CLINICAL PHARMACOLOGY 2003 (PART 33)

• Constipation: mode of action and use of drugs • Diarrhoea drug treatment importance of fluid and electrolyte replacement • Inflammatory bowel disease • Irritable bowel syndrome Constip

Intestines

SYNOPSIS

Problems of constipation, diarrhoea and

irritable bowel syndrome are common.

Infective diarrhoeal diseases are a significant

cause of morbidity and mortality worldwide,

especially in infants and children.The

management of these conditions is reviewed.

• Constipation: mode of action and use of

drugs

• Diarrhoea (drug treatment importance of

fluid and electrolyte replacement)

• Inflammatory bowel disease

• Irritable bowel syndrome

Constipation

The terms purgative, cathartic, laxative, aperient

and evacuant are synonymous They are medicines

that promote defaecation largely by reducing the

viscosity of the contents of the lower colon and are

classified as follows:

• Stool bulking agents

• Osmotic laxatives

• Faecal softeners

• Stimulant laxatives

STOOL BULKING AGENTS

Dietary fibre comprises the cell walls and supporting structures of vegetables and fruits Most of the fibre

in our diet is in the form of nonstarch poly-saccharides (NSP),1 which are not digestible by human enzymes Fibre may be soluble (pectins, guar, ispaghula) or insoluble (cellulose, hemicelluloses, lignin) Insoluble fibre has less effect than soluble fibre on the viscosity of gut contents but is a stronger laxative because it resists digestion in the small bowel and so enters the colon intact In addition it has a vast capacity for retaining water; thus one gram of carrot fibre can hold 23 grams of water.2 It has been proposed that as humans have refined the carbohydrates in their diet over the centuries, so they have deprived themselves of

fibre, the ensuing under-filling of the colon being an

important cause of constipation, haemorrhoids and diverticular disease Stool bulking agents, which add fibre to the diet, are the treatment of choice for simple constipation They act by increasing the volume and lowering the viscosity of intestinal contents to produce a soft bulky stool, which encourages normal reflex bowel activity The mode

of action of stool bulking agents is thus more physiological than other types of laxative They

1 The term 'unavailable complex carbohydrate' (UCC) is also used and refers to NSP plus undigested ('resistant') starch.

2 McConnell A A et al 1974 J Sci Food Agric 25:1427.

32 I N T E S T I N E S

should be taken with liberal quantities of fluid (at

least 2 litres daily)

Individual preparations

Bran is the residue left when flour is made from

cereals; it contains between 25% and 50% of fibre

The fibre content of a normal diet can be increased

by eating wholemeal bread and bran cereals but

over-zealous supplementation may cause

trouble-some wind (from bacterial fermentation in the colon)

Viscous (soluble) fibres, e.g ispaghula, are

effec-tive and more palatable than bran Ispaghula husk

contains mucilage and hemicelluloses which swell

rapidly in water Methylcellulose takes up water to

swell to a colloid about 25 times its original volume

and sterculia, 3 similarly, swells when mixed with

water

OSMOTIC LAXATIVES

These are but little absorbed and increase the bulk

and reduce viscosity of intestinal contents to promote

a fluid stool

Some inorganic salts retain water in the intestinal

lumen or, if given as hypertonic solution, withdraw

it from the body When constipation is mild,

magnesium hydroxide will suffice but magnesium

sulphate (Epsom4 salts) is used when a more

power-ful effect is needed Both magnesium salts act in 2-4 h

The small amount of magnesium absorbed when

the sulphate is frequently used can be enough to

cause magnesium poisoning in patients with renal

impairment, the central nervous effects of which

somewhat resemble those of uraemia Magnesium

sulphate 50% (hypertonic) is available as a single

dose retention enema to reduce cerebrospinal fluid

pressure in neurosurgery

Lactulose is a synthetic disaccharide Taken orally,

it is unaffected by small intestinal disaccharidases,

is not absorbed and thus acts as an osmotic laxative

Tolerance may develop Lactulose is also used in

3 Named after Sterculinus, a god of ancient Rome, who

presided over manuring of agricultural land.

