Hydrochlorothiazide: A savior to the heart or a foe to the skin?

Hydrochlorothiazide (HCTZ), is a thiazide-type diuretic that has been used clinically for more than half a century. It works by inhibiting the sodium-chloride cotransporter system in the kidney's distal convoluted tubules, which results in its diuretic action as water follows the increased K⁺ and Na⁺ in the nephron [1]. Hydrochlorothiazide is a commonly prescribed diuretic and it is considered a first-line treatment for hypertension. The drug has gained a lot of popularity as it is affordable, potent, and capable to improve other conditions like cardiac failure and symptomatic edema. Hydrochlorothiazide, although commonly prescribed, has few conventional adverse effects such as electrolyte imbalances, hyperglycemia, hyperlipidemia, and hyperuricemia. Even then, authorities deemed it to be the principal recommendation for the treatment of hypertension [2]. HCZT may induce hypokalemia, hyponatremia, hypercalcemia, and hypomagnesemia, and it can also cause azotemia in individuals with renal impairment [3]. The guidelines for HCTZ dosage recommend 25 mg–100mg & 25–50 mg once a day orally for patients with edema and hypertension respectively [1].

However, a recent 2020 study published in the Journal of Clinical Medicine raised new, more serious concerns – it showed that hydrochlorothiazide exposure caused a statistically significant increase in the risk of skin cancer potentially due to the photosensitizing capability of thiazide diuretics [4]. Thereafter, two more case reports were published that further strengthened the association of hydrochlorothiazide to skin's squamous cell carcinoma [5].

Since 2010, there has been increased surveillance regarding the correlation of a few antihypertensive medications with increased risk of acquiring melanoma and other malignancies. The emphasis of experimental, partially multicentric investigations in dermatological science indicates the existence of angiotensin receptors in the skin and melanoma tissue and locoregional metastases, as well as the possibility of metastasis potentiation in preexisting melanoma cells. Although it appears logical, it is uncertain to what degree these two experimental investigations have substantial clinical importance and may be regarded as a causative connection in the etiology of melanomas [6]. In vitro investigations in recent years have raised concerns regarding the potential function of angiotensin receptor blockers as carcinogens in connection to cutaneous melanoma, owing to the presence of angiotensin receptors in nevi and melanoma tissue [7].

Adalsteinsson JA et al. published a study in 2020 that concluded that the photosensitizing property of hydrochlorothiazide causes the production of free radicals and reactive oxygen species when exposed to ultraviolet radiation. As a result, mutations in the p53 and CDKN2A cell cycle regulators are increased, eventually leading to permanent UV damage. These free radicals subsequently result in neoplastic changes and give rise to keratinocyte carcinoma [8,9].

According to a cohort study published by Rouette J et al., HCZT was associated with an overall 50% increased risk of cutaneous squamous cell carcinoma (SCC), with females being at greater risk than males. However, when compared to other thiazide diuretics, HCZT was not associated with an overall increased risk of basal cell carcinoma (BCC) and melanoma [10]. The food and drug administration (FDA) recommends that clinicians inform their patients about the hazards of taking diuretics. This includes guiding patients to restrict their sun exposure and protect their skin by using broad-spectrum sunscreen and wearing protective clothing before going out in the sun. The FDA also advises patients who are on hydrochlorothiazide to get frequent testing for skin malignancies [11]. The FDA has approved drug label changes for hydrochlorothiazide (HCTZ) to forewarn healthcare professionals and patients of a slightly increased risk of non-melanoma skin cancer (basal cell skin cancer and squamous cell skin cancer) associated with HCTZ use and to encourage consumers to protect their skin from the sun [12]. Anuria and allergy to HCZT are two absolute contradictions. HCZT should not be prescribed to patients who have reported allergies to the use of sulfonamides-derived drugs. HCZT is a category B drug that can be administered throughout the gestational period. It is also secreted in breast milk but is reported to be safe to use during breastfeeding [13].

In light of these studies, the question still stands: Is Hydrochlorothiazide still safe to be considered as the first-line treatment for hypertension? The mentioned data is of chief importance to us because this drug is still widely used in different countries. Health workers should prescribe Hydrochlorothiazide with caution and should certainly rule out all the skin pathologies before prescribing this drug. If patients taking thiazides experience any sort of skin-related disturbances, they should seek immediate medical attention. Additionally, it is extremely important to promote precautionary strategies against sun exposure and frequent skin assessments to halt the mentioned deleterious consequences [14].

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The present study includes printed and published information; therefore, the formal ethical clearance was not applicable for this study.

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Author contribution

AK, P: conceived the idea, designed the study and drafted the manuscript.

AK, P, GK, SS, MMH: conducted literature search and created the illustrations.

AK, P, GK, SS, MMH: revised the manuscript critically and refined the illustrations.

AK, P, GK, SS, MMH: revised the final version of the manuscript critically and gave the final approval.

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Guarantor

Sarya Swed.

Faculty of Medicine, Aleppo University, Aleppo, Syria. Email: saryaswed1@gmail.com.

Declaration of competing interest

The authors declare that there is no conflict of interests.