Diuretics: Symptom-Drugs-Dose-MOA-Side Effects | Makpats

Diuretics

All diuretics increase the excretion of water from bodies. Alternatively, an antidiuretic is an agent or drug which reduces the excretion of water in urine.

CLASSIFICATION

1. High efficacy diuretics (Inhibitors of Na+- K+-2Cl¯ cotransport)
Sulphamoyl derivatives: Furosemide, Bumetanide, Torasemide

2. Medium efficacy diuretics (Inhibitors of Na+-Cl¯ symport)
(A) Benzothiadiazines (thiazides):

           Hydrochlorothiazide, Benzthiazide,

           Hydroflumethiazide, Bendroflumethiazide
(B)  Thiazide like (related heterocyclics):

           Chlorthalidone,
           Metolazone,
           Xipamide,
           Indapamide,
           Clopamide

3. Weak or adjunctive diuretics
(A) Carbonic anhydrase inhibitors:      Acetazolamide
(B) Potassium sparing diuretics:
(ⅰ) Aldosterone antagonist: 
     Spironolactone, Eplerenone

(ⅱ) Inhibitors of renal epithelial Na+ channel: 
     Triamterene, Amiloride
(C) Osmotic diuretics: 
     Mannitol, Isosorbide, Glycerol

MECHANISM OF ACTION

1. HIGH CEILING (LOOP) DIURETICS (Inhibitors of Na+ -K+ -2Cl¯ Cotransport)

Furosemide (Frusemide) Prototype drug: Its maximal natriuretic effect is much greater than that of other classes.

The diuretic response goes on increasing with increasing dose: upto 10 L of urine may be produced in a day. It is active even in patients with relatively severe renal failure.

The onset of action is prompt (i.v. 2–5 min., i.m. 10–20 min., oral 20–40 min.) and duration short (3–6 hours).

The major site of action is the thick AscLH (therefore called loop diuretics) where furosemide inhibits Na+- K+-2Cl¯ cotransport.

The corticomedullary osmotic gradient is abolished and positive as well as negative free water clearance is blocked. K+ excretion is increased mainly due to high Na+ load reaching DT. However, at equinatriuretic doses, K+ loss is less than that with thiazides.

Furosemide has weak CAse inhibitory action; increases HCO3 ¯ excretion as well; urinary pH may rise but the predominant urinary anion is Cl¯ . Therefore, acidosis does not develop.

furosemide causes acute changes in renal and systemic haemodynamics.

After 5 min of i.v. injection, renal blood flow is transiently increased and there is redistribution of blood flow from outer to midcortical zone; g.f.r. generally remains unaltered due to compensatory mechanisms despite increased renal blood flow.

Intravenous furosemide causes prompt increase in systemic venous capacitance and decreases left ventricular filling pressure, even before the saluretic response is apparent.

Furosemide increases Ca2+ excretion as well as Mg2+ excretion by abolishing transepithelial potential difference in the thick AscLH which drives reabsorption of these divalent cations.

Molecular mechanism of action: A glycoprotein with 12 membrane spanning domains has been found to function as the Na+ -K+ -2Cl¯ cotransporter in many epithelia performing secretory/absorbing function, including AscLH.

Recently, distinct absorptive and secretory isoforms of Na+-K+-2Cl¯ cotransporter have been isolated. The former is exclusively expressed at the luminal membrane of thick AscLH—furosemide attaches to the Cl¯ binding site of this protein to inhibit its transport function. The secretory form is expressed on the basolateral membrane of most glandular and epithelial cells.

Pharmacokinetics:

Furosemide is rapidly absorbed orally but bioavailability is about 60%.

Lipid-solubility is low, and it is highly bound to plasma proteins.

Some excretion in bile and directly in intestine also occurs.

Plasma t½ averages 1–2 hour.

Dose:

Usually 20–80 mg once daily in the morning.

In renal insufficiency, upto 200 mg 6 hourly has been given by i.m./i.v. route.

