Chapter 11 Drug treatment of gastrointestinal disorders
INTRODUCTION
Western lifestyles may be contributory factors in gastrointestinal disorders, especially malignant disease. High intake of alcohol and smoking greatly increase the risk of peptic ulcer disease developing.
DRUG TREATMENT OF DISORDERS OF THE GASTROINTESTINAL TRACT
ANATOMY AND PHYSIOLOGY
The gastrointestinal tract consists of a long, tubular structure extending from the mouth to the anus via the oesophagus, stomach and intestines. Its purpose is to digest, absorb and eliminate substances following the ingestion of food. The process of digestion is assisted by four accessory organs, namely the salivary glands, liver, gall bladder and pancreas (Fig. 11.1).
DIGESTION
Food is digested both mechanically and chemically. Mechanical digestion results from voluntary and involuntary muscle action, i.e. nervous control; chemical digestion is produced by the action of enzymes and hormones. The digestive processes taking place in each section of the gastrointestinal tract are summarised in Table 11.1.
Table 11.1 Stages of digestion
| Organ | Mechanical | Chemical |
|---|---|---|
| Mouth | Food taken in is masticated (chewed) by the teeth. The muscular action of the tongue and the presence of saliva convert the food into a moist bolus ready for swallowing. | Saliva is produced by the salivary glands under the control of the autonomic nervous system. It consists of water and the enzyme salivary amylase. Salivary amylase converts cooked starches into maltose. |
| Oesophagus | Bolus is propelled forwards first by voluntary muscle action and then under autonomic nerve control. | No chemical action initiated in the oesophagus. |
| Stomach | The muscular layers produce a churning action and assist peristalsis. The semisolid mixture produced is known as chyme. | Stimulated by the hormone gastrin, gastric juice is produced by the gastric mucosa. It is composed of: • hydrochloric acid, which acidifies food, kills micro-organisms, and converts the enzyme pepsinogen secreted by the parietal cells into pepsin, an essential factor in the digestion of protein |
| Small intestine | Onwards movement of contents by peristalsis and segmental movement. | The hormones secretin and cholecystokinin–pancreozymin stimulate the secretion of pancreatic juice, which consists of: |
| Stimulated by cholecystokinin–pancreozymin, bile, secreted by the liver but stored in the gall bladder, passes into the duodenum after a meal has been taken. Bile consists of: | ||
| Bile is essential for the emulsification of fats and the absorption of vitamin K, and it colours and deodorises the faeces. Intestinal juice is secreted by glands in the small intestine and consists of: | ||
| Large intestine | Intermittent waves of peristalsis known as mass movement, often precipitated by the gastrocolic reflex following the entry of food into the stomach. | No secretion of enzymes – the last phase of digestion depends on the presence of bacteria in the colon. |
ABSORPTION
The absorption of some nutrients begins in the stomach, and some absorption takes place in the large intestine. By far the most absorption, however, occurs in the small intestine (see Fig. 11.2). Table 11.2 summarises some aspects of the absorption of nutrient materials and drugs from the gastrointestinal tract.
Fig. 11.2 Absorption in the small intestine.
(From Waugh A, Grant A 2001 Ross and Wilson anatomy and physiology in health and illness, 9th edn. Churchill Livingstone, Edinburgh. With permission of Elsevier.)
Table 11.2 Absorption in the gastrointestinal tracta
| Organ | Site of absorption and notes | Substances absorbed |
|---|---|---|
| Stomach | Walls of the stomach. Systemic absorption influenced by acid environment and gastric emptying time. | |
| Small intestine | The villi and microvilli into the capillaries and lacteals. Largest gastrointestinal surface area for absorption. Alkaline environment may influence absorption of some substances. | |
| Large intestine | Predominantly the caecum and ascending colon. |
a Absorption of drugs from the gastrointestinal tract is very complex and may be affected by a range of factors, including dosage form, pH, gut motility, presence or absence of food, and pathology.
ELIMINATION
Undigested and unabsorbed foodstuffs, along with the bile pigments and bilirubin, are eliminated as waste from the body via the large intestine in the form of faeces. Defecation is the term used to describe the expulsion of faeces from the rectum and anal canal. Prior to the act of defecation, several physiological processes take place; these are shown in Box 11.1.
DISORDERS AND THEIR TREATMENT
DYSPEPSIA
Duodenal and gastric ulcer disease are significant causes of morbidity and mortality despite the great advances made in both their diagnosis and treatment. Well-managed treatment will bring about control of these conditions. Maintenance therapy following healing of an ulcer is frequently required. The key diagnostic features of ulcer disease are localised epigastric pain and nocturnal pain. The pain is often relieved by food and antacids. In some patients, the pain may be relieved by vomiting. Endoscopy is used to confirm the diagnosis. There are significant differences between gastric and duodenal ulcers; these are summarised in Table 11.3.
