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

gangrenosum, and Behçet’s disease (Silvis, 2001). The
usual starting dosage is 1-2 mg/kg/day. Because it generally
takes 6-8 weeks to achieve therapeutic effect,
azathioprine often is started early in the course of disease
management. Careful laboratory monitoring is
important (Silvis, 2001). The enzyme thiopurine S-
methyltransferase (TPMT) is critical for the metabolism
of azathioprine to nontoxic metabolites.
Homozygous deficiency of this enzyme may raise
plasma levels of the drug and cause myelosuppression.
TPMT enzyme activity should be measured before initiating
azathioprine therapy (see Chapter 35).
Fluorouracil. Fluorouracil (5-FU) interferes with DNA
synthesis by blocking the methylation of deoxyuridylic
acid to thymidylic acid (Dinehart, 2000). Topical formulations
(CARAC, others) are used in multiple actinic keratoses,
actinic cheilitis, Bowen’s disease, and superficial
basal cell carcinomas not amenable to other treatments.
Fluorouracil is applied once or twice daily for 2-8 weeks,
depending on the indication. The treated areas may become severely
inflamed during treatment, but the inflammation subsides after the
drug is stopped. Intralesional injection of 5-FU has been used for
keratoacanthomas, warts, and porokeratoses.
Alkylating Agents
Cyclophosphamide. This is an effective cytotoxic and
immunosuppressive agent. Both oral and intravenous
preparations of cyclophosphamide are used in dermatology
(Fox and Pandya, 2000). Cyclophosphamide is
FDA approved for treatment of advanced cutaneous T-
cell lymphoma. Other uses include treatment of pemphigus
vulgaris, bullous pemphigoid, cicatricial
pemphigoid, paraneoplastic pemphigus, pyoderma
gangrenosum, toxic epidermal necrolysis, Wegener’s
granulomatosis, polyarteritis nodosa, Churg-Strauss
angiitis, Behçet’s disease, scleromyxedema, and
cytophagic histiocytic panniculitis (Silvis, 2001). The
usual oral dosage is 2-3 mg/kg/day in divided doses,
and there often is a 4- to 6-week delay in onset of
action. Alternatively, intravenous pulse administration
of cyclophosphamide may offer advantages, including
lower cumulative dose and a decreased risk of bladder
cancer (Silvis, 2001).
Cyclophosphamide has many adverse effects, including the
risk of secondary malignancy and myelosuppression, and thus is
used only in the most severe, recalcitrant dermatological diseases.
The secondary malignancies have included bladder, myeloproliferative,
and lymphoproliferative malignancies and have been seen with
the use of cyclophosphamide alone or in combination with other
antineoplastic drugs.
Mechlorethamine hydrochloride (MUSTARGEN)
and carmustine (BICNU) are used topically to treat cutaneous
T-cell lymphoma. Both can be applied topically
as a solution or in an extemporaneously compounded
ointment form. It is important to monitor CBCs and
liver function tests because systemic absorption can
cause bone marrow suppression and hepatitis. Other
side effects include allergic contact dermatitis, irritant
dermatitis, secondary cutaneous malignancies, and
pigmentary changes. Carmustine also can cause erythema
and post-treatment telangiectases (Zackheim
et al., 1990).
Calcineurin Inhibitors
Cyclosporine. Cyclosporine (NEORAL, GENGRAF, others)
is a potent immunosuppressant isolated from the fungus
Tolypocladium inflatum. It inhibits calcineurin, a phosphatase
that normally dephosphorylates the cytoplasmic
subunit of nuclear factor of activated T cells (NFAT),
thus permitting NFAT to translocate to the nucleus and
augment transcription of numerous cytokines. In T lymphocytes,
calcineurin inhibition blocks interleukin-2
(IL-2) gene transcription and release and ultimately
results in inhibition of T-cell activation (Cather et al.,
2001). The presence of calcineurin in Langerhans cells,
mast cells, and keratinocytes may further explain the
therapeutic efficacy of cyclosporine and the other calcineurin
inhibitors (e.g., tacrolimus, pimecrolimus; see
later in this section) (Reynolds and Al-Daraji, 2002).
Cyclosporine has FDA approval for the treatment
of psoriasis. Other cutaneous disorders that typically
respond well to cyclosporine are atopic dermatitis,
alopecia areata, epidermolysis bullosa acquisita, pemphigus
vulgaris, bullous pemphigoid, lichen planus, and
pyoderma gangrenosum. The usual initial oral dosage is
2.5 mg/kg/day given in two divided doses.
Hypertension and renal dysfunction are the major adverse
effects associated with the use of cyclosporine. These risks can be
minimized by monitoring serum creatinine (which should not rise
>30% above baseline), calculating creatinine clearance or glomerular
filtration rate in patients on long-term therapy or with a rising creatinine,
maintaining a daily dose of <5 mg/kg, and regularly
monitoring blood pressure (Cather et al., 2001). Alternation with
other therapeutic modalities may diminish cyclosporine toxicity.
Laboratory monitoring during therapy is essential. As with other
immunosuppressive agents, patients with psoriasis who are treated
with cyclosporine are at increased risk of cutaneous, solid organ, and
lymphoproliferative malignancies (Flores and Kerdel, 2000). The risk
of cutaneous malignancies is compounded if patients have received
phototherapy with PUVA.
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CHAPTER 65
DERMATOLOGICAL PHARMACOLOGY