DiureticsDr Renuka Joshi, MD,DNB

Fellow National Board ( Card. Anes. )

• Diuretic : Substance that promotes the

excretion of urine

Processes performed by the kidneys in order to filter blood :-

1. Glomerular Filtration

2. Tubular Reabsorption

3. Tubular Secretion.

Classification

• Proximal Convoluted Tubule Diuretics

– Osmotic Diuretics: Mannitol, Urea, Isosorbide, Glycerol

– Carbonic Anhydrase Inhibitors: Acetazolamide

• Loop Diuretics

– Furosemide, Bumetanide, Ethacrynic Acid, Torsemide

• Distal Convoluted Tubule Diuretics

– Thiazides: Benzthiazide, Chlorthiazide, Hydrochlorothiazide,

Polythiazide, Trichlormethiazide

– Thiazide like : Metolazone, Indapamide, Chlorthalidone

• Collecting Duct Diuretics ( K+ sparing diuretics )

– Aldosterone Antagonist: Spironolactone

– Non-aldosterone Antagonist:Triamterene, Amiloride

• High efficacy diuretics (high ceiling)

Loop diuretics

• Medium efficacy diuretics (medium ceiling)

Thiazide diuretics

• Low efficacy diuretics (low ceiling)

Carbonic anhydrase inhibitors

k+ sparing diuretics

Loop diuretics

• Loop diuretics inhibit Na/K/2Cl– co transporter across the lining cells of the ascending limb of the loop of Henle .

• Drugs

Furosemide

Bumetanide

Torsemide

Pharmacokinetics

• Rapidly absorbed.

• Eliminated by tubular secretion as well as by glomerular filtration.

• Absorption of oral torsemide is more rapid (1 hour) than that of furosemide(2–3 hours) and is nearly as complete as with intravenous administration.

• Diuretic response is extremely rapid following intravenous injection.

Furosemide

• Potent, oral, diuretic, possessing halogenated salfamoyl benzene ring common to Thiazide diuretics.

• act on thick ascending loop of Henle. Blocks Na+-K+-2Cl- symport.

• IV administration increases the renal blood flow. It increases PGE2 synthesis in the kidneys, which has a locally protective, vasodilator effect.

• In physiological or pharmacological stress, it counters the intrarenal vasoconstriction.

• Furosemide attaches to the Cl- binding site of protein (Na+ K+ 2Cl-) to inhibit its transport function.

Pharmacological actions:-• Kidneys:- Excretion of Na+, K+, Cl-, PO4-2. • Excessive chloride loss →hypochloremic alkalosis. • K+ loss→ Hypokalemia.( Less marked with Furosemide than

Thiazides).• Little change in Urine pH. Potent renin releasers.• Blood vessels & BP:- IV furosemide dilates peripheral

vasculature, Lowers the arterial BP, rapid venous pooling of blood, reducing cardiac preload & afterload.

• Metabolic actions:- ↑sed blood uric acid & disturbances of glucose tolerance, ↑sed blood urea. Ca++ & Mg++ excretion also ↑ses.

Pharmacokinetics:-• Absorbed orally, Bioavailability 60-100%.• Lipid solubility is low, Food reduces bioavailability.• Excreted within 4 hours. Onset of action is quick &

short. • 50% excreted unchanged, rest conjugated with

glucuronide in kidney.Dose:-• 20-80 mg once in morning. Upto 200mg in renal

insufficiency every 6 hrs by IM/IV. In pulmonary edema40-80 mg IV.

Torsemide

• 3 times more potent than furosemide.

• Oral absorption more rapid and complete. 80% metabolized in liver.

• t1/2= 3.5 hrs. Duration of action= 4-8 hrs.

• Used in hypertension & edema.

Dose:-

• 2.5 mg OD in hypertension, 5-20 mg/day in edema, 100 mg BD in renal failure.

Bumetanide

• 40 times more potent than furosemide.

• Onset & duration and its effect on electrolyte excretion are similar to furosemide.

• 80% absorption. It is metabolized in liver & its half life is not prolonged in renal insufficiency.

• Dose:-

• 1-5 mg oral OD in the morning, 2-4 mg IM/IV, (Max 15 mg/day in renal failure).

THERAPEUTIC EFFECTS

Increase Na Excretion

to 25% of Filtered Load

Treatment for

Oliguric ARF

Increase Ca ExcretionTreatment for

Hypercalcemia

Increase Venous

Capacitance

Treatment for

Pulmonary

Edema

Increase Urine Volume

Treatment for

Severe Edema

Adverse effects of loop diuretics

1. Hypokalemia

2. Hypocalcemia

3. Hypomagnesemia

4. Metabolic Alkalosis

5. Profound ECFV Depletion

6. Hyperglycemia

7. Hyperuricemia

8. Ototoxicity

Interactions

• Potentiate all other antihypertensives.

• Hypokalaemia induced by these diuretics:

1. Enhances digitalis toxicity.

2. Produces polymorphic ventricular tachycardia with quinidine and other antiarrhythmics.

3. Potentiates competitive neuromuscular blockers .

• Loop diuretics + aminoglycoside antibiotics – both ototoxic and nephrotoxic → additive toxicity.

• Cotrimoxazole + loop diuretics- thrombocytopenia

• Indomethacin/ NSAIDs + Loop diuretics-diminishes diuretic and antihypertensive effect of loop diuretics.

• Furosemide and warfarin/ Clofibrates: Displacement of plasma protein binding of warfarin

Resistance to loop diuretics

• Renal insufficiency .Decreased access of diuretics to its site of action due to low g.f.r and low proximal tubular secretion.

• Nephrotic syndrome.Binding of diuretic to urinary protein, other pharmacodynamic causes.

