Gastrointestinal And Anti-Emetic Drugs

Question 1

Drugs for Peptic Ulcer
Disease and GERD

General Considerations
• Two main causes of PUD

Answer 1

infection from Gram –
bacteria [H. pylori]

and use of NSAIDs

Increased production of HCl acid and inadequate mucosal defenses against gastric acid may also be a cause

Treatment aimed at clearing H. Pylori, reducing gastric acid and providing agents that protect the gastric tissues from damage

Question 2

Antimicrobials in GI Medicine

Answer 2

• Those with ulcers from H. pylori are treated with antibiotics—this infection is diagnosed by EGD or serology, fecal antigen or urea
breath tests

• Clearing H. pylori can be done with a
variety of combinations of antimicrobials & acid suppression—that result in rapid healing of ulcers and low recurrence rates

Antibiotics used in GI Medicine
• Amoxicillin
• Bismuth [Pepto-Bismol;
Kaopectate]
• Clarithromycin [Biaxin]
• Metronidazole [Flagyl]
• Tetracycline

Question 3

Antimicrobials

H pylori

Answer 3

• Currently, quadruple therapy with Pepto-Bismol, Flagyl, Tetracycline + PPI is regimen of choice [eradication rates of >90%] one week regimen then 6-7 weeks of PPI therapy

• Triple therapy with PPI, Amoxicillin [or Flagyl in those who are PCN allergic] and Biaxin is a great option when rates or Clarithromycin resistance are low, and the patient has not had any recent use of a macrolide 2 weeks treatment followed by 6 weeks of PPI

Question 4

H2 Blockers

General Considerations

Answer 4

HCl- acid is stimulated by histamine, acetylcholine and gastrin

• By competitively blocking the binding to H2 receptors—these agents reduce the secretion of gastric acid

• Cimetidine [Tagamet], Famotidine [Pepcid], Nizatidine [Axid] and Ranitidine [Zantac]—these drugs inhibit basal, food stimulated and nocturnal secretion of gastric acid, reducing acid secretion by about 70%

• Cimetidine is the prototype drug in the class—its use today is limited due to ADEs

Question 5

H2 Blockers

Mechanism of Action

Answer 5

Act selectively on H2 receptors in the stomach, without effecting H1 receptors

Competitive antagonists of histamine are fully reversible

Question 6

H2 Blockers

Therapeutic Actions

Answer 6

Treatment of

Peptic Ulcers
Acute Stress Ulcers
GERD

• In PUD, all 4 drugs are effective in
healing duodenal and gastric ulcers—but recurrence is common if H. pylori is present, and the patient is treated with H2B alone

• Those with PUD from NSAID use, ulcers should be treated with PPIs—because PPIs heal and prevent future ulcers more effectively than do H2 blockers

-For stress ulcers—these drugs are given IV infusion to prevent and manage acute symptoms—because tolerance can develop to these drugs, PPIs are often used in such
cases

-H2B are effective for GERD—they act by decreasing acid secretion—thus, they may not relieve heartburn for at least 45 minutes—antacids work more quickly and
efficiently to neutralize stomach acid—but their duration of action is short
-PPIs now used 1st line in treating GERD, especially for those with severe and frequent heartburn

Question 7

H2 Blockers

Pharmacokinetics

Answer 7

• Distribute widely after oral dose—even into breast milk and across the placenta
• Excreted in the urine
• Tagamet, Zantac and Pepcid are available IV
• ½ life of these drugs are prolonged in renal disease—dosage adjustments are needed

Question 8

H2 Blockers

Adverse Drug Effects

Answer 8

These drugs are tolerated well

• Cimetidine can have endocrine ADEs—gynecomastia, galactorrhea [it acts as a nonsteroidal antiandrogen], confusion, altered mentation [mainly in older adults, and after IV administration]

• H2Bs may decrease efficacy of drugs that need an acid environment to be absorbed [ketoconazole]

• Cimetidine inhibits many CYP 450 isoenzymes—so it can interfere with metabolism of many agents—Warfarin,
Phenytoin, Clopidogrel, others

