Lower GI Pharmacology

Question 1

Non-pharmalogical steps for constipation

Answer 1

increased fiber (fruits, vegetables, whole grains), adequate hydration, regular exercise and routine toileting

Question 2

The biggest adverse effect to remember with these constipation meds

Answer 2

electrolyte derangements

Question 3

Bulk-forming laxatives mechanism and use

Answer 3

Mechanism: Resemble natural dietary fiber but are indigestible, absorb and retain water in the intestinal lumen to increase the mass. This causes mechanical distention of the intestinal wall which stimulates peristalsis.

Use: Mild constipation. They need to be taken with a full glass of water to allow for the appropriate hydration of the fiber. These come in pills, powders (even in the Splenda my husband buys - watch out for the sweetners at my house!) and are over the counter.

Question 4

Bulk-forming laxatives adverse effects

Answer 4

some gas/bloating. However, if a great deal of bulk-forming laxatives are used without enough water, it can cause an impaction. If this occurs proximal to a stricture it may rarely rupture.

Question 5

Bulk-froming laxatives examples

Answer 5

Psyllium (Metamucil)

Calcium polycarbophil (FiberCon)

Wheat dextrin (Benefiber)

Methyl cellulose (Citrucel)

Question 6

Osmotic laxatives broad mechanism

Answer 6

Increase moisture to cause intestinal distention to facilitate peristalsis.Therefore, they are dependent on adequate hydration.

Question 7

Polyethylene glycol (Miralax, Golytely) uses and side effects

Answer 7

Uses: Daily for chronic constipation, colonoscopy prep, inpatient bowel cleanouts for severe constipation.

Available over the counter as Miralax, an odorless, tasteless powder. This can be titrated at home for optimal effect and is pretty safe for all.

In a liquid formulation (—lytely, ex. Golytely or Nulytely), it is used in large volumes for bowel preparation prior to colonoscopy or for an inpatient cleanout.

Adverse Effects: Can cause some nausea, bloating and cramping.

Question 8

Lactulose mechanism, use, adverse effect

Answer 8

Mechanism: an osmotic agent to help with constipation.

Uses: Constipation (but rarely used for this as it’s a syrupy, sickly sweet, gross-tasting liquid). It’s other indication is hepatic encephalopathy in cirrhotics - it is converted to low-molecular-weight acids by colonic bacteria. These acids can convert ammonia to ammonium that can easily be disposed of, this can improve the tendency to have hyperammonemia causing confusion in patients with cirrhosis.

Adverse Effects: It can cause bloating and flatulence.

Question 9

Magnesium agents mechanism, uses, adverse effects

Answer 9

Mechanism: poorly absorbed salt leads to increased stool

Uses: As needed for acute, moderate constipation. They work within a few hours so are helpful for quicker action (as compared to stool softeners or miralax).

Adverse Effects: Can occasionally cause hypermagnesmia in renal failure patients.

Magnesium citrate - it looks like Sprite and has a slight citrus smell, but sure doesn’t taste like it. : (

Magnesium oxide (milk of magnesia) - sometimes given for chronic hypomagnesmia and has an adverse effect of diarrhea.

Question 10

Common ingredients in enemas

Answer 10

Many enemas will have osmotic agents: soap suds, SMOG (saline- mineral oil - glycerin), sodium phosphate (Fleet’s). There is somewhat of a risk of electrolyte derangment with repeated saline-containing enemas like Fleet’s.

Question 11

Surfactant laxatives example

Answer 11

Docusate (Colace)

Mineral oil is another softener that works as a surfactant - often used in enemas.

Glycerin works as a surfactant that can be placed as a suppository

Question 12

Surfactant laxative mechanism and use

Answer 12

Mechanism: Often called stool softeners because they actually incorporate water into the fatty intestinal tissue and make the stool softer and help lubricate the intestinal lumen.

