NAUSEA AND VOMITING CONSTIPATION AND DIARRHEA By Dr.

Mohamed Baraka

NAUSEA AND VOMITING

Nausea and vomiting are symptoms that have many possible causes. Nausea is usually defined as the inclination to vomit or as a feeling in the throat or epigastric region alerting an individual that vomiting is imminent. Vomiting is defined as the ejection or expulsion of gastric contents through the mouth, often requiring a forceful event.
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ETIOLOGIES OF NAUSEA AND VOMITING

DRUGS USED TO CONTROL CHEMOTHERAPYINDUCED EMESIS

nausea and vomiting may occur in a variety of conditions (for example, motion sickness, pregnancy, or hepatitis) and are always unpleasant for the patient nausea and vomiting produced by many chemotherapeutic agents demands effective management. Nearly 70 to 80 percent of all patients who undergo chemotherapy experience nausea or vomiting. Emesis not only affects the quality of life but can lead to rejection of potentially curative antineoplastic treatment. In addition, uncontrolled vomiting can produce dehydration, profound metabolic imbalances, and nutrient depletion.
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MECHANISMS THAT TRIGGER VOMITING

Two brainstem sites have key roles in the vomiting reflex pathway: The chemoreceptor trigger zone (CTZ), is outside the blood-brain barrier. Thus, it can respond directly to chemical stimuli in the blood or cerebrospinal fluid. The vomiting center, which is located in the medulla, coordinates the motor mechanisms of vomiting. The vomiting center also responds to afferent input from the vestibular system, the periphery (pharynx and gastrointestinal tract), and higher brainstem and cortical structures. The vestibular system functions mainly in motion sickness.

EMETIC ACTIONS OF CHEMOTHERAPEUTIC AGENTS

Chemotherapeutic agents (or their metabolites) can directly activate the CTZ or vomiting center (neuroreceptors, including D2 receptor & (5-HT3)) Often, the color or smell of chemotherapeutic drugs can activate higher brain centers and trigger emesis. Chemotherapeutic drugs can also act peripherally by causing cell damage in the gastrointestinal tract and releasing serotonin from the enterochromaffin cells of the small intestinal mucosa. The released serotonin activates 5-HT3 receptors on vagal and splanchnic afferent fibers, which then carry sensory signals to the medulla, leading to the emetic response.
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Summary of drugs used to treat chemotherapyinduced nausea and vomiting

ANTIEMETIC DRUGS

antiemetics represent a variety of classes and offer a range of efficacies.

Anticholinergic drugs, especially the muscarinic receptor antagonist, scopolamine, and H1-receptor antagonists, such as dimenhydrinate, meclizine, and cyclizine are very useful in motion sickness but are ineffective against substances that act directly on the CTZ.

PHENOTHIAZINES:
The first group of drugs shown to be effective antiemetic agents, prochlorperazine, acts by blocking dopamine receptors. It is effective against low or moderately emetogenic chemotherapeutic agents (for example, fluorouracil and doxorubicin. Although increasing the dose improves antiemetic activity, side effects, including hypotension and restlessness, are dose limiting. Other adverse reactions include extrapyramidal symptoms and sedation.

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5-HT3 RECEPTOR BLOCKERS:

This class of agents commands an important place in treating emesis linked with chemotherapy. They have the advantage of a long duration of action. The specific antagonists of the 5-HT3 receptor ondansetron, granisetron, palonosetron. and dolasetron selectively block 5-HT3 receptors in the periphery (visceral vagal afferent fibers) and in the brain (chemoreceptor trigger zone). can be administered as a single dose prior to chemotherapy (intravenously or orally) and are efficacious against all grades of emetogenic therapy. Metabolism in the liver & elimination is through the urine. Headache is a common side effect.
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SUBSTITUTED BENZAMIDES:

metoclopramide is highly effective at high doses against the highly emetogenic cisplatin,
preventing emesis in 30 to 40 percent of patients and reducing emesis in the majority. Antidopaminergic side effects, including sedation, diarrhea, and extrapyramidal symptoms, limit its high-dose use.
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BUTYROPHENONES:
Droperidol and haloperidol act by blocking dopamine receptors. The butyrophenones are moderately effective antiemetics. Droperidol had been used most often for sedation in endoscopy and surgery, usually in combination with opiates or benzodiazepines. High-dose haloperidol was found to be nearly as effective as high-dose metoclopramide in preventing cisplatin-induced emesis.

