CLINICAL PHARMACOLOGY 2003 (PART 32)

Drugs for peptic ulcer Neutralisation of secreted acid Reduction of acid secretion Enhancing mucosal resistance Eradication of Helicobacter pylori NSAIDs and the stomach Gastro-oesophage

SECTION 7

GASTRO-INTESTINAL

SYSTEM

Oesophagus, stomach and

duodenum

SYNOPSIS

Approximately one-third of the population in

Western societies experiences regular

dyspepsia, although more than half

self-medicate with over-the-counter antacid

preparations and do not seek medical advice.

Up to 50% of those who do will have

demonstrable pathology, most commonly

gastro-oesophageal reflux or peptic ulceration.

The remainder, in whom no abnormality is

found, are diagnosed as having nonulcer

dyspepsia.The pathophysiology and treatment

differ for each of these three conditions.

Drugs for peptic ulcer

Neutralisation of secreted acid

Reduction of acid secretion

Enhancing mucosal resistance

Eradication of Helicobacter pylori

NSAIDs and the stomach

Gastro-oesophageal reflux and vomiting

• Antiemesis and prokinetic drugs

• Treatment of various forms of vomiting

Peptic ulcer

Peptic ulcer occurs when there is an imbalance

between the damaging effects of gastric acid and

pepsin, and the defence mechanisms, which protect

the gastric and duodenal mucosa from these sub-stances (Fig 31.1) The exact mechanisms are still poorly understood A major cause of peptic ulcer

is use of nonsteroidal anti-inflammatory drugs (NSAIDs), particularly in the elderly

Treatment of peptic ulceration has traditionally centred around measures to neutralise gastric acid,

to inhibit its secretion, or to enhance mucosal defences More recently, recognition of the central

role of Helicobacter pylori has revolutionised

treat-ment Smoking is a major environmental factor and patients who smoke should be advised to stop

ACID SECRETION BYTHE STOMACH

Gastric acid is secreted by the parietal cells in gastric mucosa The basolateral membranes of these cells contain receptors for the three main stimulants

of acid secretion, namely gastrin (from antral G cells), histamine (from enterochromaffin-like cells) and acetylcholine (from vagal efferents) The action

Protective Prostaglandins Mucus Bicarbonate Mucosal blood flow

Aggressive Acid

Pepsin NSAIDs

Helicobacter pylori

Fig 3 1 1 Factors involved in maintaining acid balance

of all these is to stimulate the gastric acid (proton)

pump, which is the final common pathway for acid

secretion The pump is an H+/K+ ATPase, and when

stimulated it translocates from cytoplasmic vesicles

to the secretory canaliculus of the parietal cell

and uses energy, derived from hydrolysis of ATP, to

transport H+ out of parietal cells in exchange for K+

Hydrogen ions combine with chloride ions to form

HC1, which is secreted into the gastric lumen

On average, patients with duodenal ulcer produce

about twice as much HC1 as normal subjects, but

there is much overlap, and about half the patients

with duodenal ulcer have acid outputs in the normal

range Patients with gastric ulcer produce normal

or reduced amounts of acid

INHIBITION AND NEUTRALISATION

OF GASTRIC ACID

Healing of gastric and duodenal ulcers by

anti-secretory drugs and antacids is dependent upon:

• the degree of gastric acid suppression and

• the duration of treatment

Proton pump inhibitors, which are the most

potent antisecretory drugs, heal the majority of

peptic ulcers within 4 weeks whereas the less

powerful H2-receptor antagonists require up to

twice as long to achieve the same healing rate

Antacids modify intragastric pH only transiently,

yet relatively small daily doses (around 120 mmol)

will heal ulcers if they are taken for long enough

By the end of three months 85% of peptic ulcers

will have healed, regardless of the treatment, but

the stronger agents provide much more rapid

symptom relief In addition, numerous studies have

shown a high rate of placebo response in ulcer

healing

Antacids

Antacids are basic substances that reduce gastric

acidity by neutralising HC1 The hydroxide is the

most common base but trisilicate, carbonate and

bicarbonate are also used Therapeutic efficacy and

adverse effects depend also on the metallic ion with

which the base is combined, and this is usually

aluminium, magnesium or sodium Calcium and

bismuth have largely been abandoned for this purpose because of systemic toxicity Preparations containing calcium may cause rebound acid hyper-secretion and, with prolonged use hypercalcaemia and alkalosis This may rarely be associated with renal failure (the 'milk-alkali syndrome') Some bismuth preparations may be absorbed, causing encephalopathy and arthropathy; this is not a problem with bismuth chelate (see below)

