Survey
* Your assessment is very important for improving the workof artificial intelligence, which forms the content of this project
* Your assessment is very important for improving the workof artificial intelligence, which forms the content of this project
44-1 CONSTIPATION All Bound Up. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Level II Michelle Fravel, PharmD, BCPS CASE SUMMARY A 64-year-old woman with a history of hypertension, dyslipidemia, diabetes mellitus type 2, hypothyroidism, and osteoarthritis with recent TKA presents to the ED with complaints of constipation. She has a number of drug therapy problems that students must identify; she is also taking several medications that may be contributing to her constipation. In developing a treatment plan for constipation, students should consider general nonpharmacologic approaches such as increased dietary fiber, fluid intake, and appropriate bowel habits. A variety of medications are available for treating constipation. Students should be able to identify those that are first-line choices for chronic use and those that should be reserved for acute treatment, treatment failure, or intolerance. Given this particular case, students should be able to identify appropriate therapy for treatment and prevention of opioid-induced constipation. Students should be able to identify laxatives that are first-line choices in this setting and those that may be harmful. QUESTIONS Problem Identification 1.a. Develop a list of the potential drug therapy problems in this patient other than those related to her constipation. • Obesity: With a body mass index (BMI) of 41.3 kg/m2, the patient is considered morbidly obese; significant weight loss is indicated. • Elevated glucose: This patient has type 2 diabetes, and the fasting blood glucose is elevated; however, her A1C (a measure of blood glucose control over the past 3 months) is within target levels. No further action is needed at this time. • Cardiovascular risk: Low-dose aspirin therapy (75–162 mg daily) is recommended for patients with diabetes and increased cardiovascular risk (10-year risk >10%). This includes most men >50 years and women >60 years who have at least one additional cardiovascular risk factor (eg, premature family history, hypertension, dyslipidemia, smoking, and albuminuria). Her current aspirin dose of 325 mg daily should be decreased.1 • Drug interaction: When used with diltiazem, the dose of simvastatin should not exceed 10 mg daily due to increased risk of muscle injury, a simvastatin dose that would be considered low intensity. The patient’s current statin and dose (simvastatin 20 mg) is considered moderate intensity statin therapy. The 2015 American Diabetes Association Standards of Medical Care for diabetes recommends high-intensity statin therapy for individuals between 40 and 75 years of age with diabetes mellitus and cardiovascular risk factors (LDL >100 mg/dL, hypertension, obesity, or smoking).1 This patient’s statin therapy should be changed to one of the high-intensity regimens • A subjective report by the patient of abdominal cramping and pain, bloating, and nausea/vomiting. • A report of decreased bowel movement frequency (none in last 6 days). • Palpable stool and decreased bowel sounds on physical examination. (There was no evidence of rectal bleeding or anal fissures.) • Rectal exam indicating fecal impaction. • Abdominal computed tomography (CT) showed a large amount of stool in the colon. • The patient’s laboratory results ruled out hypokalemia, hypercalcemia, and endocrine disorders such as uncontrolled hypothyroidism that could be causing her constipation. 1.c. What are some of the possible nonpharmacologic contributors to her constipation? • Limited mobility following TKA and decreased oral intake may result in constipation. 