Treatment Of Diarrhoeas

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Chapter: Essential pharmacology : Drugs For Constipation And Diarrhoea

Diarrhoea is too frequent, often too precipitate passage of poorly formed stools. In pathological terms, it occurs due to passage of excess water in faeces.


TREATMENT OF DIARRHOEAS

 

Diarrhoea is too frequent, often too precipitate passage of poorly formed stools. In pathological terms, it occurs due to passage of excess water in faeces.

 

Diarrhoeal diseases constitute a major cause of morbidity and mortality worldwide; especially in developing countries. More than 5 million children under the age of 5 years die every year due to diarrhoea. A nationwide study has estimated that diarrhoea kills > 1 million children in India annually. Recurrent or protracted diarrhoea is also a major cause of proteincalorie malnutrition in developing countries. Even mild diarrhoea, and that in adults, is a disabling symptom and an inconvenience.

 

Relevant Pathophysiology

 

Water and electrolytes are absorbed as well as secreted in the intestine. Jejunum is freely permeable to salt and water which are passively absorbed secondary to nutrient (glucose, amino acids, etc.) absorption. In the ileum and colon active Na+K+ATPase mediated salt absorption occurs, primarily in the mature cells lining the villous tips, water follows iso-osmotically. In addition glucose facilitated Na+ absorption takes place in the ileum by Na+ glucose cotransporter; one Na+ ion is transported along with each molecule of glucose absorbed. This mechanism remains intact even in severe diarrhoeas.

 

Absorption of Cl¯ and HCO3¯ is passive (paracellular) as well as by exchange of HCO3¯ for Cl¯ (transcellular). Bicarbonate is absorbed also by the secretion of H+ (similar to that in proximal tubule of kidney) and Na+ accompanies it. K+ is excreted in faecal water by exchange with Na+, as well as by secretion into mucus and in desquamated cells. The osmotic load of luminal contents plays an important role in determining final stool water volume. When nonabsorbable solutes are present and in disaccharidase deficiency (which occurs during starvation), the stool water is increased. Inhibition of Na+K+ATPase and structural damage to mucosal cell (by Rota virus) causes diarrhoea by reducing absorption.

 

Intracellular cyclic nucleotides are important regulators of absorptive and secretory processes (Fig. 48.1). Stimuli enhancing cAMP or cGMP cause net loss of salt and water, both by inhibiting NaCl absorption in villous cells and by promoting anion secretion (Na+ accompanies) in the crypt cells which are primarily secretory. Many bacterial toxins, e.g. cholera toxin, exotoxin elaborated by Enterotoxigenic E. coli (ETEC), Staph. aureus, Salmonella, etc. activate adenylyl cyclase which enhances secretion that reaches its peak after 3–4 hours and persists until the stimulated cells are shed in the normal turnover, i.e. 36 hours after a single exposure. Concurrent inhibition of absorption adds to the rate of salt and water loss. Prostaglandins (PGs) and intracellular Ca2+ also stimulate the secretory process. All acute enteric infections produce secretory diarrhoea. The heat stable toxin (ST) of ETEC, Clostridium difficile and E. histolytica cause accumulation of cGMP which also stimulates anion secretion (less potent than cAMP) and inhibits Na+ absorption.


Diarrhoea associated with carcinoid (secreting 5HT) and medullary carcinoma of thyroid (secreting calcitonin) is mediated by cAMP. Excess of bile acids also cause diarrhoea by activating adenylyl cyclase.

 

Traditionally, hypermotility of bowel has been ascribed a crucial role in diarrhoea. However, changes in intestinal motility are now thought to be of secondary importance and may be due to fluid accumulation in the lumen. Decreased segmenting activity in the intestine may promote diarrhoea by allowing less time for the absorptive processes.

 

 

Principles Of Management

 

Rational management of diarrhoea depends on establishing the underlying cause and instituting specific therapy (only if necessary), since most diarrhoeas are self-limiting. Majority of entero-pathogens are taken care of by motility and other defence mechanisms of the gut. Therapeutic measures may be grouped into:

 

·            Treatment of fluid depletion, shock and acidosis.

·            Maintenance of nutrition.

·            Drug therapy.

