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hydrochlorothiazide (HCTZ, HydroDIURIL, Oretic, Esidrix)

Tradenames: HCTZ, HydroDiuril, Oretic. Indications: - hypertension - thiazides may be more cardioprotective in overweight than in lean patients [12] - chlorthalidone not associated with cardiovascular benefits vs HCTZ [14,18] - edema - hypocalcemia - prevention of calcium stones - nephrogenic diabetes insipidus Dosage: 1) hypertension: a) 12.5-50 mg/day b) elderly: 12.5 mg QD c) maintenance doses > 50 mg/day provide little additional benefit in controlling hypertension d) dose should rarely exceed 25 mg QD [6] e) no proof that low-dose HCTZ improves outcomes; at least 50 mg of HCTZ QD used in trials that found improved outcomes [10] 2) edema: 25-200 mg/day QD or divided BID/TID Tabs: 25, 50, 100 mg Solution: 50 mg/5 mL Pharmacokinetics: 1) bioavailability is about 70% a) decreased in patients with CHF b) absorption is increased by food [7] 2) 58% bound to plasma proteins 3) 95% of the drug is excreted unchanged into the urine 4) may not be effective in patients with creatinine clearance < 30 mL/min (< 15-20 mL/min or serum creatinine > 2.5 mg/dL [9]) 5) onset of diuresis is within 2 hours with duration of effect 6-8 hours 6) onset of hypotensive effect is 3-4 days Adverse effects: 1) hypokalemia (1-10%) less than that with chlorthalidone [14] 2) hyperuricemia 3) rash maculopapular (not itchy) 4) increased low-density lipoprotein (LDL) 5) hypochloremic alkalosis 6) dilutional hyponatremia & SIADH - incidence may be higher than that indicated on drug labeling - 2 year cumulative risk for serum sodium < 130 meq/L is < 4% [19] 7) hyperglycemia 8) glucosuria 9) orthostatic hypotension 10) GI complaints 11) photosensitivity - increased risk of lip cancer - increased incidence of skin squamous cell carcinoma [13,15,16] - increased incidence of basal cell carcinoma [15] - increased incidence of cutaneous melanoma, specifically lentigo melanoma & nodular melanoma (RR=1.2) [13] 12) generalized pruritus without rash or skin lesions [4] 13) pancreatitis 14) vasculitis 15) electrolyte imbalances less than chlorthalidone [14] a) hypercalcemia (rare) b) hypocalcemia c) hypomagnesemia d) hyponatremia 16) preserves bone mineral density (hip) [8] 17) drug-induced lupus [17] 18) acute interstitial nephritis [20] Drug interactions: 1) HCTZ may enhance hypokalemic effects of agents that lower serum K+ levels: i.e. beta-2 adrenergic agonists 2) HCTZ may decrease lithium clearance 3) HCTZ may increase requirements for oral hypoglycemic agents &/or insulin 4) probenecid a) blocks thiazide-induced uric acid retention b) enhances excretion of Ca+2, Mg+2, citrate 5) HCTZ may increase the risk of NSAID-induced renal failure Mechanism of action: 1) enhances secretion of Na+, Cl- & H2O by interfering with Na+ & Cl- transport across the renal tubular epithelium mediated by SLC12A3 2) site of action: distal tubule. 3) thiazides also effect the excretion of other electrolytes including K+ & HCO3- 4) inhibits tubular excretion of Ca+2 5) angiotensin II receptor type 2 & 4-stimulating antihypertensive

Interactions

drug interactions drug adverse effects (more general classes) monitor with thiazide diuretics

General

benzothiadiazide; benzothiadiazine sulfonamide thiazide diuretic

Properties

MISC-INFO: elimination route LIVER protein-binding 58% pregnancy-category B safety in lactation ?

