Autocoids

GI Pharmacology

PHYSIOLOGY:

• Phases of Gastric-Acid Secretion:
  • Cephalic Phase: Anticipation of food ------> vagal stimulation.
  • Gastric Phase: Stomach distension. Gastric-acid secretion also stimulated by:
    • Amino Acids: phenylalanine, tryptophan
    • Alcohol
    • Coffee: some product other than caffeine
    • Calcium
    
    
    
  • Intestinal Phase: Entry of chyme into small intestine. Stimulating factors:
    • Proteins, protein digestion-products
    • Distension of small intestine
  • Gastric acid secretion still remains relatively low 1.0 - 1.5 hours after a meal, because the food neutralizes the secreted acid.
• Formation of Gastric Acid
  • INSIDE CELL: Carbonic Anhydrase forms H⁺ and HCO₃^- from CO₂ and H₂O (products of metabolism)
    • H⁺/K⁺-ATPase: The H⁺ is then excreted into the lumen, exchanging it for K⁺
    • HCO₃^- is exchanged for a Cl^-, via a basolateral exchanger.
    • The Cl^- is then also excreted into the lumen
  • Result: net excretion of HCl
• Gastric Receptors:
  • Stimulatory:
    • Histamine H₂ receptors
    • Muscarinic receptors
    • Gastrin receptors
  • Inhibitory:
    • Somatostatin receptors
  • Suggested, but not confirmed:
    • PGE₂, PGI₂ receptors
    • EGF Receptors: They are thought to interact with PGE₂ to form new vessels (angiogenesis), which helps speed up the healing process.
    • TGF-alpha

PEPTIC ULCER DISEASE (PUD):

• DISTRIBUTION: 30% of ulcers occur in stomach, 70% in the duodenum.
• PATHOGENESIS: Excess gastric acid production, Helicobacter Pylori.
• SYMPTOMS:
  • Pain is aggravated by food.
  • Pain does not occur at stomach pH above 2.0
• DIET: The following irritate PUD
  • Alcohol, tobacco, caffeine all stimulate gastric acid secretion.
  • Pepper is corrosive to gastric mucosa.

TREATMENT of PUD:

