Drugs for Peptic Ulcer Disease and GERD Flashcards
GERD Overview
Heartburn is the major symptom
Characterized by ABNORMAL REFLUX OF STOMACH ACID into the ESOPHAGUS
Typically caused by DAMAGE TO THE LES –> damage will reduce the closing pressure between stomach and esophagus –> separation basically non-existent
40% of all adults once a month; 18 million take antacids; 10-20% of the US population seeks medical treatment
RISK FACTORS for Reduced LES Pressure/GERD
Fatty foods Anticholinergics Progesterone Caffeine Chocolates Smoking
Advise patients to elevate their head during digestion, stop smoking, avoid overeating, avoid bedtime meals
Peptic Ulcer Overview
Small defects of the gastric lining that may occur in the stomach or duodenum
GASTRIC ulcers result from a BREACH of the mucous barrier, often due to DRUGS
PEPTIC ulcers result from excessive acid overcoming the protective linings/bicarb secretions of the pancreas –> 10x MORE COMMON
4-10% of women, 10-15% of men, 15-20% healthcare workers!
Pathogenesis of Peptic Ulcers – “Good” vs. “Evil”
Evil = HCl release from PARIETAL cells when food enters the stomach; quite corrosive (pH = 1)
Pepsinogen –> proteolytic enzyme secreted from CHIEF CELLS that’s converted to active pepsin in the presence of hydrogen
Good = Extensive mucous barrier, pancreas-mediated bicarb secretion from DUODENUM to neutralize the acid, Tight Junctions to prevent invasion past the GI lining, Rapid Healing
How do ulcers actually occur?
BREACH in the barrier –> H+ ions travel through the epithelium to stimulate the VAGUS nerve –> pain! –> Vagus provides cholinergic input to ENTEROCHROMAFFIN LIKE cells which promotes the release of HISTAMINE and also the necessary influx of CALCIUM –> Histamine promotes HCl release
H. Pylori Overview
95% of gastritis cases are associated with H. Pylori!!!!
Relapse rate of 70-80% unless H. Pylori complete eradicated, in which case it drops to a 10% relapse rate
Estimated that 20% of the population is infected with H. pylori
H. pylori is HELICAL with a series of FLAGELLA that enable it to navigate and reside between the stomach’s mucous layer and epithelial lining
H. pylori is DESTROYED by stomach acid, but it secretes UREASE to protect itself!! Breaks down urea into CO2 and AMMONIA –> Ammonia serves TWO purposes –> it provides a neutralizing environment for H. Pylori AND breaks down mucous lining!!!! This is how H. pylori predisposes to ulcers
2 main mitigating factors for ulcer formation?
SMOKING SMOKING SMOKING –> nicotine binds ganglionic nerve receptors at the synapse to potentiate the pre/postsynaptic nerve effects (stimulant) –> one of the targeted nerves is the VAGUS, so nicotine enhances HCl release
NSAIDS #2 –> Act by INHIBITING COX enzymes, thus reducing the synthesis of prostaglandins (which normally help with mucous production) –> so taking NSAIDs thins the mucous layer
Goals of Peptic Ulcer therapy
Pain Relief
Promote Healing
Prevent Relapse
Polytherapy often BETTER than monotherapy, which is usually insufficient
FIRST DRUG is ALWAYS an antibiotic for H. Pylori
Drugs for Peptic Ulcer Disease (just classes)
First Drug = Antibiotic for H. Pylori
Next =
ANTACIDS to neutralize HCl
ANTICHOLINERGICS to suppress vagal nerve and decrease HCl
Proton Pump Inhibitors to prevent H+ from traversing the epithelium
H2 Receptor Blockers to lower stomach acid secretion
PROKINETICS which speed up movement of food from the stomach to the small intestine
Role of Gastrin
G cells produce gastrin in the antrum –> stimulates production of histamine in the
enterochromaffin-like cells –> active parietal cells to produce acid
Physiology of Parietal Cells 1, Histamine Receptors
Site of stomach acid production
