Drugs Used in Gastrointestinal Diseases

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DRUGS USED IN GASTROINTESTINAL DISEASES [1] PEPTIC ULCER

Definition:
The term peptic ulcer refers to ulcer in the lower esophagus, stomach or duodenum, it may be acute or chronic. Although the pathogenesis of peptic ulcer disease is not fully understood, three major factors are recognized: 1. Infection with Helicobacter pylori (H. pylori). 2. Increased hydrochloric acid secretion. 3. Inadequate mucosal defense against aggressive factors. (gastric acid and pepsin). So treatment approaches will include eradication of H. pylori, reducing gastric acid secretion or neutralizing gastric acid already secreted and/or providing agents that protect the gastric mucosa from damage. • The concept of a balance between the aggressive capacities of acid and pepsin and the defense mechanisms of the mucosa is useful. An ulcer is thought to develop when this equilibrium is disturbed either by enhanced aggressiveness or by deceased mucosal resistance. • The presence of H. pylori in the stomach, use of non-steroidal antiinflammatory drugs (NSAIDs), cigarette smoking and heredity (male sex,

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blood group O) influence the equilibrium unfavorably and associated with increased incidence of peptic ulcer. • NSAIDs act by depleting mucosal prostaglandin levels, which impairs the cytoprotection resulting in mucosal injury and ulcer. The cytoprotective effect of prostaglandin includes: i) ii) Stimulation of mucous and bicarbonate. Enhancement of blood supply to the mucosa and rapid regeneration of the damaged cells.
iii)

Prevent back – diffusion of H+ ions also supports the mucosal barrier.

Clinical features:
Peptic ulcer is a chronic disease with history of spontaneous relapses and remission for many years. Patients complain mainly of pain in the epigastric region, usually related to food. Other symptoms e.g. heart burn, flatulence, dyspepsia, bloating sensation, vomiting and bleeding are common.

Aim of therapy:
1. To relieve symptoms. 2. To accelerate healing. 3. To prevent recurrence.

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DRUGS USED TO TREAT PEPTIC ULCER DISEASE
I. Reduce Gastric Acid Concentration either by:
1- Neutralization of secreted acid by antacids. 2- Decreasing acid secretions: • H2-receptor antagonists. • Inhibitors of H+/K+ ATPase proton pump. • Antimuscarinic agents. • Prostaglandins.

ANTACIDS General Characteristics
a. Antacids are weak bases that are taken orally and partially neutralize gastric acid and reduce pepsin activity. They may have other actions as well, such as reduction of H. pylori colonization and stimulation of prostaglandin synthesis. b. Antacids reduce the pain associated with ulcers and may promote healing. High doses are required for healing: 40 mEq of the base seven times daily.

Prototype Agents: (refer to the practical book). Drug interactions
Antacids alter the bioavailability of many drugs by the following mechanisms: a. The increase in gastric pH produced by antacids decreases the absorption of acidic drugs and increases the absorption of basic drugs. b. The metal ion in some preparations can chelate other drugs (e.g., digoxin and tetracycline) and prevent their absorption. c. The renal effects of antacids increase the excretion of acidic drugs and decrease the excretion of basic drugs.

Choice and Use of Antacids:
No single antacid is satisfactory for all circumstances and mixtures are often used. They may contain sodium bicarbonate for rapid effect, supplemented by magnesium hydroxide or carbonate. Aluminium hydroxide or magnesium trisilicate is added for slow action. Disturbed bowel habit can be corrected by

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altering the proportions of magnesium salts that tend to cause laxation, and aluminium salts that tend to constipate. Tablets are more convenient for the patient at work, but they act more slowly unless they are sucked or chewed. A liquid may be acceptable for frequent use. An antacid taken when the stomach is empty may be effective for only 20-40 minutes because of gastric emptying, but if it is taken an hour after meal when the buffering action of food ceased, the effect may last 2-3 hours.