4 Epsom, a town near London, known for its now defunct

mineral spring water, and for horse racing.

the treatment of hepatic encephalopathy (see Chapter 33)

Osmotic laxatives are frequently used to clear the colon for diagnostic procedures or surgery Enemas containing phosphate or citrate effectively evacuate the distal colon and can be useful for treating obstinate constipation in elderly or debilitated patients Oral preparations containing magnesium sulphate and citric acid (Citramag) or polyethylene glycol (Klean Prep) are used in preparation for colonoscopy; they are made up with water to create an isotonic solution and some patients find the large volumes difficult to tolerate Isotonic mannitol was used for the same purpose in the early days of colonoscopy, but has since been abandoned; hydrogen liberated by the action of colonic bacteria was the cause of several intestinal explosions triggered by the use of diathermy The stimulant laxative sodium picosulphate (Picolax) is a frequently used alternative to the osmotic preparations Care should be used with all these preparations in the elderly; they can induce dehydration, hypovolaemia and electrolyte disturbances

FAECAL SOFTENERS (EMOLLIENTS)

The softening properties of these agents are useful

in the management of anal fissure (see below) and haemorrhoids

Docusate sodium (dioctyl sodium sulphosuccinate)

softens faeces by lowering the surface tension of fluids in the bowel This allows more water to remain in the faeces It appears also to have bowel stimulant properties but these are relatively weak Docusate sodium acts in 1-2 days Poloxamers, e.g poloxalkol (poloxamer 188), act similarly and are used in combination with other agents

Liquid paraffin is a chemically inert mineral oil

and is not digested It promotes the passage of softer faeces It is often presented in emulsions with magnesium hydroxide Large doses may leak out of the anus causing both physical and social dis-comfort Paraffin taken orally over long periods, especially at night, may be aspirated and cause chronic lipoid pneumonia An unusual case resulted from attempts by a patient, an amateur singer, to lubricate his larynx with liquid paraffin Because of

these disadvantages its use is declining and it

should never be used long term as a laxative

STIMULANT LAXATIVES

These drugs increase intestinal motility by various

mechanisms; they may cause abdominal cramps,

should used only with caution in pregnancy, and

never where intestinal obstruction is suspected

Bisacodyl stimulates sensory endings in the colon

by direct action from the lumen It is effective orally

in 6-10 h and, as a suppository, acts in 1 h In geriatric

patients, bisacodyl suppositories reduce the need

for regular enemas There are no important unwanted

effects

Sodium picosulphate is similar and is also used to

evacuate the bowel for investigative procedures

and surgery

Glycerol has a mild stimulant effect on the rectum

when administered as a suppository

The anthraquinone group of laxatives includes

senna, danthron, cascara, rhubarb5 and aloes In the

small intestine soluble anthraquinone derivates are

liberated and absorbed These are excreted into the

colon and act there, along with those that have

escaped absorption, probably after being chemically

changed by bacterial action

Patients taking some anthraquinones may notice

their urine coloured brown (if acid) or red (if alkaline)

Prolonged use can cause melanosis of the colon

Anthraquinone preparations made from crude

plant extracts are to be avoided as their lack of

standardisation leads to erratic results

Senna, available as a biologically standardised

preparation, is widely used to relieve constipation

and to empty the bowel for investigative procedures

and surgery It acts in 8-12 h

5 In the late 18th century Britain made approaches to trade

with China which were met with indifference; it seems that

the mandarins held the belief that the British feared death

from constipation if deprived of rhubarb (Rheum palmatum),

one of China's exports.

M I S U S E O F L A X A T I V E S

Danthron is available as a standardised preparation

in combination with the faecal softeners poloxamer

188 (danthramer) and docusate sodium (as co-danthrusate) It acts in 6-12 h Evidence from rodent studies indicates a possible carcinogenic risk and long-term exposure to danthron should be avoided

Drastic purgatives (castor oil, cascara, jalap,6 colocynth, phenolphthalein and podophyllum) are obsolete

Suppositories and enemas

Suppositories (bisacodyl, glycerin) may be used to obtain a bowel action in about 1 hour Enemas produce defaecation by softening faeces and distending the bowel They are used in preparation for surgery, radiological examination and endoscopy.7 Preparations with sodium phosphate, which is poorly absorbed and so retains water in the gut, are generally used Arachis oil is included in enemas to soften impacted faeces

Misuse of laxatives

Dependence (abuse) may arise following laxative use during an illness or in pregnancy, or the individual may have the mistaken notion that a daily bowel motion is essential for health, or that

6 In the 19th century 'young men proceeding to Africa' were advised to take pills named Livingstone's Rousers, consisting of rhubarb, jalap, calomel and quinine British Medical Journal 1964 2:1583.