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BENZODIAZEPINES:

The antiemetic potency of lorazepam and alprazolam is low. Their beneficial effects may be due to their sedative, anxiolytic, and amnesic properties. These same properties make benzodiazepines useful in treating anticipatory vomiting. Corticosteroids: Dexamethasone and methylprednisolone, used alone, are effective against mildly to moderately emetogenic chemotherapy. Most frequently, hower, they are used in combination with other agents. Their antiemetic mechanism is not known, but it may involve blockade of prostaglandins. These drugs can cause insomnia as well as hyperglycemia in patients with diabetes mellitus.
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CANNABINOIDS:

Marijuana derivatives, including dronabinol and nabilone effective against moderately emetogenic chemotherapy. they are seldom first-line antiemetics because of their serious side effects, including dysphoria, hallucinations, sedation, vertigo, and disorientation.
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SUBSTANCE P/NEUROKININ-1 RECEPTOR BLOCKER:

Aprepitant belongs to a new family of antiemetic agents. It targets the neurokinin receptor in the brain and blocks the actions of the natural substance. Aprepitant is usually administered orally with dexamethasone and palonosetron. It undergoes extensive metabolism, primarily by CYP3A4. Thus, as would be expected, it can affect the metabolism of other drugs that are metabolized by this enzyme. Aprepitant can also induce this enzyme and, thus, affect responses to other agents; for example, concomitant use with warfarin can shorten the half-life of the anticoagulant. Constipation and fatigue appear to be the major side effects.

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COMBINATION REGIMENS:
Antiemetic drugs are often combined to increase antiemetic activity or decrease toxicity. Corticosteroids, most commonly dexamethasone, increase antiemetic activity when given with highdose metoclopramide, a 5-HT3 antagonist, phenothiazine, butyrophenone, a cannabinoid, or a benzodiazepine. Antihistamines, such as diphenhydramine, are often administered in combination with high-dose metoclopramide to reduce extrapyramidal reactions or with corticosteroids to counter metoclopramideinduced diarrhea.

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Potencies of antiemetic drugs.

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Effectiveness of antiemetic activity of some drug combinations against emetic episodes in the first 24 hours after cisplatin chemotherapy.

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FACTORS TO BE CONSIDERED

Age The very young and the elderly are most at risk from dehydration as a result of vomiting. Vomiting of milk in infants less than 1 year old may be due to infection or feeding problems ANTIEMETIC USE IN CHILDREN For children receiving chemotherapy of high or moderate risk, a corticosteroid plus SSRI (ondansetron) should be administered. The best doses or dosing strategy has not been determined. For nausea and vomiting associated with pediatric gastroenteritis, there is greater emphasis on rehydration measures than on pharmacologic intervention.

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FACTORS TO BE CONSIDERED
Pregnancy Nausea and vomiting are very common in pregnancy, usually beginning after the first missed period and occurring early in the morning. Pregnancy should be considered as a possible cause of nausea and vomiting in any woman of childbearing age who presents at the pharmacy complaining of nausea and vomiting. Nausea and vomiting are more common in the first pregnancy than in subsequent ones.

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FACTORS TO BE CONSIDERED

ANTIEMETIC USE DURING PREGNANCY

Initial management of nausea and vomiting of pregnancy often involves: dietary changes and/or lifestyle modifications. Pyridoxine (10 to 25 mg one to four times daily) is recommended as firstline therapy. If symptoms persist, addition of a histamine-1 receptor antagonist, such as dimenhydrinate, diphenhydramine, or meclizine, is recommended.

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FACTORS TO BE CONSIDERED

Duration Generally, adults should be referred to the doctor if vomiting has been present for longer than 2 days.

Children under 2 years are referred whatever the duration because of the risks from dehydration.
Anyone presenting with chronic vomiting should be referred to the doctor since such symptoms may indicate the presence of a peptic ulcer or gastric carcinoma.

