Pharmacology L1-4 , Digestive System

L1

Medications Influencing Gastric Secretions and Digestion

Drugs Increasing Gastric Secretions

1. Bitters: Generally of vegetal origin, including:

   • Strychnine

   • Quinine

   • Function: Increase gastric secretion and appetite.

2. Spicy Substances:

   • Function: Cause local hyperemia and enhance peristalsis, secretions, and digestion (carminative effect).

3. Ciproheptadine (Peritol):

   • Initial Use: Treatment for hay fever;

   • Function: Known to increase appetite.

4. Cannabinoid GIT Receptors:

   • Emerging Area: Interest for appetite stimulation.

5. Other Substances:

   • Caffeine

   • Diluted Alcohol

   • Gastrin

   • Histamine

   • Function: All play roles in gastric secretions.

Lack of Gastric Acid and Pepsin (Achylia Gastrica) - Substitutive Treatment

1. 10%-Chlorhydric Acid:

   • Formulation: Acidum chloratum dilutum 10%: 10-40 drops in water (caution: dangerous for teeth).

2. Pepsin Association:

   • Combination with 1%-HCl.

3. Chlorhydric Acid Tablets:

   • Betaine Hydrochloride - 1 gram = 40 drops of diluted HCl.

4. Citric Acid:

   • Suitable for Children: (acidum citricum).

5. Buffer Tablets:

   • Example Mixture: NaH2PO4 and NaHSO4; effective in hypo- or hyperacidity, stabilizes gastric pH to 2.7.

Substitution of Digestive Enzymes

1. Pancreatic Enzymes:

   • Examples: Festal, Digestal, Triferment, Pancrebil, Zymogen, Mezym, Kreon - used with meals to aid digestion.

2. Hemicellulase and Cow Bile Extract:

   • Example: Colebil.

3. Protease: Administered intraduodenally; may inhibit enzyme production via negative feedback, beneficial in chronic pancreatitis.

4. Galactozidase: Used in galactose intolerance treatment.

5. Bile Acids: Various preparations to aid digestion, enhancing lipid absorption.

Choleretic and Cholecystokinetic Drugs

1. Ox Bile Extract: Enhances bile flow and fat digestion.

2. Dehydrocholic Acid: Promotes the excretion of bile acids.

3. Floranthyrone: Used for gallbladder function.

4. Tocamphyl: Supports gallbladder emptying.

5. Chenodeoxycholic Acid: Used in the treatment of gallstones by dissolving cholesterol stones.

Hepatoprotector Drugs

1. Silibinin (Silybin):

   • Use: Treatment for acute liver necrosis, alcoholic cirrhosis, chronic hepatitis (plant extract).

2. Firsocostat:

   • Class: Acetyl-CoA carboxylase inhibitor in development for non-alcoholic fatty liver disease.

3. Cilofexor:

   • Class: Nonsteroidal FXR agonist, useful for primary sclerosing cholangitis.

4. Acetylcysteine: Given in acute paracetamol overdose to prevent liver damage.

5. Neomycin and Lactulose:

   • Use: To prevent ammonia absorption and manage hepatic encephalopathy.

6. Thioctacid (Acidum Thiocticum, Liponic Acid):

   • Use: Treatment for Amanita mushroom poisoning.

7. Insulin-Glucagon Combination: Beneficial in managing alcoholic hepatitis.

Laxatives and Purgatives

1. Types:

   • Laxatives

   • Purgatives

   • Cathartics.

2. Indications for Laxatives and Purgatives:

   • Usage: Treat acute and chronic constipation, prescribed for elderly weak patients, post-surgery, to manage hemorrhoids, and other specific conditions.

Quantity Increasing Drugs (Bulk Forming Agents)

1. Vegetal Fibers: Daily intake should be 20-60 g; contains polysaccharides (cellulose, hemicellulose) and lignin.

2. Cereals: Bran: 25-50% fiber; 1 g of carrot can bind 23 g of water.

3. Examples:

   • Methylcellulose

   • Carboxymethylcellulose - Increase volume significantly (beneficial for weight loss).

   • Agar, pectins (found in dried fruits), psyllium.

Osmotics (Salts)

1. Anorganic Salts:

   • Examples: Magnesium Hydroxide, Magnesium Sulfate (bitter salt), Natrium Sulfuricum (Glauber salt).

2. Osmotics (Polysaccharides):

   • Examples: Lactulose (Duphalac): 3-10 g syrup; Sorbitol and Mannitol administered orally or rectally.

3. Additional Agents:

   • Glycerin (osmotic and local irritating effect), macrogolum (Forlax, polyethylene glycol, soluble powder) to facilitate passage.