• ANTACIDS:
  • EFFECTS: Should take them about 1 hour after eating for maximum effect.
    • At a pH of 3.3, 90% of gastric acid is neutralized.
    • Pepsin is reversibly inactivated at pH 6.0-7.0, and irreversibly inactivated at pH 7.0-8.0
  • ADVERSE EFFECTS:
    • Renal Dysfunction: Could form urinary stones or could accumulate metal ions in blood.
    • Excess Metals:
      • Excess NaHCO₃: Can cause metabolic alkalosis, leading to alkalinization of the urine and hence renal stones.
        • Hypercalcemia and hyperphosphatemia also contribute to formation of renal stones.
      • Excess Mg⁺²: Neurologic, CV, neuromuscular dysfunction.
      • Excess Ca⁺²: Hypercalcemia
        • Weakness, nausea vomiting
        • Mental confusion, change in mental status
        • Anorexia
    • Milk-Alkali Syndrome: NaHCO₃ and CaCO₃ can lead to hypercalcemia, alkalosis, renal failure.
• H₂-BLOCKERS:
  • PHARMACOKINETICS:
    • Food slows absorption, so don't give with food.
    • Pregnancy:
      • All the drugs cross placenta, so don't give during pregnancy.
      • Cimetidine and Ranitidine get into breast milk.
    • Metabolism decreases with age. Give about half the dose to old folks.
  • ACTION: Block histamine ------> block acid secretion
    • H⁺ blockade is cyclical, according to the secretion of histamine.
  • ADVERSE EFFECTS:
    • Cimetidine:
      • Allergic reactions: leukopenia, skin rash.
      • Mental confusion
      • Gynecomastia and impotence: 50% occurrence with chronic usage of 1 year or longer.
      • Interfere with Phase-I oxidation (Cyt-P450) ------> prolong duration of theophylline, anticoagulants, propanolol.
    • Ranitidine: Interfere with Phase-I oxidation (Cyt-P450)
    • Famotidine: Muscle cramps, headaches, constipation
    • Nizatidine: No appreciable effects found yet.
• PUMP INHIBITORS: Omeprazole has the highest initial healing rates for ulcers of all drugs.
  • ACTION: Binds irreversibly (covalently) to the H⁺/K⁺-ATPase acid-pump, completely blocking acid secretion, until more pumps are made.
    • Increases gastric levels continuously, rather than cyclically, as in the H₂-blockers.
    • Hypergastrinemia: Gastrin levels are tonically higher due to disinhibition of Gastrin secretion.
  • PHARMACOKINETICS: Acid environment is required for the drug to work.
    • Drug is administered in enteric-coated granules, which dissolve in the intestine. This protects it from premature activation in stomach.
    • Acid is required for the drug to work, so it has maximal activity when taken before meals.
    • Metabolized to active metabolites. Elimination is affected by renal and hepatic dysfunction.
  • ADVERSE EFFECTS: No significant effects found so far.
    • Stomach Cancer: Carcinoid tumors were found in one study in rats, probably due to the effects of hypergastrinemia.
    • A few reported incidents of gynecomastia and impotence.
  • DRUG INTERACTIONS:
    • Due to its action, it inactivates drugs that require an acidic pH in order to work. Ketoconazole is inactivated because it requires acidic pH.
    • Affects Cyt-P450 metabolism ------> delayed excretion of warfarin, phenytoin.
• CYTOPROTECTIVE AGENTS:
  • ACTIONS: Generally they increase production of mucus, HCO₃^-, and prostaglandins.
  • SUCRALFATE:
    • STRUCTURE: Glucose + Sulfate + Al(OH)₃
    • MECHANISM: In the stomach, the free SO₄^-2 group binds to proteins in stomach ------> increased production of mucus, HCO₃^-, prostaglandins.
      • Sucralfate should not be administered with antacids: antacids prevent sucralfate from forming its protective gel in gastric mucosa ------> neutralize its effects.
    • PHARMACOKINETICS: Sucralfate is not appreciably absorbed.
    • ADVERSE EFFECTS:
      • Constipation, 3%. Constipation often occurs with drugs that are not absorbed.
      • Aluminum Toxicity can occur in people with renal insufficiently.
      • Decreases absorption of Cyt-P450 drugs.
  • MISOPROSTOL:
    • MECHANISM: PGE₁ analog
    • PHARMACOKINETICS: Misoprostol is well-absorbed in GI tract.
    • ADVERSE EFFECTS:
      • Diarrhea, because the drug is well-absorbed. This decreases if the drug is administered with food.
      • Vaginal bleeding in post-menopausal women.
      • Spontaneous abortion in pregnancies; thus it's absolutely contraindicated.
• ANTIBIOTICS: Recommended therapy for eradication of H. Pylori, and treatment of all ulcers found to be H. Pylori-positive (~60% of ulcers).
  • Regimen 1:
    • Amoxicillin 500 mg 3X daily 14 days
    • Metronidazole 250 mg 3x daily 14 days
    • Bismuth subsalicylate 300 mg 4x daily 30 days
  • Regimen 2:
    • Omeprazole 20 mg 2 x daily 14 days
    • Amoxicillin 500 mg 3x daily 14 days

ANTI-EMETICS:

