Gastrointestinal and

Antiemetic Drugs
Department of pharmacology
A
Associate
i t professor
f
Hsieh Wen-Tsong
http://mail.cmu.edu.tw/ wthsieh
http://mail.cmu.edu.tw/~wthsieh
 Drugs used in GI

Gastrointestinal and
Antiemetic Drugs
• Drugs used in acid
acid-peptic
peptic
disease
• Drugs used to control
cemotherapy-induced
emesis
• Antidiarrheals
• Laxatives
Drugs used in acid-peptic disease

Helicobacter pylori
Drugs used in acid-peptic disease

Antimicrobial Agents Helicobacter pylori

Triple therapy for H.p. Ulcer
– A) The 1st line triple therapy (1+2)
– 1. Amoxicillin 500 mg +
Metronidazole 250 mg qid for 2 wks
– 2. One of the followings for 6 wks
• Colloidal bismuth (CBS) 120 mg
• Cimetidine
Ci tidi 400 mg bid
• Ranitidine 150 mg bid
• Famotidine 20 mg g bid
– B) Amoxicillin 1 gm bid +
Clarithromycin 500mg bid +
Omeprazloe 20 mg bid for 1 wk.
wk
Follwed by PPI or H2-antagonist therapy
Dual therapy
py for H.p.
p Ulcer
Amoxicillin 500 mg qid for 2 wks +
Omeprazole 20~40 mg q.d. for 4 wks
Drugs used in acid-peptic disease
 Drugs used in acid-peptic disease

1. H2 Histamine receptor blockers

•Cimetidine (Tagamet)
Drugs used in acid-peptic disease
•Ranitidine (Zantac)
•Famotidine (Pepcid)
•Nizatidine (Axid)
2. Proton pump inhibitor (PPI)
•Omeprazole (Prilosec) 4 1 3 7
ACh H2 PGE2 G
•Lansoprazole (Prevacid)
3. Prostaglandin analog
Adenylyl
yy
•Misoprostol
Mi t l (Cytotec)
(C t t ) + cyclase -
4. Antimuscarinic drugs ÇCa2+ ÇCa2+
•Pirenzepine
•Telenzepine
Telenzepine cAMP
AMP ATP
5. Antacids Protein kinase

•Magnesium hydroxide
•Aluminum hydroxide
H+
•Calcium carbonate H+/K+
ATPase pump
6. Mucosal protective agents 2
•Sucralfate ((Carafate))
•Carbenoxolone H+ 6
7. Pentagastrin* (Peptavlon) 5
H2-receptor
ecepto antagonists
Cimetidine:
• has a short serum half life,
• increased in renal failure.
• inactivated
i ti t d by
b the
th liver's
li '
microsomal system
• interfere in the metabolism
of many other drugs;
Ranitidine: Compared to cimetidine,
ranitidine is longer acting,
acting and is five-to
ten fold more potent
• has minimal side effects and does not
produce
d th
the antt androgenic
d i or prolactin
l ti
stimulating effects of cimetidine
Famotidine: three to twenty times more
potent than ranitidine
Nizatidine: Nizatidine is similar to ranitidine
 Drugs used in acid-peptic disease
H2-receptor blocks

Cautions:
• It should be used with caution in hepatic
impairment in renal impairment,
impairment, impairment
pregnancy, and in breast-feeding.
• It might mask symptoms of gastric cancer;
Side-effects:
id ff
• Diarrhoea and GI disturbances, headache, dizziness,
rash,, and tiredness.
• Rare side-effects: confusion, depression,
hallucinations, hypersensitivity reactions (fever,
arthralgia,
g , myalgia,
y g , anaphylaxis),
p y ), acute pancreatitis,
p ,
bradycardia, AV block, blood disorders
(agranulocytosis, leucopenia, pancytopenia,
thrombocytopenia).
• Some reports of gynaecomastia and impotence.
Interactions:
• Cimetidine binding to microsomal cytochrome P450.
P450
It avoided on warfarin, phenytoin, and theophylline.
• Famotidine, nizatidine, & ranitidine don’t.
 Drugs used in acid-peptic disease
Proton pump inhibitors

PROTON PUMP INHIBITORS (PPI)