Uses: Daily regimen for chronic constipation. It’s been used for decades for outpatient and inpatient constipation treatment and constipation prevention

Question 13

Surfactant laxatives adverse effects

Answer 13

Adverse Events: Relatively few: occasional absorption issues or rashes.

Question 14

Stimulants example

Answer 14

Senna - Naturally occuring in plants.

Combined with Docusate in a formulation called Senna S - this is the most commonly used medication in the hospital as a prophylaxis when patients are started on opioids.

My practice is to always start a preventative “bowel regimen” when a patient is on opioids that starts with senna.

Adverse Effects: overuse of this can cause melanosis coli (or a brown-staining of the colon).

Castor oil - natural

Bisacodyl (Dulcolax) - synthetic; oral and suppository

Question 15

Stimulants mechanism and use and adverse effects

Answer 15

Mechanism: Composed of natural and synethetic compounds that alter fluid secretion to stimulate peristalsis.

Uses: Short-term treatment of constipation and prevention of opioid-induced constipation

Adverse Effects: the amount of peristalsis generated here can cause abdominal cramping, electrolyte abnormalities gastric or rectal irritation.

Question 16

mu-Opioid Receptor Antagonists mechanism and use and adverse effects

Answer 16

Mechanism: only antagonize opioids at the mu-opioid receptors in the gut (but don’t cross the blood-brain-barrier) so do not prevent opioids from providing analgesia.

Use: constipation due to opioid use, those receiving opiates for palliative care, postoperative ileus following bowel resection

Adverse Effects: relatively new, so expensive and require prior auth

Question 17

mu-Opioid Receptor Antagonists examples

Answer 17

Methylnaltrexone (Relistor) - contraindicated in bowel obstruction; can cause GI upset, constipation. SQ injection

Alvimopan (Entereg)- only for hospitalized patients for <1 week due to cardiac toxicity.

Oxycodone + naloxone labeled only for pain in the US but in other countries used for chronic constipation.

Question 18

Chloride Channel Activators examples

Answer 18

Lubiprostone (Amitiza) and Linaclotide (Linzess)

Question 19

Lubiprostone (Amitiza) mechanism, use, adverse effects

Answer 19

Mechanism: Stimulation of type-2 chloride channel receptor within the small intestine increases chloride secretion which increases intestinal motility

Uses: Chronic constipation and constipation-predominant IBS as part of a daily regimen. Constipation recurs when it’s stopped.

Adverse Events: Minimal systemic absorption; however, animal studies showed increased fetal loss in guinea pigs so class C in guinea pigs. Some nausea due to delayed gastric emptying.

Question 20

Linaclotide (Linzess) mechanism, use, adverse effects

Answer 20

Mechanism: Stimulates chloride secretion by binding guanylyl cyclase-C to increase cGMP and activte CFTR.

Uses: Chronic constipation and constipation-predominant IBS as part of a daily regimen. Constipation recurs when it’s stopped.

Adverse Effects: diarrhea, class C in pregnacy (increased maternal death in rats when given >8000x human dose). Also increased mortality in juvenile mice, so not approved for peds.

Question 21

Metocloprmaide (Reglan) mechanism, use, adverse effects

Answer 21

Mechanism: dopamine (D2) antagonist that prevents relaxation of gastrointestinal smooth muscle. It generates increased tone in the esophagus and stomach - creating a propulsion machine within the esophagus and enhances gastric emptying without much effect on the intestine/colon.

Use: this helps with gastroparesis by accelerating gastric emptying. It is sometimes used for GERD, refractory constipation due to decreased motility, emesis.

Adverse Effects:

extrapyramidal symptoms (dystonia, akathisia, parkinsonism), drowsiness, insomnia, anxiety, agitation, restlessness.

Tardive dyskinesia may be irreversible after long-term use.

Elevated prolactin may cause galactorrhea, gynecomastia, impotence, menstrual disorders.

