L16 - Aggressive factors and ulcer healing drugs Flashcards
Peptic ulcer
A break in the mucosa of the stomach (gastric ulcer) or duodenum (duodenal ulcer)
Aggresive factors of peptic ulcer
Multifactorial Risk Factors (Aggresive factors):
1. Helicobacter pylori infection
- High incidence in PU
- DU (95%); GU (75%)
- Eradication of HP leads to remission & decreasing incidence of PU
2. Environmental factors:
- Smoking (Nicotine stimulates HCl production; reduces mucus)
- Alcohol (organic solvent that dissolves epithelial mucus surface)
- Drugs (e.g. analgesic, NSAIDS -> inhibits prostaglandin)
- Organic stress (e.g. stroke, burns)
3. Hormonal factor
- Male preponderance
- rare in pregnant women
4. Hypercalcemia
- stimulates gastrin production and therefore acid secretion
5. Excess production of (?)
- Pepsin
- Acid
- Gastrin
- Histamine
Defensive factors of peptic ulcer
1) Mucus
- Product mucosa from actions of acid and pepsin
2) HCO3-
- Maintaining a higher pH near mucosa by neutralizing HCl
3) Blood flow
- Provide nutrients for ulcer healing
- Pemove toxic materials that may lead to mucosal damage
4) Prostaglandins
- A vasodilator that increases blood flow (see pt 3)
- Decreases HCl production
- Increases mucus production
5) Nitric oxide
- A vasodilator that increases blood flow (see pt 3)
6) Growth factors
- Hormonal stimulant of cell growth and development, thus promoting healing
when peptic ulcer aggresive factors > defensive factors…
… Peptic ulcer may develop
Peptic ulcer treatment strategy
1) Remove risk factors (e.g. alcohol, cigarette, stress) by lifestyle modifications
2) Decrease acid secretion or neutralize acid
3) Promote mucosal defense
4) Eradicate H. Pylori
Gastric acid secretion overall mechanism
Paracrine - Histamine
- Histamine released from ECL cells
- Act on H2 receptors on parietal cells
- Histamine binding with H2 receptor will activate adenylyl cyclase, leading to increase in cAMP
- Strongest stimulant of HCl secretion (70%)
Neurocrine - vagal stimulation
- Depends on neural input from vagal nerve
- ACh acts on muscarinic receptors (M1 in ECL cells, M3 in parietal cells)
- Acetylcholine binding with muscarinic receptors will lead to IP3, increasing intracellular calcium ion concentration [Ca2+] i
- Stimulates release of HCl by parietal cells; histamine by ECL cells; (gastrin by G-cells?)
- Accounted for 20 - 30% of HCl secretion
Endorcine - Gastrin
- Secreted by G cells
- Gastrin will bind with CKKB receptor on ECL cells & parietal cells; intracellular calcium concentration will increase
- Stimulates histamine release and synthesis by ECL cells
- Trophic effects on ECL cells
- Stimulates acid secretion by parietal cells via CCKB receptors
- Accounted for 20 - 30% of HCl secretion
Increased Calcium ion & cAMP concentration will activate protein kinase.
Ultimately these intracellular secondary messagers will control the transfer of H+/K+-ATPase (aka Proton Pumps) from cytoplasmic vesicles to plasma membrane, where it can allow the secretion of H+
Agents that targets at gastric acids
decrease gastric acid secretion:
1) H2 inhibitors
2) Muscarinic antagonists
*) [Gastrin receptor inhibitor yet to be developed]
3) Proton pump inhibitors (PPI)
neutralizes gastric acid:
4) Antacids
- Sodium bicarbonate
- Calcium carbonate
- Magnesium hydroxide and aluminium hydroxide
Gastric production partition of different receptors
70%: H2 receptor
20-30%: M3 receptor and CCKB receptor (aka G receptor)
H2 antagonists (mechanism, examples)
1) Mechanism:
- Blocking binding of histamine with H2 receptors on parietal cells; thereby preventing 70% of gastric acid production as adenylyl cyclase will not be activated to produce cAMP
2) Examples (in increasing potency & action duration):
- Cemetidine (2-3 doses/ day; 200- 300mg @)
- Ranitidine
- Nizatidine
- Famotidine (2-3 doses/ day; 20mg @)
H2 antagonists side effects
Generally well-tolerated, but include side effects like:
- Gastrointestinal disturbance (e.g. constipation, diarrhea)
- Headache, dizziness
- (For cimetidine only):*
- Inhibits binding of dihydrotestosterone to androgen receptors, causing impotence and gynecomastia in men
H2 antagonist drug interaction
Inhibit cytochrome P450 metabolizing enzymes in liver, thus decreasing metabolism of other drugs (e.g. phenytoin, theophylline and warfarin)
Increase the blood level of those drugs will lead to drug toxicity and ADR:
i) Phenytoin (for epilepsy; ADR - ataxia, headache, dizziness)
ii) Theophylline (for asthma; ADR - headache, arrhythmia, diarrhoea)
iii) Warfarin (blood thinner; ADR - internal bleeding)
* Cimetidine* appears to inhibit cytochrome P450 to a greater extent than the other H2 antagonist. Therefore other H2 antagonist may be preferred when a patient is receiving other medications.