Antacids protect the gastric mucosa against acid (by neutralisation) and pepsin (which is inactive above pH 5, and which in addition is inactivated by aluminium and magnesium) Continuous elevation

of pH by intermittent administration is limited by gastric emptying If the gastric contents are liquid, half will have left in about 30 minutes, whatever their volume

Antacids are generally used to relieve dyspeptic symptoms and they are taken intermittently when symptoms occur Side effects and inconvenience limit their use as ulcer healing agents

INDIVIDUAL ANTACIDS

Magnesium oxide and hydroxide react quickly with gastric HC1, but cause diarrhoea, as do all magnesium salts (which are also used as purgatives) Magnesium carbonate is rather less effective Magnesium trisilicate reacts slowly, to form magnesium chloride, which reacts with intestinal secretions to form the carbonate: chloride is liberated and reabsorbed Systemic acid-base balance is thus not significantly altered

Aluminium hydroxide reacts with HC1 to form aluminium chloride; this in turn reacts with intestinal secretions to produce insoluble salts, especially phosphate The chloride is released and reabsorbed so systemic acid-base balance is not altered It tends to constipate Sufficient aluminium may be absorbed from the intestine to create a risk

of encephalopathy in patients with chronic renal failure Hypophosphataemia and hypophosphaturia may result from impaired absorption due to phosphate binding

Sodium bicarbonate reacts with acid and relieves pain within minutes It is absorbed and causes

alkalosis which in short-term use may not cause

symptoms Sodium bicarbonate can release enough

CO2 in the stomach to cause discomfort and belching,

which may or may not have a psychotherapeutic

effect, according to the circumstances Excess sodium

intake may be undesirable in patients with cardiac

or renal disease (see below)

Alginic acid may be combined with an antacid to

encourage adherence of the mixture to the mucosa,

e.g for reflux oesophagitis

Dimeticone is sometimes included in antacid

mixtures as an antifoaming agent to reduce flatulence

It is a silicone polymer that lowers surface tension

and allows the small bubbles of froth to coalesce

into large bubbles that can more easily be passed up

from the stomach or down from the colon It helps

distended mountaineers to belch usefully at high

altitudes

Adverse effects of antacid mixtures

Those that apply to individual antacids are described

above but the following general points are also

relevant

Some antacid mixtures contain sodium, which

may not be readily apparent from the name of the

preparation Thus they may be dangerous for

patients with cardiac or renal disease For example,

a 10 ml dose of magnesium carbonate mixture or of

magnesium trisilicate mixture contains about 6

mmol of sodium (normal daily dietary intake is

approx 120 mmol of sodium)

Aluminium- and raagnes/wra-containing antacids

may interfere with the absorption of other drugs by

binding with them or by altering gastrointestinal

pH or transit time Reduced biological availability

of iron, digoxin, warfarin and some NSAIDs has

been ascribed to this type of interaction It is

probably advisable not to co-administer antacids

with drugs that are intended for systemic effect by

the oral route

Choice and use of antacids

No single antacid is satisfactory for all

circum-stances and mixtures are often used They may

contain sodium bicarbonate for quickest effect,

H , R E C E P T O R A N T A G O N I S T S

supplemented by magnesium hydroxide or car-bonate Sometimes magnesium trisilicate or alu-minium hydroxide is added, but these are often used alone, though they are relatively slow-acting Disturbed bowel habit can be corrected by altering the proportions of magnesium salts, which cause diarrhoea, and aluminium salts, which constipate Tablets are more convenient for the patient at work but they act more slowly unless they are chewed; a liquid may be more acceptable for frequent use Patients will find their own optimal pattern of use

