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Drugs Used in Gastrointestinal Disorders
Gastric A & P
First, some background physiology….
There are 3 cells of the gastric gland:
1. Chief
 Secretes pepsinogen  pepsin
 Breaks down proteins in the diet
2. Mucoid
 Secretes mucus
 Provides a protective mucous coat to protect stomach from digestion of itself from
hydrochloric acid (HCl)
3. Parietal
 Secretes hydrochloric acid
 Keeps the pH of the stomach between 1 and 4 so as to properly digest food
The wall of the parietal cell has 3 types of receptors: acetylcholine, histamine, and
gastrin.
 When any one of these receptors is occupied, the parietal cell will produce and
secrete HCl
 The receptors can also be blocked:
 Atropine (an anticholinergic) blocks acetylcholine from binding with the
acetylcholine receptor
 Histamine-2 (H-2) blockers block histamine from the mast cell from
binding with the histamine receptor
When any of these receptors are bound, the parietal cell is stimulated. The cell must now
produce HCl, but needs hydrogen ions (H+ ions) to do so. These H+ ions are produced
by the proton pump (H+/K+ ATPase pump) of the cell. The proton pump needs energy
to function.
So: Energy  activates the H+/K+ ATPase system (proton pump)  proton pump
produces H+ ions needed for the production of HCl  HCl is secreted into the stomach
Proton pump inhibitors bind to the H+/K+ ATPase pump and irreversibly inhibit this
enzyme, resulting in a total inhibition of H+ ion secretion from the parietal cells.
The most common impairment is hyperacidity, or the overproduction of acid.
 GERD = gastroesophageal reflux disease
The most harmful is peptic ulcer disease.
Theory of how formed: aggressive (acid + pepsin) and protective (mucosal layer)
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Anti-peptic agents
Antacids
- Cheapest
- Mainstay of antiulcer therapy until the 1970s
- Neutralize acid, stimulate mucus and bicarbonate secretion, improve blood flow to
area  increase protective layer
- Problems
- Mg  diarrhea, Al  constipation
- Al, Mg, Ca  renal patients unable to eliminate
- Use caution if the antacid is high in sodium content in patients with CHF, HTN,
sodium restrictions, and other cardiac diseases
- Best acid neutralizing capacity AND lowest sodium content: Riopan Plus
(Al-Mg) and Maalox TC (Mg, Al, simethicone)
- There are many drug interactions with antacids because of the effect on
absorption of the medication that is given concurrently with the antacid…check
for interactions before ordering the medication.
- Best not to administer other meds within 1-2 hours after an antacid.
- Especially important to separate by 2 hours: dig, iron, INH, quinolones,
tetracyclines
- Antacids may result in premature dissolving of the enteric coating of meds, resulting
in stomach upset.
- Increasing the pH of the stomach with an antacid will cause drugs that are acid salts
(HCl salts) to be more ionized and less absorbed and drugs that are basic salts (sulfate
salts) to be less ionized and more readily absorbed into the bloodstream.
- The same alteration in absorption in the stomach will affect excretion of basic and
acidic drugs in the urine because the urinary pH will be elevated and acidic drugs
will be more ionized, less absorbed, and more excreted.
H2 Blockers/Antagonists
- Began being used in the 1970’s
- Bind to and block histamine receptors located on parietal cells
- This blockade renders the parietal cells less responsive to stimuli and thus acid
secretion.
- Up to 90% inhibition can be achieved with these agents (dose-related)
- Indications
- Ulcer (gastric, duodenal)
- GERD
- Upper GI bleeding
- Hypersecretory conditions (Zollinger-Ellison syndrome = non-insulin-secreting
pancreatic tumor; releases large amount of gastrin)
- Examples (and their equipotent dosages)
- Cimetidine (Tagamet) 1600 mg.
- Ranitidine (Zantac) 300 mg.
- Nizatidine (Axid) 300 mg.
- Famotidine (Pepcid) 40 mg.