• Cirrhosis of liver.Abnormal pharmacodynamic hyperaldosteronism ; mechanism not clear.

• CHF.lmpaired oral absorption due to intestinal congestion, decreased renal blood flow and glomerular filtration, lncreased salt reabsorption in PT.

Thiazide diuretics

• They inhibit Na-Cl symport inhibitors. • Inhibit NaCl reabsorption from the luminal side of

epithelial cells in the distal convoluted tubule by blocking the Na+/Cl- transporter.Drugs:

• Benzthiazide• Chlorthiazide• Hydrochlorothiazide• Polythiazide• Trichlormethiazide

THERAPEUTIC EFFECTS

Increase Na Excretion

to 5% of Filtered Load

Treatment for

Hypertension

Decrease Ca ExcretionTreatment for

Calcium stones

in the kindey

Treatment for

Nephrogenic

Insipidus

Treatment for

Mild Edema

Adverse effect of thiazides

• 1. Hypokalemia

• 2. Hypomagnesemia

• 3. ECFV Depletion

• 4. Hypercalcemia

• 5. Hyperglycemia

• 6. Hyperuricemia

• 7. Increased plasma lipids

Potassium sparing diuretics

• These are either aldosterone antagonist or directly inhibit Na+ channels in DT and CD cells to indirectly conserve K+.

• Drugs

Spironolactone

Eplerenone

Triamterene

Amiloride

Spironolactone and Eplerenone

• Slow onsets and duration of action (24-72 hrs)

• Steroid derivatives

• Pharmacologic antagonists of aldosterone in the collecting tubules

• Combine and block intracellular aldosterone receptor → reduce expression of genes controlling synthesis of sodium ion channels and Na+/K+ ATPase.

Amiloride and Triamterene

• Block sodium channels in the same portion of the nephron.

• Duration of action: 12—24 hours.• Increase sodium clearance and decrease K+ & H+

excretion.• May cause hyperkalemic metabolic acidosis.• Amiloride blocks entry of Li+ through Na+ channels in

the CD cells and mitigates diabetes insipidus induced by lithium.

• Given as an aerosol it affords symptomatic improvement in cystic fibrosis by increasing fluidity of respiratory secretions

Therapeutic uses:-• Treatment of potassium wasting caused by

chronic therapy with loop and thiazide diuretics (combination in a single pill).

• Treatment of aldosteronism in cirrhosis and heart failure.

Adverse effects:-• Hyperkalemia is the most important toxicity.• Can cause endocrine abnormalities

(gynecomastia and antiandrogenic effects).

Interactions:-• Given together with K+ supplements-dangerous

hyperkalaemia can occur.• Aspirin blocks spironolactone action by inhibiting

tubular secretion of canrenone.• More pronounced hyperkalaemia can occur in

patients receiving ACE inhibitors/ angiotensin receptor blockers (ARBs).

• Spironolactone increases plasma digoxin concentration.

Recommendations of diuretics in heart failure

• Recommendation(7.23)Diuretic therapy is recommended to restore and maintain normal volume status in patients with clinical evidence of fluid overload, generally manifested by congestive symptoms (orthopnea, edema, and shortness of breath), or signs of elevated filling pressures (jugular venous distention, peripheral edema, pulsatile hepatomegaly, and, less commonly, rales). (Strength of Evidence = A) Loop diuretics rather than thiazide-type diuretics are typically necessary to restore normal volume status in patients with HF. (Strength of Evidence = B)

• Recommendation(7.24)

• The initial dose of diuretic may be increased as necessary to relieve congestion. Restoration of normal volume status may require multiple adjustments over many days and occasionally weeks in patients with severe fluid overload evidenced by massive edema or ascites. After a diuretic effect is achieved with short-acting loop diuretics, increasing administration frequency to twice or even 3 times per day will provide more diuresis with less physiologic perturbation than larger single doses. (Strength of Evidence = B)

• Oral torsemide may be considered in patients in whom poor absorption of oral medication or erratic diuretic effect may be present, particularly those with right-sided HF and refractory fluid retention despite high doses of other loop diuretics. (Strength of Evidence = C)

• Intravenous administration of diuretics may be necessary to relieve congestion. (Strength of Evidence = A)

• Diuretic refractoriness may represent patient nonadherence, a direct effect of diuretic use on the kidney, or progression of underlying cardiac dysfunction.

Recommendation(7.25)

• Addition of chlorothiazides or metolazone, once or twice daily, to loop diuretics should be considered in patients with persistent fluid retention despite high-dose loop diuretic therapy. But chronic daily use, especially of metolazone, should be avoided if possible because of the potential for electrolyte shifts and volume depletion. These drugs may be used periodically (every other day or weekly) to optimize fluid management.

• Metolazone will generally be more potent and much longer-acting in this setting and in patients with chronic renal insufficiency, so administration should be adjusted accordingly. Volume status and electrolytes must be monitored closely when multiple diuretics are used. (Strength of Evidence = C)

Recommendation(7.26)

• Careful observation for the development of side effects, including electrolyte abnormalities, symptomatic hypotension, renal dysfunction, or worsening renal function, is recommended in patients treated with diuretics, especially when used at high doses and in combination. Patients should undergo routine laboratory studies and clinical examination as dictated by their clinical response. (Strength of Evidence = B)

Recommendation(7.27)• Patients requiring diuretic therapy to treat fluid

retention associated with HF generally require chronic treatment, although often at lower doses than those required initially to achieve diuresis. Decreasing or even discontinuing diuretics may be considered in patients experiencing significant improvement in clinical status and cardiac function or in those who successfully restrict dietary sodium intake. These patients may undergo cautious weaning of diuretic dose and frequency with careful observation for recurrent fluid retention. (Strength of Evidence = C)

Thank you