GIT Drugs

Question 1

Acid-peptic diseases

Answer 1

• Comprises of gastric ulcer & duodenal ulcer, gastroesophageal reflux disease and stress related mucosal injury.
• Hyper-secretory condition: like Zollinger- Ellison syndrome.

Question 2

Acid-peptic disease Etiopathogenesis

Answer 2

• Gastric acid
• Decreased mucosal resistance to acid
• H. pylori
• Drugs –high dose nonselective NSAIDS (due to COX inhibition and direct irritation). Concurrent use of other drugs –warfarin & corticosteroids
• Risk factors of >65 years, Stress
• Lifestyle
• Gastrinoma – a rare gastrin secreting tumor (ZES)

Question 3

Antacids

Answer 3

• Gastric antacids: they are weak bases that react with gastric HCl to form salt and water. The end result is increased gastric pH. Provide quick relief of symptoms.
• Commonly used antacids are:
• Magnesium hydroxide (Milk of Magnesia)
• Aluminum hydroxide and
• Calcium carbonate (Tums)

Adverse

• Magnesium hydroxide produce Mg salt, which is very poorly absorbed and cause diarrhea.
• Aluminum hydroxide reacts with HCl to form Aluminum chloride, which is insoluble and cause constipation. Hypophosphatemia
• Calcium carbonate: Hypercalcemia, nephrolithiasis and constipation –fecal compaction.
• Ca, Mg, Al molecules can chelate tetracyline

Factors that enhance gastric acid secretion are:

• three fundamental agonists that control the gastric acid secretion –histamine, acetylcholine and gastrin.
• Final pathway of these compounds is activation of the H+/K+ ATPase pump

Question 4

Regulation of gastric acid secretion

Answer 4

• Dicyclomine: cholinergic receptor blocker
• Cimetidine: H2-R blocker
• Misoprostol: stimulates Prostaglandin-R
• Omeprazole: PPI
• Octreotide: long-acting SST analogue to decr gastric acid
  
  • Clinical uses: carcinoid tumors, VIPoma, acute variceal bleeding and acromegaly.
  • Adverse effects: Abdominal cramps, nausea, steatorrhea, and gall stones.
    • reduce endocrine and exocrine pancreatic activity.

Question 5

H2 receptor blockers

Answer 5

• Preoperatively, they are used to prevents aspiration pneumonia.
• Ranitidine, Famotidine and Nizatidine (Axid) are longer acting and more potent than older cimetidine.
• Unlike cimetidine, newer drugs does not produce the anti-androgenic or prolactin- stimulating effects.
• They do not inhibit the mixed-function oxygenase system in the liver (CYP450 enzymes).

Adverse

• Most common side effects are nausea, headache, and dizziness.
• Cimetidine is notorious to present unwanted endocrinal adverse effects, for instance gynecomastia, elevated serum prolactin levels and confusion in elderly people.

Question 6

PPI – Proton Pump Inhibitors:

• Omeprazole (Prilosec),
• Lansoprazole (Prevacid),
• Pantoprazole (Protonix),
• Esomeprazole (Nexium)
• Rabeprazole (Aciphex)

Answer 6

• **MOA: **reacts with a cysteine residue of the H+/K+-ATPase, forming a stable covalent bond leading to irreversible inactivation of enzyme.

Indications:

• GERD, duodenal and gastric ulcers, multiple endocrine neoplasia (MEN-1) or Zollinger-Ellison syndrome.
• contribute in combination with antibiotics to eradicate H Pylori.
• NSAID-induced ulcers should be treated with PPIs. They support platelet aggrega7on & maintain clot integrity used in hemorrhagic ulcers.

Question 7

1st line regimen for H pylori eradication

Answer 7

• PPI + Clarithromycin + Amoxicillin: 10 to 14 d
• PPI + Clarithromycin + metronidazole: 10 to 14 d
• Bismuth subsalicylate + metronidazole + tetracycline + ranitidine or PPI: 10 to 14 d

Question 8

Mucosal Protec1ve Agents:

Answer 8

• Sucralfate: sulfated disaccharide used in PUD.
• Bismuth: by selectively binding to an ulcer it forms a coating and protects from acid and pepsin.
• Misoprostol: prevention of gastric ulcers induced by NSAIDs.

MOA

• drug undergoes polymerization and selective binding to necrotic tissue where it acts as a barrier to acid. It is also s7mulates endogenous prostaglandin synthesis.
• Sucralfate requires acidic pH to be activated therefore it should not be administered simultaneously with H2 – blockers, PPI or other antacids.
• Therapeutic actions of Bismuth: It appears to have some antimicrobial effect on H Pylori. When it is administered along with metronidazole and tetracycline antomicrobial drugs, ulcer healing rate of up to 90% have been reported.

