Gastrointestinal System

• Nearly 80% of peptic ulcers are

Gastrointestinal System
• Small intestine has the largest
surface area.
• About 60% of drug molecules are
absorbed at duodenum.
Peptic ulcer disease:
• Peptic ulcer disease (PUD) refers to a
group of disorders characterized by
lesions of the mucosa of the upper
gastrointestinal (GI) tract (particularly
the stomach and duodenum).
• Gastroesophageal reflux disease (GERD)
refers to the retrograde movement of
gastric contents from the stomach into
the esophagus.
• Dyspepsia is defined as persistent or
recurrent abdominal pain or abdominal
discomfort centered in the upper
abdomen.
duodenal; the others are gastric ulcers.
Other less common forms of peptic
ulcers are:-
1. Stress ulcers result from serious trauma
or illness, major burns, need for
mechanical ventilation 48 hrs, or
ongoing sepsis.
2. Zollinger–Ellison syndrome is a severe
form of peptic ulcer disease in which
intractable ulcers are accompanied by
extreme gastric hyperacidity and at
least one gastrinoma (a non– -islet cell
tumor of the pancreas or another site).
3. Drug-associated ulcers occur in patients
who chronically ingest substances that
damage the gastric mucosa, such as
non-steroidal anti-inflammatory drugs
(NSAIDs)
 H2antihistamines:
Cimetidine:
• Due to sever side effects and the
availability of new category of H2-
blockers, Cimetidine is no longer used
for peptic ulcer.
• Cimetidine inhibits several cytochrome
P-450 isoenzymes and reduces hepatic
blood flow. It inhibits the metabolism of
many drugs so that they can
accumulate to toxic levels, e.g.
theophylline, phenytoin,
carbamazepine, phenobarbitone,
sulfonylureas, metronidazole, warfarin,
imipramine, lidocaine, nifedipine,
quinidine.
• High doses given for long periods have
produced antiadrogenic effects which
include gynaecomastia, loss of libido,
impotence and temporary decrease in
sperm count.
Ranitidine:
• About 5 times more potent than
cimetidine.
Famotidine:
• It is 5–8 times more potent than
ranitidine. Antiandrogenic action is
absent.
 Proton pump inhibitors: Stress ulcers:
• Intravenous pantoprazole/ rabeprazole
Omeprazole: is as effective prophylactic.

• It is a powerful inhibitor of gastric acid: Gastroesophageal reflux disease

can totally abolish HCl Secretion.
(GERD):
• Omeprazole is inactive at neutral pH,
but at pH < 5 it rearranges to two
• Omeprazole produces more complete
charged cationic forms that react
round-the-clock inhibition of gastric
covalently with SH groups of the
acid resulting in rapid symptom relief
H+K+ATPase enzyme and inactivate it
and is more effective than H2 blockers
irreversibly.
in promoting healing of esophageal
Uses:- lesions.

Zollinger-Ellison syndrome:
Peptic ulcer: • Omeprazole is more effective than H2
blockers in controlling hyperacidity in Z-
• Omeprazole 20 mg OD is equally or
E syndrome.
more effective than H2 blockers.
Prostaglandin analogue:
• PGE2 and PGI2 are produced in the
gastric mucosa and appear to serve a
protective role by inhibiting acid
secretion and promoting mucus as well
as HCO3¯ secretion.
Misoprostol:
• The primary indication of misoprostol is
the prevention and treatment of NSAID
associated gastrointestinal injury and
blood loss.
Antacids:
• These are basic substances which
neutralize gastric acid and raise pH of
gastric contents.
• Magnesium and aluminum salts are
commonly used in the preparation of
antacids.
• Magnesium salts (Mg. hydroxide, Mg.
trisilicate) show rapid action and they
are highly prone to cause diarrhea.
Aluminum salts are slow acting and will cause
constipation.
• To overcome the problems associated
with magnesium and aluminium salts
(like laxative and constipation effects),
always a combination of Mg &Al salts
are used to prepare antacids.
The following are the advantages of the
combination:
➢ Fast (Mag. hydrox.) and slow (Alum.
hydrox.) acting components yield
prompt as well as sustained effect.
➢ Mag. salts are laxative, while alum. salts
are constipating: combination may
annul each other’s action and bowel
movement may be least affected.
Drug interactions:
• By raising gastric pH and by forming
complexes, antacids decrease the
absorption of many drugs, especially
tetracyclines, iron salts,
fluoroquinolones, ketoconazole, H2
blockers, diazepam etc.
Ulcer Protectives

Sucralfate
• It is a basic aluminum salt of sulfated sucrose.

• It preferentially and strongly adheres to ulcer base, forming a physical barrier preventing acid,
pepsin and bile from coming in contact with the ulcer base.

Drug Interaction
It inhibits absorption of almost all the drugs

Anti-helicobacter pylori drugs:

• H. pylori is a gram negative bacillus uniquely adapted to survival in the hostile environment of
stomach.

The following 3 drug combinations are used for the treatment of H. Pylori infection.

