Loop Diuretics

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.
Image result for loop diuretics
Actions:
  • Produces vasodilator action, directly or indirectly by releasing renal factor.
  • Potentiates thiazides action.

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.
  • Hyperglycemiahyperuricemia, 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
Exam Question
 
  • Hyperglycemia, Hypomagnesemia, acidosis, Hypokalemia, Ototoxicity & Hyperuricemia  are adverse effects can be caused by Loop Diuretics
  • The usual maximum dose of furosemide and spironolactone in patients with cirrhosis and portal hypertension is Furosemide 160 mg and spironolactone 400 mg
  • Loop diuretic is the mechanism of action of bumetanide
  • Loop diuretics are most likely to result in contraction alkalosis
  • Loop diuretics act on Thick ascending limb
  • Ethacrynic acid causes increased concentration of Na’ & Cl in urine with normal bicarbonate
  • Furosemide  is used in pulmonary edema
  • Ethacrynic acid is not used due to Ototoxicity
  • Loop diuretics interact with cefotaxime 
  • IV fluid with furosemide is given in Hypercalcemia
  • Drug of choice for acute left ventricular failure is I/V Furosemide
  • Furosemide is excreted unchanged in urine
  • Diuretics of choice for acute pulmonary edema is Loop diuretics
  • The site of action of the loop diuretic furosemide is Thick ascending limb of loop of Henle
Don’t Forget to Solve all the previous Year Question asked on Loop Diuretics

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