6. Brief Pharmacology of Antiulcer
agents
1) Agents that Neutralize acid: Antacids: (NaHCO3,
Al(OH)2, Ca(CO)3).
? These are weak bases that form salts with HCl
causing Chemical NEUTRALIZATION to buffer acid
in the stomach. Antacids are thought to heal ulcer
by protective effect particularly aluminum
compounds.
? Advantages:Immediate Pain Relief & Less
expensive.
? Disadvantages: i) Short Duration of Effect
8. Brief Pharmacology of H2
Receptor Antagonists.
2) Agents that reduce Gastric acid secretion:
a) H2 Receptor Antagonists: (Cimetidine, Ranitidine,
Famotidine, Nizatidine) They inhibit 90% acid
secretion in basal state as well as food-induced and
nocturnal acid production. Thus, they are helpful in
healing gastric and duodenal ulcers and prevent
their recurrence. Have benefits in preventing
increased gastric acid secretion in Zollinger-Ellison
syndrome.
? Cimetidine Has several side effects, not a choice
9. Problems with Cimetidine
? CNS: confusion, somnolesence, headache, dizziness
? Immunological: skin rashes, myalgia, itching
? Gonadal effects: Gynecomastia, loss of libido, impotence
(elevates estrogens and prolactin secretion), galactorrhea,
infertility
? Inhibits CyP450: Inhibits the metabolism of various drugs
that are concomitantly taken: phenytoin, warfarin,
theophylinne, TCA, BZD.
? These adverse effects are relatively least with ranitidine and
/none with famotidine
? Ranitidine (150 mg bid) + midazolam leads to 65% increase
in midazolam level = prolonged sedation (May 2009)
11. Proton Pump Inhibitors (PPI)
? Note: There is NO rationale in combining an H2 blocker
with a PPI for long term treatment. In ZES, to have rapid
control, they are combined. PPI takes 12-24 hr to work.
? Proton Pump (H+
K+
ATPase Inhibitors: Omeprazole)
? Irreversible inhibitor of proton pump; blocks 98% of
acid secretion in all forms of ulcer and hypersecretory
Zollinger-Ellison syndrome. The drug is given in gelatin
coated capsule to resist breakdown in stomach acid. It
reaches the intestine, well absorbed, enters blood
13. Proton Pump Inhibitors
(PPI): Safety
? Diarrhea, headache, abdominal pain < 5%
? Subnormal Vit B12 serum level
? Increased risk of enteric infections
? Drug Interaction: Ketoconazole and
Digoxin absorption is decreased due to
reduced acidity. Omeprazole may inhibit
coumadin, diazepam and phenytoin
metabolism
14. Additional Points - Omeprazole
& Pharmacology of Sucralfate
? PPI are Effective in patients - refractory to H2
receptor blockers. causes prolonged
inhibition of acid secretion.
? Note: Omeprazole and H2 blockers are most
effective in acute/chronic/prophylactic
management of ulcer.
15. 3) Cytoprotective Mucosal
Defensive Agents:
? Sucralfate: Sucrose Octasulfate
Aluminium Hydroxide is a Gel that
gives a protective coating over the
ulcerated region and prevents further
erosion. Note: It also Stimulates
PGE1 production; adsorbs pepsin.
16. Pharmacology of
Cytoprotectives. Sucralfate,
Misoprostol, Bismuth
? Disadvantages of Sucralfate: Constipation, Dry
mouth, decreases the bioavailability of other drugs
because of adsorption.
b) Misoprostol: Methyl PGE1 analog. It mimics PGE1 and
enhances the production of mucus and HCO3. Thus it is
cytoprotective, prevents ulceration. Particularly
effective in drug induced peptic ulcer by NSAIDs and
corticosteroids.
? Disadvantages: Diarrhea Contraindicated in
pregnancy.
17. Management of H. Pylori Infection
? Gram-negative rod colonizes in the gastro-duodenal
area.
? Causes Erosion of the protective epithelial cells.
? Leading to inflammatory gastritis and severe peptic
ulcer.
? Treatment with a H2 blocker or a Proton Pump
inhibitor +
? Eradication of the Helicobacter colony is very Vital.
