FORMULARY FORUM
MESALAMINE INULCERATIVE COLITIS Jill Mancini Fitzgerald and T. DonaldMarsh
ABSTRACT: Sulfasalazinehas been used for many years in the managementof ulcerativecolitis. As many as 20 percentof patients treated with it experience intolerableadverseeffects usuallyattributed to its sulfapyridinecomponent. The other active component is 5aminosalicylic acid (5-ASA); the only 5-ASA enema preparation currently availablein the U.S. is mesalamine(Rowasa, Reid-Rowell) containing5-ASA 4 g in 60 mL. In clinical trials, mesalamine has provedefficaciousin treating refractorycases of distal ulcerative colitis, proctitis, and proctosigmoiditis. Becauseof its high cost compared with more conventionaltreatmentmodalities, it should be reservedfor cases that are either refractoryor intolerantto conventional treatment. DICPAnn Pharmacother 1991;25:140-5.
IDIOP~THIC !NFLA~MATOR: BOWEL DISEASE is a group of gastromtestmal disorders mcluding ulcerative colitis and proctitis, and Crohn's disease. Estimates of the prevalence rate of ulcerative colitis range from 39 to 117 per 100 000 population. 1 The pathophysiology of ulcerative colitis (UC) is unknown, and treatment is primarily focused on symptom relief. Sulfasalazine (salicylazosulfapyridine) is currently the drug of choice for both initial treatment of mild UC and maintenance of remission. Oral and rectal corticosteroids are reserved for more severe or refractory casesof UC andare generally moreeffective thansulfasalazinein inducing remission in Crohn'sdisease. A discussion of the otherdrug therapies for inflammatory bowel disease is beyond the scope of this article and can be found elsewhere. 2 JILL MANCINI FlTZGERALD, Phann.D.• is a ClinicalSpecialistin CriticalCare. Hartford Hospital, Hartford. CT. and an AssistanlProfessorof Clinical Pharmacy, Universityof Connecticut.Storrs, CT; and T. DONALD MARSH, Phann.D.• is a Clinical AssistantProfessorof PharmacyPractice.Schoolof Pharmacy. University of NorthCarolina. ChapelHill. NC. and the Directorof Phannacy Education.MountainAreaHealth EducationCenter. Asheville.NC. Reprints: Jill M. Fitzgerald.Phann.D.• Department of PharmacyServices. HartfordHospital, 80 SeymourSt., Hartford.CT 06115.
This article is approvedfor continuingeducationcredit.
140
•
Dltl]', The Annals ofPharmacotherapy
•
Figure I. Graphic formula of 5-aminosalicylic acid (5-ASA).
Sulfasalazine was developed by Svartz in the late 1930s and, while being studied in the treatment of rheumatoid m:thritis, its efficacy in ulcerative colitis was recognized. 3 Since that time many clinical trials have proved its benefit in treating active ulcerative colitis.r" Although used with great success in maintaining UC disease remission.r" its role in Crohn's diseaseis not so specifically identified and may be limited to Crohn'sdisease involving primarily the colon. ~ul~asal~ine is composed of twocompounds, 5-arninosalicylic acid (5-ASA) and sulfapyridine, joined by an azo bond. Intestinal bacterial azoreductases cleave the azo bond after oral ingestion, releasing 5-ASA and sulfapyridineat its siteof actionin thecolon.9-12 Although the exact m~chan~sm of action is unknown, one study in patients With ~cttve dis~ ulc~rative colitisfound that 5-ASA(Fig~ 1)IS the aC~lve mOlet~ of sulfasalazine andsulfapyridine IS only a earner, a fmdmg conftrmed by other investigators.8•I1•U As manyas 20 percent of patients treated withsulfasalazine experience adverse effects (nausea, vomiting, headache, blooddyscrasias, maleinfertility, andrash)attributed to the absorbable sulfapyridine component.7.8.11,14 Sulfasalazine has also reactivated ulcerative colitis in some patients. IS The development of 5-ASA analogs and new dosage forms of the drug with fewer adverse effects has been s.ought. One. dosage form of 5-ASA currently marketed in the U.S. IS mesalarnine, a 6O-mL enemacontaining 5-ASA4 g (Rowasa, Reid-Rowell),"
