Upper GIT Drugs Flashcards
Acid Peptic Disorders
Corroding vs Protective factors
- Corroding
- Gastric acid
- Pepsin
- Bile
- Helicobacter Pylori
- Protective
- Secretion of mucus and bicarbonate
- Blood flow
- Mucosal cellular regeneration
- Prostaglandins
GERD becomes pathological when there is … (2)
Macroscopic damage to the esophagus.
AND/OR
Symptoms which reduce quality of life
List the symptoms of GERD
- Heartburn
- Regurgitation
- Water brash
- Dysphagia
list the complications of GERD
- Barret’s esophagus
- Esophageal carcinoma
Peptic Ulcer Disease (PUD) is ____ erosions d/t corroding factors overwhelming protective factors
Peptic Ulcer Disease (PUD) is mucosal erosions d/t corroding factors overwhelming protective factors
Gastric ulcers from NSAID use and epigastric pain is _____ by eating
whereas
Duodenal ulcers from H. pylori infection, epigastric pain ____ by eating
Gastric ulcers from NSAID use and epigastric pain is worsened by eating
whereas
Duodenal ulcers from H. pylori infection, epigastric pain relieved by eating
Describe the complications of peptic ulcer disease
- Can be life-threatening
- upper G.I. bleeding
- gastric/duodenal perforation
- gastric outlet obstruction
Regulation of gastic acid secretion has ____ overlapping mechanisms: (list the 3)
Regulation of gastic acid secretion has redundant overlapping mechanisms: Endocrine, Paracrine, Neural
Describe the image
Two major physiological states of gastric acid production: Basal & Meal stimulated
Antacids are weak ____ obtained without prescription
Antacids are weak bases obtained without prescription
Antacid + HCl → salt + H2O
Therapeutic neutralization of low gastric pH protects esophageal mucosa from reflux corrosion
Time of onset: 5 minutes
Duration of action: 30 mins – 1 hour
Antacids can affect absorption, bioavailability, or urinary excretion of other drugs by ____ gastric and urinary pH or by _____ gastric emptying.
All can cause ____.
Antacids can affect absorption, bioavailability, or urinary excretion of other drugs by increasing gastric and urinary pH or by delaying gastric emptying.
All can cause hypokalemia.
(Antacids)
Aluminum Hydroxide causes ____
Magnesium Hydroxide causes ____
therefore, combined to produce _____
(Antacids)
Aluminum Hydroxide causes constipation
“Aluminimum amount of feces”
Magnesium Hydroxide causes osmotic diarrhea
“Must _g_o 2 the washroom (Mg2+)”
Al and Mg combined to produce no change in bowel movements
Calcium Carbonate is an ____, CO2 causes _____, can lead to metabolic _____, aka ____ syndrome.
Calcium Carbonate is an antacid, CO2 causes belching, can lead to metabolic alkalosis, aka milk alkali syndrome.
describe antacid drug interactions
- Binding/ chelation of many drugs
- Increased gastric pH alters dissolution of weakly charged drugs
-
Decreased absorption of co-administered
- tetracyclines
- fluoroquinolones
- itraconazole
- iron
H2 receptor antagonists suppress _____ and reduce signal transduction for ____ and ____-induced gastric acid production.
H2 receptor antagonists suppress histamine-induced gastric acid secretion, and reduce signal transduction for ACh and Gastrin-induced gastric acid production.