In pulmonary edema 40–80 mg may be given i.v.

Bumetanide: It is similar to furosemide in all respects, but is 40 times more potent. It induces very rapid diuresis and is highly effective in pulmonary edema.

the site of action, ceiling effect, renal haemodynamic changes and duration of action are similar to furosemide.

Hyperuricaemia, K+ loss, glucose intolerance and ototoxicity are claimed to be less marked, but it may rarely cause myopathy.

Bumetanide is more lipid-soluble.

oral bioavailability is 80–100%.

Bumetanide is extensively bound to plasma proteins, partly metabolized and partly excreted unchanged in urine.

Plasma t½ ~60 min.

Dose: 1–5 mg oral OD in the morning, 2–4 mg i.m./i.v., (max. 15 mg/day in renal failure).

Torasemide (Torsemide): Another high ceiling diuretic with properties similar to furosemide, but 3 times more potent.

Oral absorption is more rapid and more complete.

 The elimination t½ (3.5 hours) and duration of action (4–8 hours) are longer.

Torasemide has been used in edema and in hypertension.

Dose: 2.5–5 mg OD in hypertension; 5–20 mg/day in edema; upto 100 mg BD in renal failure.

Use of high ceiling diuretics:

1.      Edema

2.      Acute pulmonary edema (acute LVF, following MI)

3.      Cerebral edema

4.      Hypertension

Hypercalcaemia of malignancy

2. Medium efficacy diuretics (Inhibitors of Na+-Cl¯ symport):

Chlorothiazide was synthesized as a CAse inhibitor variant which (unlike acetazolamide) produced urine that was rich in Cl¯ , and diuresis occurred in alkalosis as well as acidosis.

Here they inhibit Na+–Cl¯ symport at the luminal membrane.

Positive free water clearance is reduced, because tubular fluid is not maximally diluted (very dilute urine cannot be passed in theabsence of ADH), but negative free water clearance (in the presence of ADH) is not affected.

This strengthens the view that the site of action is in between thick AscLH and late DT. These drugs gain access to their site of action via organic acid secretory pathway in PT and then along the tubular fluid to the early DT, where they bind to specific receptors located on the luminal membrane. Like the Na+-K+-2Cl¯ cotransporter, the Na+-Cl¯ symporter is also a glycoprotein with 12 membrane spanning domains that binds thiazides but not furosemide or any other class of diuretics.

However, it may confer some proximal tubular action to the compounds, and accounts for the increase in HCO3 ¯ and PO4 3¯ excretion.

Under thiazide action, increased amount of Na+ is presented to the distal nephron, more of it exchanges with K+ ® urinary K+ excretion is increased in parallel to the natriuretic response. The maximal diuresis induced by different agents falls in a narrow range; though potency (reflected in daily dose) differs markedly.

Nevertheless, they are moderately efficacious diuretics, because nearly 90% of the glomerular filtrate has already been reabsorbed before it reaches their site of action.

Chlorthalidone: It is a particularly long acting compound with a t½ 40–50 hours, used exclusively as antihypertensive.

Metolazone: It has marked additive action when combined with furosemide.

Metolazone has been used mainly for edema (5–10 mg/day, rarely 20 mg), and occasionally for hypertension (2.5–5 mg/day).

Xipamide: It is used both as antihypertensive (10–20 mg/ day) and for treatment of edema (40 mg/day, max. 80 mg/day).

Indapamide: it is highly lipid soluble

Pharmacokinetics:

well absorbed orally.

There are no injectable preparations of these drugs.

Their action starts within 1 hour.

The elimination t½ of hydrochlorothiazide is 3–6 hours, but action persists longer (6–12 hours).

Uses:

1.      Edema

2.      Hypertension

3.      Diabetes insipidus

4.      Hypercalciuria

3. Weak or adjunctive diuretics

(A) Carbonic anhydrase inhibitors: 

Carbonic anhydrase (CAse) is an enzyme which catalyses the reversible reaction H2O + CO2 ↔ H2CO3. Carbonic acid spontaneously ionizes H2CO3 ↔H+ +  HCO3 ¯.

