Download GASTROINTESTINAL DRUGS

Peptic Ulcer
The etiology:
 It results due to an imbalance
between:
 the aggressive (acid, pepsin,
bile and Helicobacter pylori
infection) and
 the defensive (gastric mucus
and bicarbonate secretion,
prostaglandins, nitric oxide,
high mucosal blood flow,
innate resistance of the
mucosal cells) factors.
Regulation of gastric acid secretion
Secretion of HCl by gastric parietal
cell and its regulation
C.Ase.—Carbonic anhydrase;
Hist.—Histamine;
ACh.—Acetylcholine;
CCK2—Gastrin cholecystokinin
receptor;
M.—Muscarinic receptor;
N—Nicotinic receptor;
H2—Histamine H2 receptor;
EP3—Prostaglandin
receptor;
ENS—Enteric nervous system;
ECL cell—Enterochromaffin-like
cell;
GRP—Gastrin releasing peptide;
+ Stimulation;
– Inhibition.
Peptic ulcer
 Peptic ulcer is a chronic remitting and relapsing
disease lasting several years.
 The goals of antiulcer therapy are:
Relief of pain
Ulcer healing
Prevention of complications (bleeding,
perforation)
Prevention of relapse.
Drugs for Peptic Ulcer
1. Reduction of gastric acid secretion
H2 antihistamines: Cimetidine, Ranitidine, Famotidine
Proton pump inhibitors (PPIs): Omeprazole,
Lansoprazole, Pantoprazole, Rabeprazole
Anticholinergic drugs: Pirenzepine
Prostaglandin analogue: Misoprostol
2. Neutralization of gastric acid (Antacids)
 Systemic: Sodium bicarbonate, Sod. citrate
 Nonsystemic: Magnesium hydroxide, Mag. trisilicate,
Aluminium hydroxide gel, Magaldrate, Calcium carbonate
3. Ulcer protectives: Sucralfate, Colloidal bismuth subcitrate
(CBS)
4. Anti-H. pylori drugs: Amoxicillin, Clarithromycin,
Metronidazole, Tinidazole, Tetracycline
H2 ANTAGONISTS
 These are the highly effective drugs for acid-peptic
disease.
 Their interaction with H2 receptors has been found to
be competitive.
 Cimetidine was the first H2 blocker to be introduced
clinically and is described as the prototype, though
other H2 blockers are more commonly used now.
Pharmacological actions
 1. H2 blockade
 All H2 antagonists block histamine-induced gastric
secretion.
 They are highly selective: have no effect on H1
mediated responses.
 2. Gastric secretion
 The only significant action of H2 blockers is marked
inhibition of gastric secretion.
 The H2 blockers have antiulcerogenic effect.
 Gastric ulceration due to stress and drugs (NSAIDs,
cholinergic, histaminergic) is prevented.
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Cimetidine
Is absorbed orally
Bioavailability is 60–80%
It crosses placenta and reaches milk.
t½ is 2–3 hr.
Adverse effects
 Headache, dizziness, bowel upset, dry mouth, rashes.
Cimetidine (but not other H2 blockers) has:
antiandrogenic action,
increases plasma prolactin,
inhibits degradation of estradiol by liver.
 High doses given for long periods have produced:
Gynaecomastia,
Loss of libido,
Galactorrhea,
Impotence and temporary decrease in sperm count.
Ranitidine
 About 5 times more potent than cimetidine.
 No antiandrogenic action, does not increase prolactin
secretion or spare estradiol from hepatic
metabolism—no effect on male sexual function or
gynaecomastia.
 Overall incidence of side effects is lower: headache,
diarrhoea/constipation, dizziness have an incidence
similar to placebo.
Famotidine
 It is 5–8 times more potent than ranitidine.
 Antiandrogenic action is absent.
 Incidence of ADR is low:
only headache, dizziness, bowel upset, rarely
disorientation and rash.
H2 blockers indications
 The H2 blockers are used to suppress gastric acid secretion.
 H2 blockers control hyperacidity and symptoms in many patients, but PPIs are
the drugs of choice (because of higher efficacy and equally good tolerability).