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FACTORS TO BE CONSIDERED
Associated symptoms An acute infection (gastroenteritis) is often responsible for vomiting and, in these cases, diarrhoea may also be present. Careful questioning about food intake during the previous 2 days may give a clue as to the cause. In young children, the rotavirus is the most common cause of gastroenteritis; this is highly infectious and so it is not unusual for more than one child in the family to be affected. In such situations there are usually associated cold symptoms.

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FACTORS TO BE CONSIDERED

The vomiting of blood may indicate serious disease and is an indication for referral, since it may be caused by haemorrhage from a peptic ulcer or gastric carcinoma. Sometimes the trauma of vomiting can cause a small bleed, due to a tear in the gut lining. Vomit with a faecal smell means that the GI tract may be obstructed and requires urgent referral. Nausea and vomiting may be associated with a migraine. Any history of dizziness or vertigo should be noted as it may point to inner ear disease, e.g. labyrinthitis or Menieres diseas as a cause of the nausea.

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FACTORS TO BE CONSIDERED
Medication Prescribed and OTC medicines may make patients feel sick and it is therefore important to determine which medicines the patient is currently taking. Aspirin and NSAIDs are common causes. Some antibiotics may cause nausea and vomiting, e.g. doxycyline. Oestrogens, steroids and narcotic analgesics may also produce these symptoms. Symptoms can sometimes be improved by taking the medication with food, but if they continue, the patient should see the doctor.

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FACTORS TO BE CONSIDERED
Digoxin toxicity may show itself by producing nausea and vomiting, and such symptoms in a patient who is taking digoxin, especially an elderly person, should prompt immediate referral where questioning has not produced an apparent cause for the symptoms. Vomiting, with loss of fluids and possible electrolyte imbalances, may cause problems in elderly people taking digoxin and diuretics.

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Diarrhea

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DIARRHOEA

increased frequency of bowel evacuation, with the passage of abnormally soft or watery faeces.
The basis of treatment is electrolyte and fluid replacement; in addition, antidiarrhoeals are useful in adults and older children.

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ANTIDIARRHEALS

Increased motility of the gastrointestinal tract and decreased absorption of fluid are major factors in diarrhea.
Antidiarrheal drugs include antimotility agents, adsorbents, and drugs that modify fluid and electrolyte transport

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ANTIMOTILITY AGENTS

Two drugs that are widely used to control diarrhea are diphenoxylate and loperamide Both have opioid-like actions on the gut, activating presynaptic opioid receptors in the enteric nervous system to inhibit acetylcholine release and decrease peristalsis. At the usual doses, they lack analgesic effects. Side effects include drowsiness, abdominal cramps, and dizziness.

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ANTIMOTILITY AGENTS

When recommending loperamide the pharmacist should remind patients to drink plenty of extra fluids. Because these drugs can can contribute to toxic megacolon, they should not be used in young children or in patients with severe colitis.

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ADSORBENTS
Adsorbent agents, such as bismuth subsalicylate, methylcellulose, and aluminum hydroxide are used to control diarrhea. adsorbing intestinal toxins or microorganisms and/or by coating or protecting the intestinal mucosa. much less effective than antimotility agents. They can interfere with the absorption of other drugs.

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AGENTS THAT MODIFY FLUID AND

ELECTROLYTE TRANSPORT

Bismuth subsalicylate, used for traveler's diarrhea, decreases fluid secretion in the bowel.
Its action may be due to its salicylate component as well as its coating action.

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ORAL REHYDRATION THERAPY (ORT)

risk of dehydration is greatest in babies, and rehydration therapy is the standard treatment for acute diarrhoea in babies and young children. ORT sachets may be used with antidiarrhoeals in older children and adults. Rehydration may be initiated even with referral to doctor. Sachets of powder contain sodium chloride and bicarbonate, glucose and potassium. only water should be used to make the solution (never fruit or fizzy drinks) and that boiled and cooled water should be used for children younger than 1 year. The solution can be kept for 24 h if stored in a refrigerator. Fizzy, sugary drinks should never be used to make rehydration fluids (hyperosmolar solution & exacerbation).

