GI Drugs Flashcards
What is the most common secretory disorder of the GI tract?
acid-peptic disease
What disorders are included in the diagnosis of acid-peptic disease?
- peptic ulcer disease
- GERD
- other hypersecretory states like Zollinger-Ellison syndrome
What are the three goals when treating acid-peptic disease?
- relieved pain
- promote healing
- prevent recurrence
What two classes of drugs are available for down-regulating gastric acid secretion? Which is used more often and why?
- H2 blockers are used most often because they block several pathways that promote secretion
- anti-muscarinics are used as adjuncts to other therapies because they are relatively weak inhibitors of acid secretion
Which cells actually secrete gastric acid? What initiates this?
- parietal cells release acid in response to histamine binding their basolateral surface
- binding induces a rise in cAMP, which activates a H/K-ATPase on the luminal surface
How is gastric acid secretion regulated?
- dietary peptides and parasympathetic activity active G cells in the duodenum
- these cells release gastrin into the blood which then triggers release of histamine from ECL cells in the fundus of the stomach
- histamine and gastrin active parietal cells, inducing acid release
- additionally, parasympathetic activity directly stimulates parietal cells
- acid levels rise and active D cells in the duodenum, which then release somatostatin onto G cells, impairing their release of gastrin, serving as a feedback mechanism
Proton Pump Inhibitors
- a group of drugs that irreversibly inhibit the parietal cell H/K-ATPase, limiting gastric acid secretion
- they are pro-drugs, inactive at neutral pH and unstable at low pH
- as such, they are taken with food which stimulates acid release for activation and they are supplied as enteric coated granules that dissolve only at alkaline pH
- after passing through the stomach, the enteric coating dissolves, the pro-drug is absorbed, carried to parietal cells, and accumulates in secretory canaliculi where the pH is acidic, and there, they bind the H/K-ATPases
Describe the activation of PPIs.
- drugs ending in “-prazole”
- the most effective drugs for suppressing gastric acid secretion
- once daily dosing is effective at reducing acid secretion without affecting pepsin secretion or gastric motility
- promote healing and prevent ulcer recurrence; often effective in those unresponsive to H2 agonists
- more effective than H2 antagonists against GERD and NSAID-induced peptic ulcers
- well-tolerated with mild side effects: GI (nausea, diarrhea, colic, flatulence), CNS (headache, dizziness), and skin rashes
- diarrhea often occurs with prolonged use because of bacterial overgrowth at higher pH
- they are pro-drugs, inactive at neutral pH and unstable at low pH
- as such, they are taken with food which stimulates acid release for activation and they are supplied as enteric coated granules that dissolve only at alkaline pH
- after passing through the stomach, the enteric coating dissolves, the pro-drug is absorbed, carried to parietal cells, and accumulates in secretory canaliculi where the pH is acidic, and there, they bind the H/K-ATPases
- they are irreversible inhibitors, so inhibition persists after withdrawal of the drug
- metabolized in the liver with little renal clearance
If PPIs are dependent on a low pH for activation, and their action is to reduce acid secretion, how do they remain effective with chronic use?
they function within intracellular canaliculi of parietal cells, which is upstream from the proton pump target at the luminal membrane
How do PPIs compare to H2 antagonists?
- PPIs are usually effective when patients are unresponsive to H2 antagonists
- PPIs are also more effective for GERD and NASI-induced peptic ulcers
- PPIs inhibit 90-95% of acid secretion while H2 blockers inhibit 60-70% over 24 hours
- PPIs don’t inhibit pepsin secretion, but H2 blockers do
H2 Receptor Antagonists
- a group of drugs used to inhibit gastric acid secretion ending in the suffix “tidine”
- they are histamine analogs that block H2 receptors on parietal cells, diminishing release of gastric acid and pepsin
- effective at inhibiting acid secretion for up to 6 hours when OTC or 24 hours when prescription
- most effective against nocturnal acid secretion, which is largely drive by histamine
- given once daily at bedtime, they have a healing rate of 80-90 percent after 6-8 weeks; but declining use
- well-absorbed, rapidly acting, well-tolerated
- side effects include diarrhea, headaches, fatigue, myalgia, constipation, and bradycardia
- IV administration may cause confusion, hallucinations, or agitation if patients are elderly or have renal/hepatic dysfunction
- cimetidine has endocrine effects as well because it binds inhibits DHT binding to androgen receptors, inhibits estradiol metabolism, and increases serum prolactin; may cause gynecomastia or impotence in men, galactorrhea in women
- famotidine > nizatidine = ranitidine > cimetidine (across a 50-fold range)
- not given to pregnant or nursing women as they cross the placenta and enter milk
- interferes with P450 pathways
How do OTC H2 blockers compare to prescription ones?
