GI Drugs Part 2 Flashcards
What is constipation?
• 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.
What are three Bulk-forming Laxatives? Overview and contraindications?
• 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.
Cathartics (stimulant laxatives) action and three examples?
• 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.
Name 2 stool softeners and moa?
• Docusate
• Glycerin
• Surfactants which allow water to penetrate and
thereby soften formed stool in the bowel.
What is a lubricant laxative and moa?
• 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.
What are 3 osmotic laxatives, moa, ae, and contraindication?
• 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.
Lubiprostone moa, indications, ae, and contraindications?
• 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.
Selective Mu-Opioid Receptor Antagonists 2 examples, overview, and action.
• 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.
Name 2 opioid agonists and overview?
• 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.
Characteristics of Loperamide and dioxyphenolate? Contraindications?
• 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
Somatostatin Analogs example, indications?
• 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.
Somatostatin AE?
- 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.
Overview of Bismuth compounds?
• 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.
What is Irritable Bowel Syndrome?
• 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.
First line strategy for IBS?
• 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.
Diarrhea predominant IBS pharmacological intervention?
- Opioid agonists such as loperamide.
- The 5-HT3 antagonist alosetron - inhibits afferent 5- HT3 receptors to reduce noxious visceral sensations
such as bloating, nausea and pain. - Anticholinergics such as hyoscyamine, dicyclomine,
glycopyrrolate and methscopolamine – antispasmodic effect on the G.I. tract.
Role of Anticholinergics in IBS?
• 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.
What is Inflammatory Bowel Disease?
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
Name 3 aminosalicylates?
- Sulfasalazine
- Balsalazide
- Mesalamine
aminosalicylates use and active group?
• 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.
Aminosalicylates MoA Theories?
• 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.
Factors that determine clinical efficacy for Aminosalicylates and PK?
• 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.
Sulfasalazine overview?
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.
Sulfasalazine MOA?
- The majority of the given dose passes into the colon, where sulfasalazine is reduced by coliform bacterial enzyme, azoreductase, to sulfapyridine and 5-ASA.
- 5-ASA is able to act
therapeutically in the colon and may even “backwash” into the terminal ileum to act there.
AE of sulfasalazine?
• 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.
Overview of Balsalazide?
• 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.
Overview of Mesalamine?
• 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.
Name 3 glucocorticoids and the action of glucocorticoids?
• 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.
Glucocorticoids pk and ae?
• 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.
Overview of Budesonide?
• 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.
Name 2 immunosuppressants? Overview of action?
• 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.
Immunosuppressive Purine
Metabolites moa, ae and use guidelines?
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.
Methotrexate moa, dosage?
• 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.
Methotrexate AE?
• 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.
Anti-TNF-α Drugs?
- 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.
TNF is a key mediator of?
• Release of proinflammatory cytokines.
• Stimulation of hepatic acute phase reactants.
• Upregulation of endothelial adhesion molecules
promoting leukocyte migration.
Anti-TNF-α Drugs – Adverse Effects?
• 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.
Overview of Anti-integrins?
• 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.
Anti-integrins AE?
• Infusion reactions • Opportunistic infections • Reactivation of the human polyomavirus (JC virus) resulting in progressive multifocal leukoencephalopathy.
Define Exocrine Pancreatic insufficiency, causes, and clinical features?
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
Pancreatic enzyme Supplementation overview and AE?
• 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.
