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International Journal of Research in Medical Sciences Parakh RK et al. Int J Res Med Sci. 2018 Feb;6(2):383-393 www.msjonline.org pISSN 2320-6071 | eISSN 2320-6012

DOI: http://dx.doi.org/10.18203/2320-6012.ijrms20180005 Review Article Anaesthetic : a review of its pharmacological properties and therapeutic efficacy

Rajendra Kumar Parakh*, Neelakanth S. Patil

Department of Medicine, SDM College of Medical Sciences and Hospital, Sattur, Dharwad, Karnataka, India

Received: 13 December 2017 Accepted: 27 December 2017

*Correspondence: Dr. Rajendra Kumar Parakh, E-mail: [email protected]

Copyright: © the author(s), publisher and licensee Medip Academy. This is an open-access article distributed under the terms of the Creative Commons Attribution Non-Commercial License, which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

ABSTRACT

Anaesthetic antacids, combination of antacids ( hydroxide, hydroxide) with an anaesthetic (oxethazaine), is becoming a choice of physicians and is re-emerging across all types of GI disorders (, peptic ulcer, duodenal ulcer, , , functional dyspepsia), despite the discovery of potent and efficacious acid suppressants like H2 receptor blockers and proton pump inhibitors (PPIs). The reason being that anaesthetic antacids increase the gastric pH and provide relief from pain for a longer period of duration at considerably a lower dosage. Furthermore, it significantly increases the duration between the time of and the peak pH as compared to alone. Oxethazaine, an anaesthetic component, produces a reversible loss of sensation and provides a prompt and prolonged relief of pain, thereby broadening the therapeutic spectrum of antacids. Antacids vary widely in their in vitro acid neutralizing capacity (ANC), which measures the potency. Among marketed brands in India, Digecaine has shown the highest potency with maximum mean ANC value (28.84 mEq). The expert panel has recommended the inclusion of oxethazaine-antacid/alginate-antacid as complementary to the proton pump inhibitors in the management algorithm of gastroesophageal reflux disease. The present review summarizes the pharmacokinetic and pharmacodynamic of different components of anaesthetic antacids and its clinical use across different gastrointestinal indications, for generalists and specialists, based on existing evidences.

Keywords: , Anaesthetic antacids, Hyperacidity, , Oxethazaine, Peptic ulcer

INTRODUCTION long-term safety of antacids remains unsurpassed. Notably, both the acid suppressant classes were reported Antacids are used in the treatment of related to have certain disadvantages which could limit their use disorders for a long time and grew in popularity during in the long run. Postprandial acid control and early 19th century. They provided good symptomatic tachyphylaxis are commonly observed side effects of 2 relief from hyperacidity and other associated conditions long-term use of H2 blockers. by directly neutralizing the gastric acid and thereby raising the pH of the gastric contents, restoring acid-base Moreover, recent studies have highlighted numerous side balance, attenuating the activity and increasing the effects, ranging from an altered gut environment and bicarbonate and prostaglandin secretion.1 impaired nutrient absorption to an increased risk for cardiovascular events, kidney disease, and , with Despite the discovery of potent and efficacious acid the use of PPIs, despite being safe and a choice of 3 suppressant (anti-secretory) agents such as histamine H2 medication for most gastric-related problems. Antacids receptor blockers and proton pump inhibitors (PPIs), the are commonly prescribed for non-ulcer dyspepsia,

