EXAM #1: GI PHARMACOLOGY Flashcards
What factors are secreted by parietal cells in the stomach?
- HCl
- Intrinsic factor
Where are parietal cells located in the mucosa?
Gastric pit
What is the function of HCl produced by the parietal cells? What about intrinsic factor?
HCL
- Protein digestion
- Sterilization
- Nutrient absorption
IF
- Vitamin B12 Absorption
What cell type secretes mucous and bicarbonate in the stomach?
Superficial epithelial cells
What are the “gastroprotective” secretions of the stomach?
Mucous and bicarbonate
What cell type secretes histamine in the stomach?
ECL
What is the function of histamine in the stomach?
Promotion of HCl secretion
What is the source of Gastrin in the stomach?
G-cells
What is the function of Gastrin in the stomach?
Gastrin promotes the secretion of HCl
What is the endocrine mechanism that increases gastric acid secretion?
Gastrin
1) Gastrin is secreted into the BLOOD via G-cells of the stomach
2) Gastrin can then mediate acid secretion via direct and indirect mechanisms:
- Direct= stimulate parietal cells to secrete H+
- Indirect= stimulate ECL cells to secrete histamine, which eventually increases acid secretion
What is the paracrine mechanism to increase gastric acid secretion?
Histamine
- Histamine is released from ECL cells onto neighboring parietal cells, stimulating acid secretion
What is the effect of prostaglandins on acid secretion in the stomach?
This is the PARACRINE mechanism to negatively regulate the H+-K+ ATPase
What are the two ways that prostaglandins are gastroprotective?
- Negative regulation of the H+-K+ ATPase
- Promotes the secretion of mucous and bicarbonate from gastric epithelial cells
What cells release somatostatin? What is the function of somatostatin?
D-cells release somatostatin, which:
1) Inhibits gastrin release from G-cells
2) Inhibits histamine release from ECL cells
3) Inhibits H+-K+-ATPase activity
What are the two most common causes of ulcers in the US?
1) NSAIDs
2) H. pylori infection
How do NSAIDs lead to the development of peptic ulcers?
Cycloxygenase that leads to decreased prostaglandin synthesis
What are the hallmark symptoms of a gastric ulcer (7)?
1) Abdominal pain–exacerbated by meal
2) Nausea
3) Vomiting/ hematemesis/ coffee ground emesis
4) Melena
5) Indigestion
6) Weight loss
7) Fatigue
What is the therapeutic goal of antacids?
Neutralize gastric acid by raising the pH greater than 4
How do antacids work?
Base + Acid= Salt + Water
Sometimes these can produce CO2–note that there is NOT a target receptor for antacids, simple acid/base chemistry.
List the common antacids in order of the rate of reactivity.
1) Sodium bicarboante- fast
2) Calcium carbonate- medium
3) Magnesium hydroxide- slow
4) Aluminum hydroxide- slow
What is the duration of action for antacids? Why is this clinically relevant?
- Duration of action is 1-2 hours
- B/c of this short duration, they have to be taken often
- Frequency leads to lower compliance
What are the common adverse effects of antacids?
- Reduced drug bioavaliablity- changes in pH will alter the availability of drugs
- Greater risk of enteric infection
Why do antacids increase risk of enteric infection?
Raise in pH prevents acidic destruction of microograngisms
What are the specific adverse effects of Sodium Bicarboante?
1) Metabolic alkalosis
2) Excessive NaCl absorption
3) Gas/bloating
What are the specific adverse effects of Calcium Carbonate?
1) Gas/ bloating
2) Acid rebound
What is acid rebound?
- pH increases in stomach
- homeostatic mechanisms promote acid secretion
What antacid produces the most acid rebound?
Calcium Carbonate
What are the specific adverse effects of Magnesium Hydroxide?
Osmotic diarrhea b/c there is a large amount of salt retained in the lumen of the gut
What are the specific adverse effects of Aluminum Hydroxide?
Constipation b/c aluminum will DECREASE peristalsis
What two antacids are commonly seen together? Why?
Magnesium hydroxide and Aluminum hydroxide b/c they have opposing side effects i.e. osmotic diarrhea and constipation respectively
List the indications for antacids.
1) GERD
2) Peptic ulcers
3) Dyspepsia
How does the efficacy of antacids compare to H2 receptor antagonists to heal GERD and Peptic Ulcers?
Same but you have to take antacids more often
Describe the mechanism of action of H2 receptor antagonists.
- Competitive inhibition of H2 (histamine) receptors
- Leads to a DECREASE in gastrin-induced HCl secretion
- Partial block of muscarinic HCl secretion
This blocks the INDIRECT effects of Gastrin on acid secretion, but NOT the DIRECT effects of gastrin
What is the suffix that is common to all H2 receptor antagonists?
“Idine”
List the H2 receptor antagonists.
Cimetidine
Ranitidine
Nizatidine
Famotidine
What is the duration of H2 receptor antagonists?
6-10 hours
Note that this is much longer than antacids
What is the common adverse effect of H2 receptor antagonists?
Headache
What are the specific considerations that need to be taken into account when prescribing Cimetidine?
1) CNS effects
2) Endocrine effects
3) Inhibition of CYP metabolism i.e. potential for drug interaction
What are the adverse CNS effects Cimetidine?
