1. Regulating Gastric Acid Secretion & Treating Gastric and Duodenal Ulcers Flashcards
What drugs do you give someone who suffer from Reflux?
• Something to inhibit acid secretion o Antacids o Histamine antagonists o PPI’s + antibiotics • Something to treat his pain o Would you leave him on ibuprofen? Probably not.
Explain the Actions of PGE2 and PGI2 & Somatostatin with relation to Gastric Acid Secretion
PGE2 and PGI2 inhibit acid and stimulate mucous and bicarbonate secretion and dilate blood vessels. Somatostatin inhibits all phases of parietal cell activation
Name some Proton Pump Inhibitors
Omeprazole, Iansaprazole
What are the pharmacodynamics of PPIs?
Omeprazole
The proton pump inhibitors (PPIs) irreversible inhibit the H+/K+ATPase (proton pump) of the parietal cell.
• Reduce acid secretion regardless of the stimulus
o Inactive at neutral pH
o Weak base and accumulates preferentially in the acid environment of the canaliculi of the parietal cell where it is activated
o Available in Australia: omeprazole, Isanoprazole, pantoprazole, rabeprazole and esomeprazole.
Name some of the drug interactions of Omeprazole!
Omeprazole has an inhibitory effect on the hepatic oxidative P450 system
• Causes drug interactions
o Interactions between omeprazole and warfarin and phenytoin have been reported
o Azole antifungal have decreased absorption with increase in pH
• As yet however, other significant actions with omeprazole have not been identified
How does Iansaprazole differ in its drug interactions?
Iansaprazole is a weak inducer of the P450 system
• As yet no significant drug interactions have been identified as a problem
Why is there overuse of PPIs? What is the therapeutic dosage?
PPI use in Australia is second only to Statins
• Patient education is important
o Not always necessary to refill every single repeat
• The recommended treatment for diseases such as gastroesophageal reflux (GORD) is the use of a ‘step down’ approach: an initial 4-8 week course of a standard dose that maintains symptom relief. For most people this would mean taking one tablet every 2-3 days.
Long term complications of PPIs
- An association of PPI use and an increase in bone fractures, including hip and spinal fractures
- Acute interstitial nephritis- PPIs now the leading cause in Australia
- Hypomagnesaemia
- Enteric infections- C.difficile causing colitis in the elderly, bacterial gastroenteritis incl. traveller’s diarrhea,
- Pneumonia
- Long term suppression may impair iron or B12 absorption or may promote bacterial overgrowth, clinical significance is not established.
Describe the Therapies used in Gastro Oesophageal Reflux Disease
Initial therapy
• Standard PPI dose, daily to be taken in the morning, half an hour before food. Examples:
o Esomeprazole 20mg
o Omeprazole 20mg
o Lansoprazole 30mg
• Diet and life style changes- provoking factors: alcohol, chocolate, fatty/spicy food, tight clothing, supine position, excess weight
Maintenance therapy
• Titrate dose as low as possible, where symptoms are tolerable
o Work patient towards PPI ‘as needed’
• Other options- gastric motility drugs, surgery
Explain PPI “step down”
- 4-8 weeks of PPI therapy relives symptoms and heals oesophagitis
- Additional 4 weeks with persistent symptoms
- Step-down to lowest dose and frequency of PPI that is effective
- Intermittent symptom driven therapy
- Hospital discharge review, PPIs may not be needed
What is the aim of ulcer treatment?
- Relieve symptoms
- Prevent long-term complications
- Minimise relapse
- Cure the ulcer
Risk Factors for Ulcers
• Peptic ulcer pathogenesis is thought to involve disturbances in gastric secretions
o Excessive acid secretion
o Insufficient mucous secretion
o Lifestyle factors
• Excessive alcohol (disrupts mucous layer)
• Caffeine
• Smoking
• Diet
• NSAIDs
• Physical and psychological stress levels
What do we use to treat ulcers?
- Antacids: Symptom relief
- Histamine antagonists reduce acid secretion
- Proton pump inhibitors reduce acid secretion
- H.pylori eradication
H.pylori infection- causative?
• Helicobacter pylori- 2/3 gastric ulcers attributed
o Flagellated gram-negative bacillus bacteria
o Colonise the gastric mucosa by attaching to the surface of the mucous secreting cells
o Transmitted by the faecal-oral route
o Thought to be one of the most widespread infections in the world
• Present in up to 2/3 of the worldwide population
• In communities with poor hygiene practices (no sewage treatment etc), prevalence may be as high as 100%
• Australia: approx. 30% of adult population, higher in older people, migrants, and lower socioeconomic groups
• Most people infected with H.pylori exhibit no
• Proportion of infected patients who improve after eradication is greater than those given acid suppression and may recue long term risk of ulcer disease and cancer
• Associated with most duodenal ulcers
• WHO has classified H.pylori as a Class 1 carcinogen
o Known predisposing factor to gastric carcinoma
o Causative role in the development of MALT (mucosa associated lymphoid tissue) lymphomas
Is H.pylori eradication necessary?