Regulation of Gastric Acid Secretion:

Figure 12-1: Effects of acetylcholine, histamine, prostaglandin I2, and E2, and gastrin on gastric acid secretion by the parietal cells of stomach; GS and Gj are membrane proteins that mediate the stimulators or inhibitory effect of receptor coupling to adenyl cyclase.

Gastric acid secretion by the parietal cells of the gastric mucosa is controlled by Acetylcholine, histamine, prostaglandin E2, I2 and gastrin. The receptormediated binding of acetylcholine, histamine or gastrin results in activation of H+-K+ ATPase proton pump that secretes hydrochloric acid (HCl) into the lumen of the stomach. In contrast, receptor binding of prostaglandins E2 and

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I2 diminishes gastric acid secretion. (Note: histamine binding causes activation of adenylcyclase whereas prostaglandin E2 and I2 binding causes inhibition of adenylcyclase. Gastrin and acetylcholine acting by inducing an increase of the intracellular calcium level). (Fig. 12-1)

H2–RECEPTOR ANTAGONISTS Mechanism of actions:
They act by competitively blocking the binding of histamine to H2 receptors, these agents reduce intracellular concentrations of cyclic-AMP and thereby gastric acid secretion. The four drugs used are cimetidine, ranitidine, famotidine and nizatidine. They completely inhibit gastric acid secretion induced by histamine or gastrin. However, they only partially inhibit gastric acid secretion induced by acetylcholine or bethanechol.

Therapeutic Uses:
a- Peptic ulcers and gastro-duodenal reflux esophagitis: All four agents are equally effective in promoting healing of duodenal and gastric ulcers. However, recurrence is common when they are used as a sole agent. This can be effectively prevented by eradication of H-pylori i.e. in combination with antimicrobial drugs. b- Treatment of hypersecretory states. c- H2- receptor antagonists act as prophylaxis for recurrent ulcers in patients at risk. d- Zollinger-Ellison syndrome: It is a rare condition in which a gastrinproducing tumor causes hypersecretion of HCI, with H2-antagonists; the hypersecretion of gastric acid can be kept at safe levels. e- Acute stress ulcers: As in stress ulcers associated with major physical trauma in high-risk patients in intensive care units, and in burned patient.
f- Before anaesthesia for emergency surgery and before labour to lessen

the risk of aspirating gastric acid.

Pharmacokinetics:
Cimetidine and other H2-antagonists are given orally, distributed widely throughout the body (including breast milk and across the placenta) and

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excreted mainly in urine. Cimetidine (t ½ = 2 h), is increased in renal failure. 30% of the dose is slowly inactivated by the Liver's microsomal mixed function oxygenase system; the other 70% is excreted unchanged in urine. Ranitidine (t½ 2h), it is 5-1 0 times more potent than cimetidine. 50% of the dose is inactivated in the liver, the remainder is excreted unchanged in urine. Famotidine (t½ 3h), it is 20-160 times more potent than cimetidine and 3-20 times more potent than ranitidine. 25% of the dose is metabolized in the liver and 75% is excreted unchanged in the urine. Nizatidine (t½ 3h), is similar to ranitidine in potency and is eliminated principally by the kidney i.e. 10% of the dose is only metabolized in liver, so its bioavailability is nearly 100%.

Adverse Effects:
The adverse effects of cimetidine are usually minor and occur in small number of patients. Minor side effects include: headache, dizziness, diarrhea, and muscular pain. Major side effects include: 1. C.N.S. effects (confusions, hallucination) occur primarily in elderly patients or after prolonged administration. 2. Anti-androgenic effects (gynecomastia, galactorrhea, and reduced sperm count (reversible). 3. Microsomal enzyme inhibition: cimetidine inhibits cytochrome P-450 and so can slow the metabolism and thus potentiate the action of several drugs e.g. Warfarin, diazepam, phenytoin, quinidine, theophylline, imipramine...etc. Ranitidine, famotidine, and nizatidine are well tolerated and may have only the minor side effects observed with cimetidine. They have no C.N.S, no anti-androgenic effects and they do not affect hepatic microsomal enzymes.