Muscarinic antagonists mechanism & examples & clinical values
1) Mechanism:
- Blocking binding of Ach binding with M1 receptors on ECL cells & M3 receptors on parietal cells
- Reduced histamine synthesis and release by ECL cells
- Reduced HCl production (~20- 30%) by parietal cells as intracellular calcium level will not increase as much
2) Examples
- Pirenzepine
- Dicyclmine
3) Clinical values
Very rarely used now because:
i) Not as effective as H2 antagonists (70% HCl reduction) and PPI (100% HCl reduction)
ii) Many side effects: Dry mouth, blurred vision, cardiac arrhythmias, constipation and urinary retention
Why are muscarinic antagonists rarely used
i) The 20-30% Hcl reduction by muscarinic anatagonists is not as effective as H2 antagonists (70% HCl reduction) and PPI (100% HCl reduction)
ii) Many side effects: Dry mouth, blurred vision, cardiac arrhythmias, constipation and urinary retention
PPI (mechanism, example, side effects)
Mechanism: blocking the H+/K+ ATPase (aka proton pump), thus effectively preventing 100% of gastric acid production
Most effective agent targeting at acid secretion
Examples (all similar in potency & pharmacokinetics):
- Omeprazole
- Esomeprazole
- Lansoprazole
- Pantoprazole
- Rabeprazole
Side effects:
Generally well-tolerated, but may cause:
- Headache
- Dizziness
- GI disturbance
Antacids mechanism and examples
Mechanism:
Antacid usually contain hydroxide or bicarbonate ions, which will neutralize hydrogen ions in gastric acid:
i) H+ + OH- –> H2O
ii) H+ + HCO3- –> H2O + CO2
Quick action (for relief purposes) but short-lived
Examples:
- Sodium bicarbonate
- Calcium carbonate
- Magnesium hydroxide and aluminium hydroxide (most commonly used)
Why is calcium hydroxide not used as antacid
Strong alkali like calcium hydroxide will react quickly with HCl, producing a lot of heat that will harm the stomach.
Side effects of sodium bicarbonate
1) Belching, because a gas (CO2) is produced
2) Exacerbate fluid retention leading to oedema in patients with heart failure, hypertension and renal insufficiency (because of the sodium intake)
Side effects of calcium carbonate
1) Belching (because of the gas produced)
2) Cause hypercalcaemia and renal calculi (because of calcium intake)
3) Constipation
Side effects of magnesium hydroxide and aluminium hydroxide
- Magnesium hydroxide causes diarrhoea
- Aluminium hydroxide causes constipation
[Therefore the two are commonly administered together in proprietary formulations, to minimize the effect of GI distrubances]
- Alumnium ions are too large to be absorbed, therefore no systemic side effects
- Hypermagnesaemia is very rare because magnesium is poorly absorbed
Agents that promote mucosal defense
1) Sucralfate
2) Bismuth compounds
*) [Prostaglandins]
3) Misoprostol
Sucralfate mechanism
- It is a complex of sucrose sulphate and aluminium hydroxide
- In the presence of acid, aluminium is released:
i) Sucralfate acquired a strong negative charge
ii) bind to positively charged groups in glycoprotein in mucus
iii) form a viscous gel which adhere to the epithelial cells of the stomach, including area of ulceration
iv) The gel protects the stomach luminal surface, including areas of ulceration, from being degraded by acid and pepsin
Side effects of sucralfate
Because it is not absorbed, it is virtually devoid of systemic adverse effects
- Constipation occurs in 2 % of patients due to the aluminium salt
Drug interactions of sucralfate
1) Since it requires an acidic environment for activation, Antacid given concurrently or prior to its administration will reduce its efficiency
2) It may bind to several drugs, e.g. quinolone antibiotics, phenytoin, and warfarin, limiting their absorption
3) Take on an empty stomach because sucralfate may bind to food, reducing its efficacy
