Clinical Use of Drugs : Pharmacotherapy GI Disorders

Upper GI Disorders

GI Anatomic region

Gastric Acid Secretion
⇨ Neuronal
– –

sight, smell, taste → cholinergic pathway strecth → ↑acetylcholine & ↑gastrin

⇨ Physical ⇨ Hormonal

Stimulate parietal cells to secrete gastric acid Proton pump (H+/K+- ATPase)

⇨ Gastrin ⇨ Acetylcholine ⇨ Histamine

Acid Secretion

Physiological & Pharmacological Gastric Acid Secretion .

Pharmacotherapy of Acid – Related Disorders Acid-suppressing drugs Proton-pump Inhibitors (PPIs) ⇨ Five PPIs available in clinical use : Omeprazole. Rabeprazole. Lansoprazole. & Pantoprazole – Similar in their pharmacological properties ⇨ All PPIs have equivalent efficacy at comparable doses ⇨ PPIs diminish daily production of acid by 80 – 95% → most potent gastric suppressors . Esomeprazole.

enteric – coated granules. enteric – coated tablets. require activation in acid environment → tetracyclic sulfenamide → unable to diffuse back to canalicular membrane ⇨ Activated form of PPIs covalently bound to H+/K+-ATPase → Acid secretion resume after newly formed H+/K+-ATPase molecules → Prolong acid suppression (24 – 48 hours) ⇨ PPIs ⇨ PPIs block final steps of acid secretion ⇨ ⇨ Effective in acid suppression regardless of other stimulating factors Dosage form : Enteric – coated drugs. powdered in combination with bicarbonate → to prevent degradation by acid in the stomach .→ prodrugs.

Pharmacokinetics : ⇨ Rapidly absorbed. highly protein – bound. extensively metabolized by hepatic CYPs ● CYP2C19 & CYP3A4 – CYP2C19 genotype ● ⇨ Chronic renal failure does not lead to accumulation of PPIs with once-a-day dosing ⇨ Hepatic impairment substantially reduce clearence of esomeprazole and lansoprazole Asian vs Caucasian or African American (23% vs 3%) .

headache. flatulence. arthralgia. & rash ⇨ Inhibition of CYP2C19. slower the clearence of phenytoin. & diarrhea ● Subacute myopathy. ampicillin esters. & theophylline) ⇨ Loss of gastric acidity → affect bioavailability of ketoconazole.Adverse Effects & Drug Interactions ⇨ Most common : nausea. & iron salts ⇨ Chronic use ≈ hip fracture. possibly decreasing Ca2+ absorption . tacrin. antipsychotic drugs. disulfiram. abdominal pain. & other drugs metabolized the same enzymes) ⇨ Increase expression of CYP1A2 (increase clearence of imipramine.

disulfiram. & other drugs metabolized the same enzymes) ⇨ Increase expression of CYP1A2 (increase clearence of imipramine. antipsychotic drugs. arthralgia. tacrin. possibly decreasing Ca2+ absorption . & theophylline) ⇨ Loss of gastric acidity → affect bioavailability of ketoconazole. & diarrhea ● Subacute myopathy.Adverse Effects & Drug Interactions ⇨ Most common : nausea. ampicillin esters. headache. abdominal pain. flatulence. slower the clearence of phenytoin. & iron salts ⇨ Chronic use ≈ hip fracture. & rash ⇨ Inhibition of CYP2C19.

Therapeutic Use ⇨ Promote healing of gastric & duodenal ul- cers ⇨ Gastroesophageal reflux disease (GERD) ⇨ Hypersecretory conditions : Zolinger-Ellison syndrome ⇨ Prevention of recurrence of NSAID – associated gastric ulcers .

H2 Receptor Antagonists → competitive inhibitors of H2 receptor on basolateral membrane of parietal cells ⇨ Available drugs : Cimetidine. Famotidine. Nizatidine ⇨ H2RAs ● Differ in pharmacokinetics & propensity to cause drug interations ⇨ H2RAs ⇨ predominantly inhibit basal acid secretion → suppressing nocturnal acid secretion . Ranitidine.

Pharmacokinetics ⇨ Rapidly absorbed. peak serum concentration achieved within 1 – 3 hours ⇨ Small percentage of H2RAs are protein-bound ⇨ Liver disease per se is not indication for dose adjustment ⇨ Excreted by kidneys through filtration & tubular secretion → reduce dose on patients with reduced creatinine clearence .

fatigue.Adverse Effects & Interactions ⇨ H2RAs generally well-tolerated ⇨ Low incidence of AEs : diarrhea. hallucination. drowsiness. reduced sperm counts & impotence in men ⇨ Blood dyscrasia including thrombocytopenia have been reported ⇨ H2RAs cross the placenta & excreted in breast milk . lethargy. and gynecomastia. psychosis) ⇨ Long-term use : – Cimetidine at high doses → inhibit testosterone binding to androgen receptors & inhibition of CYP reduce hydroxylation of estradiol – Galactorrhea in women. & constipation ⇨ Neurologic : headache. headache. muscular pain. dizziness.

