Peptic Ulcer Disease

DEFINITION

• Peptic ulcer disease (PUD) refers to a group of ulcerative disorders of the upper

GI tract that require acid and pepsin for their formation.

The three common forms of peptic ulcers include

1. Helicobacter pylori (HP)–associated ulcers, 2. Non-steroidal anti-inflammatory drug (NSAID)–induced ulcers, 3. Stress-related mucosal damage (also called stress ulcers).

PATHOPHYSIOLOGY

• Most peptic ulcers occur in the presence of acid and pepsin when H. pylori

NSAIDs, or other factors disrupt normal mucosal defense and healing mechanisms.

Mucosal defense and repair mechanisms include mucus and bicarbonate secretion, intrinsic epithelial cell defense, and mucosal blood flow.

- Maintenance of mucosal integrity and repair is mediated by endogenous prostaglandin production.

1. H. pylori infection causes gastritis in all infected individuals .

-HP may cause ulcers by direct mucosal damage, altering the immune/inflammatory response, and `by hypergastrinemia leading to increased acid secretion.

2. Non-selective NSAIDs (including aspirin) cause gastric mucosal damage by

two mechanisms:

(1) a direct or topical irritation of the gastric epithelium,

(2) systemic inhibition of the cyclooxygenase-1 (COX-1) enzyme, which results in decreased synthesis of protective prostaglandins.

3. Stress ulcer

Severe physiological stress such as head injury, spinal cord injury, burns, multiple trauma or sepsis may induce superficial mucosal erosions or gastroduodenal ulcerations.

•Epidemiologic evidence links cigarette smoking to PUD, impaired ulcer

healing, and ulcer-related GI complications. The risk is proportional to the

amount smoked per day.

Box-.1 Risk factors for NSAID ulcers

Age greater than 65 yearsPrevious peptic ulceration/bleedingHigh dose of NSAID or more than one NSAID (including aspirin)Short-term history of NSAID use (<1 month)Concomitant corticosteroid or anticoagulant useCardiovascular disease

CLINICAL PRESENTATION

• Abdominal pain is the most frequent symptom of PUD.

- A typical nocturnal pain may awaken patients from sleep, especially between 12 AM and 3 AM.

• Pain from DU often occurs 1 to 3 hours after meals and is usually relieved

by food, whereas food may precipitate or ulcer pain in GU.

• Heartburn, belching, and bloating often accompany the pain. Nausea, vomiting, and anorexia are more common in GU than DU.

• The severity of symptoms varies from patient to patient .

- Many patients (especially older adults) with NSAID-induced, ulcer-related complications have no prior abdominal symptoms.

• Complications of ulcers caused by HP and NSAIDs include haemorrhage,

chronic iron-deficiency anaemia, pyloric stenosis and perforation.

-In the elderly, the presentation is more likely to be silent and gastro-intestinal bleeding may be the first clinical sign of disease. Peptic ulcer bleeding is the most frequent and severe complication of peptic ulcer disease.

DIAGNOSIS

• physical examination,. Endoscopy, Radiology, H. pylori detection

-Endoscopy is generally the investigation of choice for diagnosing peptic ulcer, and the procedure is sensitive, specific and safe

-A Gastrograffin® meal is used to diagnose peptic perforation in patients presenting with an acute abdomen, if a plain abdominal X-ray is not diagnostic

-Antibody detection tests, the urea breath test (UBT), and the stool antigen test.

-The UBT is based on urease production by HP. Testing for HP is only recommended if eradication therapy is considered &to verify HP eradication after treatment.

DESIRED OUTCOME

• The goals of treatment are relieving ulcer pain, healing the ulcer, preventing

ulcer recurrence, and reducing ulcer-related complications.

TREATMENT

NON-PHARMACOLOGIC TREATMENT

• Patients with PUD should eliminate or reduce psychological stress, cigarette

smoking, and the use of non-selective NSAIDs (including aspirin). If possible,

alternative agents. acetaminophen, or a COX-2 selective inhibitor should be used for pain relief.