? Antimicrobials such as Metronidazole with
Tetracycline or Amoxycillin/Clarithromycin. (PPI+2
or 3 antimicrobials is standard Triple pack)
18. Consensus Guidelines for Treating H. Pylori
In <50 years old with mild symptoms,
? 1st
Line: Hp ¨Cpack for either 7 days or 14 days regimen
a. Hp-Pack PPI + clarithromycin + amoxicillin 7-14 days
b. PPI + clarithromycin + metronidazole 7-14 days
c. Ranitidine+ Peptobismol + clarithromycin+
amoxicillin
(Last one c. is triple therapy to eradicate H. Pylori).
If clarithromycin and metronidazole resistance, resort to:
? 2nd
Line: Quadruple Therapy: 7 days a and 7 days b.
a. PPI+BMT (Bismuth+Metronidazole+Tetracycline)
7days
b. PPI (lansoprozole) + amoxicillin 7 days.
19. Treatment of Zollinger-Ellison Syndrome (ZES)
? Gastrinoma of the duodenum - 2/3rd
are Malignant
? Elevated Gastrin Levels -peptic ulceration, gastric
hyper
secretion presence of gastrinoma, a non beta cell
tumor
of the pancreas with high gastrin output, a type of
multiple neoplasm accompanied by neoplasm of the
pituitary and parathyroid gland.
Goal: High dose Proton pump inhibitor (omeprazole or
lansoprazole)
20. II. Drugs that Promote Upper GIT Motility
(Prokinetic agents)
? Prokinetic Agents: Agents that enhance
coordinated contraction of the gastric
antrum and the Duodenum:
? The Major Goal is to:
Increase Gastric Emptying,
Relieve Gastric stasis,
Prevent Reflux Oesophagitis, Heart burn
Prevent Regurgitation of Gastric contents
Decrease Nausea & Vomiting.
21. Prokinetic Agents Rapidly Promote Gastric
Emptying By Selectively ??Duodenal Motility
Esophagus
Gastroesophageal
Sphincter
Duodenum
Fundus
Mucus Pyloric Sphincter
Stomach
PH 2.3
HCL
H+
H+
H+
H+
H+
Choinomimetics
will be
unselective
Proknetics modulate ACh release to promote opening of the
Gastro-Duodenal Sphincter & Selectively ? Duodenal Motility.
24. Why don¡¯t we use
Cholinomimetics and
Anticholinesterases?
? Cholinomimetics (Bethanachol) & anticholinesterases
(Neostigmine) promote gastrointestinal transit. The
effects are Nonspecific & several undesirable
muscarinic effects predominate (salivation, gastric
secretion & diarrhea)
? Therefore, we use selective Dopamine (D2) Blockers, 5-
HT4 (serotonin) and Motilin Agonists as Prokinetics.
? Uses of Prokinetics: ?Gastro-oesophageal Reflux
disease, heartburn. ?Oesophageal clearance, Relaxes
25. What do Prokinetics Do?
? Prokinetic Agents: Site of Action Duodenum
? ¡ü Duodenal Motility, Intestinal Transit,
¡ü
? ¡ü Opening of the Gastro Duodenal Sphincter,
? ¡ü Rapid Passage of food, Heart Burn,
¡ý¡ý¡ý
? ¡ý¡ý Esophagitis, Nausea & Vomiting
¡ý¡ý¡ý
26. Brief Comparative Pharmacology of
Prokinetics and Specific Indications:
? Metoclopramide: D2 selective Dopamine
antagonist; crosses the blood brain barrier (BBB),
CNS related side effects are its drawback:
hyperprolactinemia, extrapyramidal (Parkinsonian)
symptoms but have no antipsychotic effect. Central
Dopamine antagonism is helpful in promoting
Antiemetic effect.
? Domperidone: D2 selective antagonist does not
cross the blood brain barrier; therefore, CNS
related symptoms are least no extrapyramidal side
effects; however, it causes hyperprolactinemia
27. Erythromycin: Prokinetic
Effect
? Besides being a Macrolide antibiotic, it activates
Motilin Receptors and enhances Duodenal Motility.
? Erythromycin does NOT exert D2 receptor, CNS or
Hyperprolactinemia Effects, It is Not an Antiemetic.
? Erythromycin also enhances Colonic motility (lower
GIT motility) and promotes watery diarrhoea. Thus,
it is useful in promoting colonic hypermotility to
relieve constipation, besides being a prokinetic
28. Why Cisapride is not used
now?
? Cisapride is a 5HT4 selective serotonin agonist. It
?cholinergic transmission in the Gastroduodenal
region, Not an antiemetic, Has No D2 receptor blockade
activity.
? Popular prokinetic agent until 1998. Not used now,
Why?
