Diuretics: Types, Mechanism of Action, Indications, Side Effects

Published by: Diana Luai Awad, Dr Pharmacist on Wednesday 14. December 2022

Diuretics are one of the most important drugs in clinical practice, which have been used for over 50 years in the treatment of a number of diseases. Although they all act by altering the reabsorption of sodium in the renal tubules, diuretics differ in their mechanism of action and have different pharmacological properties and indications.

Anatomy and physiology of the urinary system

Before describing the mechanisms of action of diuretics, it is appropriate to refresh one's memory of the structure and functioning of the kidneys. The main urine-forming unit of the kidney is the nephron: each kidney consists of 1 million nephrons. These, in turn, include Bowman's capsule, convoluted tubules, and the loop of Henle.

In the capsule plasma is filtered, as a result, coarse proteins and blood cells are retained, and the filtered primary urine enters the tubules¹.
In the proximal part of the convoluted tubules, sodium (most of it), bicarbonates, chlorine and water are reabsorbed, and protons are secreted into the lumen of the tubules.
The descending part of the loop of Henle is permeable only to water: according to the law of osmosis, water moves in a hyperosmolar direction and is reabsorbed.
In the thick segment of the ascending loop of Henle, sodium, potassium, chlorides, as well as magnesium and calcium are reabsorbed.
In the distal part of the convoluted tubules, a small amount of chlorine, calcium (regulated by parathyroid hormone), sodium is also reabsorbed in exchange for the excretion of potassium into the urine (the regulator is aldosterone).

Water is reabsorbed in the collecting ducts under the action of antidiuretic hormone.

Figure 1. The basic structure of the nephron and the main points of application of diuretics

CAI, carbonic anhydrase inhibitors; LD, loop diuretics; TD, thiazide diuretics; SP, aldosterone anatagonists; VP, vaptans; ADH, antidiuretic hormone.

Table. Reabsorbent and secretory functions of various segments of the renal tubules¹

Tubular segment	Filtered load reabsorbed or secreted, %			Tubular osmolality compared with plasma
Tubular segment	Na+	Urea	Water	Tubular osmolality compared with plasma
Proximal tubule	65	50 absorbed	65	Isosmotic due to simultaneous Na⁺ and water reabsorption
Descending thin limb of Henle loop	0	50 secreted	10	Isosmotic. No significant reabsorption
Ascending thin and thick limbs of Henle loop	25	0	0	Hypoosmotic due to active Na⁺ reabsorption
Distal tubule	5	0	0	Hypoosmotic due to active Na⁺ reabsorption
Collecting duct system	4-5	50 absorbed	(5–24) depending on the level of ADH	Hyper/hypo/isosmotic depending on ADH influence and medullary hypertonicity

Classification of diuretics by mechanism of action

There are several classifications of diuretics, but one of the most famous and frequently used in practice is this classification^1-3:

Carbonic anhydrase inhibitors block the function of carbonic anhydrase within the brush border and within the epithelial cells of the proximal tubules; main purpose is the treatment of glaucoma^1,2
Acetozolamide, dorzolamide, brinzolamide
Loop diuretics inhibit the Na⁺-K⁺-2Cl cotransporter (NKCC) in the thick ascending loop of Henle and are successfully used in patients with edema in chronic kidney disease and arterial hypertension^1,2
Furosemide, torasemide, ethacrynic acid
Thiazide and thiazide-like diuretics inhibit an electroneutral NaCl co-transport pathway at the distal convoluted tubule and represent the cornerstone of antihypertensive therapy for many years^1,2
Hydrochlorothiazide, indapamide
Potassium-sparing diuretics
Epithelial sodium channel blocking agent inhibit the epithelial Na⁺ channel in the collecting duct and are mainly used in the treatment of hypertension in combination with other diuretics to correct potassium deficiency in patients without mineralocorticoid excess^1,2

Triamterene, amiloride

Aldosterone antagonists block the aldosterone mineralocorticoid receptors in the cytoplasm of principal cells of the collecting duct. Aldosterone antagonists are traditionally used for primary aldosteronism, but recent evidence indicates that they reduce morbidity and mortality in patients with heart failure^1,2

Spironolactone, eplerenone

Osmotic diuretics exerts an osmotic effect along the renal tubule, inhibiting water and solute reabsorption without interfering with tubular electrolyte transport systems and is widely used for treatment of cerebral oedema^1,2
Mannitol.

