Drugs for Peptic Ulcer

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Chapter: Essential pharmacology : Drugs For Peptic Ulcer

Peptic ulcer occurs in that part of the gastrointestinal tract (g.i.t.) which is exposed to gastric acid and pepsin, i.e. the stomach and duodenum. The etiology of peptic ulcer is not clearly known.


DRUGS FOR PEPTIC ULCER

 

Peptic ulcer occurs in that part of the gastrointestinal tract (g.i.t.) which is exposed to gastric acid and pepsin, i.e. the stomach and duodenum. The etiology of peptic ulcer is not clearly known. It results probably due to an imbalance between the aggressive (acid, pepsin, bile and H. pylori) and the defensive (gastric mucus and bicarbonate secretion, prostaglandins, nitric oxide, innate resistance of the mucosal cells) factors. A variety of psychosomatic, humoral and vascular derangements have been implicated and the importance of Helicobacter pylori infection as a contributor to ulcer formation and recurrence has been recognized.

 

In gastric ulcer, generally acid secretion is normal or low. In duodenal ulcer, acid secretion is high in half of the patients but normal in the rest. Notwithstanding whether production of acid is normal or high, it does contribute to ulceration as an aggressive factor, reduction of which is the main approach to ulcer treatment. An understanding of the mechanism and control of gastric acid secretion will elucidate the targets of antisecretory drug action.

 

Regulation Of Gastric Acid Secretion

 

The mechanisms operating at the gastric parietal cells are summarized in Fig. 46.1. The terminal enzyme H+K+ATPase (proton pump) which secretes H+ ions in the apical canaliculi of parietal cells can be activated by histamine, ACh and gastrin acting via their own receptors located on the basolateral membrane of these cells. Out of the three physiological secretagogues, histamine, acting through H2 receptors, plays the dominant role, because the other two, gastrin and ACh act partly directly and to a greater extent indirectly by releasing histamine from paracrine enterochromaffinlike cells called “histaminocytes” located in the oxyntic glands. While H2 receptors activate H+K+ATPase by generating cAMP, muscarinic and gastrin/cholecystokinin (CCK2) receptors appear to function through the phospholipase C  IP3–DAG pathway that mobilizes intracellular Ca2+. The cAMP mediated proton pump activation also involves Ca2+. The secretomotor response to gastrin and cholinergic agonists is expressed fully only in the presence of cAMP generated by H2 activation. As such, histamine participates in the acid response to gastrin and ACh at more than one levels, and H2 antagonists suppress not only histamine, but also ACh, pentagastrin and in fact any gastric acid secretory stimulus.

 


 

Gastrin is secreted from the antrum in response to rise in antral pH, food constituents and vagally mediated reflexes. The dominant muscarinic receptor mediating vagal responses is of the M1 subtype. Its location on the ganglion cells of the intramural plexuses has been confirmed. The parietal cell muscarinic receptor is of the M3 subtype but the subtype of muscarinic receptor on histaminocytes has not been defined. Vagus releases ACh in close proximity to histaminocytes and gastrin secreting cells, but apparently at a distance from the parietal cells. As such, vagal effects are exerted largely indirectly through histamine and gastrin.

 

Prostaglandins have been ascribed a “cytoprotective” role in the gastric mucosa by augmenting mucus and bicarbonate secretion, as well as other actions. PGE2, produced by gastric mucosa, inhibits acid secretion by opposing cAMP generation (in parietal cells) and gastrin release (from antral cells).

 

Approaches For The Treatment Of Peptic Ulcer Are:

 

1. Reduction Of Gastric Acid Secretion

 

a) H2 antihistamines: Cimetidine, Ranitidine, Famotidine, Roxatidine

 

b) Proton pump inhibitors: Omeprazole, Lansoprazole, Pantoprazole, Rabeprazole, Esomeprazole

 

c) Anticholinergics: Pirenzepine, Propantheline, Oxyphenonium

 

d) Prostaglandin analogue: Misoprostol

 

2. Neutralization Of Gastric Acid (Antacids)

 

a) Systemic: Sodium bicarbonate, Sod. citrate

 

b) Nonsystemic: Magnesium hydroxide, Mag. trisilicate, Aluminium hydroxide gel, Magaldrate, Calcium carbonate

 

3. Ulcer Protectives: Sucralfate, Colloidal bismuth subcitrate (CBS)

 

4. Anti-H. Pylori Drugs: Amoxicillin, Clarithromycin, Metronidazole, Tinidazole, Tetracycline

 

H2 ANTAGONISTS

 

These are the first class of highly effective drugs for acidpeptic disease. Four H2 antagonists cimetidine, ranitidine, famotidine and roxatidine are available in India; many others are marketed elsewhere. Their interaction with H2 receptors has been found to be competitive in case of cimetidine, ranitidine and roxatidine, but competitive-noncompetitive in case of famotidine. Cimetidine was the first H2 blocker to be introduced clinically and is described as the prototype, though other H2 blockers are more commonly used now.

 

Pharmacological Actions

 

1. H2 Blockade

 

Cimetidine and all other H2 antagonists block histamine-induced gastric secretion, cardiac stimulation (prominent in isolated preparations, especially in guinea pig), uterine relaxation (in rat) and bronchial relaxation (H2 blockers potentiate histamine induced bronchospasm). They attenuate fall in BP due to histamine, especially the late phase response seen with high doses. They are highly selective: have no effect on H1 mediated responses or on the action of other transmitters/autacoids.

