GI Drugs Part 2

Question 1

What is constipation?

Answer 1

• Defined as a stool frequency of less than three per week.
• In the absence of an underlying medical condition, lifestyle modifications such as increasing dietary fiber
and physical activity are the first line strategy.
• Patients may become dependent on over-the-counter laxative use for bowel evacuation, or may abuse them in weight loss attempts.

Question 2

What are three Bulk-forming Laxatives? Overview and contraindications?

Answer 2

• Methylcellulose
• Psyllium
• Bran
• Nondigestible colloids which absorb water to form a
bulky, soft jelly that distends the colon to promote
peristalsis.
• Relatively contraindicated in immobile patients and
patients on long term opioid therapy as intestinal
obstruction may result.

Question 3

Cathartics (stimulant laxatives) action and three examples?

Answer 3

• Directly stimulate the enteric nervous system to
increase intestinal motility.
• Castor oil is broken down into ricinoleic acid in the
small intestine.
• Contraindicated in pregnancy as this intermediary may
cause uterine contractions.
• Bisacodyl acts at the level of the colon.
• Minimal systemic absorption, thus is safe for both acute and long term use.
• Senna
Occurs naturally in the plant of the same name.
Chronic use may lead to melanosis coli, which is a
harmless brown pigmentation of the colonic
mucosa that is unrelated to colon cancer risk.

Question 4

Name 2 stool softeners and moa?

Answer 4

• Docusate
• Glycerin
• Surfactants which allow water to penetrate and
thereby soften formed stool in the bowel.

Question 5

What is a lubricant laxative and moa?

Answer 5

• Mineral oil
• Coats fecal material preventing water reabsorption.
• Should not be given with docusate as the mineral
oil will be absorbed into the stool thereby negating
its laxative effect.

Question 6

What are 3 osmotic laxatives, moa, ae, and contraindication?

Answer 6

• Lactulose
• Magnesium salts such as magnesium hydroxide,
magnesium sulfate.
• Nonabsorbable sugars or salts which exert an osmotic
pull to retain water in the intestinal lumen.
• Lactulose is metabolized by colonic bacteria and can
lead to severe flatus with cramping.
• Magnesium salts should not be used for prolonged
periods in persons with renal insufficiency as they may
cause hypermagnesemia.

Polyethylene glycol (PEG)
• Water soluble polymer
• Low toxicity and negligible systemic absorption.
• Generates high osmotic pressures in the gut lumen.
• Commonly used for complete bowel preparation
before gastrointestinal endoscopic procedures.
• Does not produce significant flatus or cramping.
May be preferred for management of chronic
constipation in selected patients.

Question 7

Lubiprostone moa, indications, ae, and contraindications?

Answer 7

• Stimulates the type 2 chloride channels of the
small intestine.
• Increases the secretion of chloride à intestinal motility.
• Indications:
• Chronic constipation including irritable bowel syndrome with predominant constipation.
• Most common adverse effect - diarrhea.
• Contraindicated in children.

Question 8

Selective Mu-Opioid Receptor Antagonists 2 examples, overview, and action.

Answer 8

• Alvimopan
• Methylnaltrexone
• Both acute and chronic use of opioid analgesics causes
constipation due to decreased intestinal mobility.
• This adverse effect is not subject to tolerance.
• Selective mu-opioid receptor antagonists do not cross the blood-brain barrier and thus do not negate the
analgesic effect of opioids.
• Act at the level of the gut to maintain normal motility.

Question 9

Name 2 opioid agonists and overview?

Answer 9

• Loperamide
• Diphenoxylate
• Analogs of the opioid meperidine which activates
presynaptic mu-opioid receptors in the enteric
nervous system to inhibit ACh release and decrease
gut peristalsis.

Question 10

Characteristics of Loperamide and dioxyphenolate? Contraindications?

Answer 10

• Loperamide - low potential for addiction as it has
no analgesic/euphoric properties.
• Dioxyphenolate - higher doses can have CNS
effects and, with prolonged use, lead to opioid
dependence.
• Both drugs are contraindicated in children and patients with severe colitis

Question 11

Somatostatin Analogs example, indications?

Answer 11

• Somatostatin is a key endogenous regulatory
peptide of enteric function.
• Octreotide is a synthetic octapeptide with thirty
times the serum half-life of somatostatin.

• Indications:
• Secretory diarrhea due to neuroendocrine tumors
such as carcinoid and VIPoma.
• Diarrhea caused by vagotomy, dumping syndrome,
short bowel syndrome and AIDS.

Question 12

Somatostatin AE?

Answer 12

• Adverse effects:
• Decreased pancreatic exocrine function.
• Resultant steatorrhea can lead to deficiency of fat-soluble vitamins.
• Inhibition of gallbladder contractility leads to the formation of biliary sludge which may precipitate to gallstones.

Question 13

Overview of Bismuth compounds?

