Hyperacidity and Its Effects

Antacids and Cation Overload

• Antacids containing NaHCO3 can lead to sodium overload, causing hypertension and systemic alkalosis.
• Calcium-based antacids (Ca2+) can result in hypercalcemia, renal stones, and milk-alkali syndrome.
• Certain metal ions in antacids can chelate drugs like tetracycline, digitalis, and iron, reducing their absorption.
• It is recommended to maintain a 30-minute interval between administration of antacids and these drugs to prevent chelation.

Decrease in HCl Secretion

Selective M1 Blockers

• Selective M1 blockers, such as pirenzepine and telanzepine, reduce gastric HCl secretion by blocking M1 receptors.
• These have been largely replaced by more effective medications but may serve as adjuvant therapy alongside H2 blockers.
• High doses can produce atropine-like side effects: dry mouth, blurred vision, tachycardia, urine retention.
• Atropine is not ideal for peptic ulcer treatment due to its non-selectivity which may worsen esophageal reflux.

H2 Blockers

• H2 blockers (e.g., cimetidine, ranitidine, famotidine, nizatidine) competitively inhibit histamine H2 receptors on parietal cells, leading to decreased HCl secretion.

• Histamine is the primary mediator in acid secretion, despite other agents like gastrin and ACh also contributing.

• Therapeutic uses include:

  • Duodenal and gastric ulcers.
  • Stress ulcer prophylaxis (post-burn or major trauma).
  • Prevention of esophageal varices bleeding.
  • Reflux esophagitis treatment.
  • Zollinger-Ellison syndrome treatment, typically requiring larger doses.
  • Protective use against NSAIDs-induced gastric mucosa damage.

• Adverse effects (notable with cimetidine):

  • Anti-androgenic effects leading to decreased sperm count, impotence, and gynecomastia.
  • Inhibition of hepatic microsomal enzymes (P450), causing decreased metabolism of drugs (e.g., theophylline, warfarin).
  • Risk of reversible hepatotoxicity and anemia.
  • CNS symptoms include headache, confusion, slurred speech, and in severe cases, coma.

• Precautions with H2 blockers:

  • Avoid abrupt withdrawal to prevent rebound ulceration.
  • Contraindicated in pregnancy and lactation (cross placental barrier and secreted in breast milk).
  • Avoid combining cimetidine with drugs of narrow therapeutic index due to increased toxicity from inhibited metabolism.
  • Bioavailability of H2 blockers is significantly affected by food; should be taken 1 hour before meals.

Proton Pump Inhibitors (PPIs)

• PPIs (e.g., omeprazole) decrease gastric acid production and have similar therapeutic uses as H2 blockers, with administration doses of 20-40 mg/day for 4-6 weeks, then maintenance doses of 10-20 mg/day.
• Adverse effects include:
  • Low incidence of gastrointestinal disturbances and transient liver enzyme increase.
  • Long-term therapy (over 12 weeks) may reduce vitamin B12 absorption due to impaired intrinsic factor secretion.
  • Altered bioavailability of other drugs (e.g., ketoconazole, digoxin) due to gastric pH changes.
  • High doses of omeprazole may induce gastric carcinoid tumors in rats.

Enhancing Mucosal Defensive Mechanisms

Sucralfate

• An aluminum salt of sulfated sucrose, minimally absorbed (3%) from the gastrointestinal tract.
• Effective in acidic medium, forming a protective complex with ulcer debris and reducing pepsin secretion, while enhancing prostaglandin production.
• Should not be taken with antacids, H2 blockers, or PPIs due to interference in its mechanism of action.

Bismuth Compounds

• Examples include bismuth subsalicylate and subcitrate, which form protective barriers at the ulcer base in acidic environments.
• They also reduce pepsin secretion and enhance endogenous prostaglandin secretion, while possessing antimicrobial properties against H. pylori.

Selective M1 Blockers

• Inhibit hydrogen chloride (HCl) secretion, once used but replaced by more effective drugs.
• Occasionally administered with H2 blockers as adjuvant therapy.
• High doses can lead to anticholinergic side effects: dry mouth, blurred vision, tachycardia, urinary retention.
• Atropine is not employed for peptic ulcer treatment due to non-selectivity and potential esophageal reflux exacerbation.