1.d. What are some of the possible pharmacologic contributors to constipation in this patient? • Oxycodone: an opioid that slows peristalsis and overall bowel transit. • Diltiazem: a calcium channel blocker that causes relaxation of the smooth muscle of the intestinal tract. • Bulk-forming laxative (Metamucil): nondigestible colloids that absorb water in the gastrointestinal tract to increase bulk, thereby causing peristalsis. With opioid inhibition of peristalsis, this added bulk cannot stimulate movement, and instead may lead to worsened constipation or even bowel obstruction.2 1.e. What information should be obtained from a patient who presents with a chief complaint of constipation? It would be helpful to obtain answers to the following questions: • What are the symptoms and how long has the patient been experiencing these symptoms? • How long has it been since the last bowel movement? How many times per week does the patient typically have bowel movements? • What drugs and doses is the patient currently taking? • What high-fiber foods are included in the diet (specifically fruits, vegetables, and grains)? • How much fluid is the patient currently consuming? • What is the patient’s recent activity level? • What other symptoms is the patient experiencing (eg, bone pain or rectal bleeding) that may lead you to believe there is an underlying disease state contributing to the constipation? • What, if anything, has the patient tried in the past for constipation, and how well did it work? Desired Outcome 2. What are the goals of pharmacotherapy in treating constipation? • Assuming that an underlying condition is not suspected, the goals of therapy are to provide relief from acute constipation and to prevent further episodes of constipation with minimal adverse consequences. Copyright © 2017 by McGraw-Hill Education. All rights reserved. Constipation Beth Bryles Phillips, PharmD, FCCP, BCPS 1.b.What signs or symptoms are indicative of constipation in this patient? CHAPTER 44 44 (eg, atorvastatin 40 mg, atorvastatin 80 mg, rosuvastatin 20 mg, or rosuvastatin 40 mg), which would also eliminate the drug interaction. 44-2 SECTION 4 • In this patient, appropriate goals are increased frequency of bowel movements and prevention of recurrent constipation. Therapeutic Alternatives 3.a. What are some nonpharmacologic steps useful in treating constipation? Gastrointestinal Disorders • A diet high in fiber is beneficial to most patients with uncomplicated constipation. Patients should gradually increase dietary fiber intake to 25–35 g per day. Foods with soluble fiber, such as beans, peas, oat bran, and bananas, dissolve in water to form a gel which assists in addressing constipation. Foods containing insoluble fiber minimize constipation by increasing bulk; examples of these foods include whole grains, wheat bran, and dark green leafy vegetables.3 • Adequate fluid intake and mobility/ambulation are additional general measures that may be taken to ensure proper bowel function. • Patients may also be instructed to set a regular time aside to respond to the urge to go to the bathroom, particularly after breakfast in the morning. 3.b.What are the pharmacologic options for the treatment of constipation? • See Table 44-1 for drug therapy alternatives. 3.c. Is this patient’s current regimen for hypertension appropriate? If not, what recommendations can you make to optimize this regimen? • Diltiazem may be contributing to constipation and will increase risk for recurrent constipation in the future. Alternative therapy for blood pressure control should be considered that will not increase risk for constipation. • Patients with hypertension, diabetes mellitus, and proteinuria benefit from angiotensin-converting enzyme inhibitor (ACEI) or angiotensin receptor blocker (ARB) therapy due to renal protective effects and reduction in cardiovascular morbidity. TABLE 44-1 Pharmacologic Options for the Treatment of Constipation Onset of Action Medication Drug/Dose Mechanism of Action Bulk-forming laxatives Psyllium (Metamucil, Perdiem, Fiberall): one to two teaspoonfuls (or packets) in 8 oz of water or juice TID Methylcellulose (Citrucel): one tablespoonful in 8 oz of water daily to TID Polycarbophil (FiberCon): 1 g PO QID (maximum 6 g/day) Increase bulk and decrease transit time of stool in the colon Docusate sodium (Colace): 50–100 mg PO BID Lower stool surface tension and promote the mixture of aqueous and fatty materials, resulting in softened stool 1–3 days Coat and lubricate the stool to allow easier passage through the GI tract 1–3 days Cause water retention in the colon, which promotes intestinal motility 1–3 days Emollients Docusate calcium (Surfak): 240 mg PO daily Lubricants Osmotic laxatives Docusate potassium (Dialose): 100 mg PO daily to TID Mineral oil: 5–30 mL PO daily Poorly absorbed sugars: Lactulose: 15–30 mL (10–20 g) PO daily to BID Sorbitol: 15–30 mL of a 70% solution PO daily to BID Polyethylene glycol (PEG) PEG and electrolytes (Colyte, GoLYTELY): 17–36 g PO daily to BID PEG 3350 (MiraLAX): 17–36 g PO daily to BID Saline laxatives: Magnesium hydroxide (Phillips Milk of Magnesia): 15–30 mL PO daily to BID Sodium phosphate (Fleet Phospho-Soda): 20–45 mL PO × 1 dose Glycerin: 3-g suppository Copyright © 2017 by McGraw-Hill Education. All rights reserved. 