Omeprazole, Esomeprazole,
L
Lansoprazole,
l P Pantoprazole,
l Rabeprazole
R b l

Mechanism of action:
irreversibly blocking the H+/K+ ATPase
inhibit 90–98% of 24-hour acid secretion
Clinical Use :
• Gastroesophageal reflux disease (GERD)
• Peptic ulcer disease (PUD)
• H Pylori–Associated Ulcers
• NSAID-Associated Ulcers
• Prevention of Rebleeding from PUD
• Nonulcer dyspepsia
• Prevention of Stress-Related Mucosal
Bleeding
• Gastrinoma and Other Hypersecretory
Conditions: Zollinger-Ellison syndrome
 Drugs used in acid-peptic disease
Proton pump inhibitors

Pharmacokinetics
• Highly protein
protein-bound
bound and are
• Eliminated in the urine.
CAUTIONS.
• PPIs
PPI should
h ld bbe used d with
ith caution
ti iin patients
ti t with
ith
liver disease, in pregnancy and in breast-feeding.
• PPIs may mask symptoms of gastric cancer.
SIDE-EFFECTS.
• General: Diarrhea, headache, and abdominal pain
• Nutrition: subnormal B12 levels
• Respiratory and Enteric Infections
• Potential Problems Due to Increased Serum Gastrin:
ECL cells: hyperplasia hypergastrinemia,
• Other Potential Problems:
• Hypersensitivity
H iti it reactions
ti (rash,
( h urticaria,
ti i angioedema
i d
May increase the risk of GI infections
 Drugs used in acid-peptic disease
Mucosal protective agents

Prostaglandin E1, Misoprostol

Misoprostol,
Mi t l synthetic
th ti prostaglandin
t l di analogue
l
has antisecretory and protective properties,
promoting healing of gastric and duodenal ulcers.
• It can preventt NSAID-associated
NSAID i t d ulcers,
l
• Its for the frail or very elderly from
whom
o NSAIDs
S s ca
cannot
ot be withdrawn.
t d a
Cautions:
• It may induce abortion or labour.
• Complications: Severe hypotension
Contra-indications:
pregnancy
p g y or p
planning
gp pregnancy
g y
Side-effects: diarrhoea, abdominal pain, dyspepsia,
flatulence, nausea and vomiting, abnormal vaginal
bleedingg ((intermenstrual bleeding,g, menorrhagia,
g ,
and postmenopausal bleeding), rashes, dizziness
 Drugs used in acid-peptic disease
Antimuscarinic drugs

Antimuscarinic drugs
Pirenzepine, telenzepine

• ENS modulate GI function,

complete muscarinic block cannot totally
abolish activity in this ENS.
• Blockade of muscarinic receptors has dramatic effects
on motility and secretory functions.
• M1 receptors antagonists:
Pirenzepine, telenzepine (a more potent analog),
reduce gastric acid secretion with fewer adverse
effects than atropine and others.
others
• Contraindicate: in some gastric peptic ulcer,
may slow gastric emptying and prolong the exposure of
the ulcer bed to acid.
 Drugs used in acid-peptic disease
Antacids

Antacids

Clinical Usages:
• Relieve symptoms
y p of acid indigestion,
g , heart-burn,,
dyspepsia, or GERD..
• Prevent stress ulcers, GI bleeding, hyperphosphatemia
Adverse reactions:
• Diarrhea, constipation, electrolyte imbalances
 Drugs used in acid-peptic disease
Mucosal protective agents

Mucosal protective agents

Chelates
C e a es and
a d complexes
co p e es

Tripotassium dicitratobismuthate is a bismuth chelate

effective in healing gastric and duodenal ulcers.
ulcers
• Low but absorption has been reported;
Colloidal Bismuth Subcitrate (CBS) is used in the
management of gastric and duodenal ulcers, and in
combination with two antibacterials for the eradication
off H.
H pylori.
l i
Sucralfate may act by protecting the
mucosa from acid-pepsin
p p attack in
gastric and duodenal ulcers.
• It is a complex of aluminium hydroxide
and sulphated sucrose but has minimal
antacid properties.
Drugs used in acid-peptic disease
Drugs used to control
chemotherapy induced
chemotherapy-induced
emesis
Antiemetic drugs
Ipecac syrup Apomorphine
Antiemetic drugs
 Antiemetic drugs

