Digestive system and drug therapy have a reciprocal relationship
Some medications cause GI symptoms (e.g. EES); conversely, some GI disorders alter the absorption and metabolism of drugs (liver failure)
Drugs affecting the GI tract include: laxatives, antidiarrheals, antiemetics, drugs used in acid-peptic disorders . Others include cholinergics (Aricept) anticholinergics (atropine), corticosteroids and anti-infectives.
Prevention of diffusion of HCL from the stomach lumen back into the gastric mucosal lining
Presence of prostaglandin E
Alkalinization of gastric secretions by pancreatic juices and bile
Cell Destructive Effects in Stomach
Gastric acid, secreted by parietal cells
Paretal cells contain receptrors for acetylcholine, gastrin and histamine, all of which stimulate gastric acid production
Acetylcholine is released by vagus nerve endings in response to stimuli, such as thinking about food
Cell destructive effects cont.
Gastrin is a hormone released by the stomach and duodenum in response to food ingestion. Affects parietal cells which in turn causes gastric acid to be released in stomach.
Histamine is released from cells in the gastric mucosa and diffuses into nearby parietal cells
Pepsin is a proteolytic enzyme that helps digest protein foods and also can digest the stomach wall
H. pylori is a gram negative bacterium found in the gastric mucosa of most clients with chronic gastritis
In 75% of those with gastric ulcers and in 90% of clients with duodenal ulcers
Spread by oral fecal route or by iatrogenic spread
Thought to affect mucosal function
Peptic Ulcer Disease
Gastric Ulcers
Associated with stress, NSAIDs or H. pylori
Manifested by painless bleeding
Take longer to heal than duodenal ulcers
When associated w/stress, can occur at any age
With H. pylori and NSAIDs generally are in 6th or 7th decade
chronic
PUD cont.
Duodenal Ulcers
Can occur at any age
Occur equally in men and women
Manifested by abdominal pain
Associated with cigarette smoking
Also associated with NSAIDs and H. pylori
Peptic Ulcer and Acid Reflux Disorders
Characterized by ulcer formation in the esophagus, stomach or duodenum
Occurs in areas that are exposed to gastric acid and pepsin
Gastric and duodenal ulcers are more common than esophageal ulcers
Parietal cells contain receptors for acetylcholine—implication of which is stimulation by/of vagus
Upper GI Disorders
Gastritis—acute or chronic inflammatory reaction of gastric mucosa.
Usually will see peptic ulcers with gastritis
Non-steroidal anti-inflammatory Drug Gastropathy
Occurs with damage to mucosa by ASA or other NSAIDs
Chronic ingestion causes irritation of the gastric mucosa, inhibits the synthesis of prostaglandins (which protect mucosal lining) and increasess the synthesis of leukotrienes and other substances that can cause mucosal damage
Selected Upper Gastrointestinal Disorders
Review p. 853 in text
Include Gastritis
Nonsteroidal anti-Inflammatory Drug Gastropathy
Stress Ulcers
Zollinger-Ellison Syndrome-rare; excessive secretion of gastric acid and a high incidence of ulcers. Caused by gastrin-secreting tumors in pancreas, stomach or duodenum. Often malignant.
Gastroesophageal Reflux Disease
Most common disorder of the esophagus
Characterized by regurgitation of gastric contents into the esophagus
Occurs most often after a meal
Worse when recumbent
Caused by incompetent lower esophageal sphincter
Foods that cause relaxation include: etoh, caffeine, fats, chocolate, cigarrette smoking, gastric distention and medications (beta adrenergic blockers, calcium channel blockers, nitrates)
GERD cont.
Occurs in men, women, and children
Common during pregnancy
More common after 40 years of age
Classifications and Individual Drugs
Antacids—alkaline substances that neutralize acids. Raising the pH to approximately 3.5 neutralizes more than 90% of gastric acid and inhibits conversion of pepsinogen to pepsin. Commonly used antacids are aluminum, magnesium, and calcium compounds.
Antacids
Antacids vary in onset of active and dosage needed for neutralization
Aluminum compounds require large doses for effectiveness. They can cause constipation, hypophosphatemia and osteomalacia.