Application points, mechanism of action, indications, side effects of the most commonly used diuretics^1-4

Class1

Site of action

Enzyme/channel inhibited

Clinical uses

Side effects

Carbonic anhydrase inhibitors

Proximal segment:

acetazolamide,

brinzolamide,

dorzolamide, and

methazolamide

Carbonic anhydrase

inhibition causes acute

sodium bicarbonate

diuresis

Glaucoma, metabolic

alkalosis due to loop

diuretics, acute

mountain sickness,

hyperphosphatemia,

and urinary

alkalinization

Hyperchloremic metabolic

acidosis, hypophosphatemia,

renal stones, and

hypokalemia

Loop diuretics

Loop of Henle:

furosemide,

bumetanide,

torasemide, and

ethacrynic acid

Active Na+–K+–2Cl2

carrier. Mutation

of this carrier

results in

decreased Na⁺

reabsorption—eg,

Bartter syndrome

Acute pulmonary edema,

congestive

heart failure (CHF), hypercalcemia,

hyperkalemia,

and syndrome of inappropriate

ADH (antidiuretic hormone) secretion (SIADH)

Metabolic alkalosis,

hypomagnesemia,

hypocalcemia (only in

hypoparathyroid patients),

hypokalemia, hyperuricemia,

and ototoxicity

Thiazide diuretics

Distal tubule:

thiazides— hydrochlorothiazide,

indapamide,

chlorthalidone,

and metolazone

Active Na+–Cl2 carrier.

Mutation of this carrier

results in decreased

Na⁺ absorption—eg,

Gitelman syndrome

Hypertension, idiopathic

hypercalciuria, and

nephrogenic diabetes insipidus

Metabolic alkalosis,

hypercalcemia, hypokalemia,

hyperuricemia, hyperlipidemia,

hyponatremia, hyperglycemia,

and impotence

Potassium-sparing diuretics

Connecting segment

and collecting tubule:

aldosterone

antagonists

(spironolactone,

eplerenone),

amiloride, and

triamterene

Gradient related Na⁺

channel. Mutation

of this channel results

in increased Na⁺

reabsorption—eg,

Liddle syndrom

Spironolactone—primary

and secondary

hyperaldosteronism,

CHF, and

hyperandrogen

states

Amiloride—Bartter syndrome, Liddle syndrome,

and nephrogenic diabetes insipidus

Hyperchloremic metabolic

acidosis, hyperkalemia,

gynecomastia, and

antiandrogen effects

(with spironolactone).

Nephrolithiasis, acute renal failure (with triamterene)

Osmotic diuretics

Multiple parts of nephron:

eg, mannitol

Inhibit water

reabsorption in

proximal tubule,

descending

loop of Henle,

and collecting

tubules

Intracranial hypertension,

prevention of renal

failure after large

pigment loads,

dialysis disequilibrium

syndrome, barbiturate

intoxication

Hyponatremia, CHF,

hypernatremia with

chronic use

Bibliography

Reddy P., Mooradian A. D. Diuretics: an update on the pharmacology and clinical uses //American journal of therapeutics.2009; 16 (1): 74-85.
Brater D. C. Pharmacology of diuretics //The American journal of the medical sciences. 2000; 319 (1): 38-50.
Sarafidis P. A., Georgianos P. I., Lasaridis A. N. Diuretics in clinical practice. Part I: mechanisms of action, pharmacological effects and clinical indications of diuretic compounds //Expert opinion on drug safety. 2010; 9 (2): 243-257.
Roush G. C., Kaur R., Ernst M. E. Diuretics: a review and update //Journal of cardiovascular pharmacology and therapeutics. 2014; 19 (1): 5-13.

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