Question 9

H+/K+ ATPase Proton
Pump Inhibitors

General Considerations

Answer 9

• These drugs bind to the H+/K+-ATPase enzyme system [proton pump] and suppress
the secretion of H+ ions into the gastric lumen

• Membrane bound proton pump is final step in the secretion of gastric acid

PPIs
Lansoprazole Prevacid
Dexlansoprazole Dexilant
Omeprazole Prilosec
Esomeprazole Nexium
Pantoprazole Protonix
Rabeprazole Aciphex

Question 10

H+/K+ ATPase Proton
Pump Inhibitors

Mechanism of Action

Answer 10

• PPIs are prodrugs with an acid-resistant enteric coatings—coating is broken down in the alkaline duodenum—the prodrug, a weak base, is then absorbed and transported to the parietal cell

• There it is converted to active drug and forms a stable covalent bond with the H+/K+-ATPase enzyme—it
takes about 18° for the enzyme to be resynthesized—and during this time—no acid

• At regular doses, PPIs inhibit both basal and stimulated gastric acid secretion more than 90 percent
-There is an oral agent of Omeprazole + NaHCO3 [Zegrid] that has a faster onset of action

Question 11

H+/K+ ATPase Proton
Pump Inhibitors

Therapeutic Uses

Answer 11

• More potent than H2Bs in reducing acid and healing ulcers

• Preferred agents for GERD, erosive esophagitis, duodenal ulcers, Zollinger-Ellison [hypersecretory] syndrome

• Reduce risk of bleeding from ulcer caused by ASA and NSAIDs

• Can be used for prevention or treatment of NSAID-induced
ulcers

• Stress ulcer prevention and management

• Can be used with antibiotics to treat Helicobacter pylori

Question 12

H+/K+ ATPase Proton
Pump Inhibitors

Pharmacokinetics

Answer 12

• Effective after oral dose

• Work best when taken 30-60 minutes before breakfast or the largest meal

• Dexilant has a dual released formula—and can be taken without any relation to a meal

• Nexium, Prevacid and Protonix are available IV

• Plasma ½ life is only a few hours—but have a long duration of action because of the covalent bonding with the H+/K+-ATPase enzyme

• Metabolites are excreted in urine and feces

Question 13

H+/K+ ATPase Proton
Pump Inhibitors

Adverse Drug Effects

Answer 13

• Drugs are well tolerated

• Prilosec and Nexium decrease the effectiveness of Plavix—they inhibit CYP2C19 and prevent conversion of Clopidogrel to its active form

• PPIs may increase risk of fractures—especially if used for 1 year or more

• Prolonged acid suppression with PPIs may result in low Vitamin B12 levels [acid is needed to absorb B12 from food]

• Elevated gastric pH may impair absorption of Ca++ carbonate

• Calcium citrate should be used as a Ca++ supplement in those on PPIs

• Diarrhea and C. difficile colitis can occur from these drugs

• Low magnesium, increased incidence of pneumonia in those taking PPIs for prolonged periods

Question 14

Prostaglandins

General Considerations

Answer 14

• Prostaglandin E1 produced by gastric mucosa, inhibits secretion of acid and stimulates secretion of mucus and HCO3 [cytoprotective]

• A deficiency of prostaglandins is thought to be involved in the pathology of peptic ulcers

• Misoprostol [Cytotec] is approved for the prevention of NSAID induced gastric ulcers

• Preventative use of Cytotec can be considered in those who take NSAIDs are at risk for NSAID-induced ulcers

• Cytotec is contraindicated in pregnancy—it can stimulate uterine contractions and cause miscarriage

• Dose related diarrhea is the most common ADE and limits the use of this agent

Question 15

Antacids

Answer 15

Weak bases that react with gastric acid to form water and a salt to diminish gastric acidity—antacids also decrease pepsin activity [pepsin is inactive at pH>4]

Aluminum hydroxide [Amphojel]
Aluminum hydroxide + magnesium
hydroxide + simethicone [Maalox]
Aluminum hydroxide + magnesium
hydroxide [Mylanta]
Calcium Carbonate [Tums]
Magnesium hydroxide [MOM]
Sodium bicarbonate [Alka-Seltzer]

