Drugs 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.

Agents that Reduce Intragastric AcidityPhysiology of Acid SecretionThe 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.

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.

(gastrin-cholecystokinin-B receptors)

AntacidsNonprescription 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.

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 .

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) .

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.

H2-Receptor AntagonistsCimetidine, 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 action:6–10 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.

Clinical Uses of H2-Receptor AntagonistsGastroesophageal 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 GastritisIV 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.

Peptic Ulcer Disease:Replaced by PPI.Healing rate more than 80-90% after 6-8 weeks.Not effective in the presence of H. pylori infectionH 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.

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 women4 -Crosses placental barrier and appear in

breast milk

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.

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.

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.

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 3–4 days of daily medication are required before the full acid-inhibiting potential is reached.

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 placeboStress- 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.

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 NSAIDsRebleeding peptic ulcer:Oral or IV .

High pH may enhance coagulation and platelet aggregation.

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 )

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.

Mucosal Protective Agents1-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 1–2 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 .

SucralfateA 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.

Clinical Uses1 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 ).

Adverse EffectsBecause 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 InteractionsSucralfate may bind to other medications, impairing their absorption.

Prostaglandin AnalogsMisoprostol, 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.

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 InteractionsDiarrhea and cramping abdominal pain occur in 10–20%

of patients .it should not be used during pregnancy No significant drug interactions are reported.

Colloidal Bismuth Compounds:Bismuth subsalicylate.Bismuth subcitrate.Bismuth is minimally absorbed from GIT (< 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.

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 10–14 days).

Adverse EffectsCauses blackening of the stool and the tongue .

Prolonged usage may rarely lead to bismuth toxicity, resulting in encephalopathy.

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 .

Physiology of the Enteric Nervous SystemThe 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.

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).

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 .

Figure 62–4  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 .

Cholinomimetic AgentsBethanechol

Stimulates muscarinic M3 receptors on muscle cells and at myenteric plexus synapses. Was used for the treatment of GERD and gastroparesis .

NeostigmineAchE 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.

Dopamine D2-receptor antagonists.Metoclopramide & DomperidoneD2 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.

Clinical UsesGastroesophageal Reflux DiseaseNot 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 DyspepsiaPrevention of VomitingPostpartum Lactation StimulationDomperidone is used to promote postpartum lactation

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 effectsBoth drugs can elevate serum prolactin levels causing galactorrhea, gynecomastia, impotence and menstrual disorders.

LaxativesIntermittent 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.

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 oilClear, 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.

Osmotic LaxativesSoluble but nonabsorbable compounds that result in increased stool liquidity due to an increase in fecal fluid.

Nonabsorbable Sugars or SaltsUsed 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.

Sorbitol, LactuloseSugars 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 endoscopyFor colonic cleansing, it should be ingested rapidly( 4 L over 2-4hs).For chronic constipation, PEG powder is mixed with water or juice.

Stimulant LaxativesDirect 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 6–12 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.

BisacodylTablet 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 6–10 hours when given orally and 30–60 minutes when

taken rectally .Safe for acute and long-term use .

PhenolphthaleinRemoved from the market owing to concerns about possible cardiac toxicity

Opioid Receptor AntagonistsDo not cross the blood-brain barrier.

Block peripheral (µ) mu -opioid receptors without causing central analgesic effects .

MethylnaltrexoneUsed 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.

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.

Opioid AgonistsInhibit 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 movementsCNS effects and potential for addiction limit the usefulness of most.LoperamideDoes not cross BBB. No analgesic or addiction potential.DiphenoxylateNot 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 .

Bile Salt-Binding ResinsCholestyramine ColestipolColesevelamMalabsorption 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.

Octreotide:Is a synthetic octapeptide with actions similar to somatostatin.SomatostatinA14 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.

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).

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.

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.

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.

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.

AlosetronHighly 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.

Serotonin 5-HT4-Receptor AgonistsStimulation 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 .

PrucaloprideHigh-affinity 5-HT4 agonist. No cardiovascular toxicityUsed for the treatment of chronic constipation in women.

Chloride Channel ActivatorLubiprostonePG 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.

Antiemetic AgentsNausea 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.

PathophysiologyThe 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 .

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.

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.

Serotonin 5-HT3 AntagonistsOndansetron oral 0r IVGranisetron half-life 4–9 hDolasetronPalonosetron 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.

UsesPrevention 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.

Neurokinin 1 Receptor (NK1) AntagonistsHave antiemetic properties through central blockade in the area postrema .

AprepitantUsed 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 .

Antipsychotic drugsProchlorperazinePromethazine

DroperidolAntiemetics 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 .

BenzodiazepinesLorazepamDiazepamReduce anticipatory vomiting caused by anxiety.

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 .

CannabinoidsDronabinol, 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 .

Drugs Used to Treat Inflammatory Bowel DiseaseInflammatory 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.

Aminosalicylates5-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 .

Azo CompoundsSulfasalazine, Balsalazide, Olsalazine

5-ASA bound by an azo (N=N) bond to an inert compound or to another 5-ASA moleculeThe 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.

Mesalamine CompoundsPentasa:

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).

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.

Clinical Uses5-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.

GlucocorticoidsInhibit 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.

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.

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.

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.

UsesInduction and maintenance of remissions of

Crohn’s 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.

Anti-Tumor Necrosis Factor TherapyIf 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 cell[TH2] 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.

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-α is one of the principal cytokines mediating the TH1 (helper T cell type 1) immune response characteristic of Crohn's disease.

CD4+ lymphocytes

Infliximabis 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 weeksUsed 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.

Side Effects:Acute:

fever, chills, urticaria, or even anaphylaxisSubacute:

serum sickness–like) 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.

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 SCCertolizumab 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.

Natalizumab Humanized IgG4 monoclonal antibody against the

cell adhesion molecule α 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 therapiesGiven 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.

Pancreatic Enzyme SupplementsContain 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 .