H2 receptor antagonists

These drugs bind selectively and competitively to the histamine H2 receptor on the basolateral membrane of the parietal cell As well as inhibiting gastric acid release from histamine they inhibit acetylcholine- and gastrin-mediated acid secretion This inhibitory effect can be overcome, particularly when gastrin levels are high, as occurs postprandially In addition, tolerance may develop, probably as a result of down-regulation of receptors Peptic ulcer healing with H2 receptor antagonists correlates best with suppression of

nocturnal acid secretion and these drugs are often

given in a single evening dose The usual ulcer-healing course is 8 weeks

Cimetidine

Cimetidine was the first H2 receptor antagonist to

be used in clinical practice It is rapidly absorbed from the gastrointestinal tract and its plasma t1/2 is 2 h Adverse effects and interactions are few in short-term use Minor complaints include headache, dizziness, constipation, diarrhoea, tiredness and muscular pain Bradycardia and cardiac conduction defects may also occur Cimetidine is a weak antiandrogen, and may cause gynaecomastia and sexual dysfunction in males In the elderly particularly, it may cause CNS disturbances including lethargy, confusion and hallucinations Cimetidine inhibits cytochromes P450, in particular CYP 1A2 and CYP 3A4 and there is potential for

increased effect from any drug with a low

therapeutic index that is inactivated by these

isoenzymes, e.g warfarin, phenytoin, lidocaine,

propranolol, 5-fluorouracil and theophylline

Ranitidine, famotidine, nizatidine

The modes of action, uses and therapeutic efficacy

of these histamine H2 receptor antagonists are

essentially those of cimetidine Differences from

cimetidine lie chiefly in dose and profile of unwanted

effects Ranitidine (t1/2 2 h) is 50%, famotidine (tV2

3 h) is 25% and nizatidine (t1/2 1 h) is 10% metabolised,

in each case the remainder being excreted unchanged

by the kidney

The drugs are well tolerated but headache,

dizziness, reversible confusion, constipation and

diarrhoea may occur In addition, urticaria,

sweat-ing and somnolence are reported with nizatidine

The drugs do not inhibit hepatic microsomal

enzymes and do not block androgen receptors

H2 receptor antagonists are available as

over-the-counter preparations in the UK, albeit of lower

strength than those available on prescription The

potential danger is that patients with serious

patho-logy such as gastric carcinoma will self-medicate,

allowing their disease to progress Pharmacists are

trained to advise patients to consult their doctor if

they have recurrent symptoms or other worrying

manifestations such as weight loss

Proton pump inhibitors

(PPIs)

This class of drugs inactivates the H+/K+ ATPase

(proton pump) in parietal cells, which is the final

common pathway for acid production Omeprazole

was the first preparation to be used in clinical

practice and esomeprazole, lansoprazole, pantoprazole

and rabeprazole were subsequently introduced All

are similar in efficacy and mode of action

Omeprazole

Omeprazole is a prodrug, in common with all PPIs

It enters the parietal cell from the blood by nonionic

diffusion but becomes ionised in the acid milieu around the secretory canaliculus, where it is trapped and concentrated In this form it is a highly chemically reactive species which binds to sulphydryl groups on Na+/K+ ATPase This irreversibly inactivates the enzyme causing profound inhibition

of acid secretion: a single 20 mg dose reduces gastric acid output by 90% over 24 h Omeprazole is degraded at low pH and must be given in enteric-coated granules Systemic availability increases with dose and also with time, due to decreased inactivation

of the prodrug as gastric acidity is reduced

Adverse effects include nausea, headache,

diar-rhoea, constipation and rash but are uncommon Omeprazole inhibits the 2C family of the cytochrome P450 system, decreasing the metabolism of warfarin, diazepam, carbamazepine and phenytoin, and enhancing the action of these drugs (but inhibition

is less than with cimetidine)

