Hydrochlorothiazide

Hydrochlorothiazide (HCT or also called HTZ), a thiazide diuretic (molecular formula: C7H8ClN3O4S2 - see also structural formula), is a diuretically active drug with an acid sulfonamide group that is luminal as an inhibitor of the Na+/Cl- -symporter. Hydrochlorothiazide is used in arterial hypertension, in heart failure, or for the treatment of edema. Hydrochlorothiazide is often used in the form of fixed combinations with other active substances.

As a thiazide analogue, hydrochlorothiazide reversibly inhibits the sodium chloride symporter in the luminal cell membrane of cells of the distal tubule in the kidney, resulting in excretion of sodium chloride along with associated H2O. Furthermore, renal excretion of calcium cations decreases. That of magnesium cations increases. The increased calcium retention may lead to an increase in bone density in osteoporosis patients. At high doses, hydrochlorothiazide also has an inhibitory effect on the enzyme carbonic anhydrase. Hydrochlorothiazide is practically ineffective in chronically renal insufficient patients with creatinine clearance below 30 ml/min.

The duration of action of hydrochlorothiazide is 6-12 hours. Most of the drug is excreted >90% unchanged by the kidney. Like other thiazide diuretics, it leads to activation of the RAAS via electrolyte and fluid loss and thus to secondary hyperaldosteronism.

Hydrochlorothiazide is usually used as a second-line antihypertensive (when another agent alone does not achieve sufficient blood pressure reduction and two agents are needed).

Hydrochlorothiazide is placental. Due to the mechanism of action, fetoplacental perfusion may be impaired and jaundice, electrolyte imbalance, and thrombocytopenia may occur in the fetus or neonate during the second and third trimesters.

Hydrochlorothiazide should not be used in pregnancy edema, pregnancy hypertension, or preeclampsia because of the risk of decreased plasma volume and placental hypoperfusion.

In essential hypertension in pregnant women, hydrochlorothiazide should be used only in rare cases where no other treatment is available.

Lactation

The use of hydrochlorothiazide during lactation is not recommended because hydrochlorothiazide passes into breast milk in small amounts and may inhibit lactation at high doses.

If hydrochlorothiazide is used during lactation, the dose should be as low as possible.

The dosage is determined individually - especially according to the success of the treatment. During therapy, in addition to serum electrolytes, the concentrations of urinary substances (serum creatinine, urea), serum lipids (cholesterol and triglycerides) as well as blood sugar and uric acid should be checked regularly.

Adults:

Arterial hypertension: Initial dose is 12.5 - 25 mg hydrochlorothiazide once daily.

Maintenance dose is usually 12.5 mg hydrochlorothiazide once daily.

Cardiac, hepatic, and renal edema: Initial dose is 25-50 mg hydrochlorothiazide once daily.

The maintenance dose is usually 25-50 mg hydrochlorothiazide daily, but may be increased to 100mg in rare cases.

Adjuvant symptomatic therapy of chronic heart failure in addition to ACE inhibitors: 1x/day 25 to 37.5 mg hydrochlorothiazide is recommended.

Frequent

Electrolyte disturbances: especially decreased potassium and sodium levels with hypokalemia and hyponatremia, hypomagnesemia, hypochloremia, hypercalcemia, dry mouth and thirst.

• At high doses, weakness and dizziness, muscle pain and muscle cramps. Headache, hypotensive circulatory disturbances especially when changing from lying to standing; in case of excessive urinary excretion, hypovolemia and hemoconcentration may occur due to dehydration. The consequences are possible thromboses and embolisms.
• Furthermore, the clinical consequences of hypokalemia appear (fatigue, drowsiness, muscle weakness, paresthesias, smooth muscle adynamia.
• Hypermagnesiuria is common and only occasionally manifests as a deficiency of magnesium in the blood(hypomagnesemia).

Other metabolic changes:

• Uric acid: gout attacks due to hyperuricemia;
• Blood sugar: possible hyperglycaemia and glucosuria.
• Blood lipids: increase in blood lipids (cholesterol, triglycerides).

Occasional:

Kidney: increase in urinary substances (creatinine, urea).

Pancreas: increased levels of amylase in the blood, pancreatitis.

Other: continued loss of appetite, nausea, vomiting, diarrhoea, abdominal pain and cramps), drug fever.