Question 16

Antacids—Chemistry

Answer 16

• Antacids vary markedly amongst products

• Efficacy of an antacid depends on its capacity to neutralize gastric HCl and on whether the stomach is full or empty—
food delays stomach emptying, allowing more time for the antacid to react and prolonging the duration of action of
the medication

• Commonly used antacids—combinations of salts of aluminum and Mg++, such as aluminum hydroxide and Mg hydroxide; Ca++ carbonate reacts with HCl to form CO2 and CaCl2

• Systemic absorption of Na++HCO3 can cause transient metabolic alkalosis and produce significant Na++ loads—thus, it is not a recommended antacid

• Used for symptomatic relief of PUD, heartburn, GERD

• Should be given pc meals to be most effective

• CaCO2 [Tums] can be used as a Ca++ supplement to prevent osteoporosis

Question 17

Antacids

Adverse Drug Effects

Answer 17

• Aluminum hydroxide—constipation

• Magnesium hydroxide—diarrhea

• Preparations that combine these two help in normalizing bowel function

• Absorption of magnesium, aluminum and calcium is not a problem in those with normal renal function—but accumulation and ADEs can occur in those with renal
disease

Question 18

Mucosal Protective
Agents

General Considerations

Answer 18

• Also called cytoprotective compounds

• These drugs have actions to enhance mucosal protection mechanisms—thus preventing mucosal injury, reducing
inflammation and healing ulcers

• Sucralfate—Carafate
• Bismuth subsalicylate—Pepto-Bismol

Question 19

Sucralfate

Answer 19

• Complex of aluminum hydroxide and sulfated sucrose binds to + charged groups in proteins of both normal and necrotic mucosa

• By forming a complex gel with epithelial cells, Carafate creates a physical barrier that protects the ulcer from pepsin and acid,
allowing the ulcer to heal

• Effective to treat duodenal ulcers and prevent stress ulcers—its use is limited due to the need for multiple daily doses, drug-
drug interactions.

• It requires an acidic pH for activation—should not be given with PPIs, H2B or antacids

• Well tolerated; it can bind to other drugs and interfere with their absorption

Question 20

Bismuth subsalicylate

Answer 20

• Used as part of quadruple therapy to treat H. Pylori

• It has antimicrobial actions—it inhibits the activity of pepsin, increases secretion of mucous and interacts with glycoproteins in necrotic mucosa to coat and protect the
ulcer

Question 21

Drugs use for Nausea
and Vomiting

General Considerations

Answer 21

• Nausea and vomiting—regardless of the cause—is always unpleasant

• Nausea and vomiting produced by chemotherapy requires effective management

• Several things influence severity of nausea and vomiting from chemotherapeutic drugs—the drug prescribed—dose, route and schedule and patient variables—the young and women are more susceptible to the SE of chemotherapy

• Nausea and vomiting—regardless of the cause can cause dehydration, electrolyte imbalances and nutritional deficiencies

• Two sites in the brainstem pay a role in vomiting

• Chemoreceptor trigger zone [CTZ]—located in postrema—it is outside the blood-brain barrier—it can respond directly to chemical stimuli in the blood or CSF

• Vomiting center—located in lateral reticular formation of the medulla, coordinates the motor mechanisms of vomiting; also responds to afferent input from the
vestibular system, the periphery and higher brainstem and cortical structures

Question 22

Drugs for Nausea

Answer 22

• Anticholinergics, especially the muscarinic
receptor antagonist Scopolamine and H1Bs,
such as dimenhydrinate [Dramamine], Meclizine [Antivert], cyclizine [Bonine] useful in motion sickness but not helpful for post-operative nausea, nausea from gastroenteritis or nausea from chemotherapy

• Phenothiazines
• 5-HT3 receptor blockers
• Substituted benzamides
• Butyrophenones
• Benzodiazepines
• Corticosteroids
• Substance P / Neurokinin-1
receptor antagonists
• Combination regimens

