Hydrochlorothiazide

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Hydrochlorothiazide
Hydrochlorothiazide.svg
Hydrochlorothiazide-from-xtal-3D-balls.png
Clinical data
Trade namesApo-hydro, others
AHFS/Drugs.comMonograph
MedlinePlusa682571
License data
Pregnancy
category
Routes of
administration		By mouth (capsules, tablets, oral solution)
ATC code
Legal status
Legal status
  • US: ℞-only
  • In general: ℞ (Prescription only)
Pharmacokinetic data
BioavailabilityVariable (~70% on average)
MetabolismNot significant[2]
Elimination half-life5.6–14.8 h
ExcretionPrimarily kidney (>95% as unchanged drug)
Identifiers
CAS Number
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
CompTox Dashboard (EPA)
ECHA InfoCard100.000.367 Edit this at Wikidata
Chemical and physical data
FormulaC7H8ClN3O4S2
Molar mass297.73 g·mol−1
3D model (JSmol)
InChI
 ☒NcheckY (what is this?)  

Hydrochlorothiazide (HCTZ or HCT) is a diuretic medication often used to treat high blood pressure and swelling due to fluid build up.[3] Other uses include treating diabetes insipidus and renal tubular acidosis and to decrease the risk of kidney stones in those with a high calcium level in the urine.[3] Hydrochlorothiazide is less effective than chlortalidone for prevention of heart attack or stroke.[4] [3][5] HCTZ is taken by mouth and may be combined with other blood pressure medications as a single pill to increase effectiveness.[3]

Potential side effects include poor kidney function; electrolyte imbalances, including low blood potassium, and, less commonly, low blood sodium, gout, high blood sugar, and feeling lightheaded with standing.[3] While allergies to HCTZ are reported to occur more often in those with allergies to sulfa drugs, this association is not well supported.[3] It may be used during pregnancy, but it is not a first-line medication in this group.[3]

It is in the thiazide medication class and acts by decreasing the kidneys' ability to retain water.[3] This initially reduces blood volume, decreasing blood return to the heart and thus cardiac output.[6] It is believed to lower peripheral vascular resistance in the long run.[6]

Two companies, Merck and Ciba, state they discovered the medication which became commercially available in 1959.[7] It is on the World Health Organization's List of Essential Medicines.[8] It is available as a generic drug[3] and is relatively affordable.[9] In 2018, it was the thirteenth most commonly prescribed medication in the United States, with more than 40 million prescriptions.[10][11]

Medical uses[]

Hydrochlorothiazide is frequently used for the treatment of hypertension, congestive heart failure, symptomatic edema, diabetes insipidus, renal tubular acidosis.[3] It is also used for the prevention of kidney stones in those who have high levels of calcium in their urine.[3]

Hydrochlorothiazide is recommended as an appropriate option for initial monotherapy in patients with mild primary hypertension.[12][13] A systematic, multinational, large-scale analysis by Suchard et al. supported equivalence between drug classes for initiating monotherapy in hypertension, however thiazide or thiazide-like diuretics showed better primary effectiveness and safety profiles than angiotensin-converting enzyme inhibitors and non-dihydropyridine calcium channel blockers.[12]

Hydrochlorothiazide is less potent but not necessarily less effective than chlorthalidone in reducing blood pressure.[14][15]  More robust studies are required to confirm which drug is superior in reducing cardiovascular events.[16] Side effect profile for both drugs appear similar and are dose dependant.[14][15][16]

Hydrochlorothiazide is also sometimes used to prevent osteopenia and for treatment of hypoparathyroidism,[17] hypercalciuria, Dent's disease, and Ménière's disease. For diabetes insipidus, the effect of thiazide diuretics is presumably mediated by a hypovolemia-induced increase in proximal sodium and water reabsorption, thereby diminishing water delivery to the ADH-sensitive sites in the collecting tubules and increasing the urine osmolality.[medical citation needed]

A low level of evidence, predominately from observational studies, suggests that thiazide diuretics have a modest beneficial effect on bone mineral density and are associated with a decreased fracture risk when compared with patients not taking thiazides.[18][19][20] Thiazides decrease mineral bone loss by promoting calcium retention in the kidney, and by directly stimulating osteoblast differentiation and bone mineral formation.[21]

It may be given together with other antihypertensive agents in fixed-dose combination preparations, such as in losartan/hydrochlorothiazide (see below).[medical citation needed]

Adverse effects[]

  • Hypokalemia, or low blood levels of potassium are an occasional side effect. It can be usually prevented by potassium supplements or by combining hydrochlorothiazide with a potassium-sparing diuretic
  • Other disturbances in the levels of serum electrolytes, including hypomagnesemia (low magnesium), hyponatremia (low sodium), and hypercalcemia (high calcium)
  • Hyperuricemia (high levels of uric acid in the blood). All thiazide diuretics including hydrochlorothiazide can inhibit excretion of uric acid by the kidneys, thereby increasing serum concentrations of uric acid.This may increase the incidence of gout in doses of ≥ 25mg per day and in more susceptible patients such as male gender of <60 years old.[22] [23][24]
  • Hyperglycemia, high blood sugar
  • Hyperlipidemia, high cholesterol and triglycerides
  • Headache
  • Nausea/vomiting
  • Photosensitivity
  • Weight gain
  • Pancreatitis

