LOOP DIURETICS &

POTASSIUM SPARING DIURETICS

Presented By-Krushangi Shah. Nirma University.

Contents• Urine formation• Classification of diuretics• Several targets for diuretic action• Loop diuretics

DrugsInteractionsResistance to loop Diuretics

• Potassium sparing diureticsDrugsInteractions

• Recent advancements

Normal Physiology of kidney (Urine formation)

• Urine formation starts from Glomerular Filtration.• Around 180 Liter of fluid is filtered everyday in

glomerulus. All soluble constituents of blood except plasma proteins and lipids are filtered at glomerulus.

• But more than 99% of the glomerular filtrate is reabsorbed in the tubules. So inspite of 180 liter fluid filtration in glomerulus, only 1.5 liter of urine is produced in 24 hours.

• Hence, tubular reabsorption and secretion are the more effective steps than the glomerular filtration for the drug target, as they alter urine formation in greater extend.

Tubular reabsorption can occur at four different sites.

PROXIMAL CONVULATED TUBULE• Glucose, bicarbonate, amino acids and other

metabolites are reabsorbed.• Two-third of Na+ is reabsorbed, Chloride enters in

exchange for a base anion, such as formate and oxalate.

• Water follows passively to maintain iso-osmolarity.1. Direct entry of Na+ along with electrochemical

gradient.

2. Na+/ K+ pump. Transfer of Na+ and Ca++ coupled to active reabsorption of glucose, amino acids and other organic anions & PO4

-3 through specific symporters.

3. Exchange of H+: Proximal tubule cells secrete H+ with the help of

carbonic anhydrase.4. Large amount of HCO3

-,amino acid, acetate create driving force for Cl- to diffuse through paracellular pathway.

LOOP OF HENLE (DESCENDING LOOP OF HENLE)

• The filtrate entering here is isotonic due to water reabsorption in this area.

• Tubular fluid becomes concentrated (Hypertonic) (Three fold increase in salt concentration).

LOOP OF HENLE (ASCENDING LOOP OF HENLE)

1. ASCENDING LOOP OF HENLE (Medullary part lined by cuboidal cells).

• Unique. Impermeable to water.

• Active reabsorption of Na+, K+ & Cl- is mediated by a Na+/K+/2Cl- Cotransporter.

• Mg++ and Ca++ enter the interstitial fluid.• 25% to 30% of tubular NaCl returns to the interstitial

fluid (blood). So, Loop of Henle is called diluting region. A major site for salt reabsorption.

2. ASCENDING LOOP OF HENLE (Cortical part lined by flattened cells).

• Impermeable to water.• Salt reabsorption continues but through Na+-Cl-

symporters. • Tubular fluid gets further diluted.

DISTAL CONVULATED TUBULE

• Impermeable to water.• 10% of filtered NaCl is reabsorbed via Na+/Cl-

transporter that is sensitive to Thiazide diuretics.

• Calcium reabsorption mediated by Na+/Ca++ exchanger into the interstitial fluid.

• Ca++ excretion is regulated by parathyroid hormone in this portion of the tubule.

COLLECTING TUBULE & DUCT

• Na+, K+, water reabsorption.• Na+ enters through channels to tubular cells but

absorption in blood relies on Na+/K+-ATPase.• Aldosterone receptors in tubular cells influence

Na+ reabsorption & K+ secretion.• Absorption of Na+ at this site occurs through a

specific amiloride sensitive Na+ channel & controlled by aldosterone.

• ADH promotes reabsorption of water from the collecting tubule mediated by cAMP.

Summary of sites of renal reabsorption of filtrate

Relative magnitude of Na+ reabsorption at different tubular sites is:PT- 65-70%, Asc LH- 20-25%, DT- 8-9%, CD- 1-2%.

• According to this, diuretics acting on proximal tubule should be most efficacious but it is not because they distort acid-base balance or they are too weak.

• Loop diuretics have substantial effect because of limited capacity for salt reabsorption in distal tubule and collecting duct. And that is why K+ sparing diuretics produce only mild saluretic activity.

• Loop > Thiazide > K+ sparing > Case inhibitors.

GFR is dependant on pumping action of heart, magnitude of renal blood flow and relative dimensions of afferent & efferent glomerular vessels.

RAS with distal tubular reabsorption:-• Angiotensin2 produced in kidney has direct effect on

intrarenal vascular beds as well as salt & water reabsorption.

• Sympathetic stimulation→ ↑es renin release→ Tubular transport.

→Directly enhance reabsorption of salt & water.• PGs→ modulates renal circulation & renin release.• PGE2→inhibits ADH & has direct effect on tubular

reabsorption.

Classification of DiureticsA. Weak Diuretics:-

i. Osmotic Diuretics: Electrolytes: Sodium Chloride, Potassium citrate, Potassium carbonate,

Potassium acetate, Potassium chloride.Nonelectrolytes: Mannitol, Isosorbide, Sucrose, Urea, Glycerol.

ii. Acidifying salts: Ammonium chloride, Arginine hydrochloride.

iii. Xanthine derivatives: Aminophylline, Theophyllineiv. Carbonic anhydrase inhibitors: Acetazolamide,

Dichlorphenamide, Ethozolamide, Methazolamide

B. Moderately potent Diuretics:-i. Thiazide Diuretics : Bendrofluazide, Clopamide,

Hydrochlorthiazide,Chlorthalidone,Chloroxolone, Indapamide, Polythiazide, Cyclopenthiazide.