H2 Blockers

• Examples: Cimetidine, Ranitidine, Famotidine, Nizatidine.
• Mechanism: Competitive inhibition of histamine H2-receptors on parietal cells reduces stimulated HCl secretion.
• Predominant mediator for HCl secretion is histamine, despite gastrin and acetylcholine also being involved.

Therapeutic Uses

• Treats duodenal and gastric ulcers.
• Prophylaxis and treatment of stress ulcers (post-burn or major trauma).
• Prevents bleeding from esophageal varices.
• Manages reflux esophagitis.
• Addresses Zollinger-Ellison syndrome requiring larger doses due to gastrin-secreting tumors.
• Protects gastric mucosa when using ulcerogenic drugs like NSAIDs.

Adverse Effects (especially Cimetidine)

• Anti-androgenic effects: decreased sperm count, impotence, gynecomastia.
• Inhibits hepatic enzymes (P450), slowing metabolism of other medications (theophylline, warfarin, sulphonylureas).
• Potential for reversible hepatotoxicity and anemia.
• CNS side effects can include headache, slurred speech, delirium, and coma, particularly in the elderly with intravenous administration.

Precautions

• Avoid sudden withdrawal to prevent rebound ulceration.
• Not recommended during pregnancy or lactation due to placental crossing and milk secretion.
• Cimetidine should not be combined with drugs having a narrow therapeutic index due to increased toxicity.

Comparative Analysis of H2 Blockers

• Cimetidine:

  • Weak H2 blocking effect
  • Strong anti-androgenic effect
  • Strong liver enzyme inhibition
  • Frequent CNS side effects
  • Dose: 800 mg/day initially, reduced to 400 mg/day over 6-8 months.

• Ranitidine:

  • Potent H2 blocking effect
  • Minimal anti-androgenic effect
  • Minimal liver enzyme inhibition
  • Less frequent CNS side effects
  • Dose: 300 mg/day initially, reduced to 150 mg/day over 6-8 months.

• Famotidine:

  • More potent H2 blocking effect
  • No anti-androgenic effect
  • No liver enzyme inhibition
  • Least frequent CNS side effects
  • Dose: 20 mg/day initially, reduced to 10 mg/day over 6-8 months.

Proton Pump Inhibitors (PPIs)

• Examples: Omeprazole, Lansoprazole, Pantoprazole.
• Chemistry: All are imidazole derivatives.
• Mechanism: Prodrugs activated in gastric mucosa to irreversibly inhibit the gastric H+/K+ ATPase enzyme, significantly decreasing HCl secretion.
• Acid secretion restoration takes 3-5 days post-discontinuation due to enzyme resynthesis.
• Administered one hour before meals for optimal effect.

Therapeutic Uses

• Similar to H2 blockers, with a common dose of Omeprazole at 20-40 mg/day for 4-6 weeks, followed by continued dosage to prevent recurrence.

Adverse Effects

• Low incidence of diarrhea, abdominal pain, dizziness, and transient liver enzyme increase.
• Potential for decreased vitamin B12 absorption after prolonged use due to interference with intrinsic factor secretion.
• Alters drug bioavailability (e.g., ketoconazole, digoxin, iron).
• Inhibits microsomal P450, affecting drug metabolism (phenobarbital, warfarin, cyclosporine).

Misoprostol

• Typically dosed at 200 µg and combined with NSAIDs (e.g., Naproxen) to prevent gastric injury.

Helicobacter Pylori Eradication Therapy

• Infection with H. pylori is a leading cause of peptic ulcer recurrence.
• Effective treatment includes a bimodal approach known as "sequential protocol" over 10 days.

Management of Bleeding Peptic Ulcer

• Hospitalization may be necessary along with fresh blood transfusions.
• High-dose PPIs like Omeprazole (80 mg IV bolus, then 8 mg/h for 72 hours) are standard for acid suppression.
• Vitamin K1 (10 mg IM or SC) may be used.
• Various endoscopic therapies are available for treatment.

Antacids and Cation Overload

• Sodium (Na+) salts in antacids can lead to hypertension and systemic alkalosis.
• Calcium (Ca2+) salts may cause hypercalcemia, renal stones, and milk-alkali syndrome.
• Antacids can chelate other medications (e.g., tetracyclines, digitalis, iron), necessitating a 30-minute gap when taken together.

HCl Secretion Decrease

• Selective M1 blockers, such as Pirenzepine and Tezepine, reduce basal HCl secretion by blocking gastric M1 receptors.
• Histamine is the key mediator stimulating HCl secretion, despite the role of gastrin and ACh.

