Title: Drugs Used in the Treatment of Gastrointestinal Diseases
1Drugs Used in the Treatment of Gastrointestinal
Diseases
- Drugs used in Peptic Ulcer Diseases.
- Drugs Stimulating Gastrointestinal Motility.
- Laxatives.
- Antidiarrheal Agents.
- Drugs used in Irritable Bowel Syndrome.
- Antiemetic Agents.
- Drugs used in Inflammatory Bowel Disease.
- Pancreatic Enzyme Supplements.
2- Agents that Reduce Intragastric Acidity
- Physiology of Acid Secretion
- The parietal cell contains receptors for gastrin
CCK-B (gastrin-cholecystokinin-B receptors),
histamine (H2), and ACH (muscarinic, M3). - When ACH or gastrin (released from antral G cells
into the blood) bind to the parietal cell
receptors, they cause an increase in cytosolic
calcium, which in turn stimulates protein kinases
that stimulate acid secretion from a H/K-ATPase
(the proton pump) on the canalicular (A small
canal or duct ) surface.
3- In close proximity to the parietal cells are gut
endocrine cells called enterochromaffin -like
(ECL) cells. - ECL cells also have receptors for gastrin and
acetylcholine, which stimulate histamine release.
- Histamine binds to the H2 receptor on the
parietal cell, resulting in activation of
adenylyl cyclase, which increases intra-cellular
cAMP and activates protein kinases that stimulate
acid secretion by the H/K-ATPase. - In humans, the major effect of gastrin upon acid
secretion is mediated indirectly through the
release of histamine from ECL cells rather than
through direct parietal cell stimulation. - In contrast, acetylcholine provides potent direct
parietal cell stimulation.
4(gastrin-cholecystokinin-B receptors)
5- Antacids
- Nonprescription remedies for the treatment of
heartburn and dyspepsia. - Weak bases that react with gastric hydrochloric
acid to form a salt and water. - Given 1 hour after a meal effectively neutralizes
gastric acid for up to 2 hours. - Efficacy varies according to rate of dissolution,
water solubility, rate of reaction with acid and
the rate of gastric emptying. - May affect the absorption of other medications by
binding to drugs or by changing ph, therefore,
dissolution.
6- Sodium bicarbonate
- Reacts rapidly with HCL to produce carbon dioxide
and sodium chloride. - CO2 results in gastric distention and belching.
- Unreacted alkali is readily absorbed, potentially
causing metabolic alkalosis when given in high
doses or to patients with renal insufficiency. - may exacerbate fluid retention in patients with
heart failure, hypertension, and renal
insufficiency.
7- Calcium carbonate
- Less soluble.
- Reacts more slowly to form carbon dioxide and
calcium chloride (CaCl2). - May cause belching or metabolic alkalosis.
- Excessive doses of either sodium bicarbonate or
calcium carbonate with calcium-containing dairy
products can lead to hypercalcemia, renal
insufficiency, and metabolic alkalosis
(milk-alkali syndrome hypercalcemia caused by
repeated ingestion of calcium and absorbable
alkali (such as calcium carbonate, or milk and
sodium bicarbonate).
8- Magnesium Hydroxide.
- Aluminum Hydroxide.
- React slowly and without gas formation.
- Metabolic alkalosis is also uncommon.
- Mg salts cause diarrhea.
- Aluminum salts cause constipation.
- Usually given in combination.
- Contraindicated in renal insufficiency.
9- H2-Receptor Antagonists
- Cimetidine, Ranitidine, Famotidine, and
Nizatidine. - Rapidly absorbed from the intestine.
- Cimetidine, ranitidine, and famotidine undergo
first-pass hepatic metabolism, bioavailability
50. - Nizatidine has little first-pass metabolism.
- Duration of action610 hours, given twice daily.
- Inhibit 90 of nocturnal acid (which depends
largely on histamine). - Have a modest impact on meal-stimulated acid
secretion (which is stimulated by gastrin,
acetylcholine and histamine). - Inhibit 60 of day-time, meal stimulated, acid.
- Inhibit 60-70 of total 24-h acid secretion.
10- Clinical Uses of H2-Receptor Antagonists
- Gastroesophageal Reflux Disease (GERD)
- Taken prophylactically before meals.
- In patients with erosive esophagitis H2
antagonists afford healing in less than 50 of
patients hence proton pump inhibitors are
preferred. - Non Ulcer Dyspepsia.
- Over-the-counter agents for treatment of
intermittent dyspepsia not caused by peptic
ulcer. - Prevention of Bleeding from Stress-Related
Gastritis - IV H2 antagonists are preferable over intravenous
proton pump inhibitors because of their proven
efficacy and lower cost. - Continuous infusions of H2 antagonists are
preferred to bolus infusions because they achieve
more consistent, sustained elevation of
intragastric pH.
11- Peptic Ulcer Disease
- Replaced by PPI.
- Healing rate more than 80-90 after 6-8 weeks.
- Not effective in the presence of H. pylori
infection - H pylori should be treated with a 10- to 14-day
course of a proton pump inhibitor and two
antibiotics. - If H pylori cannot be eradicated, H2 antagonists
may be given daily at bedtime in half of the
usual ulcer therapeutic dose to prevent ulcer
recurrence. - Not effective if NSAID is continued.
