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!
PPI to KNOW
OMEPRAZOLE - Prilosec, 1st PPI
ESOMEPRAZOLE - Nexium (Purple Pill), Active S-isomer of Omeprazole, SAME
LANZEPRAZOLE - Prevacid
Side Effects of PPI
Increased risk of HIP AND THIGH FRACTURES, particularly in women
CYP2C19 inhibition –> relevant for those taking CLOPIDOGREL (anti platelet)
Too little stomach acid can actually predispose to opportunistic infections like C. Diff
ANTACIDS overview
Weak Bases that NEUTRALIZE stomach acid
More for GERD, but can be an adjunct for peptic ulcer disease
SODIUM BICARBONATE
CALCIUM CARBONATE
MAGNESIUM HYDROXIDE
ALUMINUM HYDROXIDE
Sodium Bicarbonate
Same ingredient as in baking soda
Produces highest amt of CO2 of all the antacids
Not used much anymore
Calcium Carbonate
Major ingredient of TUMS –> when it entes the body, broken down to CaCl2, H2O and CO2 after combining with HCl
Rise in serum Ca++ can actually stimulate excessive release of GASTRIN that could secondarily cause acid rebound —> Gastrin increases # of proton pumps on parietal cells, this is NOT WHAT WE WANT, but it is still sold for neutralization!
Magnesium Hydroxide
Milk of Magnesia
Complete antacid that secondarily acts as a LAXATIVE
Aluminum Hydroxide
Major ROLAIDS ingredient
Causes SIGNIFICANT CONSTIPATION
50/50 mixture?
Vast majority of antacids actually COMBINE MAGNESIUM HYDROXIDE and ALUMINUM HYDROXIDE in a 50/50 mixture!!
By pairing a laxative with a constipating compound, we CANCEL OUT THE GI EFFECTS –> only get neutralization!
Symptoms of a Peptic Ulcer?
Sub-sternal, midline, chronic low or high level pain
Acute, HIGH INTENSITY flares
Persistent NAUSEA with loss of APPETITE
Bloating, significant gas
Diarrhea
2 main causes of gastric ulcers?
H PYLORI
PLUS one of the following MITIGATING FACTORS – SMOKING #1, NSAIDS #2
LAC Therapy
Lansoprazole (PPI for pain and healing)
Amoxicillin (Antibiotic to PREVENT RELAPSE)
Clarithromycin (Antibiotic to PREVENT RELAPSE)
How do CYCLOPROTECTANTS work?
In gastric ulcers, there ends up being a CRATER of damage to the mucosal layer
Within the crater, proteins with charged N atoms fill it up
Some cycloprotectants may use this to their advantage –> they contain negatively charged compounds that form ionic bonds with N –> this forms a BARRIER along the epithelium to PREVENT FURTHER DAMAGE and allow rapid surface recovery!!!
What drug acts like that?
SULCRAFATE
Side effect? Constipation (because it is sucrose ALUMINUM sulfate)
Other Cycloprotectant?
MISOPROSTOL
Prostaglandin derivative that activates an inhibitory G protein to DECREASE adenylyl cyclase activity in the parietal cells, thereby DECREASING ACID PRODUCTION
ENHANCES mucous production!
Side effects –> Diarrhea, NEVER GIVE TO PREGGOS because it is an ABORTIFICANT
Current Peptic Ulcer Disease Recommendations?
Use H2 Blocker or PPI for 2 weeks –> if eliminates symptoms, then nothing else needed
If after two weeks they are still in pain –> test for H. Pylori infection (blood, stool, breath tests)
If positive…
COMBO THERAPY –> Bismuth Subsalicylate + Metro + Tetracycline + Ranitidine (PPI)
or
LAC therapy –> LANSOPRAZOLE (PPI) + Amoxicillin + Clarithromycin
Can add ANTACIDS (neutralize) or SULCRAFATE (protect) as adjuncts
Where do NSAID ulcers occur?
Stomach
What is GERD again?
Occurs when there is INCOMPLETE CLOSURE OF THE LES (decreased closing pressure) –> exposes the esophagus to ACID and PEPSIN
Esophagus has none of the protective mechanisms the stomach has, and contains MULTIPLE SENSORY NERVES –> PAIN!!!!! Can feel like a heart attack
HEARTBURN
Chronic GERD can progress to BARRETT’S ESOPHAGUS –> pre-malignant condition that INCREASES THE RISK FOR ADENOCARCINOMA
Thus, need to treat GERD!!!!
Goals of treating GERD
Decrease reflux from the stomach to the esophagus
Neutralize the contents
Enhance esophageal clearance from the stomach
Protect the esophagus from further damage
What can make GERD worse?
