Thiazide Diuretics

Thiazide and thiazide-like diuretics make up a group of highly important antihypertensive agents, with some drugs being 1st-line agents. The class includes hydrochlorothiazide, chlorothiazide, chlorthalidone, indapamide, and metolazone. These drugs block sodium reabsorption in the distal convoluted tubule of the kidney by inhibiting the sodium-chloride cotransporter. As a result, the increased sodium excretion causes secondary water excretion because water follows the sodium. In addition to increasing sodium and water excretion, thiazide diuretics also cause the excretion of chloride, potassium, magnesium, and protons (H+).

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Overview

Overview of antihypertensive agents

Table: Drugs used to treat hypertension
Location of actionClassSubclasses
Renal drugsDrugs affecting the RAAS
  • ACEis
  • ARBs
  • Direct renin inhibitors
Diuretics
  • Thiazide diuretics
  • Loop diuretics
  • Potassium-sparing diuretics
Extrarenal drugsDirect vasodilators
  • Calcium channel blockers
  • Potassium channel openers
  • Nitrodilators
  • Endothelin antagonists
Agents acting via the sympathetic nervous system
  • Drugs affecting CNS sympathetic outflow (e.g., clonidine)
  • Drugs affecting the ganglia (e.g., hexamethonium)
  • Drugs affecting the nerve terminals (e.g., guanethidine, reserpine)
  • Drugs affecting the α and β receptors

Drugs in the thiazide class

Drugs in this class include: 

  • Hydrochlorothiazide (HCTZ; prototypical drug in this class)
  • Chlorothiazide 
  • Chlorthalidone (1st-line agent in the treatment of hypertension)
  • Indapamide
  • Metolazone

Chemistry and Pharmacodynamics

Chemical structure

The chemical structure for HCTZ:

  • Molecular formula: C7H8ClN3O4S2
  • A benzothiadiazine that is 3,4-dihydro-2H-1,2,4-benzothiadiazine 1,1-dioxide with substitutions of:
    • A chloro group at position 6 
    • A sulfonamide at position 7
Hydrochlorothiazide

Skeletal formula of hydrochlorothiazide

Image: “Hydrochlorothiazide” by Yikrazuul. License: Public Domain

Mechanism of action (MOA)

  • Primary MOA: ↓ reabsorption of NaCl through the inhibition of the Na+/Cl cotransporter in the distal convoluted tubule (DCT)
    • With this channel blocked → ↓ Na+ reabsorption
    • Water always follows Na+:
      • Water stays with Na+ in the tubules (rather than being reabsorbed).
      • Diuresis results from the osmotic effect of Na+.
    • Diuresis → ↓ plasma volume → ↓ BP
      • Initially causes a transient ↑ in the RAAS and sympathetic tone to compensate for ↓ BP and cardiac output.
      • Transient ↑ in the RAAS explains why there is a synergistic effect between thiazides and ACEis/ARBs.
    • There is also a modest ↑ in vasodilation via an unclear mechanism.
  • Thiazide use results in:
    • ↑ Excretion of Na+, Cl, K+, and water 
    • ↑ Reabsorption of Ca2+
      • ↑ Na+ excretion → ↓ cellular Na+ levels → 
      • ↑ Compensatory exchange of Ca2+ for Na+ (via the basolateral Na+/Ca2+ exchanger)
  • Development of hypokalemia:
    • ↓ Na+ reabsorption in the DCT → 
    • ↑ Na+ delivered to the collecting ducts (CDs) → 
    • Stimulates ↑ aldosterone release
    • Aldosterone stimulates Na+/K+ exchanger to ↑ Na+ reabsorption and excrete K+ → hypokalemia
  • Development of a metabolic alkalosis:
    • ↑ K+ excretion in the CD → 
    • Aldosterone-stimulated ↑ in K+/H+ exchanger → 
    • Reabsorbs some of the extra K+ in the tubule in exchange for H+ (which is excreted) → metabolic alkalosis via H+ loss
Thiazide diuretics acting

Thiazide diuretics acting on the Na/Cl cotransporter

Image by Lecturio. License: CC BY-NC-SA 4.0

Pharmacokinetics

Table: Pharmacokinetics of thiazide diuretics
DrugAbsorptionDistributionMetabolismExcretion
HCTZ
  • Well absorbed
  • Peak effect in 4 hours
  • Bioavailability 65%–75%
  • Vd: 3.6–7.8 L/kg
  • Protein binding 40%–68%
Not metabolized
  • Urine
  • Half-life: 6–15 hours
Chlorothiazide
  • Poor oral absorption
  • Peak effect: 30 minutes IV
Distributed throughout the extracellular spaceNot metabolized
  • Urine
  • Half-life: 45–120 minutes
ChlorthalidonePeak effect 2–6 hours
  • Vd: 3–13 L/kg
  • Protein binding: 75%
Hepatic
  • Urine
  • Half-life: 40 hours
Indapamide
  • Rapid and complete absorption
  • Peak effect: 2 hours
  • Vd: 25 L
  • Protein binding: approximately 75%
Extensive hepatic metabolism
  • Urine: 75%
  • Feces: 25%
MetolazoneOnset of action: 1 hour
  • Vd: 113 L
  • Protein binding: 95%
Not metabolizedUrine
HCTZ: hydrochlorothiazide
Vd: volume of distribution

