Drugs acting on the GIT Munir Gharaibeh MD

Drugs acting on the GIT Munir Gharaibeh, MD, Ph. D, MHPE mgharaib@ju. edu. jo Summer 2015

Drugs used in Acid-Peptic Disease Agents reducing Intragastric Acidity: Antacids. H 2 - Receptor Antagonists. Proton Pump Inhibitors. Mucosal Protective agents: Sucralfate. Prostaglandin analogs. Colloidal Bismuth Compounds.

Antacids Were used long time ago, and were mainstay of treatment. Nonprescription remedies. Are weak bases that react with gastric HCl to neutralize it. Also stimulate mucosal prostaglandin production, therefore may promote mucosal defense mechanisms.

Antacids Given after the meals. Neutralize acidity for up to 2 hours. Efficacy varies. May affect the absorption of other medications by binding to drugs or by changing p. H, therefore, dissolution.

Antacids Sodium Bicarbonate (Baking Soda): – Very effective, reacts rapidly with acid to produce Na. Cl and CO 2. – CO 2 leads to gastric distension and belching. – Na. Cl may exacerbate fluid retention. – Systemic absorption leads to metabolic alkalosis.

Antacids Calcium Carbonate: – Can cause hypercalcemia, renal impairment and constipation. Magnesium salts: Oxide, Hydroxide, Trisilicate: – Not absorbed, so can cause diarrhea. Aluminum Hydroxide. – Causes constipation and renal impairment. Antacid mixtures:

H 2 - Receptor Antagonists(1970 s-1990 s) Cimetidine, prototype, many problems. Ranitidine. Famotidine. Nizatidine. – Revolutionized PUD treatment. – Inhibit 60 -70% of total 24 -h acid secretion. – Duration of action: 12 hours. – Were the most commonly prescribed drugs in the world. – Replaced by PPI.

Proton Pump Inhibitors, PPI(1990 s) Omeprazole. Rabeprazole Lanzoprazole Pantoprazole Esmoprazole – Very efficacious and safe drugs. – Have a major role in PUD, They heal more than 90% of cases within 4 -6 weeks.

PPI Pharmacokinetics: Should be given one hour before meal. Have short half lives but effect lasts for 24 hours due to irreversible inhibition.

PPI Pharmacodynamics: –Inhibit both fasting and mealstimulated secretion because they block the final common pathway of acid secretion (9098% of 24 -hour secretion).

Mucosal Protective Agents Sucalfate: – Is a salt of sucrose complexed to sulfated aluminum hydroxide. – In the stomach it forms a viscous, tenacious paste that coats the ulcers or erosions for up to 6 hours. – Forms a physical barrier that restricts further caustic damage and stimulates prostaglandin and bicarbonate secretion.

Mucosal Protective Agents Misoprostol: – Prostaglandin analog, – Stimulates mucus and bicarbonate secretion and enhances mucosal blood flow. – Also, stimulates electrolyte and fluid secretion, motility and uterine contractions.

Mucosal Protective Agents Misoprostol: Reduces NSAIDs-induced peptic 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. Cyclooxygenase 2 -selective NSAIDs are an option for such patients.

Antimicrobials H. pylori- associated ulcers: Triple Therapy: – PPI twice daily. – Clarithromycin 500 mg twice daily. – Amoxicillin 1 gm twice daily , OR, Metronidazole 500 mg twice daily.

Drugs Affecting GI Motility A. Drugs Stimulating GI Motility “Prokinetic Agents” B. Laxative Agents. C. Antidiarrheal Agents.

Drugs Stimulating GI Motility ” Prokinetic Agents” Potential Uses: • Lower esophageal sphincter: GERD. • Stomach: gastroparesis and postsurgical gastric emptying delay. • Small intestine: Postoperative ileus. • Colon: constipation.

” Prokinetic Agents” Cholinomimetic Agents: Bethanecol: Stimulates M 3 receptors on muscle cells and myenteric plexus synapses. Was used in GERD and gastroparesis. Neostigmine: AChase inhibitor. ”Acute Colonic Pseudo-obstruction”: IV can result in rapid evacuation of flatus and feces.

” Prokinetic Agents” Dopamine Receptor Antagonists: Metoclopromide Domperidone. Have actions on esophagus and stomach, but not the small or large intestine. Also inhibit the chemorecptor trigger zone( Area Postrema).

” Prokinetic Agents” Dopamine Receptor Antagonists: Adverse Effects: Metclopromide crosses BBB so can cause: Restlessness, drowsiness, insomnia, anxiety, agitation, extrapyramidal symptoms (dystonia, akathisia, parkinsonian features). Domperidone does not cross the BB, so does not cause CNS effects. Both drugs can elevate serum prolactin levels causing galactorrhea, gynecomastia, impotence and menstrual disorders.

Laxatives Nonpharmacologic Remedies: High fiber diet. Adequate fluid intake. Regular exercise. Responding to nature’s call.

Laxatives or Purgatives Bulk-Forming Laxatives: High residue foods. Natural Plant Products: Bran Psyllium. Sterculia ”Normacol” Methylcellulose. Synthetic Fibers: Polycarbophil.

Laxatives or Purgatives Bulk-Forming Laxatives: Are indigestible, hydrophilic colloids that absorb water, forming a bulky, emollient gel that distends the colon and promotes peristalsis. Depend on the ability to respond to distension. Can cause bloating and flatus.

Laxatives Stool Softeners or Emolient Purges: Liquid paraffin. Glycerin suppository. Mineral oil: – Clear viscous oil that lubricates fecal material, retarding water absorption from the stool. – Used to prevent and treat fecal impaction. – Can cause leaking from the anal sphincter. – Aspiration cause lipoid pneumonia. – Can impair absorption of fat-soluble vitamins.