12- Adverse Effects
- 1-Extremely safe drugs. Diarrhea, headache,
fatigue, myalgias, and constipation (3 of
patients) . - 2-Cimetidine inhibits binding of
dihydrotestosterone to androgen receptors,
inhibits metabolism of estradiol, and increases
serum prolactin levels. - 3- Long-term use may cause gynecomastia or
impotence in men and galactorrhea in women - 4- Crosses placental barrier and appear in breast
milk
13- 5- Other Effects
- Rarely can cause blood dyscrasias, bradycardia
and hypotension. - Mental status changes (confusion, agitation
hallucinations,) may occur with intravenous H2
antagonists - Drug Interactions
- Cimetidine can inhibit cytochrome P450 enzymes so
can increase half life of many drugs. - Ranitidine binds 4-10 times less.
- Nizatidine and famotidine binding is negligible.
14- Proton Pump Inhibitors (PPIs)
- Among the most widely prescribed drugs worldwide
due to their outstanding efficacy and safety. - Omeprazole (oral).
- Rabeprazole (oral).
- Lanzoprazole (oral and IV).
- Pantoprazole (oral and IV).
- Esmoprazole (oral and IV).
- Formulated as a prodrug which is released in the
intestine. - Immediate Release Suspension (contains sodium
bicarbonate to protect the drug from acid
degradation) results in rapid response.
15- Pharmacokinetics
- They are lipophilic weak bases (pKa 4-5).
- After absorption, they diffuse across lipid
membranes into acidified compartments such as the
parietal cell canaliculus. - The prodrug becomes protonated and concentrated
more than 1000-fold within the parietal cells. - There, it undergoes a molecular conversion to the
active form which covalently binds the H/K
ATPase enzyme and inactivates it. - Rabeprazole and immediate release omeprazole have
faster onsets of action. - Should be given one hour before meal, usually
breakfast.
16- Have short half lives but effect lasts for 24
hours due to irreversible inhibition. - Inhibit both fasting and meal-stimulated
secretion because they block the final common
pathway of acid secretion (90-98 of 24-hour
secretion). - At least 18 hours are required for synthesis of
new H/K-ATPase pump molecules. - Up to 34 days of daily medication are required
before the full acid-inhibiting potential is
reached.
17- Clinical Uses of (PPIs)
- Gastroesophageal Reflux (GERD)
- They are the most effective agents in all forms
of GERD and complications. - Nonulcer Dyspepsia
- Modest activity.10-20 more beneficial than a
placebo - Stress- Related Gastritis
- Oral immediate- release omeprazole administered
by nasogastric tube. - For patients without a nasoenteric tube, IV
H2-antagonists are preferred because of their
proven efficacy. - Gastrinoma and other Hypersecretory Conditions
- Usually high doses of omeprazole are used.
18- Peptic Ulcer Disease
- They heal more than 90 of cases within 4-6
weeks. - H.Pylori - associated ulcers
- PPI eradicate H.pylori by direct antimicrobial
activity and by lowering MIC of the antibiotics. - Triple Therapy
- PPI twice daily Clarithromycin 500mg twice
daily Amoxicillin 1gm twice daily ,OR,
Metronidazole 500mg twice daily. - NSAID-associated ulcers
- PPIs promote ulcer healing despite continued
NSAID use. Also used to prevent ulcer of NSAIDs - Rebleeding peptic ulcer
- Oral or IV.
- High pH may enhance coagulation and platelet
aggregation.
19- Adverse Effects of PPIs
- Diarrhea, headache, abdominal pain, not
teratogenic in animals, but not used in
pregnancy. - Reduction of cyanocobalamine absorption.
- Increased risk of GI and pulmonary infection.
- Increased serum gastrin levels causes
- Hyperplasia of ECL cells and Carcinoid tumors in
rats but not in humans. -
- Increase proliferative rate of colonic mucosa,
but no cancer developed. - Chronic inflammation in gastric body.
- Atrophic gastritis and intestinal metaplasia (the
transformation of epithelium, usually of the
stomach or the esophagus , to a type that bears
some resemblance to the intestine )
20- Drug Interactions
- May affect absorption of drugs due to decreased
gastric acidity like digoxin and ketoconazole. - Omeprazole can inhibit metabolism of coumadin
(Warfarin ), diazepam and phenytoin. - Rabeprazole and pantoprazole have no significant
interaction.
21- Mucosal Protective Agents
- 1-Both mucus and epithelial cell-cell tight
junctions restrict back diffusion of acid and
pepsin. - 2-Epithelial bicarbonate secretion establishes a
pH gradient within the mucous layer in which the
pH ranges from 7 at the mucosal surface to 12 in
the gastric lumen. - 3-Blood flow carries bicarbonate and vital
nutrients to surface cells. - 4-Areas of injured epithelium are quickly
repaired by restitution, a process in which
migration of cells from gland neck cells seals
small erosions to reestablish intact epithelium. - 5- Mucosal prostaglandins stimulates mucus and
bicarbonate secretion and mucosal blood flow.
