GI PUD/GERD Flashcards
What are the two types of cells present in the gastric pits?
a. Digestive cells (3)
1. Parietal (oxyntic) cells (secrete HCl)
2. Chief cells (secrete pepsinogen)
3. Endocrine cells (ECL, G, D cells)
b. Protective cells (3)
Mucous neck cells (secrete bicarb and mucus→protective barrier to prevent enzyme damage to stomach lining), Superficial epithelial cells, Stem/regenerative cells
What are the 3 stimulators of gastric acid secretion by parietal cells? What pump is responsible for acid secretion by parietal cells?
- Ach→M3-R’s
- Histamine→H2-R’s
- Gastrin→CCKB-R’s
The H+/K+ATPase (HKA) pumps H+ into the GI lumen, in exchange for K+.
What are the two pathways leading to gastric acid secretion by parietal cells?
- Direct pathway→Ach, gastrin, and histamine stimulate the parietal cell, triggering secretion of H+ into the llumen.
- Indirect pathway→Ach and Gastrin stimulate the ECL cell, resulting in secretion of histamine, which then acts on the parietal cell.
What are the 5 key receptors on the parietal cell involved in the regulation of gastric acid secretion, and how do they work?
- CCKB(gastrin)→Gq→PLC→IP3→Ca→HKA
- M3(Ach)→Gq→PLC→Ca→HKA
- H2→Gs→AC→cAMP→PKA→HKA
- Somatostatin→Gi→inhibits AC→decrease cAMP→reduced HKA activity
- Prostaglandin→Gi→inhibits AC→decrease cAMP→reduced HKA activity
Peptic Ulcer Disease (PUD) is ______ and ________?
Chronic (persistent) and Recurrent (it comes back after you treat it)
Difference in the etiologies of Gastric and Duodenal Ulcers in PUD?
PUD=digesting too much or protecting too little
- Gastric Ulcer: normal/reduced acid output, w/ altered/reduced mucosal resistance
- Duodenal: high acid output (esp at night), w/ inadequate bicarb to neutralize the increased acid
Major cause of non-NSAID PUD?
H. pylori infection→>90% of duodenal and 70% of gastric ulcers
Why is H. pylori resistant to the acidic environment of the stomach?
They produce UREASE which converts urea→ammonia(+bicarb)
Dx of H. pylori?
a. Urea Breath Test→tells you if you are currently infected
b. Blood Ab Test→tells you if you have ever been infected, not necessarily that you are currently infected
Other causes of PUD other than H. pylori?
a. NSAIDs (block PG synthesis by COX) (25% of gastric, some duodenal)
b. Cancer (Zollinger Ellison)
c. Other
Is H. pylori carcinogenic?
Yes, it is a Class I Carcinogen b/c it has been associated w/ the development of gastric corpus/antrum adenocarcinomas and MALT lymphomas
5 Classes of Drugs for PUD Rx? What type of regimen is used for management of H pylori infection?
- Antacids
- H2-Receptor Blockers
- Proton Pump Inhibitors (PPI’s)
- Mucosal Protective Agents (Cytoprotectives)
- Antibiotics
A Multi-drug regimen for H. pylori management
3 Goals for the Rx of PUD?
- Relief of Symptoms (antisecretory agents, antacids)
- Healing of Ulceration (PG agonists, Bismuth compounds, Sucrasulfate)
- Eradication of H. pylori in order to prevent recurrence (Abx)
Antacids MoA? (2)
- Weak bases that NEUTRALIZE gastric acid (bind up H+) in the stomach
NaHCO3 + HCl→ NaCl + CO2 + H2O - Goal is to raise pH>4 to prevent activation of pepsinogen to pepsin
Four ingredients used in antacids? Side effects if any?
Antacids come in Hydroxide and Carbonate forms
- Aluminum Hydroxide (constipation) + Magnesium Hydroxude (diarrhea)→usually used in combo so constipation/diarrhea cancel out
- Calcium Carbonate (Tums)→faster H+ neutralizer; can cause gas and acid reflux
- Simethicone-surfactant (basis for burping)
- Alginic Acids (often added to Al/Mg combo)→forms floating gel to prevent regurgitation, usually in anti-reflux antacids
Therapeutic uses of Antacids? (2)
- Simple dyspepsia
2. Adjuncts to primary therapy with H2 blockers or PPI’s
When should antacids be taken? DDI?
a. Should be taken 1 hr and 3 hr after a meal
b. Should also be taken at bedtime (bc of nocturnal secretion)
c. ADE: significant effects on the absorption of other drugs→do not take antacids w/in 1-2 hr of other drugs
What are the four H2 Receptor Antagonists?