Carbonic anhydrase thus functions in CO2 and HCO3 ¯ transport and in H+ ion secretion. The enzyme is present in renal tubular cell (especially PT) gastric mucosa, exocrine pancreas, ciliary body of eye, brain and RBC. In these tissues a gross excess of CAse is present, more than 99% inhibition is required to produce effects.

Acetazolamide: It is a sulfonamide derivative which noncompetitively but reversibly inhibits CAse (type II) in PT cells resulting in slowing of hydration of CO2 ® decreased availability of H+ to exchange with luminal Na+ through the Na+-H+ antiporter.

Inhibition of brush border CAse (type IV) retards dehydration of H2CO3 in the tubular fluid so that less CO2 diffuses back into the cells. The net effect is inhibition of HCO3 ¯ (and accompanying Na+) reabsorption in PT. However, the resulting alkaline diuresis is only mild, because part of the Na+ (but not HCO3 ¯ ) rejected in the PT is reabsorbed at the high capacity AscLH.

Though H+ is secreted at this site by a H+ -ATPase, it is generated in the cell by CAse mediated reaction.

When CAse inhibitors are given, the distal Na+ exchange takes place only with K+ which is lost in excess.

The extrarenal actions of acetazolamide are:

(i) Lowering of intraocular tension due to decreased formation of aqueous humour (aqueous is rich in HCO3 ¯ ).

(ii) Decreased gastric HCl and pancreatic NaHCO3 secretion: This action requires very high doses—not significant at clinically used doses.

(iii) Raised level of CO2 in brain and lowering of pH ® sedation and elevation of seizure threshold. (iv) Alteration of CO2 transport in lungs and tissues. These actions are masked by compensatory mechanisms.

Pharmacokinetics

Acetazolamide is well absorbed orally and excreted unchanged in urine. Action of a single dose lasts 8–12 hours.

Uses:

1.      Glaucoma

2.      To alkalinise urine

3.      Epilepsy

4.      Acute mountain sickness

5.      Periodic paralysis

Dose: 250 mg OD–BD

Adverse effects:

fever, rashes, Acidosis, hypokalaemia, drowsiness, paresthesias, fatigue, abdominal discomfort.

(B) POTASSIUM SPARING DIURETICS

Aldosterone antagonists and renal epithelial Na+ channel inhibitors indirectly conserve K+ while inducing mild natriuresis, and are called ‘potassium sparing diuretics’.

(ⅰ) Aldosterone antagonist:

Spironolactone It is a steroid, chemically related to the mineralocorticoid aldosterone.

Aldosterone acts by combining with an intracellular mineralocorticoid receptor (MR) ® induces the formation of ‘aldosterone-induced proteins’ (AIPs).

Spironolactone acts from the interstitial side of the tubular cell, combines with MR and inhibits the formation of AIPs in a competitive manner.

It has no effect on Na+ and K+ transport in the absence of aldosterone, while under normal circumstances, it increases Na+ and decreases K+ excretion.

Pharmacokinetics

The oral bioavailability is 75%.

completely metabolized in liver.

The t½ of spironolactone is 1–2 hours.

Dose: 25–50 mg BD–QID; max 400 mg/day

Use:

1.      To counteract K+ loss due to thiazide and loop diuretics

2.      Edema

3.      Hypertension

Adverse effects:

Drowsiness

Ataxia

mental confusion

epigastric distress

loose motions

Eplerenone It is a newer and more selective aldosterone antagonist.

it particularly suitable for longterm use in the therapy of hypertension

side effects are like spironolactone.

Pharmacokinetics:

well absorbed orally.

inactivated in liver by CYP3A4.

excreted in urine (2/3rd) as well as faeces (1/3rd).

The t½ is 4–6 hours.