Concern has arisen that long-term use of powerful antisecretory drugs may increase the risk of gastric neoplasia Differing mechanisms have been proposed When acid secretion is suppressed, gastrin is released

as a normal homeostatic response Gastrin stimulates growth of the gastric epithelium, including the enterochromaffin cells which could transform into carcinoid tumours; some rats developed these tumours after prolonged exposure to high doses of omeprazole Furthermore, prolonged hypochlorhy-dria favours colonisation of the stomach by bacteria, which have the potential to convert ingested nitrates into carcinogenic nitrosamines Surveillance studies

to date have not provided evidence that this is a real hazard, and it is certainly unlikely with short-term use, e.g up to 8 weeks

Other theoretical concerns relate to reduced absorption of vitamin B12 and increased susceptibility

to gastrointestinal infections as a result of prolonged hypochlorhydria There is as yet no real evidence for these being a clinical problem

Proton pump inhibitors are widely used and possible adverse effects from very long term exposure, e.g resistant symptoms from gastro-oesophageal reflux disease, are not yet known

Antimuscarinic drugs, e.g pirenzepine, formerly

widely used to suppress acid secretion, are now obsolete

Enhancing mucosal

resistance

Drugs can increase mucosal resistance by:

• protecting the base of a peptic ulcer (bismuth

chelate, sucralfate)

• 'cytoprotection' (misoprostol)

Bismuth chelate

Tripotassium dicitratobismuthate, bismuth subcitrate,

(De-Nol) This substance was originally thought to

act mainly by chelating with protein in the ulcer

base to form a coating, which protects the ulcer

from the adverse influences of acid, pepsin and bile

Subsequently, bismuth chelate was found to possess

an additional valuable action, namely activity against

Helicobacter pylori, especially when combined with

an antimicrobial (see below)

Bismuth chelate is used for benign gastric and

duodenal ulcer and has a therapeutic efficacy

approximately equivalent to histamine H2 receptor

antagonists Ulcers remain healed for longer after

bismuth chelate than after the histamine H2

receptor antagonists, and this may relate to the

ability of the former but not the latter to eradicate

Helicobacter pylori.

Adverse effects Bismuth chelate, particularly as a

liquid formulation, darkens the tongue, teeth and

stool; the effect is less likely with the tablet, which is

thus more acceptable There is little systemic

absorption of bismuth from the chelated preparation,

but bismuth is excreted by the kidney and it is

prudent to avoid giving the drug to patients with

impaired renal function Urinary elimination

continues for months after bismuth is discontinued

Sucralfate

This is a complex salt of sucrose sulphate and

aluminium hydroxide In the acid environment of

the stomach, the aluminium moiety is released so

that the compound develops a strong negative

charge and binds to positively charged protein

molecules that transude from damaged mucosa

The result is a viscous paste that adheres selectively

E N H A N C I N G M U C O S A L R E S I S T A N C E

and protectively to the ulcer base It also binds to and inactivates pepsin and bile acids Sucralfate has negligible acid neutralising capacity, which explains why it is ineffective in gastro-oesophageal reflux disease (see below) Its therapeutic efficacy in healing gastric and duodenal ulcers is approximately equal

to that of the histamine H2 receptor antagonists Adverse effects Sucralfate may cause constipation but is otherwise well tolerated The concentration of aluminium in the plasma may be elevated but this appears to be a problem only with long-term use by uraemic patients, especially those undergoing dialysis As the drug is effective only in acid conditions, an antacid should not be taken 30 min before or after a dose of sucralfate Sucralfate interferes with absorption of co-administered ciprofloxacin, theophylline, digoxin, phenytoin and amitriptyline, possibly by binding due to its strong negative charge

Misoprostol

Endogenous prostaglandins contribute importantly

to the integrity of the gastrointestinal mucosa by a number of related mechanisms (see Chapter 15) Misoprostol is a synthetic analogue of prostaglandin

Ej which protects against the formation of gastric and duodenal ulcers in patients who are taking NSAIDs, presumably by these 'cytoprotective' mechanisms (see below) The drug also heals chronic gastric and duodenal ulcers unrelated to NSAIDs, but here the mechanism appears related to its antisecretory properties rather than to a cyto-protective action