? Blocks cardiac K+
channels and causes ventricular
arrhythmia- torsades de pointes (long QT syndrome).
? Cardiotoxicity ?when combined with clarithromycin.
Because Clarithromycin is a CYP3A4 inhibitor and ?
the metabolism of cisapride and ? its cardiotoxicity.
? +
29. Antiemetic Drugs
? I.Vomiting: A physiological protective
antiperilstatic response resulting in forceful
expulsion of the GI contents as a result of a series
of integrated events.
? II. Sequence of Events in the act of vomiting:
? 1. Nausea: Increased salivation, mydriasis,
sweating and pallor.
? 2. Retching: Contraction of abdominal muscles,
antiperistaltic movement.
? 3. Vomiting: Contraction of diaphragm and
forceful expulsion of GIT contents through mouth.
30. III. Causes of Nausea and
Vomiting:
? III. Causes of Nausea and Vomiting:
1. Drug induced (iatrogenic)
? Cytotoxic drugs (Cisplatin, Methotrexate, Nitrogen
mustards)
? Opioids (morphine),
? Cholinomimetics
? Cardiac glycosides, Emetin, Apomorphine
? L-Dopa, Bromocriptine, High dose estrogen (ethinyl
estradiol)
2. Infectious G.I. disorders
? Bacterial and viral toxins
3. Noninfectious G.I.T. disorders
? Gastric outlet obstruction
? Gastric irritants
31. III. Causes of Nausea and
Vomiting:
4. During early pregnancy (first
trimester, morning sickness due to
high estradiol in circulation).
5. CNS related
? Motion sickness, Menier¡¯s disease,
CNS toxic agents
? Increased intracranial pressure,
Stroke
34. ANTIEMETICS ¨C Antihistamines
(1)
? 1. Anti Histamines: eg. Diphenhydramine,
Doxylamine, Dimenhydrinate, Cyclizine,
Meclizine.
? H1 receptors - in the solitary tract nucleus and
involved in transmission from the vestibular
apparatus to the emetic center. They block H1
receptors and prevent peripheral stimulation of
the emetic center.
? Uses: Most effective in Motion Sickness and inner
ear dysfunction (Menier¡¯s disease)
? Adverse effects: Drowsiness, Sedation, Blurred
vision,
? Dry mouth (Atropine-like).
35. ANTIEMETICS
2. Anticholinergics
? 2. Anticholinergics: eg. Scopalamine (and
not atropine)
? Block peripheral stimulation of the emetic
center.
? Uses: In Motion Sickness
? Adverse effects: Dry mouth, Drowsiness,
Blurred vision and Tachycardia
36. ANTIEMETICS
3. Benzodiazepines
? 3. Benzodiazepines: eg. Lorazepam,
Alprazolam
? Prevent central cortical induced
vomiting, enhance very
? Uses: For anxiety and Chemotherapy.
? Adverse effects: Drowsiness
37. 4. Dopamine antagonists:
a) Non-selective DA Antagonists: eg.
Phenothiazines
? Act at the chemoreceptor trigger zone (CTZ) by
inhibiting dopaminergic transmission and also
decrease vomiting caused by gastric irritants by
inhibiting the stimulation of peripheral Vagal and
sympathetic afferents
? Adverse effects: Acute dystonic reaction,
Orthostatic hypotension, Extrapyramidal side
effects and blood dyscrasias.
b) D2 Selective Antagonists: eg. Metoclopramide,
Domperidone
? Selective blockade of D2 receptors in the CTZ.
38. ? Antiemetics- D2 [4] & 5-HT3 Sel. Antagonists [5]
? ? Adverse effects: Metoclopramide precipitates
? extrapyramidal side effects, domperidone does
not,
? ? Uses: Both Selective and non-selective
antagonists are
? effective anti-emetic agents in controlling nausea
and
? vomiting encountered during cancer
chemotherapy.
39. 5. 5-HT3 selective
Antagonist
? 5. 5-HT3 selective Antagonist: eg.
Ondansetron, Granisetron
? ? They inhibit serotonin mediated
responses by blocking
? 5HT3 receptors that are involved in the
initiation of
? vomiting reflex. Most Effective.
? ? Uses: Vomiting encountered in Cancer
chemotherapy.
40. 6. Cannabinoids:
? 6. Cannabinoids: eg.
Tetrahydrocannabinol, Nabilone
? Uses: Control of emesis when all
other agents fail.
? Adverse effects: Hallucination,
Bulemia
41. 7. Corticosteroids
? 7. Corticosteroids: eg. Dexamethasone
Mechanism unknown.