 

2. Gastric Secretion

 

The only significant in vivo action of H2 blockers is marked inhibition of gastric secretion. All phases (basal, psychic, neurogenic, gastric) of secretion are suppressed dose-dependently, but the basal nocturnal secretion is suppressed more completely. Secretory responses to not only histamine but all other stimuli (ACh, gastrin, insulin, alcohol, food) are attenuated. This reflects the permissive role of histamine in amplifying responses to other secretagogues. The volume, pepsin content and intrinsic factor secretion are also reduced. However, normal vit B12 absorption is not interfered: no vit B12 deficiency occurs even after prolonged use.

 

The usual ulcer healing doses produce 60–70% inhibition of 24 hr acid output. The Hblockers have antiulcerogenic effect. Gastric ulceration due to stress and drugs (NSAIDs, cholinergic, histaminergic) is prevented. They do not have any direct effect on gastric or esophageal motility or on lower esophageal sphincter (LES) tone.

 

Pharmacokinetics

 

Cimetidine is adequately absorbed orally, though bioavailability is 60–80% due to first pass hepatic metabolism. Absorption is not interfered by presence of food in stomach. It crosses placenta and reaches milk, but penetration in brain is poor because of its hydrophilic nature. About 2/3 of a dose is excreted unchanged in urine and bile, the rest as oxidized metabolites. The elimination t½ is 2–3 hr. Dose reduction is needed in renal failure.

 

Adverse Effects

 

Cimetidine is well tolerated by most patients: adverse effects occur in < 5%. These are generally mild.

 

·     Headache, dizziness, bowel upset, dry mouth, rashes.

·  CNS effects like confusional state, restlessness, convulsions and coma have occurred infrequently in elderly patients, in those with renal impairment, especially with large doses infused i.v.

·  Bolus i.v. injection can release histamine—has caused bradycardia, arrhythmias and cardiac arrest: it should always be given by slow infusion.

· Cimetidine (but not other H2 blockers) has antiandrogenic action (displaces dihydrotestosterone from its cytoplasmic receptor), increases plasma prolactin and inhibits degradation of estradiol by liver. High doses given for long periods have produced gynaecomastia, loss of libido, impotence and temporary decrease in sperm count.

·    Transient elevation of plasma aminotransferases; but hepatotoxicity is rare.

Interactions

 

Cimetidine inhibits several cytochrome P450 isoenzymes and reduces hepatic blood flow. It inhibits the metabolism of many drugs so that they can accumulate to toxic levels, e.g. theophylline, phenytoin, carbamazepine, phenobarbitone, sulfonylureas, metronidazole, warfarin, imipramine, lidocaine, nifedipine, quinidine. Metabolism of propranolol and diazepam is also retarded, but this may not be clinically significant.

 

Antacids reduce absorption of all H2 blockers. When used concurrently a gap of 2hr should be allowed. Ketoconazole absorption is decreased by cimetidine (probably by other H2 blockers also).

 

Dose: For ulcer healing—400 mg BD or 800 mg at bed time orally; maintenance—400 mg at bed time; for stress ulcer— 50 mg/hr i.v. infusion.

 

CIMETIDINE 200 mg, 400 mg, 800 mg tabs, 200 mg/2 ml inj., LOCK2 200 mg tab.

 

Ranitidine

 

A nonimidazole (has a furan ring) H2 blocker, it has several desirable features compared to cimetidine:

 

a) About 5 times more potent than cimetidine. Though its pharmacokinetic profile and t½ of 2–3 hr is similar to cimetidine, a longer duration of action with greater 24 hr acid suppression is obtained clinically because of higher potency.

 

b)No antiandrogenic action, does not increase prolactin secretion or spare estradiol from hepatic metabolism—no effect on male sexual function or gynaecomastia.

 

c) Lesser permeability into the brain: lower propensity to cause CNS effects. In fact, little effect outside g.i.t. has been observed.

 

d)Does not significantly inhibit hepatic metabolism of other drugs; drug interactions mostly have no clinical relevance.

 

e) Overall incidence of side effects is lower: headache, diarrhoea/constipation, dizziness have an incidence similar to placebo.

 

Dose: for ulcer healing 300 mg at bed time or 150 mg BD; for maintenance 150 mg at bed time. Parenteral dose— 50 mg i.m. or slow i.v. inj. every 6–8 hr (rapid i.v. injection can cause hypotension), 0.1–0.25 mg/kg/hr by i.v. infusion has been used for prophylaxis of stress ulcers.

 

For gastrinoma 300 mg 3–4 times a day.

 

ULTAC, ZINETAC 150 mg, 300 mg tabs; HISTAC, RANITIN, ACILOC, RANTAC 150 mg, 300 mg tabs, 50

 

mg/2 ml inj.

 

Famotidine

 

A thiazole ring containing H2 blocker which binds tightly to H2 receptors and exhibits longer duration of action despite an elimination t½ of 2.5–3.5 hr. Some inverse agonistic action on H2 receptors (in the absence of histamine) has been demonstrated. It is 5–8 times more potent than ranitidine and antiandrogenic action is absent. Because of low affinity for cytochrome P450 and the low dose, drug metabolism modifying propensity is minimal.

 

The oral bioavailability of famotidine is 40–50% and it is excreted by the kidney, 70% in the unchanged form. Incidence of adverse effects is low: only headache, dizziness, bowel upset, rarely disorientation and rash have been reported. Because of the higher potency and longer duration, it has been considered more suitable for ZE syndrome and for prevention of aspiration pneumonia.

