Loop Diuretics

MOA:
  • Inhibitors of Na+ K+ 2Cl- Cotransporter. Inhibit Na+ & Cl- reabsorption.
  • Also produce venodilator action, directly or indirectly by releasing renal factor.
  • Increased H+ & K+ loss. Thus may produce metabolic alkalosis.
  • Loop diuretics acts on Thick ascending limb
  • Increase in Ca++ & Mg++ concentration & decreased excretion of uric acid.
  • They also potentiate the action of Thiazides.
  • The excretion of Na+ continues even if ECF is less & hence may result into dehydration & hypotension.
THERAPEUTIC USES:
  • Diuretic actions of Loop Diuretics:
  • Oedema due to cardiac failure, hepatic disease, nephrotic syndrome.
  • Acute pulmonary edema & cerebral edema, pregnancy & idiopathic edema.
  • Acute chronic renal failure.
  • Barbiturate poisoning, salicylate poisoning.
  • Drug of choice for acute left ventricular failure is I/V Furosemide
  • Nondiuretic action of Loop Diuretics:
  1. As an antihypertensive.
  2. Idiopathic calcium urolithiasis.
  3. In Hypocalcaemia.
  4. Diabetes insipidus.
  5. Hyponatremic states due to water retention.
  6. Glaucoma
ADVERSE EFFECT:
  • Hypokalemia, So used 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, possessing halogenated salfamoyl benzene ring common to Thiazide diuretics.
  • 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.
  • 160 mg furosemide in patients with cirrhosis and portal hypertension
PHARMACOLOGICAL ACTIONS:-
  • Kidneys:- Excretion of Na+, K+, Cl-, PO4.
  • 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.
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.
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.
ETHACRYNIC ACID:
  • Max. diuresis within 2-3 hrs after giving orally.
  • It can be used in edematous states, especially in patients allergic to sulphonamides.
  • Less used because prone to cause adverse effects similar to those of furosemide.
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 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 inhibits 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 is most likely to result in contraction alkalosis
  • Loop diuretics acts 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
Don't Forget to Solve all the previous Year Question asked on Loop Diuretics