LAXATIVES (Aperients, Purgatives, Cathartics)These are drugs that promote evacuation of bowels. A distinction is sometimes made according to the intensity of action.(a) Laratiae or aperient: milder actiory elimination of soft but formed stools.b) Purgatiae or cathartic: stronger action resulting in more fluid evacuation.Many drugs in low doses act as laxative and in Iarger doses as purgative.

CLASSIFICATION:

1. Bulk forming : Dietary fibre: Bran, Psyllium (Plantago) Ispaghula, Methylcellulose2. Stool softener : Docusates (DOSS), Liquid paraffin3. Stimulant purgatives : (a) Diphenylmethanes: Phenolphthalein, Bisacodyl, Sodium picosulfate (b) Anthraquinones (Emodins): Senna, Cascara sagrada (c) S-HTaagonist : Tegaserod (d) Fixed oil : Castor oil4. Osmotic purgatives: Magnesium salts: sulfate, hydroxide Sodium salts: sulfate, phosphate Sod. pot. tartrate Lactulose

MECHANISM OF ACTION :

All purgatives increase the water content of faeces by-(a) A hydrophilic or osmotic action, retaining water and electrolytes in the intestinal lumen-increase volume of colonic content and make it easily propelled.(b) Acting on intestinal mucosa, decrease net absorption of water and electrolyte; intestinal transit is enhanced indirectlyby the fluid bulk.(c) Increasing propulsive activity as primary action-allowing less time for absorption of salt and water as a secondary effect.

For some of the drugs, controversy continues as to whether they increase water content of stools as the primary action or it is a consequence of increased motility. However, certain purgatives do increase motility through an action on the myenteric plexuses. Laxatives modify the fluid dynamics of the mucosal cell and may cause fluid accumulation in gut lumen by one or more of following mechanisms:

(a) Inhibiting Na*K*ATPase of uillous cells impairing electrolyte and water absorption.

(b) Stimulating adenylyl cyclase tn crypt cellsincreasing water and electrolyte secretion.

(c) Enhancing PC synthesis in mucosa which increases secretion.

(d) Structural injury to the absorbing intestinal mucosal cells.

BULK PURGATIVES :Dietary fibre: bran Dietary fibre consists of unabsorbable cell wall and other constituents of vegetable food---<ellulose, pectins, glycoproteins and other polysaccharides. Bran is a byproduct of flour industry----consis ts of -40h dietary fibre. It absorbs water in the intestines, swells, increases water content of faeces-softens it and facilitates colonic transit. Osmotically active products may be formed in the colon by bacterial degradation of pectins, etc. which act to retain water. Dietary fibre supports bacterial growth in colon which contribute to the faecal mass. Certain dietary fibres (gums, lignins, pectins) bind bile acids and promote their excretion in faeces -+ degradation of cholesterol in liver is enhanced + plasma LDLcholesterol is lowered. Increased intake of dietary fibres is the most appropriate method for prevention of functional constipation. It is the first line approach for most patients of simple constipation. Prolonged intake of bran and other bulk forming agents reduces rectosigmoid intraiuminal pressure-relieves symptoms of irritable bowel syndrome (IBS) including pain, constipation as well as diarrhoea, and of colonic diverticulosis. It is also useful when straining at stools has to be avoided.

Drawbacks : Bran is generally safe, but it is unpalatable, large quantity (20-40 g/day) needs to be ingested. It has been included in some breakfastc ereals.F ull effect requires daily intake for at least 3-4 days. It does not soften faeces already present in colon or rectum. As such, bran is useful for prevention of constipation, but not for treating already constipated subjects Flatulence may occur. It should not be used in patients with gut ulcerations, adhesions, stenosis and when faecal impaction is a possibility.

Psyllium (Plantago) and lspaghula : They contain natural colloidal mucilage which forms ; gelatinous mass by absorbing water; 3-12 g t': refined husk freshly mixed with water or milk ar.;taken daily-acts in 1-3 days. It should not be swallowed dry (may cause esophageal impaction)

Methylcellulose : A semi-synthetic, colloidal hydrophilic derivative of cellulose; 4-6 g/ days satisfactory in most individuals.Generous amounts of water must be taken with all bulk forming agents. The choice among different bulking agents is a matter of personal preferences.