International Journal of Research in Medical Sciences | February 2018 | Vol 6 | Issue 2 Page 383 Parakh RK et al. Int J Res Med Sci. 2018 Feb;6(2):383-393 duodenal ulcer, gastric ulcer, stress gastritis, INDIVIDUAL COMPONENTS OF ANAESTHETIC gastroesophageal reflux disease (GERD), pancreatic ANTACIDS insufficiency, bile acid-mediated , biliary reflux, , urinary alkalinisation, and chronic renal (Oxethazaine) failure. The key therapeutic advantage of antacids is their rapid onset of action, thereby providing rapid relief of Oxetacaine (N,N-bis-(N-methyl-N-phenyl-t-butyl- gastric discomfort within minutes. acetamide)-beta-hydroxyethylamine) is a potent local anaesthetic agent, exceeding by far the potency of either Antacids are divided into two classes; the first class , , or dibucaine. It acts by includes those antacids that work by chemical producing a reversible loss of sensation by preventing or neutralization of gastric acid, most notably diminishing the conduction of sensory nerve impulses bicarbonate; and the second class of antacids act by near the site of its application. Unlike other local adsorption of the acid (non-absorbable antacids), such as anaesthetic compounds, it is chemically a glycine amide and magnesium . Antacids include carbonate instead of benzoate or aminobenzoate. It is given orally and bicarbonate salts (e.g., , calcium (usually in combination with an antacid) for prompt and or ), alkali complexes of aluminium prolonged relief of pain associated with peptic ulcer and/or magnesium (e.g., aluminium and magnesium disease or esophagitis. When applied to the mucous hydroxides), aluminium and magnesium phosphates, membranes, it produces a more potent anaesthesia of magnesium trisilicate, and alginate-based raft-forming longer duration than either cocaine hydrochloride or formulations (Table 1). lidocaine hydrochloride. In vitro, oxethazaine produces antispasmodic action on smooth muscle and blocks the As highlighted above, conventional antacids offer less action of on smooth muscle, though the clinical symptomatic relief from gastric related problems and relevance of this effect remains to be established. It therefore, their use has declined with the availability of shows its action after 5 minutes and the duration of action efficacious anti-acid secretory (H2 blockers ranges from 2 to 3 hours. In the stomach, it increases the and PPIs). However, in the light of recent studies pH and neutralizes the gastric acid, which further relieves highlighting the use of PPI and the risk to human health the symptoms of hyperacidity problems. Unlike most with their use, has led to a new debate on revising the use other local , it does not break down under of antacids in gastric related problems. strongly acidic conditions. Hence, it is particularly suited in combinations antacid formulations which are intended Anaesthetic antacid, prepared by combining the local to provide additional gastric pain relief besides (topical) anaesthetic (oxethazaine) with aluminium neutralization of the gastric acid. A combination of the hydroxide and magnesium hydroxide, is one such oxethazaine hydrochloride in aluminium and magnesium formulation that promises to offer better control of gastric hydroxide gel is available in the market for commercial related problems. Aluminium and magnesium hydroxide use. It also has a large margin of safety when react chemically to neutralize the acid and increases administered intragastrically and has proven to be useful gastric pH. Oxethazaine exerts a prolonged topical clinically to control pain due to a variety of gastric anaesthetic action. It is prescribed for rapid and effective disorders. Some of the conditions for which oxetacaine is relief in gastritis, esophagitis, hiatus hernia, heartburn and indicated include GERD, hemorrhoidal pain, symptoms peptic ulcer. The anaesthetic/antacid combination is used of hyperacidity symptoms, eructation, nausea, vomiting, at a considerably lower dose which reduces the risk of stomach discomfort, esophagitis, gastritis, adverse effects as compared to antacids, per se. In some gastric/duodenal ulcer, local anaesthetic, heart burn in, of the antacid formulations, has been added etc. to promote adherence of the antacid to the gastrointestinal (GI) mucosa, and it also acts as a protective covering to Simethicone/Dimethicone the gastric mucosa. Simethicone is an orally administered antifoaming agent, Given the fact that the pathogenesis of GERD is not used to reduce gas from the digestive tract in patients attributed, solely, to the acid secretion, the new algorithm complaining of recurrent . It is a mixture of has recommended the use of antacids and alginate- dimethicone (polydimethylsiloxane) and hydrated silica antacid combination in conjunction with the PPIs, as an gel (). It shows effect locally in the additional option (as ) in patients with digestive tract and not absorbed into the stream. It GERD.4 The improved therapeutic profiles of anaesthetic is being used as an effective adjunct therapy in conditions antacids as compared to the usual short-lasting simple where excessive gas is aggravating the symptoms in acid neutralizing antacids, hopes to compete with conditions such as dyspepsia, peptic ulcer, post-operative currently established medications for gastric related gaseous distention and irritable colon. Moreover, the disorders. The present review aims to assess and provide is used as a self-medication to relieve symptoms an insight on the pharmacological properties and commonly referred to as gas, including upper digestive therapeutic efficacy of anaesthetic antacids in various GI tract , pressure, fullness, or stuffed feeling. disorders.

International Journal of Research in Medical Sciences | February 2018 | Vol 6 | Issue 2 Page 384 Parakh RK et al. Int J Res Med Sci. 2018 Feb;6(2):383-393

Table 1: Important antacids and their features.1,5

Acid Antacids neutralizing Advantages Disadvantages Clinical conditions capacity# GI distress Heartburn Nausea/vomiting Calcium Acid 58 Potent and rapidly acting Hypercalcemia carbonate Upset stomach Hypo-phosphatemia milk-

alkali syndrome Low solubility and reactivity, Dyspepsia Slow but prolonged Magnesium Absorbed systemically Heart burn Low action (at larger trisilicate (problem in renally Hyperacidity doses) compromised patients) Constipation GI distress, Low used in Hyperacidity and peptic Electrolyte imbalances Magnesium combination ulcer dyspepsia heartburn Hypotension carbonate with other GERD Neuromuscular blockade products Constipation hypotension Constipation, digitalis Reacts with HCl toxicity Low solubility, no Magnesium Promptly and is an Gastric acidity 35 systemic alkalosis (mg is hydroxide efficacious antacid, low Hypomagnesaemia poorly absorbed from gut) systemic absorption Peptic ulcer Pre-eclampsia Good oral antacid with Diarrhea Gastritis 33 prompt and sustained Constipation Hyperacidity neutralizing action Intestinal pain Reflux esophagitis Indigestion and heartburn One of the most effective (dihydroxy Uraemic aluminium on long- GERD antacid substances aluminium 20 term use Duodenal ulcer Rapid neutralization of sodium Associated with dementia Gastric ulcer gastric acid carbonate) ZES Chronic diarrhoea hyper- parathyroidism Efficient, low systemic Raises the pH of the Hyper-phosphatemia (in Aluminium 29 absorption, gastric juice, renal failure), hydroxide Decreases phosphate Adsorbs pepsin nephrolithiasis, peptic via kidney ulcer, reflux esophagitis, stress ulcers Metabolic alkalosis with Heartburn Sodium Most rapidly acting 17 alkalinisation, Alkalinisation of urine bicarbonate antacid Intake of large doses Acidosis Acid neutralizing capacity (mEq/15mL of a commercially available product); Al2Cl3: Aluminium chloride; CO2: CaCl2: Calcium chloride; ; GERD: Gastroesophageal reflux disease; HCl: ; MgCl2: Magnesium Chloride; MgSO4: Magnesium sulfate; NaCl: Sodium chloride; SiO2: silicon dioxide; NaHCO3: Sodium bicarbonate; ZES: Zollinger Ellison Syndrome; #The potency of an antacid is generally expressed in terms of its acid neutralizing capacity (ANC) which is defined as the 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.