Question 23

Phenothiazines

Answer 23

• These agents act by blocking dopamine receptors in the CTZ in the brain

• Prochlorperazine [Compazine] is the prototype in this category of anti-emetics
-Used for low or moderately emetogenic chemotherapy agents
-Can also be used for post-op nausea and vomiting and for vomiting associated with gastroenteritis
-Not approved for children < 2 years

• Promethazine [Phenergan] is another phenothiazine anti-emetic—used for post-operative nausea and vomiting and GI associated nausea and vomiting; not approved in those less than 2 years

• ADEs limits high dose, prolonged use

Question 24

5-HT₃ Receptor Blockers

Answer 24

• These drugs selectively block the 5-HT3 receptors in the periphery and in the CTZ

• These are superior to other agents for chemotherapy nausea and vomiting—and can be used for nausea from other causes

• For chemotherapy—these agents can be used as a single dose [IV or oral] before chemo and work well against all stages of nausea and vomiting from chemo

• Ondansetron [Zofran]—is the prototype drug in the category

• 5-HT3 drugs not recommended in children, but Zofran can be used in those 4 and older on chemo

Question 25

5-HT₃ Receptor Blockers

Answer 25

• Dolasetron [Anzemet]
• Granisetron [Sancuso patch, Kytril, Sustrol]
• Palonosetron [Aloxi]

• Ondansetron and Granisetron prevent >50% of vomiting in patients treated with Cisplatin; and very effective in the post-op patient

• These drugs are metabolized by the liver, only Zofran requires dose reduction in those with liver disease

Question 26

5-HT₃ Receptor Blockers

Answer 26

These drugs are excreted in the urine

• QT prolongation can occur with high dose Zofran and Anzemet [dolasetron]

• Intravenous Dolasetron is no longer approved to prevent nausea and vomiting [given before the chemo infusion] because of the QT effects—but can be used for symptomatic treatment in the cancer patient

Question 27

Substituted Benzamides

Answer 27

• These agents work by inhibiting dopamine in the CTZ

• Metoclopramide [Reglan] is the prototype drug in the category

• Very effective [>30%] of vomiting from Cisplatin is prevented, and markedly reduced in most with this drug

• Because of the potential for EPS—this drug is never recommended long term or in high doses

• Effective in the treatment of diabetic gastroparesis—but even though lower doses are used—risk of EPS is still a major concern

• The other drug in this category is Trimethobenzamide [Tigan]

• Used for post-operative or gastroenteritis related nausea and vomiting

• Very effective, but risk of EPS is what limits the use of this drug long term

• Not approved to be used in children

Question 28

Butyrophenones

Answer 28

• These drugs work by blocking dopamine receptors
• Moderately effective anti-emetics

• Droperidol [Inapsine]
• Haloperidol [Haldol]
• Inapsine used most often for sedation for EGD and surgery—with opioids or benzodiazepines—these not used
commonly for nausea and vomiting—because they may prolong the QTc interval—these agents now reserved for those resistant to other anti-emetics

Question 29

Benzodiazepines

Answer 29

• Lorazepam [Ativan]
• Alprazolam [Xanax]

• The efficacy for nausea and vomiting is low—their true benefit may be from the sedative, anxiolytic and amnesic properties

• Useful in anticipatory vomiting

Question 30

Corticosteroids

Answer 30

• Dexamethasone [Decadron]
• Methylprednisolone [Depo-Medrol]
• Mildly to moderately effective for chemotherapy induced nausea and vomiting—MOA is unknown—may involve blocking prostaglandins
• Often used with other agents

Question 31

Substance P/Neurokinin-1 Receptor Antagonists

Answer 31

• These drugs target the neurokinin receptor in vomiting center and block the actions of substance P

• The oral agents are indicated for highly or moderately emetogenic chemotherapy drugs—these are usually given with dexamethasone and a 5-HT3 antagonist

• These drugs work well for the late phase of
chemotherapy nausea and vomiting—which happens 24 or more hours after the chemo infusion

Generic Agent Brand Name
Aprepitant Emend
Fosaprepitant Emend injection
Netupitant Akynzeo
Rolapitant Varubi