Table 11.3 Peptic ulceration: a comparison
| Gastric ulcers | Duodenal ulcers |
|---|---|
| Rare in patients under 40 | Prevalence highest in patients over 60 but occur in all age groups |
| Pain relief following food intake short-lived | Pain relieved by food intake, pain generally worse before meals |
| Anorexia and nausea more prominent than in duodenal ulcers | – |
| Gastric acid secretion may be normal or even below normal | Gastric acid is a major factor |
| Antisecretory therapy produces healing but more slowly than with duodenal ulcers | Antisecretory therapy often produces healing in 4 weeks; lesions smaller than in gastric ulcers |
| Healing can occur without active treatment | – |
| Recurrence rate lower than with duodenal ulcers | Ulcers recur when therapy stopped |
| Helicobacter pylori infection present in 85% of cases | H. pylori infection present in 100% of cases |
| Very important to exclude gastric cancer in patients who present with symptoms of gastric ulcer | – |
Risk factors in dyspepsia
The risk factors are summarised in Table 11.4.
Table 11.4 Risk factors in dyspepsia
| Risk factor | Notes |
|---|---|
| Acid | This is especially important in duodenal ulcer patients, who often have twice as many parietal cells as normal subjects. |
| Mucus | Reduced mucus production may be involved, because the protective effect of mucus may be lost. |
| Helicobacter pylori | H. pylori has the ability to colonise human gastric mucosa, especially the distal antral region of the stomach. The bacteria are found on the mucosal surface and do not penetrate the underlying tissues. The organism stimulates an inflammatory response and produces ammonia (an alkali), which protects the organism from gastric acid. The organism is widely distributed in the population and has a major role in dyspepsia. The mechanisms involved in acquiring H. pylori infection are not well understood. The presence of this organism can be confirmed by a breath test. Breath samples are taken before and after ingestion of an oral solution of carbon-13 urea. Laboratory analysis of the samples is required. |
| Cigarette smoking | The smoking of cigarettes is a major risk factor; peptic ulcers in smokers heal more slowly and are more likely to recur than those in non-smokers. |
| Drugs | Many NSAIDs (see p. 442) can cause serious gastric damage; the extent to which duodenal ulceration is caused by NSAIDs is still the subject of much debate and research. |
| Stress | Stress has long been associated with dyspepsia. |
| Foods | Some foods have been associated with dyspepsia – there is considerable variation between patients; avoidance of foods that cause problems is advocated. |
| Hereditary factors | There is a proven hereditary component in duodenal ulcers. |
NSAID, non-steroidal anti-inflammatory drug.
Treatment of uncomplicated dyspepsia
Various aspects of treatment are as follow.
Peptic ulcer
Histamine H2-receptor antagonists (see p. 133). The introduction of cimetidine and ranitidine (and similar drugs such as famotidine) has played a major part in improving the treatment of peptic ulcer disease. Cimetidine is given orally in a dose of 400 mg twice daily or as a single dose of 800 mg at night. A 4-week course of treatment is given in duodenal ulceration, and a 6-week course in the treatment of gastric ulceration. Once healing has been achieved, a maintenance dose must be given over a long period. Ranitidine is also given orally, 150 mg twice daily or 300 mg at night. The side-effect profile of ranitidine is lower than that of cimetidine. The use of both these drugs has greatly reduced the need for surgical treatment of peptic ulcers. Parenteral forms of the drug are available for use in conditions in which the oral route is inappropriate, for example when there is severe bleeding, for the prevention of stress ulceration in seriously ill patients, and prophylactically in patients thought to be at risk from acid aspiration syndrome. Although these two drugs have similar properties, there are significant differences (Table 11.5). Ranitidine has been combined with a bismuth compound to form a compound ranitidine bismuth citrate. This drug is used together with antibacterial agents in eradication therapy and to treat duodenal and gastric ulceration associated with Helicobacter pylori. A dose of 400 mg twice daily for 8 weeks is used to treat benign gastric ulceration. H. pylori eradication therapy (see p. 170) has replaced low-dose maintenance therapy with H2-receptor antagonists. It should be noted that a number of H2 antagonists are available without prescription from pharmacies. The indications for which these products may be sold are defined in the product licence. Dizziness, somnolence and fatigue have been reported.
