Upper GI pharmacology Flashcards
Prostaglandins have what effects on the epithelial cells vs. parietal cells of the stomach?
• Epithelial - increased mucus and bicarbonate secrtion
○ Cytoprotective
• Parietal cell
○ Inhibit cAMP which in turn down regulates the amount of protein kinases phosph and activating the H+/K ATPase
○ End result is less H+ secretion
• Thus, NSAIDs, which inhibit PG synthesis will lead to increased overall H+ secretion and decreased mucus and bicarbonate secretion to balance out the acidity
What role do antibiotics play in the treatment of upper GI disease?
- Critical role in H pylori infection eradication
- H pylori is associated with 85% of duodenal ulcers
- Antibiotic therapy to reduce rate of recurrence of gastric ulcers with 50-80% success and duodenal ulcers with 90-95% success
- Used as triple, quadruple or sequential therapy for H pylori treatment
What is “quadruple therapy”
• Add bismuth subsalicylte to the antibiotics
• Different antibiotic combo
○ Metronidazole - tetracycline
• Also the PPI is in there OR H2 antagonist
What is “triple therapy”
• In the context of H pylori treatment
• Clarithromycin-amoxicillin
• OR metronidazole (instead of amoxicillin)
• AND PPI
○ The acute ulceration problem is treated by acid suppression
What is sequential therapy for PUD?
• In the context of H pylori infection, which is pretty much the causitive agent for duodenal ulcers
• Amoxicillin + PPI
○ 5 days
• Clarithromycin - Tinidazole
• + PPI for 5 days
• Quadruple and sequential have greater eradication rates than triple by 12% or so
What are the two bolded PPIs?
- Lansoprazole and omeprazole
* Remembe the prazoles
What are the pharmacodynamic properties of PPIs that are important?
- Prodrugs - diffuse into parietal cell before being activated and trapped in the acidic secretory cannniculi
- Irreversible inactivation of the enzyme
- 18 hours is the time to produce new enzyme thus good efficacy throughout the day (though plasma 1/2 life is way less than that)
- Takes 2-5 days to reach maximum intracellular concentration
- Optimum inhibtion is 80%
- Efficacy of all the options in this class are the same at comparable doses
When should PPIs be taken?
- 1 hour before meals on an empty stomach
* Peak plasma concentration should occur with maximal proton pump secretion
How are PPI’s metabolised/eliminated?
• Rapid first pass metabolism via CYP450 enzymes
○ 2C19 and 3A4
• With severe liver disease watch out
• Do problems with normal dosing with renal failure patients
What are the 5 clinical scenarios that PPI use is indicated in?
- GERD
- Peptic ulcer disease
- NSAID-induced ulcers
- Prevention of stress gastritis
- Zollinger-Ellison syndrome
What are the adverse effects of PPIs to be aware of?
• Drug-drug interactions are the main ones
○ CYP450 interaction and potential inhibition of other liver metabolized drugs
○ There is competition, not true induction or inhibition
• In particular, clopidogrel interaction and it won’t be made into active anti-platelet form
What are the bolded H2 receptor antagonists?
• Ranitidine • Cimetidine • Famotidine • Nizatidine ○ All are OTC drugs for acute gastritis
What are the pharmacodynamic properties for the H2 receptor antagonists?
- Mechanism - reversible, competitive block at parietal cell H2 receptors on basolateral membrane
- Less efficacious than PPIs but still get 24 hour secretion down by 70%
- BETTER at blocking nocturnal secretion which is histamine mediated
- This is used for treatment of and healing of ulcers (supression of nocturnal release is key to healing)
What are the pharmacokinetic properties of H2 receptor blockers to know?
• Rapidly absorbed from GI tract
• Some enhancement with food and a small decrease if given with antacids
• Less protein binding than PPIs
• Some hepatic metabolism, but not enough to change dose in liver disease
• Major excretion is renal
○ 1/2 life of 1-4 hours depending on dose
• Must reduce dose in renal impairment
What is the elimination profile of the H2 receptor blockers?
