2. Definition
• Diuretics are medications that increase the amount of urine
excreted.
• The majority of diuretic drugs inhibit renal ion transporters,
which reduces the reabsorption of Na+ at various locations
throughout the nephron.
• In order to keep the osmotic balance, water is passively
transported into the urine together with Na+ and other ions like
Cl- in higher than usual proportions.
• Diuretics thereby increase the amount of urine produced and
frequently alter its pH as well as the ionic content of both the
urine and the blood.
3.
4. How could urine output be increased?
• Increase GFR Vs Decrease Tubular reabsorption (the most
important clinically)
• If you increase the glomerular filtration increase tubular
reabsorption ( so you cannot use glomerular filtration).
Purpose of Diuretics use:
• To maintain urine volume (e.g.: renal failure)
• To mobilize edema fluid (e.g.: Heart failure, Liver failure,
nephrotic syndrome)
• To control high blood pressure.
5. • Diagrammatic representation of nephron showing the four sites of solute reabsorption. The thick ascending limb of loop
of Henle (TAL) is impermeable to water
• Glu.—Glucose; A.A.—Amino acid; Org. An.—Organic anions.
6. Major locations of ion and water exchange in the nephron, showing sites of
action of the diuretic drugs.
8. THIAZIDES DIURETICS
The thiazides are the most widely used diuretics. They are sulfonamide derivatives. All
thiazides affect the distal convoluted tubule, and all have equal maximum diuretic effects,
differing only in potency. Thiazides are sometimes called “low ceiling diuretics,” because
increasing the dose above normal therapeutic doses does not promote further diuretic
response.
Ex:
• Chlorothiazide DIURIL, SODIUM DIURIL
• Chlorthalidone THALITONE
• Hydrochlorothiazide (HCTZ) MICROZIDE
• Indapamide
• Metolazone ZAROXOLYN
9. Mechanism of Action
• Increased excretion of Na+ and Cl-
• Loss of K+: (Because thiazides increase Na+ in the filt ate arriving at the distal tubule, more K+ is also
exchanged for Na+, resulting in a continual loss of K+ from the body with prolonged use of these drugs.)
• Loss of Mg2+ : (Magnesium deficiency requiring supplementation can occur with chronic use of thiazide
diuretics, particularly in elderly patients. The mechanism for the magnesuria is not understood.)
• Decreased Urinary Calcium excretion
• Reduced peripheral vascular resistance: (An initial reduction in blood pressure results from a decrease
in blood volume and, therefore, a decrease in cardiac output. With continued therapy, volume recovery occurs.
However, there are continued antihypertensive effects, resulting from reduced peripheral vascular resistance
caused by relaxation of arteriolar smooth muscle. How these agents induce vasodilation is unknown.)
10. Pharmacokinetics
• Orally administered
• Poor absorption
• Onset of action in ~ 1 hour
• Wide range of t ½ amongst different
thiazides, longer than loop diuretics
• Free drug enters tubules by filtration
and by organic acid secretion
11. Therapeutic Uses
• Hypertension
• Heart failure
• Hypercalciuria: prevent excess Ca2+
excretion to form stones in ducts
• Osteoporosis
• Treatment of Li+ toxicity
• Diabetes insipidus
12. Side Effects/ Adverse Effects
• Potassium depletion: Hypokalemia is the most frequent problem with
the thiazide diuretics, and it can predispose patients who are taking
digoxin to ventricular arrhythmias. Thiazides decrease the intravascular
volume, resulting in activation of the renin–angiotensin–aldosterone
system. Low-sodium diets blunt the potassium depletion caused by
thiazide diuretics.
• Hyponatremia
• Hyperuricemia
• Volume depletion: This can cause orthostatic hypotension or light-
headedness.
• Hypercalcemia
• Hyperglycemia: Therapy with thiazides can lead to glucose
intolerance, possibly due to impaired release of insulin and tissue uptake
of glucose. New-onset diabetes has been reported more often with
thiazides than with other antihypertensive agents.
13. LOOP/ HIGH-CEILING DIURETICS
• (Inhibitors of Na+-K+-2Cl¯ Cotransport)
• The major site of action is the thick ascending limb of Loop of Henle
(TAL), therefore, called loop diuretics.
Ex:
• Bumetanide
• Ethacrynic acid EDECRIN
• Furosemide LASIX
• Torsemide DEMADEX
14. Mechanism of action
• Loop diuretics inhibit the cotransport of Na+/K+/2Cl− in the luminal membrane in the
ascending limb of the loop of Henle.