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Mechanism ofAction The etiology of ulcerative colitis is unknown, although attention has focused on the metabolic products of arachidonic acid. Arachidonic acid is metabolized by two enzyme systems,cyclooxygenase and lipoxygenase, to prostaglandins and leukotrienes.":" Studies performed in vitroand in vivohaveconfirmed that the intestinal mucosa of patients withactiveulcerative colitisandCrohn'sdisease produce more of the cyclooxygenase products prostaglandins (PG~) and thromboxane (TXB2); the lipoxygenase products hydroxyeicosatetraenoic acids (l2-HETE, 5HETE, 15-HETE)and leukotriene (LTB4); and sulfidopeptide-LT than do control subjects.":" The observation that the potent cyclooxygenase inhibitors flurbiprofen and indomethacin cause exacerbation of ulcerative colitis has indicated that leukotrienes and other byproducts of the lipoxygenase pathway are importantinflammatory mediators inpatients withulcerative colitis.26 There are no chemicals synthesized to date thatselectively inhibitthe production of leukotrienes and, therefore, it is not known whetherthese inflammatory mediators are of unique importance in the disease process of ulcerative colitis. However, 5-ASA inhibited release of LTB 4 and sulfidopeptide-LT in a dosedependent mannerin normal I7 •20 and UC subjects," inhibited the release of eicosanoid from inflamed colonicmucosa obtained from patients with Crohn's disease," and inhibitedthe production of PGE2 in vitro.23 Concentrations of 5-ASAnecessary to inhibitthesemediators of inflammationoccurin the gut lumenof patients takingoral sulfasalazine," and this inhibition of the formation of 5-lipoxygenase-derived products of arachidonic acid metabolism may explain the efficacy of both sulfasalazine and 5ASA.20 Morerecently investigated, 5-ASAmayact as a freeradical scavenger in vivo, thus exerting its pharmacologic effeet." Pharmacokinetics The pharmacokinetics of5-ASAadministered asa retention enema have not been extensively studied, but the metabolism of 5-ASA has been explored as it relates to sulfasalazine administration. It is primarily metabolized by the gut wall to its acetylated form. 14.21 This metabolite is then excreted in the urine. When sulfasalazine is administered orally, approximately 20 percentof the 5-ASA dose is recovered in the urine, with 60-80 percent excreted as the acetylated metabolite. U,14.21 Although 80 percent of a 5ASA dose is recovered in the feces, there is only minimal recovery of sulfapyridine. Sulfapyridine is almostentirely absorbed from the colon and excreted in the urine as the parent compound, the acetylated metabolite, and other conjugated metabolites. The acetylation of 5-ASA occurs primarily presystemically by the intestinal wall and has beenshownto be independent of geneticphenotype." Sulfapyridine acetylation has been shownto be dependent on genetic acetylator status, and its toxicity appears to be related to this genetic polymorphism. Slow acetylators tend to have higher concentrations of sulfapyridine and, thus, show more toxicity. 14,21 Following rectal administration of 5-ASA as an enema preparation, steady-state plasmaconcentrations of 5-ASA and acetyl-5-ASA are 0.65-1.96I-LmollL and 1.46-3.41
umol/L, respectively. These concentrations correspond to those obtained with oral administration of sulfasalazine.U,29 Absorption of the enema preparation is reduced by lowering the pH, and approximates 15 percent.30 The commercially available product ranges in pH from 4.0 to 5.0. 16 Campieri et al. studied patients withactive ulcerative colitisandpatients in disease remission. 5-ASAwasadministered as a retention enema in doses of 2 g per 100 mL, 4 g per 100 ml., and 4 g per 200 mL. Urinaryrecovery of acetyl-5-ASA in patients withactiveandquiescent diseasewas reported as 10 and 19 percent, respectively. 