Drugs Affecting
GI Functions
(Summary)
Assoc. Prof. Iv. Lambev
E-mail: itlambev@mail.bg
www.medpharm-sofia.eu
I. Treatment of Peptic Ulcer
Acid-peptic diseases include hyperacidity, GERD
(gastro-esophageal reflux disease), stress induced
mucosal erosions and peptic ulcers (gastric or duodenal).
A localized loss of gastric or duodenal mucosa leads to
the formation of peptic ulcer. Peptic ulcer arises when
the mucosal protective factors are impaired and aggressive
factors dominate. Ulcers occur five times more in the
duodenum (predominantly in the duodenal bulb and pyloric
channel). Benign gastric ulcers are located mainly in the
antrum.
The Nobel Prize in Physiology or Medicine (2005) was awarded jointly
to Barry J. Marshall and J. Robin Warren "for their discovery of the
bacterium Helicobacter pylori and its role in gastritis and peptic ulcer disease"
J. Robin Warren (2005)
Barry J. Marshall (2005)
A. Antacids (Drugs Neutralizing Gastric Acid)
Antacids are weak bases that neutralize gastric hydrochloric acid. They raise the pH of the stomach contents,
decrease the acid load delivered to the duodenum and
reduce the activity of pepsin. Antacids are given between
meal and at bed time when symptoms of hyperacidity
usually occur; the presence of food in the stomach can
prolong their neutralizing capacity.
1.Systemic Antacids: Sodium bicarbonate acts rapidly,
has a brief effect and raises the pH of gastric secretion to
7.4. On neutralizing gastric asid (HCl), it forms carbon
dioxide (CO2) and sodium chloride (NaCl).
Formation of CO2 results in gastric distention and belching
that can be dangerous if ulcer is near perforation. Unreacted
alkali is absorbed and can raise the pH of blood (systemic
alkalosis) and the urine. Absorption of NaCl may increase
sodium load and this may exacerbate fluid retention in
patients with hypertension and CHF. The sudden release
of CO2 can cause “rebound acidity”.
2. Non-systemic Antacids are poorly absorbed from GIT
a) Buffer Type Non-systemic Antacids
•Aluminium hydroxide
•Magnesium trisilicate
•Magaldrate
These drugs have slow onset but longer effect and raise
the gastric pH to 3.5–4. The pepsin activity is inhibited
around pH 4. “Rebound acidity” is not a problem.
Aluminium hydroxide and Magnesium trisilicate neutralize gastric hydrochloric acid to form aluminium chloride
and magnesium chloride which further react with intestinal
bicarbonates to form aluminium carbonate and magnesium
carbonate. Sodium chloride formed in these reactions gets
reabsorbed to compensate the loss of chlorides during
gastric acid neutralization. Buffer type non-systemic
antacids do not disturb the acid-based balance of the body.
Aluminium hydroxide can cause constipation and
Magnesium trisilicate – diarrhoea, as a side effect.
Magaldrate is a hydrated complex of Aluminium and
Magnesium hydroxide sulfate.
b) Non-Buffer Type Antacids (Calcium carbonate and
Magnesium hydroxide) are powerful drugs with fast onset
of action, and raise gastric pH > 7.
Like Sodium bicarbonate Calcium carbonate may cause
belching due to liberation of carbon dioxide. It can cause
constipation too, due to formation of calcium stearate.
Magnesium hydroxide does not liberate carbon dioxide but
can cause diarrhoea.
c) Other Antacids
Simethicone (dimethyl polysiloxane) is a silicone polymer
and therefore has water-repellent properties. It acts as
an antifoaming agents and reduces gastric flatulence. It is
not absorbed from GIT.
B. Drugs, Reducing Gastric Acid Secretion
1. Proton Pump Inhibitors (PPIs)
•Esomeprazole
•Lansoprazole
•Pantoprazole
•Omeprazole
•Rabeprazole
PPIs are the most widely used drugs for peptic ulcer and
related disorders, because of their efficacy and safety.