7 Enemas may arouse complex psychosocial/sexual impulses ranging from frequent use for imagined self-cleansing (colonic lavage) to the extraordinary case of the 'Illinois enema bandit' (USA, 1966-75), a man who broke into women students' accommodation and forcibly administered enemas His exploits were immortalised in song by Frank Zappa (© 1978 Zappa Family Trust Reprinted by permission):

"The Illinois Enema Bandit

I heard he's on the loose

I heard he's on the loose Lord, the pitiful screams

Of all them college-educated women

Boy, he'd just be tyin' 'em up (They'd be all bound down!) Just be pumpin' every one of 'em up with all the bag fulla The Illinois Enema Bandit Juice '

32 I N T E S T I N E S

the bowels are only incompletely opened by nature,

and so indulge in regular purgation This effectively

prevents the easy return of normal habits because

the more powerful stimulant purges empty the

whole colon, whereas normal defaecation empties

only the descending colon Cessation of use after a

few weeks is thus inevitably followed by a few

days' constipation whilst sufficient material collects

to restore the normal state; the delay may convince

the patient of the continued need for purgatives

Laxative dependence, which may be solely emotional

at first, may be followed by physical dependence, so

that the bowels will not open without a purgative

Prolonged abuse can damage gut nerves and lead

to an atonic colon

It is easier to prevent laxative dependence than

to cure it; patients feel they understand their own

bowels far better than anyone else possibly could,

an opinion they seldom extend to other organs,

except perhaps the liver In Britain, there is a belief

that nurses have an intuitive understanding of the

bowels that is denied to doctors

Excessive use of stimulant purgatives8 may,

especially in the old, lead to severe water and

electrolyte depletion, even to hypokalaemic

para-lysis, malabsorption and protein-losing enteropathy

Purgatives are dangerous if given to patients with

undiagnosed abdominal pain, inflammatory bowel

disease or obstruction Nor should they be used

to empty the rectum of hardened faeces, for they

will fail and cause pain Initial treatment should be

with enemas, but digital removal, generally

ordered by a senior and performed by a junior

doctor, may occasionally be required A bulking

agent or a faecal softener will help to prevent

recurrence

Diarrhoea

Diarrhoea ranges from a mild and socially

in-convenient illness to a major cause of death and

8 The Roman Emperor Nero (AD 37-68) murdered his

severely constipated aunt by ordering the doctors to give her

'a laxative of fatal strength' He 'seized her property before

she was quite dead and tore up the will so that nothing could

escape him' (Suetonius (trans) R Graves).

malnutrition among children in less developed countries; acute diarrhoea from gastroenteritis causes 4-5 million deaths throughout the world annually Drugs have a place in its management but the first priority of therapy is to preserve fluid and electrolyte balance

SOME PHYSIOLOGY

In the normal adult, 7-8 litres of of water and electrolytes are secreted daily into the gastro-intestinal tract This, together with dietary fluid, is absorbed by epithelial cells in the small and large bowel Water follows the osmotic gradients which result from shifts of electrolytes across the intestinal epithelium, and sodium and chloride transport mechanisms are central to the causation and management of diarrhoea, especially that caused by bacteria and viruses The energy for the process is provided by the activity of Na+/K+ ATPase

Absorption of sodium into the epithelium is

effected by:

• Sodium-glucose-coupled entry Glucose stimulates

the absorption of sodium and the resulting water flow also sweeps additional sodium and chloride

along with it (solvent drag) This important

mechanism remains active in diarrhoea of various aetiologies and improvement of sodium and water absorption by glucose (and amino acids) is the basis of oral rehydration regimens (see below) Absorption of sodium and water in the colon is stimulated by short-chain fatty acids (see below, cereal-based ORT)

• Sodium-ion-coupled entry Na+ and Cl~ enter the epithelial cell, either as a pair or, as seems more likely, there is a double exchange: Na+

(extracellular) with H+ (intracellular) and Cl~ (extracellular) with 2OR- or 2HCO3

-(intracellular) Oral rehydration solutions (see below) contain sodium, chloride and

bicarbonate

Secretion is the opposite process to that of

absorp-tion In response to various stimuli, crypt cells actively transport chloride into the gut lumen and sodium and water follow This stimulus-secretion coupling is modulated by cyclic AMP and GMP, calcium, prostaglandins and leukotrienes

D I A R R H O E A 32

Diarrhoea results from an imbalance between

secretion and reabsorption of fluid and electrolytes;

it has numerous causes, including infections with

enteric organisms (which may stimulate secretion

or damage absorption), inflammatory bowel disease

and nutrient malabsorption due to disease It also

commonly occurs as a manifestation of disordered

gut motility in the absence of demonstrable disease

(see below) Rarely it is due to secretory tumours of

the alimentary tract, e.g carcinoid tumour or vipoma

(a tumour which secretes VIP, vasoactive intestinal

peptide)

