Page 1214 - Clinical Immunology_ Principles and Practice ( PDFDrive )

1178 Part tEN Prevention and Therapy of Immunological Diseases

COOH
NH 2 CH 3 Sulfasalazine
N CH 3 N C NHCH HOOC
N
O CH 2 HO N N SO 2 NH

H N N CH 2 N
2
N
COOH
Methotrexate HOOC
FIG 87.1 Methotrexate—chemical structure.
HO N H 2 N SO 2 NH
N
TABLE 87.1 Methotrexate: Mechanisms 5-Aminosalicylic acid Sulfapyridine
of action
FIG 87.2 Sulfasalazine—chemical structure.
Suggested Mechanism rationale
Folate antagonism Prevents purine and pyrimidine
synthesis required for the TABLE 87.2 Methotrexate: adverse Effects
proliferation of actively dividing
immune cells, such as Gastrointestinal Cardiovascular
lymphocytes Stomatitis Pericarditis
Inhibition of spermine and Reduces formation of polyamines Anorexia Thrombosis
spermidine production harmful to tissues Nausea
Alteration of cellular redox state Reversible inhibition of lymphocyte Vomiting Pulmonary
and macrophage functions Diarrhea Pulmonary fibrosis
Release of adenosine Generation of a potent Cirrhosis Interstitial pneumonitis
endogenous antiinflammatory Pancreatitis
mediator through inhibition of Others
catabolism of both adenosine Hematological
and adenosine monophosphate Leukopenia Skin rashes
Renal failure
Anemia Abortion
Thrombocytopenia Impotence
Hypogammaglobulinemia Headache
caffeine, itself a nonselective antagonist of adenosine receptors, Lymphoma Opportunistic infections
may both reduce the effectiveness of methotrexate in RA and
protect against the development of cirrhosis of the liver, a major
side effect of methotrexate. 5
less than 1 in every 1000 patients with RA but may be more
Adverse Effects common among those with psoriasis. Risk factors, such as ethanol
consumption, hepatitis B and C, diabetes, obesity, and alpha-
tHEraPEUtIC PEarLS 1-antitrypsin deficiency, identify patients most likely to develop
Methotrexate methotrexate-induced hepatic injury. However, other serious
side effects, such as pneumonitis, may be overlooked, since early
Proven safety profile symptoms (mild cough or shortness of breath) are often ignored.
Concomitant administration of folic acid advisable Early identification allows for prompt discontinuation. The risk
Antiinflammatory effects may be reduced by heavy use of caffeine of developing solid tumors is debated, since the risk of malignan-
Hepatotoxicity a rare but real concern
Risk of hepatotoxicity increased with: cies is intrinsic to some of the conditions, such as RA, for which
Alcohol use methotrexate is used. It is likely the risk of drug-induced
Hepatitis malignancy is real, since reports have documented tumor regres-
Diabetes sion following discontinuation of methotrexate, but the risk
Obesity remains extremely small.
Alpha-1-antitrypsin deficiency
SULFASALAZINE
Over the years, methotrexate has proven to be one of the safest
disease-modifying antirheumatic drugs (DMARDs) in use. Serious Sulfasalazine (Fig. 87.2) was originally introduced in the late
side effects such as cirrhosis are much less common than previ- 1930s for the treatment of RA but is now used in a wide range
ously thought (Table 87.2). The use of folic acid has decreased of inflammatory diseases, in particular, IBD and the seronegative
the occurrence of mucosal and GI side effects, without limiting arthritides. It consists of a derivative of the antiinflammatory
its antiinflammatory activity, and cytopenias are managed salicylic acid, 5-amino-salicylic acid, and the antimicrobial
adequately with regular blood counts. Although side effects, such sulfapyridine. These two moieties are joined together by an azo
as nausea and vomiting, may resolve spontaneously or respond bond. Which component is responsible for the drug’s antiinflam-
to dose reduction or folic acid supplementation, mild transami- matory actions is unclear, but it appears to vary according to
nasemia has rarely led to discontinuation of the medication. disease states. For instance, in IBD, 5-amino-salicylic acid is likely
Risk of serious hepatotoxicity over 5 years of use is likely to be the main active component, as it is poorly absorbed following