Diuretics

Diuretics
BY
SOMNATH SURAI
CHINA PHARMACEUTICAL UNIVERSITY

1. Sites of drug action
2. Osmotic diuretics
3. Carbonic anhydrase inhibitors
4. Thiazide diuretics
5. Loop diuretics
6. Potassium-sparing diuretics
Outline

Diuretic: substance that promotes the excretion of
urine
• caffeine, nettles, cranberry juice, alcohol
• Natriuretic: substance that promotes the renal
excretion of Na+
Definitions

1. To maintain urine volume ( e.g.: renal failure)
2. To mobilize edema fluid (e.g.: heart failure,liver
failure, nephrotic syndrome)
3. To control high blood pressure.
Purpose of Using Diuretics

renal epithelial transport
tubular reabsorption
proximal tubule
loop of Henle
thick ascending limb
distal convoluted tubule
collecting tubule
• tubular secretion
• collecting tubules
Renal Physiology

► The best way to classify diuretics is to look for their Site of
action in the nephron
A) Diuretics that inhibit transport in the Proximal
Convoluted Tubule ( Osmotic diuretics, Carbonic
Anhydrase Inhibitors)
B) Diuretics that inhibit transport in the Medullary
Ascending Limb of the Loop of Henle( Loop diuretics)
C) Diuretics that inhibit transport in the Distal Convoluted
Tubule( Thiazides : Indapamide , Metolazone)
D) Diuretics that inhibit transport in the Cortical Collecting
Tubule (Potassium sparing diuretics)
Classification of Diuretics

 do not interact with receptors
or directly block renal transport
 activity dependent on
development of osmotic
pressure
 Mannitol (prototype)
 Urea
 Glycerol
 Isosorbide
Osmotic Diuretics

 osmotic diuretics are not reabsorbed
 increases osmotic pressure specifically in the proximal tubule and loop of
Henle
 prevents passive reabsorption of H2O
 osmotic force solute in lumen > osmotic force of reabsorbed Na+
 increased H2O and Na+ excretion
Mechanism of Action

Mannitol
o drug of choice: non-toxic, freely filtered, non-reabsorbable and non-
metabolized
o administered prophylatically for acute renal failure secondary to
trauma, CVS disease, surgery or nephrotoxic drugs
o short-term treatment of acute glaucoma
o infused to lower intracranial pressure
o Urea, glycerol and isosorbide are less efficient
o can penetrate cell membranes
Therapeutic Uses

 increased extracellular fluid volume
 cardiac failure
 pulmonary edema
 hypernatremia
 hyperkalemia secondary to diabetes or impaired renal function
 headache, nausea, vomiting
Side Effects

limited uses as diuretics
 Acetazolamide
• prototype carbonic anhydrase
inhibitor
• developed from sulfanilamide
(caused metabolic acidosis and
alkaline urine)
Carbonic Anhydrase Inhibitors

 inhibits carbonic anhydrase in renal
proximal tubule cells
 carbonic anhydrase catalyzes
formation of HCO3- and H+ from H2O
and CO2
 inhibition of carbonic anhydrase
decreases [H+] in tubule lumen
Mechanism of Action
less H+ for for Na+/H+ exchange
increased lumen Na+, increased H2O
retention

 used to treat chronic open-angle glaucoma
 aqueous humor has high [HCO3-]
 acute mountain sickness
 prevention and treatment
 metabolic alkalosis
 sometimes epilepsy
 mostly used in combination with other diuretics in resistant
patients
Therapeutic Uses

 rapid tolerance
 Hypersensitivity reaction (because it contains sulfur)
 drowsiness
 fatigue
 nephrolithiasis (renal stones)
 Acidosis (because of decreased absorption of HCO3 )
Side Effects

active in distal convoluted tubule
Chlorothiazide (prototype)
Hydrochlorothiazide
Chlorthalidone
Metolazone
Thiazide Diuretics

 inhibit Na+ and Cl- transporter in distal convoluted tubules
 increased Na+ and Cl- excretion
 weak inhibitors of carbonic anhydrase, increased HCO3- excretion
Mechanism of Action
increased K+/Mg2+ excretion
decrease Ca2+ excretion

 hypertension
 congestive heart failure
 hypercalciuria: prevent excess Ca2+ excretion to form stones in
ducts
 osteoperosis
 nephrogenic diabetes insipidus
 treatment of Li+ toxicity
Therapeutic Uses

 orally administered
 poor absorption
 onset of action in ~ 1 hour
 wide range of T 1/2 amongst different thiazides, longer then loop
diuretics
 free drug enters tubules by filtration and by organic acid secretion
Pharmacokinetics

o hypokalemia
o increased Na+ exchange in CCD
o volume-contraction induced aldosterone release
o hyperglycemia
o diminished insulin secretion
o elevated plasma lipids
o hypercalcemia
Side Effects

active in “loop” of
Henle
 Furosemide
(prototype)
 Bumetanide
 Ethacrynic acid
Loop Diuretics

 enter proximal tubule via organic acid transporter
 inhibits apical Na-K-2Cl transporter in thick ascending loop of
henle
 competes with Cl- binding site
Mechanism of Action
enhances passive Mg2+ and Ca2+
excretion
increased K+ and H+ excretion in CCD
inhibits reabsorption of ~25% of
glomerular filtrate

 edema: cardiac, pulmonary or renal
 chronic renal failure or nephrosis
 hypertension
 hypercalcemia
 acute and chronic hyperkalemia
Therapeutic Uses

 orally administered, rapid absorption
 rapid onset of action
 bound to plasma proteins: displaced by warfarin, and clofibrate
 increase toxicity of cephalosporin antibiotics and lithium
 additive toxicity with other ototoxic drugs
 inhibitors of organic acid ion transport decrease potency (i.e.
probenecid, NSAID’s)
Pharmacokinetics

 hypokalemia
 hyperuricemia
 metabolic alkalosis
 hyponatremia
 ototoxicity
 Mg2+ depletion
Side Effects

three groups
steroid aldosterone antagonists
 spironolactone, eplerenone
 Pteridines
 triamterene
 Pyrazinoylguanidines
 amiloride
K+ sparing diuretics

K+ sparing diuretics function in CCD
decrease Na+ transport in collecting tubule
Mechanism of Action
Spironolactone
competitive antagonist for mineralocorticoid receptor
prevents aldosterone stimulated increases in Na+ transporter expression
Triamterene/Amiloride
organic bases
secreted into lumen by proximal tubule
cells
inhibit apical Na+ channel

 primary hyperaldosteronism (adrenal adenoma, bilateral
adrenal hyperplasia)
 congestive heart failure
 cirrhosis
 nephrotic syndrome
 in conjunction with K+ wasting diuretics
Therapeutic Uses

 Spironolactone
orally administered
aldactazide: spironolactone/thiazide combo
 Amiloride
• oral administration, 50% effective
• not metabolized
• not bound to plasma proteins
 Triamterine
• oral administration, 50% effective
• 60% bound to plasma proteins
• liver metabolism, active metabolites
Pharmacokinetics

 hyperkalemia: monitor plasma [K+]
 spironolactone: gynecomastia
 triamterene: megaloblastic anemia in cirrhosis patients
 amiloride: increase in blood urea nitrogen, glucose
intolerance in diabetes mellitus
Side Effects

Diuretics

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