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-
-
All are equally effective in healing ulcers; need to look at pharmacokinetics and
adverse effects
- Tagamet = shortest ½ life
- Pepcid = longest ½ life
- Caution with renal /hepatic dysfunction
Problem with Tagamet: inhibits the hepatic enzyme (cytochrome P-450 system)
metabolism of the following drugs, thereby increasing their levels and effects:
- Theophylline
- Phenytoin
- Oral anticoagulants
- Propranolol
- Procainamide
- Quinidine
- Lidocaine
- Calcium channel blockers
Adverse effects of H2 blockers (worse with patients with multiple illnesses, elderly,
those with hepatic or renal dysfunction)
- CNS effects (headache, lethargy, confusion, depression, hallucinations (<1%)
- Endocrine (impotence, increased prolactin, gynecomastia)
- GI (diarrhea, abdominal cramps, jaundice, increased LFTs)
- GU (increased BUN, creatinine)
- Hematopoietic (agranulocytosis, thrombocytopenia, neutropenia, aplastic anemia)
- Integumentary (urticaria, rash, alopecia, sweating, flushing exfoliative dermatitis)
Proton Pump Inhibitors
- More effective than H2 blockers
- More expensive than H2 blockers
- Block the final step in the acid production pathway
- Blocks all acid secretion
- Examples:
- omeprazole (Prilosec) 10, 20, 40 mg (also available OTC and generic)
- lansoprazole (Prevacid) 15, 30 mg
- rabeprazole (AcipHex) 20 mg
- pantoprazole (Protonix) 20, 40 mg
- esomeprazole (Nexium) 20, 40 mg
- dexlansoprazole (Dexilant, Kapidex) 30, 60 mg
- omeprazole/sodium bicarbonate (Zegerid) 20 mg/1.1 g; 40 mg/1.1 g
- Adverse effects
- CNS (headache, dizziness)
- GI (diarrhea, abdominal pain, N, V, anorexia)
- GU (proteinuria, hematuria, glycosuria)
- Hematopoietic (pancytopenia, thrombocytopenia, neutropenia, leukocytosis,
anemia)
- Integumentary (rash, dry skin, urticaria, pruritis, alopecia)
- Respiratory (URI, cough)
- Other (back pain, fever, fatigue)
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Used for treatment of H. pylori
- Example: 2 weeks of Prilosec 40 mg once daily plus Biaxin 500 mg 3X/day;
follow with 2 week course of Prilosec 20 mg once daily
- Example: PrevPac: 1 dose bid X 14 days (1 dose = 1 tab of lansoprazole 30 mg
[Prevacid], 2 tabs amoxiciliin 500 mg, and 1 tab clarithromycin 500 mg [Biaxin])
Sucralfate (Carafate)
- A cytoprotective agent for stress ulcerations and PUD (peptic ulcer disease)
- Binds to exposed proteins of ulcers and thus limits pepsin’s proteolytic action
- Made of sucrose, Al, sulfate
- Drug effects
- Sulfate anions bind to positively charged tissue proteins that are exposed at the
tissue surface of an ulcer or an erosion
- As a weak base, it buffers the acidic pH of the stomach
- Binds and concentrates epidermal growth factor (EGF), which accelerates the
healing process
- Simulates gastric mucosal prostaglandin E2 synthesis
- The aluminum salt stimulates the secretion of mucus and bicarbonate from the
cells of the stomach to counteract the actions of HCl
- Side effect: constipation
- Renal patients may have problems with Al
- Good drug for long-term use
- Separate drugs by 2 hours; ciprofloxin should not be used at all
Misoprostol (Cytotec)
- A synthetic prostaglandin analog
- Inhibits gastric acid secretion, enhances local production of mucus or bicarbonate
- Also helps maintain mucosal blood flow
- Used in drug induced PUD (from NSAIDs) or for gastric ulcer prophylaxis during
NSAID therapy [Arthrotec = diclofenac + misoprostol]
Upper GI Drug Regimens
For acute ulcer therapy, full dose, and for ulcer prophylaxis, ½ usual dose, given at hs.
