8. Loop diuretics
• Loop diuretics inhibit Na/K/2Cl– co
transporter across the lining cells of the
ascending limb of the loop of Henle .
• Drugs
Furosemide
Bumetanide
Torsemide
9. Pharmacokinetics
• Rapidly absorbed.
• Eliminated by tubular secretion as well as by
glomerular filtration.
• Absorption of oral torsemide is more rapid (1
hour) than that of furosemide(2–3 hours) and
is nearly as complete as with intravenous
administration.
• Diuretic response is extremely rapid
following intravenous injection.
10. Furosemide
• Potent, oral, diuretic, possessing halogenated
salfamoyl benzene ring common to Thiazide diuretics.
• act on 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.
11. 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.
12. 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.
13. 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.
14. 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).
15. THERAPEUTIC EFFECTS
Increase Na Excretion
to 25% of Filtered Load
Treatment for
Oliguric ARF
Increase Ca Excretion
Treatment for
Hypercalcemia
Increase Venous
Capacitance
Treatment for
Pulmonary
Edema
Increase Urine Volume
Treatment for
Severe Edema
17. 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 .
• Loop diuretics + aminoglycoside antibiotics – both
ototoxic and nephrotoxic → additive toxicity.
• Cotrimoxazole + loop diuretics- thrombocytopenia
18. • Indomethacin/ NSAIDs + Loop diuretics-diminishes
diuretic and antihypertensive
effect of loop diuretics.
• Furosemide and warfarin/ Clofibrates:
Displacement of plasma protein binding of
warfarin
19. Resistance to loop diuretics
• Renal insufficiency .
Decreased access of diuretics to its site of action due to low g.f.r and
low proximal tubular secretion.
• Nephrotic syndrome.
Binding of diuretic to urinary protein, other pharmacodynamic causes.
• Cirrhosis of liver.
Abnormal pharmacodynamic hyperaldosteronism ; mechanism not
clear.
• CHF.
lmpaired oral absorption due to intestinal congestion, decreased renal
blood flow and glomerular filtration, lncreased salt reabsorption in PT.
20. Thiazide diuretics
• They inhibit Na-Cl symport inhibitors.
• Inhibit NaCl reabsorption from the luminal side of
epithelial cells in the distal convoluted tubule by
blocking the Na+/Cl- transporter.
Drugs:
• Benzthiazide
• Chlorthiazide
• Hydrochlorothiazide
• Polythiazide
• Trichlormethiazide
21. THERAPEUTIC EFFECTS
Increase Na Excretion
to 5% of Filtered Load
Treatment for
Hypertension
Decrease Ca Excretion
Treatment for
Nephrogenic
Insipidus
Treatment for
Calcium stones
in the kindey
Treatment for
Mild Edema
23. Potassium sparing diuretics
• These are either aldosterone antagonist or
directly inhibit Na+ channels in DT and CD
cells to indirectly conserve K+.
• Drugs
Spironolactone
Eplerenone
Triamterene
Amiloride
24. 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.
25. 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
26. 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).
27. 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.
29. • Recommendation(7.23)
Diuretic therapy is recommended to restore and
maintain normal volume status in patients with clinical
evidence of fluid overload, generally manifested by
congestive symptoms (orthopnea, edema, and
shortness of breath), or signs of elevated filling
pressures (jugular venous distention, peripheral edema,
pulsatile hepatomegaly, and, less commonly, rales).
(Strength of Evidence = A) Loop diuretics rather than
thiazide-type diuretics are typically necessary to restore
normal volume status in patients with HF. (Strength of
Evidence = B)
30. • Recommendation(7.24)
• The initial dose of diuretic may be increased as necessary to relieve
congestion. Restoration of normal volume status may require multiple
adjustments over many days and occasionally weeks in patients with
severe fluid overload evidenced by massive edema or ascites. After a
diuretic effect is achieved with short-acting loop diuretics, increasing
administration frequency to twice or even 3 times per day will provide
more diuresis with less physiologic perturbation than larger single doses.
(Strength of Evidence = B)
• Oral torsemide may be considered in patients in whom poor absorption
of oral medication or erratic diuretic effect may be present, particularly
those with right-sided HF and refractory fluid retention despite high
doses of other loop diuretics. (Strength of Evidence = C)
• Intravenous administration of diuretics may be necessary to relieve
congestion. (Strength of Evidence = A)
• Diuretic refractoriness may represent patient nonadherence, a direct
effect of diuretic use on the kidney, or progression of underlying cardiac
dysfunction.
31. Recommendation(7.25)
• Addition of chlorothiazides or metolazone, once or twice daily, to
loop diuretics should be considered in patients with persistent
fluid retention despite high-dose loop diuretic therapy. But
chronic daily use, especially of metolazone, should be avoided if
possible because of the potential for electrolyte shifts and volume
depletion. These drugs may be used periodically (every other day
or weekly) to optimize fluid management.
• Metolazone will generally be more potent and much longer-acting
in this setting and in patients with chronic renal insufficiency, so
administration should be adjusted accordingly. Volume status and
electrolytes must be monitored closely when multiple diuretics
are used. (Strength of Evidence = C)
32. Recommendation(7.26)
• Careful observation for the development of side
effects, including electrolyte abnormalities,
symptomatic hypotension, renal dysfunction, or
worsening renal function, is recommended in
patients treated with diuretics, especially when
used at high doses and in combination. Patients
should undergo routine laboratory studies and
clinical examination as dictated by their clinical
response. (Strength of Evidence = B)
33. Recommendation(7.27)
• Patients requiring diuretic therapy to treat fluid
retention associated with HF generally require chronic
treatment, although often at lower doses than those
required initially to achieve diuresis. Decreasing or
even discontinuing diuretics may be considered in
patients experiencing significant improvement in
clinical status and cardiac function or in those who
successfully restrict dietary sodium intake. These
patients may undergo cautious weaning of diuretic
dose and frequency with careful observation for
recurrent fluid retention. (Strength of Evidence = C)