1–3 days 1–6 hours 1–6 hours <30 minutes Comments Minimal systemic absorption Relatively safe with low potential for adverse effects May cause abdominal distention and flatulence when initiating therapy; these effects tend to resolve with time It is important to take these products with plenty of water to avoid obstruction in the esophagus, stomach, and intestine Efficacy in acute bouts of constipation not well established Used primarily to prevent constipation in situations such as recovery from surgery when straining during a bowel movement may be harmful to the patient Relatively safe but may promote intestinal absorption of some drugs Long-term use can cause malabsorption of fat-soluble vitamins and anal seepage Lipoid pneumonia has occurred in patients predisposed to aspiration Adverse effects include flatulence, cramps, and diarrhea May cause electrolyte imbalances if used routinely. Avoid lactulose in lactose-intolerant patients Sorbitol is generally preferred over lactulose due to equal efficacy and lower cost Nausea, abdominal fullness, and bloating can occur May cause less cramping than other osmotic laxatives Minimal absorption PEG 3350 does not contain electrolytes and may cause less electrolyte imbalances Magnesium can be absorbed in the small intestines Hypermagnesemia can occur in patients with renal failure and in children Hyperphosphatemia can occur in patients with renal insufficiency Sodium phosphate is typically used as a bowel evacuant Generally considered safe Often used in children May cause some rectal irritation (continued) 44-3 Onset of Action Drug/Dose Mechanism of Action Stimulants Diphenylmethane derivatives: Bisacodyl (Dulcolax): 10–15 mg PO or 10 mg suppository Anthraquinone derivatives: Cascara sagrada: 5 mL or 325 mg tablet PO Senna (Senokot): dose varies depending on formulation Lubiprostone (Amitiza): 24 mcg PO BID with food Stimulates colonic motor activity Increases intestinal fluid secretion 24 hours 5-HT4 agonist Tegaserod maleate (Zelnorm) Increases gastrointestinal motility 1 week mu-Opioid antagonists Methylnaltrexone bromide (Relistor): <38 kg: 0.15 mg/kg 38–61 kg: 8 mg 62–114 kg: 12 mg >114 kg: 0.15 mg/kg Usual dose: one dose every other day; may be administered no more than once daily Alvimopan (Entereg): 12 mg PO administered 30 minutes to 5 hours prior to surgery followed by 12 mg BID for up to 7 days; maximum of 15 doses Inhibit opioid-induced slowing of gastrointestinal motility 30 minutes to 4 hours N/A Naloxegol (Movantik): 25 mg once daily, taken 1 hour prior to the first meal of the day or 2 hours after; dose may be reduced to 12.5 mg daily if full dose is not tolerated 6–12 hours Guanylate cyclase-C (GC-C) agonist Linaclotide (Linzess): 145 mcg orally once daily at least 30 minutes prior to the first meal of the day Agonism of GC-C increases levels of cyclic guanosine monophosphate (cGMP) that leads to secretion of chloride and bicarbonate into the intestinal lumen, causing an increase in intestinal fluid and faster transit 1 week Chloride channel stimulator 6–12 hours Comments May cause severe abdominal cramping Electrolyte disturbances may occur with repeated use Converted by colonic bacteria to active form Abdominal cramping may occur May cause melanosis coli Optimal Plan Approved for treatment of opioid-induced constipation in adults with chronic, noncancer pain Efficacy not established in patients taking methadone May cause nausea, diarrhea, or headache High cost may limit use to patients who failed or are intolerant of other agents Limited to use in patients 55 years of age and younger with chronic constipation or IBS in emergency situations due to cardiovascular risk; request for use must be submitted to FDA Approved for treatment of opioid-induced constipation in adults with chronic, noncancer pain May cause nausea, gas, diarrhea, dizziness, or sweating High cost and SQ administration may limit use Currently only approved for short-term