Therapeutic Uses ⇨ Promote healing of gastric & duodenal ⇨ Treat uncomplicated GERD ⇨ Prevent occurrence of stress ulcers ulcers .

Agents that Enhance Mucosal Defences Prostaglandin Analog : Misoprostol ⇨ Synthetic analog of PGE1 ⇨ Gastric acid secretion inhibition – Dose related ⇨ 100 – 200 ug significantly inhibit basal secretion ( up to 95%) or food – stimulated secretion ( 85% inhibition) ⇨ Cytoprotective role of prostaglandin toward gastric acidity ⇨ ⇨ ⇨ Stimulate Gi pathway → decreasing cAMP & gastric acid secretion Stimulate mucin & bicarbonate secretion Increase blood flow ⇨ Recommended ● dose for ulcer prophylaxis : 200 ug four times a day Frequent dosing limited its use → inconvenience ⇨ .

⇨ Misoprostol can cause exacerbation of inflammatory bowel disease ⇨ Contraindicated in pregnancy → increase uterine contractility Therapeutic Use ⇨ To prevent NSAID-induced mucosal injury .

bile reflux gastropathy . sucralfate → cross-linking → viscous & sticky polymer that adhere to epithelial cells & ulcer crater up to 6 hours after single dose ⇨ Stimulating secretion of PGs & growth factors Therapeutic Use ⇨ ⇨ In critically patients.Sucralfate ⇨ Sulfated polysaccaride → Octasulfate of sucrose ⇨ Inhibit pepsin-mediated hydrolisis of mucosal proteins contributes to mucosal erosion & ulceration ⇨ In acid environment (pH<4). sucralfate may offer advantage over PPIs & H2RAs in preventing stress ulcers Condition associated with mucosal inflammation / ulceration which is not responsive to acid suppression such as oral mucositis (radiation & aphtous ulcer).

Bismuth Salts ⇨ Binding to and protecting mucosal lesion ⇨ Enhancing cellular protective mechanims ⇨ Antimicrobial effects.pylori Prokinetic agents Metoclopramide & Betanechol ⇨ Stimulate motility of upper GI & increase LES (lower esophageal sphincter) ⇨ Patients with delayed gastric emptying or refractory to other available treatment options .py- lori ⇨ Frequently use in combination with other antibiotics to eradicate H. primarily againts H.

General Guidelines of medical management of Gastroesophageal Reflux Disease (GERD) .

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Meta-analysis of H2-receptor antagonists on Functional (Non-Ulcer) Dyspepsia .

Meta-analysis of H2-receptor antagonists on Functional (Non-Ulcer) Dyspepsia .

and Antianxiety Therapies in Functional Dyspepsia Both Mosapride and Famotidine significantly improved the symptoms of Functional Dyspepsia within 2 weeks and the improvement was maintained for 8 weeks after the beginning of the study (p < 0.001) . Acid Suppression.Comparison of Prokinetic.

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Meta-analysis : Helicobacter pylori eradication improve symptoms in non-ulcer dyspepsia ? .

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PPIs vs AH2 : Effect on persistent or rebleeding of peptic ulcer .

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prolonging therapy with proton pump inhibitor after a triple therapy for 7 days with a proton pump inhibitor and two antibiotics is not necessary to induce ulcer healing . pylori infection.In patients with peptic ulcer and H.

. switched to H2-receptor antagonists. ● randomized controlled trial ● Step-up therapy : started with antacids. but effectiveness of treatment and adverse events are similar. and then ended with proton pump inhibitors (PPIs) Step-Down therapy : reversed order – Step-Up therapy somewhat more cost effective than a step-down approach.Step-Up vs Step-Down Therapy in New-Onset Dyspepsia ⇨ Double-blind.

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opiate. & benzodiazepin receptors . neurokinin. diminished lower esophageal sphincter.Nausea & Vomiting Patophysiology of Emesis ⇨ Nausea. histaminic. pylorus. raised gastric cardia. dopaminergic. & esophageal dilatation ⇨ Chemoreceptor trigger zone (CTZ) ⇨ Neurotransmitter receptor : cholinergic. antrum. ⇨ Associated with gastric stasis ⇨ Vomit ⇨ Labored movement of thoracic & abdominal muscles before vomiting ● Forceful of GI contents caused by GI retroperistalsis Act of vomiting require coordinated contraction of abdominal muscles. serotonergic. the imminent need to vomit ● ⇨ Retching.