Question 22

Role of serotonin in GI

Answer 22

Serotonin is a big player in treating GI motility issues: it is produced and released by enterochromaffin cells in the gut, where it activates 5-HT 3 and 5-HT 4 receptors on cholinergic neurons and thereby enhances the peristalsis.Drugs that activate 5-HT4 receptors increase intestinal motility and have been used in treating constipation, whereas drugs that block 5-HT3 receptors reduce propulsive movements and are used in treating diarrhea.

Question 23

Tegaserod (Zelnorm) mechanism and use

Answer 23

Mechanism: 5-HT4 receptor agonist on presynaptic terminal of submucosal intrinsic primary afferent nerves. Enhancing release of neurotransmitters, including calcitonin gene-related peptide that then makes second-order neurons start the peristaltic reflex. Acetylcholine and Substance P stimulate contraction and NO + VIP lead to distal bowel relaxation to achieve peristalsis.

Uses: IBS-C

Question 24

Erythromycin mechanism

Answer 24

Macrolide antibiotic that directly stimulates motilin receptors on gastrointestinal smooth muscle - can be helpful in gastroparesis but tolerance develops. In patients with upper GI bleeds, erythromycin can be given to clear the stomach of blood to allow for better visualization during endoscopy.

Question 25

Main treatment for acute diarrhea

Answer 25

Much of acute infectious diarrhea does not require treatment and supportive therapy with fluid and electrolyte replacement is the cornerstone of treatment.

Question 26

Adsorbents examples and mechanism

Answer 26

These coat the walls of the GI tract and can bind any causative bacterias or toxins which will then be eliminated through the stool.

Bismuth subsalicylate (Pepto-bismol)

Activated Charcoal - also used for toxic ingestions to prevent further absorption of toxins

Question 27

Antispasmotics mechanism, adverse effect, use

Answer 27

Mechanism: Inhibition of muscarinic cholinergic receptors in enteric plexus. They theoretically work by decreasing intestinal muscle tone and peristalsis to slow the movement of fecal matter through the GI tract. However,evidence has not shown spasms to be an important contributor in IBS.

Uses: IBS-D or other chronic causes of diarrhea.

Adverse Effects: all the usual anticholinergic sx (dry mouth, visual disturbances, urinary retention

Question 28

Antispasmotics examples

Answer 28

Atropine - muscarinic antagonist; not really used because it isn’t very specific so causes other anticholinergic side effects: blurred vision, urinary retention, etc

Hyoscyamine (Levsin) - IBS-D

Dicyclomine (Bentyl) - IBS-D

Scopolamine

Question 29

Bile Salt-Binding Resins examples

Answer 29

Cholestyramine (Questran), Colestipol, Colesevelam

Question 30

Bile salt resins mechanism, use, adverse effects

Answer 30

Mechanism: Inhibits enterohepatic reuptake of bile salts. These are normally resorbed in the terminal ileum, so those with surgical resection or Crohn’s disease of the TI have malabsorption of bile salts, leading to secretory diarrhea.

Uses: Diarrhea post-cholecystectomy or terminal ileum disease

Adverse Effects: Must remember to take with meals, so can be inconvenient. Bloating, flatulence, constipation. Cholestyramine can bind other drugs, whereas colesevelam doesn’t.

Question 31

Mu-agonists examples

Answer 31

Loperamide (Immodium) - No ability to cross the blood-brain-barrier so has no abuse potential

Diphenoxylate (Lomotil)- Has some ability to cross the blood-brain-barrier in high doses. Therefore as an over the counter agent, it is combined with atropine. The idea is that if someone takes doses high enough to cause a “high” they will have significant side effects from the atropine to discourage the abuse.

Question 32

Mu-agonists mechanism, use, adverse effects

Answer 32

Mechanism: Mu-opioid receptors are located in the GI tract. When activated, they cause colonic phasic segmental activity (which means more of an up-and-down contraction). This is different than typical peristalsis and increased the colonic transit time. Since stool is in the colon longer, it allows for more water absorption, thus firming the stool up.