Doses:
Cimetidine Ranitidine Famotidine Nizatidine : 800 mg as a single dose at bed time. : 300 mg as a single dose at bed time. : 40 mg as a single dose at bed time. : 300 mg as a single dose at bed time.

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At least for 4-6 weeks in duodenal ulcers and 6-8 weeks in gastric ulcers. Those with a history of recurrent ulcer may benefit from a maintenance dose (e.g. half the dose given daily for one year).

INHIBITORS OF H+/K+ ATPase “PROTON PUMP INHIBITORS”
The membrane H+/K+ ATPase enzyme system (proton pump) of the parietal cell is the final step in the secretion of gastric acid.

Mechanism of action:
Omeprazole, lanzoprazole: are proton-pump inhibitors, they bind to H+/K+ ATpase enzyme system suppressing secretion of hydrogen ions into the gastric lumen. They inhibit more than 90% of both basal and stimulated gastric acid secretion. Acid suppression begins within 1 to 2 hr after the first dose given.

Therapeutic Uses:
• Active duodenal ulcer and erosive esophagitis. • Zollinger-Ellison syndrome. • Omeprazole is successfully used with antimicrobial regimens to eradicate H. pylori.

Pharmacokinetics:
Omeprazole and lansoprazole are enteric-coated to protect them from premature activation by gastric acid. After absorption in the duodenum, they are transported to the acid parietal cell canaliculus, where they are converted to active species. Metabolites of these agents are excreted in urine and feces.

Adverse Effects:
1. Headache, diarrhea and rash. 2. The prolonged hypochlorohydria and secondary hypergastrinemia may increase the incidence of gastric carcinoid tumors (in animal studies). 3. Increased concentration of viable bacteria in the stomach. 4. Interference with the oxidation of warfarin, phenytoin, diazepam and cyclosporine (only omeprazole).

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Anti-Muscarinic Drugs
Muscarinic receptor stimulation increases gastrointestinal motility and secretory activity. Pirenzepine is a relatively specific M1-receptor antagonist. It reduces basal and stimulated acid secretion at doses that have minimal effects on the heart, eye, and bladder... (Which involve mainly M2-or M3-receptors). It is given orally. Antimuscarinic drugs are now rarely used and only as adjuncts to H2 -receptor antagonists, especially in patient refractory for treatment with the latter or those with nocturnal pain. (refer to ANS)

Adverse Effects:
Dry mouth and/or blurring of vision in 20% of patients.

II. Mucosal Protective Agents
These compounds, known as cytoprotective, have several actions that enhance mucosal protection mechanisms, thereby preventing mucosal injury, reducing inflammation and enhancing healing of existing ulcer.

1. Bismuth chelate (colloidal bismuth subcitrate)
Mechanism of actions:
1. Antimicrobial action: it is effective against H. Pylori. If it is used alone, it eradicates the organism in 30% of patients. So it used with metronidazole and amoxycillin to reduce the relapse rate from 90% to 15%. 2. They coat the ulcer base, adsorb pepsin, enhance local prostaglandin synthesis and stimulate bicarbonate secretion.

Adverse Effects:
1. Nausea, vomiting and blackening of tongue and feces. 2. If the renal function is impaired, the small amount of bisthmus, which is absorbed, can result in encephalopathy.

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2. Sucralfate
1. It is a complex of aluminium hydroxide and sulphated sucrose. In the presence of acid, sucralfate releases aluminium, and acquires a strong negative charge that binds to the positively charged groups in proteins, glycoproteins at the base of the ulcer. 2. It adheres to both damaged and normal mucous. It can form complex gels with mucous, an action which is thought to decrease the degradation of mucous by pepsin and to limit the diffusion of hydrogen ions. 3. It also stimulates mucosal protecting mechanisms, mucous and bicarbonate secretion, and prostaglandin production.