Clarithromycin + Proton pump inhibitor + Metronidazole

or
Clarithromycin + Proton pump inhibitor + Amoxicillin
A 4 drug (quadruple) therapy is to be used for treatment failure cases with triple drug
therapy.
Bismuth subsalicylate + tetracycline + Metronidazole + PPI’s
 Emesis

Anti-emetic drugs:
• Vomiting occurs due to stimulation of the emetic (vomiting) centre situated in the
medulla oblongata. Multiple pathways can elicit vomiting.

• The chemoreceptor trigger zone (CTZ) located in the area postrema and the nucleus
tractus solitarius (NTS) are the most important relay areas for afferent impulses arising in
the g.i.t, throat andother viscera.

The main mediators which stimulate CTZ include

• Histamine

• Dopamine

• Serotonin (also known as 5-HT)

• Acetylcholine

The CTZ express a variety of receptors, e.g. histamine H1, dopamine D2, serotonin 5-HT3, cholinergic M,
neurokinin NK1 (activated by substance P), cannabinoid CB1 and opioid μ receptors through which the
emetic signals are relayed and which could be targets of antiemetic drug action.
 Anticholinergics:
• Hyoscine/scopolamine

• Dicyclomine

• Most effective drugs for motion sickness.

H1- Antihistamine:

• Cinnarizine It is an antivertigo drug having anti-motion sickness property.

Neuroleptics:

• The older neuroleptics (phenothiazines, haloperidol) are potent antiemetics; act by blocking D2
receptors in the CTZ;

They have broad spectrum antiemetic action effective in:

• (a) Drug induced and postoperative nausea and vomiting (PONV).

• (b) Disease induced vomiting: gastroenteritis, uraemia, liver disease, migraine, etc.

• (c) Malignancy associated and cancer chemotherapy (mildly emetogenic) induced vomiting.

Prokinetic drugs:
• These are drugs which promote gastrointestinal transit and speed gastric emptying by
enhancing coordinated propulsive motility.

Metoclopramide
• It speeds gastric emptying, especially if it was slow.

• It increases Lower esophageal sphincter (LES) tone and gastroesophageal reflux is opposed.

• It blocks the dopamine D2 receptors, due to which it may lead to cause extrapyramidal side
effects and hyper-prolactemia.

• Long-term use can cause parkinsonism, galactorrhea and gynaecomastia.

5-HT3 antagonists:
• Ondansetron

• Palonosetron

• These drugs are used for the management of cancer chemotherapy /radiotherapy induced
vomiting.
 Constipation

• Laxative or aperient: milder action, elimination of soft but formed stools.

• Purgative or cathartic: stronger action resulting in more fluid evacuation.

Stimulant laxatives:
• They are powerful purgatives

• Larger doses of stimulant purgatives can cause excess purgation resulting in fluid and electrolyte
imbalance.

• Hypokalaemia can occur on regular intake. Routine and long-term use must be discouraged,
because it can produce colonic atony and laxative abuse. They can reflexly stimulate uterus,
therefore are contraindicated during pregnancy.

Lubricant laxative.
• Mineral oil is the only available agent in this class.

• Onset of action. 6 to 8 hrs (oral dosing) and 5 to 15 mins (rectal dosing)

• Mineral oil can decrease absorption of fat-soluble vitamins (i.e., vitamins A, D, E, and K), so it
should not be used on a chronic basis.
 • Mineral oil should be taken on an empty stomach. Because of possible aspiration of mineral oil
into the lungs (lipid pneumonitis)

Lactulose
• It is a semisynthetic disaccharide of fructose and lactose which is neither digested nor absorbed
in the small intestine—retains water.

• In a dose of 10 g BD taken with plenty of water, it produces soft formed stools in 1–3 days.

• In patients with hepatic encephalopathy, lactulose causes reduction of blood NH3 concentration
by 25–50%.

Bulk forming laxatives:

• Onset of action is slow and ranges from 12 to 24 hrs up to 72 hrs.

• All bulk-forming agents must be given with at least 8 oz of water to prevent choking.

• Bulk-forming agents should not be used if an obstructing bowel lesion, intestinal strictures, or
Crohn’s disease are present due to the potential to worsen the situation or result in bowel
perforation.

• Unpalatable and need to drink large quantity of water.

Emollient laxatives (stool softeners)

• They are also known as surfactants, work by allowing water to move more easily into the stool.
This creates a softer stool, which is easier to pass.

• Thus, these agents are particularly useful in those who must avoid straining to pass hard stools
(e.g., recent myocardial infarction, rectal surgery).

• Onset of action: Slow onset of action (24 to 72 hrs).

Saline laxatives:
• Saline laxatives (Mg & Na salts) are not used now for the treatment of constipation because
they are inconvenient/ unpleasant, produce watery stools and after constipation. However, they
may be preferred for preparation of bowel before surgery and colonoscopy.

• Saline laxatives, which include sodium and magnesium salts, work to draw water into the colon.