 

Dose: 40 mg at bed time or 20 mg BD (for healing); 20 mg at bed time for maintenance; upto 480 mg/day in ZE syndrome; parenteral dose 20 mg i.v. 12 hourly.

 

FAMTAC, FAMONITE, TOPCID 20 mg, 40 mg tabs; FAMOCID, FACID 20, 40 mg tabs, 20 mg/2 ml inj.

 

Roxatidine

 

The pharmacodynamic, pharmacokinetic and side effect profile of roxatidine is similar to that of ranitidine, but it is twice as potent and longer acting. It has no antiandrogenic or cytochrome P450 inhibitory action.

 

Dose: 150 mg at bed time or 75 mg BD; maintenance 75 mg at bed time.

 

ROTANE, ZORPEX 75 mg, 150 mg SR tabs.

 

Uses

 

The H2 blockers are used in conditions in which it is profitable to suppress gastric acid secretion. Used in appropriate doses, all available agents have similar efficacy. However, proton pump inhibitors (PPIs), because of higher efficacy and equally good tolerability, have outstripped H2 blockers.

 

Duodenal Ulcer

 

H2 blockers produce rapid and marked pain relief (within 2–3 days); 60–85% ulcers heal at 4 weeks and 70–95% ulcers at 8 weeks.

 

Suppression of nocturnal secretion by single high bed time dose is equally efficacious and physiologically more sound (continuous achlorhydria is considered undesirable). About ½ of the patients relapse within 1 year of healing with H2 blockers. Maintenance therapy with bedtime dose reduces the relapse rate to 15–20% per year. However, when such treatment is withdrawn relapses occur with the same frequency.

 

Gastric Ulcer

 

Healing rates obtained in gastric ulcer are somewhat lower (50–75% at 8 weeks). However, doses remain the same. Maintenance therapy reduces recurrences as long as continued. H2 blockers can heal NSAID associated ulcers, but are less effective than PPIs or misoprostol. H2 blockers (i.v. or oral) are commonly administered in bleeding peptic ulcer, but benefits are uncertain.

 

Stress Ulcers And Gastritis

 

Acutely stressful situations like hepatic coma, severe burns and trauma, prolonged surgery, prolonged intensive care, renal failure, asphyxia neonatorum, etc. are associated with gastric erosions and bleeding. Intravenous infusion of H2 blockers successfully prevents the gastric lesions and haemorrhage.

 

Zollinger-Ellison Syndrome

 

It is a gastric hypersecretory state due to a rare tumour secreting gastrin. H2 blockers in high doses control hyperacidity and symptoms in many patients, but relief is often incomplete and side effects frequent. PPIs are the drugs of choice. Definitive treatment is surgical.

 

Gastroesophageal Reflux Disease (GERD)

 

H2 blockers afford symptomatic relief and facilitate healing of esophageal erosions by reducing acidity of gastric contents that are refluxed; long-term treatment, preferably with 2–3 divided daily doses, is needed. However, they are less effective in this condition than PPIs; are indicated only in mild or stage1 cases of GERD.

 

Prophylaxis Of Aspiration Pneumonia

 

H2 blockers given preoperatively (preferably evening before also) reduce the risk of aspiration of acidic gastric contents during anaesthesia and surgery.

 

Other Uses

 

H2 blockers have adjuvant beneficial action in certain cases of urticaria who do not adequately respond to an H1 antagonist alone.

 

 

PROTON PUMP INHIBITORS (PPIs)

 

Omeprazole

 

It is the prototype member of substituted benzimidazoles which inhibit the final common step in gastric acid secretion and have overtaken H 2 blockers for acid-peptic disorders. The only significant pharmacological action of omeprazole is dose dependent suppression of gastric acid secretion; without anticholinergic or H2 blocking action. It is a powerful inhibitor of gastric acid: can totally abolish HCl secretion, both resting as well as that stimulated by food or any of the secretagogues, without much effect on pepsin, intrinsic factor, juice volume and gastric motility.

 

Omeprazole is inactive at neutral pH, but at pH < 5 rearranges to two charged cationic forms (a sulphenic acid and a sulphenamide configurations) that react covalently with SH groups of the H+K+ATPase enzyme and inactivate it irreversibly, especially when two molecules of omeprazole react with one molecule of the enzyme. After diffusing into the parietal cell from blood, it gets concentrated in the acidic pH of the canaliculi because the charged forms generated there are unable to diffuse back. Moreover, it gets tightly bound to the enzyme. These features and the specific localization of H+K+ATPase to the apical membrane of the parietal cells confer high degree of selectivity of action to omeprazole. Acid secretion resumes only when new H+K+ATPase molecules are synthesized. It also inhibits gastric mucosal carbonic anhydrase.

 

 

The oral absorption of omeprazole is ~50%, because of instability at acidic pH. As the gastric pH rises, a higher fraction (up to 3/4) may be absorbed. Bioavailability of all PPIs is reduced by food; they should be taken in empty stomach, followed 1 hour later by a meal to activate the H+K+ ATPase and make it more susceptible to the PPI. Omeprazole is highly plasma protein bound, rapidly metabolised in liver by CYP2C19 and CYP3A4 (plasma t½ ~1 hr) and metabolites are excreted in urine. No dose modification is required in elderly or in renal/hepatic impairment. Because of tight binding to its target enzyme—it can be detected in the gastric mucosa long after its disappearance from plasma. As such, inhibition of HCl secretion occurs within 1 hr, reaches maximum at 2 hr, is still half maximal at 24 hr and lasts for 3 days. Because only actively acid secreting proton pumps are inhibited, and only few pumps may be active during the brief interval that the PPI is present (all have 1–2 hours plasma t½), antisecretory action increases on daily dosing to reach a plateau after 4 days. All PPIs produce 80–98% suppression of 24 hour acid output with conventional doses at steady state. Secretion resumes gradually over 3–5 days of stopping the drug.