 

The relative importance of each is governed by the severity and nature of diarrhoea.

 

REHYDRATION

 

In majority of cases, this is the only measure needed. Rehydration can be done orally or i.v.

 

Intravenous Rehydration                                                              

 

It is needed only when fluid loss is severe i.e., > 10% body weight, (if not promptly corrected, it will lead to shock and death) or if patient is losing > 10 ml/kg/hr, or is unable to take enough oral fluids due to weakness, stupor or vomiting. The recommended composition of i.v. fluid (Dhaka fluid) is:

 

NaCl 85 mM = 5 g

KCl 13 mM = 1 g

NaHCO3 48 mM = 4 g

in 1 L of water or 5% glucose solution.

 

This provides 133 mM Na+, 13 mM K+, 98 mM Cl¯ and 48 mM HCO3 ¯. Ringer lactate (Na+ 130, Cl¯ 109, K+ 4, lactate 28 mM) recommended by WHO (1991) could be used alternatively.

 

Volume equivalent to 10% BW should be infused over 2–4 hours; the subsequent rate of infusion is matched with the rate of fluid loss. In most cases, oral rehydration can be instituted after the initial volume replacement.

 

Oral Rehydration

 

Advent of oral rehydration therapy (ORT) is considered a major advance of recent times. If the fluid loss is mild (5–7% BW) or moderate (7.5–10% BW) ORT can be instituted from the very beginning.

 

Rationale Of ORS Composition

 

Oral rehydration is possible if glucose is added with salt. It capitalizes on the intactness of glucose coupled Na+ absorption, even when other mechanisms have failed or when intestinal secretion is excessive—the secreted fluid lacks glucose and cannot be reabsorbed. The composition of oral rehydration salt/solution (ORS) has been debated. The general principles are:

 

a)       It should be isotonic or somewhat hypotonic, i.e. total osmolarity 200–310 mOsm/L (diarrhoea fluids are approximately isotonic with plasma).

 

b)      The molar ratio of glucose should be equal to or somewhat higher than Na+ (excess glucose will be utilized in absorbing Na+ present in the intestinal secretions in addition to that present in ORS itself), but not exceed 110 mM.

 

c)       Enough K+ (15–25 mM) and bicarbonate/ citrate (8–12 mM) should be provided to make up the losses in stool.

 

The WHO recommended a standard formula which provided Na+ 90 mM, K+ 20 mM, Cl¯ 80 mM, citrate (base) 10 mM, glucose 110 mM and had a total osmolarity of 310 mOsm/L. Trisod. citrate was included in place of sod. bicarbonate because bicarbonate containing powder caked and developed a brown colour due to formation of furfural compounds with glucose: had a short shelf life.

 


 

It has been argued that the composition of ORS should be varied according to that of the diarrhea stool. The average electrolyte composition (mM) of 3 important infective diarrhea stools is:

 

As can be seen, the standard WHOORS is based on the composition of cholera stools, particularly in children. When used in noncholera diarrhoea, this WHOORS occasionally produces periorbital edema due to excess Na+ absorption. Based also on the Na+ content of ETEC stools, many pediatricians have favoured 60 mM Na+ and 90 mM glucose ORS for noncholera diarrhoeas.

 

New Formula WHO-ORS                                                               

 

In 2002 a new formula low Na+ low glucose ORS has been released by the WHO. Over the past 20 years WHO sponsored studies were carried out in several developing countries among children and adults suffering from diarrhoeas. It was found that maximum water absorption occurs from a slightly hypotonic solution and when glucose concentration is between 60–110 mM. At higher concentrations, glucose appears in the stools and takes its osmotic penalty—stool volume is increased. Recent studies showed that efficacy of ORS in children with acute noncholera diarrhoea is improved by reducing Na+ and glucose concentration to 75 mM, and total osmolarity to 245 mOsm/L. The need for supplemental i.v. therapy was reduced by 33%. A combined analysis of studies with low osmolarity ORS has revealed that stool volume is reduced by 20% and incidence of vomiting by 30%. The new formula ORS has proven as effective and as safe in cholera as well, both in children and in adults, but there is some risk of hyponatremia in adults with cholera.

