Gastrointestinal Pharmacology Flashcards
What are the two causes of peptic ulcers? – Aggressive factors that contriubute to their developpment?
What are the body’s defense mechanisms against the development of peptic ulcers?
- Causes
- Helicobacter pylori
- Long term use of NSAIDs (indomethacin and ibuprofen)
- Aggressive factors
- gastric acid & smoking (nicotine stimulates gastric acid)
- Defense mechanisms
- mucus
- bicarbonate
- blood flow
- prostaglandins
Describe the control of gastric acid secretion.
- When parasympathetic nervous system is activated (drink food/caffeine)
- increases gastrin level – stimulates ECL cells to
- release histamine – stimulates H2 receptor on parietal cells
- increases intracellular cAMP level
- increases activity of proton/K+ ATP pump,
- which increases gastric acid (HCl) secretion
- increases activity of proton/K+ ATP pump,
- increases intracellular cAMP level
- release histamine – stimulates H2 receptor on parietal cells
- increases release of ACh, which acts on M3 receptor on parietal cells
- increases intracellular Ca2+ level, which increases activity of proton/K+ ATP pump
- which increases gastric acid (HCl) secretion
- increases intracellular Ca2+ level, which increases activity of proton/K+ ATP pump
- increases gastrin level – stimulates ECL cells to
What are the 4 classes of drugs that can decrease gastic acidity?
- H+/K+- ATPase inhibitors
- H2 blockers
- Antacids (weak bases)
- Anticholinergics (not common b/c systemic adverse effects)
What are the PPIs & what is their mechanism of action?
- Drugs
- omeprazole (prilosec, rapine, zegerid)
- Lansoprazole (prevacid)
protom pump inhibitors
- react with H+/K+ ATPase to irreversibly inactivate the enzyme
- lasts lifetime of the pump, so long-lasting
- inhibit both fastign and meal stimulated secretion
Pharmacokinetics of PPIs?
- Prodrugs
- orally administered, absorbed in intestin & activated in parietal cells
- slow onset of action
- bioavailability is decreased by food
- except dexlansoprazole
- Rapid first-pass hepatic metabolism
- CYP2C19
- CYP3A4
Clinical uses of PPIs?
- Peptic ulcer disease: first-line drugs & most widely used
- sever symptomatic GERD
- nonulcer dyspepsia
- Prevention of stress-related mucosal bleeding
- gastric acid hypersecretion: gastrinoma
- Prevent NSAIDS-induced GI side effects
- ie. patients with arthritis
Adverse effects of PPIs?
- well tolerated & relatively safe
- nausea, diarrhea, abdominal pain
- Long-term use
- increase Clostridioides difficle-associated diarrhea
- b/c increased gastric pH
- may reduce plasma Vitamin B12, non-heme iorn, Ca2+, Mg2+ levels
- b/c the reduced release of these components from food due to the increased gastic pH
- increase Clostridioides difficle-associated diarrhea
drug-drug interaction PPIs?
- drugs that the bioavailability is affected by intragastric acidity
- itraconazole
- digoxin
- Esomerprazole and omeprazole: CYP2C19 inhibitors
- interact with
- phenytoin
- diazepam
- theophyline
- clopidogrel
- dosage adjustment
- interact with
What are the H2 Histamine receptor antagonists and what is their mechanism of action?
- Drugs
- Cimetidine (tagamet)
- Famotidine (pepcid)
- ranitidine (Zantac)
- mechanism of Action
- competitively and selectively bind to H2 receptors, therefore reduce histamine-induced acid
- therefore, do not COMPLETELY block gastric acid secretion
Clinical uses H2 receptor antagonists?
- Peptic ulcer disease: first-line drugs & most widely used
- sever symptomatic GERD
- nonulcer dyspepsia
- Prevention of stress-related mucosal bleeding
- gastric acid hypersecretion: gastrinoma
- Prevent NSAIDS-induced GI side effects
- ie. patients with arthritis
Adverse effects H2 receptor antagonist?
- extremely safe. Tolerance develops
- cimetidine: ginds to dihydrotestosterone receptors – exaggerated estrogen effects
Drug-drug interaction of H2 receptor antagonists?
- interact with drugs metabolized by
- CYP1A2
- CYP2D6 and/or
- CYP3A4 (azole antifungal agents)
- affect inhibit first-pass metabolism of ethanol
- except famotidine
What is the mechanism of action of antacids?
- neutralize gastric acid
- Mg2+, Al3+, Na+, and Ca2+ salts are the most common
- very rapid, but short duration of action
clinical uses of antacids?
short-term relief of symptoms, used as-needed basis
adverse effects of antacids?
- constipation (aluminum)
- diarrhea (magnesium)
- altered electrolyte balance
- if you combine both calcium & magnesium can reduce both constipation & diarrhea
drug-drug interactions of antacids?
- affects absorption of some antibiotics
- tetracyclines & fluroquinolones
- separate administration time by several hours
Antibiotics used to cur H. pylori infection-induced peptic ulcer
- First line
- clarithromycin
- amoxicillin
- tetracycline
- second line
- Metronidazole
- if allergic to penicillin
- Refabutin
- if clarithromycin or metronidazole resistance
- Metronidazole
What is the drug name & mechanism of action for colloidal bismuth compounds?