STOOL SOFTENERDocusates (Dioctyl sodium sulfosuccinate,DOSS) : It is an anionic detergent, soften the stools by net water accumulation in the lumen by an action on the intestinal mucosa. It emulsifies the colonic contents and increases penetration of water into faeces. By a detergent action, it can disrupt the mucosal barrier and enhanced absorption of many nonabsorbable drugs , e.g. iiquid paraffin-

should not be combined with it. it is a mild laxative; especially indicated when straining at stools must be avoided.

Adverse effects : Cramps and abdominal pain can occur . It is bitter; liquid preparations may cause nausea. Hepatotoxicity is feared on prolonged use.

liquid paraffin : It is a viscous liquid; a mixture of petroleum hydrocarbons, that was introduced as alaxative at the turn of 19th century. Taken for 2-3 days, it softens stools and is said to lubricate hard scybali by coating them.Dose: 15-30 ml/day-oil as such or in emulsified form.

Disadvantages:a) It is bland but very unpleasant to swailow because of oily consistency.b) Small amount passes into the intestinal mucosa-is carried into the lymph - may produce foreign body granulomas in the intestinal submucosa, mesenteric lymph nodes, liver and spleen.c) While swallowing it may trickle into lungs---cause lipid pneumoniad) Carries away fat soluble vitamins with it into the stools: deficiency may occur on chronic usee) Leakage of the oil past anal sphincter may embarrass.f) May interfere with healing in the anorectal region.Thus, it should be used only occasionally.

STIMULANT PURGATIVES They are powerful purgatives: often produce griping. They were thought to irritate the intestinalmucosa and thus stimulate motor activity. Though some of them do primarily increase motility by acting on myenteric plexuses, the more important mechanism of action is accumulation of water and electrolytes in the lumen by altering absorptive and secretory activity of the mucosal cell. They inhibit Na+-K+ ATPase at the basolateral membrane of villous cells-transport of Na + and accompanying water into the interstitium is reduced. Secretion is enhanced by activation of cAMP in crypt cells and by increased PG synthesis.Larger doses of stimulant purgatives can cause excess purgation -+ fluid and electrolyte imbalance. Hypokalaemia can occur on regular use. Routine and long-term use must be discouraged; produces colonic atony. They can reflexly stimulate gravid uterus-contraindicated during pregnancy. Subacute or chronic intestinal obstruction is another contra-indication.

Diphenylmethanes Phenolphthalein is an indicator and is in use as purgative from the begiruring of the 20thcentury. It turns urine pink if alkaline.Bisacodyl is a later addition and is more popular. They are partly absorbed and reexcreted in bile: enterohepatic circulation is more important in phenolphthalein which can produce protracted action. Bisacodyl is activated in the intestine by deacetylation. Their primary site of action is in the colon:

irritate the mucosa, produce mild inflammation and secretion. One or two semiformed motions occur after 6-8 hours. Optimum doses vary considerably among individual.

A/E: Allergic reactions-skin rashes, fixed drug eruption and Stevens-]ohnson syndrome have been reported. It can cause inflammation and mucosal damage.

Anthraquinones

The purgative action and uses of anthraquinones are quite similar to diphenylmethanes. Taken at bed time-a single, soft but formed evacuation generally occurs in the morning. Cramps and excessive purging occur in some cases. The active principle acts on the myenteric plexus to increase peristalsis and decrease segmentation. They also promote secretion and inhibit salt and water absorption in the colon. Senna anthraquinone has been found to stimulate PCE2 production in rat intestine-this is blocked by indomethacin and the purgative action is reduced.

A/E : Skin rashes, fixed drug eruption are seen occasionally. Regular use for 4-12 months causes colomcatony and mucosal pigmentation (melanosis).

OSMOTIC PURGATIVES :Solutes that are not absorbed in the intestine retain water osmotically and distend the bowel increasing peristalsis indirectly. Magnesium ions release cholecystokinin which may aid purgative action of Mag. salts. All inorganic salts used as osmotic (saline) Purgatives have similar action-differ only in dose, palatability and risk of systemic toxicity.

Mag. sulfate (Epsom salt): 5-15 g; bitter in taste. Mag. hydroxide (as 8% W/W suspensionmilk of magnesia) 30 ml; bland in taste, also used as

antacid. Sod. sulfate (Glauber's salt): 10-15 g; bad in taste. Sod. phosphate: 6-12 g, taste not unpleasant' Sod. pot. tartrate (Rochelle salt): 8-15 g, relatively pleasant tasting

The salts in above mentioned doses, dissolved in 150-200 ml of water, produce 1-2 fluid evacuationswithin 1-3 hours with mild cramping; cause nearly complete emptying of bowels. Smaller doses may have a milder laxative action.