Specific etiologies of Nausea & Vomiting .

Emetogenicity of Chemoterapeutic Agents .

Emetogenicity of Chemoterapeutic Agents .

Presentation of Nausea & Vomiting .

Treatment
Non pharmacologic ⇨ Dietary restriction if appropiate ⇨ Stable physical position ⇨ Psychological & behavioral intervention
Relaxation ● Bio-feedback ● Self-hypnosis ● Cognitive distraction ● Guided imagery ● Systematic desentization

⇨ Etc

Pharmacological intervention

Pharmacological Intervention
Factors that enable clinician to discriminate the choices of antiemetic must be recognized, : ⇨ The suspected etiology of symptoms ⇨ Frequency, duration, & severity of the episodes ⇨ The ability of patients to use oral, rectal, injectable or transdermal medication ⇨ The success of previous antiemetic medication

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Mechanism of Action and Indications ⇨ Anticholinergic agents (ACh blockers) Bind to and block acetylcholine (ACh) receptors in the inner ear labyrinth Block transmission of nauseating stimuli to CTZ Also block transmission of nauseating stimuli from the reticular formation to the VC Scopolamine Also used for motion sickness ⇨ ⇨ ⇨ ⇨ ⇨ .

allergy symptoms. sedation ⇨ ⇨ . meclizine (Antivert). promethazine (Phenergan) Also used for nonproductive cough. thus preventing N&V Diphenhydramine (Benadryl).Mechanism of Action ⇨ Antihistamine agents (H1 receptor blockers) ⇨ ⇨ Inhibit ACh by binding to H1 receptors Prevent cholinergic stimulation in vestibular and reticular areas.

Mechanism of Action (cont'd) ⇨ Neuroleptic ⇨ ⇨ agents ⇨ Block dopamine receptors on the CTZ chlorpromazine (Thorazine). intractable hiccups . prochlorperazine (Compazine) Also used for psychotic disorders.

enhancing emptying of stomach contents Metoclopramide (Reglan) Also used for GERD.Mechanism of Action (cont'd) ⇨ Prokinetic ⇨ ⇨ ⇨ ⇨ ⇨ agents Block dopamine in the CTZ Cause CTZ to be desensitized to impulses it receives from the GI tract Also stimulate peristalsis in GI tract. delayed gastric emptying .

CTZ. granisetron (Kytril). and VC Dolasetron (Anzemet). ondansetron (Zofran) Used for N&V for patients receiving chemotherapy and postoperative nausea and vomiting .Mechanism of Action (cont'd) ⇨ Serotonin ⇨ ⇨ blockers ⇨ Block serotonin receptors in the GI tract.

Mechanism of Action (cont'd) ⇨ Tetrahydrocannabinoids ⇨ ⇨ (THC) ⇨ Major psychoactive substance in marijuana Inhibitory effects on reticular formation. cerebral cortex Alter mood and body’s perception of its surroundings . thalamus.

Mechanism of Action (cont'd) ⇨ Tetrahydrocannabinoids ⇨ ⇨ (cont'd) dronabinol (Marinol) Used for N &V associated with chemotherapy. and anorexia associated with weight loss in AIDS patients .

Side Effects ⇨ Vary according to agent used ⇨ Stem from their nonselective blockade of various receptors .

Management Implications ⇨ Assess complete nausea and vomiting history. including precipitating factors ⇨ Assess current medications ⇨ Assess for contraindications and potential drug interactions .

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Laxative. colon extracts most of remaining fluid ⇒ ∽ 100 ml of fecal water daily ⇨ Secretory changes. extent of absorption determine the consistency of stool ⇨ ⇨ ⇨ Neurohormonal mechanisms. & Therapy of Constipation ⇨ Fluid content is principal determinant of stool content (70 – 85% contain water) ⇨ 8 – 9 L of fluid enter small intestine ⇒ 1 – 1. Cathartics. transit time.5 L crossing ileocaecal valve. pathogens. bowel movement. drugs might alter processes above Up to 60% of patients with constipation have normal colonic transit Predominant factors underlying constipation often not obvious ⇒ therapy remain empiric & non specific .

usually watery fecal material from the entire colon – The terms frequently used interchangebly ⇨ Mode – – – of Action of Laxative : Enhancing retention of intraluminal fluid by hydrophilic or osmotic mechanims Decreasing the net absorption of fluid by effects on small.⇨ Laxation : evacuation of formed fecal material from rectum) ⇨ Catharsis : evacuation of unformed.and large-bowel fluid & electrolyte transport Altering motility by either inhibiting segmenting (nonpropulsive) contractions or stimulating propulsive contractions .

