stim the myenteric plexus.Glycerol suppositories stim the rectum (glycerol is mildly irritating).Bisacodyl and Na picosulfate may act by stim sensory nerve endings – used mainly to evacuate the bowel before surgery or colonoscopy.

Fecal softeners – promote defecation by softening the stool (e.g., docusate) and/or lubricating (e.g., arachis oil, liquid paraffin) feces and assisting with evacuation.

Chronic use of liquid paraffins may impair absorption of fat-soluble vitamins.

Motility and Secretions: Antidiarrheals

• Caused by bacterial or viral (more common) infections.• Antimotility drugs: widely used to provide symptomatic relief.• Opioids (e.g., morphine, diphenoxylate, codeine) activate μ-

receptors on myenteric neurons hyperpol by incr K+ conductance.

Inhibits Ach release from the myenteric plexus and decr bowel motility.

• Loperamide is the most appropriate opioid for local effects on gut bec does not easily cross BBB.

• Rehydration Therapy – Oral sol’ns containing electrolytes and glc given with severe dehydration caused by infection with toxigenic organisms.

• Antibiotics – useful only in certain specific infections (e.g., cholera and severe dysentery) – treated with tetracycline (also the quinolones for more severe pathogens).

Drugs Used in Inflammatory Bowel Disease (IBD)

2 Types of IBD:1. Crohn’s Disease – affects the entire gut.2. Ulcerative colitis – affects only the LI.• Corticosteroids – should be used only for

acute attacks (bad side-effects for chronic).• Oral budesonide (slow release) is a

corticosteroid with decr renal absorption and may not cause adrenal suppresion.

Drugs Used in Inflammatory Bowel Disease (IBD)

• Aminosalicylates: decr symptoms in mild dis and maintenance treatment prevents relapse.

• Sulfasalazine: combo of 5-aminosalicylic acid and a sulfonamide that carries the drug to the colon where it is cleaved by bacteria, releasing 5-aminosalicylic acid, which is the active moiety, and sulfapyridine, which produces the adverse effects of the sulphonamides (e.g., nausea, rashes, blood disorders).

• Newer, less toxic drugs: mesalazine (a 5-aminosalicylate) and olsalazine (azodisalicylates).

Drugs Used in Inflammatory Bowel Disease (IBD)

• Mechanism of action of 5-aminosalicylates: unknown.

• Patients who do not seem to respond to steroids nor to 5-aminosalicylates may respond to immunosuppressants (e.g., azathioprine, mercaptopurine, methotrexate).

• Infliximab – MAB to TNFα. Inhibition of this proinflammatory cytokine can be very effective in treating severe refractory Crohn’s Disease

Drugs Used to Dissolve Gallstones

• Bile = cholesterol + bile salts.• Incr [cholesterol] or decr bile salts

cholesterol stones.• Small non-calcified stones may be dissolved by

prolonged oral administration of the bile acid, urodeoxycholic acid, which decr the cholesterol content of bile by inhibiting cholesterol biosynthetic enzyme.