Fatty foods Anticholinergics Caffeine Progesterone Chocolates
Greater STOMACH volume will also place more pressure on the LES –> this can occur while laying SUPINE, or from OBESITY/PREGNANCY
Tell patients to AVOID eating large meals, nighttime meals, or fatty foods
SMOKING EXACERBATES GERD –> stimulates VAGUS which INCREASES ACID SECRETION
Drug Therapy for GERD
Start with H2 Blocker or a PPI, as well as an ANTACID
PEPSID COMPLETE = good option = Antacid + H2 blocker combo
Sleep with multiple pillows –> clearance from the esophagus can be helped by gravity
METOCLOPRAMIDE –> cholinergic agonist activity and PROMOTES STOMACH EMPTYING which decreases stimulus for acid secretion (speeds up the process)
Emetic Center
Located in the medulla
Input to the center occurs via the CHEMO-RECEPTOR TRIGGER ZONE in the area postrema which straddles the BBB
Inputs to the center occur through 5HT3 and D2 receptors
Blood-borne emetic agents (drugs - opioids, chemo, cytotoxics, cholinomimetics) can DIRECTLY act on the chemo receptor trigger zone or INDIRECTLY on the stomach and small intestine
EMESIS can also be triggered by higher brain centers (those that utilize memory, fear, dread, anticipation, etc)
There are also VESTIBULAR inputs into the emetic center that underlie MOTION SICKNESS –> this inputs are H1 and muscarinic receptors, so they need different drugs!
EMETIC DRUGS TO KNOW
These are used in patients who have INGESTED POISONS
IPECAC syrup –> contains emetine; has fallen out of favor because of abuse my anorexic/bullemics
APOMORPHINE –> commonly used in the ER for similar reasons; structurally similar to morphine without the euphoria or analgesia; causes NAUSEA/VOMITING (so does morphine!!!); SC injection
ANTI-EMETIC DRUGS
D2 and 5-HT3 Receptor Antagonists
CHLORPROMAZINE –> D2 blocker in the phenothiazine class; given RECTALLY in patient that is vomiting (would throw it up!!), RAPID effect
ODANSETRON –> 5HT3 antagonist used in severe nausea, such as cancer patients after anesthesia
METOCLOPRAMIDE –> Dopamine and 5HT blocking drug –> also a cholinergic agonist and promotes stomach emptying to further combat nausea vomiting
CANNABINOIDS - NABILONE –> Found in marijuana and exert an ANTI-EMETIC effect through their direct inhibition of the EMETIC CENTER –> euphoria, increased appetite
Drugs for MOTION SICKNESS…what receptors?
H1 and Muscarinic!
Drugs for motion sickness?
DIMENHYDRINATE –> H1 receptor blocker
SCOPOLAMINE –> closely related to ATROPINE, can be oral/injectable; also have a PATCH that is slower, but long acting
Side effects = Dry mouth, mydriasis, Photophobia
BENADRYL –> H1 blocker that also causes sedation; Faster onset, shorter duration
Anti-Diarrheal Agents
Diarrhea is a symptom, not a disease!
Signifies EXCESS FLUID in the stool and results in altered stool consistency
When stool moves too QUICKLY through GI, there is not enough time for water to be ABSORBED and ions and results in a LOOSE, WATERY STOOL
Diarrhea often associated with DEHYDRATION and LOW K+
Anti Diarrheals to KNOW
ORAL REHYDRATION –> similar to GATORAGE or PEDIALYTE –> promotes WATER and ION absorption from the GI tract; High osmotic load of the solutions PUSH WATER ACROSS THE GUT via osmosis
NARCOTICS –> decrease peristalsis, increase muscle tone, increase transit time through the GI to allow for more fluid absorption
LAMOTIL –> not used; diphenoxylate + atropine
LOPERAMIDE –> Imodium; often used
How do we treat TRAVELER’S DIARRHEA? Prophylactic antibiotics and pepto-bismol
CONSTIPATION
HARD, DRY STOOLS (not enough water now!) are DIFFICULT TO EXPEL without PAIN
Caused by Sloooooowwww transit through the GI that allows for EXCESSIVE fluid reabsorption
Approach to constipation
Tiered approach –> tell patients to INCREASE FIBER and FLUIDS and EXERCISE MORE
Train patients to NOT ignore their urge to poop; this allows for too much water reabsorption and makes it worse
THERAPY –> aims to INCREASE fluids in the GI lumen allowing for increased bulk of stool; decrease absorption of water and electrolytes from stool hint, gatorade won’t help; INCREASE intestinal mobility
BULKING AGENTS
Psyllium Seeds – metamucil; works by forming a gelatinous mass in the stomach that increases bulk and puts pressure on intestines –> safest, takes longest to work (1-3 days)
SORBITOL
MIRALAX
Irritants that Produce Semi-Fluid Stool
SENNA
CASCARA SAGRADA
CASTOR OIL (Rinoleic Acid)
DIPHENYLMETHANSE
These drugs take about 6-8 hours to produce a bowel movement
Laxatives that cause watery evacuations within 3 hours
SALINES (Mg Citrate) - Magnesium!!
MILK OF MAGNESIA (Magnesium Hydroxide!!! Also an ANTACID!)
These drugs are essentially HYPEROSMOTIC SOLUTIONS that promote copious evacuations of the bowels and are used to prep for colonoscopy
Stool Softeners
COLACE
Make stool easier to expel
Used all the time for patients on narcotics (cause constipation)