 

Because of marked and long lasting acid suppression, compensatory hypergastrinemia has been observed. This has been found to induce proliferation of parietal cells and gastric carcinoid tumours in rats, but not in human beings. Though patients have been treated continuously for > 11 years without any problem, it may appear prudent to be apprehensive of prolonged achlorhydria and hyper-gastrinaemia, and if possible avoid long-term use of PPIs.

 

Uses

 

1. Peptic Ulcer: Omeprazole 20 mg OD is equally or more effective than H2 blockers. Relief of pain is rapid and excellent. Faster healing has been demonstrated with 40 mg/day: some duodenal ulcers heal even at 2 weeks and the remaining at 4 weeks. Gastric ulcer generally requires 4–8 weeks. It has caused healing of ulcers in patients not responding to H2 blockers. Continued treatment (20 mg daily or thrice weekly) can prevent relapse. PPIs are an integral component of anti-H. pylori therapy. PPIs are the drugs of choice for NSAID induced gastric/ duodenal ulcers. Healing may occur despite continued use of the NSAID.

 

2. Bleeding Peptic Ulcer: Acid enhances clot dissolution promoting ulcer bleed. Suppression of gastric acid has been found to facilitate clot formation reducing blood loss and rebleed. High dose i.v. PPI therapy (pantoprazole 40–120 mg/ day or rabeprazole 40–80 mg/day) profoundly inhibits gastric acid, and has been shown to reduce rebleeding after therapeutic endoscopy. Even in cases where the bleeding vessel could not be visualized, i.v. followed by oral PPI reduces recurrence and need for surgery.

 

3.  Stress Ulcers: Intravenous pantoprazole is as effective prophylactic (if not more) for stress ulcers as i.v. H2 blockers.

 

4. Gastroesophageal Reflux Disease (GERD): Omeprazole produces more complete round-the-clock inhibition of gastric acid resulting in rapid symptom relief and is more effective than H2 blockers in promoting healing of esophageal lesions. PPIs are the drugs of choice for patients with frequent or chronic symptoms and/or esophagitis/erosions; i.e. stage2 or stage3 GERD. Dose: 20–60 mg daily in 1 or 2 doses. Many patients require continued therapy since cause is not corrected.

 

5. Zollinger-Ellison Syndrome: Omeprazole is more effective than H2 blockers in controlling hyperacidity in ZE syndrome. However, 60–120 mg/day or more (in 2 divided doses) is often required for healing of ulcers. Inoperable cases have been treated for >6 years with sustained benefit and no adverse effects. Other gastric hypersecretory states like systemic mastocytosis, endocrine adenomas, etc. also respond well.

 

6. Aspiration Pneumonia: PPIs are an alternative to H2 blockers for prophylaxis of aspiration pneumonia due to prolonged anaesthesia.

 

OMIZAC, NILSEC 20 mg cap. OMEZ, OCID, OMEZOL 10, 20 mg caps, PROTOLOC 20, 40 mg caps containing enteric coated granules.

Capsules must not be opened or chewed; to be taken in the morning before meals.

 

Adverse Effects

 

These are minimal: nausea, loose stools, headache, abdominal pain, muscle and joint pain, dizziness are complained by 3–5%. Rashes (1.5% incidence), leucopenia and hepatic dysfunction are infrequent. On prolonged treatment atrophic gastritis has been reported occasionally.

 

Lately, few reports of gynaecomastia and erectile dysfunction, possibly due to reduced testosterone level, on prolonged use of omeprazole have appeared. Accelerated osteoporosis among elderly due to reduced calcium absorption has been recently associated with highdose long-term use of PPIs for GERD.

 

Interactions

 

Omeprazole inhibits oxidation of certain drugs: diazepam, phenytoin and warfarin levels may be increased. Clarithromycin inhibits omeprazole metabolism and increases its plasma concentration.

 

Esomeprazole

 

It is the Senantiomer of omeprazole; claimed to have higher oral bioavailability and to produce better control of intragastric pH than omeprazole in GERD patients because of longer t½. Higher healing rates of erosive esophagitis and better GERD symptom relief have been reported in comparative trials with omeprazole. Side effect and drug interaction profile is similar to the recemic drug.

 

Dose: 20–40 mg OD; NEXPRO, RACIPER, IZRA 20, 40 mg tabs.

 

Lansoprazole

 

Somewhat more potent than omeprazole but similar in properties. Inhibition of H+ K+ ATPase by lansoprazole is partly reversible. It has higher oral bioavailability, faster onset of action and slightly longer t½ than omeprazole. Dose should be reduced in liver disease. Side effects are similar, but drug interactions appear to be less significant; diazepam and phenytoin metabolism may be reduced.

Ulcer healing dose: 15–30 mg OD; LANZOL, LANZAP, LEVANT, LANPRO 15, 30 mg caps.