22- Sucralfate
- A salt of sucrose complexed to sulfated aluminum
hydroxide. - In the stomach, It breaks down into sucrose
sulfate (strongly negatively charged) and an
aluminum salt. - The negatively charged sucrose sulfate binds to
- positively charged proteins in the base of ulcers
or erosion, forming a physical barrier that
restricts further caustic damage and stimulates
mucosal prostaglandin and bicarbonate secretion. - Acts for up to 6 hours. Less than 3 of intact
drug and aluminum is absorbed from GIT.
23- Clinical Uses
- 1 g four times daily on an empty stomach
(administered as a slurry through a nasogastric
tube) reduces the incidence of upper
gastrointestinal bleeding in critically ill
patients hospitalized in the intensive care unit. - Used for prevention of stress-related bleeding
because of concerns that acid inhibitory
therapies (antacids, H2 antagonists, and proton
pump inhibitors) may increase the risk of
nosocomial pneumonia (an infection of the lungs
that occurs during a hospital stay ).
24- Adverse Effects
- Because it is not absorbed, sucralfate is
virtually devoid of systemic adverse effects. - Constipation occurs in 2 of patients due to the
aluminum salt. - Because a small amount of aluminum is absorbed,
it should not be used for prolonged periods in
patients with renal insufficiency. - Drug Interactions
- Sucralfate may bind to other medications,
impairing their absorption.
25- Prostaglandin Analogs
- Misoprostol,
- A methyl analog of PGE1.
- Half-life is less than 30 minutes administered
3-4 times daily. - It stimulates mucus and bicarbonate secretion and
enhance mucosal blood flow. - It binds to a prostaglandin receptor on parietal
cells, reducing histamine-stimulated cAMP
production and causing modest acid inhibition. - Stimulates intestinal electrolyte fluid
secretion, intestinal motility and uterine
contractions.
26- Clinical Uses of Prostaglandin Analogs
- Prevention of NSAID-induced ulcers in high-risk
patients. - Not widely used for this purpose because of
- a- side effects.
- b. need for multiple daily dosing.
- c. PPI may be as effective and better tolerated.
- d. Cyclooxygenase2-selective NSAIDs are
an option for such patients. - Adverse Effects Drug Interactions
- Diarrhea and cramping abdominal pain occur in
1020 of patients. - it should not be used during pregnancy
- No significant drug interactions are reported.
27- Colloidal Bismuth Compounds
- Bismuth subsalicylate.
- Bismuth subcitrate.
- Bismuth is minimally absorbed from GIT (lt 1).
- Coats ulcers and erosions, creating a protective
layer against acid and pepsin. - It may stimulate prostaglandin, mucus, and
bicarbonate secretion. - Bismuth subsalicylate reduces stool frequency and
liquidity in acute infectious diarrhea, due to
salicylate inhibition of intestinal prostaglandin
and chloride secretion. - Bismuth has direct antimicrobial effects and
binds enterotoxins, accounting for its benefit in
preventing and treating traveler's diarrhea. - Have direct antimicrobial activity against H
pylori.
28- Widely used for the nonspecific treatment of
dyspepsia and acute diarrhea. - Bismuth subsalicylate also is used for the
prevention of traveler's diarrhea. - Used as second-line therapy for the eradication
of H pylori infection (a PPI with bismuth
subsalicylate , tetracycline and metronidazole
for 1014 days). - Adverse Effects
- Causes blackening of the stool and the tongue.
- Prolonged usage may rarely lead to bismuth
toxicity, resulting in encephalopathy.
29- Drugs Stimulating Gastrointestinal Motility
- (prokinetic agents)
- Agents that increase lower esophageal sphincter
pressures may be useful for GERD. - Drugs that improve gastric emptying may be
helpful for gastroparesis and postsurgical
gastric emptying delay. - Agents that stimulate the small intestine may be
beneficial for postoperative ileus or chronic
intestinal pseudo-obstruction. - Agents that enhance colonic transit may be useful
in the treatment of constipation.
30- Physiology of the Enteric Nervous System
- The ENT is composed of interconnected networks
of ganglion cells and nerve fibers mainly located
in the submucosa (submucosal plexus) and between
the circular and longitudinal muscle layers
(myenteric plexus). - Extrinsic sympathetic and parasympathetic nerves
project onto the submucosal and myenteric
plexuses. - The enteric nervous system can independently
regulate gastrointestinal motility and secretion.
- Extrinsic primary afferent neurons project via
the dorsal root ganglia or vagus nerve to the CNS.
31- Release of serotonin (5-HT) from intestinal
mucosa enterochromaffin (EC) cells stimulates
5-HT3 receptors on the extrinsic afferent nerves,
stimulating nausea, vomiting, - or abdominal pain.
- Serotonin also stimulates submucosal 5-HT1P
receptors - of the intrinsic primary afferentnerves (IPANs).
32- IPANs) contain calcitoningene-related peptide
(CGRP) and acetylcholine and project to myenteric
plexus interneurons. - 5-HT4 receptors on the presynaptic terminals of
the IPANs enhance release of CGRP or Ach. - The myenteric interneurons control
- peristaltic reflex, promoting release of
excitatory mediators proximally and inhibitory
mediators distally. - Motilin may stimulate excitatory neurons or
muscle cells directly. - Dopamine acts as an inhibitory neurotransmitter
in the GIT, decreasing the intensity of
esophageal and gastric contractions.
