GIT Lec 1 - HCL Secretion Inhibitors Flashcards
How do peptic ulcers occur?
Peptic ulcers occur when there is an imbalance between the damaging effects of the stomach acid (HCl) and the defense mechanisms that are responsible for the protection of the gastric and duodenal mucosa.
What are the clinical features of peptic ulcers?
Peptic ulcers are chronic conditions that are characterized by recurrent abdominal pain that has the following features:
1. Epigastric in site
2. Food related
3. Episodic in nature
What are some of the defensive and damaging components within the stomach?
Defensive components include: prostaglandins, mucosa, mucosal blood flow and bicarbonate.
Damaging components include: HCl, pepsin, NSAID’s and bacteria like bacterium H. Pylori.
How do we approach patients with peptic ulcers?
General approach; by changing some of their lifestyle habits which includes getting adequate rest, eating healthier spices-less diets and steering off bad hygiene in the form of smoking, drinking, caffeine and NSAID’s.
Drug approach; by selecting the appropriate type of drug for the situation
What are the drug types that are used in the treatment of ulcers?
- Acid Secretion Reducers (inhibitors):
a. H2 receptor blockers (cimetidine, famotidine, ranitidine and nizatidine)
b. Protien-pump inhibitors (PPI’s) (omeperazole, lansoperazole, dexlansoperazole, pantoperazole, rabeperazole and esomeperaozle)
c. M receptor blockers (pirenzepine, dicyclomine and telenzipine)
d. Synthetic somatostatin analog (Octreotride) - Antacids:
a. Magnesium trisilicate and aluminum hydroxide
b. Calcium bicarbonate and sodium bicarbonate - Anti gastrin agents:
Proglumide and oxethazaine - Mucosal Resistance Enhancers:
a. Protecting the base of the ulcer (bismuth chelate, sucralfate and carbenoxolone)
b. Cytoprotection (misoprostol, a PGF1 analog) - H. Pylori infection eradicators (PPI’s + antibiotics like metronidazole)
What are the most common drugs within H2 antagonists group?
Cimetidine, famotidine, ranitidine and nizatidine
What is the MOA of H2-antagonists?
H2-antagonists competitively and reversibly bind to histaminergic receptors in the stomach, blood vessels and other sites and block the binding of histamine to those receptors inhibiting the secretion of HCL. H2-antagonists block secretion of nocturnal, food-stimulated and basal secretion of HCl by up to 90% and also decrease the concentration of pepsin in the process.
What are the pharmacokinetics of H2-antagonists?
- All medications in this class are readily and well absorbed orally.
- Taking H2-antagonists alongside antacids can decrease their absorption by 10-20%.
- They are well distributed in the body and can pass the placenta, be present in breast milk and other body sites, and they are excreted in urine.
- They all share the same efficacy but some are more potent than others.
- Cimetidine is a well-known inhibitor of the liver’s digestive, oxidizing enzyme, P450, and thus leads to decreased metabolism of certain drugs which leads to increased plasma concentrations of those drugs like warfarin, cyclosporines, Calcium channel blockers, propranolol, TAD’s, antiarrythemic medications and others.
- Ranitidine is about 10-15% more potent than cimetidine, with a longer half life of about 2 hours (50% metabolized) which means it can be taken twice daily, it also doesn’t inhibit the hepatic microsomal enzyme P450.
- Ranitidine has less prominent side effects.
- Famotidine is 20-50 times more potent than cimetidine which makes it 3-15 times more potent than Ranitidine. It also similar to ranitidine in pharmacological action and has a longer half life which means it can be taken once daily, it also doesn’t inhibit the hepatic microsomal enzyme P450.
- Nizatidine is similar to ranitidine in efficacy and potency and it has a bioavailability of around 90-100%. It’s mainly eliminated by the kidney, and it can cause hepatic toxicity.
- Cimetidine, famotidine and ranitidine have a bioavailability of about 30-50% due to first pass metabolism in contrast to nizatidine which is less affected by the first pass metabolism and has a bioavailability of 90-100%.
- All of the above drugs’ doses should be decreased in patients with renal or hepatic failure.
What are the indications of H2-antagonists?
- Peptic ulcers and non-ulcer dyspepsias.
- Acute stress ulcers and prevention of bleeding from stress-induced gastritis by giving IV infusion.
- GERD (gastroesophageal reflux disorder) in about only 50% of patients at low dose.
- Healing of NSAID induced ulcers ONLY if NSAID’s are discontinued.
- Before anesthesia for emergency surgery and during labor to prevent accidental pulmonary aspiration of gastric acids.
What are the side effects of H2-antagonists?
They have few side effects in short term use, those include:
1. Headaches, myalgias (muscle pain), dizziness and diarrhea.
Cimetidine has a few drug-specific side effects that are not found with the other drugs:
1. Bradycardia and cardiac conduction defects can occur when cimetidine is given intravenously.
2. Cimetidine can act as a weak anti-androgenic effect and it also stimulates the production of prolactin, which can lead to gynecomastia, galactorrhea and sexual dysfunctions in males.
3. Cimetidine can pass the blood-brain-barrier, which induces a risk of CNS disturbances in elderly including: lethargy, confusion and hallucinations.
What is the treatment course of H2-antagonists?
Duodenal ulcers: 4-6 weeks
Peptic ulcers: 6-8 weeks
What drugs are found in the M-receptor blockers class? And what are they used for in the GIT?
Pirenzipine, telenzipine, dicyclomine.
These agents decease the basal secretion of HCL by half but are not effective in decreasing stimulatory secretion due to the unseletivity
What are some of the drugs found in the proton pump inhibitor class?
Omeperazole, Esomeperazole, Lansoperazole, dexlansoperazole, pantoperazole, and rabeperazole
What is the MOA of PPI’s?
Proton pump inhibitor act on the final stage of acid secretion, inhibiting the H/k proton pump found on the apical surfaces of the parietal cells from working, the latter catalyzes the removal of hydrogen ions to the outside of the cell in exchange for potassium ions, inhibited, the whole sequence breaks down and the acid secretion is inhibited.
A single dose of 20mg Omeperazole can decrease acid production by 90% over 24hrs.
What are the pharmacokinetics of PPI’s?
- They are stable, lipid soluble drugs.
- All of them are effective when taken orally, 30 minutes to one hour before breakfast or the largest meal of the day, although some can be administered intravenously.
- Their metabolites are excreted in urine and feces.
- They are administered as enteric coated tablets to prevent early degradation via the stomach acids and when they reach the duodenum, their coat is removed.
- Since they are weak bases, they are absorbed in the alkaline environment of the duodenum and then transported to the parietal cells where they exert their action.
- They have a half life of around 1 hour and they reach their plasma peak concentration in about 2-3 hours.
- They have mild anti-helicobacter effects thus can be combined with other antibiotics to eliminate the infection.
- They also inhibit the hepatic microsomal enzyme P450 but not to the degree of cimetidine.
- At standard doses, all PPI’s inhibit acid production by around 90% and this could be irreversible.
