現在位置 : RA > 免疫調節藥 - 磺胺藥 (撒樂 / 斯樂腸溶錠) (sulfasalazine, salazopyrine)
認識 免疫調節藥 -- 磺胺藥 (撒樂) (sulfasalazine, salazopyrine)
免疫調節藥 = 疾病調整型抗風濕病類藥物
(DMARD, disease modified anti-rheumatic drug)
● 須使用至少 3-6 週後方可產生效果 (有時效果很快顯見)
磺胺藥 (撒樂 / 斯樂腸溶錠) (sulfasalazine, salazopyrine)
little absorption of intact Sulfasalazine: insoluble
cleaved by colonic bacteria to
(1) Sulfapyridine: 抗風濕作用 (antirheumatic effect)
(2) 5-aminosalicytic acid: 抗發炎作用 (anti-inflammatory effect)
● 發生效果 Onset: 需 4 週時間
● 類風濕性關節炎 RA: 效果等同金劑 gold or d-penicillamine, 可阻止關節破壞 able to retard erosion of RA
● 僵直性脊椎炎相關疾病 SAE: 包括乾癬性關節炎, 發炎潰瘍性大腸炎, 克隆氏症
● 每日一顆 500mg QD 先使用一週, 之後每週增加一顆
● 最大劑量: 一次2顆, 一天3次
● 白血球降低 Leukopenia: 1-3% 的病患, 和劑量有關, 多發生在頭 6 個月
(1) 皮膚過敏癢疹: 1-5% 的病患
(2) Steven-Johnson’s syndrome
● 肺部: 可逆性急性嗜酸性白血球性纖維性肺炎
● 腸胃不適: 恶心, 腹痛
● 中樞神經: 頭痛, 頭暈
(1) 若肝指數 GPT 小於 4 倍以下只須追蹤
(2) 通常 3 個月內回復正常
Sulfasalazine is an old drug still occasionally used to treat RA. It combines an aspirin-like pain reliever with an antibiotic sulfa drug. Side effects are usually mild. Nausea and abdominal discomfort are the most common complaints. The drug increases sun sensitivity. Take precautions to avoid sunburn.
Sulfasalazine for Rheumatoid Arthritis
Sulfasalazine (brand name Azulfidine in the U.S., Salazopyrin and Sulazine in Europe and Hong Kong) was developed in the 1950s specifically to treat rheumatoid arthritis. It was believed at the time that bacterial infections were the cause of rheumatoid arthritis. Sulfasalazine is a sulfa drug, (a derivative of mesalazine) and is formed by combining sulfapyridine and salicylate with an azo bond. It may be abbreviated SSZ.
Sulfasalazine is used in the treatment of inflammatory bowel disease, including ulcerative colitis and Crohn's disease. It is also indicated for use in rheumatoid arthritis and used in other types of inflammatory arthritis (e.g. psoriatic arthritis) where it has a beneficial effect. It is often well tolerated compared to other DMARDS.
In clinical trials for the treatment of chronic alcoholics,
sulfasalazine has been found to reverse the scarring associated with cirrhosis of the liver. Cells called myofibroblasts, which contribute to scar tissue in a diseased liver, also appear to secrete proteins that prevent the breakdown of the scar tissue. Sulfasalazine appears to retard this secretion.
A study at University of Newcastle found that the drug may also act to aid the healing of cirrhosis of the liver.
It is usually not given to children under 2 years of age.
The use of sulfasalazine in inflammatory bowel disease has declined due mainly to the fact that it yields the metabolite sulfapyridine which gives rise to side-effects such as agranulocytosis and hypospermia. However, the other metabolite of sulfasalazine, 5-aminosalicylic acid (5-ASA) is attributed to the drug's therapeutic effect. Therefore, 5-ASA and other derivatives of 5-ASA, are now usually preferred and given alone (as mesalazine), despite their increased cost, due to their more favourable side-effect profile.
Sulfasalazine has also been used successfully to treat cases of idiopathic urticaria that do not respond to antihistamines.
Mode of action
Sulfasalazine, and its metabolite 5-ASA, are poorly absorbed from the gut. Its main mode of action is therefore believed to be inside the intestine.
In Crohn's disease and ulcerative colitis, it is thought to be an antinflammatory drug that is essentially providing topical relief inside the intestine. It does this via a number of mechanisms such as reducing the synthesis of inflammatory mediators known as eicosanoids and inflammatory cytokines. However, unlike glucocorticoids (another class of drug used in the treatment in inflammatory bowel disease), sulfasalazine is a mild immunosuppressant.
When treatment for arthritis is successful, pain, joint swelling and stiffness will be reduced and this may slow down or stop the development of joint damage. The precise reasons why sulfasalazine are effective in various forms of arthritis is not clearly understood.
Because sulfasalazine and its metabolite 5-ASA are poorly absorbed into the bloodstream, it is surprising that the drug is effective against symptoms outside of the intestine. One possible explanation is that, given that ulcerative colitis produces arthritic symptoms, the arthritic symptoms are actually a product of unrecognized ulcerative colitis, which is effectively treated with sulfazalazine.
The other metabolite, sulfapyridine, is absorbed into the blood, and is believed to be the source of the side-effects discussed below. It is possible that the sulfapyridine is responsible for some of the anti-arthritic effects of sulfasalazine.