• Although there is no need for a special diet, patients should avoid foods

and beverages that cause dyspepsia or exacerbate ulcer symptoms (e.g.,

spicy foods, caffeine, alcohol).

PHARMACOLOGIC TREATMENT

• Eradication of HP is recommended for HP-infected patients with GU, DU,

ulcer-related complications,

1. HP-positive patients should receive eradication therapy.

2. In HP-negative patients, higher PPI doses (e.g., omeprazole 40 mg/day) heal the majority of ulcers. Continuous PPI treatment is often necessary to maintain healing. (1-2 months)

• First-line eradication therapy is a proton pump inhibitor (PPI)–based, three-drug regimen containing two antibiotics, usually clarithromycin and amoxicillin,

-OCA: omeprazole 20 mg, clarithromycin 500 mg and amoxicillin 1 g or

• OCM: omeprazole 20 mg, clarithromycin 500 mg and metronidazole 400 mg.

In patients with hypersensitivity to penicillin, the OCM regimen or substitution of amoxicillin from the OCA regimen with tetracycline 500 mg twice daily is used. Or clarithromycin–metronidazole in penicillin-allergic patient

-The PPI should be taken 30to 60 minutes before a meal along with the two antibiotics.

-Although an initial 7-day course provides minimally acceptable eradication

rates, longer treatment periods (10 to 14 days) are associated with higher

eradication rates and less antimicrobial resistance

• First-line treatment with quadruple therapy using a PPI (with bismuth,

metronidazole, and tetracycline) achieves similar eradication rates.

-All medications except the PPI should be taken with meals and at bedtime.

•If a PPI–amoxicillin–clarithromycin regimen fails, therapy should be

instituted with a PPI, bismuth subsalicylate, metronidazole, and tetracyclinefor 14 days.

• Maintenance therapy with a PPI or H2RA is recommended:-

1. for high-risk patients with ulcer complications,

2. patients who fail HP eradication,

3. with HP-negative ulcers.

• For treatment of NSAID-induced ulcers

- Nonselective NSAIDs should be discontinued (when possible) if an active ulcer is confirmed.

Most uncomplicated NSAID-induced ulcers heal with standard regimens of an H2RA,PPI, or sucralfate ,if the NSAID is discontinued.

If the NSAID must be continued, acetaminophen, a selective COX-2 inhibitor.

PPIs are the drugs of choice when NSAIDs must be continued because potent acid suppression is required to accelerate ulcer healing.

If HP is present, treatment should be initiated with an eradication regimen that contains a PPI.

EVALUATION OF THERAPEUTIC OUTCOMES

• Patients should be monitored for symptomatic relief of ulcer pain as well

as potential adverse effects and drug interactions related to drug therapy.

• Ulcer pain typically resolves in a few days when NSAIDs are discontinued

and within 7 days upon initiation of antiulcer therapy.

- Most patients with uncomplicated PUD will be symptom-free after treatment with any one of the recommended antiulcer regimens.

• The persistence or recurrence of symptoms within 14 days after the end of treatment suggests failure of ulcer healing or HP eradication, or an alternative diagnosis.

• High-risk patients on NSAIDs should be closely monitored for signs and

symptoms of bleeding, obstruction, penetration, and perforation.

Complications of peptic ulcer disease

Bleeding peptic ulcer

Peptic ulcer is the most common cause of upper gastro-intestinal bleeding.

- Endoscopic therapy is necessary only in patients who exhibit high-risk (active bleeding,) on endoscopy.

-A number of pharmacological agents have been used for endoscopic injection therapy such as 1:10,000 adrenaline (epinephrine), human thrombin and fibrin glue.

-Mechanical endoscopic treatment options include thermocoagulation using a heater probe or endoscopic clipping.