33Figure 624 Release of serotonin (5-HT) by
enterochromaffin (EC) cells from gut distention
stimulates submucosal intrinsic primary afferent
neurons (IPANs) via 5-HT1P receptors and
extrinsic primary afferent neurons via 5-HT3
receptors (5-HT1PR, 5-HT3R). Submucosal IPANs
activate the enteric neurons responsible for
peristaltic and secretory reflex activity.
Stimulation of 5-HT4 receptors (5-HT4R) on
presynaptic terminals of IPANs enhances release
of acetylcholine (ACh) and calcitoningene-related
peptide (CGRP), promoting reflex activity.
CNS, central nervous system ENS, enteric
nervous system.
34- Cholinomimetic Agents
- Bethanechol
- Stimulates muscarinic M3 receptors on muscle
cells and at myenteric plexus synapses . - Was used for the treatment of GERD and
gastroparesis. - Neostigmine
- AchE inhibitor can enhance gastric, small
intestine, and colonic emptying. - IV neostigmine used for the treatment of acute
large bowel distention (acute colonic
pseudo-obstruction). - Administration of 2 mg results in prompt colonic
evacuation of flatus and feces. - Cholinergic effects include excessive salivation,
nausea, vomiting, diarrhea, and bradycardia.
35- Dopamine D2-receptor antagonists.
- Metoclopramide Domperidone
- D2 Antagonists.
- DA inhibits cholinergic smooth muscle
stimulation. - These agents
- -increase esophageal peristaltic amplitude.
- -increase lower esophageal sphincter pressure.
- -enhance gastric emptying.
- -have no effect on small intestine or colonic
motility. - Also block dopamine D2 receptors in the
chemoreceptor trigger zone of the medulla (area
postrema), resulting in potent antinausea and
antiemetic action.
36- Clinical Uses
- Gastroesophageal Reflux Disease
- Not effective with erosive esophagitis.
- Not superior to antisecretory agents.
- Used mainly in combination with antisecretory
agents in patients with refractory heartburn. - Impaired Gastric Emptying (Gastroparesis)
- widely used in the treatment of postsurgical and
diabetic gastroparesis. - Metoclopramide is used to promote advancement of
nasoenteric feeding tubes from the stomach into
the duodenum. - Nonulcer Dyspepsia
- Prevention of Vomiting
- Postpartum Lactation Stimulation
- Domperidone is used to promote postpartum
lactation
37- Adverse Effects
- Metclopromide crosses BBB so can cause
Restlessness, drowsiness, insomnia, anxiety,
agitation, extrapyramidal symptoms (dystonia,
akathisia, parkinsonian features) and tardive
dyskinesia. - Domperidone does not cross the BBB, so does not
cause CNS effects - Both drugs can elevate serum prolactin levels
causing galactorrhea, gynecomastia, impotence and
menstrual disorders.
38- Laxatives
- Intermittent constipation is best prevented with
a high-fiber diet, adequate fluid intake, regular
exercise, and responding to nature's call. - Bulk-Forming Laxatives
- Indigestible, hydrophilic colloids that absorb
water, forming a bulky, emollient gel that
distends the colon and promotes peristalsis. - Common preparations include natural plant
products (psyllium, methylcellulose) and
synthetic fibers (polycarbophil). - Bacterial digestion of plant fibers within the
colon may lead to increased bloating and flatus.
39- Stool Surfactant Agents (Softeners)
- Soften stool material, permitting water and
lipids to penetrate. - Administered orally or rectally.
- Docusate (oral or enema) and glycerin
suppository. - Mineral oil
- Clear, viscous oil that lubricates fecal
material, retarding water absorption from the
stool. - Used to prevent and treat fecal impaction.
- Aspiration can result in a severe lipid
pneumonitis - Long-term use can impair absorption of
fat-soluble vitamins.
40- Osmotic Laxatives
- Soluble but nonabsorbable compounds that result
in increased stool liquidity due to an increase
in fecal fluid. - Nonabsorbable Sugars or Salts
- Used for the treatment of acute constipation or
the prevention of chronic constipation. - Magnesium hydroxide (milk of magnesia)
- Not used for prolonged periods in patients with
renal insufficiency due to the risk of
hypermagnesemia. - Large doses of magnesium citrate and sodium
phosphate can cause Purgation - rapid bowel evacuation within1-3 hours.
- This might cause volume depletion.
41- Sorbitol, Lactulose
- Sugars metabolized by bacteria producing severe
flatus and cramps. - Balanced Polyethylene Glycol
- PEG is an inert, nonabsorbable, osmotically
active sugar with sodium sulfate, sodium
chloride, sodium bicarbonate, and potassium
chloride. - Safe, no intrvascular fluid or electrolyte
shifts. - No cramps or flatus.
- Used for complete colonic cleansing before
endoscopy - For colonic cleansing, it should be ingested
rapidly( 4 L over 2-4hs). - For chronic constipation, PEG powder is mixed
with water or juice.
