Block 3 – Pharmacology – Gastrointestinal Drugs

Emesis
Pathogenesis
1. Vagal afferents from stomach and small intestine
2. Blood-borne (chemotherapy, opioids, ipecac)
3. Higher brain centers (fear, anticipations, memory)
4. Sensory input (sight, smell, pain)
5. Vestibular apparatus
-All of these converge on one center of the brain to induce this symptom (chemoreceptor trigger zone, or CTZ)
-Employs serotinin, dopamine, muscarinic receptors, histamine, and neurokinin NTs and receptors for signaling (targets of treatment)

Emesis
Treatment
-Serotonin receptor antagonists
-Glucocorticoids
-Substance P/Neurokinin-1 antagonists
-Benzodiazepines
-Dopamine antagonists
-Butyrophenones
-Metoclopramide

Motion Sickness
Treatment
-Scopolamine
-Antihistamines

Emetics
Gastrointestinal Drugs
-Ipecacuanha
-Apomorphine

Ulcers
Treatment
-H2 receptor antagonists
-Cholinergic antagonists
-Antacids
-Proton pump inhibitors
-Protective agents (bismuth, sucralfate)
-Promotility agents
-Antibiotics

H2 Blockers
Gastrointestinal Drugs
-Cimetidine
-Ranitidine
-Famotidine
-Nizatidine

-tidine
Mechanism
-Reversible block of histamine H2-receptors; results in decreased H+ secretion by parietal cells

-tidine
Clinical Use
-Peptic ulcer, gastritis, mild esophageal reflux, ZE syndrome
-However, only treats the symptoms, not the underlying disease pathology

Cimetidine
Toxicity
-Potent inhibitor of P-450 (multiple drug interactions; prolongs other drug half-lives)
-Antiandrogenic effects (prolactin release, gynecomastia, impotence, decreased libido in males)
-Crosses BBB (confusion, dizziness, headaches) and placenta

Cimetidine, Ranitidine
Toxicity
-Decreased renal excretion of creatinine

Propantheline, Isopropamide, Scopolamine
Clinical Use
-Decrease acetylcholine stimulated acid secretion and motility along the GI tract (rarely used alone)

Proton Pump Inhibitors
Gastrointestinal Drugs
-Omeprazole
-Lansoprazole
-Esomeprazole
-Pantoprazole
-Dexlansoprazole

-prazole
Mechanism
-Irreversibly inhibit H+/K+ ATPase in stomach parietal cells; results in decreased H+ secretion

-prazole
Clinical Use
-Peptic ulcer
-Gastritis
-Esophageal reflux
-Zollinger-Ellison syndrome
-Can be taken just once a day (advantage over histamine-receptor antagonists)

-prazole
Toxicity
-Increased risk of Clostridium difficile infection
-Pneumonia
-Hip fractures
-Decreased serum Mg2+ w/ long-term use
-Hypertrophy of gastrin producing cells; can potentially cause tumors (only animal studies at high doses)

Bismuth, Sucralfate
Mechanism
-Bind to ulcer base, providing physical protection and allowing HCO3- secretion to re-establish pH gradient in the mucous layer

Bismuth, Sucralfate
Clinical Use
-Increase ulcer healing
-Traveler’s diarrhea

Misoprostol
Mechanism
-PGE1 analog
-Increases production and secretion of gastric mucous barrier; results in decreased acid production

Misoprostol
Clinical Use
-Prevention of NSAID-induced peptic ulcers
-Maintenance of a patent ductus arteriosus
-Induction of labor (ripens cervix)

Misoprostol
Toxicity
-Diarrhea
-Contraindicated in women of child-bearing potential (abortifacient)

Octreotide
Mechanism
-Long-acting somatostatin analog

Octreotide
Clinical Use
-Acute variceal bleeds
-Acromegaly
-VIPoma
-Carcinoid tumors

Octreotide
Toxicity
-Nausea
-Cramps
-Steatorrhea

Antacids
Toxicity
-Can affect absorption, bioavailability, or urinary excretion of other drugs by altering gastric and urinary pH or by delaying gastric emptying (change in pH can affect bioavailability of other drugs)
-Hypokalemia
-Aluminum hydroxide also stimulates mucus secretion