? Uses: Controls Emesis in Motion Sickness,
Mountaineering
? Effective when combined with D2 and 5HT3
Antagonists.
? Adverse effects: Osteoporosis, Cushingoid
features, hyperglycemia, Peptic ulcer,
Psychosis, pituitary, adrenal suppression
and susceptibility to infection.
42. Laxatives:
? Laxative ¨C production of a soft formed stool over a period of 1
or more days
? Catharsis ¨C prompt, fluid evacuation of the bowel, more
intense
Indications for laxative use:
? Pain associated with bowel movements
? To decrease amount of strain under certain conditions
? Evacuate bowel prior to procedures or examinations
? Remove poisons
? To relieve constipation caused by pregnancy or drugs
Contraindications:
? Inflammatory bowel diseases
? Acute surgical abdomen
? Chronic use and abuse
44. Laxatives:
? Bulk laxatives:
? Increase in bowel content volume triggers stretch receptors in the intestinal
wall => causes reflex contraction (peristalsis) that propels the bowel content
forward
? Carbohydrate-based laxatives
? ¨C Insoluble and non-absorbable
? ¨C Non digestable; take several days for effect
? ¨C Expand upon taking up water in the bowel
? ¨C Must be taken with lots of water
? ? Vegetable fibers (e.g. Psyllium, lineseed)
? ? Bran (husks = milling waste product)
? Osmotically active laxatives
? ¨C Partially soluble, but not absorbable
? ¨C Saline-based (mostly sulfates)
? ¨C Effect in 1-3 hrs => used to purge intestine (e.g. surgery, poisoning)
? ? MgSO4 (= Epsom salt)
? ? Na2SO4 (= Glauber¡¯s salt)
45. Laxatives:
? Irritant laxatives:
? Cause irriatation of the enteric mucose => more
water is secreted than absorbed
? => softer bowel content and increased peristaltic
due to increase volume
? Small bowel irritants
? ? Ricinoleic acid (Castor oil)
? ¨C Active ingredient of Ricinus communis
? ¨C The oil (triglyceride) is inactive
? ¨C Ricinoleic acid released from oil through lipase
activity
46. Laxatives:
? Irritant laxatives:
? Large bowel irritants
? Anthraquinones
? Active ingredient of Senna sp. (Folia and
fructus sennae),
? Rhamnus frangulae (cortex frangulae) and
Rheum sp. (rhizoma rhei): contain inactive
glycosides => active anthraquinones
released in colon
? take 6-10 hours to act
47. Laxatives:
? Irritant laxatives:
? Large bowel irritants
? Diphenolmethanes
? ¨C Derivatives of phenolphtalein
? ? Bisacodyl
? ¨C Oral administration: effect in 6-8 hrs
? ¨C Rectal administration: effect in 1 hr
? ¨C Often used to prepare for intestinal
surgery
? ? Sodium picosulfate
48. Antidiarrheal drugs
? Antidiarrheal drugs: treat only symptoms!
? ¨C Diarrhea is usually caused by infection
(Salmonella, shigella, campylobacter,
clostridium, E. coli), toxins, anxiety, drugs¡
? ¨C In healthy adults mostly discomfort and
inconvenience
? ¨C In children (particularly mal-nourished) a
principal cause of death due to excessive
loss of water and minerals.
49. Antidiarrheal drugs
? Antimotility agents:
? ¨C Muscarinic receptor antagonists (not useful due to side
effects) and opiates:
? ? Morphine
? ? Codeine
? ? Diphenoxylate
? ¨C All have CNS effects - NOT useful for diarrhea treatment
? ? Loperamide
? ¨C Selective action on the GI tract
? ¨C Does not produce CNS effects
? ¨C First choice antidiarrheal opoid
? ¨C Combined with Dimethicone
? (Silicon-based gas-absorbent)
![? Antiemetics- D2 [4] & 5-HT3 Sel. Antagonists [5]
? ? Adverse effects: Metoclopramide precipitates
? extrapyramidal side effects, domperidone does
not,
? ? Uses: Both Selective and non-selective
antagonists are
? effective anti-emetic agents in controlling nausea
and
? vomiting encountered during cancer
chemotherapy.](https://image.slidesharecdn.com/git-drugs-240829103157-35b4eeb1/85/GIT-Drugs-GIT-Drugs-GIT-Drugs-GIT-Drugs-GIT-Drugs-38-320.jpg)