Magnesium based antacids have more rapid onset than Al++ but can cause diarrhea and hypermagnesemia
Calcium compounds can cause hypercalcemia and hypersecretion of gastric acid==“rebound”
Antacids
May be in combinations such as aluminum and magnesium hydroxide
Decreases the diarrhea and constipation
Most antacids are pregnancy category C
Antacids may be used in children
Antacides with magnesium are contraindicated because hypermagnesemia may result
Histamine release causes contraction of smooth muscle in bronchi, GI tract, increases permeability of capillaries,stimulation of sensory nerve endings and strong stimulation of gastric acid secretion
Vagal stimulation causes release of histamine from cells in stomach, acts on receptors in parietal cells>>>>increases HCL production.
Called H2 receptors
Histamine 2 Receptor Antagonists
Traditional antihistamines or H1 receptor antagonists generally reduce the effects of histamine in the body but do not block histamine effects on gastric acid production.
Replaced as first choice drugs by the PPIs
Prototype is cimetidine
Generally are pregnancy category B
May have multiple drug interactions and SE
Available OTC and by Rx
H2RA
Reduce dosage in pregnancy
Cimetidine affects the cytochrome p450 drug metabolizing system in the liver; may cause confusion and antiadrogenic effects (gynecomastia)
Ranitidine more powerful
Use for up to 8 weeks
May be used long term but with variable dosing
Antacids may be given concurrently to relieve pain
Proton Pump inhibitors
Strong inhibitors of gastric acid secretion
Bind irreversibly to the gastric proton pump to prevent the release of gastric acid from parietal cells
Suppresses acid secretion in response to all primary stimuli including histamine, gastric, and acetylcholine
Are the drugs of first choice in erosive esophagitis, erosive gastritis and Zollinger-Ellison
PPIs
More effective than H2RA
Faster symptom relief and faster healing
Used in prevention of esophagitis
Tx H. pylori associated ulcers
Side effects are nausea, diarrhea and HA
Long term effects??? Implications??
Prostaglandin
Naturally occurring prostaglandin E is produced by mucosal cells of the stomach and duodenum. It inhibits gastric acid secretion and increases mucous and bicarbonate, mucosal blood flow and mucosal repair. With inhibition of Prostaglandin E, erosion and ulceration of the gastric mucosa may occur.
Implications
Cytotec (misoprostol)
Synthetic form of prostaglandin E
Indicated for clients at high risk for GI ulceration and bleeding and in those who take NSAIDs
Contraindicated in women of childbearing age and during pregnancy (see text p. 862)
May induce abortion
Side effects include diarrhea and abdominal cramping
Sucralfate
Preparation of sulfated sucrose and aluminum hydroxide that binds to normal and ulcerated mucosa
Mechanism of action is unclear
Thought to possible bind to the ulcer and form a protective barrier between the mucosa and gastric acid, pepsin and bile salts; and stimulating prostaglandin synthesis
Effective in healing duodenal ulcers and in prevention of recurrence
Sucralfate
Side effects include constipation and dry mouth
Must be given Bid
Cannot be given with an antacid, H2RA or PPI
May bind other drugs and prevent their absorption
Give 2 hours before or after other drugs
Effects of Acid Suppressant Drugs on Nutrients
Dietary folate, iron and Vitamin B12 are better absorbed from an acidic environment
Less acidic environment can cause deficiencies of these nutrients
Sucralfate interferes with the absorption of the fat soluble vitamins
Vomiting is the expulsion of stomach contents through the mouth
Vomiting can occur w/o nausea
Origin of vomiting
Vomiting center is located in medulla oblongata
Stimuli are relayed to the vomiting center from the periphery (gastric mucosa, peritoneum, intestines, joints(?)) and centrally (from the cerebral cortex; vestibular apparatus and from neurons in the fourth ventricle==chemoreceptor trigger zone) sites
The vomiting center, chemoreceptor trigger zone and GI tract contain benzodiazepine, cholinergic, dopamine, histamine, opiate and serotonin receptors that are stimulated by emetogenic drugs and toxins
For example: chemotherapy may stimulate the CTZ which then signals the vomiting center
Motion sickness—changes in body motion>>stimulate receptors in inner ear>>transmitted to the CTZ and the vomiting center
Triggering the vomiting center