• Therefore, reabsorption of these ions is decreased.
• The loop diuretics may increase renal blood flow, possibly by enhancing prostaglandin
synthesis.
• NSAIDs inhibit renal prostaglandin synthesis and can reduce the diuretic action of loop
diuretics.
[Note: Unlike thiazides, loop diuretics increase the Ca2+ content of urine. In patients with
normal serum Ca2+ concentrations, hypocalcemia does not result, because Ca2+ is
reabsorbed in the distal convoluted tubule.]
15. Pharmacokinetics
• Orally administered
• Rapid absorption
• Rapid onset of action
• Bound to plasma proteins: displaced by warfarin and Clofibrate
• Duration of action is relatively brief (2 to 4 hours), allowing patients to predict the
window of diuresis.
• They are secreted into urine.
16. Therapeutic
uses
• The loop diuretics are the drugs of
choice for acute pulmonary edema &
Chronic peripheral edema caused from
heart failure or renal impairment.
• Chronic Renal failure or Nephrosis
• Hypertension
• Hypercalcemia
• Acute and chronic hyperkalemia
17. Adverse Effects
Ototoxicity: Reversible or permanent hearing loss may occur with loop diuretics,
particularly when used in conjunction with other ototoxic drugs (for example,
aminoglycoside antibiotics). Ethacrynic acid is the most likely to cause deafness.
Hyperuricemia: Furosemide and ethacrynic acid compete with uric acid for the
renal secretory systems, thus blocking its secretion and, in turn, causing or
exacerbating gouty attacks.
Acute hypovolemia: Loop diuretics can cause a severe and rapid reduction in
blood volume, with the possibility of hypotension, shock, and cardiac arrhythmias.
Potassium depletion: The heavy load of Na+ presented to the collecting tubule
results in increased exchange of tubular Na+ for K+, leading to the possibility of
hypokalemia. The loss of K+ from cells in exchange for H+ leads to hypokalemic
alkalosis. Use of potassium-sparing diuretics or supplementation with K+ can prevent
the development of hypokalemia.
Hypomagnesemia: Chronic use of loop diuretics combined with low dietary
intake of Mg2+ can lead to hypomagnesemia, particularly in the elderly. This can be
corrected by oral supplementation.
18. POTASSIUM-SPARING DIURETICS
• Potassium-sparing diuretics act in the collecting tubule to inhibit Na+
reabsorption and K+ excretion.
• These drugs should be avoided in patients with renal dysfunction because of
the increased risk of hyperkalemia. Within this class, there are drugs with
two distinct mechanisms of action: aldosterone antagonists and sodium
channel blockers.
Ex:
• Amiloride MIDAMOR
• Eplerenone INSPRA
• Spironolactone ALDACTONE
• Triamterene DYRENIUM
19. Mechanism of action
• Spironolactone is a synthetic steroid that
antagonizes aldosterone at intracellular
cytoplasmic receptor sites rendering the
spironolactone–receptor complex inactive.
• It prevents translocation of the receptor complex
into the nucleus of the target cell, ultimately
resulting in a failure to produce mediator proteins
that normally stimulate the Na+/K+-exchange sites
of the collecting tubule.
• Thus, a lack of mediator proteins prevents Na+
reabsorption and, therefore, K+ and H+ secretion.
Eplerenone is another aldosterone receptor
antagonist, which has actions comparable to those
of spironolactone, although it may have fewer
endocrine effects than spironolactone
20. Pharmacokinetics
• Both spironolactone and eplerenone are absorbed after oral administration and are
significantly bound to plasma proteins.
• Spironolactone is extensively metabolized and converted to several active
metabolites.
• The metabolites, along with the parent drug, are thought to be responsible for the
therapeutic effects.
• Spironolactone is a potent inhibitor of P-glycoprotein, and eplerenone is metabolized
by cytochrome P450 3A4.
22. Side effects/ Adverse effects
• Spironolactone can cause
Gastric upset.
Gynecomastia in male patients & Menstrual irregularities in female patients. Because
it chemically resembles some of the sex steroids.
Hyperkalemia,
Nausea
Lethargy
Mental confusion can occur.
Potassium-sparing diuretics should be used with caution with other medications that can
induce hyperkalemia, such as angiotensin-converting enzyme inhibitors and potassium
supplements.
23. CARBONIC ANHYDRASE INHIBITORS
• Acetazolamide and other carbonic anhydrase inhibitors are more often used for
their other pharmacologic actions than for their diuretic effect, because they are
much less efficacious than the thiazide or loop diuretics.