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KAOLIN

a traditional remedy for diarrhoea for many years. May absorb water in the GI tract and would absorb toxins and bacteria onto its surface, thus removing them from the gut. The use of kaolin-based preparations has largely been superseded by oral rehydration therapy, although patients continue to ask for various products containing kaolin.
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FACTORS TO BE CONSIDERED

Age Particular care is needed in the very young and the very old.

Infants (younger than 1 year) and elderly patients are especially at risk of becoming dehydrated.

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FACTORS TO BE CONSIDERED
Duration Most cases of diarrhoea will be acute and selflimiting. Because of the dangers of dehydration it would be wise to refer infants with diarrhoea of longer than 1 days duration to the doctor.

Severity The degree of severity of diarrhoea is related to the nature and frequency of stools.

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FACTORS TO BE CONSIDERED

Symptoms Acute diarrhoea is rapid in onset and produces watery stools that are passed frequently. Abdominal cramps, flatulence and weakness or malaise may also occur. Nausea and vomiting may be associated with diarrhoea, as may fever. vomiting and fever in infants; both will increase the likelihood that severe dehydration will develop. ask whether the baby has been taking milk feeds and other drinks as normal. Reduced fluid intake predisposes to dehydration. The presence of blood or mucus in the stools is an indication for referral. Diarrhoea with severe vomiting or with a high fever would also require medical advice.

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FACTORS TO BE CONSIDERED

Causes of diarrhoea Infections Most cases of diarrhoea are short-lived, the bowel habit being normal before and after. In these situations the cause is likely to be infective (viral or bacterial). Viral. Viruses are often responsible for gastroenteritis. In infants the virus causing such problems often gains entry into the body via the respiratory tract (rotavirus). Associated symptoms are those of a cold and perhaps a cough. The infection starts abruptly and vomiting often precedes diarrhoea. The acute phase is usually over within 23 days, although diarrhoea may persist.

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FACTORS TO BE CONSIDERED
Sometimes diarrhoea returns when milk feeds are reintroduced. This is because one of the milk-digestive enzymes is temporarily inactivated. Whilst in the majority the infection is usually not too severe and is self-limiting, but rotavirus infection can cause death. This is most likely in those infants already malnourished and living in poor social circumstances who have not been breastfed.

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Bacterial. These are the food-borne infections (previously food poisoning). several different types of bacteria that can cause such infections: Staphylococcus, Campylobacter, Salmonella, Shigella, pathogenic Escherichia coli and Bacillus cereus. Typical symptoms include severe diarrhoea and/or vomiting, with or without abdominal pain. Two commonly seen infections are Campylobacter and Salmonella, which are often associated with contaminated poultry, although other meats have been implicated. Contaminated eggs have also been found to be a source of Salmonella. Kitchen hygiene and thorough cooking are of great importance in preventing infection.

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FACTORS TO BE CONSIDERED
Bacillary dysentery is caused by Shigella. It can occur in outbreaks where there are people living in close proximity and may occur in travellers to Africa or Asia. B. cereus is usually associated with cooked rice, especially if it has been kept warm or has been reheated. E. coli infections are less common but can be severe with toxins being released into the body, which can cause kidney failure.

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FACTORS TO BE CONSIDERED

Antibiotics are generally unnecessary as most foodborne infections resolve spontaneously. The most important treatment is adequate fluid replacement. Antibiotics are used for Shigella infections and the more severe Salmonella or Campylobacter ones. Ciprofloxacin may be used in such circumstances. Protozoan infections are uncommon in Western Europe but may occur in travellers from further afield. Examples include Entamoeba histolytica (amoebic dysentery) and Giardia lamblia (giardiasis). Diagnosis is made by sending stool samples to the laboratory.

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PRACTICAL POINTS

Patients with diarrhoea should be advised to drink plenty of clear, non-milky fluids, such as water and diluted juice. Advice to eat soft food for 24 h may be appropriate. Breast- or bottle-feeding should be continued in infants. The severity and duration of diarrhoea are not affected by whether milk feeds are continued. A well-nourished child should be the aim, particularly where the infant is poorly nourished.