The frequency of side effects increase as the medication dose is increased and the highest occurrence of side effects occur at doses greater than 25 mg per day.[medical citation needed]

Package inserts contain vague and inconsistent data surrounding the use of thiazide diuretics in patients with allergies to sulfa drugs, with little evidence to support these statements.[25] A retrospective cohort study conducted by Strom et al. concluded that there is an increased risk of an allergic reaction occurring in patients with a predisposition to allergic reactions in general rather than cross reactivity from structural components of the sulfonamide-based drug.[26] Prescribers should examine the evidence carefully and assess each patient individually, paying particular attention to their prior history of sulfonamide hypersensitivity rather than relying on drug monograph information.[27]

There is an increased risk of non-melanoma skin cancer.[28] In August 2020, the Australian Therapeutic Goods Administration required the Product Information (PI) and Consumer Medicine Information (CMI) for medicines containing hydrochlorothiazide to be updated to include details about an increased risk of non-melanoma skin cancer.[29] In August 2020, the U.S. Food and Drug Administration (FDA) updated the drug label about an increased risk of non-melanoma skin cancer (basal cell skin cancer or squamous cell skin cancer).[30]

Mechanism of action[]

Hydrochlorothiazide belongs to thiazide class of diuretics. It reduces blood volume by acting on the kidneys to reduce sodium (Na+) reabsorption in the distal convoluted tubule. The major site of action in the nephron appears on an electroneutral NaCl co-transporter by competing for the chloride site on the transporter. By impairing Na+ transport in the distal convoluted tubule, hydrochlorothiazide induces a natriuresis and concomitant water loss. Thiazides increase the reabsorption of calcium in this segment in a manner unrelated to sodium transport.[31] Additionally, by other mechanisms, HCTZ is believed to lower peripheral vascular resistance.[6]

Dosage[]

In a double-blind, randomized study, the effects of 25 mg/day vs. 50 mg/day of hydrochlorothiazide were evaluated in geriatric patients (n = 51) with isolated systolic hypertension. Both dosages were associated with similar reductions in blood pressure; however, the higher dose (50 mg/day) caused a greater decline in serum potassium concentration. [32] For this reason 12.5 mg/day is most often initiated for the antihypertensive effects.

Society and culture[]

Co-Diovan (valsartan and HCTZ)
Two generic benazepril HCl 20 mg and HCTZ 25 mg oral tablets

Trade names[]

Hydrochlorothiazide is available as a generic drug under a large number of brand names, including Apo-Hydro, Aquazide, BPZide, Dichlotride, Esidrex, Hydrochlorot, Hydrodiuril, HydroSaluric, Hypothiazid, Microzide, Oretic and many others.[medical citation needed]

To reduce pill burden and in order to reduce side effects, hydrochlorothiazide is often used in fixed-dose combinations with many other classes of antihypertensive drugs such as:

  • ACE inhibitors — e.g. Prinzide or Zestoretic (with lisinopril), Co-Renitec (with enalapril), Capozide (with captopril), Accuretic (with quinapril), Monopril HCT (with fosinopril), Lotensin HCT (with benazepril), etc.
  • Angiotensin receptor blockers — e.g. Hyzaar (with losartan), Co-Diovan or Diovan HCT (with valsartan), Teveten Plus (with eprosartan), Avalide or CoAprovel (with irbesartan), Atacand HCT or Atacand Plus (with candesartan), etc.
  • Beta blockers — e.g. Ziac or Lodoz (with bisoprolol), Nebilet Plus or Nebilet HCT (with nebivolol), Dutoprol or Lopressor HCT (with metoprolol), etc.
  • Direct renin inhibitors — e.g. Co-Rasilez or Tekturna HCT (with aliskiren)
  • Potassium sparing diuretics: Dyazide and Maxzide triamterene[33]

Sport[]

Use of hydrochlorothiazide is prohibited by the World Anti-Doping Agency for its ability to mask the use of performance-enhancing drugs.[34]

See also[]

References[]