Therapeutic Uses of M1 Blockers

• Treats duodenal and gastric ulcers.
• Prophylactic for stress ulcers post-burn or major trauma.
• Prevents bleeding in esophageal varices.
• Addresses reflux esophagitis and Zollinger-Ellison syndrome.
• Provides mucosal protection against ulcerogenic drugs like NSAIDs.

Adverse Effects of Cimetidine

• Anti-androgenic effects leading to decreased sperm count, impotence, and gynecomastia.
• Inhibition of hepatic enzymes (CYP450), affecting drug metabolism (e.g., theophylline, warfarin).
• Reversible hepatotoxicity and anemia, and CNS effects (headaches, delirium) in the elderly.

Precautions with H2 Blockers

• Avoid abrupt withdrawal to prevent rebound ulceration.
• Not recommended during pregnancy and lactation (crosses placental barrier).
• Caution with drugs that have a narrow therapeutic index due to potential toxicity.

Proton Pump Inhibitors (PPIs)

• Same therapeutic uses as H2 blockers; omeprazole dosage: 20-40 mg/day for 4-6 weeks, then 10-20 mg/day for recurrence prevention.
• Low incidence of side effects including diarrhea, dizziness, and skin rash; can affect B12 absorption after 12 weeks.
• Long-term use may necessitate monitoring of drug interactions, as PPIs can inhibit CYP450 enzyme activity.

Carbenoxolone

• A liquorice derivative that increases gastric mucus production and viscosity, enhancing musosal resistance.
• Reduces pepsin secretion and boosts endogenous prostaglandin secretion.
• Can lead to salt and water retention, causing edema and hypertension, especially in cardiac or renal patients.

Synthetic Prostaglandin E1 Analogue: Misoprostol

• Decreases histamine-stimulated HCl secretion and enhances mucus and bicarbonate secretion.
• Increases mucosal blood flow and promotes cellular regeneration.
• Used for preventing peptic ulcers in patients on long-term NSAIDs.

H. pylori Eradication Therapy

• H. pylori infection significantly contributes to peptic ulcer recurrence.
• A "sequential protocol" over 10 days is effective for H. pylori eradication.

Therapy for Bleeding Peptic Ulcers

• Requires hospitalization and potential blood transfusions.
• Continuous intravenous infusion of high-dose PPIs is standard (e.g., omeprazole 80 mg iv bolus followed by 8 mg/h for 72 hours).
• Vitamin K1 administration and various endoscopic treatments are also employed for management.

Selective M1 Blockers

• Inhibit HCl secretion; less effective than newer drugs.
• Used as adjuvant therapy with H2 blockers.
• High doses can cause dry mouth, blurred vision, tachycardia, and urine retention.
• Atropine is a non-selective M1 blocker and may worsen esophageal reflux.

H2 Blockers

• Competitive inhibitors of histamine H2-receptors on parietal cells.
• Decrease histamine-stimulated HCl secretion.
• Examples: Cimetidine, Ranitidine, Famotidine.
• H2 blocking effect:
  • Cimetidine is weak
  • Ranitidine is potent
  • Famotidine is more potent
• Additional properties:
  • Anti-antiandrogenic effects: Cimetidine strong, others minimal to none.
  • Liver enzyme inhibition: Cimetidine strong, Ranitidine minimal, Famotidine none.
  • CNS effects: Cimetidine frequent, others less frequent.
• Duration of action varies:
  • Cimetidine: 8h, Ranitidine: 12h, Famotidine: 24h.
• Standard doses for 6-8 weeks followed by tapering doses.

Proton Pump Inhibitors (PPIs)

• Examples: Omeprazole, Lansoprazole, Pantoprazole; imidazole derivatives.
• Prodrugs activated in gastric mucosa, irreversibly inhibit gastric H+/K+ ATPase.
• Result in nearly total suppression of HCl secretion for 1-2 days.
• Full restoration of acid secretion takes 3-5 days post-treatment.
• Newer PPIs do not affect liver enzymes.
• High doses of Omeprazole have linked to gastric carcinoid tumors in rats.

Enhancing Mucosal Defense Mechanisms

Sucralfate

• An aluminum salt of sulfated sucrose.
• Small absorption (3%) from GIT; caution in renal failure.
• Requires acidic medium for activation; forms a protective barrier at ulcer base.
• Decreases pepsin secretion and increases endogenous prostaglandin secretion.
• Adverse effects: Constipation and decreased absorption of other drugs.