Aluminum Hydroxide
Toxicity
-Constipation (“minimum amount of feces”) and hypophosphatemia
-Proximal muscle weakness
-Osteodystrophy
-Seizures

Magnesium Hydroxide
Toxicity
-Diarrhea (“M”ust “g”o to the bathroom)
-Hyporeflexia
-Hypotension
-Cardiac arrest

Calcium Carbonate
Toxicity
-Hypercalcemia
-Rebound acid increase (b/c gastrin release is stimulated)
-Can chelate and decrease effectiveness of other drugs (i.e tetracyclines)

Infliximab
Mechanism
-Monoclonal antibody to TNF-alpha

Infliximab
Clinical Use
-Crohn’s disease
-Ulcerative colitis
-Rheumatoid arthritis

Infliximab
Toxicity
-Infection (including reactivation of latent TB)
-Fever
-Hypotension

Sulfasalazine
Mechanism
-Combination of sulfapyridine (anti-bacterial) and 5-aminosalicyclic acid (anti-inflammatory)
-Activated by colonic bacteria

Sulfasalazine
Clinical Use
-Ulcerative colitis
-Crohn’s disease

Sulfasalazine
Toxicity
-Malaise, nausea
-Sulfonamide toxicity
-Reversible oligospermia (semen w/ low sperm concentration)

Ondansetron
Mechanism
-5-HT3 (type 3 serotonin) receptor antagonist
-Powerful central-acting anti-emetic
(At a party feeling queasy? Keep “on danc”ing w/ this drug)

Ondansetron
Clinical Use
-Control vomiting post-op and in patients undergoing cancer chemotherapy (first drug approved to do so)
-Often combined w/ dexamethasone (corticosteroid); makes drug more efficacious

Ondansetron
Toxicity
-Headache
-Constipation

Glucocorticoids
Mechanism = unknown; possibly anti-swelling effects

Clinical Use = anti-emetic, but not currently approved by FDA for nausea and vomiting relief alone; often used on combination w/ Ondansetron

Aprepitant
Mechanism = Substance P/neurokinin 1 antagonists; blocks these receptors in the chemoreceptor-trigger zone

Clinical Use = anti-emetic; prevents post-operative nausea/vomiting and; however, takes long time to act and effects last for weeks

Metoclopramide
Mechanism
-Dopamine-2 receptor antagonist
-Increases resting tone, contractility, LES tone, and motility of GI tract smooth muscle
-Does not influence colon transport time

Metoclopramide
Clinical Use
-Diabetic and post-surgery gastroparesis
-Anti-emetic
-GERD (helps to empty stomach to prevent acid build up)

Metoclopramide
Toxicity
-Increased parkinsonian effects
-Restlessness, drowsiness, fatigue, depression, nausea, diarrhea
-Interaction w/ digoxin and diabetic agents
-Contraindicated in patients w/ small bowel obstruction or Parkinson’s disease

Lorazepam
Clinical Use
-Benzodiazepam
-Used in combination regimens to suppress chemotherapy-induced nausea and vomiting
-Sedates, suppresses anticipatory emesis, and produces anterograde amnesia (patient won’t remember what made them nauseous)

Phenothiazines
Mechanism
-Dopamine antagonists; blocks dopamine-2 receptors in CTZ

Clinical Use
-Anti-emetic in surgery, cancer chemotherapy, and toxins

Toxicity = enter CNS and cause extrapyramidal (movement disorders), anti-cholinergic effects, hypotension, and extreme sedation

Haloperidol, Droperidol
Mechanism
-Butyrophenones; blocks dopamine-2 receptors in CTZ

Clinical Use
-Anti-emetic in surgery, cancer chemotherapy, and toxins

Toxicity = enter CNS and cause extrapyramidal (movement disorders), anti-cholinergic effects, hypotension, and extreme sedation; may cause prolonged QT interval (slow conduction)

Cannabinoids
Clinical Use
-Dronabinol and nabilone; related to medical marijuana
-Anti-emetic mechanism unclear
-Potential for abuse