Motility patterns in the bowel An important factor

in diarrhoea may be loss of the normal segmenting

contractions that delay passage of contents, so that

an occasional peristaltic wave has a greater propulsive

effect Segmental contractions of the smooth muscle

in the bowel mix the intestinal contents Patients

with diarrhoea commonly have less spontaneous

segmenting activity in the sigmoid colon than do

people with normal bowel habit, and patients with

constipation have more Antimotility drugs (see

below) reduce diarrhoea by increasing segmentation

and inhibiting peristalsis

FLUID AND ELECTROLYTE

TREATMENT

Oral rehydration therapy (ORT) with

glucose-electrolyte solution is sufficient to treat the vast

majority of episodes of watery diarrhoea from acute

gastroenteritis As a simple, effective, cheap and

readily administered therapy for a potentially lethal

condition, ORT must rank as a major advance in

therapy It is effective because glucose-coupled

sodium transport continues during diarrhoea and

so enhances replacement of water and electrolyte

losses in the stool

Oral rehydration salts (ORS) The WHO/UNICEF

recommended formulation is:

Sodium chloride 3.5 g/1

Potassium chloride 1.5 g/1

Sodium citrate 2.9 g/1

Anhydrous glucose 20.0 g/1

This provides sodium 90 mmol/1, potassium 20

mmol/1, chloride 80 mmol/1, citrate 10 mmol/1,

glucose 111 mmol/1 (total osmolarity 311 mmol/1).9

Several other formulations exist, some with less sodium (see national formularies).10

Rehydration therapy with commercial soft drinks alone will fail because their sodium content is too low (usually less than 4 mmol/1) The glucose may

be replaced by another substrate such as glycine or

rice powder Indeed cereal-based ORS, relying on

starch (to produce glucose) from many sources (rice, wheat, corn, potato) have the advantage of controlling diarrhoea much more effectively than the glucose-based preparations This may be because undigested starch is fermented in the colon to short-chain fatty acids, which stimulate colonic sodium and water absorption Thus almost every household in the world can find the essential components of an effective oral rehydration mixture: cereals and salt Most cases can be adequately treated by assiduous attention to oral intake, but fluid and electrolyte depletion is especially dangerous in children and intravenous fluid replacement in hospital may be needed Antimotility drugs are inappropriate for severe diarrhoea in young children; any marginal effect they may have is liable to be counterbalanced

by hazardous adverse effects (see below)

ANTIDIARRHOEAL DRUGS

There are two types of drug which are often used in combination

Antimotility drugs

These act on bowel muscle to delay the passage of gut contents so allowing time for more water to be absorbed

Codeine (t l / 2 3 h) activates opioid receptors on the smooth muscle of the bowel to reduce peristalsis and increase segmentation contractions Tolerance may develop with prolonged use, as may dependence (rarely) It should be avoided in patients with

9 Solutions with lower sodium content and thus reduced total osmolarity (250 mmol/1) are associated with less need for unscheduled intravenous fluid infusion, lower stool volume and less vomiting, and may now be preferred Hahn

S et al 2001 British Medical Journal 323: 81-85.

10 The higher sodium content of the WHO/UNICEF formulation is based on sodium concentrations in diarrhoeal stools, but low-sodium, high-glucose formulations may be preferred for infants, whose faecal losses of sodium are less.

32, I N T E S T I N E S

diverticular disease as it increases intraluminal

pressure

Diphenoxylate (t1// 3 h) is structurally related to

pethidine and affects the bowel like codeine The

drug is offered mixed with a trivial dose of atropine

(to discourage abuse) as co-phenotrope (Lomotil)