Adverse Effects and Drug Interactions:
1. Constipation may occur in 0-15% of patients; dry mouth, nausea, vomiting. 2. It reduces the absorption of many drugs e.g. digoxin, tetracycline, theophylline, fluoroquinolone antibiotics and amitriplyline. 3. As it needs acidic media to act an antacid or H2-receptor antagonists should not be given with or prior to its administration.

3. Prostaglandins
1. Prostaglandins E2 and I2 produced by the gastric mucosa, inhibit secretion of HCI and stimulate secretion of mucous and bicarbonate (cytoprotective effect). 2. A deficiency of prostaglandins, is thought to be involved in the pathogenesis of peptic ulcers. Non-steroidal anti-inflammatory drugs (aspirin), which inhibit prostaglandin synthesis will decrease the protective effect of the mucousbicarbonate barrier. This account for the tendency of these agents to cause gastric ulceration and bleeding.

Misoprostol: (refer to autacoids)

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III. Eradication of H. Pylori and the Role of Antimicrobial Agents:
The most effective treatment consists of two antibiotics and an acid secretion inhibitor and it may include colloidal bismuth (Bismuth subcitrate). These treatments result in the cure of ulceration and eradication of H. pylori in 80 – 98% of cases.

Selected drugs:
Antibiotics: Clarithromycin (C) Amoxycillin (A) Metronidazole (M) (Anti protozoal) Antisecretory drug: Bismuth chelate Omeprazole (O) Or Lanzoprazole Bismuth subcitrate (B) 40 mg. once daily. 30 mg/12 hours. 125 mg/6 hours. 500 mg/12 hours. 500 mg/12 hours. 400 mg/12 hours.

Duration of treatment: 7 – 10 days. Compliance, side effects and metronidazole-resistance influence the success of therapy.

ANTIBIOTIC REGIMEN FOR H. PYLORI ERADICATION First Line Regimen:
OCM Duration Efficacy Cost Comment 7 days 90% +++ Effective but costly OA C 7 days 85-90% +++ Avoid side effects of metronidazole.

If the patient still infected with H. pylori the Second Line Regimen is then given:

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OAM Duration Efficacy Cost Comment 7 – 10 days 85% ++

BAM 14 days 80% + Cheap but longer duration.

If the patient still infected with H. pylori a third attempt with four drugs, e.g. Bismuth colloid + two antibiotics + omeprazole for 7-10 days. This is followed by maintenance therapy for acid suppression for 1-1.5 years. In case of resistanse to Clarithromycin and/or Metronidazole, tetracycline is the alternative.

Side effects of H. Pylori eradication therapy:
1. Treatment failure. 2. Antimicrobial agents for H pylori can increase other organism resistance as strept. Pneumonia. 3. Diarrhea: 30-50% of patients but usually mild. 4. Metronidazole causes Metallic taste (common). 5. Flushing and vomiting when taken with alcohol. 6. Nausea and vomiting. 7. Abdominal cramp. 8. Headache. 9. Rash. 10.

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ANTI-EMETICS AND TREATMNET OF SOME BOWEL DISORDERS
Learning objectives. By the end of this topic, the student will be able to: 1. Classify anti emetic drugs. 2. Discuss the mechanism of actions of anti emetics drugs. 3. Define prokinetic drugs. 4. Discuss the mechanism of action of the prokinetic drugs. 5. Discuss lines of treatment of diarrhea. 6. Define laxatives and classify them according to their mechanism of action. 7. State the therapeutic uses of laxatives.

Although nausea and vomiting may occur in a variety of conditions (for example motion sickness, pregnancy, hepatitis) and are always unpleasant for the patient, it is nausea and vomiting produced by many cytotoxic agents that demand effective management. Nearly 70%-80% of all patients given cytotoxic drugs experience nausea or vomiting.