31 The decreased absorption in patients with active disease may be partially explained byretention timedifferences or changes in pH of the inflamed mucosa. However, these low values might suggest a primarily local effect of the drug. Mean peakplasmaconcentration of total5-ASA usingthe enema containing 4 g per 100 mL wascomparable for bothgroups andreportedto be between 2 and 4 I-LglmL, whichis negligible when compared with the therapeutic range of salicylates (250-350 I-LglmL). The time to reach this peak was between three and six hours. It wasalsodetermined that5ASA does not accumulate after daily administration for 15 days." Campieri et al. demonstrated that 5-ASA enemas can reach the splenic flexure in patients with active disease. 32 The 4 g per 100mL dose does not correspondto the commercially available product (4 g/60 mL), and retrograde spreadof the enemawasvolume-dependent; furtherstudies are needed to determine the retrograde spread of the commercially available product. ClinicalStudies
The commercially available 5-ASA enema is indicated for thetreatment of activemildto moderate distalulcerative colitis, proctosigmoiditis or proctitis. 16 Because the action of the drug is dependenton contactwith the diseased intestinal mucosa, 5-ASA enema is not indicated for patients with disease extending greater than 50 em beyond the anal verge,nor forCrohn'sdiseaseunlessit is limitedto thisarea of drug contact.30 ACTIVE DISEASE
Although several forms and varying dosages of 5-ASA have beenemployed in clinicalstudies, it has demonstrated efficacy in a numberof trials. Improvement rateshavebeen reported at 73 and 77 percentwith daily 7oo-mg9 and 1.0g32 enemas, respectively, and 67 percent with 400-mg suppositories. II Clinical and sigmoidoscopic remission has been reported with 5-ASA 4-g enemas daily for two weeks." Remission of clinical symptoms occurred significantly more frequently during the first two weeks of treatment with5-ASA 1.0-genemasdaily (51 percent) than with prednisolone 25-mg enemas (31 percent; p
MESALAMINE INULCERATIVE COLITIS Jill Mancini Fitzgerald and T. DonaldMarsh
ABSTRACT: Sulfasalazinehas been used for many years in the managementof ulcerativecolitis. As many as 20 percentof patients treated with it experience intolerableadverseeffects usuallyattributed to its sulfapyridinecomponent. The other active component is 5aminosalicylic acid (5-ASA); the only 5-ASA enema preparation currently availablein the U.S. is mesalamine(Rowasa, Reid-Rowell) containing5-ASA 4 g in 60 mL. In clinical trials, mesalamine has provedefficaciousin treating refractorycases of distal ulcerative colitis, proctitis, and proctosigmoiditis. Becauseof its high cost compared with more conventionaltreatmentmodalities, it should be reservedfor cases that are either refractoryor intolerantto conventional treatment. DICPAnn Pharmacother 1991;25:140-5.
IDIOP~THIC !NFLA~MATOR: BOWEL DISEASE is a group of gastromtestmal disorders mcluding ulcerative colitis and proctitis, and Crohn's disease. Estimates of the prevalence rate of ulcerative colitis range from 39 to 117 per 100 000 population. 1 The pathophysiology of ulcerative colitis (UC) is unknown, and treatment is primarily focused on symptom relief. Sulfasalazine (salicylazosulfapyridine) is currently the drug of choice for both initial treatment of mild UC and maintenance of remission. Oral and rectal corticosteroids are reserved for more severe or refractory casesof UC andare generally moreeffective thansulfasalazinein inducing remission in Crohn'sdisease. A discussion of the otherdrug therapies for inflammatory bowel disease is beyond the scope of this article and can be found elsewhere. 2 JILL MANCINI FlTZGERALD, Phann.D.• is a ClinicalSpecialistin CriticalCare. Hartford Hospital, Hartford. CT. and an AssistanlProfessorof Clinical Pharmacy, Universityof Connecticut.Storrs, CT; and T. DONALD MARSH, Phann.D.• is a Clinical AssistantProfessorof PharmacyPractice.Schoolof Pharmacy. University of NorthCarolina. ChapelHill. NC. and the Directorof Phannacy Education.MountainAreaHealth EducationCenter. Asheville.NC. Reprints: Jill M. Fitzgerald.Phann.D.• Department of PharmacyServices. HartfordHospital, 80 SeymourSt., Hartford.CT 06115.