Database Correlations

PUBCHEM cid=3639

References

  1. The Pharmacological Basis of Therapeutics, 9th ed. Gilman et al, eds. Permagon Press/McGraw Hill, 1996.
  2. Manual of Medical Therapeutics, 28th ed, Ewald & McKenzie (eds), Little, Brown & Co, Boston, 1995, pg 123
  3. Drug Information & Medication Formulary, Veterans Affairs, Central California Health Care System, 1st ed., Ravnan et al eds, 1998
  4. Medical Knowledge Self Assessment Program (MKSAP) 11, 18. American College of Physicians, Philadelphia 1998, 2018
  5. Kaiser Permanente Northern California Regional Drug Formulary, 1998
  6. Medical Knowledge Self Assessment Program (MKSAP) 11, American College of Physicians, Philadelphia 1998
  7. Harrison's Principles of Internal Medicine, 14th ed. Fauci et al (eds), McGraw-Hill Inc. NY, 1998, pg 470
  8. LaCroix AZ et al, Low-dose hydrochlorthiazide and preservation of bone mineral density in older adults. A randomized, double-blind, placebo- controlled trial. Ann Intern Med 133:516, 2000 PMID: 11015164
  9. MicroMedex
  10. Prescriber's Letter 18(3): 2011 COMMENTARY: Thiazides for Hypertension CHART: Comparison of Commonly Used Diuretics Detail-Document#: 270304 (subscription needed) http://www.prescribersletter.com
  11. Friedman GD et al Antihypertensive Drugs and Lip Cancer in Non-Hispanic Whites Archives of Internal Medicine, August 2012 PMID: 22869299 http://archinte.jamanetwork.com/article.aspx?articleid=1307567
  12. Weber MA et al. Effects of body size and hypertension treatments on cardiovascular event rates: Subanalysis of the ACCOMPLISH randomised controlled trial. Lancet 2013 Feb 16; 381:537 PMID: 23219284 - Messerli FH and Bangalore S. Diuretic-based regimens for obese patients? Lancet 2013 Feb 16; 381:512. PMID: 23219285
  13. Pottegard A, Pedersen SA, Schmidt SAJ et al Association of Hydrochlorothiazide Use and Risk of Malignant Melanoma. JAMA Intern Med. Published online May 29, 2018. PMID: 29813157 https://jamanetwork.com/journals/jamainternalmedicine/fullarticle/2682616 - Pedersen SA, Gaist D, Schmidt SAJ et al Hydrochlorothiazide use and risk of nonmelanoma skin cancer: A nationwide case-control study from Denmark. J Am Acad Dermatol. 2018 Apr;78(4):673-681.e9. Epub 2017 Dec 4. PMID: 29217346 Free Article
  14. Hripcsak G, Suchard MA, Shea S et al Comparison of Cardiovascular and Safety Outcomes of Chlorthalidone vs Hydrochlorothiazide to Treat Hypertension. JAMA Intern Med. Published online February 17, 2020. PMID: 32065600 https://jamanetwork.com/journals/jamainternalmedicine/fullarticle/2760777
  15. FDA. Aug 20, 2020 FDA approves label changes to hydrochlorothiazide to describe small risk of non-melanoma skin cancer. https://www.fda.gov/drugs/drug-safety-and-availability/fda-approves-label-changes-hydrochlorothiazide-describe-small-risk-non-melanoma-skin-cancer
  16. Schneider R, Reinau D, Stoffel S et al Risk of skin cancer in new users of thiazides and thiazide-like diuretics: a cohort study using an active comparator group. Br J Dermatol. Published online February 20, 2021 PMID: 33609289
  17. Geriatric Review Syllabus, 11th edition (GRS11) Harper GM, Lyons WL, Potter JF (eds) American Geriatrics Society, 2022
  18. Ishani A, Cushman WC, Leatherman SM et al Chlorthalidone vs. Hydrochlorothiazide for Hypertension - Cardiovascular Events. N Engl J Med 2022. Dec 14 PMID: 26760416 https://www.nejm.org/doi/10.1056/NEJMoa2212270
  19. Andersson NW, Wohlfahrt J, Feenstra B, Hviid A, Melbye M, Lund M. Cumulative Incidence of Thiazide-Induced Hyponatremia. A Population-Based Cohort Study. Ann Inter Med 2023. Dec 19. PMID: 38109740 https://www.acpjournals.org/doi/full/10.7326/M23-1989
  20. NEJM Knowledge+

Component-of

aliskiren/amlodipine/hydrochlorothiazide (Amturnide) aliskiren/hydrochlorothiazide (Tekturna HCT) amiloride/hydrochlorothiazide; amiloride/HCTZ (Moduretic) amlodipine/hydrochlorothiazide/olmesartan (Tribenzor) amlodipine/hydrochlorothiazide/valsartan benazepril/hydrochlorothiazide; benazepril/HCTZ (Lotensin HCTZ) bisoprolol/fumarate/hydrochlorothiazide bisoprolol/hydrochlorothiazide; bisoprolol/HCTZ (Ziac) candesartan/hydrochlorothiazide captopril/hydrochlorothiazide; captopril/HCTZ (Capozide) enalapril/hydrochlorothiazide; enalapril/HCTZ (Vaseretic) eprosartan/hydrochlorothiazide fosinopril/hydrochlorothiazide guanethidine/hydrochlorothiazide; guanethidine/HCTZ (Esmil) hydralazine/hydrochlorothiazide/reserpine; hydralazine/HCTZ/reserpine (Ser Ap Es) hydralazine/hydrochlorothiazide; hydralazine/HCTZ (Apresazide) hydrochlorothiazide/irbesartan (Avalide) hydrochlorothiazide/lisinopril; HCTZ/lisinopril (Prinzide, Zestoretic) hydrochlorothiazide/losartan; HCTZ/losartan (Hyzaar) hydrochlorothiazide/methyldopa; HCTZ/methyldopa (Aldoril) hydrochlorothiazide/metoprolol/succinate hydrochlorothiazide/metoprolol; HCTZ/metoprolol (Lopressor HCTZ, Dutoprol) hydrochlorothiazide/moexipril hydrochlorothiazide/olmesartan (Benicar HCT) hydrochlorothiazide/propranolol; HCTZ/propranolol (Inderide) hydrochlorothiazide/quinapril hydrochlorothiazide/reserpine hydrochlorothiazide/spironolactone; HCTZ/spironolactone (Aldactazide) hydrochlorothiazide/telmisartan hydrochlorothiazide/timolol; HCTZ/timolol (Timolide) hydrochlorothiazide/triamterene; HCTZ/triamterene (Dyazide, Maxzide, Maxide) hydrochlorothiazide/valsartan