 

Pantoprazole

 

It is a newer H+ K+ ATPase inhibitor, similar in potency and clinical efficacy to omeprazole, but is more acid stable and has higher oral bioavailability. It is also available for i.v. administration; particularly employed in bleeding peptic ulcer and for prophylaxis of acute stress ulcers. It has lower affinity for cytochrome P450 than omeprazole or lansoprazole: risk of drug interactions is minimal.

 

Dose: 40 mg OD; PANTOCID, PANTODAC 40 mg enteric coated tab; PANTIUM 40 mg tab, 40 mg inj for i.v. use.

 

S-Pantoprazole

 

It is the active single enantiomer, twice as potent as the recemate.

 

PANPURE, ZOSECTA 20 mg tab.

 

Rabeprazole

 

This newer PPI is claimed to cause fastest acid suppression (due to higher pKa, it is more rapidly converted to the active species) and to aid gastric mucin synthesis. However, potency and efficacy are similar to omeprazole.

 

Dose: 20 mg OD; ZE syndrome — 60 mg/day. RABLET, PRORAB, RABELOC, RABICIP, RAZO 10, 20 mg tab; HAPPI 10, 20 mg tab, 20 mg/vial inj.

 

 

ANTICHOLINERGICS


 

Atropinic drugs reduce the volume of gastric juice without raising its pH unless there is food in stomach to dilute the secreted acid. Stimulated gastric secretion is less completely inhibited. Effective doses (for ulcer healing) of nonselective antimuscarinics (atropine, propantheline, oxyphenonium) invariably produce intolerable side effects. Introduction of H2 blockers and PPIs has sent them into oblivion.

 

Pirenzepine

 

It is a selective M1 anticholinergic that has been used in Europe for peptic ulcer. Gastric secretion is reduced by 40–50% without producing intolerable side effects, but side effects occur with slight excess. It has not been used in India and USA.

 
PROSTAGLANDIN ANALOGUE

 


PGE2 and PGI2 are produced in the gastric mucosa and appear to serve a protective role by inhibiting acid secretion and promoting mucus + HCO3¯ secretion (see Ch. No. 13). In addition, PGs inhibit gastrin production, increase mucosal blood flow and probably have an ill-defined “cytoprotective” action. However, the most important appears to be their ability to reinforce the mucus layer covering gastric and duodenal mucosa which is buffered by HCO3¯ secreted into this layer by the underlying epithelial cells.

 

Natural PGs have very short t½. A number of stable PG analogues which exert action for hours rather than minutes have been developed for use in peptic ulcer. Misoprostol (methylPGE1 ester) is commercially available. It inhibits acid output dose dependently. However, reduction in 24 hrs acid production is less than H2 blockers because of shorter duration of action (~3 hr.) Ulcer healing rates comparable to cimetidine have been obtained in 4–8 weeks, but misoprostol is poorer in relieving ulcer pain. Some patients may even complain of increased pain during the first week of therapy.

 

Dose: 200 μg QID; CYTOLOG 200 μg tab; MISOPROST 100 μg, 200 μg tabs.

 

Major problems in the use of misoprostol are—diarrhoea, abdominal cramps, uterine bleeding, abortion, and need for multiple daily doses. Patient acceptability is poor.

 

The primary use of PG analogues is in the prevention and treatment of NSAID associated gastrointestinal injury and blood loss. However, PPIs are more effective, more convenient, better tolerated and cheaper.

 

 

ANTACIDS

 

These are basic substances which neutralize gastric acid and raise pH of gastric contents. Peptic activity is indirectly reduced if the pH rises above 4, because pepsin is secreted as a complex with an inhibitory terminal moiety that dissociates below pH 5: optimum peptic activity is exerted between pH 2 to 4.

 

Antacids do not decrease acid production; rather, agents that raise the antral pH to > 4 evoke reflex gastrin release  more acid is secreted, especially in patients with hyperacidity and duodenal ulcer; “acid rebound” occurs and gastric motility is increased.

 

The potency of an antacid is generally expressed in terms of its acid neutralizing capacity (ANC), which is defined as number of mEq of 1N HCl that are brought to pH 3.5 in 15 min (or 60 min in some tests) by a unit dose of the antacid preparation. This takes into consideration the rate at which it dissolves and reacts with HCl. This is important because a single dose of any antacid taken in empty stomach acts for 30– 60 min only, since in this time any gastric content is passed into duodenum. Taken with meals antacids may act for at the most 2–3 hr.

 

Systemic Antacids

 

Sodium Bicarbonate

 

It is water soluble, acts instantaneously, but the duration of action is short. It is a potent neutralizer (1 g  12 mEq HCl), pH may rise above 7.

However, it has several demerits:

 

·      Absorbed systemically: large doses will induce alkalosis.

·      Produces CO2 in stomach  distention, discomfort, belching, risk of ulcer perforation.

·      Acid rebound occurs, but is usually short lasting.

·      Increases Na+ load: may worsen edema and CHF. Use of sod. bicarbonate is restricted to casual treatment of heartburn: provides quick symptomatic relief.

 

Other uses are to alkalinize urine and to treat acidosis.

 

Sodium citrate Properties similar to sod. bicarbonate; 1 g neutralizes 10 mEq HCl; CO2 is not evolved.

 

Nonsystemic  Antacids

 

These are insoluble and poorly absorbed basic compounds; react in stomach to form the corresponding chloride salt. The chloride salt again reacts with the intestinal bicarbonate so that HCO3¯ is not spared for absorption—no acid-base disturbance occurs. However, small amounts that are absorbed have the same alkalinizing effect as NaHCO3.