For example: for active duodenal ulcer, Axid 150 mg bid or 300 mg @ hs. For
maintenance therapy, Axid 150 mg @ hs
For drug-induced ulcer prophylaxis, Cytotec, 100-200 mcg qid pc and hs or 200 mcg bid
or tid
- Maximum plasma concentrations are diminished when taken with food.
Because of GI side effects of abdominal pain and nausea, manufacturer
recommends that drug be taken with food.
- Diarrhea is also a common side effect and is dose-related. It is usually selflimiting (often resolving in 8 days). The incidence of diarrhea can be
minimized by taking the drug after meals and at bedtime.
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NOTE: “Symptomatic response to therapy does not preclude the presence of gastric
malignancy.”
Nausea and Vomiting Basics
Vomiting, or emesis, is the forcible emptying or expulsion of gastric and occasionally
intestinal contents through the mouth.
Signals from 1) the gastrointestinal tract, 2) the labyrinth, and the 3) cortex go to the 4)
chemoreceptor trigger zone (CTZ) which then send the message to the 5) vomiting center
in the medulla.
These signals are sent via neurotransmitters:
- Dopamine (GI tract and CTZ)
- Histamine 1 (vestibular, vomiting center, and labyrinth pathways)
- Prostaglandins (GI tract)
- Serotonin (5 HT3) (GI tract, CTZ, and vomiting center)
- Acetylcholine (ACh) (vestibular, vomiting center, and labyrinth pathways)
The drugs used as antiemetics effect these neurotransmitters:
- ACh is blocked by anticholinergic drugs
- Histamine 1 is blocked by antihistamines (H1 receptor blockers)
- Dopamine is blocked by neuroleptic agents and prokinetic agents
- Serotonin is blocked by serotonin blockers (5-HT3 antagonists)
The drugs used as antiemetics work on each of these areas:
Antiemetics
Area
Gastrointestinal Tract
Labyrinth
Cortex
Chemoreceptor trigger zone
Vomiting center (medulla)
Types of Drugs Affecting Area
- Prokinetic drugs
- Serotonin blockers
- Anticholinergics
- Antihistamines
- Neuroleptics
- Prokinetic drugs
- THC (tetrahydrocannabinoid) =
the major psychoactive
substance in marijuana
- Neuroleptics
- Prokinetic drugs
- Serotonin blockers
- Serotonin blockers
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Let’s look at each of the categories of antiemetics:
Examples
Mechanism of Action
Therapeutic Effects
Common Drug Interactions
Adverse Effects
Category: Anticholinergics
Scopolamine
Block ACh receptors in the vestibular
nuclei and reticular formation
Motion sickness, secretion reduction before
surgery, nausea and vomiting
With antihistamines and antidepressants,
additive effect  increased anticholinergic
effects (drying effects)
Rash, erythema, difficult urination,
dizziness, drowsiness, disorientation,
blurred vision, dilated pupils, dry mouth
Category: Antihistamine (H1 receptor blockers)
Examples
Promethazine (Phenergan), meclizine
(Antivert), diphenhydramine (Dramamine)
Mechanism of Action
Block histamine 1 receptors, thereby
preventing ACh from binding to receptors
in the vestibular nuclei
Therapeutic Effects
Motion sickness, nonproductive cough,
sedation, rhinitis, allergy symptoms, N & V
Common Drug Interactions
With barbiturates, narcotics, hypnotics,
tricyclic antidepressants, alcohol, additive
effect  increased CNS depression
Adverse Effects
Dizziness, drowsiness, confusion, urinary
retention, blurred vision, dilated pupils, dry
mouth
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Category: Neuroleptic agents
Chlorpromazine (Thorazine),
prochlorperazine (Compazine)
Mechanism of Action
Block dopamine in the CTZ and may also
block ACh (** Not for use with
Parkinson’s)
Therapeutic Effects
Psychotic disorders (mania, schizophrenia,
anxiety), intractable hiccups, N & V
