Transcript GITDrugs

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 H2histamine 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 H2antagonists.
• 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
HOW IT WORKS AT THE RECEPTOR LEVEL
Combined neurocrine, endocrine and paracrine
events in the activation of gastric HCl secretion
Acetylcholine
neural input
neurocrine
ACh
receptor
PARIETAL cell
histamine
receptor
H/K
P
ECL cell
transductionactivation events
histaminesecreting cell
HCl
secretion
H/K
P
gastrin
receptor
Gastrin
hormonal input
endocrine
paracrine
release of
histamine
ECL cell =
enterochromaffin-like cell
G cell =
gastrin-secreting cell
G cell
HOW IT WORKS AT THE RECEPTOR LEVEL
Combined neurocrine, endocrine and paracrine
events in the activation of gastric HCl secretion
Acetylcholine
neural input
neurocrine
ACh
receptor
PARIETAL cell
histamine
receptor
H/K
P
ECL cell
HCl
transductionactivation events
histaminesecreting cell
secretion
H/K
P
gastrin
receptor
Gastrin
hormonal input
endocrine
paracrine
release of
histamine
G cell
H-2 receptor blockers
Tagamet
ECL cell =
Zantac
enterochromaffin-like
cell
Pepcid
H/K ATPase
pump
G cell
= inhibitors
gastrin-secreting
cell
Prilosec
Nexium
Aciphex
NSAIDS
Protective Factors
Mucus 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 Drugs
Acid Secretion Reducers
H+-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 Drugs
Mucosal Strengtheners
Sucralfate 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-withpredominant 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 fatsoluble 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 5aminosalicylic 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 5aminosalicylate) 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.