Softening and Lubricating Agents

1. Docusate (Sintolax):

   • Effect: Seen after 1-3 days; derivative of succinic acid, aids in stool softening.

2. Poloxamers: Used for their lubricating properties.

3. Paraffinum Liquidum (Paragel): Acts as an external lubricant in managing constipation.

Gut Wall Stimulators

1. Naturals:

   • Examples: Antranol glycosides (found in senna leaves, rebarbara roots, frangula cortex, aloe); included in Cortelax.

2. Synthetic:

   • Examples: Fenolphthalein (excluded in the USA), Bisacodyl (Dulcolax), Sodium Picosulfate; vary in effects.

Other Laxatives

1. Castor Oil: Strong purgative that may cause dehydration due to its potent effect.

2. Sulfur Powder: Acts as a weak irritant in the gut, facilitating bowel movement.

3. 5-HT4-Receptor Partial Agonists:

   • Examples: Tegaserod (used for irritable bowel syndrome with constipation) and Prucalopride (as a full agonist to enhance motility).

Antidiarrheal Drugs

1. Diarrhea Etiology: Major cause of infant death (4-5 million yearly); caused by infections, foods, drugs, toxins, or anxiety.

2. Symptoms: Increased gut motility and secretion of fluid/electrolytes into the gut lumen.

3. Oral Rehydration Solution: Ingredients include 20 g glucose, 3.5 g NaCl, 2.9 g Na-citrate, and 1.5 g KCl dissolved in 1000 ml water for rehydration.

4. Adsorbents and Antisecretory Agents:

   • Adsorbents: Activated charcoal, kaolin, pectin, tannic acid, diosmectin (e.g., Smecta).

   • Antisecretory Agents: Bismuth subsalicylate (for travelers' diarrhea, with anti-inflammatory effects).

5. Inhibitors of Gut Motility: Opioids (e.g., Codeine, Diphenoxylate, Loperamide - with minimal CNS effects).

Inhibitors of Gut Motility: Non-Opioids

1. Examples:

   • Mebeverine (direct musculotropic effect), Atropine, Scopolamine, Clonidine (α2 agonist), 5-HT3-receptor antagonists (e.g., Alosetron, Cilansetron).

Other Gut Motility Agents

1. Cholestyramine and Cholestypol:

   • Ion exchange resins that can cause GIT side effects, affecting drug absorption.

2. Somatostatin: Short half-life; synthetic analogue Octreotide as an effective clinical agent that decreases secretion of multiple hormones (gastrin, cholecystokinin, glucagon, insulin, growth hormone).

   • Indications: Diarrhea in neuroendocrine and GIT tumors, post-vagotomy, AIDS; dosage typically 100-250 μg administered subcutaneously.

Antiflatulants

1. Purpose: Used to relieve painful symptoms associated with gas.

2. Examples:

   • Beano (alpha-galactosidase) for gas prevention, lactase for lactose intolerance, Simethicone (a detergent that breaks mucus-coated bubbles).

Inflammatory Bowel Disease (IBD) Medications

1. Types:

   • Ulcerative Colitis: Inflammation of the entire colon or rectum.

   • Crohn's Disease: Regional enteritis with transmural lesions anywhere in GIT.

2. Therapeutics:

   • Aminosalicylates: For mild symptoms; drugs like 4-Aminosalicylic Acid (PAS), Balsalazide, Olsalazine, Sulfasalazine, Mesalazine. Side effects include abdominal pain, diarrhea, etc.

   • Corticosteroids: For moderate to severe symptoms (e.g., Budesonide).

   • Thiopurines: For active symptoms; drugs like 6-Mercaptopurine (6-MP), 6-Thioguanine (6-TG), and Azathioprine (AZA). Risk includes increased infection susceptibility.

   • Methotrexate: For both active and chronic symptoms; hepatotoxicity, stomatitis, and cytopenias are concerns.

   • New Drugs: Cyclosporin (immunosuppressant for active symptoms), Infliximab (monoclonal antibody blocking TNF-alpha for IBD), with other new drugs like Adalimumab, Certolizumab, Golimumab, Vedolizumab, Ustekinumab being utilized further when TNF blockers are ineffective.

L2

Peptic Ulcer Treatment

1. Therapeutic Goals in Ulcer Management

- Inhibition of Acid Secretion: Reducing gastric acid is a core strategy in managing ulcers to alleviate symptoms and promote healing.

- Stimulation of Protective Factors: Augmenting mucosal defenses, particularly in ulcers caused by NSAIDs, aims to counteract ulcerogenic effects.