- Confusion
- Hallucinations
- Agitation
What are the adverse endocrine effects Cimetidine?
- Inhibition of androgen receptors
- Inhibition of estradiol metabolism
- Increased prolactin level
- Produce gynecomastia in males
List the indications for H2 receptor antagonists.
1) GERD
2) Peptic Ulcers
3) Dyspepsia
4) Gastritis
What is important to remember about H2 receptor antagonists and their onset of action?
Must be ABSORBED first
What is the mechanism of action of PPIs?
- Inhibit the proton pump
- Inhibit the effects of
1) Gastrin
2) Histamine
3) ACh
Describe the absorption and mechanism of the PPIs.
1) Absorbed
2) Circulates
3) Concentrates on the proton pump via transport form the basolateral membrane
4) Antagonizes the proton pump
What type of antagonists are the PPIs?
Irreversible
I.e. activation of the pump requires new synthesis
What is the common suffix among the PPIs?
Azole
List the PPIs.
Omeprazole Lansoprazole Rabeprazole Esomeprazole Pantoprazole
How long does it take to get the max dosing effect of the PPIs? Why?
3-4 days
- Proton pumps are made in parietal cells and sequestered in vesicles
- Upon stimulation, the pumps are inserted into the apical membrane
- It takes 3-4 days to exhaust all the vesicles
- B/c proton pumps only work at apical membrane, it takes 3-4 days for maximum effect.
What are the common adverse effects of PPIs?
1) Decreased drug bioavaliablity
2) Diarrhea
3) Headache
4) Abdominal pain
What are the adverse effects that can be seen with chronic PPI therapy?
- Decreased nutrient absorption i.e. B12, iron, Ca++, and zinc
What types of infections are hospitalized patients more likely to have on a PPI?
- Enteric infection
- Respiratory infection
What are the indications for PPIs.
1) GERD
2) Peptic ulcers
3) Dyspepsia
4) Gastritis
5) Hypersecretory disease
6) NSAID-ulcers
7) H.pylori ulcers
What class of drugs is the most efficacious inhibitors of acid secretion?
PPIs
List the gastroprotective drugs.
Sucralfate
Misoprostol
Bismuth
What is the mechaism of Sucralfate?
1) Adheres to the ulcer and creates a physical barrier
2) May stimulate mucus secretion
What is the mechanism of bismuth subsalicylate?
1) Adheres to the ulcer and creates a physical barrier
2) May stimulate mucus secretion
What is the mechaism of action of Misoprostol?
Prostaglandin analog
What are the functions of ACh in the stomach?
BOTH protective and aggressive:
1) Promote mucous and bicarbonate secretion
2) Promote HCl secretion
What are the common adverse effects of sucralfate?
- Constipation
- Impaired drug absorption
What patient population requires prescribing Sucralfate with caution?
Renal insufficient
This is b/c the drug contains some Aluminum, which can be toxic in patients with renal insufficiency
What are the common adverse effects of Misoprostol?
Cramping
Diarrhea
This is b/c as a PG inducer, it increases smooth muscle contraction, leading to cramping and diarrhea.
What is the serious adverse effect of Misoprostol?
Abortificient– INDUCES ABORTION
Do NOT give to women of childbearing age, and especially not PREGNANT women–induces uterine contractions
What is the common adverse effect of Bismuth subsalicylate?
Blackening of the stool and tongue
What is the serious adverse effect of Bismuth subsalicylate?
High does of salicylate toxicity
How do the effects of Bismuth subsalicylate differ in the stomach and intestines?
- Increase PG synthesis in stomach
- Block PG synthesis in intestines
Generally, when are mucosal protective indicated?
As a 2nd line agent to PPIs
What are the specific indications for Sucralfate?
- Stress related ulcers
- Hospitalized patient when you DON’T want to prevent acid secretion (risk of enteric infection/ respiratory infection)
What is the specific indication for Misoprostol?
NSAID associated ulcers
What is the specific indications for Bismuth subsalicylate?
1) H. pylori ulcers
2) Traveler’s dirrhea
3) Dyspepsia
Explain the etiology of H.pylori associated ulcers.
- Bacteria colonizes the mucusal epithelium of the stomach
- Causes damage at the site of colonization and leads to tissue breakdown i.e. ulcer
Aside from ulcers, what more serious diseases is H.pylori associated with?
1) Gastric lymphoma
2) Gastric adenocarcinoma
What is the first line, “new triple therapy” for treating H. pylori?
1) PPI
2) Clarithromycin
3) Amoxicillin or metronidazole (PCN allergy if patient cannot take amoxicillin)
I.e. the strategy is to decrease gastric acid and administer antimicrobial agents
Why are two antibiotics given with H. pylori infection?
H. pylori has a very high level of drug resistance–giving one antibiotic may lead to the induction of a very resistant strain
What is the old triple therapy for H. pylori?
- Bismuth subsalicylate
- Tetracycline
- Metronidazole
What is quadruple therapy?
1) PPI
2) Clarithromycin
3) Amoxicillin or metronidazole (PCN allergy if patient cannot take amoxicillin)
+ Bismuth subsalicylate