PPIs are prodrugs. In the parietal cells they undergo a
molecular rearrangement to sulfenamide cation
(active metabolite). This cation makes a covalent
disulfide bond with –SH group of gastric proton pump
H+/K+-ATPase. Thereby PPIs inactivate the proton pump
irreversibly and shut off the acid secretion.
PPIs also inhibit gastric mucosal carbonic anhydrase
and reduce bicarbonate secretion to mucus.
ADRs: diarrhoea, headacke, inhibition of vitamin B12,
hypochlorhydria and risk of enteric infections.
2. Antagonist of H2-receptors (H2-blockers)
– for treatment of peptic ulcer:
•Cimetidine (? …)
•Famotidine
•Nizatidine
•Ranitidine
•Roxatidine
3. Prostaglandin analogues
•Misoprostol (PGE1) and Enprostil (PGE2)
4. Anticholinergics (M1-blockers)
•Pirenzepine and Telenzepine
C. Mucosal Protective Drugs
•Sucralfate (aluminium salt of sulfated sucrose) in acidic
environment (pH < 4) polymerizes and forms a gel over
ulcer crater which acts as acid resistant physical barrier. It
also stimulates mucosal synthesis of PGE2 and secretion
of bicarbonates. Sucralfate is administered orally. It is not
effective in preventing or healing NSAIDs induced ulcer.
•Colloidal Bismuth Subcitrate in gastric acidic media
converts into bismuth oxychloride and bismuth citrate which
chelate glucoproteins and amino acids at ulcer base to form
an acid resistant coating. It stimulates PGE, mucus and
bicarbonate secretion. It has also anti-H. pylori activity.
D. Anti-Helicobacter Pylori Drugs
Peptic ulcer, although a multifactorial disease, also occurs
due to colonisation of mucosa by H. pylori: in 90% in cases
with duodenal ulcers, 60 to 70% – with gastric ulcers and
50% in patients with non-ulcer dyspepsia. H. pylori is
accepted as a cause of chronic atrophic gastritis too. It is a
risk factor for gastric adenocarcinoma and to some
extent for non-Hodgkin’s lymphoma affecting stomach.
H. pylori produces urease which hydrolyses urea into
ammonia. Ammonia neutralizes gastric acid to create a
neutral protective cloud over the bacteria.
H. pylori infection can be detected by a “urea breath test”,
but the test is not used after the treatment with PPIs.
Since H. pylori becomes less virulent in absence of acid,
a combination of an antibiotic with PPIs (or H2-blockers) is
more efficacious in eradicating this Gram (–) bacterium.
Preferred anti-Helicobacter pylori Combinations
•Dual therapy (7–10 days).
Omeprazole (40 mg OD) + Amoxicillin (1000 mg BD)
•Triple therapy (14 days)
Omeparzole (or lanzoprazole), plus Clarithromycin,
plus Amoxicilin (resp. Metronidazole, or Tetracycline)
II. Antiemetic Drugs
Vomiting means expulsion of gastric contents through
mouth due to mass antiperistalsis. It is often preceded
by nausea. Vomiting can be life saving, physiological
response to the ingested toxic substances. It also can
be an adverse reaction of radiation and antineoplastic
agents. Vomiting also occurs in early pregnancy, during
migraine attack, in motion sickness, etc.
The CTZ at the base of the 4th ventricle has numerous
receptors: D2-, 5-HT3-, M-, H1-, for SP etc. Stimulation of
different receptors are involved in different pathways
leading to emesis.
Main Antiemetic Drugs
(1) 5-HT3-receptor antagonists (setrons)
•Dolasetron, Granisetron, Ondansetron
(Zofran – tab. 8 mg), Tropisetron
(2) Neurokinine-1 (NK1-, SP1-) receptor
antagonists: Aprepitant, Fosaprepitant (prodrug)
(3) D2-receptor antagonists
Neuroleptics: Chlorpromazine, Prochlorperzine, Haloperidol
Prokinetics: Domperidone, Metoclopramide
(4) H1-blockers: Diphenhydramine, Doxylamine, Promethazine
(5) M-cholinolytics: Scopolamine (Scopoderm TTS)
(6) Miscellaneous Antiemetic Agents
5-HT3-receptor antagonists block 5-HT3-receptors both
peripherally (on vagal nerve terminals) and centrally (CTZ).