- Eradication of Helicobacter pylori: Targeting this bacterium, strongly associated with gastric and duodenal ulcers, is essential to prevent recurrence.

2. Inhibition of Acid Secretion

A. Histamine H2 Receptor Antagonists:

- These medications block H2 receptors on parietal cells, leading to decreased acid production.

- Medications and Mechanisms:

- Cimetidine: Known for significant cytochrome P-450 inhibition, resulting in numerous drug interactions. Side effects include gynecomastia, decreased libido, and gastrointestinal issues.

- Ranitidine, Famotidine, Nizatidine: Other H2 blockers with fewer side effects on the cytochrome system. They are more potent and have fewer hormonal side effects than cimetidine.

- Indications:

- Duodenal and Gastric Ulcers: Studies show high healing rates (85-90% for duodenal and 50-70% for gastric ulcers within eight weeks).

- Zollinger-Ellison Syndrome: High-dose H2 blockers are effective due to excess acid production from gastrin-secreting tumors.

- Gastroesophageal Reflux Disease (GERD) and Stress Ulcers.

- Side Effects:

- Primarily seen with cimetidine, including cytochrome P-450 inhibition, which can prolong the effects of other drugs.

- Risk of delaying gastric cancer diagnosis due to masking symptoms.

B. Proton Pump Inhibitors (PPIs):

- Mechanism: PPIs irreversibly inhibit the H+/K+ ATPase enzyme (proton pump) in gastric parietal cells, leading to profound and prolonged acid suppression.

- Common PPIs:

- Omeprazole, Pantoprazole, Lansoprazole, Dexlansoprazole, Rabeprazole, Esomeprazole, Ilaprazole (limited to Asia).

- Indications:

- Peptic Ulcers: PPIs heal ulcers more effectively than H2 blockers.

- GERD: PPIs are particularly effective, outperforming H2 antagonists.

- Zollinger-Ellison Syndrome: Often used in high doses.

- Side Effects:

- Electrolyte Imbalance: Hypomagnesemia is a risk, especially with prolonged use.

- Infection Risks: Increased gastric pH can allow bacterial overgrowth, leading to infections.

- Other: Long-term use is associated with bone fractures, delayed gastric cancer diagnosis, and potential effects on kidney health.

C. Muscarinic (M1) Receptor Antagonists:

- Examples: Pirenzepine and telenzepine, which selectively inhibit M1 receptors, decreasing vagal-mediated gastric acid secretion.

- Indications: Primarily used for duodenal and gastric ulcers; also effective in relapse prevention.

- Side Effects: Include dry mouth, blurred vision, constipation, and tachycardia, which are typical of anticholinergics.

D. Gastrin Antagonists:

- Proglumide acts as a weak gastrin receptor blocker, reducing acid secretion.

- While not commonly used alone, it may be adjunctive in some ulcer therapies.

3. Enhancement of Mucosal Protection

A. Bismuth Compounds:

- Mechanism: Bismuth forms a protective barrier over ulcers, stimulates mucus secretion, inhibits pepsin activity, and has antimicrobial activity against H. pylori.

- Example: Trikalium dicytrate bismuthate (De-Nol).

- Indications: Effective in gastric and duodenal ulcers, comparable to H2 blockers, with lower relapse rates when combined with other treatments.

- Side Effects: Potential for mouth and tongue discoloration; long-term use may lead to encephalopathy, especially in renal impairment.

B. Sucralfat

- Mechanism: Forms a gel-like protective layer on ulcer surfaces and stimulates prostaglandin production.

- Indications: Used for gastric and duodenal ulcers, especially effective in acidic environments.

- Interactions: Antacids and H2 blockers reduce its effectiveness by raising gastric pH.

C. Prostaglandin Analogues:

- Example: Misoprostol, a synthetic analogue of PGE1.

- Indications: Primarily for NSAID-induced ulcers due to its ability to enhance mucosal defense mechanisms.

- Side Effects: Can cause diarrhea, abdominal pain, and is sometimes used for labor induction due to uterotonic effects.

4. H. pylori Eradication

- Triple Therapy: A standard 7-14 day regimen includes a PPI, clarithromycin, and amoxicillin.

- Alternative Regimens:

- Sequential Therapy: Combines PPI and amoxicillin initially, followed by metronidazole and clarithromycin.

- Concomitant and Hybrid Therapies: Combine PPIs with multiple antibiotics to improve efficacy against H. pylori.

- Bismuth-Containing Quadruple Therapy: Includes a PPI, bismuth, tetracycline, and metronidazole.

