Thiazides

Thiazides belong to the group of diuretics and were developed on the basis of carbonic anhydrase inhibitors. All thiazides have an acid sulfonamide group and are benzothiadizines or their analogues. The lead compound is hydrochlorothiazide. Inhibition of the sodium/chloride cotransporter in the luminal membrane of the tubule cells in the distal convolute increases potassium excretion and reduces calcium excretion.

Thiazide diuretics include the following agents, hydrochlorothiazide being the lead compound for this family of drugs:

• Bemeticide
• Bendroflumethiazide
• Clopamide
• Chlortalidone
• Hydrochlorothiazide
• Indapamide
• Mefruside
• Xipamide

Thiazide diuretics bind to the Na+/Cl- cotransporter in the early distal tubule and thus inhibit sodium re-transport, which subsequently increases potassium excretion and reduces calcium excretion. Some thiazide diuretics additionally inhibit carbonic anhydrase. Thiazide diuretics are renally eliminated to varying degrees. In the case of indapamide and xipamide, metabolic elimination predominates. In this respect, severe renal insufficiency prolongs the plasma half-life of some thiazides.

The following effects are further observed:

• Inhibition of renal Ca2+ excretion: this is due to the decrease in Na+ concentratin in theEpithelial celes of the earlydistal tubule. More Ca2+ is then reabsorbed via the basolateral Na+-Ca2+ antiporter and renal Ca2+ loss is inhibited.
• Increase in renal HCO3 excretion: thiazides are weak inhibitors of carbonic anhydrase.
• Increase in renal excretion of K+ and H+: this is due to increased supply of these ions to tubule cells.
• Relaxation of resistance vessels in the systemic circulation: this is not only due to increased Na+ excretion, but also to the opening of Ca2+-activated Kv channels (see potassium channels below). In vascular smooth muscle.
• Diabetogenic effect: The beta cells of the islets of Langerhans are also affected by the opening of Ca2+-activated Kv channels, which inhibits insulin release.

In the early distal tubule, the luminal Na+-Cl- symporter is responsible for Na+ reabsorption. Thiazides act luminal as inhibitors of the Na+-Cl- symporter in the early distal tubule. Inhibition of the transporter leads to an increase in urinary NaCL excretion Here, the natriuretic effect is much weaker than that of loop diuretics. In this respect, the phenomenon of postdiuretic Na+ retention is not observed with thiazides. If the glomerular filtration rate falls below 30 ml/min, the thiazides (in contrast to the loop diuretics) lose their efficacy.

See below the individual substances; the most common adverse effects of thiazides include disturbances of the electrolyte balance (hypokalemia), increased blood lipid levels, lack of appetite, nausea and skin reactions.

Rarely, hyperuricemia or hyperglycemia may occur.

Immunoallergic reactions (increased photosensitivity with UV-induced dermatitis, pruritus, urticarial and lichenoid exanthema, lichen planus, lupus erythematosus, urticaria, purpura) are not entirely uncommon.

An additional effect of thiazides is erectile dysfunction.

Note: Because of an increased risk of basal cell carcinoma and squamous cell carcinoma with hydrochlorothiazide (HCT), a Red Hand Letter was published in 2018. Here, it is likely that the photosensitizing effect of HCT is a contributing factor. Apparently, this risk also applies to melanoma (Drucker AM et al. 2021).

Thiazides must not be used:

• in case of hypersensitivity to the respective active substance or to sulphonamide derivatives in general!
• in severe liver dysfunction (praecoma and coma hepaticum)
• in therapy-resistant hypokalaemia
• severe hyponatremia
• hypercalcemia
• in hypovolaemia
• in gout
• during pregnancy
• during breastfeeding

Due to the increased excretion of potassium, monitoring of electrolytes should be performed.

1. Blakely KM et al (2019) Drug-Induced Photosensitivity-An Update: Culprit Drugs, Prevention and Management. Drug Saf 42:827-847.
2. Costagliola C et al. (2008) Retinal phototoxicity induced by hydrochlorothiazide after exposure to a UV tanning device. Photochem Photobiol 84:1294-1297.
3. Lüllmann H et al (2004) Pocket atlas of pharmacology. 5th ed. Georg Thieme Verlag, Stuttgart pp. 168-169.
4. Mauget-Faÿsse M et al. (2001) Incidental retinal phototoxicity associated with ingestion of photosensitizing drugs. Graefes Arch Clin Exp Ophthalmol 239:501-508.
5. 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.
6. Wagner SN et al. (2000) Occupational UVA-induced allergic photodermatitis in a welder due to hydrochlorothiazide and ramipril. Contact Dermatitis 43:245-246.