Gastrointestinal Drugs Flashcards
Antacids
Name the 3 most commonly used and their adverse Effects
Commonly used antacids are:
- Magnesium hydroxide
- Aluminum hydroxide and
- Calcium carbonate
Most important adverse effect of gastric (oral) antacid
- 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 is another adverse effect.
- Calcium carbonate: Hypercalcemia, nephrolithiasis and constipation – fecal compaction.
Clinical correlates of (oral) antacids and drug absorp1on:
- Increase oral absorption of weak bases (e.g. quinidine)
- Decrease oral absorption of weak acids (e.g. warfarin)
- Decreased oral absorption of Ca, Mg, Al molecules can chelate tetracyline.
H2 Receptor Blockers
- Cimetidine, Ranitidine, Famotidine and Nizatidine
- Effec1veness of H2-blockers: (indirectly) they are capable of reducing nearly 60-90% of basal secreFon of gastric acid following a single dose. No effect on gastric emptying Fme.
- They are reversible H2 receptor blockers.
- Ranitidine, Famotidine and Nizatidine are longer acting and more potent than older cimetidine.
- They are shown to be effective in promoting the healing of duodenal, gastric ulcers and relieving gastro esophageal reflux disease (GERD).
- Peptic ulcers recurrence is common ajent monotherapy with H2 antagonists is stopped.
- Preoperatively, H2 receptor blockers are used to prevents aspiration pneumonia.
- Acute Stress ulcers are usually treated with I.V. H2 receptor blocker injection or as prophylaxis.
- 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, decreased libido and confusion in elderly people. It can cross BBB and placenta.
- Cimetidine and ranitidine can decrease renal excretion of creatinine.
- Cimetidine is a strong inhibitor of cytochrome P-450 system and as a result can slow down biodegradation of certain drugs which are normally metabolized through this system. Examples comprise of: warfarin, procainamide, phynetoin, benzodiazepines theophylline, imipramine and quinidine.
Proton Pump Inhibitors
- Omeprazole, Esomeprazole, Lansoprazole, Rabeprazole, Pantoprazole
- After transportation into the parietal cell canaliculus PPIs are converted to the active form, which reacts with a cysteine residue of the H+/K+-ATPase, forming a stable covalent bond leading to irreversible inactivation of enzyme.
Clinical uses of PPI:
• GERD, duodenal and gastric ulcers, mulFple endocrine neoplasia (MEN-1) or Zollinger- Ellison syndrome.
• They contribute in combinaFon with anFbioFcs to eradicate H Pylori.
• NSAID-induced ulcers should be treated with PPIs. They support platelet aggregation & maintain clot integrity: used in hemorrhagic ulcers.
• PPIs can inhibit nearly 100% of gastric acid secreFon with single daily dose.
Side effects of PPIs:
- Usually PPIs are well tolerated. Rarely they can produce nausea or diarrhea.
- Omeprazole inhibits the metabolism of warfarin, clopidogrel, phenytoin, diazepam, and cyclosporine
- Reports of small increase in respiratory and GI infections; decrease in serum Mg2+ and Hip fractures with long term use of PPI.
- Rarely pancreatitis, hepatotoxicity, and interstitial-nephritis.
- Prolonged therapeutic use of PPI & H2 blockers may decrease bioavailability of vitamin B12; digoxin and ketoconazole –because acid is required for their absorption.
Helicobacter Pylori Treatment
First line antimicrobials for H pylori eradication
- Macrolides –Clarithromycin
- β-Lactams –Amoxicillin
- Antiprotozoals –Metronidazole
- Broad-spectrum antibiotics –Tetracycline
Mucosal Protective Agents (3)
• Sucralfate, Bismuth Subsalicylate and Misoprostol
Sucralfate is a sulfated disaccharide used in PUD.
- Mechanism of action: the drug undergoes polymerization and selective binding to necrotic tissue where it acts as a barrier to acid. It is also stimulates endogenous prostaglandin synthesis.
- Sucralfate requires acidic pH to be activated therefore it should not be administered simultaneously with H2 –blockers, PPI or other antacids.
- Bismuth Subsalicylate: by selectively binding to an ulcer it forms a coating and protects from acid and pepsin.
- Therapeutic actions: It appears to have some antimicrobial effect on H Pylori. When it is administered along with metronidazole and tetracycline antimicrobial drugs, ulcer healing rate of up to 90% have been reported –BMT regimen
- Misoprostol: it is prostaglandin E1 analogue that decrease acid secretion, stimulate mucin and bicarbonate production.
Clinical uses of Misoprostol:
- Approved for prevention of gastric ulcers induced by NSAIDs.
- Nowadays it is infrequently used because of its adverse effects and minimal benefits. It is less effective than H2 blockers or PPI in acute cases.
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).