Granisetron is the most potent antiemetic compared to
ondansetron and dolasetron. These drugs are most
effective when given i.v. 30 min prior to anticancer
chemotherapy (granisetron – 10 mcg/kg). These doses
may be repeated every 24 h.
Neurokinine-1 (NK1-, SP1-) receptor antagonists
(Aprepitant etc.) have the similar indications.
D2-receptor antagonists
Phenothiazines (prochlorperazine, thiethylperazine)
and butyrophenone group of antipsychotics (droperidol)
can be used to treat postoperative nausea and vomiting.
Emetogenic activity
Cisplatin
Carmustine
Cyclophosphamide
Mitomycin C
L-Asparginase
Fluorouracil
Methotrexate
Etoposide
Vincristine
Antiemetic activity
5-HT3-blockers
D2-blockers
Glucocorticoids
H1-blockers
Prokinetic antemetic
Metoclopramide is D2-receptor antagonists but in high doses
it also blocks 5-HT3-receptors. It crosses BBB. Its prokinetic
action (stimulation of GI motility) is connected with stimulation
of 5-HT4-receptors, present on excitatory interneurons, which
enhances ACh release from primary cholinergic neurons in
myenteric plexus. Metoclopramide is used as antiemetic and
as gastrokinetic agent to accelerate gastric empting prior to
giving emergency general anaesthesia in case the patient
has taken food less than 4 h before. This drug may also be
successful in stopping persistent hiccups. Being a central and
peripheral D2-blocker it produces sedation, muscle dystonia,
in high doses – extrapyramidal effects, galactorrhoea in
females and gynecomastia in males.
Domperidone has a similar mechanism of action as
metoclopramide, but it is a peripheral D2-blocker. Its
antiemetic efficacy is lower than metoclopramide. It is also
used to prevent the emetic side effect of levodopa or
bromocriptine without affecting their antiparkinsonian effect.
H1-blockers with anticholinergic properties (Cyclizine,
Diphenhydramine) are useful for prevention or treatment
of motion sickness and vertigo due to labirinth dysfunction.
Doxylamine can be used in morning sickness (vomiting
during the first trimester of pregnancy, due to the effect of
increased oestrogen level on CTZ.
Pyridoxine serves as a cofactor for the glutamate decarboxylase and thus increases the synthesis of GABA which
acts as inhibitory neurotransmitter at CTZ.
Anticholinergic drugs: Hyoscine (Scopolamine)
is used in motion sickness as TTS.
Miscellaneous Antiemetic Agents
•GCS: Dexamethasone, Methylprednisolone
•Canabinoides: Nabilone and Dronabinol stimulate CB1receptors present on neurons around the vomiting center
and are used in oncology. Their hallucinogenic activity
is weak.
•Anxiolytics: Aprazolam, Diazepam, Lorazepam
•Others: Benzocaine, Sodium citrate, T-ra Menthae
III. Laxative and Purgative Drugs
Laxatives provide elimination of soft semisolid stool
and Purgatives provide more watery evacuation.
Laxatives are used: to treat constipation; to avoid undue
straining at defecation in cases of hernia, haemorrhoids or
CVD; before or after surgery of any anorectal disease; in
bedridden patients.
Lactulose is an osmotic laxative drug. It is nonabsorbleindigestible disaccharide (sugar), which increases fecal
bulk by hydrophilic and osmotic action. It is given in dose
of 10 g orally. Latency period is 1 to 3 days. Lactulose is
also used for treatment of hepatic encephalopathy.
Liquid paraffin is an inert mineral oil.
Liquid pararaffin is a fecal lubricant and stool softner
as it retards water absorption from the stool. It is given 15
to 30 ml per day at bed time. Latency period is 1 to 3 days.
Purgatives are used for complete colonic cleansing prior
to GI endoscopic procedures or before intestinal operation.
Purgatives may also be needed to flush out warms after the
use of anthelmintic drugs. In low doses purgatives can
be used as laxatives too.