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or with increased stool water excretion ⇨ Abnormal . and weight. fluidity.Diarrhea frequent passage of loose stool or ⇨ Abnormal passage of stools with increased frequency.

Antidiarrheal agents ⇨ Oral rehydration solution is the CORNERSTONE OF THERAPY for patient with acute illness resulting significant diarrhea ⇨ Pharmacotherapy should be reserved for patients with persistence symptoms ⇨ .

Diarrhea (cont'd) Acute diarrhea ⇨ Sudden onset in a previously healthy person ⇨ Lasts from 3 days to 2 weeks ⇨ Self-limiting ⇨ Resolves without sequelae .

nausea. and chronic weakness . vomiting. fever. weight loss.Diarrhea (cont'd) Chronic diarrhea ⇨ Lasts for more than 3 weeks ⇨ Associated with recurring passage of diarrheal stools. loss of appetite.

.Causes of Diarrhea Acute Diarrhea Bacterial Viral Drug induced Nutritional Protozoal Chronic Diarrhea Tumors Diabetes Addison’s disease Hyperthyroidism Irritable bowel syndrome Etc.

which is then eliminated through the stool ⇨ Examples: bismuth subsalicylate (Pepto-Bismol).Antidiarrheals: Mechanism of Action Adsorbents ⇨ Coat the walls of the GI tract ⇨ Bind to the causative bacteria or toxin. attapulgite (Kaopectate) . kaolin-pectin. activated charcoal.

atropine .Antidiarrheals: Mechanism of Action (cont'd) Anticholinergics ⇨ Decrease intestinal muscle tone and peristalsis of GI tract ⇨ Result: slowing the movement of fecal matter through the GI tract ⇨ Examples: belladonna alkaloids (Donnatal).

acidophilus (Lactinex) .Antidiarrheals: Mechanism of Action (cont'd) Intestinal flora modifiers ⇨ Bacterial cultures of Lactobacillus organisms work by: ⇨ ⇨ ⇨ Supplying missing bacteria to the GI tract Suppressing the growth of diarrhea-causing bacteria Example: L.

opium tincture. allowing more time for water and electrolytes to be absorbed ⇨ Examples: paregoric. diphenoxylate (Lomotil) . loperamide (Imodium). codeine.Antidiarrheals: Mechanism of Action (cont'd) Opiates ⇨ Decrease bowel motility and relieve rectal spasms ⇨ Decrease transit time through the bowel.

dark stools ⇨ Confusion. tinnitus. blue gums . twitching ⇨ Hearing loss.Antidiarrheal Agents: Side Effects Adsorbents ⇨ Increased bleeding time ⇨ Constipation. metallic taste.

anxiety. tachycardia . flushing Blurred vision. impotence Headache. hypertension. dizziness. hesitancy. confusion. photophobia. bradycardia. rash.Antidiarrheal Agents: Side Effects (cont'd) Anticholinergics ⇨ ⇨ ⇨ ⇨ ⇨ Urinary retention. increased intraocular pressure Hypotension. drowsiness Dry skin.

hypotension Urinary retention Flushing.Antidiarrheal Agents: Side Effects (cont'd) Opiates ⇨ ⇨ ⇨ ⇨ ⇨ ⇨ Drowsiness. palpitations. dizziness. rash. constipation Respiratory depression Bradycardia. lethargy Nausea. urticaria . vomiting. sedation. anorexia.

quinidine. clindamycin.Antidiarrheal Agents: Interactions ⇨ Adsorbents decrease the absorption of many agents. and hypoglycemic agents ⇨ Adsorbents cause increased bleeding time when given with anticoagulants ⇨ Antacids can decrease effects of anticholinergic antidiarrheal agents . including digoxin.

and recent history of illness or dietary changes.Antidiarrheal Agents: Implications ⇨ Obtain thorough history of bowel patterns. general state of health. and assess for allergies ⇨ DO NOT give bismuth subsalicylate to children younger than age 16 or teenagers with chickenpox because of the risk of Reye’s syndrome .

recent bowel surgery. myasthenia gravis . BPH. urinary retention. recent bladder surgery. cardiac problems.Antidiarrheal Agents: Implications ⇨ ⇨ Use adsorbents carefully in geriatric patients or those with decreased bleeding time. clotting disorders. confusion Anticholinergics should not be administered to patients with a history of glaucoma.

during. I&O. and mucous membranes before. and after initiation of treatment ⇨ Teach patients to notify their physician immediately if symptoms persist ⇨ Monitor for therapeutic effect .Antidiarrheal Agents: Implications ⇨ Teach patients to take medications exactly as prescribed and to be aware of their fluid intake and dietary changes ⇨ Assess fluid volume status.

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Selected Antidiarrheal Agents .

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