 

The WHO and UNICEF have recommended replacement of standard (310 mOsm/L) ORS formula by the new (245 mOsm/L).

 


 

 

(available as ORETRALA, ELECTROBION, ELECTRAL 21 g sachet for 1000 ml; WALYTE, RELYTE 4.2 g sachet for 200 ml).

 

Potassium is an important constituent of ORS, since in most acute diarrhoeas K+ loss is substantial. The base (bicarbonate, citrate, lactate) is added to correct acidosis due to alkali loss in stools. It may independently promote Na+ and water absorption. However, relying on the ability of the kidney to restore acidbase balance, acidotic states have been managed without an exogenous base. Base free ORS has been found to be equally effective in rehydrating, though correction of acidosis is slower. Thus, there is a trend to consider base as a nonessential constituent of ORS, but if present it may be beneficial, especially in severe cases with overt acidosis.

 

Administration Of ORT

 

Patients are encouraged to drink ORS at ½–1 hourly intervals, initially 5–7.5% BW volume equivalent is given in 2–4 hours (5 ml/kg/hr in children). Thirst due to volume depletion provides an adequate driving force. Subsequently it may be left to demand, but should at least cover the rate of loss in stools. In a weak child who refuses to drink ORS at the desired rate—it can be given by intragastric drip; restoring hydration in 6 hours should be aimed.

 

ORT is not designed to stop diarrhoea, but to restore and maintain hydration, electrolyte and pH balance until diarrhoea ceases, mostly spontaneously. It is the best and not a second choice approach to i.v. hydration. About 300 million litre of ORS is being used annually, and is estimated to be preventing 0.5 million child deaths worldwide.

 

Non-diarrhoeal Uses Of ORT

 

a)      Postsurgical, postburn and posttrauma maintenance of hydration and nutrition (in place of i.v. infusion).

b)      Heat stroke.

c)       During changeover from parenteral to enteral elimentation.

 

Super ORS

 

This is a solution which in addition to rehydrating may lead to decrease in purging rates and improvement in diarrhoea by enhanced absorption. Improvement in ORS by adding certain actively transported amino acids (alanine, glycine which cotransport Na+) has been tried. Their efficacy is marginal, and not extended to noncholera diarrhoea; cost-effectiveness may not be favourable. There is compelling evidence, however, that a complex substrate like boiled rice powder 40–50 g/L is an efficient substitute for glucose. The rice starch is slowly hydrolysed at the brush border or in the lumen into glucose which is absorbed: does not cause osmotic diarrhoea even when larger quantity is added: more calories can be administered. Rice has 7% protein: yields amino acids which may themselves stimulate salt and water absorption. It has been found to reduce stool volume compared to WHOORS in cholera patients. Moreover, rice is cheap and widely available. Thus, rice (or wheat, maize, potato) based ORS appears to be suitable for developing countries.

 

MAINTENANCE OF NUTRITION

 

Contrary to traditional view, patients of diarrhoea should not be starved. Fasting decreases brush border disaccharidase enzymes and reduces absorption of salt, water and nutrients; may lead to malnutrition if diarrhoea is prolonged or recurrent. Feeding during diarrhoea has been shown to increase intestinal digestive enzymes and cell proliferation in mucosa. Simple foods like breast milk or ½ strength buffalo milk, boiled potato, rice, chicken soup, banana, sago, etc. should be given as soon as the patient can eat.

 

DRUG THERAPY

 

It consists of:

 

·          Specific antimicrobial drugs.

·          Nonspecific antidiarrhoeal drugs.

 

ANTIMICROBIALS

 

One or more antimicrobial agent is almost routinely prescribed to every patient of diarrhoea. However, such drugs have a limited role in the overall treatment of diarrhoeal patients; the reasons are:

 

i.   Bacterial pathogen is responsible for only a fraction of cases.

ii. Even in bacterial diarrhoea, antimicrobials alter the course of illness only in selected cases.

iii. Antimicrobials may prolong the carrier state.