Osmotic Purgatives include: Saline purgatives (Magnesium
sulfate) and Electrolyte purgatives (PEG – PolyEthylene
Glycol, which is a nonabsorbable sugar). They act on small
and on large intestine. Saline purgatives are soluble
inorganic salts which increase the fecal bulk by retaining
water by osmotic effect, thus increasing peristalsis. These
agents also release CCK which further helps in increasing
intestinal secretion and peristalsis. Saline purgatives should
be ingested with enough water to protect vomiting. These
drugs can cause electrolyte disturbances and must be
avoided in patients with CVD as well as during pregnancy.
Irritant purgatives
•Antraquinone group: Senna, Cascara and Aloë
•Organic agents: Bisacodyl, Sodium picosulfate
•Oils: Castor oils
Aloë vera
All irritant purgatives stimulate peristalsis by irritant action
of intestinal mucosa. They also stimulate colonic electrolyte
and fluid secretion by altering the absorptive and secretory
activity of the mucosal cells.
Senna, Cascara and Aloë occur naturally in plants. Senna
is more commonly used. These plant agents contain
anthraquinone glycosides with purgative action.
The organic irritants are prodrugs. The primary site of
action of their active metabolites is in the colon. Bisacodyl
is activated in the intestine by deacetylation. In the colon
Sodium picosulfate is converted to the active metabolite.
Castor oil is hydrolyzed in the intestine by pancreatic lipase
to ricinolic acid which increases the intestinal motility.
IV. Antidiarrhoeal Agents
Diarrhoea is an abnormal increase in the frequency and
the liquidity of stool. Increased motility of GIT and the
decreased ability of intestine to absorb water from the
stool are the major factors, causing diarrhoea.
Osmotic diarrhoea may cause by ingestion of some type
of meal, use of some osmotic substances, lactulose or
magnesium containing antacids, lactase enzyme deficiency.
Secretory diarrhoea occurs when the intestinal wall loses
its functional integrity or gets damaged resulting in an
increased secretion of electrolyte in the intestinal tract. This
may be due to some bacterial infection (Schigella, Salmonella),
bacterial endotoxins (from E. coli, V. cholerae, S. aureus),
viral infections (rotavirus etc.), protozoal infections (Lamblia
intestinalis, E. histolytica), underlying pathology (inflammatory bowel disease) or due to side effects of drugs (antibiotics, anticancer agents, colchicine, prostaglandins,
orlistat, acarbose). Excess of bile also causes diarrhoea.
Motility disorder diarrhoea. Increased motility reduces the
contact time of the stool with the intestinal wall, so that
lesser amount of water is absorbed back from the faces.
Motility disorders include IBS, scleroderma, diabetic neuropathy, vagotomy etc. Some drugs can increase intestinal
motility: prokinetic antiemetics, bethanechol, digitalis,
quinidine, ampicillin (causes disbiosis); neurosis, etc.
Treatment of infective diarrhoeas needs proper diagnosis
and suitable antibiotic and/or antiprotozoal drug. For
symptomatic relief of non-specific diarrhoes are used:
(1) Antimotility and Antisecretory Agents
a) Opioid agonists which does not cross BBB
• Loperamide (Imodium®) and Racecadotril (Hidrasec®)
These drugs stimulate mu- and delta-receptors, present
in the small and large intestines. Activation of mu-receptors
decreases peristaltic movements. Activation of deltareceptors contributes to their antisecretory effects.
Although all opioids such as morphine and codeine have
antidiarrhoeal effects, their CNS effects and dependence
liability limit their usefulness. Loperamide directly stimulates
mu- and delta-receptors. Racecadotril blocks enzyme
encephalinase and increases local concentration of
enkephalins in intestinal mucosa which then stimulate
mu- and delta-receptors. This drug can be used orally from
children under 5 years old (including babies), but
Loperamide is contraindicated in children < 5 years old.
b) Miscellaneous Agents
•Carbo activatus (absorbent drug)
•Bismuth subsalicylate reduces stool frequency and
liquidity in acute diarrhoea due to inhibition of
PG synthesis. Bismuth has some antimicrobial and
mucosal protective effect too.