• Some hepatic metabolism, but not enough to change dose in liver disease
• Major excretion is renal
○ 1/2 life of 1-4 hours depending on dose
• Must reduce dose in renal impairment
•
What are the clinical uses for H2 receptor blockers?
• GERD
○ Though PPIs are preferred in severe erosive esophagitis
• Peptic ulcer disease
○ More for the nocturnal suppression and healing of ulcers
○ PPIs are mainline
• Stress-related gastritis
○ Reduced bleeding when given IV
What are the adverse effects seen in H2 receptor antagonist use?
• Generally well tolerated
• Some dizziness, diarrhea, constipation, headache
• Rare
○ CNS dysfunction - mental status changes, Slurred speech, confusion
§ Cimetidine in the elderly with renal impairment and ICU patients
○ Endocrine effects - cimetidine
§ Gynecomastia, galactorrhea, decreased spearm count
○ Blood dyscrasias - cimetidne
○ Reversible liver toxicity with all H2 receptor blockers
What are the drug interactions to be aware of in H2 receptor blocker use?
• Cimetidine inhibits cytochrome P450 oxidative matabolism
○ CYP1A2, 2C9, 2D6, 3A4
• Increase effects and toxicity of other agents
○ Theophylline, warfarin, phenytoin, carbamazepine, ketoconazole, itraconazole, benzos
• Mess with ketoconazole absorption by causing an increase in gastric pH
○ antifungal
What is sucralfate?
- Mucosal protective agent
- Essentially coats the necrotic surface of an ulcer and prevents futher damage
- Sulfated disaccharide aluminum salt
- Prevents pepsin hydrolyzation of mucosal proteins
- Have to give pretty frequently, 2-4 times a day
- Constipation is really the only side effect here
What is misoprostol?
• Prostaglandin PGE1 analog
• Inhibit cAMP, decreasing overall H+ secretion
• Stimulation of bicarb secretion
• Stimulation of mucus secretion
• Rapid oral admin (30 min)
• Also 30min 1/2 life, so 3-4/day dosing
• Major indication for use is NSAID-induced GI ulceration
• Diarrhea and uterine stimulation are side effects
○ Thus can’t use in pregnancy
What are the primary neutralizing ingredients in antacid medicaitons?
• Calcium
○ Don’t use for chronic use, but safe for symptomatic relief
○ Can use as Ca supplement
○ Renal calculi and constipation and hypercalcemia possible with chronic use
• Aluminum
○ Either hydroxide, carbonate or phosphate
○ Widely used
○ Binds phosphate in gut, so used in chronic renal failure
○ Chronic use may lead to CNS toxicity by way of encephalopathy
• Magnesium
• Sodium bicarbonate
○ Potent, effective
○ Systemic effects - Na overload and alkalosis
○ Avoid in - pregnancy, CHF, hypertension, edema, renal failure
Can you use antimuscarinics for upper GI problems?
- Yes, but they aren’t great, and they have nasty side effects within the doses needed for upper GI relief
- Clinidium
- Glycopyrrolate
- propantheline
What are the 5 bolded promotility drugs?
• Erythromycin
○ Agonist at excitatory neural and smooth muscle motilin receptors
• Cisapride
○ Excitatory agonist at neural 5-HT4 receptors (ENS, cholinergic)
• Metoclopramide
○ Antagonist and inhibitory stimulation of presynaptic dopamine receptors
○ Inhibit ach release indirectly
• Neostigmine
○ Inhibits breakdown of ach by inhibiting ache
○ Thus, overall stimulation of motility
• Bethanechol
○ Direct excitatory agonist at M3 smooth muscle receptors
○ Pro-motility
Does direct M3 activation result in increased, coordinated peristalsis?
- Nope. It’s more like overall contaction and motility, but not propulsive
- Tend to increase gastric and pancreatic secretions
- The better way to go is neuronal stimulation or ach release stimulation