- Resistance Concerns: Novel combinations, including levofloxacin-based triple or quadruple therapies and culture-guided therapies, address antibiotic resistance.

Antiemetic Therapy

1. Receptor-Specific Antiemetics

A. Dopamine D2 Antagonists:

- Examples: Metoclopramide (central action, also 5-HT3 blocking), domperidone (peripheral action).

- Indications: Effective for general nausea and vomiting, including that caused by medications or motion sickness.

- Side Effects: Metoclopramide is associated with extrapyramidal side effects (tardive dyskinesia); domperidone may cause less central nervous system (CNS) toxicity.

B. 5-HT3 Receptor Antagonists:

- Examples: Ondansetron, granisetron, dolasetron, and palonosetron.

- Indications: Primarily for chemotherapy-induced nausea and vomiting, and postoperative nausea.

- Side Effects: Generally mild, including constipation, headache, and, in rare cases, transient blindness.

C. Muscarinic M1 Receptor Antagonists:

- Example: Scopolamine, commonly used for motion sickness.

- Side Effects: Typical anticholinergic effects like dry mouth, blurred vision, and drowsiness.

D. Histamine H1 Receptor Antagonists:

- Examples: Cyclizine, diphenhydramine, and promethazine.

- Indications: Effective for motion sickness and vestibular-related nausea.

- Side Effects: Can cause sedation, blurred vision, and anticholinergic effects.

E. NK1 (Substance P) Receptor Antagonists:

- Example: Aprepitant, effective for both acute and delayed chemotherapy-induced vomiting.

- Side Effects: Includes dizziness, diarrhea, and hiccups.

2. Other Antiemetic Agents

A. Cannabinoids:

- Example: Dronabinol, derived from THC, with uses in chemotherapy-induced nausea, chronic pain, and to stimulate appetite.

- Side Effects: Hallucinations, increased appetite, and orthostatic hypotension are common.

B. Corticosteroids:

- Examples: Dexamethasone, used as adjunctive therapy with other antiemetics, especially for chemotherapy-related nausea.

3. Prokinetic Agents

A. Dopamine Antagonists: Metoclopramide and domperidone enhance GI motility by blocking D2 receptors, often used for GERD and gastroparesis.

B. Serotonin Receptor Modulators:

- Examples: Cisapride (5-HT3 blocker and 5-HT4 agonist) and prucalopride (5-HT4 agonist) stimulate gastrointestinal motility.

C. Motilin Receptor Agonists:

- Example: Erythromycin, a macrolide antibiotic that enhances motilin receptor activity to stimulate gastric emptying.

Lippincott:

1. Drugs for Peptic Ulcers and GERD

- Proton Pump Inhibitors (PPIs):

- Examples include omeprazole, lansoprazole, esomeprazole, dexlansoprazole, and ilaprazole (often used in Asia). Dexlansoprazole has dual delayed-release technology beneficial for nocturnal GERD, while ilaprazole provides a longer half-life and is highly effective in acid suppression.

- Mechanism: PPIs irreversibly inhibit the H+/K+ ATPase (proton pump) in parietal cells, reducing acid production significantly.

- Indications: These drugs are widely used for peptic ulcers, GERD, and Zollinger-Ellison syndrome.

- Adverse Effects: Long-term use may lead to hypomagnesemia, osteoporosis, vitamin B12 deficiency, increased risk of Clostridioides difficile infection, and kidney disease.

- Histamine H2-Receptor Antagonists:

- Examples include cimetidine, ranitidine, famotidine, nizatidine, roxatidine, and lafutidine. Roxatidine and lafutidine offer improved safety profiles regarding cytochrome P450 interactions, beneficial for patients on multiple medications.

- Mechanism: These drugs block H2 receptors on parietal cells, reducing both basal and stimulated acid secretion.

- Uses: Effective for mild GERD and peptic ulcers but less potent than PPIs.

- Adverse Effects: Cimetidine may cause gynecomastia, galactorrhea, and has multiple drug interactions due to cytochrome P450 inhibition.

- Antacids:

- Common agents include aluminum hydroxide, magnesium hydroxide, calcium carbonate, and sodium bicarbonate.

- Mechanism: They neutralize existing stomach acid, providing symptomatic relief.

- Side Effects: Magnesium-based antacids may cause diarrhea, aluminum-based ones may cause constipation, and calcium carbonate can lead to a rebound increase in acid after its effects wear off.

- Mucosal Protective Agents:

- Sucralfate forms a gel-like barrier on ulcers, protecting them from acid and pepsin.

- Bismuth Subsalicylate creates a protective coating on ulcers and has antibacterial action against Helicobacter pylori.