hospital use to accelerate the time to upper and lower GI recovery following surgeries that include partial bowel resection with primary anastomosis Increased incidence of MI was seen in clinical trials with long-term use This medication is only available through the restricted ENTEREG Access Support and Education (E.A.S.E) Program Approved for treatment of opioid-induced constipation in adults with chronic, noncancer pain Dose reduction is necessary when used in combination with CYP3A4 inhibitors High cost may limit use to patients who failed or are intolerant of other agents Discontinuation of laxatives is recommended prior to initiation of naloxegol Currently only approved for chronic idiopathic constipation and constipation associated with irritable bowel syndrome (higher dose indicated for irritable bowel syndrome) Contraindicated in pediatric patients (up to 6 years old) and patients with gastrointestinal obstruction Severe diarrhea may occur 4.After nonpharmacologic measures have been attempted, what is the most appropriate drug regimen for her, including dose and schedule? Provide the rationale for your answer. opioid-induced constipation: slowed transit (offset by a stimulant laxative) and decreased fluid content in the stool, due to increased time in the gastrointestinal tract (addressed by stool softener).2,4 Refer to Table 44-1 for dosing guidelines. Therapy should be continued until oxycodone is discontinued. • Although randomized controlled trial evidence supporting the use of nonprescription laxatives for the treatment of opioidinduced constipation is lacking, a combination stool softener/ stimulant regimen, such as docusate plus senna, is a common recommendation in clinical practice because these medications address the two main physiological issues occurring in • The selective mu-receptor antagonists, methylnaltrexone, alvimopan, and naloxegol, comprise a newer class of medications with a mechanism of action specific for reversal of opioidinduced constipation. These medications antagonize the effects that opioids have on the mu-receptors in the periphery (ie, gastrointestinal tract). Due to their pharmacology, these Copyright © 2017 by McGraw-Hill Education. All rights reserved. Constipation Medication CHAPTER 44 TABLE 44-1 Pharmacologic Options for the Treatment of Constipation (continued) 44-4 SECTION 4 Gastrointestinal Disorders agents do not cross the blood–brain barrier, and therefore do not reduce the analgesic effect of opioids. Although mechanistically and theoretically ideal for treatment of all opioidinduced gastrointestinal adverse effects, the agents have been studied in selected patient populations with small numbers of patients and currently possess limited therapeutic indications. Additional limiting factors for use of these agents include the need for subcutaneous administration of methylnaltrexone, restriction of alvimopan to in-hospital use, and high cost with all three agents. Currently, no selective mu-receptor antagonist is FDA approved for use in the treatment of constipation due to acute opioid therapy. Furthermore, although efficacy has clearly been demonstrated in certain populations and conditions, these agents may not be effective in all patient populations; 50% of patients in clinical trials failed to respond to this type of therapy.5,6 • Lubiprostone is also approved for treatment of opioid-induced constipation in patients with chronic noncancer pain. It opposes the antisecretory effects of opioids by activating gastrointestinal chloride channels and increasing intestinal fluid secretion to improve fecal transit. Limitations to widespread use of lubiprostone include lack of demonstrated efficacy in patients taking methadone and high cost.7 • The patient’s use of a bulk-forming laxative should be discontinued due to the acute worsening of constipation it may cause, as described previously. • Although not likely to cure the current issues with opioidinduced constipation, the patient’s diltiazem may be switched to an alternative agent, as described previously, to prevent future issues with recurrent constipation. • The patient still requires pain control, so discontinuation of the main offending agent (oxycodone) is not a feasible option. Dose reduction may be considered; however, incomplete pain control would be a major concern. Outcome Evaluation 5.a. How