Patients with diarrhoea might be best advised to avoid cows milk, because during diarrhoea the enzyme in the gut that digests milk (lactase) is inactivated. Temporary lactose intolerance can therefore be produced, which makes the diarrhoea worse.

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Constipation

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CONSTIPATION

is a condition that is difficult to define and is often selfdiagnosed by patients. Generally it is characterised by the passage of hard, dry stools less frequently than the persons normal pattern. Associated symptoms abdominal discomfort, bloating and nausea. In some cases constipation can be so severe as to obstruct the bowel. This obstruction or blockage usually becomes evident by causing colicky abdominal pain, abdominal distension and vomiting. When symptoms suggestive of obstruction are present, urgent referral is necessary as hospital admission is the usual course of action. Constipation is only one of many possible causes of obstruction(bowel tumours or twisted bowels)

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Blood in the stool The presence of blood in the stool can be associated with constipation and although alarming, is not necessarily serious. In such situations blood may arise from piles (haemorrhoids) or a small crack in the skin on the edge of the anus (anal fissure). Both these conditions are thought to be caused by a diet low in fibre that tends to produce constipation. The bleeding is characteristically noted on toilet paper after defecation. The bright red blood may be present on the surface of the motion (not mixed in with the stool) and splashed around the toilet pan.

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LAXATIVES
commonly used to accelerate the movement of food through the GIT. These drugs can be classified on the basis of their mechanism of action as irritants or stimulants of the gut, bulking agents, and stool softeners. They all have a risk of being habit-forming. They also increase the potential of loss of pharmacologic effect of poorly absorbed, delayedacting, and extended-release oral preparations by accelerating their transit through the intestines. may cause electrolyte imbalances when used chronically.

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IRRITANTS AND STIMULANTS

Senna is a widely used stimulant laxative. Active ing: group of sennosides (anthraquinone glycosides). Taken orally, causes evacuation of the bowels within 8 to 10 hours. It also causes water and electrolyte secretion into the bowel. In combination products with a docusate-containing stool softener, it is useful in treating opioid-induced constipation. Bisacodyl, available as suppositories and enteric-coated tablets, is a potent stimulant of the colon. It acts directly on nerve fibers in the mucosa of the colon. Adverse effects include abdominal cramps and the potential for atonic colon with prolonged use.

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IRRITANTS AND STIMULANTS

Antacids should not be taken at the same time with the enteric-coated tablets. The antacid would cause the enteric coating to dissolve prematurely in the stomach, resulting in stomach irritation and pain. The same adverse effects could be expected with H2-receptor antagonists, and PPIs.

Docusate sodium appears to have both stimulant and stoolsoftening

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IRRITANTS AND STIMULANTS

Castor oil is broken down in the small intestine to ricinoleic acid, which is very irritating to the gut, and promptly increases peristalsis. It should be avoided by pregnant patients, because it may stimulate uterine contractions.
no longer recommended since there are better preparations available

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BULK LAXATIVES
include hydrophilic colloids They form gels in the large intestine, causing water retention and intestinal distension, thereby increasing peristaltic activity.

Similar actions are produced by methylcellulose, psyllium seeds, and bran.

should be used cautiously in patients who are bedbound, due to the potential for intestinal obstruction.
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BULK LAXATIVES
advise the patient that an increase in fluid intake would be necessary. In the form of granules or powder, the preparation should be mixed with a full glass of liquid (e.g. fruit juice or water) before taking. Fruit juice can mask the bland taste of the preparation. Intestinal obstruction may result from inadequate fluid intake in patients taking bulk laxatives, particularly those whose gut is not functioning properly as a result of abuse of stimulant laxatives

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SALINE AND OSMOTIC LAXATIVES

Saline cathartics, such as magnesium citrate, magnesium sulfate, sodium phosphate, and magnesium hydroxide are nonabsorbable salts (anions and cations) that hold water in the intestine by osmosis and distend the bowel, increasing intestinal activity and producing defecation in a few hours. Electrolyte solutions containing polyethylene glycol (PEG) are used as colonic lavage solutions to prepare the gut for radiologic or endoscopic procedures.