 

Diarrhoea patients can generally be placed in one of the two categories:

 

a) Abundant watery diarrhoea lacking mucus or blood, usually dehydrating with frequent vomiting, but little or no fever—are generally caused by adhesive but noninvasive enterotoxigenic bacteria such as cholera, ETEC, Salmonella enteritidis or by rota virus and other viruses which stimulate massive secretion by activating cAMP: ORS and not antimicrobials are the main therapy.

 

b) Slightly loose, smaller volume stools, frequently with mucus and/or blood, mild dehydration, usually attended with fever and abdominal pain, but not vomiting—are indications of mucosal invasion, generally caused by entero-invasive organisms like Shigella, enteropathogenic E. coli (EPEC), Campy. jejuni, Salmonella typhimurium, Yersinia enterocolitica, E. histolytica, Clostri. difficile; antimicrobials are needed in many of these.

 

A. Antimicrobials Are Of No Value In diarrhoea due to noninfective causes, such as:

 

·          Irritable bowel syndrome (IBS)

·          Coeliac disease

·          Pancreatic enzyme deficiency

·          Tropical sprue (except when there is secondary infection)

·          Thyrotoxicosis.

 

Rotavirus is an important pathogen of acute diarrhoea, especially in children in developed countries. It along with other diarrhoea causing viruses, is not amenable to chemotherapy.

 

Salmonella food poisoning is generally a self-limiting disease. Antibiotics have been widely used, but may be harmful rather than beneficial—treated patients pass organisms in stool for longer periods than untreated patients. However, very severe illness or that in infants, elderly or immune-compromized patients may be treated with ciprofloxacin/azithromycin/i.v. ceftriaxone.

 

B. Antimicrobials Are Useful Only In Severe Disease (but not in mild cases):

 

i) Travellers’ Diarrhoea: mostly due to ETEC, Campylobacter or virus: cotrimoxazole, norfloxacin, doxycycline and erythromycin reduce the duration and total fluid needed only in severe cases.

 

ii) EPEC: is less common, but causes Shigellalike invasive illness. Cotrimoxazole, colistin, nalidixic acid or norfloxacin may be used in acute cases and in infants. Efficacy of ampicillin has declined due to development of resistance.

 

iii) Shigella enteritis: only when associated with blood and mucus in stools may be treated with ciprofloxacin, norfloxacin or nalidixic acid; cotrimoxazole and ampicillin are alternatives, but many strains are resistant to these.

 

iv) Salmonella typhimurium enteritis is often invasive; severe cases may be treated with a fluoroquinolone, cotrimoxazole or ampicillin.

 

v) Yersinia enterocolitica: common in colder places, not in tropics. Cotrimoxazole is the most suitable drug in severe cases; ciprofloxacin is an alternative.

 

C. Antimicrobials Are Regularly Useful in:

 

i) Cholera: Though not life saving, tetracyclines reduce stool volume to nearly ½. Cotrimoxazole is an alternative, especially in children. Lately, multidrug resistant cholera strains have arisen: can be treated with norfloxacin/ciprofloxacin. Ampicillin and erythromycin are also effective.

 

ii) Campylobacter jejuni: Norfloxacin and other fluoroquinolones eradicate the organism from the stools and control diarrhoea. Erythromycin is fairly effective and is the preferred drug in children.

 

iii) Clostridium difficile: produces antibiotic associated pseudomembranous enterocolitis. The drug of choice for it is metronidazole, while vancomycin given orally is an alternative. Offending antibiotic must be stopped.

 

iv) Diarrhoea associated with bacterial growth in blind loops/diverticulitis may be treated with tetracycline or metronidazole.

 

v) Amoebiasis metronidazole, diloxanide furoate,

 

vi) Giardiasis  are effective drugs (see Ch. No. 60).

 

NON-SPECIFIC ANTIDIARRHOEAL AGENTS

 

These are classified and their uses listed in Table 48.2.

 


 

1. Absorbants

 

These are colloidal bulk forming substances which absorb water and swell. They modify the consistency and frequency of stools and give an impression of improvement, but do not reduce the water and electrolyte loss. They are of value in selected conditions (Table 48.2). Ispaghula and other bulk forming colloids are useful in both constipation and diarrhoea phases of IBS and reduce abdominal pain as well.