OTC inhibit acid secretion for up to 6 hours while prescriptions inhibit 60-70% of acid secretion over a 24 hour period
Which ulcers are PPI particularly effective against?
- those refractory to H2 blockers
- NSAID-induced ulcers
H2 blockers are particularly effective against what kind of acid secretion?
nocturnal secretion, which is largely driven by histamine
What side effect of cimetidine is unique amongst the H2 blockers?
- it has endocrine effects - may cause gynecomastia or impotence in men and galactorrhea in women
- elevates serum prolactin, inhibits DHT binding to androgen receptors, and inhibits estradiol metabolism
How are H2 blockers used clinically? How are they prescribed?
- prescribed as 1x daily dosing to be taken at bedtime
- produce ulcer healing in 80-90% of cases after six to eight weeks
Why is H2 blocker use declining?
due to discovery of PPIs and knowledge about the role H. pylori plays in peptic ulcer disease
Why can’t you combine PPIs with H2 blockers?
because the H2 blockers inhibit activation of the PPIs in parietal cell canaliculi
Antacids
- a group of weak bases that neutralize gastric acid, forming salt and water
- may also provide some mucosal protection by stimulating prostaglandin synthesis
- inactivates pepsin as well
- preparations include aluminum or magnesium hydroxide alone or in combination with sodium bicarb or a calcium slat
- seldom used due to the advent of more convenient and effective drugs
- antacid tablets are generally weak and needed in large numbers before having a small effect on active peptic ulcers
- single dose given 1 hour after eating increases pH for 2 hours, second dose given 3 hours after eating extends the effect for 4 hours
- most common adverse effects are diarrhea for magnesium and constipation for aluminum
- may interfere with the absorption of other drugs
What are the most common side effects of antacids?
- diarrhea for magnesium
- constipation for aluminum
Through what mechanism do mucosal protective agents treat peptic-acid disease?
they ofter a protective coating on peptic ulcers that limits exposure to acid and pepsin, which permits healing
What are the three primary mucosal protective agents that are used for peptic-acid disease?
- sucralfate
- misoprostol
- bismuth subsalicylate
Sucralfate
- a mucosal protective agents
- polymerizes in an acid environment to produce a viscous, sticky gel that selectively binds and protects ulcer craters
- effective in healing duodenal ulcers
- poorly absorbed systemically, so it has few adverse effects; most common side effect is constipation
- requires acid pH for activation and should not be given with a drug that inhibits acid secretion like PPIs or antacids
Misoprostol
- a mucosal protective agent
- an analog of PGE2 that binds PG receptors on parietal cells to inhibit acid secretion
- used to prevent NSAID-induce ulcers since NSAIDs inhibit PG formation
- most frequent side effects are diarrhea and abdominal pain
- may cause abortion by stimulating uterine contractions
Bismuth Subsalicylate
- aka Pepto-BIsmol
- it is a colloidal bismuth that offers a protective coating to ulcers and is an antibacterial against H. pylori
- minimal adverse effects but will darken tongue and stools as the bismuth sulfide forms a black solid
- OTC use estimated at 60% of American households
- also used for the management of infectious diarrhea by inhibiting intestinal secretions
H. pylori
- a gram-negative bcteria
- causes inflammatory gastritis that may lead to peptic ulcers
- treatment requires triple therapy for 10-14 days: clarithromycin, amoxicillin, and a PPI
How is H. pylori treated?
triple therapy of:
- clarithromycin
- amoxicillin
- PPI
What causes most gastric ulcers?
not acid but actually an H. pylori infection
On a western diet, what is a typical frequency for bowel movements?
at least 3 times per week
How is constipation defined?
it is a motility disorder that may refer to:
- decreased frequency
- difficult initiation or passage
- passage of from or small-volume stools
- feeling of incomplete evacuation
Who is likely to abuse laxatives?
patients with eating disorders who want to lose body weight
Why are laxatives usually unnecessary in the treatment of constipation?