- Misoprostol is a synthetic prostaglandin analog used to prevent NSAID-induced ulcers by increasing mucus and bicarbonate secretion.

- Carbenoxolone, a derivative of glycyrrhizic acid, enhances mucosal protection by increasing mucus secretion but may cause hypertension and hypokalemia.

- Potassium-Competitive Acid Blockers (P-CABs):

- Vonoprazan is a newer acid suppressant that inhibits the potassium-binding site of H+/K+ ATPase, potentially offering faster and more sustained acid suppression than traditional PPIs, useful in treating H. pylori infections and refractory GERD.

2. Drugs for Helicobacter pylori Eradication

- Standard triple therapy (PPI + clarithromycin + amoxicillin or metronidazole) and quadruple therapy (PPI, bismuth, tetracycline, and metronidazole) improve ulcer healing and reduce recurrence by targeting H. pylori.

- Newer dual and quadruple therapies are suggested in Lippincott to address antibiotic resistance, with levofloxacin or rifabutin as second-line or rescue therapy options.

3. Antiemetics

- 5-HT3 Receptor Antagonists:

- Examples: Ondansetron, granisetron, dolasetron.

- Mechanism: Block serotonin receptors in the chemoreceptor trigger zone (CTZ) and on vagal afferents, effective for chemotherapy-induced nausea and vomiting.

- Dopamine D2 Antagonists:

- Examples: Metoclopramide, prochlorperazine, droperidol (used in postoperative nausea but may cause QT prolongation).

- Mechanism: Block dopamine receptors in the CTZ, making them effective for various causes of nausea.

- Side Effects: Extrapyramidal symptoms, especially with metoclopramide, which can cause tardive dyskinesia with long-term use.

- Neurokinin-1 (NK1) Receptor Antagonists:

- Examples: Aprepitant, netupitant, fosnetupitant. Netupitant is often combined with 5-HT3 antagonists like palonosetron for extended antiemetic effects.

- Mechanism: Block NK1 receptors to prevent both acute and delayed chemotherapy-induced vomiting.

- Antihistamines and Anticholinergics:

- Examples: Diphenhydramine (antihistamine), scopolamine (anticholinergic).

- Indications: Effective for motion sickness by blocking H1 and M1 receptors involved in vestibular signaling.

- Cannabinoid Receptor Agonists:

- Examples: Dronabinol (THC), nabilone (synthetic), used in refractory chemotherapy-induced nausea.

- Side Effects: Hallucinations, increased appetite, and orthostatic hypotension.

4. Prokinetic Agents

- Metoclopramide stimulates gastric motility as a dopamine antagonist and a weak serotonin agonist, aiding in the treatment of gastroparesis and as an adjunct in GERD.

- Erythromycin activates motilin receptors to improve gastric emptying in gastroparesis, though long-term use is limited by tachyphylaxis.

- Prucalopride and tegaserod are 5-HT4 agonists that treat chronic constipation and IBS with constipation; tegaserod has restricted use due to cardiovascular risks.

5. Drugs for IBS and Constipation

- Antispasmodics: Dicyclomine and hyoscyamine relieve cramping and spasms in IBS.

- Guanylate Cyclase-C Agonists: Linaclotide and plecanatide increase fluid secretion in the intestines to treat IBS with constipation.

- Chloride Channel Activators: Lubiprostone improves bowel movements in chronic constipation and IBS with constipation.

6. Drugs for Diarrhea and IBS with Diarrhea

- Opioid Receptor Agonists: Diphenoxylate (often with atropine in Lomotil) and loperamide reduce GI motility, preferred for their limited CNS penetration.

- Mixed Opioid Receptor Modulators: Eluxadoline acts as a mixed mu- and kappa-opioid receptor agonist and delta-opioid receptor antagonist for IBS-D, reducing bowel contractions and improving stool consistency.

- Bile Acid Sequestrants: Cholestyramine, colestipol, and colesevelam treat bile acid diarrhea, particularly useful post-ileal resection.

7. Pancreatic Enzyme Supplements

- For pancreatic insufficiency (e.g., chronic pancreatitis or cystic fibrosis), pancrelipase (brands: Creon, Pancreaze, Zenpep) provides digestive enzymes to aid in nutrient absorption.

- Combining Antiemetics: For chemotherapy-induced nausea, combining antiemetics with different mechanisms (e.g., NK1 antagonist + 5-HT3 antagonist + corticosteroid) is highly effective.

- Caution with Long-Term PPI Use: Chronic use of PPIs may increase risks of kidney disease, fractures, and B12 deficiency.