The drug can cause nausea, vomiting, abdominal

pain and CNS depression Following overdose with

Lomotil respiratory depression may be serious, and

can occur up to 16 h after ingestion because gastric

emptying is delayed

Loperamide (t1/, 10 h) is structurally similar to

diphenoxylate Its precise mode of action remains

obscure but it impairs propulsion of gut contents by

effects on intestinal circular and longitudinal muscle

that are at least partly due to an action on opioid

receptors Loperamide may cause nausea, vomiting

and abdominal cramps Its potential for abuse

appears to be low

The actions of codeine, diphenoxylate and

loperamide are antagonised by naloxone

Warning Antimotility drugs should not be used

for acute diarrhoea in children, especially babies, or

in patients with active inflammatory bowel disease,

for there is danger of causing paralytic ileus and, in

babies, respiratory depression

Drugs that directly increase the viscosity

of gut contents

Kaolin and chalk are adsorbent powders Their

therapeutic efficacy is marginal as is shown by the

fact that they are often combined with an opioid

Bulk-forming agents such as ispaghula, methylcellulose

and sterculia (see above) are useful for diarrhoea in

diverticular disease, and for reducing the fluidity of

faeces in patients with ileostomy and colostomy

TRAVELLERS' DIARRHOEA

So familiar is diarrhoea to travellers that it has

acquired regional popular names: the Aztec 2-step,

Montezuma's Revenge, Delhi Belly, Rangoon Runs,

Tokyo Trots, Gyppy Tummy, Hong-Kong Dog,

Estomac Anglais and Casablanca Crud, all indicate

some of the areas deemed dangerous by visitors

The Mexican name 'turista' indicates the principal

sufferers

Most cases are infective, and up to half of the diarrhoea that afflicts visitors to tropical and sub-tropical countries is associated with enterotoxigenic

strains of Escherichia coli; other bacteria including

Shigella and Salmonella spp, viruses including the

Norwalk family, and parasites (particularly Giardia

lamblia) have also been implicated Recognition that

transmission is almost invariably by ingestion of contaminated food and water points to the most effective way of reducing the risk

Acute watery diarrhoea in adults can usually be

controlled by oral rehydration solutions and one of the antimotility drugs, although in mild cases the abdominal bloating produced by the latter may be less acceptable than the loose stools While diarrhoea usually lasts only 2-3 days, this may still be socially inconvenient, and if symptomatic remedies fail, an aminoquinolone, e.g ciprofloxacin 500 mg b.d will

be effective The use of antimicrobials for travellers' diarrhoea continues to evoke controversy (see below) but most sufferers will appreciate the relief that even one or two tablets can bring

Prophylactic antimicrobial therapy has been shown to reduce the incidence of attacks of diarrhoea but its routine use carries the risk of hindering the diagnosis of serious infection A wider issue is the possible development and spread of antibiotic-resistant organisms Thus any benefits to the

individual must be weighed against the risk to the

community in the future In most instances

pro-phylactic antimicrobials should not be used but ciprofloxacin (500 mg once daily) may be justified for individuals who must remain well while travelling for short periods to high-risk areas

SPECIFIC INFECTIVE DIARRHOEAS

Chemotherapy is available for certain specific organisms, e.g amoebiasis, giardiasis, typhoid fever (see Index)

DRUG-INDUCED DIARRHOEA

Antimicrobials are the commonest drugs that cause

diarrhoea, probably due to alteration of bowel flora

It may range from a mild inconvenience to

life-threatening antibiotic-associated (pseudomembranous

colitis), due to colonisation of the bowel with Clostridium difficile The condition particularly affects

elderly patients in hospital Clindamycin and third

generation cephalosporins are especially prone to

cause this complication, whereas it is uncommon

with the quinolone and aminoglycoside groups

Treatment is with vancomycin or metronidazole

Magnesium-containing antacids may also produce

diarrhoea, as may NSAIDs and lithium

SECRETORY DIARRHOEAS

Octreotide, a synthetic peptide which shares amino

acid homology with somatostatin (see p 710), inhibits

the release of peptides that mediate certain alimentary

secretions, and may be used to relieve diarrhoea

due to carcinoid tumours and vipomas

Inflammatory bowel

disease

The pathogenesis of inflammatory bowel disease is

still poorly understood Immune mechanisms are

probably involved, and potential antigens include

intestinal bacteria and intestinal epithelium

Abnormalities in inflammatory mediators have also

been described; it has been suggested that an

imbalance between proinflammatory and

anti-inflammatory cytokines may determine susceptibility,

although the abnormalities observed could simply

be secondary to the disease process

The main drugs used in the treatment of ulcerative

colitis and Crohn's disease are the aminosolicylates

and corticosteroids Their mode of action is obscure.