42- Stimulant Laxatives
- Direct stimulation of the enteric nervous system
and colonic electrolyte and fluid secretion. - Anthraquinone Derivatives
- Aloe, senna, and cascara
- Occur naturally in plants. Poorly absorbed and
after hydrolysis in the colon, produce a bowel
movement in 612 hours when given orally and
within 2 hours when given rectally. - Chronic use leads to a brown pigmentation of the
colon known as "melanosis coli. - Not carcinogenic.
43- Bisacodyl
- Tablet and suppository for treatment of acute and
chronic constipation. - It also is used in conjunction with PEG solutions
for colonic cleansing prior to colonoscopy. - It induces a bowel movement within 610 hours
when given orally and 3060 minutes when taken
rectally. - Safe for acute and long-term use.
- Phenolphthalein
- Removed from the market owing to concerns about
possible cardiac toxicity
44- Opioid Receptor Antagonists
- Do not cross the blood-brain barrier.
- Block peripheral (µ) mu -opioid receptors without
causing central analgesic effects. - Methylnaltrexone
- Used for opioid- induced constipation in patients
with advanced illness not responding to other
agents. - Given by S.C. injection every 2 days.
- Alvimopan
- Short-term use for postoperative ileus in
hospitalized patients. - Given orally within 5 hours before surgery and
twice daily after surgery until bowel function
has recovered, but for no more than 7 days,
because of possible cardiovascular toxicity.
45- Antidiarrheal Agents
- Should not be used in patients with bloody
diarrhea, high fever, or systemic toxicity
because of the risk of worsening the underlying
condition. - Used to control chronic diarrhea caused by
irritable bowel syndrome (IBS) or inflammatory
bowel disease.
46- Opioid Agonists
- Inhibit presynaptic cholinergic nerves in the
submucosal and myenteric plexuses and lead to
increased colonic transit time and fecal water
absorption. - They also decrease mass colonic movements
- CNS effects and potential for addiction limit the
usefulness of most. - Loperamide
- Does not cross BBB. No analgesic or addiction
potential. - Diphenoxylate
- Not analgesic in standard doses.
- Higher doses have CNS effects.
- Can cause dependence.
- Commercial preparations contain small amounts of
atropine which contribute to the antidiarrheal
action.
47- Bile Salt-Binding Resins
- Cholestyramine
- Colestipol
- Colesevelam
- Malabsorption of bile salts (e. g . Crohn's
disease or after surgical resection), can cause
diarrhea. - The drugs can bind bile salts and decrease
diarrhea caused by excess fecal bile acids. - Can cause bloating, flatulence, constipation and
fecal impaction. - Cholestyramine and colestipol reduce absorption
of drugs and fat. - Colesevelam have no effects on absorption of
other drugs.
48- Octreotide
- Is a synthetic octapeptide with actions similar
to somatostatin. - Somatostatin
- A14 amino acid peptide released in the GIT and
pancreas as well as from the hypothalamus - 1. Inhibits release of many hormones.
- 2. Reduces intestinal fluid and pancreatic
secretions. - 3. Slows GIT motility and gallbladder
contraction. - 4. Contracts blood vessels.
- 5. Inhibits secretion of some anterior pituitary
hormones.
49- Clinical Uses
- 1. Inhibition of endocrine tumor effects
- Carcinoid and VIPoma (neuroendocrine tumors
that secrete vasoactive intestinal polypeptide
(VIP) ) can cause secretory diarrhea, flushing
and wheezing. - 2. Diarrhea due to vagotomy or dumping syndrome
(ingested foods bypass the stomach too rapidly)
or short bowel syndrome and AIDS. - 3. To stimulate motility in small bowel
bacterial overgrowth or intestinal
pseudo-obstruction secondary to scleroderma (a
disease affecting the skin and other organs that
is one of the autoimmune rheumatic diseases).
50- 4- Because it inhibits pancreatic secretion, it
is used in patients with pancreatic fistula
(leakage of pancreatic secretions from damaged
pancreatic ducts ). - 5- treatment of pituitary tumors (e.g.,
acromegaly) - 6- Sometimes used in gastrointestinal bleeding.
- Adverse Effects
- Impaired pancreatic secretion may cause
steatorrhea (the presence of excess fat in feces
), which can lead to fat-soluble vitamin
deficiency. - Nausea, abdominal pain, flatulence, and diarrhea.
- Formation of sludge or gallstones, because of
inhibition of gallbladder contractility and fat
absorption. - Hyper or hypoglycemia due to hormonal imbalance.
- Hypothyroidism.
- Bradycardia.
51- Drugs Used in the Treatment of Irritable Bowel
Syndrome - IBS is an idiopathic chronic, relapsing disorder
characterized by - Abdominal discomfort (pain, bloating, distention,
or cramps) in association with alterations in
bowel habits (diarrhea, constipation, or both). - Pharmacologic therapies for IBS are directed at
relieving abdominal pain and discomfort and
improving bowel function.
52- Antispasmodics (Anticholinergics)
- Dicyclomine and Hyoscyamine .
- Inhibit muscarinic cholinergic receptors in the
enteric plexus and on smooth muscle. - Their efficacy for relief of abdominal symptoms
has never been convincingly demonstrated. - Low doses cause minimal autonomic effects.