A. ANTICHOLINERGICS Vomiting Center Muscarinic Anticholinergic

atropine
hyoscine
B. ANTIHISTAMINES Vomiting Center Histiminac Sedation,
diphenhydramine Anticholinergic
C. PHENOTHIAZINES Chemoreceptor Trigger Dopamine
Dystonias
i
prochlorperazine Zone (CTZ) Histamine
Hypotension
chlorpromazine
D. BUTYROPHENONES CTZ Dopamine Dystonias
h l
haloperidol
id l
droperidol
E. CANNABINOIDS Cortex Unknown Sedation,
THCC Dysphoria
ysp o a
F. BENZAMIDES Peripheral CTZ Serotonin Dystonias
metoclopramide Dopamine Diarrhea
trimethobenzamide
G. GLUCOCORTICOIDS Unknown Dysphoria
?Prostaglandins
dexamethasone
H. BENZODIAZEPINES Cortex BZ1, BZ2, Sedation,
lorazepam CTZ GABA? Amnesia
I. 5HT ANTAGONISTS Peripheral 5HT3-M Headache
ondansetron Serotonin
granisetron
 Antiemetic drugs

1. Motion sickness*-scopolamine, dimenhydrinate and meclizine

2. Motion sickness -promethazine
3. Pregnancy* -dimenhydrinate and meclizine
4. Post-operative -metoclopramide, odansetron, promethazine,
dimenhydrinate hydroxyzine
dimenhydrinate,
5. Bacterial GI infections - promethazine
6. Influenza -promethazine
7. Peptic ulcer -metoclopramide
8. Ulcerative colitis -metoclopramide
9 GI cancer
9. -metoclopramide
metoclopramide
10.Chemotherapy-metoclopramide,
dexamethasone,ondansetron
11 Radiation therapy-metoclopramide,
11.Radiation therap metoclopramide meclizine,
mecli ine ondansetron
12.Vertigo of vestibular origin -dimenhydrinate and meclizine
((Meniere’s disease))
*: prophylaxis
 Antidiarrheal agents

Antidiarrheal agents
 Antidiarrheal agents
Antidiarrheal agents
• The first line of treatment in acute diarrhoea is
prevention or treatment of fluid and electrolyte depletion.
• Severe dehydration requires immediate admission to
hospital and urgent replacement of fluid and electrolytes.
Adsorbents and bulk-forming drugs
• Adsorbents such as kaolin are not
recommended for acute diarrhoeas.

• Bulk-forming drugs, such as ispaghula, methylcellulose,

and sterculia are useful in controlling faecal consistency
in ileostomy and colostomy, and in controlling diarrhoea
associated with diverticular disease. They are used in the
management of uncomplicated acute diarrhoea in adults;
fluid and electrolyte replacement may be necessary in
case of dehydration.
 Antidiarrheal agents

Antimotility drugs
• Codeine phosphate
Opioid analgesics are usually used it
constipation side effect to treatment diarrhea
• Co-Phenotrope
C Ph
A mixture of diphenoxylate hydrochloride and
atropine sulphate in the mass proportions 100 / 1
Indications: adjunct to rehydration in acute
diarrhoea, chronic mild ulcerative colitis
• Loperamide HCl
Indications: symptomatic treatment of acute
diarrhoea; adjunct to rehydration in acute
diarrhoea in adults and children over 4 years
• Morphine
Opioid analgesics are usually used it constipation
side effect to treatment diarrhea
Antidiarrheal agents
 Laxatives

Laxatives
• 1. Bulk-forming laxatives
• 2. Stimulant laxatives
• 3. Faecal softeners
• 4. Osmotic laxatives
• 5. Bowel cleansing solutions
Laxatives
 Laxatives