-Combination therapies are superior to monotherapy and a combination of adrenaline 1:10,000 with either thermal or mechanical treatment is recommended –

Ulcer-healing drugs

Proton pump inhibitors

-The PPIs are all control gastric acid secretion by inhibition of gastric H+, K+-ATPase, the enzyme responsible for the final step in gastric acid secretion from the parietal cell

- PPIs are inactive pro drugs that are carried in the bloodstream to the parietal cells in the gastric mucosa. Under these acidic conditions the pro drugs are converted to their active form, which irreversibly binds the proton pump, inhibiting acid secretion. Since the ‘active principle’ forms at a low pH it concentrates selectively in the acidic environment of the proton pump and results in extremely effective inhibition of acid secretion. The different PPIs (omeprazole, esomeprazole,

lansoprazole, pantoprazole and rabeprazole) bind to different sites on the proton pump, which may explain their differences in potency .

-PPIs require an enteric coating to protect them from degradation in the acidic environment of the stomach.

Clinical use

-PPIs relieve symptoms and heal peptic ulcers faster than H2-receptor antagonists. They also heal ulcers that are refractory to H2-receptor antagonists.

- All PPIs provide similar H. pylori eradication rates and ulcer healing when used at their recommended doses.

-Standard doses of PPIs are used concomitantly with non-selective NSAIDs and with low-dose aspirin in patients at risk of peptic ulcers or ulcer bleeding.

-Intravenous PPIs are most frequently used to prevent recurrent ulcer bleeding in high-risk patients

Bismuth chelate

- Bismuth is toxic to H. pylori and was one of the first agents to be used to eradicate the organism and reduce ulcer recurrence.

-Tripotassium dicitratobismuthate in combination with tetracycline, metronidazole and a PPI is used in quadruple therapy regimens in patients resistant to triple therapy

Sucralfate

-Sucralfate is the aluminium salt of sucrose octasulphate. Although it is a weak antacid, It has mucosal protective effects including stimulation of bicarbonate and mucus secretion and stimulation of mucosal prostanoids.

-sucralfate is effective in the treatment of NSAID-induced duodenal ulcers, if the NSAID is stopped &It has also been used in the prophylaxis of stress ulceration.

Patient care

Patient education

1. Patients should be advised to seek the pharmacist's advice when purchasing over-the-counter analgesic preparations.

2. Patients with risk factors for peptic ulcer disease should be advised to avoid over-the-counter aspirin and NSAIDs and to use paracetamol-based products.

3. Taking aspirin or NSAIDs with or after food may decrease the risk of dyspepsia symptoms but does not decrease the risk of ulcer complications.

-Before prescribing NSAID or aspirin therapy, patients should be assessed in terms of both cardiovascular and gastro-intestinal risk

4. If NSAIDs are necessary in those at risk of ulcer complications, prophylaxis should be prescribed..

5. Patients need to know the importance of adherence to eradication therapy for successful treatment and to avoid development of resistance to antibiotics.

6. Previous adverse reactions should be established; for example, patients who are sensitive to penicillin need an eradication regimen which does not include amoxicillin.

Gastro-intestinal infections

Gastro-intestinal infections represent a major public health and clinical problem worldwide. Many species of bacteria, viruses and protozoa cause gastro-intestinal infection, resulting in two main clinical syndromes.

1. Gastroenteritis is a non-invasive infection of the small or large bowel that manifests clinically as diarrhoea and vomiting.

2. Other infections are invasive, causing systemic illness

-Gastro-intestinal infections can be transmitted by consumption of contaminated food or water or by direct faecal–oral spread.

-Air-borne spread of viruses that cause gastroenteritis also occurs.

Pathophysiology

Development of symptoms after ingestion of gastro-intestinal pathogens depends on two factors.

First, sufficient organisms must be ingested and then survive host defence mechanisms,

second, the pathogens must possess one or more virulence mechanisms to cause disease.

Clinical manifestations

-Many cases of gastro-intestinal infection are asymptomatic or cause subclinical illness.

- Gastroenteritis is the most common syndrome of gastro-intestinal infection, presenting with symptoms such as vomiting, diarrhoea and abdominal pain.

-The term ‘dysentery’ is sometimes applied to infections with Shigella (bacillary dysentery) and Entamoeba histolytica (amoebic dysentery), where severe colonic mucosal inflammation causes frequent diarrhoea with blood and pus.

