Thiazide diuretics

Definition and Therapeutic Category
Thiazide diuretics are a class of sodium chloride symport inhibitors that act primarily on the distal convoluted tubule of the nephron in the kidneys. Their primary mechanism is to inhibit sodium and chloride reabsorption, promoting diuresis and resulting in reduced extracellular fluid volume and blood pressure. These drugs are extensively used in the management of hypertension, edema, congestive heart failure, nephrolithiasis, and nephrogenic diabetes insipidus.

Thiazide diuretics are subdivided into:

• True thiazides (e.g., hydrochlorothiazide)

• Thiazide-like diuretics (e.g., indapamide, chlorthalidone, metolazone)

Thiazide-like diuretics share similar pharmacologic properties but differ structurally.

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Mechanism of Action

• Thiazides inhibit the Na⁺/Cl⁻ cotransporter (NCC) in the distal convoluted tubule

• This action reduces sodium and chloride reabsorption

• Increased sodium in the distal nephron leads to increased potassium and hydrogen loss (due to compensatory aldosterone-sensitive sodium exchange)

• The resulting natriuresis and diuresis decrease plasma volume, which reduces cardiac output and blood pressure

• Long-term blood pressure-lowering effect is mainly due to reduced peripheral vascular resistance, not volume loss

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List of Generic Drugs in the Thiazide Class

True Thiazides

1. Hydrochlorothiazide

2. Bendroflumethiazide

3. Chlorothiazide

4. Methyclothiazide

5. Trichlormethiazide

Thiazide-Like Diuretics

6. Chlorthalidone

7. Indapamide

8. Metolazone

9. Clopamide (less commonly used)

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Indications

Clinical Use	Preferred Agents
Essential Hypertension	Hydrochlorothiazide, Chlorthalidone, Indapamide
Heart Failure (adjunct)	Metolazone (especially in diuretic resistance)
Edema (renal, hepatic, cardiac)	Any thiazide or thiazide-like agent
Nephrolithiasis (calcium stones)	Hydrochlorothiazide, Indapamide
Nephrogenic Diabetes Insipidus	Hydrochlorothiazide (paradoxical antidiuretic)
Osteoporosis (off-label)	Thiazides reduce urinary calcium loss

Pharmacokinetics

• Absorption: Oral bioavailability ranges from 60–90%

• Onset of Action: 1–2 hours

• Duration:

  • Hydrochlorothiazide: 6–12 hours

  • Chlorthalidone: up to 48–72 hours

  • Indapamide: 24–36 hours

• Metabolism:

  • Indapamide: Hepatic

  • Others: Largely excreted unchanged in the urine

• Excretion: Renal; dose adjustment in renal impairment may be required

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Dosing Guidelines (Common Agents)

• Hydrochlorothiazide: 12.5–25 mg once daily (max 50 mg)

• Chlorthalidone: 12.5–25 mg once daily (max 50 mg)

• Indapamide: 1.25–2.5 mg once daily (sustained release); 2.5 mg (immediate release)

• Metolazone: 2.5–10 mg once daily (can be intermittent dosing)

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Adverse Effects

System	Adverse Effects
Electrolyte	Hypokalemia, hyponatremia, hypomagnesemia, hypercalcemia
Metabolic	Hyperuricemia (may precipitate gout), hyperglycemia, dyslipidemia
Renal	Decreased GFR in volume-depleted patients, azotemia
Cardiovascular	Hypotension, orthostatic hypotension
Other	Photosensitivity, rash, sexual dysfunction

Drug Interactions

• NSAIDs: May blunt antihypertensive and diuretic effects

• Lithium: Reduced renal clearance → increased lithium toxicity risk

• Digoxin: Hypokalemia increases digoxin toxicity risk

• Antidiabetic drugs: Thiazides may reduce efficacy (hyperglycemia)

• ACE inhibitors/ARBs: Potentiate hypotensive and renal adverse effects

• Loop diuretics: Increased risk of profound diuresis and electrolyte imbalance

• Corticosteroids: Enhanced risk of hypokalemia

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Contraindications

• Anuria

• Severe renal impairment (particularly GFR <30 mL/min/1.73 m²)

• Hypersensitivity to sulfonamides (cross-reactivity potential)

• Gout (uncontrolled)

• Hyponatremia

• Pregnancy (relative): May reduce placental perfusion

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Clinical Considerations

• First-line treatment for hypertension per many guidelines (especially in Black and elderly populations)

• Chlorthalidone and indapamide have longer half-lives and may be superior to hydrochlorothiazide in sustained BP control

• Thiazide-induced hypokalemia can be mitigated by:

  • Potassium supplements

  • Potassium-sparing diuretics (e.g., amiloride, triamterene)

  • ACE inhibitors or ARBs

• Monitor electrolytes (especially sodium, potassium, magnesium), renal function, uric acid, and glucose periodically

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Thiazide vs Loop vs Potassium-Sparing Diuretics

Feature	Thiazide	Loop	Potassium-Sparing
Site of action	Distal tubule	Loop of Henle	Collecting duct
Sodium excretion potency	Moderate	High	Weak
Potassium loss	Yes (↓K⁺)	Yes (↓K⁺)	No or ↑K⁺
Calcium effect	↓ excretion (↑Ca²⁺)	↑ excretion (↓Ca²⁺)	Minimal effect
Use in renal failure	Limited (GFR >30)	Effective	Caution (↑K⁺ risk)

Use in Special Populations

• Elderly: Effective in isolated systolic hypertension; monitor for hyponatremia

• Diabetes: Use caution due to hyperglycemia risk; benefit in reducing stroke and CV events may outweigh risk

• Gout patients: Consider alternatives (e.g., ARBs or CCBs)

• CKD: May be less effective; loop diuretics preferred if GFR <30

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Current Guideline Recommendations

• JNC 8 / ACC/AHA: Thiazide-type diuretics are first-line agents for uncomplicated hypertension

• NICE (UK): Prefer thiazide-like diuretics (e.g., indapamide) over hydrochlorothiazide for long-term BP control

• KDIGO: Avoid or use with caution in advanced chronic kidney disease

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Advantages

• Proven efficacy in reducing cardiovascular morbidity and mortality

• Low cost, widely available

• Long-term BP control and stroke prevention

• Some agents (indapamide) do not adversely affect glucose or lipid profile

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Limitations

• Risk of electrolyte disturbances

• Less effective in severe renal impairment

• Metabolic adverse effects (e.g., hyperuricemia, glucose intolerance)

• Require laboratory monitoring

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Monitoring Parameters

• Baseline and periodic:

  • Serum electrolytes (Na⁺, K⁺, Cl⁻, Mg²⁺)

  • Renal function (creatinine, eGFR)

  • Blood pressure

  • Uric acid

  • Fasting blood glucose and lipid profile

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Notable Combinations

• With ACE inhibitors: Counteracts hypokalemia, improves BP control

• With ARBs: Useful in metabolic syndrome

• Fixed-dose combinations:

  • Hydrochlorothiazide + losartan (Hyzaar)

  • Indapamide + perindopril (Preterax)

  • Chlorthalidone + atenolol (Tenoretic)