It has also been used for the gastroscopy to enhance ordinary conditions is not clear; however, the drug also visualization and prior to radiography of the intestine to has been shown to be effective in relieving these minimize gas shadows. Although there is gastroscopic symptoms. Simethicone has been reported as an effective evidence that simethicone aids in the elimination of gas antiflatulent agent but there is currently no conclusive from the digestive tract and reduces postoperative gas evidence available to demonstrate that immediate pains, the relationship of gas accumulation to what postprandial upper abdominal distress (IPPUAD) is patients commonly refer to as symptoms of gas under caused by excessive gas, despite the fact that a majority

International Journal of Research in Medical Sciences | February 2018 | Vol 6 | Issue 2 Page 385 Parakh RK et al. Int J Res Med Sci. 2018 Feb;6(2):383-393 of patients related symptoms of the distress to gas. In kidneys play a major role in its clearance, individuals addition, more data is needed to confirm the efficacy of with renal failure are at risk of with simethicone to show that it provides the symptomatic long-term consumption due to deficient magnesium relief from IPPUAD, a complex symptom that commonly excretion. The acid neutralization capacity (ANC) of each occurs within 30 minutes after a meal and consists of mg of Mg(OH)2 is expected to be 0.0343 mEq. sensations of bloating, distention, fullness, or pressure with upper abdominal discomfort but not aerophagia or Aluminium hydroxide hyperacidity. Aluminium hydroxides found to be absorbed, in only Dimethicone is a silicone polymer, also known as relatively small amounts, into the digestive tract. polydimethylsiloxane (PDMS) having viscoelastic Approximately 17-30% of the Al2Cl3 formed in the properties. Dimethicone is used as a surfactant, stomach is absorbed. The onset of action of aluminium antifoaming agent, and carminative in various products hydroxides ranges from 5-10 minutes and its action lasts such as medical devices, food products, and lubricants. It for about 100 minutes. It is eliminated fast, chiefly via has been reported as a common additive to antacids, renal route. The ANC of each mg of Al(OH)3 is expected although its value in the treatment of reflux esophagitis is to be 0.0385 mEq. unproven. A double blind clinical study has investigated its efficacy comparing the effect of a dimethicone- Oxetacaine (Oxethazaine) containing antacid gel (Asilone Gel) with a simple antacid gel in patients with reflux esophagitis. The 10 mL of alumina gel with magnesium hydroxide inclusion of dimethicone in the antacid gel formulation containing 20 mg oxetacaine (oxethazaine), the peak was reported inefficacious in terms of conferring any oxethazaine plasma level of approximately 20 ng/mL was benefit of symptomatic pain relief, however, it conferred reached after about one hour after dosing following oral a small advantage with regard to objective markers of administration. Oxethazaine has been reported to undergo esophageal inflammation, indicating that a dimethicone- rapid and extensive hepatic which results in a containing antacid could be of value in the treatment of short plasma half-life (T1/2) of approximately one hour. symptomatic gastro-esophageal.5 Less than 0.1% unchanged oxethazaine was found to be recovered in the urine within 24 hours. Alginate-antacid Beta-hydroxy-mephentermine and beta-hydroxy- Alginates are natural polysaccharide polymers isolated phentermine have been identified as the primary from brown seaweed (Phacophycae) which upon coming metabolites of oxetacaine. Mephentermine and in contact with gastric acid precipitates into low phentermine were found in the plasma in viscous gel of near neutral pH within few seconds (in pharmacologically insignificant amounts and only 0.1% vitro) or a few minutes (in vivo). It forms a protective of the dose administered was excreted in the urine after barrier and increases the viscosity and adherence of 24-hour of the duration.7 mucus to the esophageal mucosa. Therefore, formulations containing alginates have a quite different mode of action Simethicone than antacids. Alginate-based raft-forming formulations usually contain sodium or potassium bicarbonate. In the Simethicone is pharmacologically inert. It is not absorbed presence of gastric acid, the bicarbonate is converted to from the digestive tract and does not interfere with gastric carbon dioxide which becomes entrapped within the gel secretion or absorption of nutrients. Following oral precipitate, converting it into foam that floats on the administration, the drug is excreted unchanged in feces. surface of the gastric content, providing a relatively pH- As, it is not absorbed by the body into the bloodstream neutral barrier.6 and is therefore considered relatively safe.