Question 32

Substance P/Neurokinin-1 Receptor Antagonists

Answer 32

• Aprepitant and Rolapitant undergo hepatic
metabolism—primarily by CYP34A—coadministration with inhibitors/inducers of CYP34A [Biaxin or St. John’s Wort] should be avoided

• Aprepitant induces CYP34A and CYP2C9 and shows a dose-dependent inhibition of CYP3A4—therefore, it can affect the metabolism of many other drugs that are substrates of these isoenzymes—many drug-drug interactions with Emend

• Rolapitant moderately inhibits CYP2D6

• ADEs—fatigue, diarrhea, abdominal pain and hiccups

Question 33

Combination Regimens

Answer 33

• Dexamethasone increases anti-vomiting activity when given with high-dose Reglan, 5-HT3 antagonists, phenothiazines, butyrophenones or a benzodiazepine

• Antihistamines, such as Dramamine, can be used with high dose Reglan to reduce EPS reactions or with corticosteroids to reduce Reglan induced diarrhea

Question 34

Antidiarrheals

General Considerations

Answer 34

• These drugs include antibody agents, adsorbents and drugs that modify fluid and electrolyte transport

Antimotility Agents

• Diphenoxylate + atropine [Lomotil]
• Loperamide [Imodium]
• These drugs are analogs of Demerol and have opioid like actions on the gut [no analgesic effects at usual dosages]
• They activate presynaptic opiate receptors in the enteric NS to inhibit acetylcholine release and decrease peristalsis
• Imodium is first line to treat acute diarrhea, traveler’s diarrhea
• Both of these agents can cause toxic megacolon, so they should not be prescribed in young children or in those with severe colitis

Question 35

Other Antidiarrheals

Absorbents

Answer 35

• Aluminum hydroxide [Amphojel]
• Methylcellulose [Citrucel]
• Use to control diarrhea
• These agents act by absorbing intestinal toxins or bacteria and/or by coating or protecting the intestinal mucosa
• Less effective than antimotility drugs
• They can interfere with absorption of other drugs

Question 36

Other Antidiarrheals

Agents that Modify Fluid and
Electrolyte Transport

Answer 36

• Bismuth subsalicylate [Pepto-Bismol]
• Used to prevent and treat Traveler’s
diarrhea, it decreases fluid secretion in the gut
• Action may be from its salicylate component as well as its coating action
• ADEs include black tongue and black stools
• Avoid in children under 12 years—because of the subsalicylate

Question 37

Laxatives

General Considerations

Answer 37

• These drugs increase the potential for loss of drug effects of poorly absorbed, delayed-acting and extended release oral preparations by accelerating their transit through the intestines

• These drugs may also cause electrolyte imbalances if used chronically

Question 38

Irritants and Stimulants

Senna

Answer 38

• Ex-Lax
• Senokot

• Stimulant—active ingredient is a complex of anthraquinone glycosides
• After oral dose, bowels evacuate in 6-12°
• Pulls water and electrolytes into the bowel
• It can be combined with stool softeners [docusate] for severe constipation—
Pericolace

Question 39

Irritants and Stimulants

Bisacodyl

Answer 39

• Correctol
• Dulcolax

• Available as suppositories and enteric
coated tablets
• Potent stimulant of the colon
• It acts directly on nerve fibers in the mucosa of the colon

Question 40

Irritants and Stimulants

Castor Oil

Answer 40

Generic

• Castor oil is broken down in small bowel into ricinoleic acid, which irritates the
stomach and increase peristalsis
• Avoid in pregnancy—it could stimulate contractions
• Not a DOC because it tastes bad and has potential for GI adverse SE

Question 41

Bulk Laxatives

Answer 41

• Methylcellulose [Citrucel]; Psyllium [Metamucil]

• Hydrophilic colloids [undigestible parts of fruits and vegetables]—that form gels in the large colon, causing water retention and intestinal distention—thereby increasing peristalsis

• Citrucel, Metamucil and Bran all have similar actions

• Use cautiously in those that are immobile because they can cause intestinal obstruction