Indications

Indications

Most thiazide diuretics share similar indications, including:

  • Hypertension
  • As an adjunctive therapy for edema in the following conditions:
    • Heart failure
    • Hepatic cirrhosis resulting in ascites
    • Mild to moderate renal dysfunction (CKD stages 1–3): 
      • Includes CKD due to nephrotic syndrome, glomerulonephritis, chronic renal failure
      • Note: Thiazides are relatively contraindicated in patients with anuria/severe renal failure (CKD stages 4 and 5).
    • Corticosteroid use
    • Estrogen therapy
  • Off-label uses: 
    • Hypercalciuria 
    • Diabetes insipidus 

Clinical pearls

  • All patients should be monitored for BP, creatinine, Na+, and K+.
  • Chlorthalidone and indapamide:
    • 1st-line agents for monotherapy when treating hypertension
    • 1.5–2× as potent and longer half-life than HCTZ 
    • ALLHAT (Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial) showed reduction in cardiovascular events (has the most evidence of all the thiazides).
    • May have ↑ side effects and risk of hypokalemia
  • HCTZ:
    • Commonly used as 1st-line agent for hypertension, though less effective than chlorthalidone or indapamide
    • Comes in combination pills with ACEis, ARBs, and/or calcium-channel blockers
    • Not as effective with creatinine clearance < 30 ml/min
  • Metolazone:
    • May be more effective than other thiazides with CrCl < 30 ml/min
    • Often combined with other diuretics

Adverse Effects and Contraindications

Adverse effects

Table: Adverse effects of thiazide diuretics
Thiazide adverse effectsMechanismManagement
Hypokalemia↑ Urinary Na+ causes ↑ K+ exchange in the CD → ↑ K+ excretion↑ Dietary intake of K+ or supplementation
Hyponatremia and hypovolemia↓ Na+ reabsorption results in ↓ serum Na+; water follows Na+, potentially leading to hypovolemia (most likely to occur in the 1st few weeks of therapy)
  • ↓ Starting dose
  • Without overt hypovolemia: ↓ Free water intake
  • With overt hypovolemia: Replete Na+ with IV saline.
Metabolic alkalosis↑ Exchange of K+ for H+ ions in the CDPotassium supplementation and/or lower dose/switch agents
HypomagnesemiaNot fully elucidatedMg2+ supplementation
HyperuricemiaThiazides ↑ urate reabsorptionAvoid thiazides in patients with untreated gout or at high risk for gout.
HypercalcemiaThiazide-induced ↑ of Ca2+ reabsorptionTypically inconsequential in absence of CKD or hyperparathyroidism
Hyperglycemia
  • ↓ K+ → hyperpolarization in pancreatic β cells → ↓ insulin secretion
  • Seen in higher doses in patients with underlying diabetes
  • Consider alternative agents in patients with diabetes.
  • ↓ Thiazide dose
  • Correct hypokalemia.
  • Treat diabetes.
Dyslipidemia
  • Not fully elucidated
  • Risk is ↓ with indapamide.
  • Lipid monitoring
  • Lipid-lowering diet and medications
PhotosensitivityNot fully elucidatedWear sunscreen and protective clothing.
HypersensitivityUnderlying sulfonamide allergyAvoid thiazides.

Contraindications

  • Thiazide contraindications:
    • Hypersensitivity reactions
    • Anuria and/or renal failure
    • Hypotension
    • Hypokalemia
    • Allergy to sulfa drugs
    • Gout
  • Thiazide precautions:
    • Diabetes
    • Hypercalcemia
    • Hepatic impairment
    • Certain medications:
      • Lithium
      • Carbamazepine 
      • Corticosteroids 
      • NSAIDs
    • Pregnancy and lactation

Comparison of Medications

Some of the other most common diuretics include loop diuretics (e.g., furosemide), potassium-sparing diuretics (e.g., spironolactone), carbonic anhydrase inhibitors (e.g., acetazolamide), and osmotic diuretics (e.g., mannitol).