PHARMACOKINETIC PROPERTIES OF Dimethicone COMPONENTS OF ANAESTHETIC ANTACIDS Information on the pharmacokinetic properties of Magnesium hydroxide dimethicone remains less studied. However, dimethicone has been reported to influence pharmacokinetic of several Nearly 15%-50% of magnesium hydroxide is absorbed other .8 very slowly through the small intestine. Its peak action and distribution are reported as variable, and it does not Dimethicone has been reported to improve GI tolerability bind with plasma proteins. A very little amount is of non-steroidal anti-inflammatory drugs (NSAIDs). A absorbed in the intestine unless the patient has study investigating the alleviation of the NASAIDs hypomagnesemia. Overall, about 15%-50% of the induced epigastralgic effects, dimethicone did not affect magnesium hydroxide suspension is absorbed the efficacy of the ketoprofen treatment and altered other systemically which does not undergo any metabolism as pharmacokinetic parameters but it did not significantly it is rapidly excreted in the urine via kidney. Since the change the of ketoprofen.

International Journal of Research in Medical Sciences | February 2018 | Vol 6 | Issue 2 Page 386 Parakh RK et al. Int J Res Med Sci. 2018 Feb;6(2):383-393

PHARMACODYNAMIC PROPERTIES OF hyperacidity problems. It acts as a with COMPONENTS OF ANAESTHETIC ANTACIDS antacids, and has antispasmodic actions.

Magnesium hydroxide Dimethicone

Magnesium hydroxide suspension neutralizes gastric acid Activated dimethicone has been used to relief excessive by reacting with hydrochloric acid in the stomach to form gas (flatulence) by dispensing and preventing formation magnesium chloride and water. It is practically insoluble of mucus surrounding gas pockets in the gastro-intestinal in water and does not have any effect until it reacts with tract. It lowers the surface tension of the gas bubbles and the stomach acid. There, it decreases the direct acid bringing together all the small bubbles of gas (coalesce) irritant effect and increases the pH in the stomach leading to form a large bubble, which is then expelled. Thus, the to inactivation of pepsin. Magnesium hydroxide enhances gas is released by belching or passing flatus. the integrity of the mucosal barrier of the stomach as well Antiflatulents have been combined to an antacid gum as improving the tone of both the gastric and esophageal coating to be effective antigas materials and eliminate sphincters. Unabsorbed magnesium cause osmotic trapped gas. The most common antigas material is diarrhea and aluminium salts cause constipation, hence dimethicone and when mixed with silicone dioxide these two are commonly administered together in a ratio becomes simethicone. of 2:1 to minimize the impact on bowel function. As a laxative, it works by increasing the osmotic effect in the Simethicone intestinal tract and drawing water in. This creates distension of the colon resulting in an increase in Simethicone is a liquid dimethicone activated with finely peristaltic movement and bowel evacuation. divided silicon dioxide to enhance the defoaming properties of the silicone. It acts by decreasing the surface Aluminium hydroxide tension of gas bubbles, thus facilitating their coalescence and expulsion as flatus or belching. It also prevents the Aluminium hydroxide is the one of the compounds formation and accumulation of mucus-enclosed pockets amongst the many different aluminium salts, used most of gas in digestive tract. Simethicone also facilitates the commonly in antacid formulations more often in passage of gas through bowel lumen and allows patients combination with magnesium hydroxide and used rarely to excrete a greater volume of gas at one time, thereby alone as a single substance. It dissolves slowly in the reducing the number of flatus events. Thus, less residual stomach and forms polymers of varied compositions. gas is present to cause uncomfortable or painful pressure Together with phosphate and bile salts, it forms an in the stomach and intestines. insoluble compound. It has a weaker effect and is a slower acid-neutralizer as compared to magnesium salts. INDICATIONS OF ANAESTHETIC ANTACIDS Aluminium ion causes the relaxation of the GI smooth muscle, which can postpone gastric emptying and can Antacids were commonly prescribed in multiple cause constipation. Aluminium hydroxide inhibits pepsin gastrointestinal disorders like hyperacidity, peptic ulcer, activity by increasing pH and through adsorption and GERD, irritable bowel syndrome, functional dyspepsia, exerts cytoprotective effects through increases in flatulence and abdominal distension blotting. bicarbonate ion and prostaglandins. It also binds dietary phosphate in patients with chronic renal failure. This Hyperacidity is a set of symptoms caused by an increased reduces phosphate load and decreases the level of acid formation in the stomach. The currently used hyperphosphataemia seen in patients with chronic renal drugs for treatment of hyperacidity include acid blockers failure. (which reduce gastric acid secretion for a prolonged duration), PPIs, antacids (neutralize gastric acid), Oxetacaine (Oxethazaine) protecting agents and caused due to (H. pylori) .9 Oxethazaine, Oxethazaine, has been reported as the most potent local also produces antispasmodic action, is used in anaesthetic (amide type), and is claimed to be 2000 times combination with aluminium and magnesium hydroxide more potent than lignocaine and 500 times more potent for symptomatic relief of hyperacidity associated with than cocaine as assessed in rabbit’s eyes.7 Currently, peptic ulceration, gastritis, esophageal reflux, and gastric oxethazaine is used in an antacid preparation for the hyperacidity.10 The results from different studies showing topical relief of pain in conditions such as hiatus hernia, improved treatment and pain alleviation with oxethazaine where the local pH is very low. It produces a reversible containing antacids likely to increase its use in future. loss of sensation by preventing or diminishing the conduction of sensory nerve impulses near the site of its Peptic ulcer is characterized by disruption in the mucosal application. This also decreases the permeability of the lining of the stomach or , with depth to the nerve cell membrane to sodium ions (membrane submucosa, by more than 5 mm. PPIs and H2 blockers stabilizing effect). In the stomach it increases the pH and afford effective ulcer healing in most patients with neutralizes the gastric acid, which relieves the uncomplicated gastric and duodenal ulcers. For patients