 1. Duodenal ulcer
 2. Gastric ulcer
 3. Stress ulcers and gastritis
 4. Zollinger-Ellison syndrome (It is a gastric
hypersecretory state due to a rare tumour secreting
gastrin). But PPIs are the drugs of choice.
 5. Gastroesophageal reflux disease (GERD)
PROTON PUMP INHIBITORS (PPIs)
Omeprazole, Lansoprazole, Pantoprazole, Rabeprazole
 The PPIs have overtaken H2 blockers for acid-peptic
disorders.
 The only significant pharmacological action of PPIs are
suppression of gastric acid secretion; without anticholinergic
or H2 blocking action.
 PPIs are a powerful inhibitors of gastric acid: can totally
abolish HCl secretion.
 PPIs inactivate the H+K+ATPase enzyme irreversibly. The
specific localization of H+K+ATPase to parietal cells confer
high degree of selectivity of PPIs action.
 Acid secretion resumes only when new H+K+ATPase
molecules are synthesized (reactivation half time - 18 hours).
At steady-state all PPIs produce 80–98% suppression of 24 hour acid output
with conventional doses.
Secretion resumes gradually over 3–5 days of stopping the drug.
PPIs indications
 1. Peptic ulcer:
 More effective than H2 blockers.
 Relief of pain is rapid and excellent.
 PPIs are the drugs of choice for NSAID induced
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gastric/duodenal ulcers.
2. Bleeding peptic ulcer
3. Stress ulcers
4. Gastroesophageal reflux disease (GERD)
5. Zollinger-Ellison syndrome
Adverse effects
PPIs produce minimal adverse effects:
Nausea,
Loose stool,
Headache,
Abdominal pain,
Dizziness
On prolonged treatment - atrophic gastritis.
Because of marked and long-lasting acid suppression,
compensatory hypergastrinemia has been observed.
If possible, avoid long-term use of PPIs.
 No harmful effects of PPIs during pregnancy are known. Though manufacturers
advise to avoid, PPIs have often been used for GERD during pregnancy.
ANTICHOLINERGICS
 Atropinic drugs reduce the volume of gastric juice without
raising its pH.
 Effective doses (for ulcer healing) of nonselective
antimuscarinic drugs (atropine, etc.) invariably produce
intolerable side effects.
 Introduction of H2 blockers and PPIs has sent them into
oblivion.
Pirenzepine
 It is a selective M1 anticholinergic that has been used in
Europe for peptic ulcer.
 Gastric secretion is reduced by 40–50% without producing
intolerable side effects, but side effects do occur with slight
excess.
 It has not been used in the USA.
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.
 “Cytoprotective” action - to reinforce the mucus layer covering gastric and
duodenal mucosa.
Misoprostol
 is a longer acting synthetic PGE1 derivative which inhibits acid output
 Reduction of acid production is less than H2 blockers.
 Is poorer in relieving ulcer pain.
Indication:
 the prevention and treatment of NSAID associated gastrointestinal injury
and blood loss. However, it is seldom employed now because PPIs are more
effective, more convenient, better tolerated and cheaper.
ADR
 Diarrhoea,
 Abdominal cramps,
 Uterine bleeding,
 Abortion,
 Need for multiple daily doses.
ANTACIDS
 These are basic substances which neutralize gastric acid.
 Antacids do not decrease acid production;
 A single dose of any antacid taken in empty stomach acts
for 30–60 min only.
Uses
 Antacids are no longer used for healing peptic ulcer,
because they are needed in large and frequent doses.
 Antacids are now employed only for intercurrent pain
relief and acidity, mostly self-prescribed by the patients as
over-the-counter drugs.
 They continue to be used for non-ulcer dyspepsia and
minor episodes of heartburn.
Systemic Antacids
Sodium bicarbonate
 It is a potent neutralizer, acts instantly, but the duration
of action is short.
 However, it has several demerits:
Absorbed systemically: induce alkalosis.
Produces CO2 in stomach → distention, discomfort,
belching, risk of ulcer perforation.
Acid rebound occurs, but is usually short lasting.