- Higher doses cause anticholinergic effects,
including dry mouth, visual disturbances, urinary
retention, and constipation. - For these reasons, antispasmodics are
infrequently used.
53- Serotonin 5-HT3-Receptor Antagonists
- Inhibition of afferent GIT
- 5-HT3 receptors reduce
- nausea, bloating, and pain.
- Blockade of central 5-HT3
- receptors also reduces the
- central response to visceral afferent
stimulation. - 5-HT3-receptor blockade on the terminals of
enteric cholinergic neurons inhibits colonic
motility, especially in the left colon,
increasing total colonic transit time.
54- Alosetron
- Highly potent and selective antagonist of the
5-HT3 receptor. - Rapidly absorbed and has a plasma half-life of
1.5 hours but a much longer duration of effect. - Alosetron is restricted to women with severe
diarrhea-predominant IBS not responding to
conventional therapies. - Can cause ischemic colitis, severe constipation
requiring hospitalization and surgery. - Its efficacy in men has not been established.
55- Serotonin 5-HT4-Receptor Agonists
- Stimulation of 5-HT4 receptors
- on the presynaptic terminal
- of submucosal intrinsic primary
- afferent nerves enhances the
- release of their neurotransmitters,
- which promote the peristaltic reflex.
- Tegaserod
- was approved for the short-term treatment of
women with IBS who had predominant constipation. - Removed from the market due to an increased
number of cardiovascular deaths. - Prucalopride
- High-affinity 5-HT4 agonist. No cardiovascular
toxicity - Used for the treatment of chronic constipation in
women.
56- Chloride Channel Activator
- Lubiprostone
- PG analog
- Stimulates the type 2 chloride channel (ClC-2) in
the small intestine and this increases liquid
secretion in the intestine which stimulates
intestinal motility and bowel movement within 24
hours of taking one dose. - Used in the treatment of chronic constipation.
- Approved for the treatment of women with IBS with
predominant constipation. - Its efficacy for men with IBS is unproven.
- Should be avoided in women of child-bearing age.
- May cause nausea in up to 30 of patients due to
delayed gastric emptying.
57- Antiemetic Agents
- Nausea and vomiting may be manifestations of a
wide variety of conditions, including - Adverse effects from medications.
- systemic disorders or infections.
- Pregnancy.
- Vestibular dysfunction.
- CNS infection or increased pressure.
- Peritonitis.
- Hepatobiliary disorders.
- Radiation or chemotherapy.
- GIT obstruction, dysmotility, or infections.
58- Pathophysiology
- The brainstem "vomiting center" coordinates
vomiting through interactions with cranial nerves
VIII and X and neural networks in the nucleus
tractus solitarius that control respiratory,
salivatory, and vasomotor centers. -
- Vomiting center contains high concentrations of
Muscarinic M1 receptors. - Histamine H1 receptors.
- Neurokinin 1 (NK1) receptors.
- Serotonin 5-HT3 receptors.
59(No Transcript)
60- There are four important sources of afferent
input to the vomiting center (VC) - 1-The "chemoreceptor trigger zone (CTZ) or area
postrema is outside the blood-brain barrier but
is accessible to emetogenic stimuli in the blood
or cerebrospinal fluid. - It is rich in dopamine D2 receptors, opioid
receptors, serotonin 5-HT3 receptors and
neurokinin NK1 receptors. - 2- The vestibular system is important in motion
sickness via cranial nerve VIII. - It is rich in muscarinic M1 and histamine H1
receptors.
61- 3- Vagal and spinal afferent nerves from the GIT
are rich in 5-HT3 receptors. - Irritation of the GI mucosa by chemotherapy,
radiation therapy, distention, or acute
infectious gastroenteritis leads to release of
mucosal 5-HT and activation of these receptors,
which stimulate vagal afferent input to the VC
and CTZ. - 4- The CNS plays a role in vomiting due to
psychiatric disorders, stress, and anticipatory
vomiting prior to cancer chemotherapy. - Combinations of antiemetic agents with different
mechanisms of action are often used.
62- Serotonin 5-HT3 Antagonists
- Ondansetron oral 0r IV
- Granisetron half-life 49 h
- Dolasetron
- Palonosetron half-life 40 h
- Block central 5-HT3 and peripheral (main effect)
5-HT3 receptors on extrinsic intestinal vagal and
spinal afferent nerves. - They prevent emesis due to vagal stimulation and
chemotherapy. - Other emetic stimuli such as motion sickness are
poorly controlled.
63- Uses
- Prevention of acute chemotherapy-induced nausea
and emesis and postoperative nausea and vomiting. - Their efficacy is enhanced by combination therapy
with dexamethasone and NK1-receptor antagonist. - Prevention and treatment of nausea and vomiting
in patients undergoing radiation therapy. - Adverse effects
- Headache, dizziness, and constipation.
- Cause a small prolongation of the QT interval.
64- Neurokinin 1 Receptor (NK1) Antagonists
- Have antiemetic properties through central
blockade in the area postrema. - Aprepitant
- Used in combination with 5-HT3-receptor
antagonists and corticosteroids for the
prevention of acute and delayed nausea and
vomiting from chemotherapy. - Adverse effects
- May cause fatigue, dizziness, and diarrhea.
