Week 8: Peptic Ulcer related Drugs Flashcards
What is the cause of most acid-peptic disease (PUD, GERD and mucosal injury)?
Mucosal erosion or ulceration
An imbalance of what two factors causes erosion or ulcerations?
Acid, pepsin or bile overwhelm the defensive factors of the GI mucosa – an imbalance between aggressive and defensive factors
What are the two primary causes of an imbalance between aggressive and defensive factors?
H.pylori (causes 90% of peptic ulcers)
NSAIDS (inhibit prostaglandins)
What are two general ways in which drugs can treat acid-peptic disorders?
Drugs that reduce intragastric acidity
Drugs that promote mucosal defens
What are the 3 drug classes that reduce gastric acidity?
Antacids, H2-Receptor Antagonists, PPIs
List some agents that promote mucosal defense
Sucralfate, Prostaglandin analogs, bismuth compounds
How do antacids work?
Antacids are weak bases that react with gastric hydrochloric acid to form a salt and water
What are some antacid options?
Sodium bicarbonate
Calcium carbonate
Magnesium hydroxide
Aluminum hydroxide
What are some side effects of the different antacid options?
Sodium bicarbonate – reacts rapidly with HCl to produce carbon dioxide and sodium chloride = gastric distention and belching
Calcium carbonate – slower reaction, may cause belching or metabolic alkalosis
**excessive doses of either sodium bicarb or calcium bicarb products with dairy products can lead to hypercalcemia, renal insufficiency and metabolic alkalosis (milk-alkali syndrome)
Magnesium hydroxide – can cause osmotic diarrhea
Aluminum hydroxide – can cause constipation
** both drugs react slowly with HCl to create magnesium chloride or aluminum chloride and water. Often given together to counteract GI side effects
What are the pros and cons of antacid use?
Rapid acid neutralization
Short duration – usually 1-2 hours
Doesn’t solve the root of the problem, provides short term relief
Name some H2 receptor antagonists
There are 4: cimetidine, ranitidine, famotidine, nizatidine
True or false: H2 receptor antagonists are poorly absorbed
False: all four drugs are rapidly absorbed from the intestine. Nizatidine has minimal first-pass metabolism, the other 3 drugs undergo first-pass metabolism with a bioavailability of 50%
How do H2 receptor antagonists work?
By competitively inhibiting the parietal cell H2 receptor and suppressing basal and meal stimulated acid secretion
Reduce acid secretion stimulated by histamine and by gastrin and cholinomimetic agents – histamine release is blocked by binding to the parietal cell H2 receptor and direct stimulation of the parietal cell by gastrin or acetylcholine has a diminished effect on acid secretion in the presence of H2 receptor blockade
T/F: H2 receptor antagonists are highly selective for only gut H receptors
True, do not effect H1 or H3 receptors
At usual prescribed doses, what percentage of acid-secretion is inhibited by H2 receptor antagonists?
60-70% of total 24 hour acid secretion is inhibited
True or false: dose reduction of H2 receptor antagonists is required in renal insufficiency
True: cleared by a combination of hepatic metabolism, glomerular filtration and renal tubular secretion
T/F: H2 receptor antagonists are typically prescribed once daily
False: acid inhibition typically lasts for 10 hours, so H2 receptor antagonists are generally prescribed BID
Fun fact: H2 receptor antagonists are specifically effective for inhibiting nocturnal acid secretion which depends largely on histamine, not as useful for meal stimulated acid secretion
T/F: PPIs are inactive prodrugs
True
T/F:PPIs are absorbed in the acidic environment of the stomach
False: Oral meds are acid-resistant delayed release enteric-coated formulations. After passing through the stomach to the alkaline intestinal lumen the enteric coatings dissolve and the prodrug is absorbed
Describe the chemical properties and distribution of PPIs
PPIs are lipophilic weak bases. After intestinal absorption, they diffuse readily across lipid membranes into acidified compartments. Prodrug rapidly undergoes molecular conversion to the active form – a reactive thiophilic sulfenaminde cation
What is the action of PPIs (what does their binding cause)?
Irreversibly inactivate H+K+ATPase
What is the result of inactivation of H+K+ATPase?
Inhibits both fasting and meal-stimulated secretion by blocking the final common pathway of acid secretion, the proton pump
Name some PPIs
Omeprazole, esomeprazole, lansoprazole, dexlansoprazole, rabeprazole, pantoprazole
Few clinical differences between drugs
What are some conditions that PPIs are indicated for?
GERD, PUD (h.pylori and NSAID associated ulcers), non-ulcer dyspepsia, prevention of stress-related mucosal bleeding, gastrinona and other hypersecretory conditions
What are some adverse effects of PPIs
Diarrhea, headache, abdominal pain, acute interstitial nephritis, B12 deficiency, increased risk of fracture related to calcium absorption interruption, gastric bacterial or fungal infection
What about PPIs might cause drug reactions?
Decreased gastric acidity may alter absorption of drugs for which intragastric acidity affects drug bioavailability
Drugs this may effect: ketoconazole, itraconazole, digoxin, atazanavir
Also – PPIs are metabolized by hepatic P450 cytochromes so have potential to be inhibitors of other substances or enhance their metabolism.
What does sucralfate do?
In water or acidic solutions sucralfate forms a viscous, tenacious paste that binds selectively to ulcers or erosions for up to 6 hours
Breaks down into sucrose sulfate and an aluminum salt
Used to reduce the incidence of clinically significant upper GI bleeding in critically ill patients
What about sucralfate might cause drug reactions?
May bind to other medications and impair their absorption
What is an example of a prostaglandin analog drug?
Misoprostol
What is misoprostol used for (in GI)?
Can reduce the incidence of NSAID-induced ulcers to less than 3% and the incidence of ulcer complications by 50%
What are the GI effects of misoprostol?
Has acid inhibitory and mucosal protective properties – stimulates mucous and bicarbonate secretion and enhances mucosal blood flow
Pharmacokinetic specifics of misoprostol
With oral administration, rapidly absorbed and metabolized to a metabolically active free acid
Half life less than 30 mins – so dosed 3-4 times/day
Excreted in urine, but dose reduction not needed in renal insufficiency
T/F: Bismuth compounds are available in two forms, both are OTC medications
False: bismuth subsalicylate is non-prescription/OTC, bismuth subcitrate potassium is prescription
bismuth subcitrate potassium is available in a combination prescription format which also includes metronidazole and tetracycline for the treatment of which condition?
H.pylori infection
Bismuth subsalicyclate undergoes rapid dissociation in the stomach – what happens to the components?
The salicylate is absorbed, 99% of the bismuth appears in the stool, but it can be stored in many tissues and has slow renal excretion
What are the effects of bismuth?
Coats ulcers and erosion, creating a protective layer against acid and pepsin
May also stimulate mucus and bicarbonate secretion – MOA not known
Also has direct antimicrobial activity against H.pylori (How?)
What are some names of bismuth compounds?
Pepto-bismol
Kaopectate
What are some uses of bismuth compounds?
Nonspecific treatment of dyspepsia and acute diarrhea
Preventing traveler’s diarrhea
Used in four-drug regimens for eradication of H. pylori
What are bismuth side effects?
Excellent safety profile
Harmless blackening of stool
Liquid formulation can cause harmless darkening of the tongue
Prolonged use may lead to toxicity resulting in encephalopathy