• Infection confers a lifetime risk of peptic ulcer of 15-20% and gastric cancer of 2%
• H.pylori eradication reduces the incidence of recurrence
o Recurrence rates are below 5% with eradication
o Without eradication recurrence of ulceration is -80%
o All infected people develop active chronic gastritis
o Strogly indicated in infected people with a close family history of gastric cancer and anyone who has had gastric cancer
Use of 2 abx avoids resistance. What are the 3 things we need to do?
- Inhibit microbial protein synthesis
- Interfere with the bacterial DNA helix, inhibiting nucleic acid synthesis
- Interfere with the synthesis of the bacterial cell wall peptidoglycan and inactivate inhibitors of autolytic enzymes (bactericidal)
How do we do this?
• Inhibit microbial protein synthesis
o Tetracyclines (bacteriostatic)
• Tetracycline, oxyterracycline, doxycycline
o Macrolides (wide spectrum)
• Erythromycin, clarithromycin (potent P450 inhibitor) and azithromycin.
• Interfere with the bacterial DNA helix, inhibiting nucleic acid synthesis
o Nitroimidazole antibiotics
• Metronidazole
• Interfere with the synthesis of the bacterial cell wall peptidoglycan and inactivate inhibitors of autolytic enzymes (bactericidal)
o B-lactam antibiotics, eg. Amoxycyclin (a penicillin)
Triple therapy is the standard eradication regimen used in Australia,
• Success rate 90-95%
o Omeprazole (20mg orally twice daily) plus clarithromycin (500mg orally, twice daily), plus amoxicillin (1g, twice daily) for 7 days.
o Lasonoprazole (30mg twice daily) plus clarithromycin (500mg orally, twice daily) plus amoxicillin (1g, twice daily) for 10 days.
o Omeprazole (20mg orally, twice daily) plus clarithromycin (500mg twice daily) plus metronidazole (if penicillin is contraindicate) (400mg, three times daily) for 7 days
If eradication fails, what are some more aggressive therapies?
o Bismuth (120mg, orally, four times daily)
o Metronidazole (400mg three times daily)
o Tetracycline (500mg four times daily)
o Proton pump inhibitor (omeprazole 20mg, twice daily)
• Treatment course 7-14 days
• 80-85% success rate
o Rifabutin (150mg twice daily) o Amoxycillin (1g twice daily) o Proton Pump inhibitor (omeprazole 20mg, twice daily) • Treatment course 10 days • 60-70% success rate
What is Bismuth Citrate?
• A chelating agent
• Toxic to bacillus
• Prevents adherence to mucosa
• Thought to have other mucosal protecting actions
o Coating ulcer base
o Absorbing pepsin
o Enhancing local prostaglandin synthesis and stimulating bicarbonate secretion
• Available through a special access scheme
What is Rifabutin?
• Belongs to the Rifamycin family
o Rifampicin and rifabutin
• A broad-spectrum antibiotic
o Inhibits DNA dependent RNA polymerase activity in susceptible cells
• Interacts with bacterial RNA polymerase but does not inhibit the mammalian enzyme
• Bactericidal and has a broad spectrum of activity against most gram-positive and mycobacteria
• Usually used as prophylaxis against disseminated mycobacterium avium complex infection. Also used to treat infections from Pseudomonas aeruginosa and mycobacterium tuberculosis
How do histamine antagonists reduce acid secretion? Name Histamine Antagonists!
• Cimetidine, ranitidine famotidine and nizatinide
o Competitively inhibit histamine actions at the H2 receptors
• Inhibit all histamine stimulated acid secretion
• Triggered directly by histamine or indirectly by gastrin and/or acetylcholine
• The histamine antagonists can decrease basal and food stimulated acid secretion by up to 60-90%
• Can promote the healing of duodenal ulcers
o Relapse after termination of treatment is common.
Reflux in Pregnancy?
- Common and existing symptoms often exaggerated
- Recommend low fat meals
- Best to avoid drugs, but antacids and H2RA’s (ranitidine) appear to be safe
- PPIs listed as B3 (rabeprazole B1)
- If PPI required, greatest experience is with omeprazole.
Paediatric Reflux?
• Regurgitation in infants is common
o Especially in the first 1-6 months
• Immature or weak oesophageal sphincter
• Usually mild
• No treatment required
• Positioned on side when sleeping or feeding, elevate head in cot
o Thicken food
• Can be chronic and due to gastro-oesophageal reflux and oesophagitis
• Can cause failure to thrive, haematemesis, apnoea
• 24 hour oesophageal pH monitoring, oesophageal biopsy
• Recommended treatment (therapeutic guidelines)
o Ranitidine syrup (Zantac) 2-3 mg/orally, 3 times daily
o 2nd Line: PPI
o Lasoprazole 15mg daily in child less than 30kg.
Drugs that may induce/exacerbate dyspepsia/ulceration
- Anticholinergic drugs
- Beta blockers
- Biphosphonates
- CCBs
- Clopidogrel
- Corticosteroids
- Levodopa
- Iron and potassium supplements
- Nitrates
- NSAIDs
- Tetracycline