Efferent impulses cause glottic closure
Contraction of abdominal muscles and diaphragm
Relaxation of the GE sphincter
Reverse peristalsis
Projection or expulsion
Causes of nausea and vomiting
Pain
Emotional disturbances
Radiation therapy
Motion sickness
Drug therapy: especially with alcohol, ASA, digoxin, anticancer drugs, antimicrobials, estrogen preparations and Opioids
Causes of Nausea and Vomiting
GI disorders such as inflammation of the GI tract, liver, gallbladder, pancreas, impaired GI motility and muscle tone (gastroparesis) and ingestion of food that is irritating to the mucosa
Cardiovascular, infectious, neurologic or metabolic disorders
Antiemetic Drugs
Most have anticholinergic, antidopaminergic, antihistaminic or antiserotonergic effects
Generally are more effective in prophylaxis than treatment
Most act on the vomiting center, the chemoreceptor trigger zone, the cerebral cortex, vestibular apparatus or any of the above
Antiemetic Drugs
Phenothiazines—CNS depressants used in psychoses
Block dopamine from receptor sites in the brain
Act on CTZ and the vomiting center
Not all phenothiazines are anti-emetics
Cause drowsiness
Prochlorperazine (Compazine) and promethazine (Phenergan) are examples
Some are pregnancy category B, others C, should check 1st
Side effects continued
Extrapyramidal symptoms which include:
Dyskinesias (rhythmic movements), dystonias (rhythmic jerks) and akathesia (inability to sit still) related to dopamine receptor blockade
Antihistamines
Prevent histamine from exerting its widespread effects on the body
Classic antihistamines or H1 receptor blocking agents are thought to block the action of acetylcholine in the brain (anticholinergic)
Indicated in Motion sickness
Examples are Dramamine, hydroxyzine (Vistaril), meclizine (Antivert)
Corticosteroids
May affect prostaglandin activity in the cerebral cortex
Dexamethasone and methyprednisolone are commonly used in the management of chemotherapy induced emesis, usually in combination with other anti-emetics
Benzodiazepine antianxiety drugs
Not classic anti-emetics but often used in multidrug regimens to prevent nausea and vomiting associated with cancer chemotherapy
Inhibit cerebral cortex input to the vomiting center
May give to those with anticipatory nausea before chemotherapy
Example is Ativan (lorazepam)
5 Hydroxytryptamine (5-HT3 or Serotonin)Receptor Antagonists
Ondansetron, granisetron and dolasetron are used to prevent or treat moderate to severe nausea and vomiting r/t cancer chemotherapy, radiation therapy and postoperatively
Some anticancer drugs seem to affect a subset of 5-HT3 recptors in the CTZ and the GI tract
These drugs antagonize receptors both peripherally (GI) and in the CTZ to prevent activation
5-HT3 receptor antagonists cont.
Can be given IV or orally
Side effects are mild to moderate and include: diarrhea, headache, dizziness, constipation, muscle aches and transient liver enzymes elevation
Ondansetron (Zofran) is the prototype
Metabolized by the liver
Miscellaneous Antiemetics
Dronabinol (Marinol) is a cannabinoid used in the management of nausea and vomiting associated with anticancer drugs and unrelieved by other drugs.
Schedule III under federal narcotic laws
Withdrawal S/S may occur
Sleep disturbances
Reglan
Prokinetic that increases GI motility and the rate of gastric emptying by increasing the release of acetylcholine from nerve edings in the GI tract
Can cause decreased n/v associated with gastroparesis
Has central antiemetic effects, antagonizes the action of dopamine
Can be given IV, PO or IM
Reglan continued
Side effects include sedation, restlessness, and extrapyramidal reactions
May increase the effects of alcohol and cyclosporine and decrease the effects of cimetidine and digoxin (decrease time for passage)
Emetrol
Phosphorated carbohydrate solution
Hyperosmolar solution with phosphoric acid
OTC
Felt to work by reducing smooth muscle contraction in the GI tract
Reglan is relatively contraindicated in Parkinson’s disease because it further dples dopamine
Management Considerations
5-HT3 antagonists 1st choice in chemotherapy induced or postoperative N/V
Drugs with anticholinergic and antihistaminic properties are preferred for motion sickness
If ambulatory, opt for drug that causes less sedation
Phenergan is used for its antihistaminic, antiemetic and sedative effects
Management Considerations cont.