B lk f
Bulk-forming
i llaxatives
ti

• B
Bulk-forming
lk f i llaxatives
ti relieve
li constipation
ti ti by
b
increasing faecal mass which stimulates peristalsis.
• Bulk-forming g laxatives are useful in the management
g of
patients with colostomy, ileostomy, haemorrhoids, anal
fissure, chronic diarrhoea associated with diverticular
disease, irritable bowel syndrome, and as adjuncts in
ulcerative colitis.
• Adequate fluid intake must be maintained to avoid
intestinal obstruction.
obstruction
• Unprocessed wheat bran, taken with food or fruit juice,
is a most effective bulk-forming gppreparation.
p
• Methylcellulose, ispaghula, and sterculia are useful in
patients who cannot tolerate bran. Methylcellulose also
acts as a faecal softener
softener.
 Laxatives

Stimulant laxatives

• Stimulant laxatives include bisacodyl and members of the

anthraquinone group, senna and dantron (danthron).
• Docusate Na both as a stimulant and as a softening agent.
• Stimulant laxatives increase intestinal motility and often
cause abdominal cramp; avoided in intestinal obstruction.
obstruction
• Prolonged use of stimulant laxatives can precipitate the
onset of atonic non-functioning colon and hypokalaemia.
• Glycerol suppositories act as a rectal stimulant by virtue
of the mildly irritant action of glycerol.
The parasympathomimetics bethanechol, distigmine,
neostigmine, pyridostigmine increase intestinal motility.
• Organic obstruction of the gut must first be excluded and
they should not be used shortly after bowel anastomosis.
anastomosis
 Laxatives

Castor oil is hydrolysed in the small intestine to

ricinoleic acid, a local irritant that increases
intestinal motility until the compound is
excreted via the colon.
Cascara senna,
Cascara, senna and aloes
Contain emodin alkaloids that are liberated after
absorption
p from the intestine and are excreted
into the colon, where peristalsis is stimulated.
Their onset of activity is delayed for 6-8 hrs.
Chronic stimulation of the colon is thought to lead
to chronic colonic distention and perpetuation of
the perceived need for laxatives.
Ph
Phenolphthalein
l hth l i and d bisacodyl,
bi d l
They are potent colonic stimulants.
Their action may be prolonged by an
enterohepatic circulation.
 Laxatives

F
Faecal
l softeners
ft

• Liquid paraffin
paraffin, the classical lubricant,
lubricant has
disadvantages.
• Bulk laxatives and non-ionic surfactant
wetting
etting agents e.g.
e g docusate
doc sate sodium
sodi m also
have softening properties.
• Such drugs are useful for oral administration
i the
in th managementt off haemorrhoids
h h id andd anall
fissure;
• Glycerol suppositories are useful for rectal use.
• Enemas containing arachis oil (ground-nut oil,
peanut oil) lubricate and soften impacted
faeces and promote a bowel movement.
 Laxatives

O
Osmotic
ti laxatives
l ti

• Th
These actt b
by retaining
t i i fluid
fl id iin the
th bowel
b l by
b osmosis
i or by
b
changing the pattern of water distribution in the faeces.
• Saline ppurgatives
g such as magnesium
g hydroxide
y are
commonly abused but are satisfactory for occasional use;
adequate fluid intake should be maintained.
• Magnesium salts are useful where rapid bowel evacuation.
• Sodium salts should be avoided as they may give rise to
sodium and water retention in susceptible individuals.
• Phosphate enemas are useful in bowel clearance before
radiology, endoscopy, and surgery.
• Lactulose is a semi-synthetic disaccharide which is not
absorbed from the gastro-intestinal tract. It produces an
osmotic diarrhoea of low faecal pH, and discourages the
proliferation of ammonia-producing
ammonia producing organisms.
It is useful in the treatment of hepatic encephalopathy.
 Laxatives

Bowell cleansing
l i solutions
l i
• Bowel cleansing g solutions are used before colonic
surgery, colonoscopy, or radiological examination to
ensure the bowel is free of solid contents.
• They are not treatments for constipation.
constipation
• Cautions: pregnancy; renal impairment; heart
disease; ulcerative colitis; diabetes mellitus; reflux
oesophagitis; impaired gag reflex; unconscious or
semiconscious or possibility of regurgitation or
aspiration
• Contraindications: gastrointestinal obstruction,
gastric retention, gastro-intestinal ulceration,
perforated bowel,, congestive
p g cardiac failure;; toxic
colitis, toxic megacolon or ileus
• Side-effects: nausea and bloating; less frequently
abdominal cramps,
cramps vomiting
The End