C. Very Potent Diuretics:-ii. Loop Diuretics: Furosemide, Ethacrynic acid,

Torsemide,Bumetamide,Peretanide,Indacrinone.iii. Mercurials:Mersalyl,Mercaptomerin,Meralluride,

Chlormerodin, Mercurous chloride (Mersalyl).D. Potassium sparing Diuretics:-

Triamterene, Spironolactone, Amiloride.

Classification of Diuretics(According to the site of action)

Classification of Diuretics(According to the site of action)

DRUGS USED IN RENAL DISORDERS

Drugs that modify Drugs that modify salt excretion water excretion

PCT TAL DCT CCT Osmotic diuretics ADH ADH agonist antagonist

K+-sparing diuretics

Thiazides Loop

diuretics Carbonic anhydrase inhibitors

LOOP DIURETICS

Loop Diuretics (High ceiling diuretics)

• 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.

• 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:1. Oedema due to cardiac failure, hepatic disease,

nephrotic syndrome.2. Acute pulmonary edema & cerebral edema, pregnancy &

idiopathic edema.3. Acute chronic renal failure.4. Barbiturate poisoning, salicylate poisoning.Nondiuretic action of Loop Diuretics:5. As an antihypertensive.6. Idiopathic calcium urolithiasis.7. In Hypocalcaemia.8. Diabetes insipidus.5. Hyponatremic states due to water retention.

6. Glaucoma• Adverse effects:1. Hypokalemia, So used with potassium sparing

diuretics.2. Hyponatremia, dehydration & metabolic acidosis.3. Hyperglycemia, hyperuricemia.4. Weakness, fatigue, dizziness, cramps & myalgia.5. Prostatic hypertrophy, ototoxicity, cardiac arrest

after IV injection.6. Hepatic insufficiency, gastric upset.7. Orthostatic hypotension.

1) 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.

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 edema 40-80 mg IV.

→LASIX 40 mg tab., 20 mg/2ml inj., SALINEX 40 mg tab., FRUSENEX 40 mg, 100 mg tab.

2) 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.

→DIURETOR 10,20 mg tabs., DYTOR 10,20,100 mg tabs.

3) 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).

→BUMET 1mg tab., 0.25 mg/ml inj.

Axosemide, Tripamide, Piretanide are other diuretics belonging to the furosemide group.

Ethacrynic acid• An unsaturated ketone derivatives of

Phenoxyacetic acid, is a potent oral diuretic like furosemide.

• Chemically unrelated to diuretic drugs but same effects as of furosemide.

• 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 which are similar to those of furosemide.

Interactions1. Potentiate all other antihypertensives. This

interaction is intentionally employed in therapeutics.2. 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.3. Loop diuretics + aminoglycoside antibiotics – both

ototoxic and nephrotoxic → additive toxicity.4. Cotrimoxazole + loop diuretics- thrombocytopenia.

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

6. Probenecid + furosemide and thiazides-competitively inhibits tubular secretion of furosemide and thiazides,decreases their action by reducing the concentration in the tubular fluid, while diuretics diminish uricosuric action of probenecid.

7. Serum lithium level rises when diuretic therapy is instituted. This is due to enhanced reabsorption of Li+ (and Na+) in PT.

8. Furosemide and warfarin/ Clofibrates: Displacement of plasma protein binding of warfarin

Resistance to high ceiling diuretics1. Renal insufficiency .• Decreased access of diuretics to its site of action due to low

g.f.r and low proximal tubular secretion.2. Nephrotic syndrome.• Binding of diuretic to urinary protein, other

pharmacodynamic causes.3. Cirrhosis of liver.• Abnormal pharmacodynamic hyperaldosteronism; mechanism not clear.4. CHF.• lmpaired oral absorption due to intestinal congestion,

decreased renal blood flow and glomerular filtration, lncreased salt reabsorption in PT.

K+ SPARING DIURETICS

POTASSIUM SPARING DIURETICS• These are either aldosterone antagonist or directly

inhibit Na+ channels in DT and CD cells to indirectly conserve K+.

→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.

Recent advancements• CRE 10904 [2-(p-fluorophenoxy), 1-(o-hydroxyphenyl)-

ethane, the leading compound of a new family of loop diuretic and antihypertensive agents: 1-aryl, 2-aryloxy-ethanes] induced high-ceiling natriuretic action in dogs and rats, but was completely inactive in pigs.

• A series of sulphonylthioureas related to Torsemide, a high ceiling loop diuretic, were synthesized. The four most active compounds were examined for their dose-dependent diuresis. Three of them showed a potency, water and electrolyte excretion similar to Torsemide. The fourth molecule, a sulphonylthiourea (BM 20), exhibited relative potassium-sparing properties and a minimal diuretic dose of 0·001 mg kg−1, 200 times lower than Torsemide.

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• http//jpet.aspetjournals.org/content/255/2/415.short

• http//onlinelibrary.wiley.com/doi/10.1111/j.2042-7158.1993.tb07096.x/abstract