International Journal of Research in Medical Sciences | February 2018 | Vol 6 | Issue 2 Page 387 Parakh RK et al. Int J Res Med Sci. 2018 Feb;6(2):383-393 in which peptic ulcer is caused by H pylori, initial The treatments of IBS include addressing abdominal management includes complete eradication of H. pylori symptoms such as pain, cramping, bloating, or bowel and subsequent withdrawal of offending drugs and symptoms, including diarrhea and constipation. In IBS contributing factors. Among antacids, both systemic and patients with predominant diarrhea along with pain and non-systemic antacids are used in the management of bloating, antispasmodics, particularly hyoscine, and peptic ulcer of either gastric or duodenal origin. peppermint oil, should be used as first line therapy. Other Aluminium-containing antacids show constipation as a anti-diarrheal agents, such as loperamide, improve stool most common side effect, which may progress to form and frequency in IBS patients. intestinal obstruction, faecal impaction and development should be used in patients failing antidiarrheal drugs. In a of haemorrhoids and anal fissures. In addition, the most study on IBS patients, around one in five patients self- frequent adverse effect of magnesium containing antacids medicated inappropriately and the antacid class had the is diarrhoea, which is due to poor absorption of the highest incidence of inappropriate medication use.17 A relatively insoluble magnesium salts and subsequent similar study on 374 patients in Sweden showed that osmotic effect in the bowel, and these antacids acid-suppressive agents were the most commonly used components have been combined to counteract each other drugs for abdominal complaints by IBS patients, for non- weaknesses.2 Oxethazaine containing antacids relieves abdominal complaints, 13.3% of IBS patients self- the pain by producing numbing effect at considerably, medicated with antidepressants.18 According to a lesser dose in patients with oesophagitis, gastritis, and previous study, antacids were regularly prescribed during peptic ulcer.11 This combination produced rapid rise in the high-dose steroid therapy to prevent gastritis, and in PH, a significantly higher peak PH, a greater period of this context, oxethazaine-antacid is expected to provide anacidity from the time of medication until the PH greater pain relief and control of symptoms in gastritis. returned to the acid range. Unlike other local anaesthetic, Given the fact that IBS has broad range of physiological oxethazaine has proven successful as it remained and psychological alterations, the optimal treatment nonionized in acidic medium and increased the gastric pH strategy for its management has yet to be identified. above 3.5 for varying length of time. Furthermore, it However, the existing treatment is largely focused on the easily penetrates the lipid membrane of myelin sheath symptomatic control in which anaesthetic antacids can and produce satisfactory and prolonged anaesthesia. play a vital role. Further research with the role of Antacid combinations utilising oxetacaine has given anaesthetic antacids is necessarily recommended. satisfactory relief of ulcer pain and reduced the pain episode as compared to antacids alone.12 These Functional dyspepsia is a chronic or recurrent pain or impressive features of anaesthetic antacids have led it as discomfort centered in the upper part of the abdomen. one of the most promising candidate for treating peptic Antacids have been commonly prescribed as the first line ulcer. treatment which patient try before consulting a physician. However, many patients get satisfied with antacids and Gastroesophageal reflux is a normal physiological they get relief from commercial (especially the liquid) process, normally of short duration, often remain formulations during episodes. This may be attributed to asymptomatic, and limited to the distal part of mucoprotective effect or to the antiflatulent agents esophagus.13 The American College of Gastroenterology (simethicone) that are often combined in these defined GERD as, “chronic symptoms or mucosal formulations, but independent of the acid neutralizing damage produced by the abnormal reflux of gastric effect.19 The oxetacaine-antacids may provide additional contents into the esophagus”.14 benefits of pain suppression besides acid neutralization.

The management of GERD includes antacids and Flatulence is a buildup of gas causing discomfort and alginate, prokinetic drugs, sucralfate, H2 blocker and distress in the digestive system. Probiotics and rifaximin PPIs. Antacids neutralize stomach acid to cut down on (Xifaxan) have been shown to reduce total number of heartburn, sour stomach, acid indigestion, and stomach flatus episodes and associated discomfort. Simethicone upset. Some antacids also contain simethicone that helps has been recommended for treatment of flatulence and to get rid of gas from the body. A recent meta-analysis bloating; however, no benefit has been shown for concluded that the relative benefit increase was up to common flatulence.20 60% with alginate/antacid combinations, and 11% with antacids as compared with the placebo response.15 In A combination of simethicone and loperamide (Imodium summary, there are insufficient data supporting a Advanced) is effective in relieving abdominal bloating recommendation for anaesthetic antacids as a treatment and gas associated with acute diarrhoea (more than either option for symptomatic heartburn. However, treatment alone); however, it has not been studied in alginate/antacid combinations appear to be superior to the nondiarrhoea-associated flatus.21 per se use of antacid in patients with GERD. Bloating is more commonly seen in patients with IBS, Irritable bowel syndrome (IBS) is a chronic functional whereas distension is more readily seen in patients with disorder defined by the presence of abdominal pain or constipation and pelvic floor dysfunction in whom discomfort, with altered bowel habits.16 plethysmographic studies confirm an increase in