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SALINE AND OSMOTIC LAXATIVES

Lactulose is a semisynthetic disaccharide sugar that also acts as an osmotic laxative. It is a product that cannot be hydrolyzed by intestinal enzymes. Oral doses are degraded in the colon by colonic bacteria into lactic, formic, and acetic acids. This increases osmotic pressure, thereby accumulating fluid, distending the colon, creating a soft stool, and causing defecation.

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SALINE AND OSMOTIC LAXATIVES

Epsom salts (magnesium sulphate) is a traditional remedy that is no longer recommended. It acts by drawing water into the gut; the increased pressure results in increased intestinal motility. A dose usually produces a bowel movement within a few hours. Repeated use can lead to dehydration. Glycerin suppositories have both osmotic and irritant effects and usually act within 1 h. They may cause rectal discomfort. Moistening the suppository before use will make insertion easier.

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STOOL SOFTENERS (EMOLLIENT LAXATIVES OR SURFACTANTS)

Surface-active agents that become emulsified with the stool produce softer feces and ease passage. These include docusate sodium, docusate calcium, and docusate potassium. may take days to become effective. They should not be taken together with mineral oil because of the potential for absorption of the mineral oil. Lubricant laxatives Mineral oils (e.g. liquid paraffin) are considered to be lubricants. They facilitate the passage of hard stools. Mineral oil should be taken orally in an upright position to avoid its aspiration and potential for lipoid pneumonia.

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STOOL SOFTENERS (EMOLLIENT LAXATIVES OR SURFACTANTS)

Liquid paraffin works by coating and softening the faeces; it prevents further absorption of water in the colon. Long-term use can result in impaired absorption of fatsoluble vitamins (A, D, E, K). Leakage of liquid paraffin through the anal sphincter may occur, causing embarrassment and unpleasantness. If liquid paraffin is inadvertently inhaled into the lungs, lipid pneumonia can develop. Inhalation could occur during vomiting or if acid reflux (regurgitation) is present. The unpleasant and dangerous effects of liquid paraffin have led to restrictions in many countries.

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FACTORS TO BE CONSIDERED
Diet Insufficient dietary fibre is a common cause of constipation. Ask the patient what would normally be eaten during a day, looking particularly for the presence of wholemeal cereals, bread, fresh fruit and vegetables. Changes in diet and lifestyle, e.g. following a job change, loss of work, retirement or travel, may result in constipation. An inadequate intake of food and fluids, e.g. in someone who has been ill, may be responsible.

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FACTORS TO BE CONSIDERED
Medication Failure of OTC medication may indicate that referral to the doctor is the best option. Chronic overuse of stimulant laxatives can result in loss of muscular activity in the bowel wall (an atonic colon) and thus further constipation. Many drugs can induce constipation such as opioids The details of prescribed and OTC medications being taken should be established.

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FACTORS TO BE CONSIDERED
Constipation in children Numerous factors can cause constipation in children, including a change in diet and emotional causes. Simple advice about sufficient dietary fibre may be all that is needed. If the problem is of recent origin and there are no significant associated signs, a single glycerin suppository together with dietary advice may be appropriate. Referral to the doctor would be best if these measures are unsuccessful.

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FACTORS TO BE CONSIDERED

Constipation in pregnancy Constipation commonly occurs during pregnancy hormonal changes are responsible and it has been estimated that one in three pregnant women suffers from constipation. Dietary advice concerning the intake of plenty of highfibre foods and fluids can help. Oral iron, often prescribed for pregnant women, may contribute to the problem. Stimulant laxatives are best avoided during pregnancy Bulkforming laxatives are preferable, although they may cause some abdominal discomfort to women when used late in pregnancy

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FACTORS TO BE CONSIDERED

Laxative abuse Two groups of patients are likely to abuse laxatives:

those with chronic constipation who get into a vicious circle by using stimulant laxatives, which eventually results in damage to the nerve plexus in the colon and those who take laxatives in the belief that they will control weight, e.g. those who are dieting or, more seriously, women with eating disorders (anorexia nervosa or bulimia), who take very large quantities of laxatives.

The pharmacist is in a position to monitor purchases of laxative products and counsel patients as appropriate. Any patient who is ingesting large amounts of laxative agents should be referred to the doctor.

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Summary of drugs used to treat diarrhea and constipation.

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