DƯỢC LÍ Goodman & Gilman's The Pharmacological Basis of Therapeutics 12th, 2010

1820 CYTOTOXIC AND IMMUNOSUPPRESSIVE
DRUGS
SECTION IX
SPECIAL SYSTEMS PHARMACOLOGY
Cytotoxic and immunosuppressive drugs are used in
dermatology for immunologically mediated diseases
such as psoriasis, auto-immune blistering diseases, and
leukocytoclastic vasculitis. These agents are discussed
in detail in Sections IV and VII. An overview of their
mechanisms of action is included in Table 65–9.
Antimetabolites
Methotrexate. The antimetabolite methotrexate is a folic
acid analog that competitively inhibits dihydrofolate
reductase. Methotrexate has been used for moderate to
severe psoriasis since 1951. It suppresses immunocompetent
cells in the skin, and it also decreases the expression
of cutaneous lymphocyte-associated antigen
(CLA)–positive T cells and endothelial cell E-selectin,
which may account for its efficacy (Sigmundsdottir
et al., 2004). It is useful in treating a number of other
dermatological conditions, including pityriasis
lichenoides et varioliformis, lymphomatoid papulosis,
sarcoidosis, pemphigus vulgaris, pityriasis rubra pilaris,
lupus erythematosus, dermatomyositis, and cutaneous
T-cell lymphoma.
Table 65–9
Mechanism of Action for Selected Cytotoxic
and Immunosuppressive Drugs
Methotrexate
Azathioprine
Fluorouracil
Cyclophosphamide
Mechlorethamine
hydrochloride
Carmustine
Cyclosporine
Tacrolimus
Pimecrolimus
Mycophenolate
mofetil
Imiquimod
Vinblastine
Bleomycin
Dapsone
Thalidomide
Dihydrofolate reductase inhibitor
Purine synthesis inhibitor
Blocks methylation in DNA
synthesis
Alkylates and cross-links DNA
Alkylating agent
Cross-links in DNA and RNA
Calcineurin inhibitor
Calcineurin inhibitor
Calcineurin inhibitor
Inosine monophosphate
dehydrogenase inhibitor
Interferon- induction
Inhibits microtubule formation
Induction of DNA strand breaks
Inhibits neutrophil migration,
oxidative burst
Cytokine modulation
Despite its widespread acceptance for decades
as a first-line systemic monotherapy for the treatment
of psoriasis, methotrexate (RHEUMATREX, others) was
subjected only recently to a randomized, controlled
clinical trial comparing its efficacy with that of orally
administered cyclosporine for the treatment of moderate
to severe chronic plaque psoriasis (Heydendael
et al., 2003). Both medications were equally effective
in achieving partial or complete clearing of psoriasis.
Methotrexate often is used in combination with
phototherapy and photochemotherapy or other systemic
agents, and it also may be useful in combination
with the biologicals (Saporito and Menter, 2004)
(see “Biological Agents”).
A usual starting dosage for methotrexate therapy is 5-7.5
mg/wk (maximum of 15 mg/wk). This dosage may be increased
gradually to 10-25 mg/wk if needed. Widely used regimens include
three 2.5-mg oral doses given at 12-hour intervals once weekly, or
weekly intramuscular injections of 10-25 mg (maximum of 30
mg/wk). Doses must be decreased for patients with impaired renal
clearance. Methotrexate should never be co-administered with
trimethoprim–sulfamethoxazole, probenecid, salicylates, or other
drugs that can compete with it for protein binding and thereby raise
plasma concentrations to levels that may result in bone marrow suppression.
Fatalities have occurred because of concurrent treatment
with methotrexate and nonsteroidal anti-inflammatory agents.
Methotrexate exerts significant anti-proliferative effects on the bone
marrow; therefore, CBCs should be monitored serially. Physicians
administering methotrexate should be familiar with the use of
folinic acid (leucovorin) to rescue patients with hematological crises
caused by methotrexate-induced bone marrow suppression. Careful
monitoring of liver function tests is necessary but may not be adequate
to identify early hepatic fibrosis in patients receiving chronic
methotrexate therapy. Methotrexate-induced hepatic fibrosis may
occur more commonly in patients with psoriasis than in those with
rheumatoid arthritis. Consequently, liver biopsy is recommended
when the cumulative dose reaches 1-1.5 g. A baseline liver biopsy
also is recommended for patients with increased potential risk for
hepatic fibrosis, such as a history of alcohol abuse or infection with
hepatitis B or C. Patients with significantly abnormal liver function
tests, symptomatic liver disease, or evidence of hepatic fibrosis
should not use this drug. Many clinicians routinely administer folic
acid along with methotrexate to ameliorate side effects; this does
not reduce efficacy of the methotrexate. Pregnancy and lactation are
absolute contraindications to methotrexate use.
Azathioprine. Azathioprine (IMURAN, others) is discussed
in detail in Chapter 35. In dermatological practice,
the drug is used off label as a steroid-sparing agent
for auto-immune and inflammatory dermatoses,
including pemphigus vulgaris, bullous pemphigoid,
dermatomyositis, atopic dermatitis, chronic actinic
dermatitis, lupus erythematosus, psoriasis, pyoderma