 

2. Antisecretory Drugs



Sulfasalazine (Salicylazosulfapyridine)



 

It is a compound of 5aminosalicylic acid (5ASA) with sulfapyridine linked through an azo bond that has a specific therapeutic effect in inflammatory bowel diseases (IBDs) like ulcerative colitis and Crohn’s disease.

 

Having low solubility, it is poorly absorbed from the ileum. The azo bond is split by colonic bacteria to release 5ASA and sulfapyridine. The former exerts a local anti-inflammatory effect, the mechanism of which is not clear. Though it inhibits both COX and LOX, decreased PG and LT production appears to play a minor role in the therapeutic effect. Inhibition of cytokine, PAF, TNFα and nuclear transcription factor (NFκB) generation seems to be more important. Migration of inflammatory cells into bowel wall is interfered and mucosal secretion is reduced— affords considerable relief in ulcerative colitis and related inflammatory bowel diseases. Given during an exacerbation it reduces number of stools, abdominal cramps and fever, but is less effective than corticosteroids; may be employed for mild to moderate exacerbation. A dose of 3– 4 g/day induces remission over a few weeks in many cases, but relapses are common after stoppage. Maintenance therapy with 1.5–2 g/day has been found to postpone relapse as long as taken. The primary value of sulfasalazine is in maintaining remission, while corticosteroids are reserved to treat acute exacerbations.

 

The beneficial effect of sulfasalazine is clearly not due to any antibacterial action (bowel flora remains largely unaffected): sulfapyridine moiety only serves to carry 5ASA to the colon without being absorbed proximally. However, part of the released sulfapyridine is absorbed in the colon and is responsible for adverse effects like rashes, fever, joint pain, haemolysis and blood dyscrasias. Nausea, vomiting, headache, malaise and anaemia are other frequent side effects. Upto 1/3rd patients suffer intolerable adverse effects. Oligozoospermia and male infertility is reported. Sulfasalazine interferes with folate absorbtion; folic acid supplementation should be given during its use.

 

Sufasalazine has also been used as a disease modifying drug in rheumatoid arthritis: the absorbed sulfapyridine appears to be responsible for the therapeutic effect.

 

SALAZOPYRIN, SAZOEN 0.5 g tab.

 


Mesalazine (Mesalamine)

 

These are the official names given to 5ASA. Realizing that 5ASA is the active moiety in ulcerative colitis, but is not effective orally because of inability to reach the large bowel (it is absorbed in the small intestine), it has been formulated as delayed release preparations by coating with acrylic polymer. The pattern of release over the length of jejunum, ileum and colon differs among the different formulations, but most of them do effectively deliver 5ASA to the distal small bowel and colon. A daily dose of 2.4 g has been found to improve over 50% patients of ulcerative colitis (upto 80% mild-to-moderate cases). Less than half of the 5ASA released from these preparations is absorbed, acetylated in the liver and excreted in urine. Like sulfasalazine, the primary use of mesalazine is in preventing relapses, though it may also be employed to treat mild-to-moderate exacerbations.

 

MESACOL, TIDOCOL 400 mg tab, ETISA 500 mg sachet.

 

Adverse Effects

 

Coated mesalazine is better tolerated than sulfasalazine. Side effects noted are nausea, diarrhoea, abdominal pain and headache, but are mild and less frequent. Rashes and hypersensitivity reactions are rare. Bone marrow depression and decreased sperm count has not occurred. Mesalazine has nephrotoxic potential, because 30–40% of 5ASA is released in the ileum and is absorbed. It is contraindicated in renal and hepatic impairment.

 

Drug Interactions Coated mesalazine may enhance the gastric toxicity of glucocorticoids and hypoglycaemic action of sulfonylureas. Interaction with coumarins, furosemide, spironolactone, methotrexate and rifampicin are possible.

 

5-ASA Enemas: Another mode of delivery of 5-ASA to colon is to administer it by a retention enema: 1–2 g enema once or twice daily is effective in distal ulcerative colitis, including some refractory cases.

 

MESACOL ENEMA 4 g/60 ml.

 

Olsalazine

 

It consists of two molecules of 5ASA coupled together by azo bond. It is poorly absorbed in the ileum, the azo bond is split in the colon to provide 5ASA locally. No separate carrier moiety is needed. Olsalazine is probably the most reliable preparation for delivery of 5ASA to the colon. However, it often aggravates diarrhoea initially by decreasing transit time through the bowels.