Vomiting Reflex
The vomiting reflex is a coordinated reflex, controlled by a bilateral vomiting center in the medulla. The vomiting center receives inputs from several sources: a. Chemoreceptor trigger zone (CTZ). b. Vestibular nucleus. c. Peripheral afferents from the pharynx, gastrointestinal tract, and genitals. d. Psychic input from the central nervous system (CNS). Serotonin (5-HT3)-receptors, which are the predominant mediators of the reflex, are present in the CTZ, and in the periphery. The vomiting center contains many muscarine cholinergic receptors and the CTZ is rich in dopamine D2-receptors as well as 5HT3 receptors

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Dopamine type 2-receptors are present in the C.T.Z and play an important role in the vomiting reflex caused by chemotherapeutic agents. Muscarinic cholincrgic receptors are presents in the vomiting center and play an important role in the vomiting reflex caused by motion sickness and vertigo.

Emetic Actions of Chemotherapeutic Agents:
(1) Central action: Chemotherapeutic agents can directly activate the medullary C.T.Z. and or vomiting centre. Several neuroreceptors including dopamine type 2 and serotonin type 3 (5HT3), play critical roles. (2) Peripheral action: Chemotherapeutic agents can also act peripherally by causing cell damage in the gastrointestinal tract and releasing serotonin from the endocromaffin cells of the small intestinal mucosa. The released serotonin activates 5 HT receptors, which then stimulate afferent fibers carry sensory signals to the medulla, leading, to the emetic response.

ANTIEMETICS
1. Cholinergic antagonists
a. Cholinergic antagonists reduce the excitability of labyrinthine receptors and depress conduction from the vestibular apparatus to the vomiting center. b. Cholinergic antagonists are used to treat motion sickness, nauea of pregnancyand preoperative situations. They are not useful in treating nausea caused by chemotherapy. c. Cholinergic antagonists produce adverse effects that include drowsiness, dry mouth, and blurred vision. Transdermal delivery of scopolamine via a skin patch applied behind the ear [Transderm Scop] decreases the Incidence of adverse effects and produces relief for 72 hours.

2. Histamine-1 (H1) -receptor antagonists
a. H1-receptor antagonists include diphenhydramine, meclizine, cyclizine, dimenhydrinate, and promethazine.

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b. These agents most likely act by inhibiting cholinergic pathways of the vestibular apparatus. It appears probable that the significant antimuscarinic and sedative effects and the H1 blocking effect contribute to the anti emetic efficacy. c. H1-receptor antagonists are used to treat motion sickness, true vertigo, and the nausea of pregnancy. d. These agents produce sedation and dry mouth.

3. Dopamine antagonists
a. Metoclopramide [Primperan] 1. Metoclopramide blocks D2, 5HT3 receptors within the CTZ. 2. Metoclopramide increases the sensitivity of the gastrointestinal tract to the action of acetylcholine (ACh); this enhances gastrointestinal motility and gastric emptying and increases lower esophageal sphincter tone. (Prokinetic action) 3. High doses of metoclopramide antagonize serotonin (5-HT3)-receptors in the vomiting center and gastrointestinal tract. 4. Metoclopramide is used to treat nausea due to chemotherapy (caused by agents such as cisplatin and doxorubicin) and narcotic-induced vomiting.

Side Effects:
1- Extrapyramidel dystonia, commonly in children and young adult. it is treated by benzatropine I.V. 2. Diarrhea. 3- Prolactine release, gynaecomastia and lactation. 4- Restlessness, sedation, headache. b. Phenothiazines and butyrophenones 1. These agents include and chlorpromazine and prochlorperazine and domperidone

(phenothiazines)

haloperidol,

droperidol

(butyrophenones), Domperidone penetrate blood brain barrier poorly so it has no extra pyramidal side effects.