• Psyllium can reduce the absorption of other oral drugs and other drugs should be separated from Metamucil by at least 2 hours or more

Question 42

Saline and Osmotic Laxatives

Answer 42

• Magnesium citrate
• Magnesium hydroxide [MOM]
• Nonabsorbable salts that hold water in the gut by osmosis

Polyethylene glycol [GoLytely]
• Electrolyte solution used as colonic prep prior to radiology or endoscopic procedures
• PEG powder for solution without electrolytes is also used as a laxative [MiraLAX]
• Thought to cause less cramping and flatus than others in this category

Lactulose [Chronulac; Enulose]
• Semisynthetic disaccharide solution that acts as an osmotic laxative—not hydrolyzed by GI enzymes
• The oral solution gets into the gut and broken down by colon bacteria into lactic, formic and acetic acids—which increases osmotic pressure, causing fluid
accumulation into the gut, distention of the bowel, soft stools and defecation
• Can also be used for hepatic encephalopathy, because it decreases NH3 levels

Question 43

Stool Softeners

Answer 43

• Emollient Laxatives or Surfactants

• Surface active agents that soften stools and ease its passage through the gut
• Docusate sodium [Colace]
• Docusate calcium [Surfak]

• May take days to work and can be used to prevent [rather than acutely treat] constipation
• Should not be used with mineral oil because of the potential to absorb the mineral oil

Question 44

Lubricant Laxatives

Answer 44

• Mineral oil
• Glycerin suppositories
• Lubricants that facilitate the passage of hard stools
• Patient should take mineral oil orally in an upright position

Question 45

Chloride Channel Activators

Answer 45

Lubiprostone [Amitiza]

• Activates Cl- channels to increase fluid secretion in the gut—which eases the passage of stools and causes little change in electrolytes
• Used to treat chronic constipation and IBS-C because there is no evidence of dependency and tolerance to this
medication

Question 46

Irritable Bowel Syndrome

General Considerations

Answer 46

• Syndrome of chronic abdominal pain and altered bowel habits in the absence of pathology

• Classified as either constipation predominant [IBS-C], diarrhea predominant [IBS-D] or combined IBS

• Several options for treatment—based on the patient’s presentation

Question 47

Drugs for IBS

Answer 47

Linaclotide [Linzess]

IBS-C

MOA
↑ intestinal fluid via
↑ cGMP

ADE
Diarrhea; abdominal pain;
flatus; not for those <17 yrs

Question 48

Drugs for IBS

Answer 48

Lubiprostone [Amitiza]

IBS-C
[women]

MOA
Cl- channel activator

ADE
Dyspepsia, n/v, HA, dizziness, low BP

Question 49

Drugs for IBS

Answer 49

Alosetron
[Lotrenex]

IBS-D
[women;
severe dx]

MOA
5-HT3 antagonist

ADE
Constipation; n/v; heartburn; ischemic colitis [rare]

Question 50

Drugs for IBS

Answer 50

Eluxadoline
[Viberzi]

IBS-D

MOA
μ Opioid receptor
agonists

ADE
Constipation; n/v; abdominal pain; pancreatitis [rare]; risk of dependence and OD

Question 51

Drugs for IBS

Answer 51

Rifaximin
[Xifaxan]

IBS-D
[short-term
use]

MOA
↓ bacterial load

ADE
Fatigue; HA; nausea; dizziness; edema; risk of C. difficile

Question 52

Drugs for IBS

Answer 52

Dicyclomine
[Bentyl]

IBS-C
IBS-D

MOA
Antimuscarinic ↓ GI
spasms & motility

ADE
Drowsiness; dry mouth

Question 53

Drugs for IBS

Answer 53

Hyoscyamine
[LevBid]
[Levsin]

IBS-C
IBS-D

MOA
Antimuscarinic ↓ GI
spasms & motility

ADE
Dizziness; dry mouth; if OD—hallucinations, n/v, arrhythmias

Question 54

Drugs Used to Treat
Inflammatory Bowel
Disease [IBD]