• This class of laxatives includes magnesium citrate, magnesium hydroxide (e.g., Milk of Magnesia,
Phillips caplets), and sodium phosphate (e.g., Fleet’s Enema).

• Onset of action is 30 mins to 3 hrs when given orally and 2 to 5 mins when given rectally.
 • Sodium-containing salts should be avoided in those individuals with sodium restrictions (e.g.,
heart failure, edema, renal failure) and magnesium-containing products should be avoided in
individuals with severe kidney disease.

Diarrhoea

Antimotility drugs

• These are opioid drugs which increase small bowel tone and segmenting activity, reduce
propulsive movements and diminish intestinal secretions while enhancing absorption.

• Loperamide It is an opiate analogue with major peripheral μ opioid and additional weak
anticholinergic property.

2. Risk of physical dependence when used at higher doses/long term use

Inflammatory bowel disease

• IBD is a chronic relapsing inflammatory disease of the ileum, colon, or both, that may be
associated with systemic manifestations. The two major types of IBD are ulcerative colitis (UC)
and Crohn’s disease (CD).

• UC is a chronic inflammatory condition of the gastrointestinal tract mucosa and is primarily

found in the rectum and colon.

• CD is chronic transmural inflammation of the gastrointestinal mucosa and can be found

throughout the gastrointestinal tract from the mouth to the anus. CD most commonly affects
the small bowel and colon.

• Irritable bowel syndrome (IBS) is a disorder that interferes with the normal motility functions of
the gastrointestinal tract. The disorder is characterized by a principle symptom of abdominal
pain. (supplements like probiotics Lactobacillus, Saccharomyces and prebiotics nondigested
 carbohydrates with the goal of facilitating growth of normal gut flora and antispasmodic agents
like hyoscine can be used to relieve pain)

Typical presenting symptoms of UC are as follows:

• Increased stool frequency

• blood and mucous in the stools

• Lower left quadrant pain

• Nausea, vomiting, and weight loss (usually only in severe disease)

Typical presenting symptoms of CD are as follows:

• Abdominal pain

• Diarrhea

• Weight loss

• Fever

Drugs used in IBD can be grouped into:

• 5-Amino salicylic acid (5-ASA) compounds

• Examples: sulfasalazine, mesalamine (mesalazine), balsalazide

• Corticosteroids

• Examples: Prednisolone, dexamethasone, budesonide

• Immunosuppressants

• Examples: methotrexate, azathioprine

• TNFα inhibitors

• Examples: infliximab

5-amino salicylic acid:

Sulfasalazine

It is a compound of 5-aminosalicylic acid (5-ASA) with sulfapyridine linked through an azo bond.

5-aminosalicylic acid + sulfapyridine

• 5-aminosalicylic acid exerts a local anti-inflammatory effect, migration of inflammatory cells into
bowel wall is interfered affording symptomatic relief in Ulcerative Colitis.

• Sulfasalazine has also been used as a disease modifying drug in rheumatoid arthritis. The
absorbed sulfa-pyridine moiety appears to be responsible for the therapeutic effect.
Most common adverse effects
• Fever, dizziness, headache, itching, rash, photosensitivity, GI upset, nausea, vomiting, diarrhea

Less common adverse effects

• Stevens–Johnson syndrome, leucopenia, thrombocytopenia, aplastic anemia, hemolytic anemia,
and hepatitis. Intolerance of the sulfapyridine moiety of sulfasalazine is common and is
implicated in many adverse events associated with sulfasalazine.

• Sulfasalazine can interfere with the absorption of folic acid, thus it is advisable for such patients
to take folic acid supplements.

Other 5-aminosalicylates:
• Mesalamine, olsalazine, balsalazide.

Corticosteroids:
• Prednisolone (40–60 mg/day) or equivalent are highly effective in controlling symptoms as well
as in inducing remission in both UC and CrD.

• They are the drugs of choice for moderately severe exacerbations.

• Important: because of their adverse effects steroids should never be used for long term.
Corticosteroids are generally used for short term, and discontinued after remission is
induced.

Immunosuppressants:
• Immunosuppressants have now come to play an important role in the long-term management
of IBD, especially CD.
 • About 60% patients with CD and substantial number of UC patients require immunosuppressive
therapy.

Azathioprine
• It is the most effective and commonly used immuno-suppressant in IBD.

• *It is indicated in steroid dependent, steroid-resistant and relatively severe cases of IBD, or
those who experience frequent flareups.

Immunosuppressants:

Methotrexate
• This dihydrofolate reductase inhibitor with immunosuppressant property is a 2nd line drug in
IBD, especially Crohn’s disease.

• Dose of methotrexate 2.5mg to 10mg given ONCE weekly

Cyclosporine
• This potent immunosuppressant is occasionally used in severe UC patients who do not improve
with methotrexate/corticosteroid therapy.

TNFα inhibitors

Infliximab
• It is chimeric anti-TNFα antibody that is indicated in severe active CD, fistulating CD and severe
UC which has not improved with i.v. corticosteroids and immunosuppressants.

Adverse effects: high risk of infections.