would you monitor this patient to ensure that your pharmacotherapeutic goals have been achieved? How would you follow-up with her to ensure resolution of the constipation? • It is appropriate to monitor for a decrease in the subjective feeling of constipation. In addition, an increase in the frequency of bowel movements, a decrease in straining and abdominal distention, and the presence of adverse events associated with the medications are all appropriate symptoms or signs to monitor. • A follow-up phone call in 1 week to assess this patient’s response to your interventions is appropriate. She could be asked to be seen in the outpatient clinic in approximately 1 month for a more thorough follow-up of all of her medical problems. Clinical Course 5.b. You reassure the patient that this problem can be prevented with her next surgery and that you will discuss options with her physicians. What regimen would you recommend for preventing opioid-induced constipation in this patient if she chooses to go through with the second TKA procedure? • Because the docusate/senna combination regimen you recommended for the first episode was effective, this regimen would be optimal to recommend for prevention with future opioid use. • Use of stool softener monotherapy for the treatment of opioidinduced constipation should be avoided due to questionable efficacy.8 Copyright © 2017 by McGraw-Hill Education. All rights reserved. Patient Education 6.a. What education would you provide to this patient who has concerns about recurrence of drug-induced constipation? • It is essential to explain to the patient about all of the factors that contributed to her past constipation and inform her as to how these issues can be addressed in the future to prevent constipation when opioids are used again. • This conversation should include: (1) a warning against use of bulk-forming agents while taking opioids; (2) an emphasis on the importance of maintaining adequate hydration and ambulation; (3) an explanation that a laxative regimen should be started with the first dose of opioid therapy; and (4) a recommendation that open communication with a provider regarding any signs or symptoms of constipation should occur immediately. 6.b. What education would you provide to this patient regarding her concerns about laxative addiction? • Medications such as oxycodone have a direct effect on the gastrointestinal tract, which causes constipation. Once analgesia is no longer needed and opioid therapy can be discontinued, bowel habits return to normal without the need for a laxative. 6.c. When instructing this patient on using a stimulant laxative, what information should you convey to ensure appropriate use of this product? • Senna (Senokot) is a stimulant laxative that causes movement in the intestine resulting in a bowel movement. • The dose of senna depends on the individual product. Refer to the dosing directions on the label of the product selected. • Senna may be used as needed for constipation. In general, senna is reserved for short-term use. • Senna works relatively quickly: between 6 and 12 hours after a dose is taken. • Common adverse effects may include abdominal cramping and diarrhea. REFERENCES 1.American Diabetes Association. Standards of medical care in diabetes—2016. Diabetes Care 2016;39:S1–S112. 2. Panchal SJ, Muller-Schwefe P, Wurzelmann JI. Opioid-induced bowel dysfunction: prevalence, pathophysiology and burden. Int Clin Pract 2007;61:1181–1187. 3.Shah BJ, Rughwani N, Rose S. Constipation. Ann Intern Med. 2015;162:ITC1. doi:10.7326/AITC201504070. 4. National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology: Palliative Care. V.1.2016 [Online]. Available at: http://www.nccn.org/professionals/physician_gls/pdf/palliative.pdf. Accessed September 3, 2016. 5.Thomas J, Darver S, Cooney GA, et al. Methylnaltrexone for opioid-induced constipation in advanced illness. N Engl J Med 2008;358:2332–2343. 6. Chey WD, Webster L, Sostek M, et al. Naloxegol for opioid-induced constipation in patients with noncancer pain. N Engl J Med 2014;370:2387–2396. 7. Davis M, Gamier P. New options in constipation management. Curr Oncol Rep 2015;17:55. 8. Tarumi Y, Wilson MP, Szafran O, et al. Randomized, double-blind, placebo-controlled trial of oral docusate in the management of constipation in hospice patients. J Pain Symptom Manage 2013;45:2–13.