Bismuth Compounds

• Includes Bismuth subsalicylate and subcitrate.
• Form protective barriers at ulcer sites and reduce pepsin secretion.
• Possesses antimicrobial properties against H. pylori.
• Adverse effects: Discoloration of stools and teeth; potential encephalopathy in renal failure.

Carbenoxolone

• A liquorice derivative with a steroid structure.
• Increases mucus production and mucosal resistance; decreases pepsin secretion.
• Adverse effects may lead to salt and water retention, causing edema and hypertension.
• Contraindications include hypertension and renal failure.

Misoprostol

• Synthetic analogue of prostaglandin E1.
• Reduces HCl secretion by acting on gastric parietal cells and enhances mucus and bicarbonate secretion.
• Improves mucosal blood flow and encourages cellular regeneration.
• Used to prevent ulcers in high-risk patients (e.g., NSAID users).
• Adverse effects: Diarrhea, cramping, and potential uterine contractions in pregnancy.

Eradication Therapy for H. pylori

• H. pylori infection is a major cause of peptic ulcer recurrence.
• A sequential protocol over ten days is effective for eradication.

Management of Bleeding Peptic Ulcer

• Hospitalization and possible blood transfusion are essential.
• Acid suppression using high-dose PPIs via continuous IV infusion is standard (e.g., Omeprazole).
• Vitamin K1 may be administered.
• Endoscopic therapy options are available for treatment.

Antacids and Their Effects

• Antacids often contain NaHCO3 and can lead to cation overload causing systemic issues.
• Na+ salts may contribute to hypertension and systemic alkalosis.
• Ca2+ salts can result in hypercalcemia, renal stones, and milk-alkali syndrome.
• Antacids can decrease absorption of other drugs, particularly tetracyclines, digitalis, and iron due to chelation.
• A minimum 30-minute interval is recommended between antacids and the aforementioned drugs to avoid interactions.

Decrease of HCl Secretion

• Selective M1 blockers (e.g., Pirenzepine) reduce gastric HCl secretion by blocking M1 receptors.
• They are less effective than newer drugs and may cause side effects such as dry mouth, blurred vision, tachycardia, and urinary retention.

H2 Blockers

• Drugs such as Cimetidine, Ranitidine, Famotidine, and Nizatidine inhibit histamine H2-receptors in parietal cells, decreasing HCl secretion.
• Therapeutic uses include treatment of duodenal and gastric ulcers, stress ulcer prophylaxis, and reflux esophagitis.
• Cimetidine has notable adverse effects, including anti-androgenic effects (impotence, gynecomastia), inhibition of hepatic enzyme P450 (impacting drug metabolism), and CNS symptoms.

Precautions with H2 Blockers

• Avoid abrupt discontinuation to prevent rebound ulcers.
• Not recommended during pregnancy and lactation since they cross the placental barrier.
• Caution with drugs that have a narrow therapeutic index due to potential toxicity.

Proton Pump Inhibitors (PPIs)

• Omeprazole is commonly used, with doses varying during treatment to prevent recurrence.
• Potential side effects include gastrointestinal issues, changes in liver enzyme levels, and decreased absorption of vitamin B12 after prolonged use.
• PPIs can impact the bioavailability of other drugs, especially those requiring acidic environments for absorption.

Carbenoxolone

• A liquorice derivative that increases gastric mucus production and viscosity.
• It inhibits pepsin secretion and enhances endogenous prostaglandin production.
• Side effects include salt and water retention, leading to edema and hypertension, manageable by thiazide diuretics.
• Contraindications for use include hypertension and renal failure due to aldosterone-like effects.

Misoprostol

• A synthetic PGE1 analogue that targets specific receptors in gastric parietal cells to reduce HCl secretion.
• It enhances mucus and bicarbonate secretion for cytoprotection and increases mucosal blood flow, promoting cellular regeneration.
• Useful in preventing peptic ulcers in high-risk patients, especially those on long-term NSAIDs.

This quiz examines the relationships between hyperacidity, cation overload, and various health conditions such as hypertension and hypercalcemia. It focuses on the roles of sodium and calcium salts and their implications in medical terms. Test your understanding of these concepts and their physiological impacts.