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2. Phenothiazines and butyrophenones block dopaminergic receptors in the CTZ and appear to inhibit peripheral transmission to the vomiting center. 3. These agents are used to treat nausea due to chemotherapy and radiation therapy and to control postoperative nausea. 4. Adverse effects (less pronounced with butyrophenones) include anticholinergic effects (drowsiness, dry mouth, and blurred vision)' extrapyramidal effects, and orthostatic hypotension. These agents are contraindicated in Parkinson’s disease because of their extrapyramidal effects.

4.

5-HT3 antagonists
e.g. Ondansetron [Zofran] and Granisetron [ Kytril ] The 5HT3 receptor antagonists block the 5HT3 receptors in the CTZ and in the gut. They are particularly effective against the acute vomiting induced by highly emetogenic chemotherapeutic agents used for treating malignancy (e.g. cisplatin) and postoperative vomiting that is resistant to other agents. Ondansetron is more effective than metoclopramide against nausea induced by high- dose cisplatin. Granisetron has a greater affinity for 5-HT3-receptors than ondansetron. Granisetron is longer acting and more potent than Ondansetron or metoclopramide. Granisetron and Ondansetron are administered either orally or by intravenous infusion. The common adverse effect of this group are headache, flushing and gastrointestinal upset.

5. Cannabinoids
1. Cannabinoids include dronabinol (∆-9-tetrahydrocannabinol) and a synthetic derivative, nabilone. 2. Cannabinoids may act by inhibiting the vomiting center, but the mechanism is unclear, and the effectiveness of these agents remains controversial. 3. Cannabinoids are used to control nausea induced by chemotherapy.

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4. Cannabinoids produce sedation, psychoactive effects, dry mouth, and orthostatic hypotension.

6. Glucocorticoids
1. Glucocorticoids include dexamethasone and betamethasone. 2. These agents can be effective as a treatment for vomiting caused by highly emetic agents. High doses are given as an intravenous (IV) bolus or orally for delayed nausea, often combined with metoclopramide, haloperidol, diphenhydramine, or ondansetron. 3. Glucocorticoids cause adrenal suppression and metabolic disturbances.

7. Benzodiazepines
1. Benzodiazepines include lorazepam and diazepam. 2. Benzodiazepines act as anxiolytic agents to reduce anticipatory emesis. Diazepam is useful as a treatment for vertigo, and it controls symptoms in Meniere's disease in 60%-70% of patients. 3. These agents also cause amnesia, which lasts 4-6 hours.

Combination Regimens
Antiemetic drugs are often combined to increase the antiemetic activity or decrease toxicity. Corticosteroids most commonly dexamethasone, increase antiemetic activity when given with high dose of metoclopramide, a 5HT3 antagonist, phenothiazines, butyrophenon, a cannabionid or benzodiazepines. Anthistamines like diphenhydramine + high dose of metochlopramide reduce the extrapyamidal reaction e.g coticosteroids + metoclopramide reduce metoclopramide induced diarrhea.

Vomiting of Pregnancy:
• Pyridoxin B6 (non-specific treatment). • Pyridoxin + hyoscine or antihistamines. • Pyridoxin + hyoscine + phenothiazines.

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PROKINETIC DRUGS
A group of drugs which act by enhancing the action of acetylcholine at muscarinic nerve endings in the gut. It raises the tone of the lower esophageal sphincter, relaxes the pyloric antrum and duodenal cap and increases peristalsis and emptying of the upper gut.

Therapeutic Uses:
1. To empty the stomach before emergency anaesthesia and in labour. 2. Gastro-esophageal reflux and in disorders of gastric emptying e.g. in diabetes mellitus. 3. Reflux esophagitis

Metoclopramide (Primperan):
It is a D2-antagonist having double actions: 1. Antiemetic action. 2. Prokinetic action

Therapeutic uses:
1. As antiemetic in emesis due to chemotherapy, postanaesthetic, post-radiation. 2. As prokinetic, in emergency operation, intubation and

gastroesophageal reflux.

Domperidone (Motilium):
Action, therapeutic uses, and side effects are the same as metoclopramide except it does not cross the blood brain barrier. So it has an antiemetic effect with fewer side effects on extrapyramidal system.