Lactulose : It is a semislmthetic disaccharide of fructose and lactose which is neither digestednor absorbed in the small intestine-retains water. Further, it is broken down in the colon by bacteria to osmotically more active products. In a dose of 10 g BD taken with plenty of water, it produces soft formed stools in 1-3 days. Flatulence and flatus is common, cramps occur in few. Some patients feel nauseated by its peculiar sweet taste. Lactulose causes reduction of blood NH3 concentration by 25-

50% inPatients with hepatic encephalopathy. The breakdown products of lactulose are acidic-reduce the pH of stools.

CHOICE AND USE OF PURGATIVESLaxatives are as important for their harmfulness as they are for their value in medicine.All laxatives are contraindicated in :

(i) A patient of undiagnosed abdominal pain, colic orvomiting.

(ii) Organic (secondary) constipation due to stricture or obstruction in bowel, hypothyroidism,hypercalcaemia, malignancies and certain drugs, e.g.-opiates, sedatives, anticholinergics including antiparkinsonian, antidepressants and antihistaminics, oral iron, clonidine, verapamil and laxativeabuse itself.

The primary cause should be treated in these cases.Valid indications of laxatives are:

1. Functional constipation : Constipation is infrequent production of hard stools requiring straining to pass, or a sense of incomplete evacuation. Constipation is a symptom rather than a disease. Various aspects of the patient's lifestyle may contribute: (a) Misconception about the normal/necessary frequency, amount or consistency of stools. (b) lnadequate fibre in diet,less fluid intake. (c) Lack of exercise, sedentary nature of work. (d) Irregular bowel habits, rushing out for job.Proper assessment of the causative factor in the patient and its correction leaves only a minority of cases to be treated by drugs. Constipation may be spastic or atonic.

(i) Spastic constipation (irritable bowel): The stools are hard, rounded, stone like and difficult to pass. The first choice laxative is dietary fibre or any of the bulk forming agents taken over weeks/months. Tegaserod is a new option available now. Stimulant purgatives are contraindicated.

(ii) Atonic constipation (sluggish bowel) : mostly due to advanced age, debility or iaxative abuse. Non-drug measures like plentl. of fluids, exercise, regular habits and reassurance should be tried. In resistant cases a bulk forming agent should be prescribed. In case of poor compliance or if the patient is not satisfied-bisacodyl or senna may be given once or twice a week for as short a period as possible.

2. Bedridden patients (myocardialinfarction, stroke, fractures, postoperative): bowel movementmay be sluggish and constipation can be anticipated.

To prevent constipation: Give bulk forming agents on a regular schedule; docusates, lactulose and liquid paraffin are alternatives.

To treat constipation: Enema (soap-water,/ glycerine) is preferred; bisacodyl or senna may be used.

3. To avoid straining at stools : (hernia, cardiovascular disease, eye surgery) and in perianal afflictions (piles, fissure, anal surgery) it is essential to keep the faeces soft. One should not hesitate to use adequate dose of a bulk forming agent, lactulose or docusates. L Preparation of bowel for surgery, colonoscopy, abdominal X-ray The bowel needs to be emptied of the contents including gas. Salinepurgative, bisacodyl or senna may be used; castor oil only in exceptional circumstances.

5. After certain anthelmintics : (especially for tapeworm) Saline purgative or senna may be used to flush out the worm and the anthelmintic drug. Fixed dose combinations of an anthelmintic (other thanpiperazine) with a purgative is banned in lndia, as are laxatives with enzyme preparations

6. Food/drug poisoning : The idea is to drive out the unabsorbed irritant/poisonous material from the intestines. Only saline purgatives are satisfactory. The choice of a purgative depends on the latency of action and type of stools desired.

Purgative abuse :Some individuals are obsessed with using purgatives regulary,. This may be the reflection of a psychological problem. Others use a purgative casually, obtain thorough bowel evacuation, and by the time the colon fills up for a proper motion (2-3 days) they get convinced that they are constipated and start taking the drug regularly. Chronic use of purgatives must be discouraged. Once the purgative forms, it is difficult to break. Dangers of purgative abuse are:

1. Flairing of intestinal pathology, rupture of inflamed appendix.2. Fluid and electrolyte imbalance, especially hypokalaemia.3. Steatorrhoea, malabsorption syndrome4. Protein losing enteropathy.5. Spastic colitis.