H2 receptor antagonists are highly selective _____ inhibitors at the ____ cell H2 Gs protein coupled receptor
Time of onset: 2.5 hours
Duration of action: 4- 10 hours
_____ develops in 2- 6 weeks
H2 receptor antagonists are highly selective competitive inhibitors at the parietal cell H2 Gs protein coupled receptor
Time of onset: 2.5 hours
Duration of action: 4- 10 hours
Tachyphylaxis develops in 2- 6 weeks
list the H2 Receptor Antagonists
- Cimetidine – prototype with many adverse effects
- Ranitidine, Famotidine, Nizatidine – 2nd generation with no anti-androgenic or CNS adverse effects
describe the effect of H2RAs on Gastric Acid Secretion
- H2RAs strongly suppress basal gastric acid secretion
- Modest effect on meal stimulated secretion
list the H2 receptor antagonist indications
- GERD
- PUD
- Nonulcer dyspepsia
- Prophylaxis against stress-related gastritis
what is the only H2 receptor antagonist with adverse effects
CIMETIDINE
AEs of Cimitidine
- acts as nonsteroidal anti-androgen and prolactin stimulant → gynecomastia, galactorrhea, and male impotence
- Crosses BBB → confusion, dizziness and headaches
- Increases gastric pH → B12 deficiency and myelosuppression (long term use)
-
Potent CYP450 inhibitor increasing serum [] of:
- Warfarin, Diazepam, Phenytoin
______ are the most potent inhibitors of gastric acid secretion → inhibit 90–98% of 24-hour acid secretion
Proton pump inhibitors are the most potent inhibitors of gastric acid secretion → inhibit 90–98% of 24-hour acid secretion
PPIs ____ bind and inhibit the ____ ATPase pump of gastric ____ cells
PPIs irreversibily bind and inhibit the H+-K+ ATPase pump of gastric parietal cells
PPIs suppress the final ____ pathway of gastric acid secretion
PPIs suppress the final common pathway of gastric acid secretion
describe the image
PPIs effectively suppress both basal and meal stimulated gastric acid production
list PPIs
- Omeprazole
- Esomeprazole
- Lansoprazole
- Rabeprazole
- Pantoprazole
list the indications for PPIs
- Patients who fail twice-daily H2RA therapy
- Severe symptoms of GERD that impair quality of life
- PUD
- H. pylori eradication
- NSAID associated ulcers
- Prevention of peptic ulcer rebleeding
- Gastrinoma
- Nonulcer dyspepsia
- Prophylaxis against stress-related gastritis
PPI adverse effects
- Vitamin B12 deficiency – d/t reduced pepsin function
- Increased risk of CAP and C. difficile colitis
- Hypomagnesemia
- Osteopenia – possibly via reduced Ca2+ absorption or osteoclast inhibition
- All PPIs carry an FDA-mandated warning of a possible increased risk of hip, spine, and wrist fractures
- Diarrhea, abdominal pain and headache reported in less than 5% of patients
____ and ____ inhibit CYP450 decreasing metabolism of which drugs?
Omeprazole and Cimitidine inhibit CYP450 decreasing metabolism of Warfarin, Diazepam, Phenytoin
Clopidogrel is a prodrug that requires activation by the hepatic P450 _____ isoenzyme
Clopidogrel is a prodrug that requires activation by the hepatic P450 CYP2C19 isoenzyme
list the drugs that inhibit CYP2C19 and their effect on clopidogrel
(LEO) Lansoprazole, Esomeprazole, Omeprazole inhibit CYP2C19
May reduce clopidogrel activation in some patients
____ and ____ are preferred in persons taking clopidogrel
pantoprazoleor and rabeprazole are preferred in persons taking clopidogrel
H. Pylori is a Gram ____ bacterium, contains ____ and _____ making it highly motile.
It causes inflammatory response, with increased risk of:
H. Pylori is a Gram negative bacterium, contains urease and flagella making it highly motile.
It causes inflammatory response, with increased risk of:
- Peptic ulcer disease (esp. duodenal)
- Gastritis
- Gastric lymphoma
- Gastric adenocarcinoma
H. Pylori eradication triple therapy combines two ____ with a ____, resulting in <15% recurrence
H. Pylori eradication triple therapy combines two antibioticts with a PPI, resulting in <15% recurrence
describe how PPIs promote eradication of H. pylori
- Direct antimicrobial properties
- Raising intragastric pH → lowers minimal inhibitory concentrations of antibiotics needed to clear the organism
Triple therapy for ____ days - which drugs?
