DIURETICS USE IN HYPERTENSION & OTHER INDICATIONS

DIURETICS USE IN HYPERTENSION & OTHER INDICATIONS

Thiazide Diuretics

Became available in late 1950s.

Diuretic therapy for hypertension originated in 1937.

The term thiazide diuretic, includes all diuretics believed to act on distal tubule.

Chlorothiazide, a benzothiadiazine derivative.

Discovered: while searching for carbonic anhydrase inhibitor.

Primary action: upstream portion of distal convoluted tubules.

Interfere with sodium reabsorption

Pharmacokinetics

Extensively bound to plasma proteins.

Onset of action after 2-3 hours.

Most thiazides have half-life about 8 to 12 hours

Chlorthalidone is long-acting with half-life 50-60 hours.

Pharmacdynamics:

Hemodynamic effects can be separated into:

short term and

long term phases

Blood pressure decreases initially due to reduction in extracellular fluid volume and plasma volume. It leads to depressed cardiac preload and output.

Low level of prolonged diuresis produced by long-term thiazide administration may maintain a nominal state of volume contraction, thus maintaining downward shift in vascular resistance.

Tolerance to diuretics

Refers to a gradual return of the sodium-chloride balance to an electroneutral level.

Persistent volume removal appears to trigger long-term activation of the renin-angiotensin-aldosterone system, increasing circulating angiotensin II levels, which promotes increased proximal sodium reabsorption and limits the overall delivery of sodium to the distal tubule.

Tolerance to diuretics can be overcome by administering higher doses or combinations of diuretics.

Diuretics for Hypertension

Low-renin and salt-sensitive hypertension responds to diuretic therapy. E.g. of these include, elderly, blacks, and patients with high cardiac output (e.g. obesity)
Thiazides potentiate other antihypertensive agents, when used in combination.
Dose: Hydrochlorthiazide 12.5 to 25 mg per day. Usually 50% of patients respond to these low doses. Dose can be increased to achieve higher response. BUT increased electrolyte losses at higher doses may preclude their routine use.

Diuretics for Renal Impairment

Thiazides do not work when glomerular filtration rate decreases below 30 to 40 ml per minute per 1,73 m² of body-surface area.
Two reasons:
– The reduced eGFR limits the filtered sodium load to reaching the distal tubule.
– Reabsorption in distal tubule is only modestly effective as compared with large thick ascending limb.

Metalozane ( a quinazoline derivative ) is an exception among thiazide diuretics, because it retains its efficacy in patients who have renal insufficiency or other diuretic-resistant states.
Metazolan should be reserved for use in combination with loop diuretics in patients with volume overload whose fluid and electrolyte balance are being closely monitored.
It is administered daily for a short period (3-5 days) with administration reduced to thrice weekly after this period or after euvolemia is achieved.

Loop Diuretics
Acts in the loop of Henle. Less effective for blood pressure in the long run than thiazide diuretic.
Loop diuretics should be given twice daily.
Most loop diuretics has duration of action of 6 hours.
It results in initial diuresis that is followed closely by a period of antinatriuresis lasting up to 18 hours per day when the drug is administered once daily.
These agents are most appropriate for the treatment of hypertension complicated by a reduced eGFR (< 30-40 ml per minute per 1.73m² of body surface area) or volume overload (e.g. in congestive heart failure or the nephrotic syndrome);

Potassium-sparing agents & Mineralocorticoid-receptor antagonists

These agents induce only minimal natriuresis and are relatively ineffective in lowering blood pressure.
Their primary role is in reducing the potassium loss, when they are used with thiazides.
They also prevent urine magnesium loss. ( Magnesium balance is necessary for optimal correction of diuretic-induced hypokalemia.

Examples:

Spironolactone, a non-selective mineralocorticoid-receptor antagonist, half life 20 hours, well absorbed. It corrects thiazide induced potassium and magnesium losses, and in low doses (12.5 to 50 mg per day) provides additive hypotensive effects in resistant to treat hypertension. It still works, when renal function is impaired. Potassium levels need to be monitored.
Eplerenone
Finerenone
These are newer agents which are more selective for aldosterone than androgens and progesterone.

Common clinical Problems encountered with thiazide, and possible solutions:

Attack of acute gouty arthritis

Obtain uric acid level, and discontinue thiazide if level is elevated. Recheck levels after resolution of the attack. Give prophylaxis, if needed.

OR change to another antihypertensive agent if uricosuric prophylaxis is not tolerated.

Hypokalemia (s. potassium ≤ 3.5 mmol/L

Correct hypomagnesemia, if present. Add potassium-sparing agent or supplemental potassium chloride. Add RAAS inhibitor, if BP not controlled.

Increase in s. creatinine from baseline level.

Assess hydration status, and discontinue nephrotoxic medications. ( e.g. NSAIDs)*

No apparent response to hydrochlorothiazide at a dose of 25 mg/ day

Advise salt restriction. Consider increase in diuretic dose; switch to long acting diuretic, chlorthalidone. OR add RAAS inhibitor.

Dizziness on standing

Check for orthostasis. Reduce diuretic dose if necessary. Assess hydration status and ensure diuretic is taken in the morning. Instruct the patient to stand up slowly.

Discovery of symptomatic hyponatremia

Assess concurrent medications (e.g. SSRIs) and determine risks and benefits of continuing thiazides. Evaluate patient for excessive water intake.

Thiazide therapy recommended for patient with documented history of allergy to a sulfa antibiotics.

Sulfa antibiotic allergy is not a contraindication to receiving a thiazide. If true allergy to thiazide is documented, ethcrynic acid ( a non-sulfa-containing diuretic) can be used.

Report of muscle cramps

Check serum potassium level and normalize if low. If electrolytes are normal, then consider another diuretic.

Impaired fasting blood glucose or diabetes at baseline.

Institute proper management of cardiovascular risk factors. Thiazide use is not precluded.

Development of diabetes during thiazide therapy

Institute appropriate management of diabetes and related cardiovascular risk factors.

Nocturia or Incontinence

Avoid thiazide in afternoon or evening. Limit water intake near bedtime. OR replace diuretic

Baseline GFR <30-40 ml/min/1.73m² of body surface area

Substitute furosemide or torsemide.

Reference:

Ernst ME, Moser M. Use of diuretics in patients with hypertension. N Engl J Med. 2009 Nov 26;361(22):2153-64. doi: 10.1056/NEJMra0907219. Erratum in: N Engl J Med. 2010 Nov 4;363(19):1877. PMID: 19940300.