DIARRHOEA

Diarrhea is defined by the World Health Organization as having three or more loose or liquid stools per day, or as having more stools than is normal for that person. Acute diarrhea is defined as an abnormally frequent discharge of semisolid or fluid fecal matter from the bowel, lasting less than 14 days, by World Gastroenterology Organization. It often lasts for a few days and can result in dehydration due to fluid loss. Signs of dehydration often begin with loss of the normal stretchiness of the skin and changes in personality. This can progress to decreased urination, loss of skin color, a fast heart rate, and a decrease in responsiveness as it becomes more severe. Loose but non watery stools in babies who are breastfed, however, may be normal.

The most common cause is an infection of the intestines due to either a virus, bacteria, or parasite; a condition known as gastroenteritis. These infections are often acquired from food or water that has been contaminated by stool, or directly from another person who is infected. It may be divided into three types:

i)short duration watery diarrhea

ii) short duration bloody diarrhea

iii) if it lasts for more than two weeks, persistent diarrhea

The short duration watery diarrhea may be due to an infection by cholera. If blood is present it is also known as dysentery. A number of non-infectious causes may also result in diarrhea, including hyperthyroidism, lactose intolerance, inflammatory bowel disease, a number of medications, and irritable bowel syndrome. In most cases stool cultures are not required to confirm the exact cause. If there is blood visible in the stools, it is also known as dysentery. The blood is trace of an invasion of bowel tissue. Dysentery is a symptom of, among others, Shigella, Entamoeba histolytica, and Salmonella.

About 1.7 to 5 billion cases of diarrhea occur per year. It is most common in developing countries, where young children get diarrhea on average three times a year. Total deaths from diarrhea are estimated at 1.26 million in 2013 – down from 2.58 million in 1990. In 2012, it is the second most common cause of deaths in children younger than five (0.76 million or 11%).Frequent episodes of diarrhea are also a common cause of malnutrition and the most common cause in those younger than five years of age.[2] Other long term problems that can result include stunted growth and poor intellectual development.

Causes :

Sanitation :

Open defecation is a leading cause of infectious diarrhea leading to death. Poverty is a good indicator of the rate of infectious diarrhea in a population. This association does not stem from poverty itself, but rather from the conditions under which impoverished people live. The absence of certain resources compromises the ability of the poor to defend themselves against infectious diarrhea. "Poverty is associated with poor housing, crowding, dirt floors, lack of access to clean water or to sanitary disposal of fecal waste (sanitation), cohabitation with domestic animals that may carry human pathogens, and a lack of refrigerated storage for food, all of which increase the frequency of diarrhea... Poverty also restricts the ability to provide age-appropriate, nutritionally balanced diets or to modify diets when diarrhea develops so as to mitigate and repair nutrient losses. The impact is exacerbated by the lack of adequate, available, and affordable medical care.”

Water :

One of the most common causes of infectious diarrhea, is a lack of clean water. Often, improper fecal disposal leads to contamination of groundwater. This can lead to widespread infection among a population, especially in the absence of water filtration or purification. Human feces contains a variety of potentially harmful human pathogens.

Nutrition :

Proper nutrition is important for health and functioning, including the prevention of infectious diarrhea. It is especially important to young children who do not have a fully developed immune system. Zinc deficiency, a condition often found in children in developing countries can, even in mild cases, have a significant impact on the development and proper functioning of the human immune system. Indeed, this relationship between zinc deficiency reduced immune functioning corresponds with an increased severity of infectious diarrhea. Children who have lowered levels of zinc have a greater number of instances of diarrhea, severe diarrhea, and diarrhea associated with fever. Similarly, vitamin A deficiency can cause an increase in the severity of diarrheal episodes, however there is some discrepancy when it comes to the impact of vitamin A deficiency on the rate of disease.

Relevant pathophysiology :

Water and electrolytes are absorbed as well as secreted in the intestine. jejunum is freely permeableto 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 isoosmotically. 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.

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 enteropathogens are taken care of by motility and other defence mechanisms of the gut. Therapeuticmeasures may be grouped into: (a) Treatment of fluid depletion, shock and acidosis. (b) Maintenance of nutrition. (c) Drug therapy.The relative importance of each is governed by the severity and nature of diarrhea.

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 > 70 rnl/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:

Volume equivalent to 10% BW should be infused over 24 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 (7.5-70%BW) ORT can be instituted from the very beginning.