  1. ^ Jump up to: a b "Hydrochlorothiazide Use During Pregnancy". Drugs.com. 30 July 2019. Retrieved 19 January 2020.
  2. ^ Beermann B, Groschinsky-Grind M, Rosén A (1976). "Absorption, metabolism, and excretion of hydrochlorothiazide". Clin Pharmacol Ther. 19 (5 (Pt 1)): 531–37. doi:10.1002/cpt1976195part1531. PMID 1277708. S2CID 22159706.
  3. ^ Jump up to: a b c d e f g h i j k "Hydrochlorothiazide". The American Society of Health-System Pharmacists. Archived from the original on 10 May 2017. Retrieved 30 November 2016.
  4. ^ Roush GC, Messerli FH (January 2021). "Chlorthalidone versus hydrochlorothiazide: major cardiovascular events, blood pressure, left ventricular mass, and adverse effects". Journal of Hypertension. 39 (6): 1254–1260. doi:10.1097/HJH.0000000000002771. PMID 33470735. S2CID 231649367.
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  8. ^ World Health Organization (2019). World Health Organization model list of essential medicines: 21st list 2019. Geneva: World Health Organization. hdl:10665/325771. WHO/MVP/EMP/IAU/2019.06.
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  10. ^ "The Top 300 of 2021". ClinCalc. Retrieved 18 February 2021.
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  12. ^ Jump up to: a b Suchard MA, Schuemie MJ, Krumholz HM, You SC, Chen R, Pratt N, et al. (November 2019). "Comprehensive comparative effectiveness and safety of first-line antihypertensive drug classes: a systematic, multinational, large-scale analysis". Lancet. 394 (10211): 1816–1826. doi:10.1016/S0140-6736(19)32317-7. PMC 6924620. PMID 31668726.
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  16. ^ Jump up to: a b Dorsch MP, Gillespie BW, Erickson SR, Bleske BE, Weder AB. Chlorthalidone Reduces Cardiovascular Events Compared With Hydrochlorothiazide: A Retrospective Cohort Analysis. Hypertension. 2011;57(4):689-94.
  17. ^ Mitchell DM, Regan S, Cooley MR, Lauter KB, Vrla MC, Becker CB, Burnett-Bowie SA, Mannstadt M (December 2012). "Long-term follow-up of patients with hypoparathyroidism". J. Clin. Endocrinol. Metab. 97 (12): 4507–14. doi:10.1210/jc.2012-1808. PMC 3513540. PMID 23043192.
  18. ^ Aung K, Htay T, et al. (Cochrane Hypertension Group) (October 2011). "Thiazide diuretics and the risk of hip fracture". The Cochrane Database of Systematic Reviews (10): CD005185. doi:10.1002/14651858.CD005185.pub2. PMID 21975748.
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  20. ^ Solomon DH, Ruppert K, Zhao Z, Lian YJ, Kuo IH, Greendale GA, Finkelstein JS (March 2016). "Bone mineral density changes among women initiating blood pressure lowering drugs: a SWAN cohort study". Osteoporosis International. 27 (3): 1181–1189. doi:10.1007/s00198-015-3332-6. PMC 4813302. PMID 26449354.
  21. ^ Dvorak MM, De Joussineau C, Carter DH, Pisitkun T, Knepper MA, Gamba G, et al. (September 2007). "Thiazide diuretics directly induce osteoblast differentiation and mineralized nodule formation by interacting with a sodium chloride co-transporter in bone". Journal of the American Society of Nephrology. 18 (9): 2509–16. doi:10.1681/ASN.2007030348. PMC 2216427. PMID 17656470.
  22. ^ Musini VM, Nazer M, Bassett K, Wright JM, et al. (Cochrane Hypertension Group) (May 2014). "Blood pressure-lowering efficacy of monotherapy with thiazide diuretics for primary hypertension". The Cochrane Database of Systematic Reviews (5): CD003824. doi:10.1002/14651858.CD003824.pub2. PMID 24869750.
  23. ^ Hueskes BA, Roovers EA, Mantel-Teeuwisse AK, Janssens HJ, van de Lisdonk EH, Janssen M (June 2012). "Use of diuretics and the risk of gouty arthritis: a systematic review". Seminars in Arthritis and Rheumatism. 41 (6): 879–89. doi:10.1016/j.semarthrit.2011.11.008. PMID 22221907.
  24. ^ Wilson L, Nair KV, Saseen JJ (December 2014). "Comparison of new-onset gout in adults prescribed chlorthalidone vs. hydrochlorothiazide for hypertension". Journal of Clinical Hypertension. 16 (12): 864–8. doi:10.1111/jch.12413. PMID 25258088.
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  26. ^ Strom BL, Schinnar R, Apter AJ, Margolis DJ, Lautenbach E, Hennessy S, et al. (October 2003). "Absence of cross-reactivity between sulfonamide antibiotics and sulfonamide nonantibiotics". The New England Journal of Medicine. 349 (17): 1628–35. doi:10.1056/NEJMoa022963. PMID 14573734.
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  28. ^ Pedersen SA, Gaist D, Schmidt SA, Hölmich LR, Friis S, Pottegård A (April 2018). "Hydrochlorothiazide use and risk of nonmelanoma skin cancer: A nationwide case-control study from Denmark". J. Am. Acad. Dermatol. 78 (4): 673–681.e9. doi:10.1016/j.jaad.2017.11.042. PMID 29217346. Lay summary.
  29. ^ "Hydrochlorothiazide". Therapeutic Goods Administration (TGA). 24 August 2020. Retrieved 22 September 2020.
  30. ^ "FDA approves label changes to hydrochlorothiazide". U.S. Food and Drug Administration (FDA). 20 August 2020. Retrieved 28 August 2020. Public Domain This article incorporates text from this source, which is in the public domain.
  31. ^ Uniformed Services University Pharmacology Note Set #3 2010, Lectures #39 & #40, Eric Marks
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  34. ^ "Prohibited List" (PDF). World Anti-Doping Agency. January 2018.

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