Adverse effects of Misoprostol:

• Diarrhea in up to 30% of patients who take this drug.
• Abortions due to induction of uterine contractions during pregnancy
• Exacerbations of inflammatory bowel disease (IBD).

Question 9

Metoclopramide

Answer 9

PROKINETIC DRUGS USED IN GI DISORDERS;

• also indicated in Diabetic, Parkinson’s and post-op
• reduces nausea and vomiting associated with chemotherapeutic agents.

MOA: 3 mechanisms

• 5-HT3 and D2 receptors blocker – acts as anti-emetic.
• prokinetic activity of metoclopramide is mediated by muscarinic activity via 5-HT4 receptor agonist activity. It accelerates gastric emptying and intestinal motility.
• At higher doses, 5-HT3 antagonist activity may also contribute to the anti-emetic effect.

Adverse

due to anti-dopaminergic –sedation, diarrhea, and Parkinsonian effects limit its high-doses and long term use.

Question 10

Cisapride

Answer 10

• Prokinetic agent
• 5HT4 agonist. Use: gastroparesis, GERD and constipation via stimulatinng Ach.
• ADR: arrhythmias

Question 11

Macrolide

Answer 11

• acting as a prokinetic agent
• Erythromycin acts on motilin receptors of GIT used I.V.
• Used for gastric emptying before upper GI endoscopic procedures.
• Tolerance may develop in gastroparesis.

Question 12

Emesis pharmacology

Answer 12

• D2, 5HT3, Opioid / Ach and substance P receptors
• Muscarinic and H1 receptors.
• GI distention, or acute GI infections, activates the 5-HT3

Question 13

ANTIEMETIC AGENTS

Answer 13

• 5-HT3 inhibitors – Ondansetron
• H1 antihistamines & antimuscarinics –
• Diphenhydramine & Scopolamine
• Corticosteroids – Dexamethasone
• NK1–receptor blocker – Aprepitant
• D2 Receptor antagonist – Prochlorperazine
• Benzamide – Metoclopramide
• Marijuana – Dronabinol (Marinol)

Question 14

Ondansetron and other 5-HT3 antagonists:

Answer 14

• block 5-HT3 in the gut and CNS
• Clinical indications of the anti-emetics are:
• Chemotherapy induced – moderate to severe emesis or post-operative nausea and vomiting.
• Route of administration usually I.V. and for prophylaxis they are given orally.

Question 15

Aprepitant

Answer 15

• NK1 –receptor blocker in CNS
• Effective in both decreasing the early and delayed emesis in cancer chemotherapy.
• Route of administration is PO.
• Fosaprepitant is for I.V.
• Adverse effects are dizziness, fatigue, diarrhea CYP interaction may occur.

Question 16

Phenothiazines –Prochlorperazine

Answer 16

• Antagonist at D2 receptors and muscarinic receptors
• Side effects: Extrapyramidal symptoms, hypotension and sedation.
• Metoclopramide (MCP): Effective at high doses against the highly emetogenic cisplatin
• Anti-dopaminergic side effects of MCP: Sedation, diarrhea, and extrapyramidal symptoms, limit its high-dose use.

Question 17

Benzodiazepines:

Answer 17

• Anti-emetic potency of lorazepam, alprazolam and diazepam is low.
• Their beneficial effects may be due to their sedative, anxiolytic, and amnesic properties
• Useful for anticipatory vomiting

Question 18

Anti-emetic drug combo

Answer 18

1. Dex
2. Ondansetron
3. Aprepitant

Choice of CINV (Chemotherapy induced nausea & vomiting):

Question 19

INFLAMMATORY BOWEL DISEASE –IBD

Answer 19

• Crohn’s disease and Ulcera1ve coli1s
• Drugs used in IBD are: Sulfasalzine, glucocorticoids (Budesonide), azathioprine, Methotrexate, Cyclosporine, Infliximab and Natalizumab

Question 20

Sulfasalazine

Answer 20

• inhibits the pro-inflammatory mediators –IL1, and TNF-α
• It is a sulfa derivative. So, it should be avoided in pt with sulfa allergy.
• In the GIT, sulfapyridine (anti-bacterial) and 5- Aminosalicylic acid (5-ASA) (anti-inflammatory) released from sulfasalazine by colonic bacteria.
• It is used in mild to moderate Crohn’s disease or UC

Adverse

• Nausea, vomiting, diarrhea,
• hypersensitivity
• reversible oligospermia.
• Bone morrow suppression is related to the sulfapyridine release from sulfasalazine.

Question 21

Mesalamine (5-ASA)

Answer 21

• Balsalazide: releases mesalamine (5-ASA) in the large intestine at the active site of UC
• Sulfasalazine: Proximal, distal colon and rectum.