Table: Comparison of diuretics
MedicationMechanismPhysiologic effectIndication
Thiazide diuretic: Hydrochlorothiazide↓ Reabsorption of NaCl in the DCT through the inhibition of Na+/Cl cotransporter
  • ↓ Blood pressure
  • ↓ Edema
  • Hypertension
  • Edema
Loop diuretic: FurosemideInhibits the luminal Na+/K+/Cl cotransporter in the thick ascending limb of the loop of Henle
  • ↓ Edema
  • ↓ Blood pressure
  • Edema/ascites
  • CHF
  • Hypertension
Potassium-sparing diuretic: Spironolactone
  • ↓ Reabsorption of Na through the ENaC channels in the CD
  • Inhibition of aldosterone receptors in the CD
  • ↓ Blood pressure
  • ↓ Edema
  • Does not cause ↑ excretion of K+
  • Anti-androgenic effects
  • CHF
  • Edema/ascites
  • Hypertension
  • Hirsutism in females
  • Primary hyperaldosteronism
Carbonic anhydrase inhibitor: AcetazolamideInhibits both the hydration of CO2 in the PCT epithelial cells and the dehydration of H2CO3 in the PCT lumen; results in ↑ HCO3 and Na+ excretion
  • ↑ Urinary excretion of HCO3 → metabolic acidosis
  • ↓ Intraocular pressure
  • Edema in patients with metabolic alkalosis
  • Altitude sickness
  • ↑ Intraocular pressure
  • Off label: normal pressure hydrocephalus
Osmotic diuretics: Mannitol↑ Osmotic pressure in the glomerular filtrate → ↑ tubular fluid and prevents water reabsorption
  • ↓ Free water
  • ↓ Cerebral blood volume
  • Increased intracranial pressure
  • Increased intraocular pressure
PCT: proximal convoluted tubule
DCT: distal convoluted tubule
CHF: congestive heart failure
Diuretics

The sites of action within the nephron for the diuretic drug classes

Image by Lecturio. License: CC BY-NC-SA 4.0

References

  1. Akbari P, Khorasani-Zadeh A. (2020). StatPearls. https://www.ncbi.nlm.nih.gov/pubmed/30422513
  2. Heymann WR. (2019). The expanding saga of hydrochlorothiazide and skin cancer. J Am Acad Dermatol https://www.ncbi.nlm.nih.gov/pubmed/30529707
  3. Dhayat NA, et al. (2018). Efficacy of standard and low dose hydrochlorothiazide in the recurrence prevention of calcium nephrolithiasis (NOSTONE trial): protocol for a randomized double-blind placebo-controlled trial. BMC Nephrol. https://www.ncbi.nlm.nih.gov/pubmed/30526528
  4. Roush GC, Abdelfattah R, Song S, Ernst ME, Sica DA, Kostis JB. (2018). Hydrochlorothiazide vs chlorthalidone, indapamide, and potassium-sparing/hydrochlorothiazide diuretics for reducing left ventricular hypertrophy: a systematic review and meta-analysis. J Clin Hypertens (Greenwich). https://www.ncbi.nlm.nih.gov/pubmed/30251403
  5. Musini VM, Nazer M, Bassett K, Wright JM. (2014). Blood pressure-lowering efficacy of monotherapy with thiazide diuretics for primary hypertension. Cochrane Database Syst Rev. https://www.ncbi.nlm.nih.gov/pubmed/22526259
  6. Roush GC, Holford TR, Guddati AK. (2012). Chlorthalidone compared with hydrochlorothiazide in reducing cardiovascular events: a systematic review and network meta-analyses. Hypertension. https://www.ncbi.nlm.nih.gov/pubmed/22526259
  7. Sica DA, Carter B, Cushman W, Hamm L. (2011). Thiazide and loop diuretics. J Clin Hypertens (Greenwich). https://www.ncbi.nlm.nih.gov/pubmed/21896142
  8. Mann, J.F. (2020). Choice of drug therapy in primary (essential) hypertension. In Forman, J.P. (Ed.), UpToDate. Retrieved June 14, 2021, from https://www.uptodate.com/contents/choice-of-drug-therapy-in-primary-essential-hypertension 
  9. Mann, J.F., Hilgers, K.F. (2020). Use of thiazide diuretics in patients with primary (essential) hypertension. In Forman, J.P. (Ed.), UpToDate. Retrieved June 14, 2021, from https://www.uptodate.com/contents/use-of-thiazide-diuretics-in-patients-with-primary-essential-hypertension
  10.  Lexicomp Drug Topic Pages: Hydrochlorothiazide; Chlorothiazide; chlorthalidone; indapamide; metolazone. Retrieved June 14, 2021, from https://www.uptodate.com/contents/hydrochlorothiazide-drug-information
  11. Akbari, P. (2020). Thiazide diuretics. StatPearls. Retrieved June 14, 2021 from https://www.statpearls.com/articlelibrary/viewarticle/30055/

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