MAINTENANCE OF NUTRITION : Contrary to traditional view, patients of diarrhea 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 1∕2 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:-

(i) Specific antimicrobial drugs. (ii) 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 generallybe 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 enterotoxrgenic 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. usuallv attended with fever and abdominal pain, but not vomiting-are indications of mucosal invasion, generally caused by enteroinvasive organisms llke Shigella, enteropathcgenic E. coli (EPEC), Campy. jejuni, Salmonel.; typhimurium, Ye rsinia enterocoliticaE, . histoluti t.;. Clostri. dfficile; antimicrobials are needed in many of these.

Travellers'diarrhoea: mostly due to ETIC Campylobacteor virus: cotrimoxazole, norfloxacin, doxycycline and erythromycin reduce the duration and total fluid needed only in sever cases.

Shigella enteritis: only when associated with blood and mucus in stools may be treated withciprofloxacin, norfloxacin or nalidixic acid; cotrimoxazole and ampicillin are alternatives,lt many strains are resistant to these.Diarrhoea associated with bacterial growth in blind loops/diverticulitis may be treated with tetracycline or metronidazole.Amoebiasis : metronidazole, diloxanide furoate.

NONSPECIFIC ANTIDIARRHOEAL AGENTS

1. Absorbants :These ale colloidal bulk forming substances which absorb water and swell They modifythe 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 Ispaghula and other bulk forming colloids are useful in both constipation and diarrhoea phases of IBS and reduce abdominai pain as well

2. Antisecretory drugs : Sulfasalazine(Salicylazosulfapyridine ) is a compound of 5-aminosalicylic acid (5-ASA) 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.

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 opioid receptors located on enteric neuronalnetwork, but direct action on intestinal smooth muscle and secretory / absorptive epithelium hasalso been demonstrated .

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.

Loperamide : It is an opiate analogue with major peripheral opioid and additional weak anticholinergic property. As a constipating agent it is much more potent than codeine. Because ofpoor 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 antidiarrhoeal 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-fatalitieshave occurred, probably due to absorption of toxins from the intestines: contraindicated in children < 4 yt.Loperamide appears to be the most effective and most suitable of the antimotility drugs.

Antimotility drugs can be used to induce deliberate short-term constipation, e.g. after analsurgery, and to reduce the volume, fluidity and bag cleaning frequency in ileostomy/colostomipatients.

Prevention:

Sanitation : Numerous studies have shown that improvements in drinking water and sanitation (WASH) lead to decreased risks of diarrhoea. Such improvements might include for example use of water filters, provision of high-quality piped water and sewer connections. In institutions, communities, and households, interventions that promote hand washing with soap lead to significant reductions in the incidence of diarrhea. The same applies to preventing open defecation at a community-wide level and providing access to improved sanitation. This includes use of toilets and implementation of the entire sanitation chain connected to the toilets (collection, transport, disposal or reuse of human excreta).

Hand washing : Basic sanitation techniques can have a profound effect on the transmission of diarrheal disease. The implementation of hand washing using soap and water, for example, has been experimentally shown to reduce the incidence of disease by approximately 42–48%. Hand washing in developing countries, however, is compromised by poverty as acknowledged by the CDC: "Handwashing is integral to disease prevention in all parts of the world; however, access to soap and water is limited in a number of less developed countries. This lack of access is one of many challenges to proper hygiene in less developed countries." Solutions to this barrier require the implementation of educational programs that encourage sanitary behaviours.

Water : Given that water contamination is a major means of transmitting diarrheal disease, efforts to provide clean water supply and improved sanitation have the potential to dramatically cut the rate of disease incidence. In fact, it has been proposed that we might expect an 88% reduction in child mortality resulting from diarrheal disease as a result of improved water sanitation and hygiene. Similarly, a meta-analysis of numerous studies on improving water supply and sanitation shows a 22–27% reduction in disease incidence, and a 21–30% reduction in mortality rate associated with diarrheal disease. Chlorine treatment of water, for example, has been shown to reduce both the risk of diarrheal disease, and of contamination of stored water with diarrheal pathogens.