 

Mag. hydroxide has low water solubility: its aqueous suspension (milk of magnesia) has low concentration of OH¯ ions and thus low alkalinity. However, it reacts with HCl promptly and is an efficacious antacid (1 g  30 mEq HCl). Rebound acidity is mild and brief.

 

MILK OF MAGNESIA 0.4 g/5 ml suspension: 5 ml neutralizes 12 mEq acid.

 

Magnesium trisilicate has low solubility and reactivity; 1 g can react with 10 mEq acid, but in clinical use only about 1 mEq is neutralized.

 

About 5% of administered Mg is absorbed systemically—may cause problem if renal function is inadequate.

 

All Mg salts have a laxative action—by generating osmotically active MgCl2 in the stomach and through Mg2+ ion induced cholecystokinin release. Soluble Mg salts are used as osmotic purgatives.

 

Aluminium Hydroxide Gel

 

It is a bland, weak and slowly reacting antacid. On keeping it slowly polymerizes to variable extents into still less reactive forms. Thus, the ANC of a preparation gradually declines on storage. Also, the product from different manufacturers may have differing ANCs; usually it varies from 1–2.5 mEq/g. Thus, 5 ml of its suspension may neutralize just 1 mEq HCl. As such, little worthwhile acid neutralization is obtained at conventional doses.

 

The Al3+ ions relax smooth muscle. Thus, it delays gastric emptying. Alum. hydrox. frequently, causes constipation due to its smooth muscle relaxant and mucosal astringent action.

 

Alum. hydrox. binds phosphate in the intestine and prevents its absorption—hypophosphatemia occurs on regular use. This may:

 

·      cause  osteomalacia

·      be used therapeutically in hyperphosphatemia and phosphate stones.

 

Small amount of Al3+ that is absorbed is excreted by kidney which is not possible in renal failure—aluminium toxicity (encephalopathy, osteoporosis) can occur.

 

ALUDROX 0.84 g tab, 0.6 g/10 ml susp.

 

Magaldrate

 

It is a hydrated complex of hydroxymagnesium aluminate that initially reacts rapidly with acid and releases alum. hydrox. which then reacts more slowly. The freshly released alum. hydrox. is in the unpolymerized more reactive form. Thus, magaldrate cannot be equated to a physical mixture of mag. and alum. hydroxides. It is a good antacid with prompt and sustained neutralizing action. Its ANC is estimated to be 28 mEq HCl/g.

 

STACID 400 mg tab, 400 mg/5 ml susp.; ULGEL 400 mg with 20 mg simethicone per tab or 5 ml susp.

 

Calcium Carbonate

 

It is a potent and rapidly acting acid neutralizer (1 g  20 mEq HCl), but ANC of commercial preparations is less and variable due to differing particle size and crystal structure. Though it liberates CO2 in the stomach at a slower rate than NaHCO3, it can cause distention and discomfort. The Ca2+ ions are partly absorbed.

 

The greatest drawback of CaCO3 as an antacid is that Ca2+ ions diffuse into the gastric mucosa—increase HCl production directly by parietal cells as well as by releasing gastrin. Acid rebound is marked. Cal. carbonate is constipating in most individuals, but in some it causes loose motions. The absorbed calcium can be dangerous in renal insufficiency.

 

Milk Alkali Syndrome

 

In the past, large quantity of milk was prescribed with CaCO3 (or NaHCO3) for peptic ulcer. Such regimen often produced a syndrome characterized by headache, anorexia, weakness, abdominal discomfort, abnormal Ca deposits and renal stones due to concurrent hypercalcaemia and alkalosis. It is rare now.

 

Antacid Combinations

 

A combination of two or more antacids is frequently used. These may be superior to any single agent on the following accounts:

 

·      Fast (Mag. hydrox.) and slow (Alum. hydrox.) acting components yield prompt as well as sustained effect.

 

·      Mag. salts are laxative, while alum. salts are constipating: combination may annul each other’s action and bowel movement may be least affected.

 

·      Gastric emptying is least affected; while alum. salts tend to delay it, mag./cal. salts tend to hasten it.

 

·    Dose of individual components is reduced; systemic toxicity (dependent on fractional absorption) is minimized.

 

Some available antacid combinations are:

 

ACIDIN: Mag. carb. 165 mg, dried alum. hydrox. gel 232 mg, cal. carb. 165 mg, sod. bicarb. 82 mg, with kaolin 105 mg and belladonna herb 30 μg per tab.

 

ALMACARB: Dried alum. hydrox. gel 325 mg, mag. carb. 50 mg, methyl polysilox. 40 mg, deglycyrrhizinated liquorice 380 mg per tab.

 

ALLUJELDF: Dried alum. hydrox. gel 400 mg, mag.

 

hydrox. 400 mg, methyl polysilox. 30 mg per 10 ml susp.

 

DIGENE: Dried alum. hydrox. gel 300 mg, mag. alum. silicate 50 mg, mag. hydrox. 25 mg, methylpolysilox. 10 mg per tab.

 

DIGENE GEL: Mag. hydrox. 185 mg, alum. hydrox. gel 830 mg, sod. carboxymethyl cellulose 100 mg, methylpolysilox. 25 mg per 10 ml susp.

 

GELUSIL:  Dried        alum. hydrox. Gel 250 mg, mag. trisilicate 500 mg per tab.