- name
- bismuth subsalicylate (pepto-bismol)
- mechanism of action
- coat ulcer and erosions
- stimulate the secretion of prostaglandin, mucus, and bicarbonate
- antimicrobial effects: bind to bacteria and enterotoxins
- reduced stool frequencey and liquidity
Clinical uses of Bismuth compounds?
- nonprescription: treat dyspepsia dn prevent traveler’s diarrhea
- combined with PPI and antibiotics: H. pylori infection-caused peptic ulcer
Adverse effects & contraindications for bismuth compounds?
- adverse effects
- black tongue and stool
- contraindication
- renal insufficiency and allergies to salicylates
Sucralfate mechanism of action?
- pepsin inhibitor
- activated by acid – treating w/ antacid will decrease efficiency
- Mechanism of action (protect mucosa)
- physical barrier
- inhibit pepsin mediated hydrolysis of mucosal protein
- stimulates mucosal prostaglandin and bicarbonate secretion
Clinical uses of sucralfate?
- prophylaxis of stress gastritis
- peptic ulcer
- ulcers not caused by acid: oral mucositits and bile reflux gastropathy
Adverse effects & drug-drug interactions of sucralfate?
- adverse effects
- may develop constipation due to the aluminum salt
- drug-drug interaction
- may reduce the absorption of some oral medications
- time-lapse is important
Draw this
What is the 3 step treatmetn strategy for H. pylori peptic ulcer?
Provide example of the triple therapy.
Provide example of quadruple therapy.
- elimate the bacteria (antibiotics)
- reduce stomach acid (protom pump inhibitor)
- protect the mucus membrane (bismuth subsalicylate)
- Triple therapy
- PPI-CA: PPI + clarithromycin + amoxicillin
- PPI-CM: PPI + clarithromycin + metronidazole
- penicillin allergy
- PPI + amoxicillin + rifabutin
- clarithromycin or metronidazole resistance
- Quadruple therapy
- Bismuth-based quadruple therapy
- bismuth subsalicylate + mtronidazole + tetracycline + a PPI
- Clarithromycin-based quadruple therapy
- amoxicillin + clarithromycin + metronidazole + a PPI
- Bismuth-based quadruple therapy
What are the therapeutic strategies to treating inflammaoryt bowel disease?
What are the two common inflammatory bowel diseases?
- Therapeutic strategies
- inhibit the inflammatory responses
- suppress immune responses
- Inflammatory boewl disease
- Ulcerative colitis (UC)
- Crohn’s disease (CD)
What is the inflammatory supressor? What is it ised to treat?
Inflammatory bowel
- 5-Aminosalicylates (5-ASA, mesalamine:
- Sulfasalazine: 5-ASA-AZO bond-sulfapyridine
- sulfapyridine can be absorband & causing adverse effects
- Olsalazine: 5-ASA-AZO bond-5-ASA
- Balsalazie: 5-ASA-AZO bound-inert compound
- Sulfasalazine: 5-ASA-AZO bond-sulfapyridine
5-ASA mechanism of action?
- not fully understood
- Thought to inhibit the following:
- IL-1 and TNF-alpha expression
- lipoxygenase pathway
- NG-kB
- reactive oxygen species
Clinical uses of 5-Aminosalicylates?
- induce and maintain remissionof mild or moderate ulcerative colitis (inflammatory bowel disease)
- Rheumatoid arthritis (sulfasalazine)
Adverse effects & drug-drug interactions of 5-Aminosalicylates?
- Adverse Effects
- sulfasalazine
- more adverse effects
- others: well tolerated
- dyspepsia (indegestion)
- skin rash
- headache
- abdominal pain
- rare but serious: nephrotoxicity
- sulfasalazine
- Drug-drug interactions
- fomulations with pH sensitive enteric coatings shouldn ot be co-administerd with anti-acids
- if co-administered with anti-acid drugs, they will not make it to the intestines
What the glucocorticoid/corticosteroids? What are they used to treat?
Used to treat inflammtory bowel disease
- prednisone and prednisolone: oral
- Budesonide
- oral
- synthetic analogue of prednisolone
- extensive first-pass metabolism by CYP3A4 – low bioavailability – les change to cause systemic adverse effects
- Hydrocortisone: enemas, foam or suppositories
Glucocorticoid/corticosteroids mechanism of action?
- Overview
- produced by adrenal glands
- only free form will enter into the cells
- bind to specific receptors
- will dimerize into the nucleus
- bind to glucocorticoid response element in the gene
- effect gene expression & protein expression
- alter cellular function
- effect gene expression & protein expression
- MOA
- inhibit expression inflammatory mediators
- increase expression of antiinflammatory mediators
Clincal uses of glucocorticoid/corticosteroids?
- Budesonide
- induce remission in mild adn moderate IBD
- Prednisone and prednisolone
- induce remission and control acute moderate to severe active IBD
- more potent than 5-ASAs
Adverse effects and drug-drug interactions with glucocorticoid/corticosteroids?
- Adverse Effects
- prolonged use (except budesonide) can cause lots of adverse effects adn the drugs have to be tapered gradually when discontinuing
- mood changes, fluid retention, increased appetite and glucose level
- increase chances of infection, peptic ulcers, osteoporosis, glaucoma, and cataract
- High dose:
- hypothalamic-pituitaty-adrenal axis suppression
- temorarily show growth rate in children
- prolonged use (except budesonide) can cause lots of adverse effects adn the drugs have to be tapered gradually when discontinuing
- Drug-drug ineractions
- budesonide interacts wtih CYP3A4