Vaccination : Immunization against the pathogens that cause diarrheal disease is a viable prevention strategy, however it does require targeting certain pathogens for vaccination. In the case of Rotavirus which was responsible for around 6% of diarrheal episodes and 20% of diarrheal disease deaths in the children of developing countries, use of a Rotavirus vaccine in trials in 1985 yielded a slight (2-3%) decrease in total diarrheal disease incidence, while reducing overall mortality by 6-10%. Similarly, a Cholera vaccine showed a strong reduction in morbidity and mortality, though the overall impact of vaccination was minimal as Cholera is not one of the major causative pathogens of diarrheal disease. Since this time, more effective vaccines have been developed that have the potential to save many thousands of lives in developing nations, while reducing the overall cost of treatment, and the costs to society. A rotavirus vaccine decrease the rates of diarrhea in a population. New vaccines against rotavirus, Shigella, Enterotoxigenic Escherichia coli (ETEC), and cholera are under development, as well as other causes of infectious diarrhea.

Nutrition : Dietary deficiencies in developing countries can be combated by promoting better eating practices. Supplementation with vitamin A and/or zinc. Zinc supplementation proved successful showing a significant decrease in the incidence of diarrheal disease compared to a control group. The majority of the literature suggests that vitamin A supplementation is advantageous in reducing disease incidence. Development of a supplementation strategy should take into consideration the fact that vitamin A supplementation was less effective in reducing diarrhea incidence when compared to vitamin A and zinc supplementation, and that the latter strategy was estimated to be significantly more cost effective.

Breastfeeding : Breastfeeding practices have been shown to have a dramatic effect on the incidence of diarrheal disease in poor populations. Studies across a number of developing nations have shown that those who receive exclusive breastfeeding during their first 6 months of life are better protected against infection with diarrheal diseases. Exclusive breastfeeding is currently recommended during, at least, the first six months of an infant's life by the WHO.

Others : Probiotics decrease the risk of diarrhea in those taking antibiotics.

ANTIAMOEBIC DRUGS

These are drugs useful in infection caused by the protozoa Entamoeba histolytica. Amoebiasis has a worldwide distribution (over 40 million people are infected), but it is endemic in most parts of India and other developing countries. Poor environmental sanitation and low socio-economic status areimportant factors in the spread of the disease, which occurs by faecal contamination of food and water. Amoebic cysts reaching the intestine transform into trophozoites which either live on the surface of colonic mucosa as commensalsform cysts that pass into the stools (luminal cycle) and serve to propagate the disease, or invade the mucosa-form amoebic ulcers and cause acute dysentery (withblood and mucus in stools) or chronic intestinal amoebiasis (with vague abdominal symptoms, amoeboma). Occasionally the trophozoites pass into the blood stream, reach the liver aia portal vein and cause amoebic liver abscess

CLASSIFICATION :1.Tissue amoebicides : (a) For both intestinal and extraintestinal amoebiasis: Nitroimidazoles: Metronidazole ,Tinidazole, Secnidazole,Ornidazole,

Satranidazole

AIkaloids : Emetine, Dehydroemetine (b) For extraintestinal amoebiasis only: Chloroquine2.Luminal amoebicides : (a) Amide: Diloxanide furoate, Nitazoxanide b) 8-Hydroxyquinolines: Quiniodochlor (Iodochlorohydroxyquin, Clioquinol),

Diiodohydroxyquin (Iodoquinol) (c) Antibiotics : Tetracyclines

Metronidazole & Tinidazole

Metronidazole, a nitroimidazole is the drug of choice in the treatment of extraluminal amebiasis. It kills trophozoites but not cysts of E histolytica and effectively eradicates intestinal and extraintestinal tissue infections.

Mechanism of action: Mefronidazole is selectively toxic not only for amebae but also for anaerobic organisms (including bacteria), and for anoxic or hypoxic cells. Some anaerobic protozoan parasites(including amebae) possess ferrodoxin-like, low-redox potential, electron transport proteins that participate in metabolic electron removal reactions. The nitro group of mefronidazole is able to serve as an electron acceptor, forming reduced cytotoxic compounds that bind to proteins and DNA to result in cell death.

Antimicrobial spectrum: Metronidazole is the agent of choice for treating infections caused by E. histolytica in which it kills the E. histolytica trophozoites, Giardia lamblia, and Trichomonas vaginalisin both males and females. Metronidazole also finds extensive use in the treatment of infections caused by anaerobic cocci and anaerobic gram-negative bacilli (for example, bacteroides species). Anaerobic gram-posilive bacilli, such as Clostridia, which cause pseudomembranous colitis, are also sensitive. The drug is effective in the treatment of brain abscesses caused by these organisms.