Other immunosuppressives also have a role and

recent studies into the mechanisms of inflammation

are leading to the introduction of novel therapies to

inhibit the inflammatory process

In acute exacerbations of inflammatory bowel

disease a gastrointestinal infection should always

be excluded by stool microscopy and culture, and

testing for Clostridium difficile toxin Measures to

correct anaemia, fluid and electrolyte abnormalities

and to improve the general nutritional state are also

important Antidiarrhoeals should be used with

extreme caution in active colitis and are

contra-indicated if the disease is severe They can lead to

toxic dilatation of the colon, with perforation

I N F L A M M A T O R Y B O W E L D I S E A S E

ULCERATIVE COLITIS Aminosalicylates

Aminosalicylates maintain remission in patients with ulcerative colitis (relapses are reduced by a factor of 3), and may also be used for treatment of

an acute attack (corticosteroids may also be needed)

S u l f a s a l a z i n e ( s a l i c y l a z o s u l f a p y r i d i n e ,

Salazopyrin) consists of two compounds, sulpha-pyridine and 5-aminosalicylic acid, joined by an azo-bond Sulfasalazine is poorly absorbed from the small intestine and colonic bacteria split the azo-bond to release the component parts The therapeutically active moiety is 5-aminosalicylic acid (5-ASA) Sulphapyridine is well absorbed, is acetylated in the liver and excreted in the urine; it has no therapeutic action in colitis but contributes

to a mechanism for delivering 5-ASA to the colon Sulfasalazine is also used as a disease-modifying agent in rheumatoid arthritis (see p 292), the condition for which it was originally introduced in the 1930s It is available as a tablet, retention enema

or suppository

Adverse effects are due largely to the sulph-onamide moiety and include headache, malaise, anorexia, nausea and vomiting; these are dose-related and commoner in slow acetylators (of the sulphonamide) Allergic reactions include rash, fever and lymphadenitis; rarely leucopenia and agranulo-cytosis occur Males may become infertile due to oligospermia and reduced sperm motility; this reverses if salazopyrin is replaced with mesalazine

Mesalazine Patients intolerant of salazopyrin

usually tolerate mesalazine, which is 5-ASA Mesalazine is absorbed rapidly and completely in the upper jejunum, and is presented in various

formulations which delay its release Asacol tablets

are coated in a resin, which dissolves only at a pH

of 7 or higher, favouring its release in the ileum and

colon In contrast Pentasa has a slow-release but pH

independent coating so that 5-ASA is liberated throughout the gastrointestinal tract 5-ASA that enters the blood is rapidly cleared by acetylation in the liver and renal excretion In addition to oral formulations, mesalazine is available as an enema The profile of adverse effects includes nausea, abdominal pain, watery diarrhoea (which can lead

32 I N T E S T I N E S

to diagnostic confusion in patients with inflammatory

bowel disease) and interstitial nephritis Renal

function should be monitored regularly in patients

taking 5-ASA, particularly preparations extensively

released in the small intestine

Two other 5-ASA preparations effectively delay

release of the active moiety until the preparation

reaches the colon: Olsalazine is two molecules of

5-ASA acid linked by an azo-bond, while balsalazide

comprises one molecule of 5-ASA acid linked by an

azo-bond to an inert carrier 5-ASA is liberated after

cleavage of the azo-bonds by colonic bacteria

Corticosteroids

Enemas and suppositories When ulcerative colitis

is restricted to the left hemicolon, exacerbations that

do not respond to an aminosalicylate alone can

often be controlled by steroid enemas Properly

administered, these will reach the splenic flexure,

and for this to occur the patient should be instructed

to lie down for at least 30 minutes after insertion of

the enema The foam-based preparations appear to

coat the colonic mucosa more efficiently than the

aqueous formulations

In patients with disease limited to the distal few

centimetres of the rectum, steroid enemas may be

ineffective because they will be delivered proximal

to the inflamed segment In this situation steroid

suppositories are often helpful Patients with distal

colitis are prone to faecal loading above the inflamed

segment and this can lead to overflow diarrhoea

and worsening of inflammation Faecal loading can

be detected on straight abdominal x-ray and is

treated with laxatives; this is safe provided the

inflammatory process is restricted to the distal colon

On no account should antidiarrhoeals be used as

these will exacerbate the problem Adequate

quantities of dietary fibre and fluid should be

encouraged, and stool bulking agents can also be

helpful in protecting against faecal loading

Systemic corticosteroid Moderately severe attacks of

ulcerative colitis should be treated with systemic

corticosteroid, and oral preparations usually suffice

It is important to give enough drug to bring the

inflammatory process under control (starting dose

prednisolone 60 mg/d) A response should start within 10-14 d and if it does not the patient should

be admitted to hospital for more intensive treatment including intravenous corticosteroid Once re-mission has been attained the dose can be tailed down over a period of 6-8 weeks It is important not to do this too quickly; the rapidly tailing regimes used for treating asthma are not appropriate for inflammatory bowel disease