Adverse effects Diarrhoea and abdominal pain, transient and dose-related, are the commonest Women may experience gynaecological disturbances such as vaginal spotting and dysmenorrhoea; the

drug is contraindicated in pregnancy or for women

planning to become pregnant, for the products of conception may be aborted Indeed, women have resorted to using misoprostol (illicitly) as an abortifacient in parts of the world where provision

of contraceptive services is poor.1

Liquorice derivatives (carbenoxolone) and

degly-cyrrhizinised liquorice, formerly used for peptic ulcer, are now obsolete

HELICOBACTER PYLORI ERADICATION

Colonisation of the stomach with Helicobacter pylori

is seen in virtually all patients with duodenal ulcer

and 70-80% of those with gastric ulcers;2 this close

association is not seen in ulcers complicating

NSAID therapy In patients with duodenal ulcer

there is an associated antral gastritis whereas with

gastric ulcer, gastritis is more diffuse throughout

the stomach It is not known how Helicobacter pylori

predisposes to peptic ulceration, but chronic

infection with the organism, which establishes itself

within and below the mucus layer, is associated

with hypergastrinaemia and hyperacidity The

hypergastrinaemia may result from reduced antral

production of somatostatin, which inhibits gastrin

formation Production of ammonia by urease by

Helicobacter pylori may also play a role With more

extensive gastritis there is a reduction in parietal

cell mass and decreased acid secretion Although all

patients colonised with Helicobacter pylori develop

gastritis, only about 20% have ulcers or other lesions,

and host factors are likely to be important

Other possible effects of long-term infection with

Helicobacter pylori include gastric carcinoma and

lymphoma, particularly of the MALT (Mucosa

Associated Lymphoid Tissue) type Eradication of

the organism may lead to resolution of the latter

tumour

Helicobacter pylori can be detected histologically

from antral biopsies obtained at gastroscopy, or

biochemically In the CLO test an endoscopic

biopsy specimen is incubated in a medium

contain-ing urea and an indicator which chages colour if

ammonia is produced Proton pump inhibitors and

bismuth compounds suppress but do not eradicate

Helicobacter pylori, and results may be falsely

nega-tive if any of these tests is carried out within a

month of taking these drugs

1 Gonzales C H et al 1998 Lancet 351:1624-1627.

2 First reported by B Marshall and R Warren (Lancet 19831:

1273 and 1273-1274) The association was initially greeted

with widespread disbelief and sometimes hostility Warren

reports: "I was just doing my day-to-day pathology I like

looking for funny things and this day, I saw a funny thing

and started wondering." In a gastric biopsy he saw

"numerous bacteria in close contact with the surface

epithelium They appeared to be actively growing and not

a contaminant." The story of Helicobacter pylori had begun.

(Lancet 2001 345: 694.)

TREATMENT OF HELICOBACTER

PYLORI INFECTION

Successful eradication of Helicobacter pylori infection

usually results in long-term remission of the ulcer because reinfection rates are low, particularly in areas of low endemicity The organism is sensitive

to metronidazole, amoxicillin, clarithromycin, tetracycline and bismuth salts, but eradication is difficult because

of its location below the mucus layer Numerous regimens have been proposed but none can offer more than 80-90% efficacy (see also Table 11.1) Therapy with one or two drugs is ineffective and current regimens comprise three or four drugs The efficacy of antimicrobials can be increased con-siderably by mucosal protection with a proton pump inhibitor, ranitidine or bismuth citrate (in the latter case, in addition to its antimicrobial action) It

is important that treatment be as short, simple and palatable as possible to encourage compliance, because failure to complete the course encourages antimicrobial resistance Regimens containing bismuth compounds as the only mucosal protectant are less popular because they involve dosing four times daily and are unpalatable to some Effective regimens include:

• Proton pump inhibitor or ranitidine bismuth citrate3 (as Ranitidine Bismutrex) b.d + clarithromycin 500 mg b.d + amoxycillin Ig b.d for 7 days