Table 11.5 Similarities of, and differences between, cimetidine and ranitidine
| Cimetidine | Ranitidine | |
|---|---|---|
| Mode of action | Selective histamine H2-receptor antagonist | As cimetidine |
| Indications | Peptic ulcer disease, Zollinger–Ellison syndrome | As cimetidine |
| Oral dose | 400 mg twice daily | 150 mg twice daily |
| Maintenance | 400 mg at night | 150 mg dose at night |
| Availability | Tablets, syrup; parenteral | As cimetidine – also granules |
| Contraindications and warnings | Dose reduced in patients with impaired renal function | As cimetidine |
| Prolongs elimination of drugs metabolised by oxidation in the liver | Some changes (transient) have been reported in liver function | |
| May mask symptoms of gastric carcinoma | As cimetidine | |
| Some drug interactions, especially with oral anticoagulants and phenytoin (dosage reduction of these drugs may be needed) | Few drug interactions have been reported | |
| Rare reports of bradycardia and arteriovenous block | As cimetidine | |
| H2-receptor antagonism may potentiate falls in blood cell counts caused by other factors (e.g. disease or other drug treatment) | Leucopenia and thrombocytopenia have been rarely reported | |
| Gynaecomastia has been reported but is reversible on stopping treatment | Few reports with ranitidine |
Although some degree of freedom to adjust dosage (note, not in eradication therapy) may be an acceptable part of controlling symptoms, primary carers should be alert for any tendencies the patient may have to increase the dose prior to a planned episode of overindulgence.
Chelates and complexes.
Prostaglandin analogues (see also p. 443). Misoprostol is a synthetic compound similar to prostaglandin E1. It acts by inhibiting acid secretion, and it promotes the healing of both gastric and duodenal ulcer. It may be given to treat gastric ulceration caused by non-steroidal anti-inflammatory drugs (NSAIDs). Combination products (NSAID and misoprostol) are claimed to be safer than NSAIDs alone for ‘at risk’ patients (e.g. older people).
Proton pump inhibitors.
The mode of action is based on the property of blocking the hydrogen potassium ATP enzyme system (see Fig. 11.3) in the parietal cell. This is also a very effective treatment for Zollinger–Ellison syndrome (see below) and reflux oesophagitis. An oral dose of 20 mg daily for 4 weeks is often effective but can be increased in refractory cases to 40 mg daily. It should be noted that the degree of acid suppression achieved is directly related to the rate of ulcer healing. Omeprazole 20 mg daily can produce healing within 4 weeks. This rate of healing can be achieved with H2 antagonists given in higher doses (e.g. ranitidine 300 mg twice daily). The dosage range of the other proton pump inhibitors is similar to that of omeprazole.
Triple therapy.
or, if allergic to penicillin,
If the patient’s symptoms persist, this may or may not indicate ‘success’ of the eradication therapy. If a breath test, carried out 4 weeks after the completion of a course of eradication therapy, indicates the continuing presence of infection, a second but different course of eradication therapy should be given. It is important to check patient compliance before commencing a second course of therapy.
Patients receiving eradication therapy must avoid alcohol because of severe interactions.
The availability of H2 antagonists and a wide variety of antacids over the counter may lead to difficulties if patients receiving prescribed medicines purchase additional medicines. Community nurses (and community pharmacists) will need to be alert to any inappropriate or overuse of non-prescription medicines, especially anti-inflammatory pain-relieving medicines (see pp. 42, 442).
ZOLLINGER–ELLISON SYNDROME
Surgery and/or cytotoxic therapy may be valuable if the growth of secondaries is not advanced.
GASTRO-OESOPHAGEAL REFLUX DISEASE (HEARTBURN)
Treatment of GORD
Because the pain of GORD is caused by refluxing of gastric contents on to very sensitive oesophageal mucosa, it follows that antacids are the first-line agents (Fig. 11.4). Combinations of antacids with alginates are very useful. If reflux does occur, the stomach contents have been ‘neutralised’ to some extent and therefore are less likely to cause irritation. If simple antacid therapy does not provide relief, omeprazole or an alternative proton pump inhibitor should be considered. Proton pump inhibitors are more effective than H2 antagonists and are the treatment of choice.
Fig. 11.4 Sites of action of drugs used to treat gastro-oesophageal reflux disease
(From Page CP, Hoffman BF, Curtis M et al. 2006 Integrated pharmacology. Mosby, Edinburgh. With permission of Mosby.)
Metoclopramide may be useful, because this drug improves gastric emptying times, stimulates small intestinal transit and increases the strength of the oesophageal sphincter contraction. Domperidone (a dopamine antagonist) has actions similar to metoclopramide. If medical treatment fails (this is rare), consideration has to be given to surgical intervention.
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