Diuretic drugsAssoc. Prof. Ivan Lambev (itlambev@mail.bg)

FurosemideTorsemide

AmilorideTriamterene

Spironolactone

MannitolAcetazolamide

FurosemideTorsemide

HydrochlorothiazideChlorthalidoneIndapamide

Diuretics exert their effect directly on the kidneys. Most of them lead to electrolyte excretion andconsequently toosmotic excretionof water, whichincreases the 24-hrurine volume.

1. Salidiuretics (thiazides and their analogues)

They increase equivalently Na+ and Cl- excretion (1:1) in distal renal tubules andthis increases diuresis. They lead toexcretion of 5 to 10% from filtrated Na+ ionsand have moderate diuretic action. Theycan be classified as sulfonamides with free –NH2 group, without antimicrobial activity.

Salidiuretics (saluretics)

Thiazides•Hydrochlorothiazide•Cyclopenthiazide

Thiazide analogues•Clopamide•Chlorthalidone

Vasodilators with antihypertensive effect•Indapamide (stimulates synthesis of renal PGs with vasodilating action)

HydrochlorothiazideChlorthalidone

Indapamide

5–10%

Indapamide SR(does not havemetabolic effects)•cardioprotector•nephroprotector

Thiazides have a weak antihypertensiveeffect because they reduce arterial wall sensitivityto NA (noradrenaline) and AT (Angiotensin).

They potentiate significantly the effectof other antihypertensive drugs.

Thiazides increase plasma renin levels.

Reduction of plasma Sodium and osmolarity leads to “paradoxal” antidiuretic effect in diabetes insipidus.

Adverse reactions (ARs) of saluretics:

Hypokalemia and enhancing therapeutic andtoxic effects of CGs, hypochloremic alkalosis,GI disorders, skin rashes and photosensibi-lization, muscle weakness and fatigue, hypo-natremia, hypoglycemia, increased plasma levelof uric acids, hypercholesterolemia, impotence.Thiazides decrease GF (glomerul filtration).They reduce plasma volume in pregnantwomen and decrease fetal oxygenation (PRC: D).

2. Loop Diuretics

Furosemide has p.o. bioavailability 65%and t1/2 30–60 min. It acts on the ascendinglimb of Henley's loop by increasing urine excretion of Na+, Cl , Mg2+ andCa2+. Its diuretic effect is achieved in20–30 min after p.o. administrationand lasts 4–6 h. Its effect after i.v. administration begins in 3–5 min andlasts 2 h. In low doses (5 to 10 mg p.o.)furosemide has antihypertensive effect.It does not disrupt GF.

Furosemide – indications:

Oedemas of different origin, acute ischemicrenal failure (in high DD, togetherwith mannitol), anuria and eclampsia, forceddiuresis in acute intoxications, hypertension, resistant cardiac failure.

Furosemide enhances the action of antihypertensive drugs and non-depolarazing neuromuscular blockers.

Furosemide – ARs:

Hypokaliemia, skin rashes, hyperglycemia,increased plasma levels of uric acid. In fast i.v. administration – transienthearing disturbances with temporarydeafness and orthostatic collapse. Ototoxic risk is increased in co-medicatonwith aminoglycosides, cephalosporines, polymyxins, sulfonamides or quinolones.

3. Carbonic anhydrase inhibitors

Acetazolamide inhibits carbonicanhydrase (CA) mainly in proximal tubules.

H2O + CO2 CA

H2CO3 H2CO3– + H+

Acetazolamide has weak diuretic action. It significantly enhances urine K+ excretion.The loss of HCO3

– anions decreases blood alkaline reserve (for 48–72 h) and causes metabolic acidosis. In this state the drugbecomes ineffective.

Acetazolamide blocks not only renal CA, butalso CA in the ciliary body in the eye (reducing production of eye liquid) and in thebrain (facilitates GABA synthesis).

3%

AmilorideTriamterene

Spironolactone

4. Potassium- sparing diuretics

They have weakdiuretic actionand save K+.

Often they are usedin combination withdiuretics, causinghypokalemia.

Potassium-sparing diuretics

Competitivealdosteroneantagonists:•Spironolactone

Blockers of the amiloride-sensitiveNa+ channels:•Amiloride•Triamterene

Spironolactone is a steroid compound, which is a competitive aldosterone antagonist.It increases Na+ excretion and decreases K+ and urea excretion. Its diuretic action isweak and is achieved slowly.

Spironolactone is effective in oedemas, caused by increased production of aldosterone ascites in liver cirrhosis andoedemas in congestive heart failure.

Spironolactone in low doses (25 mg/24 h) potentiates the effect of ACE inhibitors. Itsaves K+ and Mg2+ ions and has antiarrhyth-mic effect. It also prevents the development ofmyocardial fibrosis, caused by aldosteroneand in this way contributes to enhancing myocardial contractility.

Diuretidin® (triamterene/hydrochlorothiazide)is indicated in oedemas cardiac, renal,liver or other origin and for the treatment of hypertension withother antihypertensive drugs.

Moduretic®

(amiloride/hydrochlorothiazide)has the same indications too.

60–80%

5. Osmotic diuretics

After oral administration Mannitol is notabsorbed and has laxative effect. After i.v.administration it is not metabolized, itfiltrates in the glomerulus and not reabsorbedin renal tubules, causing increased osmoticpressure and excretion of isoosmotic equivalentof water. It increases blood flow in 30%.

Мannitol does not influence renin synthesis.

It does not cross tissue barriers (BBB neither),does not penetrate to the eye and brain andin osmotic way reduces intraocular and intra-cranial pressure.

It is included in the treatment of brain oedema,initial stages of acute renal failure, chronicrenal failure, glaucoma, intoxications withdrugs, excreted in the urine.

6. Phytodiuretics

Rhizoma Graminis(Couch-grass)Stipites Cerasorum(Cherry)Fructus Faseoli sine semine(Haricot)

Fructus Petroselini(Parsley)Stigmata Maydis(Maize, corn)

Rubia tinctorum L. (madder). Radix Rubiae contains 2–3% di- or trioxyanthraquinonesglycosides, flavonoids and other bioactive substances with diuretic, urolitholytic and spasmolytic effects.

Infusions (1:10) made from madder facilitate dilution of calculi, containing calcium and magnesium sulfatein the renal pelvis and bladder.

It is an important ingredient of many phytoproducts(Cystenal©, Rowatinex©), indicated in urolithiasis.