Lec6

Drugs acting on gastrointestinal tract

Drugs acting on gastrointestinal tract
Drugs used for peptic ulcer disease
Drugs used for to control chemotherapy induced emesis
Antidiarrheals
Laxatives
Drugs acting on inflammatory bowel diseases.
Drugs used to treat peptic ulcer diseasePeptic ulcer
P sychosomatic disorder in about 10% of adults, due to imbalance between gastric acid secretion and mucosal resistance (production of mucus and bicarbonate).
The major causative factors for peptic ulcer
Non-steroidal anti-inflammatory drugs (NSAIDs)
Infection with gram negative Helicobacter pylori (H. Pylori ): in 70% of G.U and 90% of D.U
Increased hydrochloric acid secretion
Inadequate mucosal defense against gastric acid and pepsin
Treatment approaches include
Antimicrobial therapy : Eradication the H. pylori infection.
Drugs that decrease gastric acid secretion: use of H2 antagonists and /or proton pump inhibitors.
Drugs that neutralize gastric acid: Use of non absorbable antacids.
Drugs that enhance mucosal defense: Providing agents that protect the gastric mucosa from damage, such as misoprstol and sucralfate.
Stop smoking


1- Antimicrobial agents
To document infection with H. pylori, endoscopic biopsy of the gastric mucosa or various noninvasive methods are utilized including serologic tests and urea breath tests.
Eradication of H. pylori is closely associated with the gastric ulcers and low recurrence rates
Currently, either triple therapy consisting of a PPI with either metronidazole or amoxicillin plus clarithromycin, or quadruple therapy of bismuth subsalicylate and metronidazole plus tetracycline plus a PPI.
Course: administered for a 2-week course.

This usually results in a 90 percent or greater eradication rate.

Note:
Single antimicrobial drug is less effective
Switching of antibiotics is also not recommended (do not substitutes one antibiotic with other)
2-Drugs that decrease gastric acid secretion:
H2 -receptor antagonist
Inhibition of the H/K- ATPase proton pump
Prostaglandins
Antimuscarinic agents (anticholinergic agents)
2- Regulation of gastric acid secretion
H2 -receptor antagonist
By blocking the binding of histamine to H2 receptor, these agents reduce the intracellular concentrations of cyclic AMP and thereby secretion of gastric acid. They inhibit basal, food stimulated and nocturnal secretion of gastric acid after a single dose.
Cimetidine (prototype, its utility is limited because of adverse effects and drug interaction).
Ranitidine
Famotidine
Niatidine
Therapeutic uses
Peptic ulcer ( G. U, D.U)
Gastrophageal reflux disease (GERD)
Hhypersecretory conditions :
Zollinger ellison syndrome ( gastrin secreting tumor)
Systemic mastocytosis
Multiple endocrine neoplasia ( MEN ) .
pre-anesthesia: (emergency and labour) to decrease incidence of mendelson's syndrome (aspirating gastric acid causing aspirating pneumonitis).
Controlling symptoms of gastric carcinoma.
Hiatus hernia (H.H).
Acute stress ulcer
Iatrogenic ulcer.
Side effects
Headache, diarrhea, dizziness, and muscle pain
For cimetidine can also have antiandrogen effects gynecomasa and galactorrhea. Cemitidine also inhibit liver metabolism cause many drug interactions


Inhibitors of the H⁺/K⁻-ATPase proton pump
Omeprazole- the prototype
Lansoprazole
Pantoprazole
Rabeprazole
Esomeprazole
Erosive esophagitis and active duodenal ulcer
Long-term treatment of pathologic hypersecretory condition conditions (Zollinger-Ellison syndrome in which gastrin is increased)
In the treatment of GERD
Reduce risk of bleeding from an ulcer by NSAIDs
Adverse effects
Generally well tolerated, but concerns about long term safety have been raised due to increased secretion of gastrin (in animal studies with increase in gastric carcinoid tumors)
Drug interaction in the oxidation of many drugs such as warfarin.