 

Balsalazine

 

This is 5-ASA linked to 4aminobenzoylβalanine as the carrier. The 5-ASA is released in the colon and the carrier is poorly absorbed.

 

Corticosteroids

 

Prednisolone (40 mg/day) or equivalent are highly effective in controlling symptoms/inducing remission in both ulcerative colitis and Crohn’s disease. They are the drugs of choice for moderately severe exacerbations. Hydrocortisone enema, or foam (ENTOFOAM 10%) can be used for topical treatment of proctitis and distal ulcerative colitis. Corticosteroids are generally discontinued after remission is induced, and mesalazine started during steroid therapy is continued to prevent relapses.

 

A sizeable percentage of severe IBD patients either relapse on stoppage of the steroid (steroid-dependent) or do not respond to it (steroid-resistant). Increasing use of specific immunosuppressant drugs is now being made in such IBD patients, particularly to avoid long-term steroid therapy which carrys hazards.

 

Immunosuppressants

 

Azathioprine is the most commonly used immunosuppressant in IBD. Though the response is delayed— occurring after weeks or months, it has lower toxicity. Azathioprine is used for moderate-to-severe Crohn’s disease as well as ulcerative colitis, especially as a steroid sparing drug or in steroid resistant cases. It has good remission maintaining property.

 

Methotrexate is also effective in IBD and acts faster, but higher doses are needed than for rheumatoid arthritis. In IBD, efficacy by oral route is lower. Thus, it has a limited role in severe Crohn’s disease only.

 

Cyclosporine can be used to maintain remission in both Crohn’s as well as ulcerative colitis, but is not a first line immunosuppressant because of renal toxicity, and poor oral efficacy in IBD.

 

Infliximab: This chimeric antiTNFα immunoglobulin has shown promising effect in IBD and is being increasingly used for severe uncontrolled cases.

 

Bismuth Subsalicylate

 

Taken as suspension (60 ml 6 hourly) it is thought to act by decreasing PG synthesis in the intestinal mucosa, thereby reducing Cl¯ secretion. It has some prophylactic value in travellers’ diarrhoea; (probably due to weak antibacterial action also), but it is rather inconvenient to carry and take.

 

Anticholinergics

 

Atropinic drugs can reduce bowel motility and secretion, but have poor efficacy in secretory diarrhoeas. They may benefit nervous/drug (neostigmine, metoclopramide, reserpine) induced diarrhoeas and provide some symptomatic relief in dysenteries, diverticulitis.

 

Octreotide

 

This somatostatin analogue has a long plasma t½ (90 min) as well as potent antisecretory/ antimotility action on the gut. It has been used to control diarrhoea in carcinoid and vasoactive intestinal peptide (VIP) secreting tumours, and for refractory diarrhoea in AIDS patients, but needs to be given by s.c. injection.

 

Opioids

 

In addition to their well recognized antimotility action, opioids reduce intestinal secretion. Loperamide has been clearly shown to reduce secretion, probably through specific opioid receptors, but does not affect mucosal cAMP or cGMP levels.

 

Racecadotril

 

This recently introduced prodrug is rapidly converted to thiorphan, an enkephalinase inhibitor. It prevents degradation of endogenous enkephalins (ENKs) which are mainly δ opioid receptor agonists. Racecadotril decreases intestinal hypersecretion, without affecting motility, by lowering mucosal cAMP due to enhanced ENK action. It is indicated in the shortterm treatment of acute secretory diarrhoeas. In contrast to loperamide/diphenoxylate, it is not contraindicated in children. The elimination t½ as thiorphan is 3 hr. Side effects are nausea, vomiting, drowsiness, flatulence.

 

Dose: 100 mg (children 1.5 mg/kg) TDS for not more than 7 days.

 

CADOTRIL, RACIGYL 100 mg cap, 15 mg sachet; REDOTIL 100 mg cap.