General Considerations

Answer 54

IBD is a group of immune mediated GI disorders—inflammation in the intestine in response to bacterial antigens in the lumen of the bowel
• Ulcerative Colitis [UC]
• Crohn’s Disease [CD]

CD can involve any part of the bowel from mouth to the anus in a non-continuous fashion—transmural inflammation

UC usually involves rectum, it may extend continuously to other parts of the bowel—inflammation of the mucosal surface of the colon

Severity and extent of disease determines drugs that are prescribed for IBD

• Remission can be obtained with 5-aminosalicylates [rectal or oral]; corticosteroids [rectal, oral, IV]; biologics [TNF-ἀinhibitors; integrin inhibitors; IL-12/23 inhibitors]

• Drugs used to maintain the remission are the same as the inducers—in addition, the immunomodulators can be used to keep the patient in remission—Azathioprine, 6-
mercaptopurine and methotrexate

Question 55

5-Aminosalicylates

General Considerations

Answer 55

Two formulas of 5-ASA compounds
• Azo agents
• Mesalamine agents

• Azo compounds are prodrugs that consist of 5-ASA bound to an Azo with another molecule

• Mesalamine agents are a single 5-ASA molecule enclosed within an enteric coat or a semipermeable membrane

• Azo agents—Balsalazide [Giazo]; Olsalazine [Dipentum]; Sulfasalazine [Azulfidine]

• Mesalamine agents—Asacol or Pentasa [oral agents]; Rowasa [rectal enema]; Canasa [rectal suppository]

Question 56

5-Aminosalicylates

Answer 56

The prototype drug is Sulfasalazine

• It is a prodrug consisting of 5-ASA linked to
sulfapyridine; colon bacteria cleave Sulfasalazine to produce 5-ASA [mesalamine] and sulfapyridine

• When it was discovered that 5-ASA was the reason that sulfasalazine was effective [and the sulfapyridine was causing the ADEs], unlinked formulas of this agent were made—unfortunately, these unlinked formulas
are not as effective—thus the birth of newer azo agents and the different formulations of mesalamine products

Question 57

5-Aminosalicylates—Actions

Answer 57

• These newer mesalamine formulations and the newer azo compounds are better tolerated with similar efficacy to Sulfasalazine—making them the mainstay of UC therapy

MOA—anti-inflammatory and immunosuppressant properties—exact MOA of 5-ASA is unknown, but thought to be:

• Inhibition of cytokine synthesis
• Inhibition of leukotriene and prostaglandin synthesis
• Scavenging of free radicals
• Inhibition of T-cell proliferation, activation and differentiation
• Impairment of leukocyte adhesion and function

• 5-ASA is thought to act by topical interaction with the intestinal mucosa—whether given orally or rectally

• Uses—workhorses in treatment of UC; ALL 5-ASA products and Sulfasalazine are used for induction and maintenance of remission in UC

• EBG call for these agents as first line in mild to moderate UC

• Use of 5-ASA in CD is limited as they are not very efficacious

Question 58

5-Aminosalicylates—Pharmacokinetics

Answer 58

5-ASA pharmacokinetics vary based on route, type of formulation prescribed and severity of disease activity
• Absorption of 5-ASA is increased with more severe disease, and is decreased with lower pH
• In UC, 5-ASA work by local effect
• Absorption of these agents given rectally and systemic exposure depends on length of rectal retention
• Differences in systemic exposure may explain some of the ADEs
• Sulfasalazine is given orally, with 60-80% absorption

Question 59

5-Aminosalicylates—ADEs

Answer 59

• ADEs occur in 45% of those that take Sulfasalazine—headache, nausea, fatigue are the most common
• Rare—but more serious ADEs—hemolysis, myelosuppression, hepatitis, pneumonitis, nephrotoxicity, fever, rash and SJS
syndrome
• Drug must be stopped if a rash occurs
• Sulfasalazine reversibly impairs male fertility
• Sulfasalazine inhibits intestinal folate absorption and folate supplements are needed in the patient taking this rug chronically
• Newer mesalamine agents are well tolerated—headache, dyspepsia are the most common ADEs; acute interstitial nephritis [rare] ADE