because it can usually be resolved by increasing water or fiber content in the diet, appropriate bowel training, improved physical activity or exercise, and attention to psychosocial/emotional factors
Saline Laxatives
- non-absorbable salts containing magnesium cations or phosphate anions
- used to relieve constipation
- being non-absorbable, they act by osmotic force to hold water inside the intestines; this distends the intestines and stimulates peristalsis
- usually combined with a citrus juice because they have an intensely bitter taste
- well-tolerated but avoid in those with renal insufficiency, heart disease, or electrolyte imbalance or who are using a diuretic
Glycerin Laxative
- used to relieve constipation
- acts as a lubricant and hygroscopic agent (improves water retention in the bowel, stimulating peristalsis)
What do glycerin, lactulose, sorbitol, and mannitol all have in common?
they are non-digestible sugars and alcohols used to relieve constipation as hygroscopic agents
How do lactulose, sorbitol, and mannitol relieve constipation?
- they are non-absorbable sugars
- they get hydrolyzed to organic acids, acidify the luminal contents, draw water into the lumen, and increase colonic propulsive motility
List six osmotically active laxatives.
- saline laxatives (magnesium citrate or sodium phosphate)
- glycerin
- lactulose
- sorbitol
- mannitol
- PEGylated-electrolyte solutions
PEG-Electrolyte Solutions
- osmotically active laxatives
- poorly absorbed and retain added water by their high osmotic pressure
- found as mixtures of sodium sulfate, sodium bicarb, sodium chloride, and potassium chloride in isotonic solution containing 60g of polyethylene glycol per liter
What laxative is used for colonoscopy preparation?
3-4 liters of PEG-electrolyte solution over 3-4 hours
How do stimulant or irritant laxatives relieve constipation?
they act directly on enterocytes, enteric neurons, and muscle to produce a low-grade inflammation that causes water and electrolytes to accumulate in the luminal space, increasing intestinal motility
Bisacodyl
- a diphenylmethane derivative used as an irritant laxative
- available as an enteric coated tablet taken at bedtime to take effect the next morning
- swallowed without chewing to avoid activation in the stomach as this might cause gastric irritation and cramping
Ricinoleic Acid
- aka castor oil
- it is an irritant laxative that increases intestinal secretion and motility
- seldom used because of it’s unpleasant taste and toxic potential
Anthraquinones
- irritant laxatives like aloe, cascara sagrada, or senna
- poorly absorbed in the small intestine and activated in the colon
- laxative effects 6-12 hours after use
- long-term use causes melanoma pigmentation of colonic mucosa and a “cathartic colon” (dilated and ahaustral)
What is cathartic colon?
- a dilated and ahaustral colon
- commonly seen as a side effect of long-term anthraquinone use
Bulk-Forming Laxatives
- dietary supplements that add bulk and hold water to intestinal contents
- includes methyl cellulose, lactulose, and polycarbophil
- require drinking lots of water to maintain movement of this bulk
Stool Softeners
- agents that soften stools to facilitate expulsion
- includes mineral oil, glycerin suppositories, and docusate sodium
- can be given orally or rectally
What is often prescribed to hospitalized patients to prevent straining during defecation?
docusate, a stool softener
Loperamide
- an anti-diarrheal that acts on intestinal opioid receptors to inhibit ACh release and decrease motility
- 40-50 more effective than morphine for diarrhea without CNS effects
- acts quickly (3-5 hours after ingestion) for quick relief of non-specific diarrhea
- effective against traveler’s diarrhea but should be discontinued if clinical improvement does not occur within 48 hours (risk constipation)
- more effective than diphenoxylate and with fewer side effects
Difenoxin
- an anti-diarrheal that acts on intestinal opioid receptors to inhibit ACh release and decrease motility
Diphenoxylate
- an anti-diarrheal that acts on intestinal opioid receptors to inhibit ACh release and decrease motility
- less effective than loperamide
- requires supplementation with atropine to deter abuse
Kaolin and Pectin
- essentially a chalk that absorbs compounds and binds potential intestinal toxins
- relieves diarrhea
Which anti-diarrheal is used for each of the following cases:
- acute, nonspecific
- infectious
- traveler’s diarrhea
- acute, nonspecific: loperamide
- infectious: bismuth subsalicylate (peptobismol)
- traveler’s: loperamide
Somatostatin/Octreotide
- antidiarrheals reserved for severe cases
- inhibit secretion of gastrin, CCK, glucagon, GH, insulin, secretin, etc. so they’re very dirty drugs reserved for severe, refractory diarrhea
- reduce intestinal fluid and pancreatic secretion, slow GI motility, inhibit gallbladder contraction, and reduce portal and splanchnic blood flow
Which part of the CNS controls emesis?
the nucleus tractus solitarus
What is the role of the nucleus tractus solitarus?
it receives lots of inputs and controls the efferent output that mediates vomiting
Which GI disorders are controlled with H1 blockers? H2 blockers?