Triple therapy for 10-14 days - which drugs?
Clarithromycin + Amoxicillin + PPI
Clarithromycin + Metronidazole + PPI
Quadruple therapy for ___ days - which drugs?
Quadruple therapy for 14 days
Bismuth Subsalicylate + Metronidazole + Tetracycline + PPI
list the mucosal protective agents
- Misoprostol
- Sucralfate
- Bismuth Subsalicylate
Misoprostol is a ____ analog,
binds to EP3 receptor on parietal cells →
stimulates ___ pathway → decreasing _____ secretion
Stimulates ___ and ___ secretion.
Enhances mucosal ____.
Misoprostol is a PGE1 analog,
binds to EP3 receptor on parietal cells →
stimulates Gi pathway (decr. cAMP) → decreasing gastic acid secretion
Stimulates mucus and bicarbonate secretion.
Enhances mucosal blood flow.
Misoprostol is approved for prevention of _______ ulcers in high-risk patients.
Misoprostol is approved for prevention of NSAID-induced ulcers in high-risk patients (NSAIDS block PGE1 production)
Misoprostol AEs/contraindications
- Diarrhea, abdominal pain and/or cramps, occur in 30% of patients
- Contraindicated in pregnancy d/t abortifacient effects
Sucralfate MOA
- Sucralfate: salt of sucrose + sulfated aluminum hydroxide
- Forms viscous paste that binds selectively to ulcers
- (-)charged sucrose sulfate binds (+)charged proteins forming a physical barrier → restricting further caustic damage
- Stimulates mucosal prostaglandin and bicarbonate secretion
Sucralfate clinical use
Limited to the initial management of gastroesophageal reflux disease in pregnancy
Bismuth subsalicylate (BSS) suppresses ____.
Does it have a neutralizing action on gastric acid?
Bismuth subsalicylate (BSS) suppresses H. pylori.
NO neutralizing action on gastric acid.
Bismuth Subsalicylate clinical use
- Quadruple antibiotic therapy of H. pylori-positive ulcers
- Pepto-Bismol is widely used for dyspepsia and acute diarrhea
Bismuth toxicity and contraindications
- Rare
- Metabolite bismuth sulfide causes harmless blackening of the stool → may be confused with gastrointestinal bleeding
- BSS can cause salicylate toxicity in combination with other salicylate products
- Contraindicated in patients with renal failure.
Prokinetic agents MOA
Ideally should act ___ of ACh.
- Enhance coordinated GI motility
- Ideally should act “upstream” of ACh, at receptor sites on the enteric neuron itself, or higher
Why are muscarinic (M1) receptor agonists not currently preferred for treating GI motility disorders?
Activated muscarinic (M1) receptors enhance contractions in a relatively uncoordinated fashion, producing little or no net propulsive activity.
Thus, bethanechol (cholinomimetic agent) and Neostigmine (ACh esterase inhibitor) are not currently preferred for treating GI motility disorders
Erythromycin is an ____. It has ____ effects at the ___ receptor. Rapid down-reguation of this receptor leads to ______→ use is limited to short courses.
Erythromycin is an antibiotic/macrolide. It has agonistic effects at the motilin receptor. Rapid down-reguation of this receptor leads to early tolerance → use is limited to short courses.
Best established indication for Erythromycin
Diabetic gastroparesis
Describe Cisapride
- 5-HT4 Agonist
- 5-HT3 Antagonist
- Direct smooth muscle stimulant
- Was commonly used for gastroesophageal reflux disease and gastroparesis
- No longer available in the U.S. because of its potential to induce serious and occasionally fatal cardiac ventricular arrhythmias
describe Metoclopramide
- 5-HT4 receptor agonist
- Vagal and central 5-HT3 Antagonist
- Dopamine (D2) receptor antagonist
- Effects confined to upper digestive tract
- Increases LES tone
- Stimulates antral and small intestinal contractions
Metoclopramide clinical indications
- Gastroparesis
- Anti-emetic
- Previously used in GERD for symptomatic relief. Acid suppression therapy is far more efficacious/preferred.