(2) Fluid and Electrolyte Replacement
During diarrhoea, a glucose-coupled transport continues
in the intestines which causes water and electrolyte losses
through the stools.
V. Treatment of Inflammatory Bowel Disease
Ulcerative colitis and Crohn’s disease are two important
inflammatory bowel diseases. The pathogenesis of these
diseases involves autoimmune mechanism and imbalance
between proinflammatory and anti-inflammatory cytokines.
The main drugs, used in the treatment of these diseases are
aminosalicylates, GCS and some immunosuppressants.
Antidiarrhoeal agents must be avoided in active and
severe ulcerative colitis as they can lead to dilatation of
the colon and its perforation.
Aminosalicylates (sulfasalazine, olsalazine) contain a
5-aminosalicylic acid (5-ASA) moiety bound by an azo
(N=N) bond to an inert moiety or by another 5-ASA
molecule. 5-ASA inhibits the synthesis of PGs by inhibiting
COX, like salicylates, as well as inhibiting the production of
cytokines. 5-ASA also inhibits the activity of nuclear
factor-kB, which is an important transcription factor for
pro-inflammatory cytokines. It suppresses the generation
of superoxide free radicals. Aminosalicylates induce and
maintain remission in patients with ulcerative colitis.
GCS (Prednisone, Prednisolone) have been the mainstay
of the treatment for acute/severe exacerbations of irritable
bowel disease. Moderately severe attacks of ulcerative
colitis should be treated orally with systemic GCS.
Immunosuppressive Agents
•Cyclosporine may induce remissions in case of severe
ulcerative colitis unresponsive to GCS.
•Azathioprine, mercaptopurine
•Methotrexate is useful in controlling relapse of Crohn’s
diseases unresponsive to GCS or azathioprine
•Infliximab is a chimeric (25% mouse and 75% human)
anti-TNF-alpha-monoclonal antibody, which inhibits T-cells
and macrophage functions. Consequently, the release of
other proinflammatory cytokines (IL-1, 2, 8; collagenase
and metaloproteinases) is prevented. It is administered
by i.v. infusion. A single dose of infliximab (5 to 10 mg/kg)
induces remission in approximately 40% of patients with
Crohn’s disease. An additional dose after 8 weeks
produces long-lasting remission.
•Adalimumab is a recombinant human anti-TNF-alphamonoclonal antibody. It is given s.c. and has a longer
plasma half life. It has lesser side effects
compared to infliximab.
VI. Drugs used in Pancreatic Insufficiency
Pancreatic enzyme agents contain a mixture of amylase,
lipase and proteases. They are the mainstay of the treatment
of the pancreatic enzyme insufficiency which is most
commonly caused by cystic fibrosis, chronic pancreatitis or
pancreatic resection. Exocrine pancreatic enzyme insufficiency
leads to fat and protein indigestion
which in turn causes steatorrhoea,
azotorrhoea, vitamin deficiency and
weight loss.
•Festal, Kreon,
•Mezym forte, Panzytrat
VII. Hepatoprotectors
Drugs which stimulate regenerative processes
•Acidum oroticum, Essentiale, Silymarin
Drugs which stimulate fat infiltration
•Thioctic acid (Acidum aphfa-lipoicum)
Derivatives of Methionine: Ademethionine
Interferons (in viral hepatitis)
•Interferon alfa-2a
•Peginterferon alfa-2a
•Interferon alfa-2b
Antiviral vaccines: Hepatitis A and B vaccine,
•Hepatitis A vaccine, Hepatitis B vaccine
VIII. Drugs Acting on Biliary tract
Choleretic Drugs: Cholagol, Cholamin, Febichol
Cholekinetic Drugs: Oleum olivarum, Rowachol
Drugs which improve the solubility
of cholesterol gallstones: Ursodeoxycholic acid
IX. Probiotics – regulators of intestinal
or other bacterial flora
BioGaia, Linex, Lactoflor, Lactagyn® (vaginal flora),
Normoflor, Probien®