Rare:

Dermatologic UAW:

• The spectrum of dermatologic ADRs is extensive. Allergic, toxic and lymphoproliferative skin reactions are described. These manifest clinically in:
• Pruritus, in urticarial and lichenoid exanthema in urticaria (Aouam K et al. 2009) and clear cases of lichen planus (Sin B et al. 2016).
• Photosensitivity/phototoxicity: Increased photosensitivity with UV (UVA/UVB)-induced dermatitides (Blakely KM et al. 2019, Wagner SN et al. 2000). Photosensitivity can also be provoked by laser therapy when a UV-emitting light source is used (e.g., from an excimer laser emitting in the 308-nm narrow-band - Rosenthal A et al. 2019). Masuoka E et al. (2011) described a (chronic) melanocyte dysfunction under therapy with hydrochlorothiazide which manifested clinically as "photoleukomelanoderm".
• Several times described under hydrochlorothiazide therapy are acute as well as cases of subacute cutaneous lupus erythematosus -SLE; SCLE - (Callen JP 2010, Srivastava M et al. 2003).

Furthermore:

• Purpura
• Pustulosis acuta generalisata: unusual occurrence of pustulosis acuta generalisata associated with hydrochlorothiazide therapy (Pétavy-Catala C et al 2001).
• Lymphoproliferative T-cell reactions: Reeder MJ et al (2015) described a generalized lymphoproliferative T-cell reaction (pseudo-Sezary syndrome) during hydrochlorothiazide therapy; Jahan-Tigh RR et al (2013) were able to establish an association between cutaneous T-cell lymphoma(mycosis fungoides and Sezary syndrome) and hydrochlorothiazide therapy in a large collective. These study results suggest an association between therapy with hydrochlorothiazide and benign or malignant lymphoproliferative skin manifestations.
• Carcinomas of the skin: Importantly, pharmacoepidemiologic studies have demonstrated an increased risk of basal cell carcinoma or squamous cell carcinoma with exposure to increasing cumulative doses of hydrochlorothiazide (Pedersen SA et al. 2018, Geyer S et al. 2019). The clustered occurrence of lip carcinomas (Pottegård A et al. 2017) and Merkel cell carcinomas (Pedersen SA et al. 2019) have further been reported.

Ophthalmological UAW: acute retinal phototoxicity under short-term high UV- exposure ( Costagliola C et al. 2008, Mauget-Faÿsse M et al. 2001);

furthermore: visual disturbances (e.g. blurred vision, color vision disturbances, yellow vision), xerophthalmia

Nephrological adverse events: acute tubulointerstitial nephritis, vasculitis

Haematological adverse reactions: leucopenia, thrombocytopenia, aplastic anaemia

Other: Potency disorders

Monopreparations

• Disalunil (D)
• Esidrex (D,CH)
• numerous generics (D)

Combination products (HCT+)

• + Aliskiren: Rasilez HCT (D, A, CH)
• + Amiloride: Comiloride (CH), Diursan (D), Ecodurex (CH), Escoretic (CH), Loradur (A), Moduretic (A, CH), Rhefluin (CH)
• + Benazepril: Cibadrex (D, CH), numerous generics (D)
• + Bisoprolol: Bilol comp. (CH), Concor plus (D, CH), Rivacor plus (A), Lodoz (CH), numerous generics (D)
• Candesartan: Atacand plus (D, A, CH), Blopress plus (D, A, CH), many generics (D)
• + Captopril: ACE inhibitor (D), Adocomp (D), Capozide forte (A), Cardiagen (D), Jutacor comp. (D), Tensobon comp. (D), numerous generics (D)
• + Cilazapril: Dynorm Plus (D), Inhibace Plus (CH)
• + Enalapril: Co-Acepril (CH), Co-Reniten (CH), Coenytyrol (A), Corvo HCT (D), Elpradil HCT (CH), Renacor (D), Renitec plus (A, CH), numerous generics (D)
• + Eprosartan: Emestar plus (D), Teveten plus (D, A, CH)
• + Fosinopril: Dynacil comp. (D)
• + Irbesartan: CoAprovel (D, A, CH), Karvezide (D, A)
• + Lisinopril: Acecomp (A), Acercomp (D), Co-Lisinostad (A), Co-Lisinopril (A), Prinzide (CH), Zestoretic (CH), numerous generics (D)
• +Losartan: Cosaar Plus (CH), Fortzaar (A), Lanosar comp. (A), Lorzaar plus (D), Losathia (A), many generics (D)
• + Metoprolol:Beloc-ZOK comp. (D), Seloken retard plus (A), many generics (D)
• + nebivolol: Hypoloc plus HCT, (A), Nomexor plus HCT (A)
• Olmesartan: Olmetec (D, A, CH), Votum plus (D, CH)
• + Quinalapril: Accuzide (D, A, CH)
• + Ramipril: Delix plus (D), Lannapril plus (A), Triatec comp. (CH), Tritazide (A), Vesdil plus (D), numerous generics (D)
• + spironolactone: spironothiazide (D)
• + Telmisartan: Kinzalkomb (D, A, CH), Micardis plus (D, A, CH), Pritor plus (A)
• Triamterene: Diuretic Verla (D), Diu Venostasin (D), Dytide H (D, A), Nephral (D), Tri-Thiazide (D), Turfa gamma (D)
• +Valsartan: Co-Diovan (D, A, CH), Cordinate (D), Provas (D), numerous generics (D)
• +verapamil: Isoptin RR plus (D)
• + zofenopril: Bifril plus (A)

