Reticulated phototoxic eruption in a patient on long-term diltiazem therapy

Journal of Drugs in Dermatology, August, 2008 by Miriam Hanson, Vesna Petronic-Rosic

ABSTRACT: Ditiazem hydrochloride is a commonly prescribed medication in the treatment of cardiovascular disease. A case of diltiazem-induced hyperpigmentation in a patient after significant sun exposure is reported. The morphological appearance was reticulated and slate gray to blue in color. The pathogenesis of the hyperpigmentation is discussed and possible treatment options are reviewed.

INTRODUCTION

Diltiazem hydrochloride is a calcium channel blocker commonly used in the treatment of coronary artery disease and hypertension. The spectrum of cutaneous eruptions in association with diltiazem is extensive, ranging from urticaria and exanthems to serious adverse events, such as Stevens-Johnson syndrome, toxic epidermal necrolysis, and vasculitis. (1) Recently, a characteristic reticulated hyperpigmentation on sun-exposed areas in patients on long-term administration of diltiazem has been described. A case of an African American male who developed a phototoxic eruption on the head and neck during treatment with diltiazem is reported.

CASE REPORT

A 52-year-old African American male presented with a 3-month history of asymptomatic hyperpigmentation first noted after substantial sun exposure on the face and neck. His past medical history was significant for coronary artery spasms, which had been treated with diltiazem for the last 5 years. The patient denied any other history of inflammatory skin diseases, photosensitivity, or systemic illness. A physical examination demonstrated slate-gray, reticulated photodistributed patches over the face and neck. There was an area of sparing on the central posterior neck caused by an external device worn during the sun exposure. A histopathological examination revealed scattered necrotic keratinocytes within the epidermis at all levels. There was a superficial perivascular infiltrate composed of lymphocytes and histiocytes and a significant number of melanophages with fine granular pigment scattered throughout the dermis. There was no increase in dermal mucin or basement membrane thickening suggestive of lupus. On the basis of the clinical history and histopathological findings, the diagnosis of diltiazem-induced phototoxic eruption was established. The patient was instructed to practice sun avoidance and protection. He was also given a trial of topical fluocinonide 0.05% ointment, which resulted in mild improvement in the degree of pigmentation.

DISCUSSION

Phototoxic eruptions are nonimmunologic reactions which cause a markedly increased sunburn response. The rash usually appears hours after ultraviolet A (UVA) exposure and may occur from both externally applied substances, such as furocoumarins and tar, or internally administered medications. (2) Most phototoxic drug reactions occur from the following classes of medications: tetracyclines, nonsteroidal anti-inflammatory drugs, amiodarone, and phenothiazines. (2) Recently, a characteristic phototoxic eruption in patients on diltiazem has been described.

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Scherschun et al (3) reported the first 4 cases of diltiazem-induced hyperpigmentation in 2002. In all of the cases, the patients were African American and had been taking long-acting diltiazem for at least 6 months. The morphological appearance of the hyperpigmentation was reticulated and slate-gray to blue-gray in color. The hyperpigmentation was reversible after the discontinuation of diltiazem, sun avoidance, and treatment with hydroquinone cream. Similar clinical and histological findings have been reported in the literature. (4), (5) The pathogenesis of this unusual reticulated hyperpigmentation is not entirely understood. Ultrastructural analysis by Scherschun et al (3) demonstrated fully melanized melanosomes within the dermal cells without deposits of drugs or metabolites. It has been hypothesized that sun exposure may induce free-radical complexes with either the drug or its metabolites. The 2 primary metabolites of diltiazem are desacetyldiltiazem and desmethyldiltiazem; however, as many as 9 metabolites have been identified. (5) It is also unclear what role pharmacokinetics play in this process. The photodistributed hyperpigmentation has only been noted in patients on long-term treatment or extended release formulations. (5) Numerous pharmacologic studies have demonstrated bioequivalence of the extended release and conventional formulations with similar pharmacokinetics. (5), (6) A recent study showed the absorption range for diltiazem to be 220 to 300 nm (within the ultraviolet B spectrum) although the UVA range is thought to be the major contributing factor for photosensitivity reactions. (7) The onset of pigmentary changes is within 6 to 24 months after the use of diltiazem. (7)

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CONCLUSION

From the few cases reported, no correlation has been made between the dosage of diltiazem and the time of the onset of pigmentation. (5) Avoidance of sun exposure and adequate sun protective measures are prudent in patients undergoing diltiazem therapy.