-Table 37.2 shows the most important causative agents of gastroenteritis together with a brief description of the typical illness that each causes.

Investigations

-Many cases of gastroenteritis outside hospital are mild and short lived, and microbiological investigation may not be necessary. However, investigations are always recommended where antibiotic therapy is being considered.

Treatment

-Many gastro-intestinal infections are mild and self-limiting and never reach medical attention. Where treatment is required, there are three main therapeutic considerations.

1. Fluid and electrolyte replacement is the cornerstone of treatment of diarrhoeal disease. Most patients can be managed with oral rehydration regimens, but severely dehydrated patients require rapid volume expansion with intravenous

fluids.

2. Symptomatic treatment with antiemetics and antimotility (antidiarrhoeal) agents is sometimes used, especially as self-medication.

3. Antimicrobial agents may be useful both in effecting symptomatic improvement and in eliminating faecal carriage of pathogens and therefore reducing the risk of transmitting infection to others.

Antibiotic therapy

-The requirement for antibiotic treatment in gastro- intestinal infection depends on 1.the causative agent,

2. the type and severity of symptoms and

3.the presence of underlying disease.

-Antibiotics are ineffective in some forms of gastroenteritis, including bacterial intoxications and viral infections.

Conditions for which antimicrobial therapy is usually indicated

Shigellosis.

-Antibiotic therapy for shigellosis is usually recommended in order to eliminate faecal carriage, and therefore prevent person-to-person transmission.

-In developing countries, Shigella species that are multiple antibiotic resistant

are an increasing problem.

-The fluoroquinolones are highly effective in shigellosis and resistance is rare; therefore, they are often considered to be the treatment of choice, especially in adults .The dose of ciprofloxacin is 500 mg twice daily orally in adults (7.5 mg/kg twice daily in children ???).

-Amoxicillin is an alternative first-line drug. The dose of amoxicillin is250–500 mg three times daily in adults, and 62.5–125 mg three times daily in children. –

-Azithromycin (azithromycin 500 mg (children 10 mg/kg)once daily for 3 days are also effective.) is increasingly recommended as an alternative agent for shigellosis, especially in children .

Third-generation cephalosporins such as ceftriaxone are another option for severe shigellosis.

-Antibiotic therapy is usually given for a maximum of 5 days.

Enteric fever, resulting from infection with S. enterica serovars Typhi and Paratyphi, presents with symptoms such as headache, malaise and abdominal distension after an incubation period of 3–21 days. During the first week of the illness, the temperature gradually increases, but the pulse characteristically remains slow. Without treatment, during the second and third weeks, the symptoms become more pronounced. Diarrhoea develops in about half of cases. Examination usually reveals splenomegaly,. Serious gastro-intestinal complications such as haemorrhage and perforation are most common during the third week. Symptoms begin to subside slowly during the fourth week. In general, paratyphoid fever is less severe than typhoid fever.

-Treatment should be commenced as soon as a clinical diagnosis of enteric fever is made. Fluoroquinolones remain widely used as the first-choice treatment for typhoid and paratyphoid fevers.

-Resistance to other antibiotics that have been commonly used to treat enteric fever, such as co-trimoxazole, chloramphenicol and ampicillin, is now frequent. So may be useful in patients with bacterial isolates that are confirmed as sensitive.

Ciprofloxacin given orally at a dose of 500–750 mg twice daily in adults (7.5–12.5 mg/kg twice daily in children ?) or 200 mg intravenously twice daily in adults (5–7.5 mg/kg twice daily in children) .

The usual dose of chloramphenicol is 50 mg/kg/day in four divided doses, and for ampicillin 100 mg/kg/day in four divided doses. Two weeks of antibiotic therapy is usually recommended, although shorter courses of ciprofloxacin (7–10 days) may be as effective.

-Alternative agents that have been reported to be successful where treatment failure with fluoroquinlones has occurred include intravenous carbapenems or third-generation cephalosporins (e.g. ceftriaxone 75 mg/day; maximum dose 2.5 g/day) or oral azithromycin at a dose of 20 mg/kg/day (maximum1000 mg) for at least 5 days.