• Proton pump inhibitor or ranitidine bismuth citrate b.d + clarithromycin 500 mg b.d + metronidazole 400 mg b.d for 7 days

Metronidazole resistance is a particular problem, with a prevalence of up to 80% in some countries, particularly sub-Saharan Africa It probably reflects extensive use of this antimicrobial for pelvic and other infections, and is more common in women Resistance to clarithromycin is less common but it may reach 10-15% of some communities

It is not usually necessary to check for successful eradication unless the patient continues to have symptoms Under these circumstances the urea breath test4 is a useful noninvasive technique

3 A complex of ranitidine with bismuth and citrate from which ranitidine and bismuth are released.

Antimicrobial regimens used in eradication are

not without risk for cases of antibiotic-associated

(pseudomembraneous) colitis have resulted

A cautionary note Helicobacter pylori infection is

acquired in early childhood, probably by the

faecal-oral route The prevailing wisdom that 'the

only good Helicobacter pylori is a dead Helicobacter

pylori' is now tempered by the possibility that the

organism (or at least certain subtypes) may perform

a useful function This view is based on evidence

that gastro-oesophageal reflux symptoms may

sometimes be worsened, and response to proton

pump inhibitors diminished, after eradication of

Helicobacter pylori More worrying is the increased

incidence of carcinoma at the gastro-oesophageal

junction which correlates epidemiologically with

reduced prevalence of Helicobacter pylori infection.

In summary, Helicobacter pylori eradication therapy

is:

• indicated for gastric and duodenal ulcer not

associated with NSAID use, and gastric

lymphoma (especially MALT lymphoma),

• not indicated for reflux oesophagitis, and

• equivocal in value for nonulcer dyspepsia, after

incidental detection, and for prophylaxis of

gastric cancer

NSAIDs and the stomach

Some 500 million prescriptions for NSAIDs are

written each year in the UK, and 10-15% of patients

develop dyspepsia whilst taking these drugs

Gastric erosions develop in up to 80%, but these are

usually self-limiting Gastric or duodenal ulcers

occur in 1-5% The incidence increases sharply with

age in those over 60, and the risk of ulcers and their

complications is doubled in patients over 75 and

those with cardiac failure or a history of peptic

ulceration or bleeding Ibuprofen may be less prone

to cause these problems than other NSAIDs

4 The urea breath test measures radiolabelled CO 2 in expired

air after ingestion of labelled urea, exploiting the fact that the

organism produces urease and can convert urea to ammonia.

N S A I D s A N D T H E S T O M A C H

MECHANISM OF GASTRIC MUCOSAL TOXICITY

Aspirin and the other NSAIDs exert their anti-inflammatory effect through inhibition of the enzyme cyclo-oxygenase (COX) (see Chapter 15) This enzyme

is present in two isoforms COX-1 is involved in the

formation of prostaglandins, which protect the

gastric mucosa, while COX-2 is induced in response

to inflammatory stimuli and is involved in the

formation of cell-damaging cytokines Most NSAIDs

inhibit both isoforms so the beneficial anti-inflam-matory effect is offset by the potential for gastric mucosal injury by depletion of prostaglandins The latter leads to deleterious effects including reduction

of mucosal blood flow and a reduced capacity to secrete protective mucus and bicarbonate ion Aspirin

is particularly potent in this respect, perhaps due to the fact that it inhibits COX irreversibly, unlike the other NSAIDs where inhibition is reversible and concentration dependent Gastrointestinal bleeding can complicate use of low-dose aspirin

NSAIDs are weak organic acids and the acid milieu of the stomach facilitates their nonionic diffusion into gastric mucosal cells Here the neutral intracellular pH causes the drugs to become ionised and they accumulate in the mucosa because they cannot diffuse out in this form Nabumetone differs from other NSAIDs in that it is nonacidic, and therefore is not so avidly concentrated in gastric mucosa, which may partially explain why this drug has less tendency to produce peptic ulceration