Metoclopramide AEs
-
Extrapyramidal effects d/t DA antagonism
- MC in children/young adults, at higher doses
- Galactorrhea → blocks inhibitory effect of dopamine on prolactin release. Rarely seen clinically.
Molecular Targets of the Vomiting Reflex
describe the 2 phases of Chemotherapy Induced Nausea and Vomiting (CINV)
- Acute phase - universally experienced (within 24 hours)
- Delayed phase - affects only some patients (days 2-5)
list drugs to prevent CINV
- Antimuscarinics: Scopolamine
- H1 Antagonists: Diphenhydramine, Meclizine, Cyclizine
- 5-HT3 Antagonists: Ondansetron, Granisetron
- NK1 Antagonists: Aprepitant, Fosaprepitant
- D2 Antagonists: Promethazine, Droperidol
- Corticosteroids: Dexamethasone, Methylprednisolone
- Benzodiazepines: Lorazepam, Alprazolam, Diazepam
- Cannabinoids: Dronabinol
describe Scopolamine
- Antimuscarinic
- Prevention & treatment of motion sickness
- May have some activity in postoperative nausea and vomiting
- Anticholinergic agents are NOT 1st-line DOC for CINV
describe Diphenhydramine, Meclizine, and Cyclizine
- H1 Antagonists for CINV
- Act on vestibular afferents and brainstem
- Useful for motion sickness and postoperative emesis
describe Ondansetron and Granisetron
- 5-HT3 Antagonists
- Ondansetron = prototypical drug of this class
- 5-HT3 receptors are present in several critical sites involved in emesis, including vagal afferents, the STN, CTZ and AP
What is the DOC for prophylaxis against immediate CINV?
5-HT3 receptor antagonists
- Also effective against hyperemesis gravidarum
- Not very effective against:
- Delayed CINV
- Motion sickness
- Well tolerated
describe Aprepitant/Fosaprepitant
- NK1 Antagonists
- Fosaprepitant - Parenteral formulation
- Antagonists of the NK1 receptors for substance P
- Indicated for prophylaxis against delayed CINV, caused by moderate to highly emetogenic drugs
- Given orally in combination with dexamethasone and a 5-HT3 receptor antagonist
Which NK1 Antagonist undergoes extensive CYP3A4 metabolism? What are the affects of this?
- Aprepitant undergoes extensive CYP3A4 metabolism
- may affect the metabolism of warfarin and oral contraceptives
describe Promethazine and Droperidol
- D2 Antagonists
- D2 receptor antagonism at the CTZ
- Antihistaminic and anticholinergic properties effectively treat motion sickness
- Not very effective in CINV
- Potential for adverse extrapyramidal effects
describe Lorazepam, Alprazolam, Diazepam
- Benzodiazepines
- No intrinsic antiemetic effects
- Useful adjuncts d/t sedative, amnesic, and anti-anxiety effects → reduces anticipatory component of nausea & vomiting
- Facilitate GABA-A action in the central nervous system by increasing the frequency of chloride channel opening
- AE: CNS depression and dependence
describe Dronabinol (Δ-9-tetrahydrocannabinol)
- Naturally occurring cannabinoid
- Synthesized chemically or extracted from marijuana plant, Cannabis sativa
- Stimulates CB1 receptors in the brainstem
- Prophylactic agent in patients receiving cancer chemotherapy, when other anti-emetic medications are not effective
Dronabinol AEs
- Marijuana-like “highs”
- Prominent central sympathomimetic activity
- Palpitations, tachycardia, vasodilation, hypotension
- conjunctival injection (bloodshot eyes)
- Paranoid reactions/ thinking abnormalities
- Abrupt withdrawal of dronabinol → an abstinence syndrome (irritability, insomnia, and restlessness)
- Great caution prescribing to persons with substance abuse Hx