• Limited uses as diuretics
• Developed from sulfanilamide (caused metabolic acidosis and alkaline urine)
Ex:
• Acetazolamide DIAMOX
24. Mechanism of action
• Acetazolamide inhibits carbonic anhydrase located intracellularly (cytoplasm) and on the
apical membrane of the proximal tubular epithelium.
• The decreased ability to exchange Na+ for H+ in the presence of acetazolamide results in
a mild diuresis. Additionally, HCO3− is retained in the lumen, with marked elevation in
urinary pH . The loss of HCO3− causes a hyperchloremic metabolic acidosis and
decreased diuretic efficacy following several days of therapy. Changes in the composition
of urinary electrolytes induced by acetazolamide. Phosphate excretion is increased by an
unknown mechanism.
[Note: Carbonic anhydrase catalyzes the reaction of CO2 and H2O, leading to H2CO3,
which spontaneously ionizes to H+ and HCO3− (bicarbonate).]
25. Pharmacokinetics
• Acetazolamide is well absorbed orally and excreted unchanged in
urine.
• Action of a single dose lasts 8–12 hours.
• It is approximately 90% protein bound and eliminated renally by both
active tubular secretion and passive reabsorption.
26. Therapeutic use
• Glaucoma: as adjuvant to other ocular hypotensive
• To alkalinize urine: for urinary tract infection or to promote excretion
of certain acidic drugs.
• Epilepsy: as adjuvant in absence seizures when primary drugs are not
fully effective; but tolerance to antiepileptic action develops.
• Mountain sickness
• Periodic paralysis.
27. Adverse Effects
• Metabolic acidosis (mild)
• Potassium depletion
• Renal stone formation
• Drowsiness
• Paresthesia may occur.
• The drug should be avoided in patients with hepatic cirrhosis, because it could lead to a
decreased excretion of NH4
+.
28. OSMOTIC DIURETICS
• A number of straightforward, hydrophilic chemical compounds that pass through the
glomerulus, like mannitol and urea, cause some degree of diuresis.
• A decrease in reabsorption from filtered compounds will result in a rise in urine output.
These compounds raise the osmolarity of the tubular fluid and stop more water from being
absorbed, which causes osmotic diuresis.
• Only a tiny bit of extra salt might also be excreted.
• Osmotic diuretics are ineffective for treating diseases where Na+ retention develops because
they are used to promote water excretion rather than Na+ excretion.
Ex:
• Mannitol OSMITROL
• Urea
[Note: Mannitol is not absorbed when given orally and should be given intravenously.]
29. Mechanism of action
• Osmotic diuretics are not reabsorbed.
• Increase osmotic pressure specifically in the proximal tubule and loop of Henle.
• Prevents passive reabsorption of H2O
• Increase H2O and Na+ excretion.
30. Therapeutic use
• Mannitol: Drug of choice, Non-toxic, freely filtered, non re-absorbable and non-
metabolized.
• Administered prophylactically for acute renal failure secondary to trauma, CVS disease,
surgery or nephrotoxic drugs.
• Short-term treatment of acute glaucoma.
• Infused to lower intracranial pressure
• Urea, Glycerol and Isosorbide are less efficient can penetrate cell membranes.
31. Side Effects
• Increase extracellular fluid volume
• Cardiac failure
• Pulmonary edema
• Hypernatremia
• Headache
• Nausea
• Hyperkalaemia secondary to diabetes or impaired renal function
32.
33.
34. References
• W. Karen, F. Richard, Panavelil Thomas A. “Chapter 18: Diuretics, Lippincott Illustrated
reviews: Pharmacology, Sixth Edition”, published by wolters kluwer Page- 241-253.
• Katzung Bertram G., “Chapter 15: Diuretic Agents, Basic & Clinical Pharmacology, 14th
Edition,” Published by Mc Graw Hill education, Page: 254- 275.
• Hall John E., Chapter 31: “Diuretics, Kidney diseases, Guyton and Hall Textbook of Medical
Physiology, 12th Edition,” published by Saunders Elsevier, Page: 397-409.
• Tripathi KD, “Chapter 42: Diuretics, Essentials of Medical Pharmacology, 8th Edition,”
published by The health sciences publisher, Page: 625-638.
• Tripathi KD, “Chapter 8: Drugs acting on Kidney, Pharmacological Classification of drugs
with doses and preparations, 5th edition,” published by Jaypee brothers medical publishers ltd,
Page: 102-103.