Laxatives Osmotic Laxatives( Purgatives): Soluble nonabsorbable compounds that result in increased stool liquidity due to an increase in fecal fluid. Magnesium oxide ( ﺍﻟﻤﻠﺢ ﺍﻻﻧﺠﻠﻴﺰﻱ , Epsom Salt): Can cause hypermagnesemia. Can cause Purgation: rapid bowel evacuation within 13 hours. This might cause volume depletion. Sorbitol. Lactulose. – Sugars metabolized by bacteria producing severe flatus and cramps. – Takes several days to work.

Laxatives Osmotic Laxatives: Balanced Polyethylene Glycol: – Safe solution: no intrvascular fluid or electrolyte shifts. Does not cause cramps or flatus. – Used for complete colonic cleansing before endoscopy. – PEG is an inert, nonabsorbable, osmotically active sugar. – Sodium sulfate, chloride, bicarbonate and potassium chloride. – For colonic cleansing, it should be ingested rapidly( 4 L over 2 -4 hs). – For chronic constipation, PEG powder is mixed with water or juice.

Laxatives Stimulant Laxatives(Cathartics): Absorbed into the circulation and act on the large intestine causing increased peristalsis. Direct stimulation of the enteric system. Can lead to dependence and destruction of the myenteric plexus resulting in colonic atony and dilation. May be needed in neurologically impaired patients and in bed- bound patients in long term care facilities.

Laxatives Stimulant Laxatives( Cathartics): Anthraquinone Derivatives: – Aloe. – Senna. – Cascara. Poorly absorbed. After hydrolysis, produce bowel movement in (6 -12) hours. Cause brown pigmentation of the colon” Melanosis Coli”.

Antidiarrheal Agents (Intestinal Sedatives) Can be used in mild to moderate acute diarrhea. Should not be used in the presence of infective diarrhea. Can be used to control chronic diarrhea, like in irritable bowel syndrome or inflammatory bowel disease.

Antidiarrheal Agents Opioid Agonists: Morphine: historical. Codiene Loperamide: Does not cross BBB. No analgesic or addiction potential. Diphenoxylate: Has CNS effects and addiction potential. Was used by astronauts. Usually combined with atropine to reduce dependence (Lomotil).

Drugs used in Irritable Bowel Syndrome Idiopathic, chronic, relapsing disorder characterized by abdominal discomfort (pain, bloating, distension, or cramps) in association with alterations in bowel habits( diarrhea, constipation, or both).

Drugs used in Irritable Bowel Syndrome Antispasmodic or Anticholinergic Agents: – Dicyclomine – Hyoscyamine. Spasm is not an important symptom in IBS. They inhibit muscarinic cholinergic receptors in the enteric plexus and on smooth muscle. At usual low doses, have minimal side effects.

Drugs used in Irritable Bowel Syndrome Serotonin 5 -HT 3 - Receptor Antagonists: Alosterone: – Selective antagonist of 5 -HT 3 receptors. – Approved for women with severe IBS in whom diarrhea is the prominent symptom. – Efficacy in men is not established. – Can cause ischemic colitis, severe constipation requiring hospitalization and surgery.

Emetic Agents Rarely needed, in intoxications. Could be induced by mechanical stimulation (gag reflex) Many drugs. Hypertonic saline. Apomorphine. Ipecac syrup.

Emetic Agents Apomorphine: – Stimulates dopamine receptors in CTZ. – Can cause CNS depression. Ipecac syrup: – Irritates the stomach. – First aid for drug overdose if: Patient is fully conscious. Overdose is not of corrosive substances or petroleum products. Early(1 hr) after ingestion.

Antiemetic Agents Afferent Inputs to the Vomiting Center: – Chemoreceptor trigger zone: DA 2, 5 -HT 3, and opioid receptors. – Vestibular system involved with motion sickness through cranial nerve VIII. Rich in M and H 1 receptors. – Pharyngeal irritation through the vagus. – GIT afferents through the vagus and spinal afferent nerves, rich in 5 -HT 3 receptors. – Central mechanisms due to psychiatric disorders, stress, and anticipatory vomiting of cancer chemotherapy (5 -HT 3).

Antiemetic Agents Serotonin 5 -HT 3 - Receptor Antagonists: – Ondansetron. – Granisetron. – Dolasetron. – Palonosetron. Used before chemotherapy, activity enhanced by dexamethasone. Can also be used in postoperative and post radiation vomiting. Safe drugs but can cause headache, dizziness and constipation.

Antiemetic Agents Antipsychotic drugs: –Promethazine. Inhibit dopamine and muscarinic receptors. Can cause sedation, extrapyramidal effects, hypotension and prolong QT interval.

Antiemetic Agents Antihistamines and anticholinergic Drugs: – Diphenhydramine – Meclizine. – Hyoscine (scoplamine). Particularly useful in motion sickness. Can cause dizziness, sedation, confusion, dry mouth, cycloplegia, and urinary retention. Hyoscine can be used as a transdermal patch.

Antiemetic Agents Benzodiazepines: – Lorazepam. – Diazepam. Reduce anticipatory vomiting caused by anxiety.

Antiemetic Agents Corticosteroids: – Dexamethasone: Useful in cancer chemotherapyinduced vomiting

Antiemetic Agents Cannabinoids: – From marijuana, useful for chemotherapy-induced vomiting. – Mechanism not understood. – Can cause euphoria, dysphoria, sedation, hallucinations, dry mouth, and increased appetite. – Also, hypotension, tachycardia, and conjunctival injection.