International Journal of Research in Medical Sciences | February 2018 | Vol 6 | Issue 2 Page 388 Parakh RK et al. Int J Res Med Sci. 2018 Feb;6(2):383-393 abdominal girth of as much as 12 cm. Fortunately, new efficacy rates well exceeding those of drug therapies, therapies involving dietary manipulation (low-FODMAP such as antibiotics and prokinetic agents. The role of diet) have proved highly successful in relieving anaesthetic antacid in various indications has been symptoms of bloating and abdominal distension, with presented in Table 2.

Table 2: Advantages of anaesthetic antacids across different indications.

Author, year Type of study Study characteristic Finding Hyperacidity Bhoir and Bhagwat, Compared the ANC of 7 Anaesthetic antacid, digecaine has the In-vitro 201322 anaesthetic antacids highest ANC amongst all marketed antacids Duodenal ulcer Siffert, 197223 Double-blind Arm 1: Antacid + Oxethazaine Less dose of anaesthetic antacid is required (n=34) clinical study Arm 2: Antacid only for symptom control Pontes et al., 197513 Double blind Arm 1: Antacid + Oxethazaine Less dose of anaesthetic antacid is required (n=17) clinical study Arm 2: Antacid only for ulcer pain control Double-blind Novaes et al., 197511 Arm 1: Antacid + Oxethazaine Increased anacidity period with anaesthetic crossover (n=20) Arm 2: Antacid only antacid combination study Reduction in the doses of medication Zanni et al., 198624 Double-blind Arm 1: Antacid + Oxethazaine needed to achieve adequate symptomatic (n=40) clinical study Arm 2: Antacid only relief Gastroesophageal reflux disease (Heartburn) Double- Patients took anaesthetic Majority showed preference for anaesthetic Carne, 196425 blinded clinical antacids and antacids only on antacids and also these patients reported (n=36) study alternate days complete relief from heartburn Arm 1: Antacid + Oxethazaine Kovacs et al., 199026 Double-blind Anaesthetic antacids relieved symptoms of Arm 2: Antacid only (n=50) parallel study heartburn better than antacid used alone Arm 3: Placebo Functional dyspepsia Double- Holtmann et al., simethicone (105 mg t.d.s.) dummy Simethicone is efficacious in functional 200227 Arm 2: Cisapride (10 mg placebo dyspepsia treatment compared to cisapride (n=185) t.d.s.) controlled and placebo Arm 3: placebo (t.d.s.) study ANC: Acid Neutralizing Capacity; t.d.s: thrice a day

CLINICAL STUDIES INCLUDING IN VITRO AND containing a known amount and concentration of the HCl IN VIVO STUDIES solution. The amount of excessive HCl (non-reacted acid) that remained in the solution was determined by back- The measurement of ANC remains one of the most titration of the solution to neutrality with a standardized widely known in vitro tests used to evaluate the efficacy solution of NaOH. The amount of NaOH solution of antacids intended to reflect their in vivo efficacy. A required was used to estimate the amount of HCl which strong acid-strong base titration has been used to test the was neutralized by each antacid. The study observed a capacity of various commercial antacids to neutralize an significant variation in the in vitro ANC of different acidic environment (simulated acidic stomach). antacids including a batch to batch variation for each brand of antacid which reflected that all the seven In 2013, Bhoir and Bhagwat conducted an in vitro study commercially marketed antacids containing oxethazaine to compare the ANC of seven randomly selected, were different in terms of their relative efficacy. commonly prescribed oxethazaine containing antacid However, it should be noted that, the effects of antacid suspensions from India.22 The study tested the concept of might significantly vary in vivo, as individual variations the relative effectiveness and batch-to batch variations of also contribute to the eventual efficacy of an antacid. different antacids formulations, wherein the ANC of Antacids having a higher ANC is generally considered to reference antacids AD* (with oxethazaine as local be more efficacious requiring the lowest dosage volume. anaesthetic feature) was compared with the ANC of the The study utilized the relative effectiveness as a other available products. To ensure reproducibility of the parameter to compare potency of antacids. In the study, result, the study undertook six trials from each batch of antacid formulation which was found to have higher antacids. Antacid samples were dissolved in the solution ANC was indicated to be efficacious (Table 3) and hence,

International Journal of Research in Medical Sciences | February 2018 | Vol 6 | Issue 2 Page 389 Parakh RK et al. Int J Res Med Sci. 2018 Feb;6(2):383-393 such antacids would require lower dosage volume pregnancy. The similar results were reported from a compared to other antacids to neutralize the acid. From large, randomized placebo-controlled trial demonstrating the table, reference antacids AD* was highly efficacious that magnesium sulphate supplementation halves the risk antacid followed by antacids in the following order: of eclampsia compared with placebo, and could also reference antacids AD*>5> 4>1>3>2. (* stands for reduce the risk of maternal death, with no serious short- Digecaine). term side-effects.32