Prokinetic Drugs used in GI disorders
• These agents are used to relieve GI symptoms of abdominal discomfort, bloaFng, heart burn, nausea, vomiFng that could be associated with GERD or gastroparesis or GI movement disorders.
Prokinetic Drugs:
• Metoclopramide, 5HT4 agonists, Cholinomimetics, Macrolides
Metoclopramide
- Mechanism of action of Metoclopramide: 5- HT3 and D2 receptors blocker – acts as anti- emetic.
- The 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.
- Used in diabetic, Post-operative gastroparesis and relief of symptoms in GERD.
- Metoclopramide also used in nausea and vomiting associated with chemotherapeutic agents.
Adverse effects of Metoclopramide:
• Side effects are due to anti-dopaminergic – sedation, diarrhea, and Parkinsonian effects limit its high-doses and long term use.
Cisapride
Prokinetics –Cisapride
Cisapride: 5HT4 agonist.
Use: gastroparesis, GERD and constipation via stimulating Ach.
Side effects: arrhythmias
Cholinomimetics
Prokinetics –Cholinomimetics:
• Neostigmine is used in the colonic pseudo- obstruction in hospitalized patients.
• Bethanechol: resistant to cholinesterase; long duration of action, used in post operative bowel & bladder atony.
Erythromycin
Macrolides:
- Erythromycin acts on motilin receptors of GIT used I.V.
- Used for gastric emptying before upper GI endoscopic procedures.
- Tolerance may develop in gastroparesis.
Ondansetron
- Ondansetron and other 5-HT3 antagonists:
- They block 5-HT3 in the gut and CNS
- Clinical indications of the antiemetics 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.
Cyclizine and Meclizine
• H1 antihistaminics –Diphenhydramine, Cyclizine, Meclizine are moderately effective in motion sickness and chemotherapy induced emesis.
Scopolamine
• Antimuscarinics –Scopolamine is effective in emesis due to motion sickness.
Aprepitant and Fosaprepitant
NK1–receptor blockers –Aprepitant & Fosaprepitant
- Aprepitant:
- It is a NK1 –receptor blocker in CNS (a receptor to
substance P)
- 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.
Dexamethasone or Methylprednisolone
Corticosteroids –Dexamethasone or Methylprednisolone
- Corticosteroids can be combined with Ondansetron to provide greater anti-emetic effect.
- Choice of CINV (Chemotherapy induced nausea & vomiting):
- Dexamethasone or Methylprednisolone + Ondansetron or aprepitant combination is quite effective in CINV.
Name the 3 D2 Receptor antagonists:
Phenothiazines – Prochlorperazine
- Antagonist at D2 receptors and muscarinic receptors
- Side effects: Extrapyramidal symptoms, hypotension and sedation.
Promethazine: anti-dopaminergic and anticholinergic. Used as antiemetic (↓motion sickness), antipsychotic effects and sedative.
Droperidol: anti-dopaminergic, antiemetic, antipsychotic and neuroleptic analgesic agent.
Lorazepam, Alprazolam and Diazepam
Benzodiazepines –lorazepam, alprazolam and diazepam
- Antiemetic potency of lorazepam, alprazolam and diazepam is low.
- Their beneficial effects may be due to their sedative, anxiolytic, and amnesic properties
- Useful anticipatory vomiting
Dronabinol
Cannabinoids –Dronabinol
• Dronabinol acts on CB1 receptors as an agonist.
(Antiemetic)
Antidiarrheals
Opioid agonists
- Loperamide
- Diphenoxylate
Somatostatin analogs
• Octreotide
Bismuth compounds
• Bismuth subsalicylate
Loperamide and Diphenoxylate
• Loperamide (Imodium)and Diphenoxylate (Lomotil) 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.
Ocreotide
Somatostatin analogues– Octreotide as subcutaneous injection
- A potent inhibitor of GH, Glucagon and insulin
- Used in diarrhea and flushing associated with carcinoid syndrome and diarrhea in people with VIP–secreting tumors (VIPomas)
Bismuth subsalicylate
- Used as muco-protective (antacid) and antidiarrheal.
- ↓inflammation binds with toxins (E Coli)
Senna and Bisacodyl
LAXATIVES –Stimulants
- Castor oil, Senna & Bisacodyl.
- May cause cramping.
- Chronic use may lead to habit of perceived need for laxatives.
Methycellulose, Psyllium, Bran
LAXATIVES –Bulk forming agents
- These are insoluble indigestible derivatives from fruits and vegetables; hydrophilic colloids.
- They are non-absorbable; increase water retention and stools become bulky. The distention of bowel leads to peristaltic stimulation of gut.
Magnesium citrate, Magnesium hydroxide and Lactulose and Polyethylene Glycol
LAXATIVES –Osmotic agents
- Magnesium citrate, Magnesium hydroxide are saline cathartics. Lactulose, non-digestible sugar.
- 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 hepatic 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.