Prostaglandins

Misoprostol Synthetic analog of PGE1,
Therapeutic Uses
it prevents G.U in patients taking NSAIDs, chronic D.U and G.U.Side Effects: Dysmenorhea and rash
Contraindications: Pregnancy

Antimuscarinic agents

Dicycamine, a cholinergic antagonist, can be used as an adjunct in the management of peptic ulcer and zollinger-Ellison syndrome.
Side effects:
cardiac arrhythmias
2- urinary retention limit its use.


3- Neutralization of gastric acid:
Antacid
They are weak bases that react with gastric acid to form water and salt.
Pepsin is inactive at a pH greater than 4.
Antacid reduces H. pylori and stimulate prostaglandin synthesis.
Therapeutic uses
Combination of aluminum and magnesium can be used for duodenal ulcer.
Aluminum hydroxide- causes constipation
Magnesium trisilicate- causes diarrhea
Calcium carbonate is used as calcium supplement for the treatment of osteoporosis
Side effects:
Antacid containing sodium such as sodium bicarbonate should be considered in patients with hypertension or congestive heart failure.
4-Enhancement of mucosal resistance:
Mucosal protective agents
Sucralfate
This complex of aluminum hydroxide and sulfated sucrose binds to positively charged groups in proteins of both normal and necrotic mucosa. By forming complex gels with epithelial cells. Sucralfate creates a physical barrier that impairs that diffusion of HCl and prevents degradation of mucus by pepsin and acid.
It also stimulates prostaglandin release as well as mucus and bicarbonate output.

Bismuth chelate: Colloidal bismuth

In addition to their antimicrobial actions, they inhibit the activity of pepsin, increase secretion of mucus, and interact with glycoprotein in necrotic mucosal tissue to coat and protect the ulcer crater الحفر


3- Drugs used to control vomiting
Vomiting : is a protective mechanism to remove harmful or irritant substances from upper GIT , controlled by vomiting center in medulla
Anticholinergic : Hyosine or Scopolamine (Atropine)
H1-blockers: Cyclizine , Meclizine , Diphenhydramine, dimenhydrinate , promethazine
Dopamine ( D2) antagonists:
-Metoclopramide ( plasil) , Domperidone (CRTZ , gut).
-Haloperidol (CRTZ).
-Chlorpromazine(largactil), Promazine , prochlorperazine (Stemetil) (CRTZ,vomiting center)
5-HT3-Blockers : Ondansetron, Tropisetron & granisetron.
Others : Dexamethasone , methylprednisolone , Diazepam & lorazepam.

Phenothiazines

Prochlorperazine acts by blocking dopamine receptors. Although increasing the dose improves antiemetic activity, side effects including:
Hypotension and restlessness are dose limiting.
Extrapyramidal symptoms and sedation.
5-HT3 serotonin-receptor blockers
Ondansetron, granisetron are selectively block 5-HT3 receptor in the periphery (visceral vagal afferent fibers) and in the brain. (chemoreceptor trigger zone).
Headache is the common side effect. These drugs are costy.
Substituted benzamides
Metoclopramide (plasil) Prokinetics(drugs promoting GIT motility ):
Antiemetic , prokinetic , blocks dopamine receptors in CRTZ , enhances actions of Ach on M-receptors in GIT, elevates the tone of lower esophageal sphincter, increasing peristalsis & emptying upper GIT , it also stimulates prolactin secretion leading to galactorrhea .
Antidopaminergic
side effects, including sedation, diarrhea and extrapyramidal symptoms.
The adverse reaction are most common in younger patients
Indications:
Nausea , vomiting , pre-anesthesia , GERD , radiotherapy , endoscopy & migraine .
is highly effective at high doses against the highly emetogenic cisplatin.
Side effects :
-extrapyramidal dystonia , torticollis , Parkinsonism , gynaecomastia & lactation .
Oculogyric crisis :
Oculogyric Crisis usually occurs as a side effect of neuroleptic drug treatment. It is one of the acute dystonic reaction(torticollis & blepharospasm) , treated by procyclidine or diphenhydramine & diazepam
Drug interactions:
Atropine(anti-M) as it enhances the action of Ach on M-receptors .


