Antihypertensive Pharmacobezoar

Abstract

Most antihypertensive drugs have known side effects that are elicited by the careful clinician taking care of hypertensive patients. However, many antihypertensive medications utilize drug delivery systems that prolong the duration of blood pressure reduction. The gastrointestinal therapeutic system that is used with nifedipine, isradipine, and verapamil has a unique side effect. Obstruction may occur at the site of a previous surgical repair (pyloric stenosis or gastroplasty) or stenosis of the esophagus, small intestine, or colon. The same delivery system is used with methylphenidate, oxy‐butynin, glipizide, and doxazosin. Although this complication is rare, physicians who prescribe and care for hypertensive patients should recognize this potential problem.

When we think about adverse drug reactions, we usually consider known side effects of the drug class: hypokalemia, hyperuricemia, or sexual dysfunction with diuretics; ¹ gynecomastia with spironolactone; ² bradycardia or cold extremities with β blockers; cough or angioneurotic edema with angiotensin‐converting enzyme inhibitors; ³ peripheral edema or gingival overgrowth with calcium antagonists; ⁴ priapism or incontinence with α₁ blockers; or xerostomia or somnolence with α₂ stimulants. What we do not often consider is the adverse reactions associated with the specific drug delivery system used with an antihypertensive agent. ⁵

While the purpose of a novel delivery system is to prolong the duration of action of an antihypertensive drug, there are new adverse reactions to consider. ⁶ , ⁷ For instance, although the clonidine transdermal therapeutic system needs to be replaced every 7 days, many patients experience a localized skin reaction that requires cessation of therapy. ⁸ Hyperpigmentation and depigmentation also occur. Felodipine, nifedipine coat‐core extended‐release, and nisoldipine coat‐core use a coat‐core system, a hydrophilic gel surrounding the active drug; however, the tablet must be swallowed whole since splitting the tablet releases the active drug acutely and causes headache, flushing, hypotension, and tachycardia. Other problems with drug dispensing systems include delayed attainment of pharmacodynamic effect on initiation of therapy, sustained toxicity, and altered absorption with diarrhea.

There are unique problems associated with the gastrointestinal therapeutic system (GITS), used with nifedipine GITS, isradipine GITS, and verapamil controlled‐onset extended‐release. The same delivery system is used with methylphenidate, oxybutynin, glipizide, and doxazosin. Pharmacobezoars are bezoars comprised of medications that cause obstruction in a background of altered motility or anatomy of the gastrointestinal tract. ⁹ , Figure 1 displays three nifedipine tablets obstructing the proximal esophagus at the site of a stricture due to squamous cell carcinoma in a 68‐year‐old African‐American woman, similar to a previously reported case. ¹⁰ Obstruction at a gastroplasty site was reported when the dose of nifedipine GITS was titrated from 30 mg to 60 mg. ¹¹ A case of obstruction was also described in a 48‐year‐old woman who had undergone a vertical banded gastroplasty 3 years earlier. ¹² Another case described 25 retained tablets at a postbulbar stricture in a patient who had not taken nifedipine for 13 months. ¹³ In addition, 31 tablets were retrieved from the afferent and efferent limbs after a II gastrectomy in a patient presenting with weight loss, nausea, and vomiting. ¹⁴ Moreover, 300 tablets were removed from a 70‐year‐old man who presented with abdominal pain and underwent a resection of an obstructed small bowel. ¹⁵ Other reports have described GITS pharmacobezoars at the sites of peptic esophageal strictures, ¹⁶ gastric and duodenal ulcers, ¹⁷ operated pyloric stenosis, ¹⁸ enteric strictures, ¹³ , ¹⁵ , ¹⁹ , ²⁰ small bowel tumors, ²¹ and rectosigmoid anastomotic strictures after a hemicolectomy and sigmoid colectomy for adenocarcinoma. ²² Reduced motility due to the calcium antagonist, aging, or other mechanisms may predispose to colonic bezoars. ²³ , ²⁴ , ²⁵ Furthermore, the retained shells have the appearance of polyps on endoscopy, ²⁶ causing a false‐positive result on barium enema study, ²⁷ and mimic benign cystic pneumatosis intestinalis. ¹⁵

Figure 1.

Nifedipine gastrointestinal therapeutic system associated with dysphagia and obstruction at the site of esophageal carcinoma in a 68‐year‐old woman

The GITS tablet is very hard and, thus, has the potential for chipping teeth (if the tablet is bitten) and the theoretic possibility of eroding through diverticula. The tablet consists of an osmotically active drug core surrounded by a cellulosic semipermeable membrane that is permeable to water but not to the active drug or osmotic excipients (Figure 2). ²⁸ There is an overcoating with drug identifiers that dissipates when exposed to gastrointestinal fluid, which makes tablet identification less likely. ²⁹ The core itself is divided into an “active” layer containing the drug and a “push” layer containing pharmacologically inert (but osmotically active) components. The push layer contains polyethylene oxide and tablet‐forming excipients. As water from the gastrointestinal tract enters the tablet, pressure increases in the osmotic layer and pushes against the drug layer, extruding drug through a precision, laser‐drilled hole in the membrane on the drug side of the tablet. Verapamil has a special delay coat of 4 to 6 hours to produce an increasing release in the hours before awakening. ³⁰ Unlike the other drugs that use the GITS delivery system, there are two laser drill holes for drug release. All of the drugs using GITS depend on the existence of an osmotic gradient between the contents of the bilayer core and the fluid in the gastrointestinal tract. Thus, drug delivery is constant as long as the osmotic gradient remains constant and then gradually declines. The biologically inert components of the tablet remain intact during gastrointestinal transit and are eliminated in the feces as an insoluble shell. Since the ghost tablet does not degrade, patients should be advised that they might observe them in their stool.

Figure 2.

Gastrointestinal therapeutic system

The manufacturer advises avoidance of the GITS delivery system in patients with marked gastrointestinal narrowing. ³¹ The incidence of significant GITS adverse events, including esophageal, gastric, and intestinal irritation, injury, and obstruction, is approximately one case per 76 million tablets dispensed. ³² One case in 29 million tablets was reported in patients taking nifedipine GITS. Older patients are more likely to experience this complication. ³² Esophageal and lower gastrointestinal obstruction occurs in patients with preexisting abnormalities or disease, as illustrated in Figure 1 and a previous report. ¹¹ Although this is a rare complication, physicians prescribing and caring for hypertensive patients should recognize the potential for this problem.