Resistance: Resistance is not a therapeutic problem, although strains of trichomonads resistant to metronidazole have been reported.

Pharmacokinetics :

Administration and distribution: Mefronidazole is completely and rapidly absorbed after oral adm-inistration and for the treatment of amebiasis, is usually administered with a luminal amebicide, such as diloxanide furoate. It distributes well throughout body ,tissues and ,fluids. Therapeutic levels can be found in vaginal and seminal fluids, saliva, breast milk and cerebrospinal fluid (CSF).

Fate: Metabolism depends on hepatic oxidation of the metronidazole side-chain by mixed function oxidase, followed by glucuronidation. Therefore, concomitant treatment with inducers of this enzymatic system, such as phenobarbital, enhances the rate of metabolism. Conversely, those that

inhibit this system, such as cimetidine prolong the plasma half-life . The drug accumulates in patients with severe hepatic disease. The parent drug and metabolites are excreted in the urine.

Indication :

1.Amoebiasls : Metronidazole is a first line drug for all forms of amoebic infection. Many dosage regimens have been tried; the current recommendations are:For invasive dysentery and liver abscess-8O0 mg TDS (children 30-50 mg/kg/ day) for 7-10 days.In serious cases of liver abscess 1 g may be infused i.v. slowly followed by 0.5 g every 8-12 hr till oraltherapy is instituted.For mild intestinal disease---400 mg TDS for 5-7 days. Metronidazole is less effective than manyluminal amoebicides in eradicating amoebic cysts from the colon, because it is nearly completelyabsorbed from the upperbowel.

2. Giardiasis : It is highly effective in a dose of 400 mg TDS f or 7 days. A shorter course of 3 dayswith 2 g / day is equally effective.

3. Trichomonasvaginitis : It is the drug of choice; 400 mg TDS for 7 days achieves nearly 100% cure.Additional intravaginal treatment has been given, but is not necessary except in refractory cases.The male partner should be treated concurrently in cases of recurrent infections. Nonspecific bacterial vaginosis also responds.

4.Anaerobic bacterial infections : Metronidazole is an effective drug for these and is generally used in combination with gentamicin or cephalosporins5. Pseudomembranous enterocolitis : due to Cl. dfficile is generally associated with use of antibiotics. Oral metronidazole 800 mg TDS is more effective, more convenient, less toxic, and therefore preferred over vancomycin .

6. Ulcerative gingivitis : trench mouth 200-400 mg TDS (15-30 mg/kg/day) is quite effective because anaerobes are involved. Metroridazole / tinidazole are the drugs of choice for acute necrotizing ulcerative gingivitis, in which they are often combined with amoxicillin, tetracycline or erythromycin.

7. Helicobacter pylori gastritis/peptic ulcer : Metronidazole or tinidazole alone are relatively ineffective in eradicating H. pylori; resistance develops. However, metronid azole 400 mg TDS or tinidazole 500 mg BD is frequently used along with amoxicillin/clarithromycin and a proton pump inhibitor in triple drug 2 week regimens .

Adverse effects : Side effects to metronidazole are relatively frequent and unpleasant, but mostlynonsenous.

Anorexia, nausea, metallic taste and abdominal cramps are the most common. Loosenessof stool is occasional.

Less frequent side effects are-headache, glossitis, dryness of mouth, dizziness, rashesand transient neutropenia.

Prolonged administration may cause peripheral neuropathy and CNS effects. Seizures

have followed very high doses. Thrombophlebitis of the injected vein occurs if the solution is not well diluted.

Contraindications :Metronidazole is contraindicated in neurological disease, blood dyscrasias,first trimester of pregnancy (though no teratogenic effect has yet been demonstrated, its mutagenicpotential warrants caution), and chronic alcoholism.

Interactions: A disulfiram-like intolerance to alcohol occurs in some patients taking metronidazole;

they should be instructed to avoid drinking. Enzyme inducers (phenobarbitone, rifampin) may reduce its therapeutic effect. Cimetidine can reduce metronidazole metabolism: its dose may need to be decreased. Metronidazole enhances warfarin action by inhibiting its metabolism. It can decrease renal

elimination of lithium.

EMETINE

It is an alkaloid frorn Cephaelis ipecacuanha. Emetine is a potent and directly acting amoebicide-kills trophozoites.