Answer 13

• Bismuth subsalicylate (e.g. Pepto-Bismol)
• Controls traveler’s diarrhea by decreasing fluid
secretion in the enteric tract.
• This effect is due to both its coating action and the
salicylate component.

Question 14

What is Irritable Bowel Syndrome?

Answer 14

• Functional disorder of chronic abdominal pain
associated with altered bowel habits in the absence
of an organic gastrointestinal disease.
• Classified according to predominance of diarrhea or
constipation.
• Patients treated according to symptomatic subtype.

Question 15

First line strategy for IBS?

Answer 15

• First line strategy does not involve medication.
• Patients may keep a food diary and try sequential:
1. Exclusion of gas-producing foods.
2. Low fermentable oligo-, di-, and
monosaccharides and polyols (FODMAPs).
3. Lactose and/or gluten omission.

• Moderate to severe symptoms of irritable bowel
syndrome (IBS) that impair quality of life qualify for
pharmacologic intervention.
• Constipation predominant IBS - chloride channel
activator laxative lubiprostone.

Question 16

Diarrhea predominant IBS pharmacological intervention?

Answer 16

1. Opioid agonists such as loperamide.
2. The 5-HT3 antagonist alosetron - inhibits afferent 5- HT3 receptors to reduce noxious visceral sensations
   such as bloating, nausea and pain.
3. Anticholinergics such as hyoscyamine, dicyclomine,
   glycopyrrolate and methscopolamine – antispasmodic effect on the G.I. tract.

Question 17

Role of Anticholinergics in IBS?

Answer 17

• Small or large bowel spasm has not been found to be an important cause of IBS symptoms.
• Also, cholinergic blockade results in many
unpleasant side effects.
• The use of anti-cholinergics is now limited to shortterm relief of acute diarrhea predominant
episodes.

Question 18

What is Inflammatory Bowel Disease?

Answer 18

Ulcerative colitis and Crohn’s disease together
comprise the clinical entity of Inflammatory
Bowel Disease (IBD).
The selection of pharmaceutic treatments for
IBD is guided by:
1.Symptom severity and responsiveness
2.Anatomic distribution of disease
3.Drug toxicity

Question 19

Name 3 aminosalicylates?

Answer 19

• Sulfasalazine
• Balsalazide
• Mesalamine

Question 20

aminosalicylates use and active group?

Answer 20

• Used for long term maintenance of IBD remission.
• Active group is 5-aminosalicylic acid (5-ASA).
• Exact mechanism of action of 5-ASA remains
unknown.

Question 21

Aminosalicylates MoA Theories?

Answer 21

• Modulation of both the cyclooxygenase and lipoxygenase pathways.
• Inhibition of the activity of nuclear factor-κB (NF-κB), an
important transcription factor for proinflammatory
cytokines.
• Inhibition of cellular immunity mechanisms.
• Scavenges reactive oxygen metabolites.

Gross reduction of inflammatory
mediators with resultant control of IBD
processes.

Question 22

Factors that determine clinical efficacy for Aminosalicylates and PK?

Answer 22

• The clinical efficacy of 5-ASA depends on achieving
high concentrations at the target sites.
• Suppository or enema forms are useful in patients
with isolated sigmoid colon or rectal disease.

PK:
• Orally administered 5-ASA would be almost
completed absorbed in the jejunum.
• No therapeutic effect in the more distal ileum,
colon and rectum would be obtained.

Question 23

Sulfasalazine overview?

Answer 23

Sulfasalazine consists of 5-ASA linked to sulfapyridine by an azo bond.
• The sulfapyridine group functions to reduce
absorption of this formulation in the jejunum after
oral ingestion, resulting in higher drug availability
in the distal small intestine and colon.

Question 24

Sulfasalazine MOA?

Answer 24

1. The majority of the given dose passes into the colon, where sulfasalazine is reduced by coliform bacterial enzyme, azoreductase, to sulfapyridine and 5-ASA.
2. 5-ASA is able to act
   therapeutically in the colon and may even “backwash” into the terminal ileum to act there.

Question 25

AE of sulfasalazine?

Answer 25

• Up to 40% of patients are unable to tolerate sulfasalazine. • Adverse effects are dose related and commonly include nausea, GI upset, headaches, arthralgias, myalgias, bone marrow suppression and hypersensitivity reactions. • Most of these side effects are attributed to systemic absorption of the sulfapyridine group.

Question 26

Overview of Balsalazide?

Answer 26

• Balsalazide consists of one 5-ASA linked to an inert, unabsorbed carrier molecule. • Similarly, this formulation will deliver maximal amounts of 5-ASA to the colon. • The inert carrier molecule causes no adverse effects. Balsalazide is generally well tolerated.

Question 27

Overview of Mesalamine?