• Olsalazine—causes diarrhea in 20% of those that take it

• Some mesalamine drugs depend on the pH for their effective release—and use of drugs that increase the pH [PPIs, H2Bs, antacids] cause increased systemic absorption and premature release of the 5-ASA before it
gets to its site of action

Question 60

Corticosteroids

General Considerations

Answer 60

Used for anti-inflammatory effects, as they are in other diseases
• Effective in inducing remission in IBD—but long-term maintenance should be avoided because of marked ADEs
• Rectal formulas [hydrocortisone enemas and budesonide foam] have fewer ADEs than systemic steroids—but they are only effective in left sided disease
• Enteric released drugs of oral budesonide deliver the steroid to a portion of the inflamed bowel—few ADEs due to low bioavailability from extensive 1st pass effect

Delayed release budesonide delivers drug to terminal ileum and proximal large bowel and it is used in ileocecal CD

• ER budesonide delivers drug throughout the colon and is used in UC patients that have pancolitis—this agent, although effective, is not used in long term maintenance of remission because of risk of ADEs of steroids

Question 61

Biologics for GI
Disease

General Considerations

Answer 61

• TNF-ἀ inhibitors
• ἀ-4 integrin inhibitors
• IL 12/23 inhibitor

• Used in the management of IBD
• Are associated with increased risk of infections
• Patients must be checked for TB and treated for latent TB should be considered BEFORE these drugs are initiate

Question 62

TNF-α Inhibitors

Answer 62

• Infliximab [prototype drug] Remicade
• Adalimumab—Humira
• Certolizumab—Cimzia
• Golimumab—Simponi

• Remicade & Humira indicated for moderate to severe CD and UC

• Cimzia indicated for moderate to severe CD

• Simponi indicated for moderate to severe UC

• These drugs are 2nd line in those with UC who have failed 5-ASA, are unresponsive to or dependent upon steroids or who present with more severe disease

• In CD, the TNF-α inhibitors are 1st line in those with moderate to severe disease and those at high risk of progression

• These drugs are associated with development of immunogenicity and antidrug antibodies that can result in loss of response in a large number of patients

Question 63

α-Integrin Inhibitors

Answer 63

• Vedolizumab [Entyvio]

• Adhesion molecules that promote WBC migration to sites of inflammation
• These drugs reduce WBC migration into the intestine mucosa and inflammation
• This drug in IBD is reserved for refractory cases, that have failed TNF-α drugs
• Entyvio exhibits specific binding to α-4/ß-7 integrin and is indicated for refractory UC and CD
• ADEs—HA, arthralgia, nausea, fatigue, MSK pain

Question 64

IL-12/23 Inhibitors

Answer 64

Ustekinumab [Stelera]

• Inhibits cytokines IL-12 and IL-23 involved in lymphocyte activation

• Indicated for psoriasis, psoriatic arthritis, induction and maintenance of remission in CD in those refractory to or intolerant to an TNF-α , immune modulators or steroids

• ADEs—HA, arthralgia, infection, nausea and
nasopharyngitis

Question 65

Immune Modulators

General Considerations

Answer 65

Immune modulators most commonly used in IBD:

• Methotrexate
• Azathioprine [Imuran]
• 6-Mercaptopurine
• MTX is also used in cancer, RA and psoriasis
• Imuran is sometimes used in kidney transplant

Question 66

Immune Modulators

Methotrexate

Answer 66

• Structural analogue of folic acid that inhibits the production of folinic acid

• MOA in CD is unknown
• Only IM or SQ MTX works in CD
• It is recommended as monotherapy for maintenance of remission in CD, but is NOT recommended in UC

• ADEs—headache, n/v, abdominal discomfort, elevated LFTs, rash
• Daily folic acid supplement helps reduce GI SE and is recommended

Question 67

Thiopurines

Answer 67

Azathioprine and 6-mercaptopurine are oral meds that have steroid sparing effects in those with UC or CD

• 1st line as monotherapy to maintain remission
• Use of these agents in IBD is limited due to concerns regarding toxicity, including BM suppression and liver toxicity
• Monitoring of CBC and LFTs is necessary