 

GELUSIL LIQUID: Mag. Trisilicate 625 mg, alum. hydrox. gel 312 mg per 5 ml susp.

 

MUCAINE: Alum. hydrox. 290 mg, mag. hydrox. 98 mg, oxethazaine 10 mg per 5 ml susp.

 

TRICAINEMPS: Alum. hydrox. gel 300 mg, mag. hydrox. 150 mg, oxethazaine 10 mg, simethicone 10 mg per 5 ml gel.

 

MAYLOX: Dried alum. hydrox. gel 225 mg, mag. hydrox. 200 mg, dimethicone 50 mg per tab and 5 ml susp.

 

POLYCROL FORTE GEL: Mag. hydrox. 100 mg, dried alum. hydrox. gel 425 mg, methylpolysilox. 125 mg per 5 ml susp.

 

 

Drug Interactions

 

By raising gastric pH and by forming complexes, the nonabsorbable antacids decrease the absorption of many drugs, especially tetracyclines, iron salts, fluoroquinolones, ketoconazole, H2 blockers, diazepam, phenothiazines, indomethacin, phenytoin, isoniazid, ethambutol and nitrofurantoin. Stagger their administration by 2 hours. The efficacy of nitrofurantoin is also reduced by alkalinization of urine.

 

Uses

 

Antacids are no longer used for healing peptic ulcer because they are needed in large and frequent doses, are inconvenient, can cause acid rebound and bowel upset, afford little nocturnal protection and have poor patient acceptability. Antacids are now employed only for intercurrent pain relief and acidity, mostly selfprescribed by the patients as over the counter preparations. They continue to be used for nonulcer dyspepsia and minor episodes of heartburn.

 

Gastroesophageal reflux Antacids afford faster symptom relief than drugs which inhibit acid secretion, but do not provide sustained benefit. May be used off and on for acid eructation and heartburn.

 

 

ULCER  PROTECTIVES

 

Sucralfate

 

It is a basic aluminium salt of sulfated sucrose; a drug of its own kind. Sucralfate polymerizes at pH < 4 by cross linking of molecules, assuming a sticky gel-like consistency. It preferentially and strongly adheres to ulcer base, especially duodenal ulcer; has been seen endoscopically to remain there for ~ 6 hours. It precipitates surface proteins at ulcer base and acts as a physical barrier preventing acid, pepsin and bile from coming in contact with the ulcer base. Dietary proteins get deposited on this coat, forming another layer.

 

Sucralfate has no acid neutralizing action, but delays gastric emptying—its own stay in stomach is prolonged. Augmented gastric mucosal PG synthesis may supplement physical protective action of sucralfate.

 

Sucralfate is minimally absorbed after oral administration; action is entirely local. It promotes healing of both duodenal and gastric ulcers; efficacy has been found similar to cimetidine at 4 weeks. It is considered to be superior in patients who continue to smoke. However, sucralfate is infrequently used now because of need for 4 large well-timed daily doses and the availability of simpler H2 blockers/PPIs.

 

DoseThe ulcer healing dose of sucralfate is 1 g taken 1 hour before the 3 major meals and at bed time for 4–8 weeks. Antacids should not be taken with sucralfate because its polymerization is dependent on acid pH.

 

ULCERFATE,  SUCRACE,  RECULFATE  1  g  tab.

 

Side Effects are few; constipation is reported by 2% patients. It has potential for inducing hypophosphatemia by binding phosphate ions in the intestine. Dry mouth and nausea are infrequent.

 

Other uses Bile reflux, gastritis and prophylaxis of stress ulcers.

 

In intensive care units, acid suppressant (with i.v./ intragastric H2 blocker/PPI) prophylaxis of stress ulcers is almost routinely used now. This practice is argued to contribute to occurrence of pneumonia due to overgrowth of bacteria in the stomach. Intragastric sucralfate provides effective prophylaxis of stress ulcers without acid suppression, and is being tried.

 

As a suspension in glycerol, it has been tried in stomatitis. A  topical  formulation  of  sucralfate  PEPSIGARD LIGHT  GEL  is  available  for  application  on  burns, bedsores, diabetic/radiation ulcers, excoriated skin, etc. as a protective.

 

Interactions

 

Sucralfate adsorbs many drugs and interferes with the absorption of tetracyclines, fluoroquinolones, cimetidine, phenytoin and digoxin. Antacids given concurrently reduce the efficacy of sucralfate.

 

Colloidal Bismuth Subcitrate (CBS; Tripotassium Dicitratobismuthate)

 

It is a colloidal bismuth compound; water soluble but precipitates at pH < 5. It is not an antacid but heals 60% ulcers at 4 weeks and 80–90% at 8 weeks. The mechanism of action of CBS is not clear; probabilities are:

 

·  Increased secretion of mucus and bicarbonate through stimulation of mucosal PGE2 production.

 

·   CBS and mucus form a glycoproteinBi complex which coats the ulcer and acts as a diffusion barrier to HCl.

 

·      Detaches H. pylori from the surface of mucosa and directly kills this organism involved in causation of ulcers and relapses.

 

Gastritis and no-nulcer dyspepsia associated with H. pylori are also improved by CBS. The regimen for CBS is 120 mg (as Bi2O3) taken ½ hr before 3 major meals and at bedtime for 4–8 weeks. Milk and antacids should not be taken concomitantly.

 

TRYMO, DENOL 120 mg tab.

