Thiazide and Thiazide-Like Diuretics

Mechanism of Action and Indications For Use

• Thiazide and thiazide-like diuretics block the Na⁺/Cl⁻ cotransporter in the early distal convoluted tubule.
• This increases excretion of sodium, chloride, water, potassium, and magnesium.
  They reduce urinary calcium excretion, promoting calcium reabsorption.
  Most (except metolazone) also inhibit carbonic anhydrase, ↑ bicarbonate excretion.
  Metolazone additionally inhibits sodium reabsorption in the proximal tubule and loop of Henle.

Adobe stock images

Fig 1: Diuretics and the kidney

Antihypertensive effects

Beyond diuresis, they lower peripheral vascular resistance and enhance the effects of other antihypertensives.

Indapamide (2.5mg): produces a maximal antihypertensive effect with a sub-clinical diuretic effect. Mechanisms include:

• Reduction in vascular smooth muscle contractility due to alteration of calcium transmembrane exchange
• Stimulation of the synthesis of prostaglandin PGE2 and platelet antiaggregant prostacyclin PGI2
• Potentiation of the vasodilator action of bradykinin

Onset of maximal antihypertensive effect may take several months.

Bendroflumethiazide is used for essential hypertension and oedema associated with conditions such as nephrotic syndrome, liver cirrhosis and congestive heart failure (CHF). 

Chlortalidone and metolazone are also used to relieve oedema due to CHF, and are used at lower doses for hypertension. Chlortalidone is also used for diabetes insipidus, where it reduces polyuria (the mechanism behind this is unknown).

Pharmacokinetics 

Thiazide and thiazide-like diuretics act quickly within 1-2 hours of administration, and the effect lasts for 12-24 hours, meaning once daily dosing is often suitable. The following table describes the absorption, distribution, metabolism and excretion for commonly used thiazide and related diuretics:

Contraindications 

General: hypercalcaemia, hyponatraemia, refractory hypokalaemia, symptomatic hyperuricaemia (gout), Addison’s disease.

Ineffective in renal impairment: avoid if CrCl <30 mL/min (ineffective), except metolazone which retains efficacy at CrCl <20 mL/min (though used cautiously).

Hepatic insufficiency: risk of hepatic encephalopathy → avoid in severe impairment.

Chlortalidone: contraindicated with sulfonamide hypersensitivity and concomitant lithium use.

Cautions and Adverse Effects 

Use with caution in:

• Diabetes: may cause hyperglycaemia (adjust insulin/oral antidiabetics).
  
• Gout: cause hyperuricaemia (↓ urate clearance).
  
• Systemic lupus erythematosus (SLE): can exacerbate symptoms.
  

Adverse effects

• Electrolyte imbalances:
  
  • Hypokalaemia (↑ risk to those on digoxin (↑ risk of toxicity), severe cardiovascular disease, cirrhosis (can worsen encepthalopathy), elderly, malnourished)
    
  • Hyponatraemia → dehydration, postural hypotension
    
  • Hypomagnesaemia (notably with alcohol-related cirrhosis)
    
  • Hypercalcaemia (usually mild) due to reduction in calcium excretion, marked and continuous hypercalcaemia may be due to hyperparathyroidism
    
  • Hypochloraemic alkalosis
• Endocrine/metabolic: hyperglycaemia, hyperlipidaemia (↑ cholesterol/triglycerides), hyperuricaemia.
• Other:
  
  • GI upset (diarrhoea, constipation)
    
  • Rare blood dyscrasias (agranulocytosis, leucopenia)
    
  • Sulfonamide-related ocular effects (acute angle-closure glaucoma, myopia, choroidal effusion). Acute angle-closure glaucoma is more likely in patients with sulfonamide or penicillin allergy
    
  • Photosensitivity
    
  • Pancreatitis (secondary to hyperlipidaemia or hypercalcaemia)
    

Note: In hypokalaemia + hypomagnesaemia, magnesium correction should be administered first, otherwise potassium replacement is ineffective.

Interactions

Many drug interactions that are seen with thiazide and related diuretics involve worsening potential side effects. For example, with drugs that may enhance the hypotensive effect (e.g. antihypertensives,  phenothiazines antipsychotics: chlorpromazine and prochlorperazine, MAOIs and TCAs (postural hypotension)) may increase risk of hypotension, which could lead to falls in the elderly. 

Furthermore, drugs that increase the risk of hypokalaemia when used with thiazide and related diuretics include amisulpride, reboxetine, amphotericin, other diuretics e.g. loop diuretics, salbutamol, tacrolimus, theophylline, laxatives, liquorice and corticosteroids. There is also an increased risk of hyponatraemia with concomitant administration of thiazide and related diuretics with carbamazepine.

Hypokalaemia resulting from thiazide and related diuretics, also increases risk of ventricular arrhythmias, when taken concomitantly with torsades de pointes inducing drugs such as amiodarone, disopyramide, flecainide, sotalol, haloperidol and amisulpride.

Hypokalaemia and/or hypomagnesaemia that may occur due to thiazide and related diuretic use increases risk of toxicity with digitalis preparations such as digoxin, therefore careful monitoring is required. 

Patients taking calcium salts and vitamin D alongside thiazides and related diuretics are at risk of hypercalcaemia and milk-alkali syndrome.

In addition there is an increased risk of nephrotoxicity with NSAIDs, ACE-inhibitors, ARBs and iodinated contrast media. NSAIDs such as indomethacin and ketorolac also antagonise the diuretic effect of bendroflumethiazide. 

Co-administration of thiazide diuretics may also increase the frequency of hypersensitivity reactions to allopurinol. 

Changes in sodium resulting from thiazide and related diuretic use may lead to decreased urinary lithium excretion. For example bendroflumethiazide inhibits the tubular elimination of lithium, resulting in an elevated plasma lithium concentration and risk of toxicity.

Created in BioRender. Boucher, M. (2025) https://BioRender.com/yi7a8zy

Fig 2: Drugs that can cause hypokalaemia

References 

1. Diuretics | Treatment summaries | BNF | NICE accessed 26/2/25
2. Amiloride 5mg Tablets – Summary of Product Characteristics (SmPC) – (emc) (medicines.org.uk) accessed 1/10/24
3. Indapamide 2.5mg Tablets – Summary of Product Characteristics (SmPC) – (emc) (medicines.org.uk) accessed 6/10/24
4. Bendroflumethiazide 2.5mg Tablets – Summary of Product Characteristics (SmPC) – (emc) accessed 26/2/25
5. Indapamide 2.5mg Tablets – Summary of Product Characteristics (SmPC) – (emc) Last updated on emc: 03 Mar 2023. Accessed 26/2/25
6. Xaqua 5 mg Tablets – Summary of Product Characteristics (SmPC) – (emc) last updated on emc: 06 Jan 2023. Accessed 27/2/25
7. Chlortalidone 25mg tablets SPC. Last updated: 03/10/2024. Accessed from: MHRA website Microsoft Word – 4821786617358000502_spc-doc.doc
8. Beermann, B., Groschinsky-Grind, M. Clinical Pharmacokinetics of Diuretics. Clin Pharmacokinet 5, 221–245 (1980). https://doi.org/10.2165/00003088-198005030-00003