Chronic carriers of Salmonella. Patients may become chronic carriers after Salmonella infection, especially in the presence of underlying biliary tract disease. Oral ciprofloxacin 500–750 mg twice daily continued for 2–6 weeks is usually effective in eradicating carriage.

Cholera.

-Fluid and electrolyte replacement is the key aspect of the management of cholera. However, antibioticsdo shorten the duration of diarrhoea and therefore reduce the overall fluid loss, and also rapidly terminate faecal excretion of the organism. Effective agents include tetracyclines, erythromycin, trimethoprim, ampicillin or amoxicillin chloramphenicol, ciprofloxacin and furazolidine .

-Tetracycline 250 mg four times daily, or doxycycline 100 mg once daily by mouth, is probably the most widely used therapy in adults.

Ampicillin, amoxicillin or erythromycin are generally the preferred agents for children.

treatment is usually given for 3–5 days to ensure eradication of V. cholerae from faeces.

C. difficile infection.

-The clinical spectrum of CDI ranges from asymptomatic carriage to life-threatening pseudomembranous colitis (so called because yellow-white plaques or membranes consisting of fibrin, mucus, leucocytes and necrotic epithelial cells are found adherent to the inflamed colonic mucosa).

-The first objective is to diagnose CDI as soon as possible so that appropriate treatment. \. Clinicians must consider the diagnosis in any patient where there is no clear alternative diagnosis for their diarrhoea. Stool samples must be sent .

-treatment of all hospitalised patients with diarrhoea due to C. difficile is recommended, to shorten the duration of illness and to reduce environmental contamination and therefore the risk of nosocomial transmission.

Oral metronidazole 400 mg three times daily for 10 days is the treatment of choice for mild to moderate CDI.

For severe CDI, oral vancomycin is recommended at a dose of 125 mg four times daily for 10 days.

In patients unable to take oral medication, either drug can be administered via a nasogastric tube. Where there is no response to initial treatment, the dose of vancomycin can be increased to up to 500 mg four times daily, together with intravenous metronidazole 500 mg three times daily.

Addition of oral rifampicin (300 mg twice daily) or administration of intravenous immunoglobulin (400 mg/kg) can also be considered.

Giardiasis.

Metronidazole is the treatment of choice for giardiasis. Various oral regimens are effective, for example

,400 mg three times daily (7.5 mg/kg in children) for 5 days, or 2 g/day (children 500 mg to 1 g) for 3 days.

Alternative treatments are tinidazole 2 g as a single dose, or mepacrine hydrochloride 100 mg (2 mg/kg in children) three times daily

for 5–7 days. Nitazoxanide is a new thiazolide antiparasitic drug (a dose of 500 mg twice daily (adults and children aged 12 years and over) for 3 days (children 1–3 years 100 mg bd; 4–11 years 200 mg bd)

-In such cases, all affected family members should be treated simultaneously.

Amoebiasis.

The aim of treatment in amoebiasis is to kill all vegetative amoebae and also to eradicate cysts from the bowel lumen.

Metronidazole is highly active against vegetative amoebae and is commonly the treatment of choice for acute amoebic dysentery and amoebic liver

abscess. The dose for adults is 800 mg (children 100–400 mg) three times daily for 5–10 days. To eradicate cysts, metronidazole therapy is followed by a 5-day course of diloxanide furoate 500 mg three times daily (20 mg/kg daily in three divided doses for children).

Tinidazole has recently been shown to reduce clinical failure and be better tolerated than metronidazole . The dose of tinidazole for adults is 2 g daily for 2–3 days, and for children, 50–60 mg/kg daily for 3 days.

Patient care

-People excreting gastro-intestinal pathogens are potentially infectious to others. Liquid stools are particularly likely to contaminate the hands and the environment. -All cases of gastro-intestinal infection should be excluded from work or school at least until the patients are symptom free;

-hospitalised patients should be isolated in a single room.

-Patients should be advised on general hygiene, and in particular, on

thorough hand washing and drying after visiting the toilet and before handling food.