Phenothiazines can have serious side effects
Reglan may be preferred for non-obstructive gastric retention
Herbals
Efficacy still debatable
Chemotherapy-induced Nausea and Vomiting
Chemo may be given during sleeping hours
Decrease food intake few hours before Tx
Antiemetics should be given before the emetogenic Tx and may be given for 2-3 days
5-HT2 receptor antagonists are drugs of choice for this indication
Reglan is valid option but may need to give diphenhydramine to prevent the EPS
Sometimes combo of steroid and 5-HT3 RA useful
Laxatives and Cathartics
When stomach and duodenum are distended with food, gastrocolic and duodenocolic reflexes are initiated
The cerebral cortex controls the defecation reflex so that defecation can occur at acceptable times and places
In people who inhibit the defecation reflex or fail to respond to the urge to defecate, constipation develops
Laxatives are chemical substances that act to facilitate passage of bowel contents
Cathartics—a purgative action of the bowels, action is stronger and generally produces elimination of liquid stools
Indications for Use
Reduce cholesterol
Obtain stool sample
Accelerate excretion of parasites after anthelminthics started
Accelerate elimination of potentially toxic substances (Kayexalate)
Pre-op
Prevent straining at stool w/CAD, hemorrhoids
Relieve constipation in pregnancy, in the elderly; in children with megacolon, and in those w/decreased motility
Laxatives and cathatics should not be used in the presence of undiagnosed abdominal pain
Could cause an inflamed organ to rupture
Oral agents are contraindicated in intestinal obstruction and fecal impaction
Laxatives
Bulk-forming laxatives—Citrucel, Metamucil
Surfactant Laxatives—mainly prevent straining. They allow water to penetrate stool and act as detergent to facilitate admixing of fat and water in the stool. Colace (docusate) or Surfak.
Saline—magnesium citrate. Nulytely.Increase osmotic pressure in intestinal lumen.Not safe for frequent use. Affect fluids and lytes.
Cathartics
Stimulant type are the strongest and most abused
Cascara,bisacodyl, castor oil and senna products
Mineral oil is a lubricant laxative. It slows colonic absorption of water.
Other
Lactulose—a disaccharide that is not absorbed from the GI tract. Pulls water into intestinal lumen. Used to treat constipation and hepatic encephalopathy. Lactulose reduces production of ammonia in the intestine. Can affect lyte and water balance.
Sorbitol—monosaccharide that puls water into the intestinal lumen and has laxative effects. It is given with Kayexalate (potassium removing resin to treat hyperkalemia).
Laxative Abuse
Public health problem in elderly
Use in patients with cancer
What is normal?
What are some measures to prevent constipation?
Safety in Use
Saline cathartics must be used cautiously in the renally impaired
Lactulose may be indicated in those with hepatic encephalopathy
Seen frequently in form of enemas in hyperkalemia in hospital
Antidiarrheals
Diarrhea is a symptom of numerous conditions that increase bowel motility; cause secretion or retention of fluids in the intestinal lumen and cause inflammation or irritation of the GI tract. End result: bowel contents are rapidly propelled and absorption of fluids and electrolytes is limite.d
Causes of Diarrhea
Abuse of laxatives
Intestinal infections—E. Coli 0157:H7 (can result in a hemolytic uremic syndrome), Traveller’s diarrhea (E. coli), Campylobacter jejuni, Salmonella, Shigella, rotatvirus
Inflammatory bowel diseases
Drug therapy—pseudomembranous colitis—Clostridium difficile (anaerobic, spore forming rods)
Antidiarrheals
Opiate related drugs
Paregoric
Defenoxin with atropine—Motofen
Diphenoxylate with atropine--Lomotil
Antibacterials
Azithromycin for Traveller’s diarrhea
Cipro—E.coli, Camylobacter, Shigella
EES—amebiasis
Flagyl—Clostridium difficile
Bactrim-Traveller’s diarrhea
Vancomycin—Clostridium difficile, even in form of enemas
Miscellaneous
Questran—Crohns’. Binds and inactivates bile salts in the intestine.
Octreotide—diarrhea associated with HIV, carcinoid tumors, cancer therapies or intractable diarrhea caused by other drugs.
Pancreatin—pancreatic enzymes used for replacement in patients w/deficiency of pancreatic enzymes