Glycerine
- It induces a hyperosmotic effect.
- Used as rectal suppository for laxative effect.
- Can be used as enema (2-10ml) form; it may irritate anal mucosa.
Mineral oil and Docusate Sodium (Colace)
LAXATIVES –Stool sokeners
- Mineral oil and docusate sodium (Colace) – they emulsify stool and soften it, lubricate – making its easy passage.
- Senna is used in combination with a docusate (make stools softer and easier to pass), to treat cases of opioid-induced constipation.
Lubiprostone
LAXATIVES – Lubiprostone
• Prostanoic acid derivative, Chloride channel activator ↑secretion into GI –increase fluid content.
Alvimopan & Methylnaltrexone
LAXATIVES – Opioid receptor antagonists Alvimopan & methylnaltrexone
- Opioid receptor antagonists block GI mu- receptors but do not enter CNS.
- Useful in opioid induced constipation
Drugs used in Crohn’s disease and Ulcerative colitis
INFLAMMATORY BOWEL DISEASE –IBD
Drugs used in Crohn’s disease and Ulcerative colitis
- Aminosalicylates
- Glucocorticoids
- Immunosuppressants
- Anti-TNF-α-drugs
- Anti-integrins
Sulfasalazine, Balsalazide & Mesalamine
Aminosalicylates –Sulfasalazine, Balsalazide & Mesalamine
- Mechanism of action of Sulfasalazine: inhibits the pro-inflammatory mediators –IL1, and TNF-α
- It is a sulfa derivative. So, it should be avoided in patients with sulfa allergy.
- In the GIT, sulfapyridine (antibacterial) 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 ulcerative colitis
- Sulfasalazine: Effects on proximal, distal colon and rectum.
Sulfasalazine adverse effects:
• Nausea, vomiting, diarrhea, hypersensitivity, and reversible oligospermia. Bone marrow suppression is related to the sulfapyridine release from sulfasalazine.
Balsalazide:
It is a prodrug, releases mesalamine (5-ASA) in the large intestine at the site of ulcerative colitis.
Hydrocortisone, prednisone, prednisolone & Budesonide
Glucocorticoids –hydrocortisone, prednisone, prednisolone & Budesonide
- Corticosteroids: are generalized anti- inflammatory drugs used in acute cases.
- Inhibit TNF-α, IL-1, IL-8
- Budesonide: controlled released formulation in the distal ileum and colon.
6-mercaptopurine (6-MP), Azathioprine –a prodrug of 6-MP and Methotrexate (MTX)
Immunosuppressants:
6-mercaptopurine (6-MP), Azathioprine –a prodrug of 6-MP and Methotrexate (MTX)
- 6-MP may promote apoptosis of immune response. MTX blocks dihydrofolate reductase (DHFR)
- They cause generalized immune suppression
- They are used in moderately severe to severe Crohn’s disease and ulcerative colitis.
- GI mucositis, myelosupression. Hepatotoxicity can occur with 6-MP. Toxicities are rare with MTX at low doses.
Infliximab & Adalimumab
Anti-TNF-α-drugs: Infliximab & Adalimumab
• Mechanism of action of Infliximab: it is a 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. It is also used in rheumatoid arthritis.
Infliximab adverse effects:
• Reactivation of latent tuberculosis and other infections. It is given IV – fever, chills, urticarial reaction, hypotension may occur. Antibodies to infliximab may develop.
• Adalimumab: TNF-α inhibitor
Natalizumab
Anti-integrins: Natalizumab
• Natalizumab blocks leukocyte integrins can produce multifocal leukoencephalopathy.
Used In UC and Crohn
Hyoscyamine, Dicyclomine, Glycopyrrolate and Methscopalamine
Anticholinergics in IBS:
Hyoscyamine, Dicyclomine, Glycopyrrolate and Methscopalamine
- Non-selective action on the gut can be used in IBS.
- Anticholinergic effects on GI, UT, RT, Eye, secretions and on heart may have effects.
Alosetron
5-HT3 antagonist in IBS –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.
Loperamide
Opioid agonist in IBS –Loperamide
- Acts via GI mu-opioid receptors. Inhibit acetylcholine release and decrease peristalsis
- Used in IBS with diarrhea
Lubiprostone
Chloride channel activator in IBS –Lubiprostone
• Used in constipation-associated IBS (IBS-C).
Pancrelipase
Pancreatic insufficiency - Pancrelipase:
- A replacement enzyme from animal pancreatic extract
- Improve the digestion of dietary fat, protein and carbohydrates. ↑A, D, E, K vit absorption
- Use: patients with chronic pancreatitis, after pancreatectomy, steatorrhea and cystic fibrosis associated insufficiencies.
Orlistat
• Orlistat is a gastric and pancreatic lipase inhibitor used in weight loss. ↓A, D, E, K vit absorption