65- Antipsychotic drugs
- Prochlorperazine
- Promethazine
- Droperidol
- Antiemetics due to inhibition of dopamine and
muscarinic receptors. - Sedative effects due to antihistamine activity.
- Droperidol is extremely sedating.
- Extrapyramidal effects and hypotension may occur.
- Droperidol may prolong the QT interval, rarely.
66- Benzodiazepines
- Lorazepam
- Diazepam
- Reduce anticipatory vomiting caused by anxiety.
67- H1 Antihistamines Anticholinergic Drugs
- Particularly useful in motion sickness.
- May cause dizziness, sedation, confusion, dry
mouth, cycloplegia, and urinary retention. - Diphenhydramine, Dimenhydrinate
- Have significant anticholinergic properties.
- Meclizine
- Minimal anticholinergic properties and less
sedating. - Used for the prevention of motion sickness and
the treatment of vertigo due to labyrinth
dysfunction. - Hyoscine (scopolamine)
- Very high incidence of anticholinergic effects.
- It is better tolerated as a transdermal patch.
68- Cannabinoids
- Dronabinol, Nabilone
- Delta-9- tetrahydrocannabinol from marijuana.
- Psychoactive agents.
- Used as appetite stimulants and for
chemotherapy-induced vomiting. - Mechanisms for these effects are not understood.
- Adverse effects
- Euphoria, dysphoria, sedation, hallucinations,
dry mouth, and increased appetite. - May result in tachycardia, conjunctival injection
(redness of the white sclera of the eye) and
orthostatic hypotension.
69- Drugs Used to Treat Inflammatory Bowel Disease
- Inflammatory bowel disease (IBD) comprises two
distinct disorders - Ulcerative colitis and Crohn's disease.
- Etiology and pathogenesis are unknown.
- For this reason, the drugs used belong to
different classes and have nonspecific mechanisms
of anti-inflammatory action. - Drugs used are chosen on the basis of disease
severity, responsiveness, and drug toxicity.
70- Aminosalicylates
- 5-aminosalicylic acid (5-ASA)
- Aminosalicylates work topically (not
systemically) in areas of diseased
gastrointestinal mucosa. - Up to 80 of unformulated 5-ASA is absorbed from
the small intestine and does not reach the distal
small bowel or colon in appreciable quantities. - A number of formulations deliver 5-ASA to various
distal segments of the small bowel or the colon.
71- Azo Compounds
- Sulfasalazine, Balsalazide, Olsalazine
- 5-ASA bound by an azo (NN) bond to an inert
compound or to another 5-ASA molecule - The azo structure markedly reduces absorption of
the parent drug from the small intestine. - In the terminal ileum and colon, resident
bacteria cleave the azo bond by means of an
azoreductase enzyme, releasing 5-ASA. - Consequently, high concentrations of active drug
are made available in the terminal ileum or colon.
72- Mesalamine Compounds
- Pentasa
- Timed-release microgranules that release 5-ASA
throughout the small intestine . - Asacol
- 5-ASA coated in a pH-sensitive resin that
dissolves at the pH of the distal ileum and
proximal colon). - 5-ASA also delivered as
- Enema (Rowasa)
- Suppositories (Canasa).
73- The mechanism of action of 5-ASA is not certain.
- 5-ASA modulates inflammatory mediators derived
from both the cyclooxygenase and lipoxygenase
pathways. - Other potential mechanisms
- -Interferes with the production of inflammatory
cytokines. - -Inhibits the activity of nuclear factor- B (NF-
B), an important transcription factor for
proinflammatory cytokines. - -May also inhibit cellular functions of natural
killer cells, mucosal lymphocytes, and
macrophages, and it may scavenge reactive oxygen
metabolites.
74- Clinical Uses
- 5-ASA drugs are first-line agents for treatment
of mild to moderate active ulcerative colitis. - Their efficacy in Crohn's disease is unproven,
although used as first-line therapy for mild to
moderate disease involving the colon or distal
ileum. - Adverse Effects
- Due to systemic absorption especially in slow
acetylators - Nausea, headache, arthralgia, myalgia, bone
marrow suppression, and malaise. - Also allergic reactions, oligospermia, and folate
deficiency.
75- Glucocorticoids
- Inhibit production of inflammatory cytokines and
chemokines reduce expression of inflammatory
cell adhesion molecules and inhibit gene
transcription of nitric oxide synthase,
phospholipase A2, cyclooxygenase-2, and NF- B. - Clinical Uses
- Moderate to severe active IBD.
- Not useful for maintenance.
- Prednisolone Orally or IV.
- Hydrocortisone Rectally, preferred for rectal and
sigmoid involvement. - Budesonide
- A controlled-release oral formulation ,releases
the drug in the distal ileum and colon. - For ileal and proximal colon involvement.
76- Antimetabolites
- Azathioprim
- 6-Mercaotopurine.
- Are purine analogs which produce thioguanine
nucleotides (Active form). - Immunosuppressants.
- Inhibit purine nucleotide metabolism and DNA
synthesis and repair, resulting in inhibition of
cell division and proliferation and may promote
T-lymphocyte apoptosis.