Severe attacks of ulcerative colitis should be

treated in hospital with intravenous corticosteroid The main danger is toxic dilatation of the colon and perforation, which can occur insidiously Regular measurements of abdominal girth and straight x-ray of the abdomen are useful in monitoring response, which should be seen within 72 h If there is no improvement a trial of ciclosporin (see below) may induce response Treatment otherwise is by emergency colectomy

Ciclosporin may induce remission in some patients

with severe ulcerative colitis unresponsive to cortico-steroid The drug is given in a dose of 2-4 mg/kg i.v until remission is attained Renal function should

be monitored closely as ciclosporin is nephrotoxic

(see p 620) For maintenance therapy azathioprine

(see below) is often substituted Ciclosporin use only delays surgery for many patients; after 1 year 50% will have relapsed and undergone colectomy Smoking aggravates Crohn's disease but (perversely) improves ulcerative colitis Nicotine patches may provide benefit in ulcerative colitis but the effect is not sufficiently great to justify their routine use in management

Maintenance of remission

Corticosteroids can be reduced slowly (see above) and maintenance therapy with an aminosalicylate started If the disease is corticosteroid dependent, azathioprine or another immunosuppressive agent may be used (see below) Surgery is indicated if medical therapy fails to control the disease or is associated with unacceptable adverse effects

CROHN'S DISEASE

Treatment depends on the site of disease

Manage-ment of colonic Crohn's disease is very similar to

that of ulcerative colitis, with aminosalicylate and

corticosteroid These drugs are of less value in

maintaining remission in Crohn's disease than in

ulcerative colitis, although they do help to reduce

recurrence of disease at sites of surgical anastamoses

Topical enema preparations are less useful because

of the patchy distribution of inflammation and

rectal sparing

In contrast to ulcerative colitis, about 50% of

patients with Crohn's colitis will respond to

metronidazole given for up to 3 months, although

adverse effects including alcohol intolerance, and

peripheral neuropathy from such prolonged therapy

often limit its use The drug is also helpful in

controlling perianal and small bowel disease and it

decreases the incidence of anastamotic recurrence

after surgery Other antimicrobials, particularly

ciprofloxacin may also be effective.

Crohn's disease of the small bowel classically

affects the ileocaecal region, although any part of

the gastrointestinal tract may be involved, from the

mouth downwards Patients with small bowel

in-volvement are frequently malnourished and specialist

dietetic input is essential; enteral or parenteral

nutrition may be required Osteoporosis is common,

particularly if corticosteroid consumption has been

high

Sulfasalazine, olsalazine and balsalazide are

ineffective in small bowel Crohn's disease because

these drugs are designed to liberate 5-ASA in the

colon Mesalazine preparations release 5-ASA higher

in the gut and control mild to moderate exacerbations

of ileocaecal disease in approximately 50% of

patients, although high doses are needed (Asacol

2.4 g in divided doses, Pentasa 2 g b.d.)

In more severe disease corticosteroids are needed

to induce remission (prednisolone 60 mg/day until

remission induced, tailing the dose by 5 mg/week)

Approximately 75% of patients respond Budesonide,

a potent topically active corticosteroid, is an

alternative which can be administered either orally

or as an enema The oral preparation is presented as

a delayed release formulation which delivers drug

to the terminal ileum and ascending colon Extensive

first pass metabolism in the liver limits its systemic

availability and potential for adverse effects

Budesonide is also useful as maintenance therapy

of the 30% of patients with Crohn's disease who are

steroid dependent

I N F L A M M A T O R Y B O W E L D I S E A S E

Maintenance of remission may require addition of

azathioprine or another immunosuppressive drug (see below) Tobacco smoking definitely contributes

to relapse and should be strongly discouraged Crohn's disease may be complicated by intestinal strictures, fistulae and intra-abdominal abscesses Surgery is often necessary but strictures may be amenable to endoscopic balloon dilatation and abscesses can be drained under radiographic control

Dietary therapy

There is evidence that liquid diets based on amino-acids (elemental diets) or oligopeptides for 4-6 weeks are as effective as corticosteroids in controlling Crohn's disease although relapse is common when the treatment stops Elemental preparations are not particularly palatable and they often have to be administered through a nasogastric tube, which is not popular with patients They are worth trying in steroid resistant cases, and are particularly favoured

by paediatricians who prefer to avoid adrenal steroid because of its adverse effects on growth

Antibodies to tumour necrosis factor (TNF)