Table 3: Relative effectiveness and ANC of different A clinical study has also reported the efficacy of antacid formulation used by the study of Bhoir and oxethazaine in the treatment of suggesting Bhagwat, 2013.22 that treatment with anaesthetic antacid could go beyond GI tract.33 A meta-analysis by Tran et al. (2007) reported ANC Relative Antacid efficacy of OTC medications in treating symptomatic (mEq) effectiveness GERD. They reported that the relative benefit increase Digecaine (known antacid) 29.0 100 was up to 41% with H2 blockers while with Antacid 1 (unknown) 17.0 58.3 alginate/antacid combinations and antacids, alone were Antacid 2 (unknown) 13.3 46.1 60% and 11%, respectively.15 Antacid 3 (unknown) 14.5 49.4 Antacid 4 (unknown) 17.1 59.4 ADVANTAGES OF ANAESTHETIC ANTACID Antacid 5 (unknown) 18.7 64.8 OVER ANTACIDS Antacid 6 (unknown) 14.4 50.0 ANC: Acid neutralizing capacity In the light of the above discussed in vitro, in vivo and the available clinical studies, it may be strongly advocated Another in vivo study compared four different antacids in that therapeutic efficacy of oxethazaine-antacid term of their ANC, bile salt binding capacity, cost, and formulations far exceeds than that of older antacid patient acceptance. The antacid preparations were mixtures. The anaesthetic component of the oxethazaine- reported to differ significantly in ANC and bile acid antacid formulations helped them gain an important place binding capacity, as well as cost. It was observed that in therapeutic algorithm of GERD and other gastric dimethicone containing antacid demonstrated the highest related disorders. The prominence of oxethazaine ANC and bile acid binding capacity. The study concluded containing antacids can be measured from the fact that that individuals requiring antacid therapy should be these formulations are being recommended as allowed to choose from a range of preparation, in order to complementary to PPIs in GERD and related disease. achieve maximize compliance.28 Another in vivo study Thus, anaesthetic antacid now has clear-cut advantages has suggested that addition of dimethicone in the antacid over older simple antacid mixtures. The older antacid formulation would be of value the treatment of formulation primarily consisted of calcium and symptomatic gastroesophageal reflux. magnesium and aluminium-salts in various combinations and had acceptability problem including debated long- In the past, a battery of clinical studies involving term use. The topical local anaesthetic agent helps relieve oxethazaine, reported effective management of the pain caused due to hyperacidity and aluminium and esophagitis, peptic ulcer and esophagitis, duodenal ulcer magnesium hydroxides react with stomach acid to and hiatus hernia, and gastritis.11,29,30 All these studies neutralize it. Oxethazaine is a strong local anaesthetic have highlighted the efficacy of oxethazaine in gastric allowing it to be used in very dilute solutions. It acts in a diseases. The clinical studies showing advantage of number of ways to numb the walls of the stomach and anaesthetic antacids across different indications were relieve the pain. Antacids provided good alternative for presented in Table 2. quick symptomatic relief, but they presumably have little long-term effect and on overall disease progression, and Antacids have been fast and effective at relieving the the development of potent efficacious medication such as symptoms of heartburn and are therefore, preferred by H2-blockers and PPIs led to the significantly decline in patients because of immediate relief from symptoms. It their use clinically for duodenal and gastric ulcers and has been reported that about 30-50% of women required GERD. Also, their use was reported as controversial in only antacids to ease their heartburn of pregnancy. the management of nonulcer dyspepsia or nonsteroidal Further, magnesium, aluminium, or calcium containing anti-inflammatory drug related upper GI mucosal antacids have been reported to have no teratogenic risk, damage. The therapeutic spectrum of anaesthetic antacid and also magnesium and aluminium hydroxide containing will increase manifold, if also contains antiflatulent antacids were reported safe during lactation. A recent agents (dimethicone/simethicone) beside the local European consensus conference have recommended anaesthetic component. Thus, the greater acceptability of Ca/Mg-based antacids for pregnant women because of anaesthetic-antacid compared to usual antacid their safety profile.31 Additionally, according to the combinations. Over the recent years, several double blind experts, calcium based antacids have added benefit of clinical studies have reported complete pain relief with increasing calcium supplementation to prevent the the use of anaesthetic antacid. The dose of anaesthetic and pre-eclampsia associated with antacid was also significantly reduced in comparison to