Uses: These can be helpful for chronic diarrhea either from a needed medication or other cause such as IBS.

Question 33

Serotonin 5-HT3 Receptor Antagonists example

Answer 33

Alosetron (Lotronex)

Question 34

Serotonin 5-HT3 Receptor Antagonists mechanism, use, adverse effects

Answer 34

Mechanism: inhibition of 5-HT3 afferent receptors in the GI tract to decrease visceral pain/nausea/bloating.

Uses: Severe IBS-D with relief of lower abdoinal pain, cramps, urgency and diarrhea

Adverse Effects: worse than those used for emesis.

Rare but serious GI toxicity, constipation in up to 30% and very rarely requires hospitalization and even 3 cases of ischemic colitis. Only studied in women so restricted to those with severe disease that hasn’t responded to everything else.

Question 35

Somatostatin Analogue example

Answer 35

Octreotide

Question 36

Somatostatin Analogue mechanism, use

Answer 36

Mechanism: works like somatostatin

Uses:

Most commonly for upper GI bleeding, particularly with concern for esophageal variceal bleed - reduces portal and splanchnic blood flow.

Reducing GI neuroendocrine tumor symptoms (carcinoid, VIPoma) - reduces intestinal and pancreatic fluid secretion.

Severe dumping syndrome - diarrhea from short bowel syndrome or AIDS. Can stimulate motility at low doses and decrease motility at high doses.

Many endocrine effects (including inhibition of anterior pituitary hormones)

Question 37

Somatostatin Analogue adverse effects

Answer 37

Adverse Effects:

Not very clinically useful with a short half-life, so for patients with GI bleeds, the IV is a continuous drip. For someone needing longer action, subcutaneous injection will last 6-12h.

Impaired pancreatic secretion could lead to steatorrhea and fat-soluble vitamin deficiency.

Nausea, abdominal pain, flatulence, diarrhea.

Hyperglycemia, hypothyroidism, bradycardia.

Question 38

Main complaints of IBD

Answer 38

cramping, pain, diarrhea, bloody stool:

Question 39

Two ways to approach IBD TX

Answer 39

#1 Step-up - can try with mild disease - starting with less potent medications that have less adverse effects and going up the ladder until the disease improves

#2 Top-down for moderate/severe disease - starting with the most potent therapies (such as steroids and biologics) that have more severe side effects

Most IBD specialists will start with top-down and achieve stability of disease before backing down to the lowest level of treatment needed to keep things in check.

Question 40

TX for IBD flares that require hospitaliztion

Answer 40

infectious causes excluded, receive IV fluids + steroids and potentially topical treatments dependng on location of disease.

Question 41

Examples of glucorticoids for IBD

Answer 41

Methylprednisolone (Solumedrol) - IV formulation, if absorption is questionable or for severe disease while inpatient.

Prednisone - the most common glucocorticoid used in IBD; if severe symptoms, will slowly tape off.

Budesonide - controlled ileal release formation with a high first-pass hepatic metabolism so is great for ileitis in Crohn’s if they can’t tolerate glucocorticoids.

Hydrocortisone (Cortifoam, Proctocort) - available as a suppository or a foam for distal UC.

Question 42

GLucorticoids side effects

Answer 42

must be tapered off slowly and even so rebound symptoms may arise. Prolonged usage has a host of side effects, so alternative agents may be required.

Question 43

Aminosalicyclates (5-ASA) mechanism and use

Answer 43

Mechanism: The verdict is out on what the exact mechanism is, but there is anti-inflammatory modulationat work (postulations include: inhibition of leucocyte chemotaxis by reducing cytokine formation, reduced free radical generation and inhibition of the production of lipid inflammatory mediators).

Uses: Helpful to induce and maintain remission of mild ulcerative colitis but are less effective in Crohn’s disease. Can be given topically to distal disease (enema/suppository). Also used in conjunction with some of the “stronger meds” covered below.