Mechanism of action : It acts by inhibiting protein synthesis in amoeba by arresting intraribosomaltranslocation of tRNA-amino acid complex.The stool in acute dysenterv is rapidly cleared of thetrophozoites and symptomatic relief occurs in 1-3 days even faster than metronidazole), but it is not curative in the sense that the patient continues to pass cysts in the stool. It is highly efficacious in amoebic liver abscess also.

Pharmacokinetics : Emetine cannot be given orally because it will be vomited out. It is administered by s c or i m injection: 60 mg OD. It should be given only till acute symptoms subside; not more than 10 days in any case .It is conncentrated in liver, kidney, spleen and lungs. Emetine is very slowly excreted in urine taking 1-2 months .Thus, a second course should not be repeated within 6 weeks, otherwise cumulative toxicity can occur.

Uses : Emetine is now seldom used as a reserve drug in severe intestinal or extrarntestinal amoebiasis, or for patients not responding to or not tolerating metronidazole. A luminal amoebicidemust always follow emetine to eradicate the cyst forming trophozoites. It is also effective in liver fluke infestation.

Toxicity of emetine is high.Local: It is an irritant; pain, stiffiness and eczematous lessions occur at the site of injection

Nausea and vomiting are frequent After parenteral admimstration this is central in origin due to stimulation of CTZ Vomiting due to oral dose of emetine ls primarily because of gastric irritation.

Abdorninal cramps and diarrhoea due to emetine toxicity may be confused with that due to entestinal amoebiasis itself.

Weakness and stiffness of muscles; a myosrtis like picture may be present. Hypotension, tachycardia, ECG changes and myocarditis are the most serious complications. To

avoid these, strict bed rest must be imposed during emetine therapy and exercise should be prohibited for another 1-2 months.

Emetine is contraindicated in presence of cardiac or renal disease and during pregnancy.

CHLOROQUINE

It kills trophozoites of E.h istolytica and is highly concentrated in liver. Therefore, it is used in hepatic amoebiasis only. Because it is completely absorbed from the upper intestine and not so highly concentrated in the intestinal wall it is neither effective in invasive dysentery nor in controlling the luminal cycle (cyst passers). Efficacy of chloroquine in amoebic liver abscess approaches that of emetine, but duration of treatment is longer and relapses are relatively more frequent. Amoebae do not develop resistance to chloroquine. Because of the relative safety of chloroquine it may be given concurrently or immediately after a course of metronidazole to ensure complete eradication of the trophozoites in liver. A luminal amoebicide must always be given with or after chloroquine to abolish the luminal cycle. Dose for amoebicl iver abscess:600m g (base) for two days followed by 300 mg daily for 2-3 weeks. It is now employed only when metronidazole is not effective or not tolerated.

AMIDES :

Diloxanide furoate : It is a highly effective luminal amoebicide: directly kills trophozoites responsible for production of cysts. The furoate ester is hydrolysed in intestine and the released diloxanide is largely absorbed. Diloxanide is aweaker amoebicide thanits furoate ester : no systemic antiamoebic activity is evident despite its absorption. It is primarily metabolized by glucuronidation and is excreted in urine. Diloxanide furoate exerts no antibacterial action. It is less effective in invasive amoebic dysentery, because of poor tissue amoebicidal action. Howeveq, a single course produces high(80-90%) cure rate in mild intestinal amoebiasis and in asymptomatic cyst passers.

Diloxanide furoate is very well tolerated; the only side effects are flatulence, occasional nausea,itching and rarely urticaria. It is the drug of choice for mild intestinal,/asymptomatic amoebiasis,and is given after any tissue amoebicide to eradicate cysts. Combined use with metronidazole/tinidazole is quite popular.

Nitaeoxanide :This salicylamide congener of the anthelmintic niclosamide, recently introduced for the treatment of giardiasis is also active against E. histolytica, T. anginalis, Cryptosporidium, H. pylori, Ascaris, H. nana and some other protozoa and helminths. It is a prodrug which on absorption is converted to the active form tizoxonide, an inhibitor of PFOR enzyme that is an essential pathway of electron transport energymetabolism in anaerobic organisms. Activity against metronidazole-resistant Giardia has also been demonstrated. Tizoxanide produced in the body is conjugated and excreted in urine andbile.Nitazoxanide is indicated in giardiasis, cryptosporidiasis, as well as in amoebic dysentery as luminal amoebicide. Abdominal pain, vomiting and headache are mild and infrequent side effects

Prepared by -

Tamal Baulia

B.Pharm

JUST