Motilin and its analogues:
Motilin is a peptide, which stimulates gastric emptying and postprandial gastric contraction. Erythromycin antibiotic is a motilin agonist, which has a prokinetic action.

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DIARRHEA
• Diarrhea involves both an increase in motility of gastro–intestinal tract (GIT) and decreased fluid absorption and thus a loss of electrolytes (particularly Na) and water. Diarrhea may be acute or chronic. • Acute diarrhea is common and usually due to Fecal–Oral transmission of bacterial toxins, viruses, bacteria or protozoal organism. Infective diarrhea is usually short-lived. (5 days) and viral (Rota virus) diarrhea is usually self-limited. • A variety of drugs including: Antibiotics, cytotoxic drugs, and NSAIDs may be responsible for acute diarrhea. NB. Patients who present with a history of diarrhea more than ten days rarely have an infection cause .

Lines of treatment of diarrhea:
1. Non- Specific antidiarrheals: The aim is to decrease fecal water content by increasing solute absorption and decreasing intestinal secretion and motility. Increased transit time, facilitate water reabsorption. This includes: a. Maintenance of fluid and electrolyte balance by oral rehydration solutions (ORS). b. Antimotlity drugs c. Adsorbant. d. Drugs that modify fluid and electrolyte transport. 2. Anti diarrheals for specific causes e.g. Octreotide, sulfasalazines and olsalazine and antimicrobials.

(1) Non – specific antidiarrheals:
a. Maintenance of fluid and electrolyte balance: Oral rehydration solutions: are balanced solutions that may be life saving in 99% of acute cases of diarrhea in childhood.

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Rehydrane solution: Composition: 4g. glucose, 0.7g. Sodium chloride 0.3g. potassium chloride 0.5g. sodium bicarbonate or subcitrate. Each packet 5.5 g. dissolved in 200 ml water, given orally in mild cases of diarrhea as 50 mg/ Kg body wt. In sever cases 100 mg/kg orally or as intravenous drip Infusion + food intake and breast-feeding. Advantages: simple, cheap and effective b. Antimotility drugs: • Anticholinergic drugs as atropine, scopolamine inhibits colonic

peristalsis and they have little effect on diarrhea. • Two drugs are widely used to control diarrhea (in adults): Diphenoxylate (Lomotil): diphenoxylate 2.5 mg + 0.25 mg atropine tablet (atropine is added to diphenoxylate to reduce the potential for abuse and to furthur reduce motility). • Loperamide (Imodium) 2 mg / capsule. They are synthetic analogues of pethidine and have opioid–like actions on the gut activating presynaptic opioid receptors in the enteric nervous system to inhibit acetylcholine and prostaglandin release thereby reducing the peristalsis and secretion of G.I.T.

Side effects: drowsiness, dizziness, and constipation.
They can cause toxic megacolon (paralytic ilieus) in children, so they should not be used in young children or in adults with sever colitis. c. Adsorbant e.g. kaolin, pectin, smecta (dioctahedral smectate) and dietary fiber. They adsorb toxin and coat the intestine.

Side effects: They can interfere with the absorption of other drugs.
d. Agents that modify fluid and electrolyte transport: e.g. Bismuth subsalicylate (pepto–Bismol) These agents inhibit prostaglandin production in the intestine and reduce fluid secretion. Its action may be due to its salicylate component. It is effective in treatment and prophylaxis of traveler’s diarrhea. Its main side effect is tinnitus.