Butyrophenon
Domperidone and haloperidol act by blocking dopamine receptor. They are moderately effective antiemetics.

Benzodiazepines

The antiemetic potency of lorazepam and alprazolam is low. Their beneficial effects may be due to their sedative, anxiolytic and amnesic properties

Corticosteroids

Dexamethazone and methylprednizolone, used alone, are effective against mildly to moderately emetogenic chemotherapy. They are used in combination with other agents.
Their antiemetic mechanism is not known, but it may involve blockade of prostaglandins.

Drugs used to treat diarrhea (Antidiarrheals)

Treatment of the cause
Correction of fluids and electrolytes imbalance
Treatment is by increasing viscosity (pectin ,kaolin ,chalk ) ,binding toxines ,delaying passage of contents (opiods) ,and decreasing the motility of intestine (by inhibiting Ach. Release ).
Antimotility drugsAdsorbents
Agents that modify fluid and electrolyte transportDiphenoxylate, loperamide are analogues of meperidine and have opioid like action on the intestine.
Side effects
Drowsiness,
abdominal cramp,
dizziness,
toxic megacolon.
They should not be used in young children and in patients with severe colitis.
Kaolin
Pectin
methyl cellulose
Aluminum silicate
Aluminum hydroxide
They act by adsorbing intestinal toxins or microorganisms and /or by coating or protecting the intestinal mucosa.
They are much less effective than antimotility agents.
They can interfere with the absorption of other drugs.Bismuth subsalicylate, used for traveler diarrhea, decreases fluid secretion in the bowel.
Its action may be due to its salicylate component as well as its coating action.


Laxatives
Laxatives are commonly used to accelerate of food through the gastrointestinal tract.
Laxative- ملين
Cathartic - مسهل
Small doses of these drugs are laxative
High doses (except balk are cathartics)

Irritant and stimulants

Caster oil- promptly increases peristalsis.
Cascara, senna, aloe- delayed for 6-8 hours, because they contain emodin which is excreted into the colon after these agents are absorbed.
Bisacodyl is a potent stimulant of the colon
Side effects
Abdominal cramps and the potential of atonic colon with prolonged use.

bulk laxatives

Hydrophilic colloids (indigestible parts of fruits and vegetables. They form gels in the large intestine, causing water retention and intestinal distension, thereby increasing peristaltic activity.
Similar actions are produced by agar, and bran

Saline cathartics

Magnesium sulfate and hydroxide are non absorbable salts that hold water in the intestine by osmosis and distinct the bowel increasing intestinal activity
Lactulose is a semisynthetic disacharide (fructose and galactose) also act as an osmotic laxative


Stool softeners (emollient laxatives or surfactants)
Surface-active agents that become emulsified with the stool produce softer feces and ease passage.
Docusate sodium
Mineral oil
Glycerin suppositories

Drugs used to treat Irritable Bowel Disorders: (Crohns disease , Ulcerative colitis)

1-Sulphasalazine: Its a combination of sulphapyridine and 5-aminosalicylic acid ,used to treat ulcerative colitis more than crohns disease.
MOA: cytoprotective action ,or inhibition of breakdown of PGF2 alpha ,or by suppressing immune response.
Side Effects: serum sickness ,bone marrow suppresion ,and oligospermia.
2-Prednisolone
3-Azathioprime
4-Mercaptopurine

Drugs used to treat Hemorrhoids:
1-Soothing agents:
a-Astringents: Bismuth , Zinc oxide , and Benzylbenzoate .
b-Local anesthetics: Lignocaine.
2-Corticosteroids: Betamethasone , hydrocortisone , and prednisolone.
3-Rectal sclerosants: Oily phenol injection 5%.
Drugs used to treat gall bladder disease:
1-Ursodiol
2-Chenodiol
MOA: supress hepatic synthesis of cholesterol and cholic acids.
Side Effects: change hepatic function and diarrhea.










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Dr. Nahla Othman
Pharmacology lecture
3rd class
Medical college