TREATMENT OF NSAID-INDUCED PEPTIC ULCERS

Withdrawal of NSAIDs and acid suppression with standard doses of antisecretory drugs will allow prompt resolution of these ulcers, which should not recur unless the drugs are resumed Many patients are prescribed NSAIDs inappropriately when their symptoms could be controlled by paracetamol or

by local treatment Topical NSAID creams applied over an affected joint may be helpful, but peptic ulcers can complicate therapy with NSAIDs administered as rectal suppositories Prodrugs such

as sulindac, which are metabolised to form anti-inflammatory derivatives, can also produce ulcers

PREVENTION OF NSAID-INDUCED

PEPTIC ULCERS

This is particularly relevant for the elderly and

other high-risk patients (see above) The synthetic

prostaglandin misoprostol in a dose of 800

micro-grams daily in 2-4t divided doses reduces the

incidence of gastric and duodenal ulceration and

their complications by about 40% when

co-administered with NSAIDs Abdominal pain and

diarrhoea limit its use; halving the dose reduces the

incidence of adverse effects, but at the expense of a

reduced protective effect The proton pump

inhibitors, in healing doses, are similar in efficacy to

the higher dose of misoprostol H2 receptor

antagonists offer some protection against duodenal

ulcers but none against gastric ulcers

Evidence for the benefit of Helicobacter pylori

eradication is controversial

Selective inhibition of COX-2 has the objective of

preserving anti-inflammatory activity whilst

avoiding gastric mucosal toxicity Rofecoxib, celecoxib

and meloxicam vary in their selectivity for COX-2.

The incidence of peptic ulcers and their

com-plications with rofecoxib is similar to that seen

when proton pump inhibitors are co-administered

with nonselective NSAIDs The adverse effect

profile of these drugs remains fully to be evaluated

Gastro-oesophageal reflux

disease (GORD)

Transient gastro-oesophageal reflux occurs in almost

everybody and it is only when episodes become

frequent, with prolonged exposure of the oesophageal

mucosa to acid and pepsin, that problems develop

Factors contributing to pathological reflux include:

• Incompetence of the gastro-oesophageal

sphincter

• Delayed oesophageal clearance of acid

• Delayed gastric emptying

The commonest symptom is heartburn, and as

many as 15% of people in Western populations

experience this regularly Approximately 50% will

have oesophagitis, the severity of which does not

correlate with symptoms The other main com-plications are acute or chronic bleeding, oesophageal stricture and Barrett's metaplasia, which carries an increased risk of oesophageal carcinoma There is

no evidence that Helicobacter pylori is involved in

pathogenesis of GORD

MANAGEMENT OF GORD

Patients should be advised to lose weight, if it is appropriate, and smokers to quit, as nicotine relaxes the gastro-oesophageal sphincter Raising the head

of the bed by 15-20 cm helps to diminish nocturnal reflux Patients should be advised to avoid heavy meals and situations predisposing to reflux (such as lying down or prolonged bending within

3 hours of a meal) Drugs that encourage reflux should be avoided if possible, e.g those with antimuscarinic activity (tricyclic antidepressants), smooth muscle relaxants (nitrates and calcium channel blockers) or theophylline compounds

Antacids are helpful in controlling mild reflux symptoms when taken regularly after meals with additional doses as needed Preparations in which

an antacid is combined with alginate are particularly useful: the alginate produces a viscous floating gel, which blocks reflux and protectively coats the oesophagus

Acid suppression H 2 -receptor antagonists in

conventional peptic ulcer healing doses are useful

in the short-term management of mild oesophagitis but are less effective in the longer term and on maintenance treatment only one-third of patients

will be in remission Proton pump inhibitors are

currently the most effective drugs Conventional ulcer healing doses rapidly relieve reflux symptoms and heal oesophagitis in the majority of patients Sometimes higher doses are needed, particularly for maintenance therapy Over three-quarters of patients will still be in remission after 12 months' treatment with a proton pump inhibitor

Pro-kinetic drugs The antidopaminergic compounds

metoclopramide and domperidone can alleviate GORD

symptoms by increasing the tone of the gastro-oesophageal sphincter and stimulating gastric