Dose: 25–50 mg BD

(ⅱ) Inhibitors of renal epithelial Na+ channel

Triamterene and amiloride are two nonsteroidal organic bases with identical actions. Their most important effect is to decrease K+ excretion, particularly when it is high due to large K+ intake or use of a diuretic that enhances K+ loss. This is accompanied by a small increase in Na+ excretion. The excess urinary Na+ is matched by Cl¯ and variable amounts of HCO3 ¯ ; urine is slightly alkalinized.

Mechanism of action

The luminal membrane of late DT and CD cells expresses a distinct ‘renal epithelial’ or ‘amiloride sensitive’ Na+ channel through which Na+ enters the cell down its electrochemical gradient which is generated by Na+K+ ATPase operating at the basolateral membrane.

This Na+ entry partially depolarizes the luminal membrane creating a –15 mV transepithelial potential difference which promotes secretion of K+ into the lumen through K+ channels.

Though there is no direct coupling between Na+ and K+ channels, more the delivery of Na+ to the distal nephron—greater is its entry through the Na+ channel—luminal membrane is depolarized to a greater extent—driving force for K+ secretion is augmented. As such, all diuretics acting proximally promote K+ secretion.

The intercalated cells in CD possess an ATP driven H+ pump which secretes H+ ions into the lumen. This pump is facilitated by the lumen negative potential. Amiloride, by reducing the lumen negative potential, decreases H+ ion secretion as well and predisposes to acidosis. Thus, amiloride conserves both K+ and H+ while marginally increasing Na+ excretion.

Triamterene:

Pharmacokinetics:

It is incompletely absorbed orally.

largely metabolized in liver.

excreted in urine.

Plasma t½ is 4 hours.

Side effects:

nausea, dizziness, muscle cramps and rise in blood urea.

Dose: 50–100 mg daily

Amiloride It is 10 times more potent than triamterene

Pharmacokinetics:

Only ¼ of an oral dose is absorbed.

It is not bound to plasma proteins and not metabolized.

The t½ (20 hours) and duration of action are longer than triamterene.

side effects:

nausea, diarrhoea and headache.

(C) OSMOTIC DIURETICS

Mannitol

It is minimally metabolized in the body; freely filtered at the glomerulus and undergoes limited reabsorption: therefore excellently suited to be used as osmotic diuretic.

Mannitol appears to limit tubular water and electrolyte reabsorption in a variety of ways:

1. Retains water isoosmotically in PT—dilutes luminal fluid which opposes NaCl reabsorption.

2. Inhibits transport processes in the thick AscLH by an unknown mechanism.Quantitatively this appears to be the largest contributor to the diuresis.

3. Expands extracellular fluid volume (because it does not enter cells, mannitol draws water from the intracellular compartment)— increases g.f.r. and inhibits renin release.

4. Increases renal blood flow, especially to the medulla—medullary hypertonicity is reduced (due to washing off)—corticomedullary osmotic gradient is dissipated—passive salt reabsorption is reduced. Though the primary action of mannitol is to increase urinary volume, excretion of all cations (Na+, K+ , Ca2+, Mg2+) and anions (Cl¯ , HCO3 ¯ , PO4 3¯ ) is also enhanced.

Pharmacokinetics

Mannitol is not absorbed orally.

has to be given i.v. as 10–20% solution.

It is excreted with a t½ of 0.5–1.5 hour.

Uses

1.      Increased intracranial or intraocular tension

2.      To maintain urine flow in impending acute renal failure

3.      To counteract low osmolality of plasma/e.c.f. due to rapid haemodialysis or peritoneal dialysis (dialysis disequilibrium).

side effect

headache

Nausea and vomiting may occur; hypersensitivity reactions are rare.

Isosorbide and glycerol These are orally active osmotic diuretics which may be used to reduce intraocular or intracranial tension.

Intravenous glycerol can cause haemolysis.

Dose: 0.5–1.5 g/kg as oral solution