Increases Na+ load: may worsen edema and CHF.
 Use of sod. bicarbonate is restricted to casual treatment of
heartburn. It provides quick symptomatic relief.
Nonsystemic Antacids
 These are insoluble and poorly absorbed basic compounds.
Mag. Hydroxide
Magnesium trisilicate
 About 5% of administered Mg is absorbed systemically—
may cause toxicity if renal function is inadequate.
 All Mg salts have a laxative action.
Aluminium hydroxide
 The Al3+ ions relax smooth muscle.
 Thus, all Al3+ salts causes constipation.
 Small amount of Al3+ is absorbed systemically— may cause
aluminium toxicity (encephalopathy, osteoporosis) if renal
function is inadequate
Antacid combinations
A combination of two or more antacids is frequently
used.
1) Fast (Mag. hydrox.) and slow (Alum. hydrox.) acting
components yield prompt as well as sustained effect.
2) Mag. salts are laxative, while alum. salts are
constipating: combination may annul each other’s
action and bowel movement may be least affected.
3) Gastric emptying is least affected; while alum. salts
tend to delay it, mag./cal. salts tend to hasten it.
4) Dose of individual components is reduced; systemic
toxicity (dependent on fractional absorption) is
minimized.
ULCER PROTECTIVES
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Sucralfate
It preferentially and strongly adheres
to ulcer base only at acidic pH .
Surface proteins at ulcer base are
precipitated, together with which it
acts as a physical barrier preventing
acid, pepsin and bile from contact
with the ulcer base.
Its action is local(minimal
absorption).
Sucralfate has no acid neutralizing
action.
Antacids should not be taken with
sucralfate because its polymerization
is dependent on acidic pH.
ADR are few:
constipation, dry
mouth and nausea
Colloidal bismuth subcitrate (CBS)
 It is a colloidal bismuth compound;
 The mechanism of action of CBS:
May precipitate (only at pH < 5) mucus glycoproteins
and coat the ulcer base.
May inhibit H.pylori directly.
 Uses: as a component of triple drug anti-H. pylori regimen
Milk and antacids should not be taken concomitantly.
 Side effects:
 Blackening of tongue, dentures and stools
 Diarrhoea
 Headache and dizziness
ANTI-HELICOBACTER PYLORI DRUGS
 90% patients of ulcer have tested positive for H. pylori.
 All H. pylori positive ulcer patients should receive H.
pylori eradication (“extermination”) therapy.
 Single antibiotic is ineffective (Resistance develops
rapidly)
 Triple therapy: PPIs + 2 antimicrobials
oPPI + Amoxicillin+ Clarithromycin
oPPI + Amoxicillin+ Metronidazole
 Quadruple therapy: PPIs + 2 antimicrobials + CBS
oPPI + Tetracycline + Metronidazole + CBS
Antiemetic Drugs
 Vomiting occurs due to
stimulation of the emetic
(vomiting) centre situated in the
medulla oblongata.
 The chemoreceptor trigger zone
(CTZ) is the most important relay
areas for afferent impulses arising
from the g.i.t, throat, drugs,
hormones, toxins, etc.
 Cytotoxic drugs, radiation and
other g.i. irritants release 5-HT
from enterochromaffin cells → acts
on 5-HT3 receptors → send
impulses to CTZ
 The vestibular apparatus generates
impulses → vomiting centre
EMETICS
 These are drugs used to evoke vomiting:
1. Act on CTZ : Apomorphine
2. Act reflexly and on CTZ :
Ipecacuanha
 Vomiting needs to be induced only when
an undesirable substance (poison) has
been ingested.
 Powdered mustard suspension or strong
salts solution may be used in emergency.
 They act reflexly by irritating the
stomach.
ANTIEMETICS
1. Anticholinergics
 Hyoscine
2. H1 antihistaminics
 Promethazine
 Diphenhydramine
3. Neuroleptics (D2 blockers)
 Chlorpromazine
 Haloperidol
4. Prokinetic drugs
 Metoclopramide
 Domperidone
 Cisapride
5. 5-HT3 antagonists
 Ondansetron,
 Granisetron
6. Others antiemetics
 Dexamethasone
 Benzodiazepines
 Dronabinol
ANTIEMETICS USES
 Hyoscine is the most effective drug for motion
sickness.