Common Drug Interactions
Blocks levodopa, which may cancel the
beneficial effects of levodopa in treatment
of Parkinson’s disease. With quinidine,
additive effect  increased adverse cardiac
effects
Adverse Effects
Orthostatics hypotension, ECG changes,
tachycardia, blurred vision, dry eyes, dry
mouth, N & V, anorexia, constipation,
urinary retention, extrapyramidal
symptoms, pseudoparkinsonism,
akathisia, dystonia, tardive dyskinesia,
headache
Examples
Category: Prokinetic Agents
Examples
Metoclopramide (Reglan), cisapride
(Propulsid)**
** Problem with Cytochrome P450 (with
Biaxin, emycin, -azoles  ventricular
arrhythmias)
Mechanism of Action
Block dopamine in the CTZ or stimulate
ACh receptors
Therapeutic Effects
Increases gastric emptying, GERD, N & V
Common Drug Interactions
With alcohol, additive effect  CNS
depression
With anticholinergics and analgesics, block
 antagonism of motility effects of
metoclopramide
Adverse Effects
Sedation, fatigue, restlessness, headache,
dystonia, dry mouth, N & V, hypotension,
SVT
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Examples
Mechanism of Action
Therapeutic Effects
Common Drug Interactions
Adverse Effects
Category: Serotonin blockers
Ondansetron (Zofran), granisetron (Kytril)
Block serotonin receptors in the GI tract,
CTZ, and vomiting center
N & V associated with cancer
chemotherapy, postop N & V
Headache, diarrhea, increased AST and
ALT levels, rash, bronchospasm
Category: Tetracannabinoids
Examples
Dronabinol (Marinol)
Mechanism of Action
Has inhibitory effects on the reticular
formation, thalamus, and cerebral cortex
Therapeutic Effects
N & V associated with cancer
chemotherapy
Common Drug Interactions
Additive effect with other CNS depressants
Adverse Effects
Drowsiness, dizziness, anxiety, confusion,
dry mouth, visual disturbances
NOTE: Antiemetics in general should be given before any chemotherapy agent is
administered, often 1 to 3 hours beforehand.
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Problems of Gastrointestinal Motility: Diarrhea and Constipation
Diarrhea:
- Leading cause of morbidity and mortality in third world countries
- 5-8 million deaths per year in infants and children
- Loss of time and productivity at work has an enormous financial impact with
an estimated cost of $23 billion per year or $108 per person per year in the
U.S.
- Most acute diarrhea is self-limiting, subsiding in 3 days to 2 weeks
- Fluid and electrolyte replacement is vital
- Causes of acute diarrhea:
o Bacterial
o Drug-induced
o Viral
o Nutritional
o Protozoal
o Other
- Causes of chronic diarrhea:
o Tumors
o Diabetes mellitus
o Hyperthyroidism
o Addison’s disease
o Irritable bowel syndrome
o Other
Constipation: Causes
- Metabolic and endocrine disorders (DM, hypothyroidism, pregnancy,
hypercalcemia, hypokalemia)
- Neurogenic disorders (autonomic neuropathy, intestinal pseudo-obstruction,
multiple sclerosis, spinal cord lesions, Parkinson’s disease, CVA)
- Adverse drug effects (analgesics, anticholinergics, iron supplements,
aluminum antacids, calcium antacids, opiates, calcium channel blockers,
Vinca alkaloids)
- Lifestyle
o Poor bowel movement habits (voluntary refusal to defecate resulting in
constipation)
o Diet (poor fluid intake and/or low-residue (roughage) diets or excessive
consumption of dairy products)
o Physical inactivity (lack of proper exercise, especially in elderly
individuals)
o Psychologic (anxiety, stress, hypochondria)
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Drugs affecting gastrointestinal motility
Dealing with Diarrhea
Drugs therapy for diarrhea includes:
- Adsorbents
- Anticholinergics
- Opiates
- Intestinal flora modifiers
Examples