Scopolamine
Mechanism
-CNS muscarinic antagonist

Toxicity
-Dry mouth, blurred vision, sedation

Scopolamine
Clinical Use
-Motion sickness

Ipecacuanha
Clinical Use
-Emetic drug to induce vomiting in conscious patients

Apomorphine
Clinical Use
-Derivative of morphine
-Emetic drug that induces vomiting by acting on the CTZ (induces dopamine receptors)

Domperidone
Mechanism = peripheral dopamine-receptor antagonist; regulates the motility of gastric and small intestine smooth muscle

Clinical Use = short-term relief of GERD

Laxatives
Gastrointestinal Drugs
-Bulk forming
-Emollient
-Osmotic/Saline
-Stimulant
-Peripherally-acting opioid antagonists

Toxicity = electrolyte imbalances (can cause arrhythmia in elderly)

Bulk Forming
Mechanism
-Laxative
-High fiber; absorbs water to increase bulk, which distends bowel to initiate reflexive bowel activity
-Includes psyllium and methylcellulose

Bulk Forming
Indications
-Acute and chronic constipation
-Irritable bowel syndrome
-Diverticulosis

Emollient
Mechanism
-Laxative
-Softens and lubricates stool; promotes more water and fat in the stools
-Includes docusate salts (stool softener) and mineral oil (lubricant)

Emollient
Indications
-Acute and chronic constipations
-Fecal impaction
-Facilitation of bowel movements in anorectal conditions (want stool smooth)

Osmotic Laxatives
Gastrointestinal Drugs
-Magnesium hydroxide (saline)
-Magnesium citrate (saline)
-Polyethylene glycol (hyperosmotic)
-Lactulose (hyperosmotic)

Magnesium Hydroxide, Magnesium Citrate, Polyethylene Glycol
Mechanism
-Laxative
-Provide osmotic load to draw water out into the GI tract (former two drugs by generating salt gradient)

Magnesium Hydroxide, Magnesium Citrate, Polyethylene Glycol
Clinical Use
-Chronic constipation
-Diagnostic and surgical preps

Magnesium Hydroxide, Magnesium Citrate, Polyethylene Glycol, Lactulose
Toxicity
-Diarrhea
-Dehydration
-May be abused by bulimics

Lactulose
Mechanism
-Laxative
-Provide osmotic load to draw water out into the GI tract
-Gut flora degrade it into metabolites (lactic and acetic acid), which promotes nitrogen excretion as NH4+

Lactulose
Clinical Use
-Constipation
-Treatment of hepatic encephalopathy

Stimulant
Mechanism
-Laxative
-Increases peristalsis via intestinal nerve (however, can cause severe cramps)
-Includes Senna, Bisacodyl

Stimulant
Indications
-Acute constipation
-Diagnostic and surgical preps

Peripherally-acting Opioid Antagonists
Mechanism
-Blocks entrance of opioid into bowel (thus, treats constipation caused by opioids); allows bowel to function properly w/ opioid use (strict regulations)
-Includes Methylnaltrexone and Alvimopan

Diarrhea
Treatment
-Adsorbents
-Anticholinergics
-Opioid preparations (i.e. Loperamide)
-Intestinal flora modifiers

Adsorbents
Mechanism
-Anti-diarrheal
-Coats the walls of the GI tract
-Bind to causative bacteria or toxin, which is then eliminated through the stool
-Includes Bismuth subsalicylate, activated charcoal, and aluminum hydroxide

Anticholinergics
Mechanism
-Anti-diarrheal, anti-motility
-Decrease intestinal muscle tone and peristalsis of GI tract, resulting in slowed movement of fecal matter
-Includes belladonna alkaloids (atropine, hyoscyamine)

Opiates
Mechanism
-Anti-diarrheal, anti-motility
-Decrease bowel motility and relieve rectal spasms
-Increases transit time through the bowel, allowing more time for water and electrolytes to be absorbed and relieves pain of rectal spasms
-Includes paregoric, opium tincture, codeine, loperamide, diphenoxylate

Intestinal Flora Modifiers
Mechanism
-Anti-diarrheal
-Probiotics or bacterial replacement drugs
-Bacterial cultures of Lactobacillus organisms work by supplying missing bacteria to the GI tract, suppressing the growth of diarrhea-causing bacteria

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