- H1: emesis
- H2: peptic-acid disease
H1 Antagonists
- a group of anti-emetic drugs including dimenhydrinate, diphenhydramine, cyclizine, and meclizine
- serve as H1 antagonists in the tractus solitarus
- produce sedation and antimuscarinic activity to prevent motion sickness
Name four groups of antagonists used in the treatment of emesis?
- H1 antagonists
- D2 antagonists
- 5-HT3 antagonists
- NK-1 antagonists
Which anti-emetics are used for n/v during chemotherapy?
5-HT3 antagonists like ondansetron, granisetron, and dolasetron
Metoclopramide
a D2 antagonists used to treat emesis
Trimethobenzamide
a D2 antagonist used to treat emesis
Ondansetron
a 5-HT3 antagonist used to treat emesis, particularly in those undergoing chemotherapy
Granisetron
a 5-HT3 antagonist used to treat emesis, particularly in those undergoing chemotherapy
Dolasetron
a 5-HT3 antagonist used to treat emesis, particularly in those undergoing chemotherapy
Aprepitant
an NK-1 antagonist used to treat emesis
Fosaprepitant
an NK-1 antagonist used to treat emesis
Rolapitant
an NK-1 antagonist used to treat emesis
Chlorpromazine
a phenothiazine used to treat emesis
Prochlorperazine
a phenothiazine used to treat emesis
Lorazepam
a benzodiazepine used to treat emesis
Alprazolam
a benzodiazepine used to treat emesis
THC
a marijuana derivative used to treat emesis through an unknown mechanism
Dronabinol
a marijuana derivative used to treat emesis through an unknown mechanism
Phenothiazines
a group of drugs used as anti-emetics
Benzodiazepines
a group of drugs used as anti-emetics
Pancreatic enzyme deficiencies can lead to what symptoms?
steatorrhea, azotorrhea, vitamin malabsorption, and weight loss
Pancreatic Enzyme Supplements
- pancreatin and pancrelipase
- administered with each meal and snack
- replace pancreatic enzyme deficiencies
- can lead to hyperuricosuria and renal stones because of their high purine content
Orlistat
- a newer anti-obesity medication
- works in the gut by blocking GI lipase, thereby reducing absorption of fats
- may cause flatulence, steatorrhea, and fecal incontinence
Sibutramine
- a newer anti-obesity medication
- works as a SERT/NET inhibitor in the CNS to reduce appetite
- may cause tachycardia or hypertension
Rimonabant
- a newer anti-obesity medication
- works as a CB1 receptor antagonist in the CNS to reduce appetite
- may cause depression, anxiety, or nausea
TCAs
- antidepressants that at low doses can be used to treat the abdominal pain associated with IBS
- use amitriptyline or desipramine
Amitriptyline
an antidepressant that at low doses can be used to treat the abdominal pain associated with IBS
Desipramine
an antidepressant that at low doses can be used to treat the abdominal pain associated with IBS
Dicyclomine
an anticholinergic used as an antispasmodic in the treatment of IBS
Hyoscyamine
an anticholinergic used as an antispasmodic in the treatment of IBS
Tegaserod
- a partial 5-HT4 agonist
- used in the emergent treatment of IBS
- limited by serious cardiovascular events
Alosetron
- a 5-HT3 antagonist used in the treatment of IBD when conventional therapy has failed
- best for diarrhea-predominant IBS
- risk of serious cardiovascular events
Eluxadoline
- a kappa opioid receptor agonist and delta opioid receptor antagonist
- used in the treatment of diarrhea-predominant IBS
- reduces neuronal drive on peristalsis
- may cause spasm in the sphincter of Oddi, resulting in pancreatitis
Rifaximin
- an antibiotic used to treat diarrhea-predominant IBS
- similar to rifampin
- may alter bacterial content of GI tract