Question 44

Aminosalicyclates (5-ASA) adverse effects

Answer 44

Don’t give if sulfa allergy is present. Nausea, GI upset, headache, arthralgia, myalgias, bone marrow suppression, malaise. They can impair folate absorption so are often administered with folate.

Question 45

Aminosalicylates examples

Answer 45

Sulfasalazine - combination of sulfapyradine + 5-ASA (abx + antiinflammatory). In the gut, it is converted to 5-ASA. Due to the azo, is not well absorbed systemically so works great for GI disease.

Mesalamine (Asacol, Pentasa, Rowasa) - active metabolite of sulfasalazine; 5-aminosalicyclic acid (5-ASA).Rectal suppository, rectal suspension, or delayed-release oral tablet. Less side effects as administered locally.

Question 46

Immunosuppressants examples

Answer 46

Cyclosporine, Azathioprine (Imuran), methotrexate

Question 47

Cyclosporine mechanism, use, adverse effects

Answer 47

Mechanism: potent immunosuppression (blocks transcription of cytokines in activated T cells)

Use: when steroids + 5-ASA fail to induced remission or with fistulizing disease, cyclosporine can be used as a bridge while awaiting longer-acting medications to work (6MP or anti-TNFalpha). Really not used much any longer now that biologics more readily available.

Adverse Effects: can lead to high relapse rates. Nonspecific supression.

Question 48

Azathioprine mechanism, use, adverse effects

Answer 48

Mechanism: inhibits mitosis which helps suppress immune response.

Use: Can use in the induction and maintenance of moderate IBD to reduce long-term steroids.

Adverse Effects:

Prior to treatment, thiopurine methyltransferase TPMT activity should be checked checked and dosing can be adjusted based on patient-specific metabolism (catabolism of 6-MP is low in ~10% of the population).

Can have serious side effects: nausea, vomiting, transaminitis, bone marrow supression

6-mercaptopurine (6MP) - active metabolite of azithioprine

Question 49

Methotrexate mechanism, use, adverse effects

Answer 49

Mechanism: Dihydrofolate reductase inhibitor. At lower doses for IBD, likely no decrease in cellular proliferation (as at chemo doses) but rather anti-inflammatory.

Uses: Used for autoimmune disease remission maintenance (IBD, RA, Psoriasis). Intramuscular while getting disease under control then changed to weekly oral dose. This is often in conjunction with a steroid +/- a biologic agent.

Adverse Effects:

Nausea, vomiting, alopecia, mucositis, bone marrow suppression, megaloblastic anemia

Folic acid deficency are common side effects; given in conjunction with folic acid to help the latter.

Question 50

What are biologics

Answer 50

These are monoclonal antibodies against TNF-alpha - chimeric with murine + human (=mab).

Question 51

Biologics mechanism and use

Answer 51

Mechanism: They reduce all of the following: production of pro-inflammatory cytokines (IL-1 and IL-6),leukocyte migration and infiltration and activation of neturophils and eosinophils.

Use: These changed the game on IBD treatment - especially severe Crohn’s disease. Great for acute and chronic treatment of moderate to severe IBD, especially when refractory to other therapies.

Question 52

Biologics adverse effects

Answer 52

Adverse Events: serious events in about 6% of patients.

They all can cause gastrointestinal upset, decompensation of heart failure, hypersensitivity reactions, fever, headache, pancytopenia.

These can increase risk of serious infections and patients are really counseled on what to do if they have a fever/infectious symptoms. Screening for tuberculosis is important as latent infections may be reactivated.

They may need to be rotated as antibodies to the antibody can develop and decrease the response. This is less likely to occur when patients are on continuous rather than episodic bursts of therapy - importnat to remind patients to followup and continue therapy to keep it effective.

Question 53

Biologics examples

Answer 53

Infliximab (Remicade) - IV infusions

Adalimumab (Humira) - subcutaneous injection

Etanercept (Enbrel) - subcutaneous injection