Sulfsalazine metabolizes to sulfapyridine. Serum levels should be monitored every three months, and more frequently at the outset. Serum levels above 50 μg/l are associated with side effects. In rare cases, Sulfasalazine can cause severe depression in young males. It can also cause temporary infertility. Immune thrombocytopenia has been reported.
Sulfasalazine inhibits dihydrofolate reductase, and can cause folate deficiency and megaloblastic anemia.
Sulfasalazine can cause hemolytic anemia in people with G6PD deficiency.
Sulfasalazine Tablets, USP
Sulfasalazine tablets contain Sulfasalazine, 500 mg, for oral administration.
Therapeutic Classification: Anti-inflammatory agent.
5-([p-(2-pyridylsulfamoyl)phenyl]azo) salicylic acid.
Molecular Formula: C18H14N4O5S
Sulfasalazine - Clinical Pharmacology
The mode of action of Sulfasalazine (SSZ) or its metabolites, 5-aminosalicylic acid (5-ASA) and sulfapyridine (SP), is still under investigation, but may be related to the anti-inflammatory and/or immunomodulatory properties that have been observed in animal and in vitro models, to its affinity for connective tissue, and/or to the relatively high concentration it reaches in serous fluids, the liver and intestinal walls, as demonstrated in autoradiographic studies in animals. In ulcerative colitis, clinical studies utilizing rectal administration of SSZ, SP, and 5-ASA have indicated that the major therapeutic action may reside in the 5-ASA moiety.
In vivo studies have indicated that the absolute bioavailability of orally administered SSZ is less than 15% for parent drug. In the intestine, SSZ is metabolized by intestinal bacteria to SP and 5-ASA. Of the two species, SP is relatively well absorbed from the intestine and highly metabolized, while 5-ASA is much less well absorbed.
Following oral administration of 1 g of SSZ to 9 healthy males, less than 15% of a dose of SSZ is absorbed as parent drug. Detectable serum concentrations of SSZ have been found in healthy subjects within 90 minutes after the ingestion. Maximum concentrations of SSZ occur between 3 and 12 hours post-ingestion, with the mean peak concentration (6 μg/mL) occurring at 6 hours.
In comparison, peak plasma levels of both SP and 5-ASA occur approximately 10 hours after dosing. This longer time to peak is indicative of gastrointestinal transit to the lower intestine where bacteria mediated metabolism occurs. SP apparently is well absorbed from the colon with an estimated bioavailability of 60%. In this same study, 5-ASA is much less well absorbed from the gastrointestinal tract with an estimated bioavailability of from 10 to 30%.
Following intravenous injection, the calculated volume of distribution (Vdss) for SSZ was 7.5 ± 1.6 L. SSZ is highly bound to albumin (>99.3%) while SP is only about 70% bound to albumin. Acetylsulfapyridine (AcSP), the principal metabolite of SP, is approximately 90% bound to plasma
As mentioned above, SSZ is metabolized by intestinal bacteria to SP and 5-ASA. Approximately 15% of a dose of SSZ is absorbed as parent and is metabolized to some extent in the liver to the same two species. The observed plasma half-life for intravenous Sulfasalazine is 7.6 ± 3.4 hours. The primary route of metabolism of SP is via acetylation to form AcSP. The rate of metabolism of SP to AcSP is dependent upon acetylator phenotype. In fast acetylators, the mean plasma half-life of SP is 10.4 hours while in slow acetylators, it is 14.8 hours. SP can also be metabolized to 5-hydroxy-sulfapyridine (SPOH) and N-acetyl-5-hydroxy-sulfapyridine. 5-ASA is primarily metabolized in both the liver and intestine to N-acetyl-5-aminosalicylic acid via a non-acetylation phenotype dependent route. Due to low plasma levels produced by 5-ASA after oral administration, reliable estimates of plasma half-life are not possible.
Absorbed SP and 5-ASA and their metabolites are primarily eliminated in the urine either as free metabolites or as glucuronide conjugates. The majority of 5-ASA stays within the colonic lumen and is excreted as 5-ASA and acetyl-5-ASA with the feces. The calculated clearance of SSZ following intravenous administration was 1 L/hr. Renal clearance was estimated to account for 37% of total clearance.
Elderly patients with rheumatoid arthritis showed a prolonged plasma half-life for SSZ, SP, and their metabolites. The clinical impact of this is unknown.
Small studies have been reported in the literature in children down to the age of 4 years with ulcerative colitis and inflammatory bowel disease. In these populations, relative to adults, the pharmacokinetics of SSZ and SP correlated poorly with either age or dose.
The metabolism of SP to AcSP is mediated by polymorphic enzymes such that two distinct populations of slow and fast metabolizers exist. Approximately 60% of the Caucasian population can be classified as belonging to the slow acetylator phenotype. These subjects will display a prolonged plasma half-life for SP (14.8 hours vs. 10.4 hours) and an accumulation of higher plasma levels of SP than fast acetylators. The clinical implication of this is unclear; however, in a small pharmacokinetic trial where acetylator status was determined, subjects who were slow acetylators of SP showed a higher incidence of adverse events.
Gender appears not to have an effect on either the rate or the pattern of metabolites of SSZ, SP, or 5-ASA.