This article is approvedfor continuingeducationcredit.
140
•
Dltl]', The Annals ofPharmacotherapy
•
Figure I. Graphic formula of 5-aminosalicylic acid (5-ASA).
Sulfasalazine was developed by Svartz in the late 1930s and, while being studied in the treatment of rheumatoid m:thritis, its efficacy in ulcerative colitis was recognized. 3 Since that time many clinical trials have proved its benefit in treating active ulcerative colitis.r" Although used with great success in maintaining UC disease remission.r" its role in Crohn's diseaseis not so specifically identified and may be limited to Crohn'sdisease involving primarily the colon. ~ul~asal~ine is composed of twocompounds, 5-arninosalicylic acid (5-ASA) and sulfapyridine, joined by an azo bond. Intestinal bacterial azoreductases cleave the azo bond after oral ingestion, releasing 5-ASA and sulfapyridineat its siteof actionin thecolon.9-12 Although the exact m~chan~sm of action is unknown, one study in patients With ~cttve dis~ ulc~rative colitisfound that 5-ASA(Fig~ 1)IS the aC~lve mOlet~ of sulfasalazine andsulfapyridine IS only a earner, a fmdmg conftrmed by other investigators.8•I1•U As manyas 20 percent of patients treated withsulfasalazine experience adverse effects (nausea, vomiting, headache, blooddyscrasias, maleinfertility, andrash)attributed to the absorbable sulfapyridine component.7.8.11,14 Sulfasalazine has also reactivated ulcerative colitis in some patients. IS The development of 5-ASA analogs and new dosage forms of the drug with fewer adverse effects has been s.ought. One. dosage form of 5-ASA currently marketed in the U.S. IS mesalarnine, a 6O-mL enemacontaining 5-ASA4 g (Rowasa, Reid-Rowell),"
/991 February. Volume 25
Downloaded from aop.sagepub.com at CORNELL UNIV on August 21, 2016
Mechanism ofAction The etiology of ulcerative colitis is unknown, although attention has focused on the metabolic products of arachidonic acid. Arachidonic acid is metabolized by two enzyme systems,cyclooxygenase and lipoxygenase, to prostaglandins and leukotrienes.":" Studies performed in vitroand in vivohaveconfirmed that the intestinal mucosa of patients withactiveulcerative colitisandCrohn'sdisease produce more of the cyclooxygenase products prostaglandins (PG~) and thromboxane (TXB2); the lipoxygenase products hydroxyeicosatetraenoic acids (l2-HETE, 5HETE, 15-HETE)and leukotriene (LTB4); and sulfidopeptide-LT than do control subjects.":" The observation that the potent cyclooxygenase inhibitors flurbiprofen and indomethacin cause exacerbation of ulcerative colitis has indicated that leukotrienes and other byproducts of the lipoxygenase pathway are importantinflammatory mediators inpatients withulcerative colitis.26 There are no chemicals synthesized to date thatselectively inhibitthe production of leukotrienes and, therefore, it is not known whetherthese inflammatory mediators are of unique importance in the disease process of ulcerative colitis. However, 5-ASA inhibited release of LTB 4 and sulfidopeptide-LT in a dosedependent mannerin normal I7 •20 and UC subjects," inhibited the release of eicosanoid from inflamed colonicmucosa obtained from patients with Crohn's disease," and inhibitedthe production of PGE2 in vitro.23 Concentrations of 5-ASAnecessary to inhibitthesemediators of inflammationoccurin the gut lumenof patients takingoral sulfasalazine," and this inhibition of the formation of 5-lipoxygenase-derived products of arachidonic acid metabolism may explain the efficacy of both sulfasalazine and 5ASA.20 Morerecently investigated, 5-ASAmayact as a freeradical scavenger in vivo, thus exerting its pharmacologic effeet." Pharmacokinetics The pharmacokinetics of5-ASAadministered asa retention enema have not been extensively studied, but the metabolism of 5-ASA has been explored as it relates to