77- Clinical Use
- Onset delayed for 17 weeks.
- Used in induction and maintenance of remission.
- Allow dose reduction or elimination of steroids.
- Adverse Effects
- Nausea, vomiting, bone marrow suppression,
hepatic toxicity and allergic reactions( fever,
rash, pancreatitis, diarrhea and hepatitis). - Allopurinol increases levels of the drugs.
78- Methotrexate
- Antimetabolite, Used in cancer chemotherapy,
rheumatoid arthritis and psoriasis. - Mechanism of action
- Inhibition of dihydrofolate reductase enzyme
which is important in the synthesis of thymidine
and purines. - - At high doses it inhibits cellular
proliferation. - - At low doses used in IBD, it interferes with
the inflammatory actions of interleukin-1,
stimulates adenosine release, apoptosis and death
of activated T lymphocytes.
79- Uses
- Induction and maintenance of remissions of
Crohns Disease. - Adverse effects
- At high doses, can cause bone marrow depression,
megaloblastic anemia, alopecia and mucositis. - Renal insufficiency may increase risk of hepatic
accumulation and toxicity. - Side effects counteracted by folate
supplementation.
80- Anti-Tumor Necrosis Factor Therapy
- If the epithelial barrier is impaired, bacterial
antigens can gain access to antigen-presenting
cells (APC) such - as dendritic cells in the lamina propria.
- These cells then present the antigen(s) to CD4
- lymphocytes and also secrete cytokines such
- interleukin (IL)-12 and IL-18, thereby inducing
the differentiation of TH1 cells in Crohn's
disease or IL-4, type 2 helper T cellTH2 in
Ulcerative colitis. - The TH1 cells produce cytokines, including
interferon (IFN) and TNF , which in turn
activate macrophages. - Macrophages positively regulate TH1 cells by
secreting additional cytokines, including IFN
and TNF .
81- Recruitment of a variety of leukocytes is
mediated by activation of resident immune cells
including neutrophils. - Cell adhesion molecules such as integrins are
important in the infiltration of leukocytes. - Anti- Integrin Therapy aimed at blocking
leukocyte recruitment are effective at reducing
inflammation. - Site-specific intervention involve intestinal
bacteria and therapy directed at TNF or IL-12. - TNF-a is one of the principal cytokines mediating
the TH1 (helper T cell type 1) immune response
characteristic of Crohn's disease.
82CD4 lymphocytes
83- Infliximab
- is a chimeric immunoglobulin (25 mouse, 75
human) that binds to and neutralizes TNF . - Infliximab binds membrane-bound TNF and may
cause lysis of these cells by antibody-dependent
or cell-mediated cytotoxicity. - Half life 8-10 days with persistence of
antibodies in plasma for 8-12 weeks - Used in acute and chronic treatment of patients
with moderate to severe Crohn's disease. - Given in repeated doses at 0, 2, and 6 weeks for
induction by IV infusion. - If response is adequate, infusions are repeated
every 8 weeks. - Response might be lost due to development of
antibodies to infliximab. - Infliximab is effective for refractory ulcerative
colitis.
84- Side Effects
- Acute
- fever, chills, urticaria, or even anaphylaxis
- Subacute
- serum sicknesslike) reactions may develop after
infliximab infusion, but lupus-like syndrome
occurs only rarely. - Antibodies to infliximab can decrease its
clinical efficacy. - Therapy is associated with increased incidence of
respiratory infections reactivation of TB. - Infliximab also is contraindicated in patients
with severe congestive heart failure. - there is concern about the possible increased
incidence of non-Hodgkin's lymphoma.
85- Adalimumab
- is a humanized recombinant human IgG1 monoclonal
antibody against TNF . - It is effective in inducing remission in mild to
moderate and severe Crohn's disease,given SC - Certolizumab pegol
- is a pegylated (Polyethylene glycol ) humanized
fragment antigen binding (Fab) that binds TNF . - Also given SC.
- As effective as adalimumab and infliximab for the
treatment of Crohn's disease. - With both adalimumab and certolizumab pegol,
immunogenicity appears to be less of a problem
than that associated with infliximab.
86- Natalizumab
- Humanized IgG4 monoclonal antibody against the
cell adhesion molecule a 4-integrin subunit. - prevents binding of several integrins on
circulating inflammatory cells to vascular
adhesion molecules - Used for patients with moderate to severe Crohn's
disease who have failed other therapies - Given by IV infusion every 4 weeks, and patients
should not be on other immune suppressants to
prevent the risk of progressive multifocal
leukoencephalopathy (rare and usually fatal viral
disease ) - Adverse effects include acute infusion reactions
- a small risk of opportunistic infections.
87- Pancreatic Enzyme Supplements
- Contain a mixture of amylase, lipase, and
proteases. - Used to treat pancreatic enzyme insufficiency.
- Pancrelipase.
- Available in both non-enteric-coated (given with
acid suppression therapy ) and enteric-coated
preparations. - Administered with each meal and snack.
- Excessive doses may cause diarrhea and abdominal
pain. - The high purine content of pancreas extracts may
lead to hyperuricosuria and renal stones.