Pharmacology of diuretics

Dr.Datten Bangun MSc,SpFK

Dept. Farmakologi & Therapeutik

Fak.Kedokteran
UHN
 Objectives:
By the end of this lecture all students should be able to
know:
- Different classes of diuretics
Their site of action
Their mechanism of action
Their clinical uses
Their side effects
- How to solve the problem of diuretic-induced
hypokalemia
- Major drugs and chemicals that produce toxicity to
kidneys
 Definitions

Diuretic: substance that promotes the excretion of

urine

= caffeine, cranberry juice, alcohol

•Natriuretic: substance that promotes the renal

excretion of Na+
Good cartoons
► How could urine output be increased ?
↑ Glomerular filtration Vs ↓ Tubular reabsorption (the
most important clinically)
o If you increase the glomerular filtriation  increase tubular
reabsorption (so you cant use glomerular filtiration)

► Purpose of Using Diuretics

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.

Anatomy and Physiology of Renal system

► Remember the nephron is the most important

part of the kidney that regulates fluid and
electrolytes.

► Urine formation:
1. Glomerular filtration rate = 180L/day
2. Tubular re-absorption (around 98%)
3. Tubular secretion
►Percentage of reabsorption in each
segment:
– Proximal convoluted tubule 60-70%

– Thick portion of ascending limb of the loop of

Henle. 25%

– Distal convoluted tubule 5-10%

– Cortical collecting tubule 5% (Aldosterone and

ADH)
Sites of Action & % reabsorption

5-10%

60-70% 5%

25%
 Physiology of tubular reabsorption

The filtirate
here is
isotonic

The filtirate
here is
hypertonic
 Proximal Tubule

• Na+ flows down concentration gradient

• Na/K ATPase maintains gradient
• Water follows passively
• 67% of Na and water reabsorption
 Loop of Henle
• TDL permeable to water but not Na+
• TAL impermeable to water and
transports Na+
• Differences in permeabilities creates
the countercurrent multiplier
• Countercurrent multiplier creates
interstitial osmolar gradient
• 20% of filtered load of Na absorbed by
the TAL
Tal = thick ascending loop
t
Tdl =Thin descending loop
 Distal Convoluted Tubule

• 5% of filtered load of Na+ reabsorbed

• Segment mostly impermeable to
water
 Cortical Collecting Duct
• Water permeability controlled by
antidiuretic hormone (ADH)
• Driving force for water reabsorption is
created by the countercurrent multiplier
• 2-3% of filtered Na+ reabsorbed here via
Na+ channels that are regulated by
aldosterone
• Major site of K+ secretion
 Classes of Diuretics:

Definitions
• Diuretic: substance that promotes
the excretion of urine
• Natriuretic: substance that promotes
the renal excretion of sodium
 CLASSIFICATION

• High effect diuretics: Lasix

• Mediate effect: Thiazide diuretics
• Mild (Low)effect: K+ sparing diuretics
• Osmotic diuretics: Mannitol
• Others
 CLASSIFICATION
1.Osmotic diuretics
2. Carbonic anhydrase inhibitors

3. Thiazide diuretics

4. Loop diuretics

5. Potassium-sparing diuretics
 Increased K+ Excretion Due To:
• Increased urine flow per se
• Increased Na+-K+ exchange
• Increased aldosterone release

Na+/K+
exchange in the
cortical
collecting duct
 Osmotic Diuretics

do not interact with receptors or

directly block renal transport

activity dependent on
development of osmotic pressure

Mannitol (prototype)

Urea

Glycerol

Isosorbide
 Mechanism of Action
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

 Therapeutic Uses
Mannitol

drug of choice: non-toxic, freely filtered, non-reabsorbable

and non-metabolized

administered prophylatically 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

 Side Effects

increased extracellular fluid volume

cardiac failure

pulmonary edema

hypernatremia

hyperkalemia secondary to diabetes or impaired

renal function

headache, nausea, vomiting

 Carbonic Anhydrase Inhibitors

limited uses as diuretics

Acetazolamide

•prototype carbonic anhydrase

inhibitor

•developed from sulfanilamide (caused

metabolic acidosis and alkaline urine)
 Mechanism of Action
inhibits carbonic anhydrase in renal proximal tubule cells
carbonic anhydrase catalyzes formation of HCO3- and H+
from H2O and CO2 : CA
H2O + CO2 ------------------ HCO3- + H +
inhibition of carbonic anhydrase decreases [H+] in tubule
lumen

less H+ for for Na+/H+

exchange
increased lumen Na+, increased
H2O retention
 Therapeutic Uses
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
 Side Effects
rapid tolerance

increased HCO3- excretion causes metabolic acidosis

drowsiness

fatigue

CNS depression

paresthesia (pins and needles under skin)

nephrolithiasis (renal stones)

K+ wasting
 Thiazide Diuretics

active in distal convoluted tubule

Chlorothiazide (prototype)

Hydrochlorothiazide

Chlorthalidone

Metolazone
 Mechanism of Action
inhibit Na+ and Cl- transporter in distal convoluted tubules

increased Na+ and Cl- excretion

weak inhibitors of carbonic anhydrase, increased HCO3-

excretion

increased K+/Mg2+
excretion

decrease Ca2+ excretion

 Therapeutic Uses
hypertension

congestive heart failure

hypercalciuria: prevent excess Ca2+ excretion to form

stones in ducts

osteoperosis

nephrogenic diabetes insipidus

treatment of Li+ toxicity

 Pharmacokinetics
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
 Side Effects of Thiazides
hypokalemia
increased Na+ exchange in CCD
volume-contraction induced aldosterone release
hyponatremia
hyperglycemia
diminished insulin secretion
elevated plasma lipids
hyperuricemia
hypercalcemia
 Loop Diuretics
active in “loop” of Henle

Furosemide (prototype)

Bumetanide

Torsemide

Ethacrynic acid
 Mechanism of Action 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

enhances passive Mg2+ and

Ca2+ excretion
increased K+ and H+ excretion
in CCD
inhibits reabsorption of ~25%
of glomerular filtrate
 Loop diuretics
• They are the best diuretics for 2 reasons:
• 1- they act on thick ascending limb which
has large capacity of reabsorption.
• 2- action of these drugs is not limited by
acidosis
 Therapeutic Uses

edema: cardiac, pulmonary or renal

chronic renal failure or nephrosis

hypertension

hypercalcemia

acute and chronic hyperkalemia

 Pharmacokinetics
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)
 Side Effects of Loop diuretics
hypokalemia

hyperuricemia

metabolic alkalosis

hyponatremia

ototoxicity

Mg2+ depletion
 K+ sparing diuretics

three groups

steroid aldosterone antagonists:

=spironolactone, eplerenone

Pteridines

= triamterene

Pyrazinoylguanidines

= amiloride
 Mechanism of Action
K+ sparing diuretics function in CCD(cortical
collecting duct)
decrease Na+ transport in collecting tubule
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
 Therapeutic Uses

primary hyperaldosteronism (adrenal adenoma,

bilateral adrenal hyperplasia)

congestive heart failure

cirrhosis

nephrotic syndrome

in conjunction with K+ wasting diuretics

 Pharmacokinetics
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
 Side Effects
hyperkalemia: monitor plasma [K+]

spironolactone: gynecomastia

triamterene: megaloblastic anemia in

cirrhosis patients

amiloride: increase in blood urea nitrogen,

glucose intolerance in diabetes mellitus
Thank you for your attention