Mechanism of Action
Adverse Effects
Drug Interactions
Category: Adsorbents
Bismuth subsalicylate (Pepto Bismol),
attapulgite (Kaopectate)
Coat walls of GI tract, absorbing bacteria
or toxins causing diarrhea, and eliminating
them with stool
With bismuth subsalicylate: increased
bleeding time, constipation, dark stools,
confusion, twitching, hearing loss, tinnitus,
metallic taste, blue gums
With digoxin, clindamycin, quinidine:
decreased absorption
With oral anticoagulants: increased
bleeding time, bruising
With methotrexate: increased toxicity
With probenecid: decreased probenecid
effects
With hypoglycemia agents: decreased
hypoglycemic effects
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Examples
Mechanism of Action
Adverse Effects
Drug Interactions
Examples
Mechanism of Action
Adverse Effects
Drug Interactions
Category: Anticholinergics
Atropine
Decreased intestinal muscle tone and
peristalsis, thereby slowing the movement
of fecal matter through the GI tract. Often
combined with other antidiarrheals to
increase their effectiveness
Urinary retention and hesitancy, impotence,
headache, dizziness, confusion, anxiety,
drowsiness, hypotension, HTN,
Bradycardia, tachycardia, dry skin, rash,
flushing, blurred vision, photophobia,
increased pressure in the eye
With antacids, decreased anticholinergic
effects
With amantadine, tricyclic antidepressants,
MAOIs, antihistamines  increased
anticholinergic effects
Category: Opiates
Opium tincture, paregoric, codeine
diphenoxylate (Lomotil), loperamide
(Imodium)
Cause constipation by lowering the motility
of the bowel and relieving rectal spasms.
By slowing the time it takes to pass food
through the intestines, water and
electrolytes have a greater chance of being
absorbed, with reduces tool frequency and
volume
Drowsiness, sedation, dizziness, lethargy,
N & V, anorexia, constipation, respiratory
depression, bradycardia, palpitations,
hypotension, urinary retention, flushing,
rash, urticaria
Increased CNS depressant effects with
CNS depressants, alcohol, narcotics,
sedative hypnotics, antipsychotics, skeletal
muscle relaxants
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Examples
Mechanism of Action
Adverse Effects
Drug Interactions
Category: Intestinal Flora Modifiers
Lactobacillus acidophilus
Suppress the growth of diarrhea-causing
bacteria and help reestablish the normal
intestinal flora that has been depleted by
the diarrhea
N/A
N/A
NOTE: alosetron HCl tablets (Lotronex) –
 was used for irritable bowel syndrome, diarrhea-dominant
 Withdrawn from US Market in 2000 due to deaths from bowel obstruction
Dealing with Constipation: Laxatives and Stool Softeners
Drugs for constipation include 5 types:
- Bulk-forming
- Emollient
- Hyperosmotic
- Saline
- Stimulant/Irritant
Examples
Mechanism of Action
Therapeutic Effects
Adverse Effects
Drug Interactions
Category: Bulk-forming
Psyllium, methylcellulose (Metamucil)
Absorbs water to increase bulk, distending
bowel to initiate reflex bowel activity
(onset of action 12 hours to 3 days)
Acute constipation, IBS, diverticulosis
Impaction above strictures, fluid overload
Increased absorption of antibiotics,
digoxin, nitrofurantoin, salicylates,
tetracyclines, oral anticoagulants
Note: Bulk-forming agents: Drug of Choice
Note: Psyllium contains sugar: give cautiously in DM
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Examples
Mechanism of Action
Therapeutic Effects
Adverse Effects
Drug Interactions
Category: Emollient/Surfactants
Docusate salts (Surfak, Colace), mineral oil
Wetting agent used to soften fecal mass
(onset of action 1-3 days)
Acute constipation, softens fecal impacts,
facilitates bowel movements in anorectal
conditions