 

Most of the ingested CBS passes in the faeces. Small amounts absorbed are excreted in urine. Side effects reported are diarrhoea, headache and dizziness. Prolonged use has the potential to cause osteodystrophy and encephalopathy due to bismuth toxicity. Patient acceptance of CBS is compromised by blackening of tongue, dentures and stools; and by the inconvenience of dosing schedule. Presently, it is used occasionally as a component of triple drug antiH. pylori regimen, but not by itself to heal peptic ulcer.

 

 

ANTI-HELICOBACTER PYLORI DRUGS

 

H. pylori is a gram negative bacillus uniquely adapted to survival in the hostile environment of stomach. It attaches to the surface epithelium beneath the mucus, has high urease activity— produces ammonia which maintains a neutral microenvironment around the bacteria, and promotes back diffusion of H+ ions. It has been found as a commensal in 20–70% normal individuals, and is now accepted as an important contributor to the causation of chronic gastritis, dyspepsia, peptic ulcer, gastric lymphoma and gastric carcinoma. H. pylori infection starts with a neutrophilic gastritis lasting 7–10 days which is usually asymptomatic. Once established, H. pylori generally persists for the life of the host. Up to 90% patients of duodenal and gastric ulcer have tested positive for H. pylori.

 

Eradication of H. pylori concurrently with H2 blocker/PPI therapy of peptic ulcer has been associated with faster ulcer healing and markedly lower relapse rate. Anti-H. pylori therapy is, therefore, now recommended in all ulcer patients who test positive for H. pylori. In the absence of such testing, all cases with failed conventional ulcer therapy and relapse cases may be given the benefit of H. pylori eradication.

 

Antimicrobials that have been found clinically effective against H. pylori are: amoxicillin, clarithromycin, tetracycline and metronidazole/ tinidazole. However, any single drug is relatively ineffective. Resistance develops rapidly, especially to metronidazole/tinidazole. Since bismuth (CBS) is active against H. pylori and resistance does not develop to it, early combination regimens included bismuth, but had poor patient acceptability; are infrequently used now. In the meantime, it was observed that omeprazole monotherapy reduces the population of H. pylori in gastric antrum, probably by altering the acid environment as well as direct inhibitory effect. Rise in intragastric pH enhances the antiH. pylori action of the antibiotics. A number of 2drug and 3drug regimens of 1 or 2 weeks duration have been tested reporting 60– 96% eradication rates, but the optimum regimen is difficult to proclaim. Some of the 2 week regimens are:

 

Two Week Regimens (mg)m

g

1.     Amoxicillin 750 + Tinidazole 500 + Omeprazole 20 all BD

2.     Amoxicillin 750 + Tinidazole 500 + Lansoprazole 30 all BD

3.     Clarithromycin 250 + Tinidazole 500 + Lansoprazole 30 all BD

4.     Clarithromycin 500 + Amoxicillin 1000 + Lansoprazole 30 all BD

5.     Clarithromycin  500  BD/Amoxicillin 750 BD + Omeprazole 20 BD

6.     Amoxicillin  500  TDS/Tetracycline 500 QID + Metronidazole 400 QID/ Tinidazole 500 BD + Bismuth 120 QID

7.     Amoxicillin 750 TDS + Metronidazole 500 TDS + Ranitidine 300 OD

8.     Amoxicillin 750 BD + Clarithromycin 250 BD + Lansoprazole 30 BD

 

The US-FDA approved regimen is: lansoprazole 30 mg + amoxicillin 1000 mg + clarithromycin 500 mg all given twice daily for 2 weeks. It has achieved 86–92% eradication rate.* High prevalence of in vitro nitroimidazole resistance among H. pylori now being detected, especially in tropical regions, and better tolerability of regimens which exclude the nitroimidazole, favour the triple drug regimen of a PPI + amoxicillin + clarithromycin. The 2 week treatment is considered more appropriate, because higher relapse rate after one week regimen indicates incomplete eradication leading to recrudescence. A 4 drug regimen (PPI + tetracycline + CBS + metronidazole) has also been advocated.

 

All regimens are complex and expensive, side effects are frequent and compliance is poor. Higher failure rates (20–40%) of H. pylori eradication have been reported from India. Also, 5 year recurrence rate of H. pylori infection is higher. Three week treatment is now being advocated. Nevertheless, long-term benefits of anti-H. pylori therapy include lowering of ulcer disease prevalence and prevention of gastric carcinoma/lymphoma; but benefits in nonulcer dyspepsia are equivocal.

 

H. pylori vaccines are under development.

 

Some available anti-H. pylori kits (one kit to be taken daily in 2 doses)

 

HPKIT, HELIBACT, OMXITIN: Omeprazole 20 mg 2 cap + Amoxicillin 750 mg 2 tab + Tinidazole 500 mg 2 tab.

 

PYLOMOX: Lansoprazole 15 mg 2 cap + Amoxicillin 750 mg 2 tab + Tinidazole 500 mg 2 tab.

 

LANSI KIT: Lansoprazole 30 mg 1 cap + Amoxicillin 750 mg 1 tab + Tinidazole 500 mg 1 tab (one kit twice a day)

 

PYLOKIT, HELIGO: Lansoprazole 30 mg 2 cap + Clarithromycin 250 mg 2 cap + Tinidazole 500 mg 2 tab. LANPRO AC: Lansoprazole 30 mg 2 cap + Clarithromycin 250 mg 2 tab + Amoxicillin 750 mg 2 tab.

 

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