BASAL SURFACE houses numerous receptors that act via different second messengers to modulate the H+/K+ proton pump on the cell’s apical surface
1) HISTAMINE RECEPTORS –> Remember H1 (bronchospasm, decreased BP, wheal/flare, increased GI motility) NOT part of the parietal cell; instead H2 (increased HR and promote STOMACH ACID RELEASE) are in charge
Enterochromaffin-like cells get stimulated by the VAGUS or BY GASTRIN –> release HISTAMINE –> Binds H2 RECEPTORS –> activate adenylate cyclase –> cAMP formation –> protein kinase activation –> H+/K+ pumps activate (NEEDS Ca2+)
Physiology of Parietal Cells 2, Muscarinic Receptors
When the PSNS is stimulated during digestion, the VAGUS NERVE input stimulates ACh RELEASE –> Binds to MUSCARINIC RECEPTORS of the parietal cells –> this is what causes the necessary Ca++ influx necessary for the H+/K+ pumps to work
PSNS and Histamine Pathway WORK IN UNISON to activate the H+/K+ pump (histamine activates, muscarinic makes it possible) and promote the release of stomach acid
Physiology of Parietal Cells 3, Prostaglandin Receptors
DIRECTLY OPPOSE THE HISTAMINE PATHWAY
By stimulating an inhibitory G-protein, PGs DECREASE adenylate cyclase activity, thereby HALTING cAMP production, thus LOWERING stomach acidity (H+/K+ don’t activate)
So NSAIDs block this pathway!! Thus NSAIDs promote more stomach acid release, predispose to ulcers
PGs ALSO increase the mucous layer!
Drugs for H. Pylori
Original Therapy = BISMUTH SUBSALICYLATE + METRONIDAZOLE + TETRACYCLINE
Bismuth = Pepto Bismol = controls acid secretion and has bactericidal properties, Metronidazole and Tetracycline are both ANTIBIOTICS for H. Pylori
Effective, but caused SIGNIFICANT side effects (black tongue, black tarry stool, can’t take alcohol with Metro)
AMOXICILLIN + CLARITHROMYCIN combination works just as well
Anticholinergics for Ulcers
ATROPINE –> first line until H2 receptor blockers invented
Vagus provides cholinergic input to ECL cells which promote the release of HISTAMINE which binds to H2 receptors to activate H+/K+ pumps; also ACh stimulates the influx of Ca2+ needed for the pump to work
PREVENTING these actions via anticholinergics like ATROPINE stops this acid production
NOT specific for the GI tract, and has plenty of side effects –> photophobia, lack of secretions, urinary retention, increased body temperature, mydriasis (PSNS usually constricts pupil), etc
H2 RECEPTOR BLOCKERS Overview
Overall BULKY drugs that competitively antagonize histamine at parietal cells
Specifically target H2 receptors, so there is no activation of the pumps!
Inhibit the release of stomach acid and lower HR (don’t see the normal effects of sedation, and other H1 blocking effects)
These drugs DECREASE PAIN and PROMOTE HEALING, but they DO NOT PREVENT RELAPSE*
H2 Blockers to Know
CIMETIDINE
RANITIDINE
FIMOTIDINE
CIMETIDINE
CIMETIDINE –> first on market, 2x/d at least, 4-5 hrs, inhibits ~80% of H2 receptors
SIDE EFFECTS
Originally said NONE, BUT –> mental cloudiness and confusion, androgen receptor antagonist (decreased sperm, gynecomastia, tender breasts), CYP3A4 inhibitor, Hepatotoxic Effects (nonpolar, easily crosses membranes and gets to the liver!!)
RANITIDINE
Zantac
Contains a POLAR furan ring, so there is much less liver penetration and the CYP3A4 system is less inhibited
FIMOTIDINE
Pepsid
Even more polar thiazole ring
Proton Pump Inhibitors Overview
FIRST LINE FOR ALLEVIATING PAIN and PROMOTING HEALING
When they are ingested, they are taken to the parietal cell and TRANSFORMED into SULFHYDRYL COMPOUNDS in the stomach’s acidic environment
Resulting molecules have potent –SH groups that INHIBIT the H+/K+ pumps
Normal dose of PPI inhibits 80-90% of the parietal cell proton pumps!!! Last up to 12 hours!