Skin rashes, decreased absorption of
vitamins, lipid pneumonia
With mineral oil, increased effect of oral
anticoagulants, decreased absorption of fatsoluble vitamins (A, D, E, K)
Note: Lipid pneumonia – especially in elderly (inhale the mineral oil)
Leakage of oil can cause pruritis ani; disturbs normal defecation reflex
Examples
Mechanism of Action
Therapeutic Effects
Adverse Effects
Drug Interactions
Category: Hyperosmotic
Lactulose, sorbitol, glycerine
Osmotic molecules (like excess sugar)
pulls water into GI tract (onset of action
24-48 hours)
Chronic constipation, diagnostic and
surgical preparations
Caution with diabetics, galactose or lactose
intolerance
Abdominal bloating, rectal irritation
With oral antibiotics, decreased effects of
lactulose
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Examples
Mechanism of Action
Therapeutic Effects
Adverse Effects
Drug Interactions
Category: Saline
Magnesium sulfate, magnesium phosphate,
magnesium citrate, MOM
Increases water content of feces, resulting
in distention, peristalsis, and evacuation
(onset of action 1-3 hours)
Constipation, removal of anthelmintics and
parasites, diagnostic and surgical
preparations
Magnesium toxicity (with renal
insufficiency)
With barbiturates, general anesthetics,
narcotics, and antipsychotics  increased
CNS depression
With neuromuscular blockers, increased
effects
Caution: MOM contains high concentration of sodium  Watch renal disease!
Examples
Mechanism of Action
Therapeutic Effects
Adverse Effects
Drug Interactions
Category: Simulant/Irritant
Castor oil, bisacodyl (Dulcolax)
Direct action on intestinal mucosa (onset of
action 6-10 hours)
Acute constipation, diagnostic and surgical
bowel preparations
Nutrient malabsorption, skin rashes, gastric
irritation, rectal stimulation
With antacids and H2 blockers  gastric
irritation
With antibiotics, digoxin, nitrofurantoin,
salicylates, tetracyclines, oral
anticoagulants  decreased absorption
Stimulant/Irritant Laxatives: Most commonly abused by teens and elderly
NOTE: Long-term use may lead to laxative dependence.
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Zelnorm (tegaserod maleate):
 New medication (2004) for constipation-dominant IBS
 A serotonin 5-HT4 receptor partial agonist
 For short-term treatment of women who have IBS with constipation as their main
bowel problem
 FDA warning in May 2004: Zelnorm associated with serious consequences of
diarrhea and ischemic colitis
 Withdrawn from market in 2007 due to risks of serious CV events
Amitiza (lubiprostone)
 For treatment of chronic idiopathic constipation in adults
 Locally acting chloride channel activator that enhances a chloride-rich intestinal
fluid secretion without altering sodium and potassium concentrations in the serum
 Contraindicated in patients with a history of mechanical GI obstruction, severe
diarrhea
 Adverse effects: nausea, diarrhea….Take with food to decrease nausea
 Dose: 24 mcg twice daily orally with food
Linzess (linaclotide)
 For treatment of both irritable bowel syndrome with constipation and chronic
idiopathic constipation
 Is a guanylate cyclase-C (GC-C) agonist; acts locally on the luminal surface of the
intestinal epithelium to increase cyclic guanosine monophosphate (cGMP) which
stimulates secretion of chloride and bicarbonate into the intestinal lumen.
 Adverse effects: diarrhea, abdominal pain
 Dose: 290 mcg capsule taken once daily on an empty stomach at least 30 minutes
before the first meal of the day.
Drugs for chronic inflammatory bowel:
 Ulcerative colitis
o Sulfasalazene 2 Gm (Azulfidine)
o Steroids helpful during symptom flare, but not useful for prevention of
flare

Crohn’s
o Azothioprine (Imuran), Cromolyn