Answer 27

• Mesalamine - physically packaged 5-ASA in timed-release or pH sensitive microgranules that release the active drug into the desired specific portion of the gut actively affected by IBD. • Balsalazide is generally well tolerated.

Question 28

Name 3 glucocorticoids and the action of glucocorticoids?

Answer 28

• Prednisone • Prednisolone • Budesonide • Used to induce remission of acute exacerbations of IBD. • Not indicated for maintaining remission. • Immunosuppressive and anti-inflammatory effects via : • interaction with intracellular glucocorticoid response elements. • inhibition of phospholipase A2 and cyclooxygenase. • inhibition of nuclear factor-κB.

Question 29

Glucocorticoids pk and ae?

Answer 29

• Prednisone and prednisolone have an intermediate duration of action which allows for once daily dosing. • Glucocorticoids of choice for oral therapy in IBD. • Hydrocortisone is administered via enema for sigmoid and rectal IBD flares. • IBD patients treated with these drugs are subject to steroid adverse effects including adrenal suppression, hyperglycemia, immunosuppression and osteoporosis.

Question 30

Overview of Budesonide?

Answer 30

• Budesonide – used for topical effects on the luminal surface of inflamed bowel. • Following enteric absorption, undergoes rapid first- pass metabolism thus has low systemic bioavailability. • The benefit of using budesonide is the significantly decreased rate of systemic adverse effects as compared to prednisolone.

Question 31

Name 2 immunosuppressants? Overview of action?

Answer 31

• Mercaptopurine (6-MP) • Azathioprine • Immunosuppressive purine metabolites. • Indicated for induction and maintenance of IBD remission. • Steroid sparing effect. • Dose related toxicities - nausea, vomiting, hepatotoxicity and bone marrow depression.

Question 32

Immunosuppressive Purine | Metabolites moa, ae and use guidelines?

Answer 32

ol markedly reduces xanthine oxidase activity. • Xanthine oxidase breaks down 6-MP. • Co-administration of allopurinol with 6-MP can precipitate life threatening leucopenia. • Allopurinol is to be used with caution in patients taking 6-MP or azathioprine.

Question 33

Methotrexate moa, dosage?

Answer 33

• Methotrexate • Inhibits dihydrofolate reductase, an enzyme important in the production of thymidine and purines. • Given at relatively low doses which do not have antiproliferative effects. • Reduces the inflammatory actions of Interleukin-1.

Question 34

Methotrexate AE?

Answer 34

• Adverse effects - bone marrow depression, megaloblastic anemia and mucositis. • The risk of these adverse effects is reduced by folate supplementation. • Folate supplementation does not reduce the antiinflammatory actions of the drug.

Question 35

Anti-TNF-α Drugs?

Answer 35

* Infliximab * Adalimumab • Bind and inactivate human Tumor Necrosis Factor (TNF). • Indicated in acute and chronic treatment of IBD. • Infliximab - for moderate to severe colitis which is not responsive to mesalamine or corticosteroids.

Question 36

TNF is a key mediator of?

Answer 36

• Release of proinflammatory cytokines. • Stimulation of hepatic acute phase reactants. • Upregulation of endothelial adhesion molecules promoting leukocyte migration.

Question 37

Anti-TNF-α Drugs – Adverse Effects?

Answer 37

• Suppression of Th1 activity -> • Severe infections including invasive fungal disease. • Reactivation of latent tuberculosis. • Antibodies may develop against these biologics -> • Elimination of clinical response to therapy. • Acute or delayed infusion reactions. • Increased risks of lymphoma, acute hepatic failure and congestive heart failure have also been reported.

Question 38

Overview of Anti-integrins?

Answer 38

• Natalizumab • Humanized monoclonal antibody targeting several integrins on circulating inflammatory cells. • Disruption of leukocyte vascular wall adhesion and subsequent tissue migration. • Indicated in moderate to severe, unresponsive Crohn’s disease.

Question 39

Anti-integrins AE?

Answer 39

``` • Infusion reactions • Opportunistic infections • Reactivation of the human polyomavirus (JC virus) resulting in progressive multifocal leukoencephalopathy. ```

Question 40

Define Exocrine Pancreatic insufficiency, causes, and clinical features?

Answer 40

When secretion of pancreatic enzymes falls below 10% of normal, fat and protein digestion is impaired. ``` CAUSED BY • Cystic fibrosis • Chronic pancreatitis • Pancreatic resection CLINICAL FEATURES • Steatorrhea • ADEK vitamin malabsorption syndromes • Weight loss ```

Question 41

Pancreatic enzyme Supplementation overview and AE?

Answer 41

• Pancrelipase – combination of amylase, lipase, and proteases which are rapidly degraded by gastric acids. • Enteric-coated formulations should be used or non- coated forms given with acid suppression therapy. • Given by mouth with each meal. • Adverse effects - diarrhea, abdominal pain. Rarely; hyperuricosuria, renal stones and colonic strictures.