as a dual combination (HCT+/+)

• + amiloride + timolol: Moducrin (D)
• + amlodipine + valsartan: Dafiro HCT (D), Exforge HCT (D, CH)
• + Atenolol + Amiloride: Kalten (CH)
• + propranolol + triamterene: Beta-Turfa gamma (D), Dociteren (D)
• + Triamterene + Verapamil: Confit (A)

Use in doping: Hydrochlorothiazide is on the World Anti-Doping Agency's banned list.[14] Although not directly used to enhance performance, it can be used to mask such doping, it is therefore called a masking agent.

Other drugs with common photosensitizing effects include: amiodarone, chlorpromazine, doxycycline, nalidixic acid, naproxen, piroxicam, tetracycline, thioridazine, vemurafenib, and voriconazole (Blakely KM et al. 2019).

1. Aouam K et al. (2009) Lichenoid eruption associated with hydrochlorothiazide and possible cross reactivity to furosemide. Therapy 64:344-347.
2. Blakely KM et al. (2019) Drug-Induced Photosensitivity-An Update: Culprit Drugs, Prevention and Management. Drug Saf 42:827-847.
3. Callen JP (2010) Drug-induced subacute cutaneous lupus erythematosus. Lupus 19:1107-1111.
4. Costagliola C et al (2008) Retinal phototoxicity induced by hydrochlorothiazide after exposure to a UV tanning device. Photochem Photobiol 84:1294-1297.
5. Geyer S et al (2019) Hydrochlorothiazide and nonmelanoma skin cancer Hydrochlorothiazide and nonmelanoma skin cancer. Dermatologist 70:148-149.
6. Jahan-Tigh RR et al (2013) Hydrochlorothiazide and cutaneous T cell lymphoma: prospective analysis and case series. Cancer 119:825-831.
7. Lüllmann H et al (2004) Pocket atlas of pharmacology. 5th ed. Georg Thieme Verlag, Stuttgart pp. 168-169.
8. Mauget-Faÿsse M et al. (2001) Incidental retinal phototoxicity associated with ingestion of photosensitizing drugs. Graefes Arch Clin Exp Ophthalmol 239:501-508.
9. Masuoka E et al (2011) Dysfunction of melanocytes in photoleukomelanoderma following photosensitivity caused by hydrochlorothiazide. Photodermatol Photoimmunol Photomed 27:328-30.
10. Pedersen SA et al (2018) Hydrochlorothiazide use and risk of nonmelanoma skin cancer: A nationwide case-control study from Denmark. J Am Acad Dermatol 78:673-681.
11. Pedersen SA et al. (2019) Hydrochlorothiazide use and risk for Merkel cell carcinoma and malignant adnexal skin tumors: A nationwide case-control study. J Am Acad Dermatol 80:460-465
12. Pétavy-Catala C et al (2001) Hydrochlorothiazide-induced acute generalized exanthematous pustulosis. Acta Derm Venereol 81:209.
13. Pottegård A et al (2017) Hydrochlorothiazide use is strongly associated with risk of lip cancer. J Intern Med 282:322-331.
14. Reeder MJ et al (2015) Drug-induced pseudo-sezary syndrome: a case report and literature review. Am J Dermatopathol 37:83-86.
15. Rosenthal A et al. (2019) Hydrochlorothiazide-induced photosensitivity in a psoriasis patient following exposure to narrow-band ultraviolet B excimer therapy. Photodermatol Photoimmunol Photomed 35:369-371.
16. Sin B et al (2016) Hydrochlorothiazide Induced Lichen Planus in the Emergency Department. J Pharm Pract 30:266-269.
17. Srivastava M et al (2003) Drug-induced, Ro/SSA-positive cutaneous lupus erythematosus. Arch Dermatol 139:45-49.
18. Wagner SN et al. (2000) Occupational UVA-induced allergic photodermatitis in a welder due to hydrochlorothiazide and ramipril. Contact Dermatitis 43:245-246.