Bismuth mechanism
1) Bismuth combines with mucus glycoproteins to form a barrier, protecting the ulcerated area from acid and pepsin damage
2) It also stimulates the secretion of mucus, bicarbonate and prostaglandin
3) Has direct antimicrobial activity against H. Pylori
Side effects of bismuth
i) Darkening of teeth and tongue
ii) Darkening of stool, which may confused with gastrointestinal bleeding
iii) In patient with renal failure, bismuth cannot be effectively removed. Prolong use of bismuth may cause toxicity, and if circulated into the brain will result in encephalopathy (ataxia, headache, confusion, seizures)
Drug interaction of bismuth
Take on an empty stomach because bismuth may bind to food, reducing its efficacy
prostaglandins mechanism
- Act on PGE1 receptors of parietal cells to decrease acid secretion
- Increase mucus and bicarbonate secretion
- Vasodilator, Increases blood flow to increase nutrients for repair & remove toxic materials
- clinically NOT used because it is quickly metabolized, thus require high and frequent dose (30-40 doses/ day)
Misoprostol mechanism
- A Prostaglandin analogue with higher stability & longer life (lower dose around 2-3 times per day required)
- Act on PGE1 receptors of parietal cells to decrease acid secretion
- Increase mucus and bicarbonate secretion
- Vasodilator, Increases blood flow to increase nutrients for repair & remove toxic materials
Side effects of misoprostol
Because it will stimulate PGE1 receptors in GIT and uterus:
- Cause Gastrointestinal discomfort (diarrhoea, abdominal cramps) as intestinal motility increases
- Should not be used during pregnancy because misoprostol stimulates uterine contraction
Agents used for eradication of HP
Mneumonic: Tummy And Cardia Better Right Now Please
1) Tetracycline
2) Amoxillin
3) Clarithromycin
4) Bismuth compounds
- Pepto-Bismol (bismuth subsalicylate)
- DeNol (tripotassium dicitrato bismuthate)
- Pylera (bismuth-metronidazole-tetracycline)
5) Ranitidine bismuth citrate
6) Nitroimidazoles
- *- metronidazole**
- tinidazole
7) PPI (proton-pump inhibitors)
- Omeprazole
- Esomeprazole
- Lansoprazole
(- Pantoprazole - Rabeprazole)
Amoxicillin mechanism
- ß-lactam
- Inhibits transpeptidase, thus preventing the formation of pentaglycine bridge between NAMA & NAG
- Interferes with the synthesis of bacterial cell wall
- Without cell wall, H. pylori will swell & burst
Side effects of amoxicillin
- Hypersensitivity reactions (rash, fever, anaphylactic shock)
- Gastrointestinal disturbance (e.g. diarrhoea, because it alter the bacterial flora in the gut)
Clarithromycin mechanism
- macrolide antibiotic
- Binds to 50-S subunit of ribosomes
- Inhibits the translocation process of peptide from A-site (synthesis) to P-site (storage) of ribosome during the synthesis of protein
Side effects of clarithromycin
- Hypersensitivity reactions (rash, fever, anaphylactic shock)
- Gastrointestinal disturbance (e.g. diarrhoea) because it alter the bacterial flora in the gut
Metronidazole mechanism
- The nitro group of metronidazole is chemically reduced by the redox enzyme pyruvate-ferredoxin oxidoreducatase (PFOR)
- The product disrupts the DNA helical structure, thus inhibiting DNA synthesis
- Metronidazole is selectively toxic for anaerobic organism (and H. Pylori) because PFOR is expressed in anaerobic but not in mammalian systems
Side effects of metronidazole
- Metallic taste
- Gastrointestinal disturbance
- Dizziness
- headaches
- occasionally sensory neuropathy (e.g. tingling feeling of finger tips)
Recommended regimens for treating H. Pylori-associated peptic ulcer
1) Triple therapy (PPI-based)
2) Triple therapy (bismuth-based)
3) Ranitidine bismuth citrate-based therapy
4) Quadruple therapy and second- / third-line treatment
5) Sequential therapy
(see GI L13)