sulfasalazine administration. It is primarily metabolized by the gut wall to its acetylated form. 14.21 This metabolite is then excreted in the urine. When sulfasalazine is administered orally, approximately 20 percentof the 5-ASA dose is recovered in the urine, with 60-80 percent excreted as the acetylated metabolite. U,14.21 Although 80 percent of a 5ASA dose is recovered in the feces, there is only minimal recovery of sulfapyridine. Sulfapyridine is almostentirely absorbed from the colon and excreted in the urine as the parent compound, the acetylated metabolite, and other conjugated metabolites. The acetylation of 5-ASA occurs primarily presystemically by the intestinal wall and has beenshownto be independent of geneticphenotype." Sulfapyridine acetylation has been shownto be dependent on genetic acetylator status, and its toxicity appears to be related to this genetic polymorphism. Slow acetylators tend to have higher concentrations of sulfapyridine and, thus, show more toxicity. 14,21 Following rectal administration of 5-ASA as an enema preparation, steady-state plasmaconcentrations of 5-ASA and acetyl-5-ASA are 0.65-1.96I-LmollL and 1.46-3.41
umol/L, respectively. These concentrations correspond to those obtained with oral administration of sulfasalazine.U,29 Absorption of the enema preparation is reduced by lowering the pH, and approximates 15 percent.30 The commercially available product ranges in pH from 4.0 to 5.0. 16 Campieri et al. studied patients withactive ulcerative colitisandpatients in disease remission. 5-ASAwasadministered as a retention enema in doses of 2 g per 100 mL, 4 g per 100 ml., and 4 g per 200 mL. Urinaryrecovery of acetyl-5-ASA in patients withactiveandquiescent diseasewas reported as 10 and 19 percent, respectively. 31 The decreased absorption in patients with active disease may be partially explained byretention timedifferences or changes in pH of the inflamed mucosa. However, these low values might suggest a primarily local effect of the drug. Mean peakplasmaconcentration of total5-ASA usingthe enema containing 4 g per 100 mL wascomparable for bothgroups andreportedto be between 2 and 4 I-LglmL, whichis negligible when compared with the therapeutic range of salicylates (250-350 I-LglmL). The time to reach this peak was between three and six hours. It wasalsodetermined that5ASA does not accumulate after daily administration for 15 days." Campieri et al. demonstrated that 5-ASA enemas can reach the splenic flexure in patients with active disease. 32 The 4 g per 100mL dose does not correspondto the commercially available product (4 g/60 mL), and retrograde spreadof the enemawasvolume-dependent; furtherstudies are needed to determine the retrograde spread of the commercially available product. ClinicalStudies
The commercially available 5-ASA enema is indicated for thetreatment of activemildto moderate distalulcerative colitis, proctosigmoiditis or proctitis. 16 Because the action of the drug is dependenton contactwith the diseased intestinal mucosa, 5-ASA enema is not indicated for patients with disease extending greater than 50 em beyond the anal verge,nor forCrohn'sdiseaseunlessit is limitedto thisarea of drug contact.30 ACTIVE DISEASE
Although several forms and varying dosages of 5-ASA have beenemployed in clinicalstudies, it has demonstrated efficacy in a numberof trials. Improvement rateshavebeen reported at 73 and 77 percentwith daily 7oo-mg9 and 1.0g32 enemas, respectively, and 67 percent with 400-mg suppositories. II Clinical and sigmoidoscopic remission has been reported with 5-ASA 4-g enemas daily for two weeks." Remission of clinical symptoms occurred significantly more frequently during the first two weeks of treatment with5-ASA 1.0-genemasdaily (51 percent) than with prednisolone 25-mg enemas (31 percent; p
