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

1812
SECTION IX
SPECIAL SYSTEMS PHARMACOLOGY
photophobia, myalgia, arthralgia, headaches, alopecia,
nail fragility, and increased susceptibility to staphylococcal
infections. Some patients develop a “retinoid
dermatitis” characterized by erythema, pruritus, and
scaling.
Very rarely, patients may develop pseudotumor cerebri, especially
when systemic retinoids are combined with tetracyclines (tetracycline
or minocycline; the mechanism for this adverse drug event is
unknown). There are reports that chronic administration at higher
doses can cause diffuse idiopathic skeletal hyperostosis (DISH) syndrome,
premature epiphyseal closure, and other skeletal abnormalities
(Vahlquist et al., 2008).
Systemic retinoids are highly teratogenic. There
is no safe dose during pregnancy. Common malformations
include craniofacial, cardiovascular, thymic, and
central nervous system (CNS) abnormalities. Although
there appears to be minimal, if any, risk of retinoid
embryopathy in fetuses conceived by males taking systemic
retinoids, it is commonly recommended that men
avoid retinoid therapy when actively trying to father
children. Prescribing of isotretinoin in the U.S. is
restricted via the risk-mitigation iPLEDGE system
(Goldsmith et al., 2004).
Serum lipid elevation is the most common laboratory abnormality.
This may be due to increased expression of apolipoprotein
C-III by systemic retinoids, which prevents the uptake of lipids
from very-low-density lipoproteins into cells (Vahlquist et al.,
2008). Other, less common, laboratory abnormalities include elevated
transaminases, decreased thyroid hormone, and leukopenia.
A baseline evaluation of serum lipids, serum transaminases, and
complete blood count (CBC) and a pregnancy test should be
obtained prior to starting any systemic retinoids. Laboratory values
should be checked monthly for the first 3-6 months and once every
3 months thereafter.
Isotretinoin
Isotretinoin (ACCUTANE, others) is approved for the treatment of
recalcitrant and nodular acne vulgaris. The drug has remarkable
efficacy in severe acne and may induce prolonged remissions
after a single course of therapy. It normalizes keratinization in
the sebaceous follicle, reduces sebocyte number with decreased
sebum synthesis, and reduces P. acnes (Vahlquist et al., 2008).
Clinical effects generally are noted within 1-3 months of starting
therapy.
Approximately one-third of patients will relapse, usually
within 3 years of stopping therapy (Vahlquist et al., 2008).
Preteens, males, and patients with acne conglobata or androgen
excess are at increased risk of relapse. Although most relapses are
mild and respond to conventional management with topical and
systemic anti-acne agents, some may require a second course of
isotretinoin.
There are several reports of patients developing signs of
depression while on isotretinoin. However, large studies have failed
to prove an association between isotretinoin use and depression.
Since it is possible that an idiosyncratic reaction occurs in a small
group of otherwise healthy individuals, current guidelines recommend
monthly monitoring of all patients on isotretinoin for signs of
depression.
Acitretin
Acitretin (SORIATANE, SORIATANE CK) is approved for use in the cutaneous
manifestations of psoriasis. It is especially useful in pustular
psoriasis, although all forms of cutaneous psoriasis are responsive to
acitretin. Clinical effect typically begins within 4-6 weeks, with the
full clinical benefit occurring at 3-4 months.
Although acitretin has a t 1/2
of ~50 hours, when combined with
alcohol, acitretin is esterified in vivo to produce etretinate, which has
a t 1/2
of >3 months (Vahlquist et al., 2008). It is not known how much
alcohol (i.e., cough syrup or other alcohol-based medications) is
required to induce this conversion. Therefore, female patients of
childbearing age should avoid pregnancy for 3 years after receiving
acitretin to avoid retinoid-induced embryopathy.
Bexarotene
Bexarotene (TARGRETIN) is a retinoid that selectively binds RXRs.
Oral and topical formulations of bexarotene are approved for use in
patients with cutaneous T-cell lymphoma. Although the exact mechanism
of action is unknown, studies suggest that bexarotene induces
apoptosis of malignant cells (Budgin et al., 2005). Because it is
metabolized by CYP3A4, inhibitors of CYP3A4 (e.g., imidazole
antifungals, macrolide antibiotics) will increase and inducers of
CYP3A4 (e.g., rifamycins, carbamazepine, dexamethasone,
efavirenz, phenobarbital) will decrease plasma levels of bexarotene.
Laboratory side effects are more common than with other retinoids,
with an increased incidence of significant lipid abnormalities and
hypothyroidism secondary to a reversible RXR-mediated suppression
of TSH gene expression (Sherman, 2003), pancreatitis, leukopenia,
and gastrointestinal (GI) symptoms. Unlike other retinoids,
thyroid function should be measured before initiating therapy and
periodically thereafter. Mucocutaneous side effects are less than with
other systemic retinoids.
VITAMIN ANALOGS
-Carotene. -Carotene is a precursor of vitamin A that
is present in green and yellow vegetables. Solatene has
been discontinued, and no -carotene products are
currently approved by the U.S. Food and Drug
Administration (FDA).
Dietary supplementation with -carotene is used in dermatology
to reduce skin photosensitivity in patients with erythropoietic
protoporphyria. The mechanism of action is not established but may
involve an anti-oxidant effect that decreases the production of free
radicals or singlet oxygen (Alemzedeh, 2004). However, a recent
meta-analysis concluded that -carotene, vitamin A, and vitamin E
given singly or combined with other anti-oxidant supplements actually
increase mortality (Bjelakovic et al., 2007). FDA’s Maximum
Recommended Therapeutic Dose (MRTD) database (http://www.
fda.gov/AboutFDA/CentersOffices/CDER/ucm092199.htm) lists
0.05 mg/kg/day as the MRTD for -carotene.