TNFoc causes activation of immune cells and release

of inflammatory mediators The inhibitors of TNF, infliximab and etanercept (see p 293), have been found to benefit Crohn's disease A single dose of anti-TNFa will induce remission in approximately one-third of patients with Crohn's disease resistant

to conventional therapies, with improvement in a further third A further dose after 8 weeks appears

to produce longer lasting remissions This treatment

is also useful in treating Crohn's fistulae Adverse reactions include headache, nausea and malaise; repeat infusions after prolonged intervals (1-2 years) may lead to hypersensitivity reactions Its efficacy and potential for adverse effects in the long term (including development of malignancy) remain to

be established There is no good evidence that anti-TNFa antibodies are effective for ulcerative colitis

Immunosuppressive drugs

Azathioprine is effective as a steroid sparing agent

in maintenance therapy of Crohn's disease Use of

32 I N T E S T I N E S

this drug in a dose of up to 2 mg/kg may allow

corticosteroid to be withdrawn altogether It is also

used for the same purpose in ulcerative colitis

although evidence for its efficacy in this disorder is

less persuasive As the onset of action of azathioprine

is delayed for about 8 weeks, it is not effective for

inducing remission, and reduction in steroid dose in

the first few weeks of azathioprine treatment may

lead to relapse Azathioprine can cause bone marrow

suppression and the blood count should be monitored

weekly for the first two months of therapy and every 2

months thereafter for as long as the drug is taken

Intolerance of azathioprine is shown by malaise,

abdominal discomfort and sometimes fever

Pan-creatitis occurs in up to 5% These effects are

usually due to the imidazole side chain of the

molecule, and mercaptopurine (which is azathioprine

without the side chain) may be better tolerated The

dose is 1-1.5 mg/kg

Ciclosporin There is no good evidence that

ciclosporin is effective in Crohn's disease

Methotrexate can be helpful in controlling relapses

of Crohn's disease unresponsive to corticosteroid or

azathioprine It has also been used with benefit in

ulcerative colitis Its short- and long-term use are

limited by a wide profile of adverse effects

including bone marrow suppression and

pulmonary and hepatic fibrosis (see p 291)

Other conditions

MICROSCOPIC COLITIS

This condition presents with diarrhoea: the colonic

mucosa is macroscopically normal but histologically

shows either lymphocytic infiltration of the mucosa

(lymphocytic colitis) or subendothelial fibrosis

(collagenous colitis) Treatment with aminosalicylate

induces remission in about 50% and corticosteroid

may also be needed

BILE SALT MALABSORPTION

Failure of the terminal ileum to reabsorb bile salts

may result from Crohn's disease, or ileal resection,

and it occurs in many patients with microscopic

colitis Bile salts in the colon cause diarrhoea which is

relieved by colestyramine The dose required is titrated against symptoms, starting with 8 g bd Colestyramine can also bind to many drugs and reduce their bioavailability (see p 131)

IRRITABLE BOWEL SYNDROME (IBS)

This condition affects 20% of the population and is the commonest reason for referral to a gastro-enterologist It is manifested by a variety of gastrointestinal symptoms including disordered bowel habit (constipation, diarrhoea or both), abdominal pain and bloating Upper gastrointestinal symptoms manifest as nonulcer dyspepsia (see Chapter 31) All these symptoms occur in the absence

of demonstrable pathology in the gastrointestinal tract, although patients with IBS often have ab-normalities of gut motility Another feature of the condition is visceral hypersensitivity; patients with IBS have lower thresholds for pain from colonic distension induced by inflating balloons placed in the bowel A proportion of patients develop their IBS symptoms after an episode of gastroenteritis and in many emotional stress is an important precipitating factor Associated psychopathology, with anxiety and sometimes depression, are common The mainstay of treatment, after investigation when appropriate, is to reassure the patient of the entirely benign nature of the disorder and the good

prognosis Those with predominant constipation

should be encouraged to increase the fluid and fibre content of their diet Unprocessed bran can lead to troublesome bloating and wind and a bulking agent such as ispaghula husk is often better tolerated

Diarrhoea can be treated with an antimotility

drug such as loperamide, the dose being adjusted to symptoms Codeine phosphate is effective although

it may cause sedation

Antispasmodics (see below) are given for abdominal

pain, although there is little objective evidence for

their efficacy from controlled clinical trials The generation of evidence is complicated by the variable nature of IBS symptoms, the patients who suffer from them, and the high rate of placebo response in this condition There are two main classes of antispasmodic, the antimuscarinic drugs and drugs which are direct smooth muscle relaxants