- *the “-TIDINE’s”**
1. Cimetidine
2. Ranitidine
3. Nizatidine
4. Famotidine
H2 Antagonists MoA?
a. Competitive inhibitors of H2-R’s that block H2 stimulation by histamine, reducing both volume and H+ concentration of gastric acid secretion
c. They also reduce secretory response to gastrin and Ach due to loss of potentiation
Which phases of gastric acid secretion do H2 blockers inhibit?
They inhibit all phases→ inhibition of basal, food stimulated, and nocturnal gastric acid secretion
T/F: H2 blockers are associated with widespread ADEs? Why or why not?
False, they have minimal side effects b/c specificity for H2 (minimal H1 activity) and secondary importance of H2’s outside the stomach result in infrequent and mild ADEs.
Fundamental difference between the 4 H2 blockers?
Potency (they have equal efficacy but differ in potency)
Which H2 blocker is least potent/has shortest duration?
Cimetidine
Which H2 blocker is most potent/has longest duration?
Famotidine
Which H2 blocker has a unique issue?
CIMETIDINE→potent inhibitor of CYP450s and thus slows metabolism of many drugs. If interactions possible, choose a different H2 blocker.
What are the 5 PPI’s?
- *the “-PRAZOLE’s”**→the MOST POTENT inhibitors of gastric acid secretion
1. Omeprazole
2. Esomeprazole
3. Lansoprazole
4. Pantoprazole
5. Rabeprazole
PPI MoA?
Noncompetitive/Irreversible (covalent) inhibitors of H/K-ATPase Pump:
a. Enteric coating allows release of prodrug in the intestine, where it is stable in the neutral environment
b. B/c lipid soluble, prodrug gets absorbed into blood stream and carried to parietal cells
c. PPI’s then diffuse into secretory canaliculi, where ACIDIC pH causes PROTONATION and trapping of drug near the proton pump
d. Protonated PPI is active and covalently/IRREVERSIBLY binds to HKA pumps, preventing secretion of H+.
Result of PPI action?
Achlorhydria→ALL gastric acid secretion is blocked
Why is it significant that PPI’s are irreversible inhibitors?
They kill/eliminate the pumps they covalently bind to, so in order to return to normal acid secretion, the parietal cell must synthesize new HKA pumps.
Which phases of gastric acid secretion do PPI’s inhibit?
They inhibit all phases because they block the final common pathway of secretion. They are the MOST potent/powerful inhibitors of HCl secretion.
Which two PPI’s can be gotten OTC?
Omeprazole
Lansoprazole
Which two PPI’s are given orally once daily?
Omeprazole
Esomeprazole
They have the longest duration of action
Which PPI is less effective in severe esophagitis?
Lansoprazole
Which PPI is metabolized to a much lower extent by CYPs?
Rabeprazole
Clinical Uses of PPI’s? (3)
- Active PUD (short-term), erosive gastritis
- GERD symptoms, esophageal ulcers
- ZE Syndrome (refractory ulcers)
What are the 3 Cytoprotective Agents (aka mucosal protective agents)?
- Bismuth Subsalicylate (Peptobismol)
- Sucralfate
- Misoprostol
4 Functions of Bismuth Subsalicylate?
- Enhances secretion of mucus and bicarbonate
- Inhibits pepsin activity
- Chelates w/ proteins at base of ulcer→protective barrier against acid/pepsin
- Inhibits H. pylori (bacteriostatic)
2 Uses of Bismuth Subsalicylate?
- Effective adjunct for Tx and prophylaxis of duodenal/gastric ulcers, GERD, and diarrhea
- Tx of traveler’s diarrhea in Mexico
Sucralfate MoA?
Forms sticky, viscous gel that adheres to gastric epithelial cells, protecting them from acid/pepsin
Unique requirement of Sucralfate compared to other cytoprotectives? Why is this important?
It is the only cytoprotective that requires an ACIDIC pH for maximal activity. Therefore, if you neutralize the stomach, it doesn’t work as well (interesting for PUD treatment).
When is Sucralfate taken?
1 hr before meals and at bedtime to promote gastric healing
What is unique use of Sucralfate?
H2 blocker-/PPI-induced Pneumonia in bedridden patients:
a. H2Bs/PPIs alkalinize stomach which re-introduces harmful bacteria to the stomach (alters flora)→aspiration pneumonia.
b. B/c Sucralfate works at acidic pH, it is usually substituted in chronically bedridden patients.
