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 by binding the Cl⁻  site. This transporter reabsorbs 5-10% of filtered sodium, leading to the following effects:

• Increased excretion of sodium, chloride, water, potassium, and magnesium (similar to loop diuretics).
• Reduced urinary calcium excretion, promoting calcium reabsorption (opposite effect to loop diuretics).
• Most thiazide diuretics (except metolazone) inhibit carbonic anhydrase, increasing bicarbonate excretion.
• Metolazone inhibits sodium reabsorption in the proximal tubule and loop of Henle.

Thiazides are weaker than loop diuretics, however demonstrate a synergistic effect when used alongside loop diuretics, as loop diuretics increase the fraction of sodium delivered to the distal convoluted tubule.

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Fig 1: Diuretics and the kidney

Antihypertensive effects

Beyond diuresis, thiazide and thiazide like diuretics lower peripheral vascular resistance and enhance the effects of other antihypertensives.

Indapamide at a dose of 2.5mg produces a maximal antihypertensive effect with a sub-clinical diuretic effect, however the onset of maximal antihypertensive effect may take several months. The initial antihypertensive effect is seen due to diuresis. 

Mechanisms behind this effect 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

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. Thiazides are excreted in the urine, mainly by tubular secretion via the organic anion transporter (OAT). The following table describes the absorption, distribution, metabolism and excretion for commonly used thiazide and related diuretics:

Contraindications

General contraindications for this drug class include hypercalcaemia, hyponatraemia, refractory hypokalaemia, symptomatic hyperuricaemia (gout) and Addison’s disease.

Thiazide and thiazide like diuretics are ineffective in renal impairment, therefore administration should be avoided if CrCl <30 mL/min, except metolazone which retains efficacy even when CrCl <20 mL/min (though is used cautiously).

There is a risk of hepatic encephalopathy in hepatic insufficiency so use is generally avoid in severe impairment.

Furthermore, chlortalidone is contraindicated with sulfonamide hypersensitivity and with concomitant lithium use.

Cautions and Adverse Effects

Thiazide and thiazide-like diuretics should only be used cautiously in the following conditions:

• Diabetes: may cause hyperglycaemia (may require adjustment of insulin/oral antidiabetics).
  
• Gout: cause hyperuricaemia (due to reduced urate clearance due to competition at the OAT transporter).
  
• Systemic lupus erythematosus (SLE): can exacerbate symptoms.
  

Adverse Effects

Like with other diuretics, electrolyte and metabolic imbalances can commonly occur with thiazide and thiazide-like diuretics.

• Hypokalaemia can occur, which may poses additional risk to patients on digoxin (increase the risk of digoxin toxicity), severe cardiovascular disease, cirrhosis (can worsen encepthalopathy), elderly and in malnourishment.
  
• Hypomagnesaemia is more common with alcohol-related cirrhosis
  • Note: in hypokalaemia + hypomagnesaemia, magnesium correction should be administered first, otherwise potassium replacement is ineffective.
• Hyponatraemia can also occur, leading to dehydration and postural hypotension
  
• Hypercalcaemia (usually mild) due to reduction in calcium excretion, marked and continuous hypercalcaemia may be due to hyperparathyroidism
  
• Hypochloraemic alkalosis
• Hyperglycaemia can occur due to inhibition of insulin secretion thought to arise from activation of the ATP-activated potassium channels in the pancreatic islet cells
• Hyperlipidaemia (↑ cholesterol/triglycerides)
• Hyperuricaemia due to competition at the OAT transporter for uric acid excretion

Other general side effects include the following:

• 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)
  
• Increased urinary frequency (usually mitigated by avoiding evening dosing)
• Dose dependent impotence

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. Furthermore, 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. 

Lastly, changes in sodium resulting from thiazide and related diuretic use may lead to decreased urinary lithium excretion. Due to thiazides causing sodium depletion, the kidney compensates by increasing proximal tubular reabsorption of sodium and lithium ions. Furthermore, bendroflumethiazide inhibits the tubular elimination of lithium, resulting in an elevated plasma lithium concentration and risk of toxicity.

References

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