• LOCALLY-ACTING: Temporarily numb receptors in the GI tract, preventing vomiting
  • Viscous Lidocaine: Topical anesthetic increases the threshold of receptor-activity to vomiting.
  • Adsorbents and Demulcents: Act on stomach mucosa and/or GI receptors to make them less sensitive.
    • Kaolin and Pectin
    • Activated charcoal
    • Bismuth subsalicylate
    • Attapulgite
    • Cholestyramine
  • Cola Syrup, Phosphorylated Carbohydrate Solution: They decrease GI muscle spasm^-fewer inputs into vomiting centers.
• DOPAMINE-ANTAGONISTS: Centrally-acting compounds that suppress dopamine also suppress the chemoreceptor trigger zone in the medulla.
  • PHENOTHIAZINES: Anti-psychotic agents are also anti-emetic.
    • Very low dose required. But still only administered for this purpose when other agents have failed.
    • INDICATIONS: Post-operative nausea, radiation sickness, ingestion of toxins.
  • METOCLOPRAMIDE:
    • STRUCTURE: Derivative of procainamide
    • MECHANISM: Is anti-emetic and pro-kinetic. It blocks dopamine receptors.
      • Anti-Emetic: Block dopamine-receptors in the brain.
      • Pro-Kinetic: Promote gastric motility, via blocking dopamine receptors in the GI tract.
    • ACTIONS:
      • Stimulates motility in upper GI tract
      • Increases rate of gastric emptying, without speeding up secretions.
      • Increased serum prolactin levels
    • INDICATIONS:
      • Gastroparesis: Relieves delayed gastric emptying. Particularly used with Diabetic Gastroparesis.
      • GERD
      • Prevents nausea and vomiting associated with cancer chemotherapy
      • Treats anorexia nervosa
      • Enhances absorption of ergotamines, used in migraine headaches
• ANTICHOLINERGICS (SCOPOLAMINE): Centrally-acting; effective for treating motion sickness
  • ADVERSE EFFECTS: Causes blurred vision and xerostomia at therapeutic doses.
  • CONTRAINDICATIONS: Use with caution in glaucoma, pyloric obstruction, urinary obstruction.

LAXATIVES:

• CONTACT-STIMULANT LAXATIVES: Castor Oil, Cascara Sagrada
  • MECHANISM: They stimulate the intestinal wall, producing an increase in peristalsis.
    • Increase cAMP, which increases secretion of electrolytes
    • Release prostaglandins
  • CONTRAINDICATION: Pregnancy. Castor oil gets into breast milk too.
• BULK-FORMING AGENTS: Dried fruits have the same effect
  • MECHANISM: They absorb water into the fecal contents and expand, giving more bulk to the stool.
    • Several days may be required before achieving maximal effect.
    • Evacuate only the colon and not the small bowel, thus they are less likely to be habit-forming.
  • Always administer with a full glass of liquid, to avoid impaction.
  • INDICATIONS:
    • Constipation in the elderly.
    • Diverticulosis, Irritable Bowel Syndrome
    • Hemorrhoids, to relieve painful defecation.
• OSMOTIC LAXATIVES:
  • MECHANISM: They pull solutes and water into the bowel, increasing intestinal contents and bulk.
  • INDICATIONS: Powerful, fast-acting cathartics. Active 2-6 hrs after administration.
    • Cleansing the entire GI-tract for diagnostic tests.
    • Flushing poisons or removing parasites from the GI tract.
• FECAL SOFTENERS: Stool softeners
  • MECHANISM: They soften the intestinal contents and retard water absorption.
  • INDICATION: Only to prevent constipation. No catharsis occurs.
• LUBRICANTS: Mineral Oil
  • INDICATIONS: Onset 6-8 hours after administration
    • Treat tearing of hemorrhoids or fissures.
    • Temporary relief of constipation
• LACTULOSE SYRUP:
  • INDICATION: Acidifies the colon, pulling NH₃ into the bowel, thus it is used for hepatic encephalopathy.
  • CONTRAINDICATIONS:
    • Absolute Contraindication: anybody who can't tolerate galactose
    • Pregnant women
    • Patients concurrently receiving neomycin, because neomycin evacuates colonic bacteria, nullifying the effects of lactose.
    • Diabetic patients, because of its high sugar content
  • ADVERSE EFFECTS:
    • Flatulence, intestinal cramps, gas, belching
    • Excessive dose: Diarrhea, hypokalemia, nausea
• ADVERSE EFFECTS:
  • Excessive GI Activity: Nausea, diarrhea, vomiting
  • Perianal irritation, due to frequent stools
  • Abdominal cramps, bloating, flatulence
• CONTRAINDICATIONS: Cathartics are contraindicated in:
  • Undiagnosed abdominal pain (which may be appendicitis)
  • Pregnancy
  • Hemorrhoids
  • Intestinal obstruction
  • After abdominal surgery

INFLAMMATORY BOWEL DISEASE: Crohn's disease usually cannot be managed pharmacologically. Ulcerative Colitis is managed with Sulfasalazine, Mesalamine, Olsalazine Sodium.