1. LOOP DIURETICS
&
POTASSIUM SPARING DIURETICS
Presented By-
Krushangi Shah.
Nirma University.

2. Contents
• Urine formation
• Classification of diuretics
• Several targets for diuretic action
• Loop diuretics
Drugs
Interactions
Resistance to loop Diuretics
• Potassium sparing diuretics
Drugs
Interactions
• Recent advancements

3. Normal Physiology of kidney
(Urine formation)

4. • 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.

5. 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.

6. 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.

8. 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.

9. • 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.

11. 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.

13. 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.

15. Summary of sites of renal reabsorption of
filtrate

16.  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.

17. 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.

18. Classification of Diuretics
A. 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, Theophylline
iv. Carbonic anhydrase inhibitors:
Acetazolamide, Dichlorphenamide, Ethozolamide,
Methazolamide

19. B. Moderately potent Diuretics:-
i. Thiazide Diuretics : Bendrofluazide, Clopamide,
Hydrochlorthiazide,Chlorthalidone,Chloroxolone,
Indapamide, Polythiazide, Cyclopenthiazide.
C. Very Potent Diuretics:-
i. Loop Diuretics: Furosemide, Ethacrynic acid,
Torsemide,Bumetamide,Peretanide,Indacrinone.
ii. Mercurials:Mersalyl,Mercaptomerin,Meralluride,
Chlormerodin, Mercurous chloride (Mersalyl).
D. Potassium sparing Diuretics:-
Triamterene, Spironolactone, Amiloride.

20. 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

23. LOOP DIURETICS

24. 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.

25. • 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:
1. As an antihypertensive.
2. Idiopathic calcium urolithiasis.
3. In Hypocalcaemia.
4. Diabetes insipidus.
5. Hyponatremic states due to water retention.

26. 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.

28. 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.

29. 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.

30. 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.

31. 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.

32. 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.

33. 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.

34. Interactions
1. 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.

35. 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

36. Resistance to high ceiling diuretics
1. 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.

37. K+ SPARING DIURETICS

38. 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.

39. →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.

40. 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).

42. 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.

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