Loop Diuretics

MOA:

• Inhibitors of Na+ & Cl- reabsorption.
• By inhibiting Na+ K+ 2Cl- cotransporter on thick ascending limb.
• Hence, excreting Na2+.
• Na2+ excretion continues even if ECF is less & hence causes dehydration & hypotension. 
• Na2+ excretion accompanies increased H+ & K+ loss. 
• May cause metabolic alkalosis.

THERAPEUTIC USES:

Diuretic actions:

• Reduces edema due to cardiac failure, hepatic disease, nephrotic syndrome.
• Eg: Acute pulmonary edema, cerebral edema, acute chronic renal failure, pregnancy & idiopathic edema.
• Drug of choice for acute left ventricular failure is I/V Furosemide.
• Useful in Barbiturate poisoning, salicylate poisoning.

Nondiuretic action of Loop Diuretics:

• As an antihypertensive.
• Idiopathic calcium urolithiasis.
• Hyponatremic states due to water retention.
• Glaucoma.

ADVERSE EFFECT:

• Hypokalemia – Combined with potassium-sparing diuretics.
• Hyponatremia, dehydration & metabolic acidosis.
• Hyperglycemia, hyperuricemia, Hypomagnesemia .
• Weakness, fatigue, dizziness, cramps & myalgia.
• Prostatic hypertrophy, ototoxicity, cardiac arrest after IV injection.
• Hepatic insufficiency, gastric upset.
• Orthostatic hypotension.

FUROSEMIDE:

• Potent oral diuretic.
• Has halogenated sulfamoyl benzene ring common to Thiazide diuretics.
• Acts on thick ascending loop of Henle, blocking Na+-K+ 2Cl– symport.
• Furosemide attaches to Cl- binding site of protein (Na+ K+ 2Cl-) inhibiting its transport function.
• 160 mg furosemide – Cirrhosis & portal hypertension.

PHARMACOLOGICAL ACTIONS:-

Kidneys:- 

• Excretion of Na+, K+, Cl-, PO4.
• IV administration increases renal blood flow.
• Increases PGE2 synthesis in kidneys – Has locally protective & vasodilator effect.
• In physiological or pharmacological stress – Counteracts intrarenal vasoconstriction.
• 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:- 

• ↑ blood uric acid, ↑ blood urea & disturbances of glucose tolerance.
• ↑  Ca++ & Mg++ excretion.

PHARMACOKINETICS:-

• Absorbed orally.
• Bioavailability 60-100%.
• Food reduces bioavailability.
• Onset of action is quick & short.
• Low lipid solubility.
• Excreted within 4 hours.
• 50% excreted unchanged, rest conjugated with glucuronide in kidney.

TORSEMIDE:

• 3 times more potent than furosemide.
• Oral absorption more rapid & complete. 
• 80% metabolized in liver.
• t1/2= 3.5 hrs. 
• Duration of action= 4-8 hrs.
• Used in hypertension & edema.

BUMETANIDE:

• 40 times more potent than furosemide.
• Onset & duration and its effect on electrolyte excretion are similar to furosemide.
• 80% absorption. 
• Metabolized in liver & its half-life is not prolonged in renal insufficiency.

ETHACRYNIC ACID:

• Max. diuresis within 2-3 hrs after giving orally.
• Used in edematous states, especially in patients allergic to sulphonamides.
• Less used because prone to cause adverse effects (Ototoxicity mainly)similar to those of furosemide.

INTERACTIONS:

• Potentiate all other antihypertensives. 

Hypokalaemia induced by these diuretics:

• Enhances digitalis toxicity.
• Produces polymorphic ventricular tachycardia with quinidine and other antiarrhythmics.
• Potentiates competitive neuromuscular blockers and reduces sulfonylurea action.
• 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.
• Probenecid + furosemide and thiazides competitively inhibit tubular secretion of furosemide and thiazides.
• Serum lithium level rises when diuretic therapy 
• Furosemide and warfarin/ Clofibrates: Displacement of plasma protein binding of warfarin