International Journal of Research in Medical Sciences | February 2018 | Vol 6 | Issue 2 Page 390 Parakh RK et al. Int J Res Med Sci. 2018 Feb;6(2):383-393 antacid mixtures which also helped reduce side effects The study concluded that Spanish Primary Care encountered with these antacids that taken mostly in large physicians observed that a significant number of patients dose and more number of times. Some investigators have of GERD continued to suffer from symptoms during PPI reported that oxethazaine containing antacid produces treatment alone. They considered that on-demand persistent increase in gastric pH to 3.5 or above.22 "combined therapy" (PPI plus antacid) was an efficient option to control reflux symptoms in patients which TREATMENT ALGORITHM continued to be troublesome following treatment with PPI treatment alone.35 Acid reflux is one of the single most important components in the GERD pathogenesis and acid Self-care suppression has remained cornerstone pharmacological therapy.34 PPIs constitute as the main medication in the The expert panel has advised on using low-dosed PPIs as classical treatment algorithm for this condition. a treatment option for GERD patients at the self-care According to the expert consensus panel, the treatment of level. However, it was observed that the most important GERD requires a symptom-based approach in the factors determining the choice of OTC therapy should beginning followed by a pathogenesis-based approach, have been the speed of action and onset of symptom where symptoms that respond to adequate acid relief. Antacids or alginate-antacids offer the most rapid suppressant therapy confirm the role of acid reflux and symptom relief and can be taken ‘as required’. The panel symptoms nonresponsive to acid suppression confirm the believed that antacids or alginate-antacids offered role of other factors. In 2007, Tran et al. reported a meta- symptom relief more rapidly than alternative treatments analysis covering the period 1972 to 2005. They and therefore, the panel were of the opinion that antacids concluded that over-the-counter (OTC) medications were or alginate-antacids could be used in combination with effective in treating symptomatic GERD, and antacids acid suppressants to treat remaining or breakthrough and alginate-antacids were effective in treating of gastric symptoms. In comparison to former two types of symptoms which most often appear after a meal.15 antacids, oxetacaine-antacid combination would offer Further, the revised algorithm, somehow, considerably great and faster symptom relief. However, patients who maximized the satisfaction of patient and the disease presented with alarm symptoms were strongly advised to management. It has tried to optimize the management of contact primary care physician for referral to specialist symptoms by dividing symptom management into three car.38-40 levels of care: self-care, primary care and secondary care. While, at the primary care level, PPIs remains the Primary care mainstay therapy for most the stomach acid-related pathologies, which, however, take much longer time to The expert panel opined that PPIs should not have been work and even longer than the H2 blockers. Further, the only drugs of choice for GERD as symptoms of accumulating evidence from newer clinical studies GERD could not be only attributed to the secretion of reported that PPIs were ineffective in treating some acid. According to the panel recommendations, antacids patients including PPI-refractory GERD patients.35 This or alginate-antacids could be an additional option for formed the basis for the expert panel to recommend patients presenting at primary care with symptoms of antacids, alginate-antacids, among others at the self-care reflux, or for patients with ongoing symptoms level besides PPIs. Also, at all the levels of GERD incompletely controlled with acid suppressants. In this treatment, antacids or alginate-antacids got a more context, therapeutic antacid (oxethazaine-antacid), which prominent place both independently and in combination contain local anaesthetic component, could particularly with acid suppressive therapies (H2 blockers and PPIs). benefit patients. Hence, PPI or a combination of alginate- The most palpable difference between antacids and PPIs antacid and or oxethazaine-antacid, and acid suppressive (including H2 blockers) is the rapid onset of action, and therapy could be prescribed with clinical judgement of antacids and alginate-antacids have shown a rapid and the physician. As combination therapy, it may potentially adequate relief from symptoms of GERD.36 The be more beneficial than acid suppressive therapy alone.38- formation of a raft-like structure in the acid pocket by 40 alginate-antacids treatment have reduced the injury caused by pepsin and bile acids.37 In patient refractory to Secondary care treatment with PPIs, in GERD, the expert panel recommended combining antacids or alginate-antacids Specialists at the secondary care level are entrusted with among other complementary therapy with PPIs. In 2013, the task of dealing with more complex cases, e.g. patients a survey on primary care in Spain have been carried out who are partially or completely unresponsive to to assess “the perceptions of primary care physicians on treatment. Endoscopic examination has been included in the effectiveness of the isolated use of PPI in controlling the new algorithm as an option for further therapy (or as symptoms in GERD patients, as well as to know the method of investigation), because of differing clinical degree of implementation of use of combined therapy practice in the various countries which represented at the (PPI plus antacid) and utilization patterns of this therapy expert panel meeting. In general, patients with GERD to achieve a better control of symptoms in such patients.” who were found to have evidence of erosive esophagitis

International Journal of Research in Medical Sciences | February 2018 | Vol 6 | Issue 2 Page 391 Parakh RK et al. Int J Res Med Sci. 2018 Feb;6(2):383-393 on endoscopy should be placed on maintenance PPI due inhibitors: Risks of long-term use. J Gastroenterol to the high risk of relapse off PPI. However, patients with Hepatol. 2017;32(7):1295-302. NERD may achieve symptom control on H2 blockers or, 4. Tytgat GN, McColl K, Tack J, Holtmann G, Hunt alternatively, with on-demand PPI. If symptoms persist, RH, Malfertheiner P, et al. New algorithm for the maintenance PPI should be considered. According to the treatment of gastroesophageal reflux disease. advice of the expert panel, at the secondary care level Aliment Pharmacol Ther. 2008;27:249-56. also, the adjuvant therapy (oxethazaine-antacid/alginate- 5. Ogilvie AL, Atkinson M. Does dimethicone antacid) could complement therapy with PPI.38-40 increase the efficacy of antacids in the treatment of reflux esophagitis? 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