Question 22

6-mercaptopurine (6-MP) and Methotrexate (MTX)

Answer 22

• Indications: moderately severe to severe Crohn’s disease and UC
• GI mucositis, myelosupression. Hepatotoxicity can occur with 6-MP. Toxicities are rare with MTX at low doses.

Question 23

Infliximab

Answer 23

• monoclonal antibody targets TNF-α, a principal mediator in Crohn’s disease.
• Used in conditions associated with flare up of IBD –particularly in Crohn’s related fistulas and acute flares.
• Also used in rheumatoid arthritis

Adverse

• reactivation of latent tuberculosis and other infections (CMV). It is given IV
• fever, chills, urticarial reaction, hypotension may occur. Antibodies to infliximab may develop.
• Adalimumab: TNF-α inhibitor
• Natalizumab **blocks leukocyte integrins can produce multifocal leukoencephalopathy. **

Question 24

Drugs used for IBS

Answer 24

Alosetron:

• 5-HT3 antagonist with long duration of action, has high potency.
• Reduces smooth muscle activity in the gut (For IBS-D).
• Recommended for sever diarrhea associated IBS.
• Rare, serious constipation; ischemic colitis and infarction may occur.

Anticholinergics: non-selective action on the gut can be used in IBS

• Hyoscyamine, Dicyclomine, Glycopyrrolate, Methscopalamine

Chloride channel activator: Lubiprostone used in constipation-associated IBS (IBS-C).

Question 25

ANTIDIARRHEAL DRUGS:

Answer 25

* Loperamide and Diphenoxylate are opiate derivatives. They slow gut motility with negligible CNS effects * Acts via GI mu-opioid receptors. Inhibit acetylcholine release and decrease peristalsis. * Diphenoxylate is formulated with atropine to reduce abuse potential. High doses of Diphenoxylate can cause CNS effects. * Risk of toxic megacolon in children or pts. with severe colitis. * Kaolin + Pectin: are adsorbents available as OTC

Question 26

Bile salt-binding resins –cholesterol lowering agents valuable in diarrhea:

Answer 26

* Prevent diarrhea of IBS & IBD by blocking osmotic and irritating actions of bile salts. * form insoluble complexes with bile acids in the intes1ne

Question 27

LAXATIVES:

Answer 27

Classified by mechanism of action as Stimulants, Osmotic agent, Bulk forming agents and Stool Sofeners. * Stimulants: Castor oil, Senna (Senokot), Bisacodyl (Dulcolax). * May cause cramping. * Chronic use may lead to habit of perceived need for laxatives. * Bulk forming agents: These are insoluble indigestible derivatives from fruits and vegetables; hydrophilic colloids. Methycellulose, Psyllium, Bran * They are non-absorbable; increase water retention and stools become bulky. The disten7on of bowel leads to peristaltic stimulation of gut. * Osmotic agents: * Magnesium citrate, Magnesium hydroxide are saline cathartics. Lactulose and sorbitol are non-digestible sugars. * They osmotically draw water into the lumen of GIT, which then stimulate motility. * Used in simple constipation, bowel prep for endoscope. * Lactulose is a semi-synthetic disaccharide sugar acts as an osmotic laxative. Large doses are degraded by colonic bacteria to form lactic, formic and acetic acid –which increases osmotic effect too. * Lactulose also used in hepa1c encephalopathy. It helps to “draw out” ammonia (NH3) from the body and is useful for preventing hyperammonia. * PEG (polyethylene glycol) is used for colonic lavage for endoscopic and radiological procedures. * Lubiprostone –prostanoic acid derivative, stimulates chloride secretion into GI – increase fluid content.

Question 28

Pancreatic insufficiency drugs

Answer 28

Pancrelipase: * A replacement enzyme from animal pancreatic extract * Improve the digestion of dietary fat, protein and carbohydrates. ↑A, D, E, K vit absorp7on * Use: patients with chronic pancreatitis, afer pancreatectomy, steatorrhea and cystic fibrosis associated insufficiencies.

Question 29

Bile acid resin (cholestyramine, colestipol, colesevelam) therapy for Gallstones:

Answer 29

Prevent intestinal absorption of bile acids; liver must use cholesterol to make more Side effects: Bad taste, GI discomfort, decrease fat soluble vitamins

Question 30

Ursodiol

Answer 30

* has enterohepatic circulation * It reduces cholesterol absorption by breaking up micelles containing cholesterol. * Used in patient who refuses or not eligible for surgery. * Adverse effect: diarrhea.

Question 31

Drugs used in Variceal hemorrhage:

Answer 31

* Non-selective β-blockers (Propranolol & Nadolol) are effective in reducing portal pressures. * β1 & β2 blockade result in ↓CO &↑VC -\> Improves GI blood vessel tone -\> ↑systemic vasoconstriction & ↓vasodilation