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(2) Anti diarrheal for specific causes
1) Octreotide is a synthetic 8-amino-acid analogue of somatostatin used in sever diarrhea caused by excessive release of G.I.T. hormones that mediate certain alimentary secretion e.g. vasoactive intestinal peptide tumor and metastatic carcinoid tumors. 2) Sulfasalazines and olsalazine in ulcereative colitis. 3) Antimicrobial agent: used only in specific cases eg. in cholera, tetracyclines are the drug of choice, trimethoxazole is used. 4) In amoebiasis and giardiasis metronidozole is the drug of choice. in shigella dysentery, co

LAXATIVES
Laxatives are commonly used to accelerate the movement of gut content through the gastrointestinal tract. These drugs can be classified on the basis of their mechanism of action as irritants (stimulants) of the gut, bulking agents and stool softeners.

A- Irritants and Stimulants:
Many agents increase peristalsis by stimulation of the mucosa of the gut, the impulses arising in the mucosa transmitted to the intramural plexuses to the smooth muscle of the intestine. These Include: • Phenolphthaline and bisacodyl: stimulates sensory ending in the colon by direct action from the colon. • Anthraquinone group includes: cascara, senna: These agents are absorbed then the active substance emodin is excreted in the colon. • Castor oil: is broken down in the small intestine to ricinoleic acid, which is a mild, irritant to the gut. The onset of activity of this group is delayed 6-10 hours. Chronic use of irritant agents may result in cathartic colon, a condition of colonic distention and development of laxative dependence.

Adverse effects:
• Abdominal cramps and potential for atonic colon with prolonged use.

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• Emodin may pass in the breast milk. • Emodin can cause urine colouration. (Brown-red).

B- Bulking agents:
The bulk laxatives include hydrophylic colloids and osmotic laxatives: a) The hydrophylic colloids (indigestible parts of fruits and vegetables, methyl cellulose, agar and bran). These agents are polysaccaride polymer not broken down by the digestive enzymes and have a vast capacity to retain water, causing intestinal distension thereby increasing peristaltic activity. They take 1-3 days to work, adequate hydration is required. These agents are the treatment of choice for chronic constipation e.g. methylcellulose. b) Osmotic laxatives include saline cathatrics e.g. magnesium sulphate, magnesium hydroxide and lactulose. Saline cathartics are

non-absorbable salts that hold water in the intestine by osmosis, distending the bowel and increasing intestinal activity. They act in about one hour. These agents are used for rapid evacuation of the bowel before surgery or after anthelmintic administration.

Lactulose: is a semisynthetic disaccharide (fructose + galactose). In the
colon, bacteria convert it to its two component sugars, which are not absorbed and thus act as an osmotic laxatives. Lactulose is also used in hepatic encephalopathy, as lactulose is fermented to lactic and acetic acids, which inhibit the growth of colonic ammonia producing organism. It takes 2-3 days to act.

Adverse Effects:
• Bulk purgatives (Hydrophylic fibers) if taken repeatedly with little fluids can cause intestinal obstruction. • Magnesium absorbed in patients with renal failure may cause cardiac depression, neuromuscular disorders, and CNS depression. • Lactulose in high doses can cause flatulence, abdominal cramps, diarrhea and electrolyte disturbance.

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C- Stool softeners:
Surface-active agents that become emulsified with the gut content producing soften feces and ease passage. e.g. docusate sodium, mineral oil (paraffin oil) and glycerin suppositories. Suppositories: Bisacodyl and glycerin suppositories may be used to obtain a bowel action in about one hour. Enemas: Produce defecation by softening feces and distending the bowel (evacuant enema) e.g Na acid phosphate enemas. Uses: In preparation for surgery, radiological examination and endoscopy. Sometimes enema may be used to provide topical therapy for ulcerative colities, or to provide nutrition (glucose) or to decrease intracranial pressure (Mg sulphate) and this is called retained enema.

Therapeutic uses of purgatives or laxatives.
The need for laxatives to treat constipation may arise in the following conditions: 1. Habitual constipation. 2. Painful anal lesion (piles, fissure). 3. Pregnancy. 4. Elderly and acute illness. 5. Drugs: • Opiod analgesics. • Antimuscarinic, antiparkinsonian. • Aluminium containing antacids. • Iron, Calcium channel blockers and benzodiazepines.

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