 Antihistaminics are useful mainly in motion
sickness, morning sickness, postoperative forms of
vomiting.
 Neuroleptics act by blocking D2 receptors in the
CTZ:
 Drug induced and postoperative vomiting
 Disease induced vomiting: gastroenteritis,
uraemia, liver disease, migraine, etc.
 cancer chemotherapy induced vomiting.
 Radiation sickness vomiting (less effective).
Metoclopramide
 is an effective antiemetic:
 D2 antagonism
 5-HT3 agonism
 Adverse effects:
 Sedation, dizziness, loose stools, muscle
dystonias
 Long-term use can cause parkinsonism,
galactorrhoea and gynaecomastia
 Uses: all types of vomiting— postoperative, drug
induced, disease associated, radiation sickness, etc,
but is not effective in motion sickness.
5-HT3 ANTAGONISTS
 It is a class of antiemetic drugs to control cancer
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chemotherapy/radiotherapy induced vomiting
Cytotoxic drugs/radiation produce vomiting by causing
cellular damage → release of mediators including 5-HT
from intestinal mucosa → activation of vagal afferents in
the gut → emetogenic impulses to the NTS and CTZ.
Side effects:
Headache
Dizziness
constipation
Hypotension
Bradycardia
LAXATIVES
(Aperients, Purgatives, Cathartics)
 These are drugs that promote evacuation of bowels.
 A distinction is sometimes made according to the
intensity of action.
Laxative or aperient: milder action, elimination of
soft but formed stools.
Purgative or cathartic: stronger action resulting in
more fluid evacuation.
 Many drugs in low doses act as laxative and in larger
doses as purgative.
CLASSIFICATION
1. Bulk forming
 Dietary fibre: Bran, Psyllium (Plantago), Ispaghula,
Methylcellulose
2. Stool softener
 Docusates (DOSS), Liquid paraffin
3. Stimulant laxative
 Diphenylmethanes
 Phenolphthalein, Bisacodyl, Sodium picosulfate
 Anthraquinones (Emodins)
 Senna, Cascara sagrada
 Fixed oil
 Castor oil
4. Osmotic purgatives
 Magnesium salts: sulfate, hydroxide
 Sodium salts: sulfate, phosphate
 Lactulose
MECHANISM OF ACTION
 Osmotic action- retaining water and electrolytes in the
intestinal lumen—increase volume of colonic content and
make it easily propelled.
 Acting on intestinal mucosa, decrease net absorption of
water and electrolyte; intestinal transit is enhanced
indirectly by the fluid bulk.
 Increasing propulsive activity as primary action—allowing
less time for absorption of salt and water as a secondary
effect.
ADR
 Larger doses of stimulant purgatives can cause excess
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purgation resulting in fluid and electrolyte imbalance.
Hypokalaemia can occur on regular intake.
Routine and long-term use can produce colonic atony.
Steatorrhoea
Malabsorption syndrome
Protein losing enteropathy.
Spastic colitis
Osmotic purgatives
 Saline purgatives 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; in food/drug
poisoning and as after-purge in the treatment of
tapeworm infestation.
TREATMENT OF DIARRHOEAS
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Rehydration
Specific antimicrobial drugs (only in severe disease)
Probiotics (BIFILAC, BIFILIN, ENTEROGERMINA)
Nonspecific antidiarrhoeal drugs:
 Absorbants (methyl cellulose)
 Adsorbants (kaolin, pectin)
 Antimotility drugs:
 Codeine
 Loperamide (IMODIUM)
 It is an opiate analogue with peripheral μ opioid property.
 As a constipating agent it is much more potent than codeine.
 Because of poor water solubility—little is absorbed from the
intestines.
 Entry into brain is negligible—CNS effects occur only with
high doses;
 no abuse liability.
 ADR: Abdominal cramps and rashes,Paralytic ileus, toxic
megacolon.