Misoprostol MoA?
Slowly metabolized PGE1 Analog→stimulates mucus and HCO3- production
ADEs of Misoprostol?
Intolerable/poorly tolerable side effects; Diarrhea in 40% of patients
Use of Misoprostol?
a. Cytoprotective effects in patients who MUST use NSAIDs (block PG production)
b. Abortions
What 4 Abx are used for the eradication of H. pylori in the Rx of PUD?
CFAM
- Clarithromycin
- Amoxicillin (effective for G-‘s)
- Metronidazole (effective for obligate anaerobes)
- Furazolidine
Which Abx is contraindicated in patients allergic to penicillin?
Amoxicillin. If pt has penicillin allergy, substitute in Metronidazole or Tetracycline
When is Tetracycline used in the Rx of PUD?
It’s a 2nd line drug used instead of Amoxicillin in patients allergic to penicillin
How are these MD regimens generally put together in the Rx of PUD?
Triple or Quadruple therapy (3-4 drugs)
- PPI (or H2 blocker)
- 2 Abx
- +/- Bismuth salicylate
How are Abx given in the Rx of PUD? Why?
Abx are given as a multi-drug (MD) regimen in order to:
- Decrease the incidence of resistance
- and Increase the efficacy of these drugs
If resistance to Clarithromycin, replace it with what drug?
Metronidazole
How is H. pylori resistance to an Abx determined?
Urea breath test or fecal antigen test
If resistant to bothe Clarithromycin and Metronidazole, use what instead?
Furazolidine
Which Abx must always be given with a second Abx? Why?
Metronidazole b/c H. pylori resistance to Metronidazole is common, so give a 2nd Anx to prevent resistance.
What is GERD?
Condition associated with involuntary regurgitation of gastric contents particularly at night (nocturnal) or when the stomach is full (after eating).
Why is it important to eradicate H. pylori w/ Abx in the Rx of PUD?
If you eradicate H. pylori, recurrence is prevented. If not, recurrence is common
Pathophys leading to GERD?
a. Transient relaxation of LES
b. Incompetence of LES and delayed gastric emptying are common
a & b lead to impaired resistance of esophageal mucosa to injury by acid which results in erosive esophagitis
What two conditions cause a gastric reflux episode to occur in GERD?
- GI contents must be present in stomach and ready to reflux
- The anti-reflux mechanism at the LES is compromised
What two types of drugs are used in the Rx of GERD to improve LES insuffiency?
Condition 2= LES insufficiency/compromise
- Prokinetics (enhance gastric motility)→Metoclopramide
- Anti-secretory agents→H2 Blockers/PPIs
Prokinetic Agent? What do Prokinetics do?
- Metoclopramide
3 Functions/effects of Prokinetic Agents?
They stimulate GI smooth muscle.
- Improve LES tone and competence
- Enhance esophageal clearance
- Improve delayed gastric emptying
MoA of Metoclopramide? (2)
- D2 Receptor blockers→blocks inhibitory effects of dopaminergic signaling on Ach release
- 5HT4-Receptor agonism→increased Ach release
Net: Decreased inhibition of Ach release+ Increased Ach release→Increased Ach release to LES→increased LES tone
Pharmacological effects of Metohlopramide? (4)
Which is the main anti-reflux action of prokinetics?
- Stimulates GI smooth muscle
- Increases amplitude of esophageal contraction
- Accelerates gastric emptying
- Increase LES tone/pressure
Main anti-reflux effect=enhanced gastric emptying (therefore called prokinetics)
ADE of Metochlopramide? What does this mean dosing wise?
Central dopaminergic antagonism leads to TARDIVE DYSKINESIA.
Therefore, they are only prescribed for short time periods (1-2 weeks).
What are the Postural/Dietary therapies for GERD? (5)
These tend to target Condition 1:
- Decrease size of meals (reduces gastric contents) and avoid food before bedtime
- Weight loss
- Elevate head of bed
- Low fat diet
- Avoid Coffee/Peppermint and other agents that decrease LES tone (cause LES insufficiency)
What antisecretory drugs can be used in Rx of GERD?
- PPI’s
2. H2 blockers
How do anti-secretory agents work in the Rx of GERD?
a. Acid suppression relieves symptoms and helps heal esophagitis. (Lots of GERD patients secrete excess gastric acid)
b. They do NOT effect LES pressure, esophageal peristalsis, or gastric emptying. They work because they increase gastric pH.