 

3. Antimotility Drugs

 

These are opioid drugs which increase small bowel tone and segmenting activity, reduce propulsive movements and diminish intestinal secretions while enhancing absorption. The major action appears to be mediated through μ opioid receptors located on enteric neuronal network, but direct action on intestinal smooth muscle and secretory/absorptive epithelium has also been demonstrated. The δ receptors are believed to promote absorption and inhibit secretion, while the μ receptors enhance absorption and decrease propulsive movements. Overall they increase resistance to luminal transit and allow more time for the absorptive processes. No tolerance develops to their constipating action.

 

Codeine

 

This opium alkaloid has prominent constipating action at a dose of 60 mg TDS. The antidiarrhoeal effect is attributed primarily to its peripheral action on small intestine and colon. It does have central effects, but dependence producing liability is low. Side effects are nausea, vomiting and dizziness. It should be used only for short periods and with caution in children.

 

Diphenoxylate (2.5 mg) + atropine (0.025 mg): LOMOTIL tab and in 5 ml liquid.

 

Dose: 5–10 mg, followed by 2.5–5 mg 6 hourly.

 

It is a synthetic opioid, chemically related to pethidine; used exclusively as constipating agent; action is similar to codeine. The anti-diarrhoeal action is most prominent, but because it is absorbed systemically and crosses blood-brain barrier—CNS effects do occur. Atropine is added in sub-pharmacological dose to discourage abuse by taking several tablets. Abuse liability is rated low, and overdose will produce disturbing atropinic side effects. It has caused respiratory depression, paralytic ileus and toxic megacolon in children. Response is more variable in them—contraindicated below 6 years of age.

 

Loperamide

 

It is an opiate analogue with major peripheral μ opioid and additional weak anticholinergic property. As a constipating agent it is much more potent than codeine. Because of poor water solubility—little is absorbed from the intestines. Entry into brain is negligible—CNS effects are rare and occur only with high doses; no abuse liability. The duration of action is longer (12 hr) than codeine and diphenoxylate.

 

In addition to its opiate like action on motility, loperamide also inhibits secretion: directly interacts with calmodulin—this may be responsible for the anti-diarrhoeal action. It improves faecal continence by enhancing anal sphincter tone.

 

Adverse Effects: Abdominal cramps and rashes are the most common side effects. Paralytic ileus, toxic megacolon with abdominal distension is a serious complication in young children—fatalities have occurred, probably due to absorption of toxins from the intestines: contraindicated in children < 4 yr. Loperamide appears to be the most effective and most suitable of the antimotility drugs.

 

Dose: 4 mg followed by 2 mg after each motion (max. 10 mg in a day); 2 mg BD for chronic diarrhoea.

 

IMODIUM, LOPESTAL, DIARLOP: 2 mg tab, cap.

 

Liquid formulation has been withdrawn.

 

The utility of antimotility drugs in diarrhoea is limited to noninfective diarrhoea, mild traveller’s diarrhoea, and when diarrhoea is exhausting or idiopathic diarrhoea in AIDS patients. Their use is a shortterm measure only.

 

Antimotility drugs are contraindicated in acute infective diarrhoeas because they delay clearance of the pathogen from the intestine. If invasive organisms (Shigella, EPEC, EH, etc.) are present, antimotility drugs can be disastrous. They are contraindicated in irritable bowel syndrome, ulcerative colitis and diverticulosis because they increase intraluminal pressure.

 

Antimotility drugs can be used to induce deliberate shortterm constipation, e.g. after anal surgery, and to reduce the volume, fluidity and bag cleaning frequency in ileostomy/colostomy patients.

 

NOTE: Drugs Controller General of India has banned the following category of antidiarrhoeal drugs:

 

·         Containing adsorbants like Kaolin, pectin, attapulgite, activated charcoal, etc.

·  Containing phthalylsulfathiazole, succinylsulfathiazole, sulfaguanidine, neomycin, streptomycin, dihydrostreptomycin.

·  For pediatric use containing diphenoxylate, loperamide, atropine, belladonna, hyosciamine, halogenated hydroxyquinolines.

·          Fixed dose combinations of antidiarrhoeals with electrolytes.

·          Fixed dose combination of loperamide with furazolidone.

·          Fixed dose combination of antidiarrhoeals with antihistaminics

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