Diuretics

Professor Peter Carroll

Sydney Medical School
University of Sydney
Northern Clinical School
Royal North Shore Hospital

COMMONWEALTH OF AUSTRALIA
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 Learning Objectives
• Believe in yourself but seek the wise counsel of
others - always remember, however, that even
when no one else agrees with you it doesn’t mean
that you are wrong
• Discuss the mechanism of action of
- loop diuretics
- thiazide diuretics
- potassium sparing diuretics
• Give representative examples from each group,
discuss their major side effects and describe their
actions on potassium and sodium excretion
 Renal Function
• The kidneys filter the blood, excrete waste
products and help regulate fluid volume, pH
and electrolyte levels
• The functional unit of the kidney is the nephron
• The kidneys receive approximately 25% of the
cardiac output
• Around 150-180 litres of filtrate are produced
each day
• The vast majority of filtered water and
electrolytes are reabsorbed
 Nephron

www.vebidoo.de

https://www.studyblue.com/notes/note/n/bio-
236-study-guide-2013-14-little-/deck/10770612
 Reabsorption of Fluid and Solute in
the Kidney

Filtered/day Excreted/day % Reabsorbed

+
Na (mmol) 25 000 150 99+
+
K (mmol) 600 90 93+
−
Cl (mmol) 18 000 150 99+
−
HCO3 (mmol) 4900 0 100
H2O (litres) 180 ∼1.5 99+

Rang and Dale’s Pharmacology, Table 29.1 (modified), page 356, 8th Edition.
Lehne RA – Pharmacology for Nursing Care, 3rd Edition
 Terminology
• Diuresis is an increased production and
output of urine (increased volume and
excretion of urine)
• Natriuresis is the excretion of sodium in
the urine
• Diuretics are drugs which increase the
volume and output of urine - they cause
diuresis
 Diuretics
• Osmotic diuretics e.g. mannitol (administered
intravenously - hospital use)
• Carbonic anhydrase inhibitors e.g. acetazolamide
(very seldom used as diuretics - used in the
treatment of glaucoma, generally as eye drops)
• Loop diuretics e.g. frusemide
• Thiazide diuretics e.g. hydrochlorothiazide
• Potassium sparing diuretics e.g. spironolactone,
amiloride and triamterene
 Diuretics
• Diuretics increase the volume and output of
urine - diuresis
• The three major classes of diuretics used in
clinical practice are
- loop diuretics e.g. frusemide
- thiazide diuretics e.g. hydrochlorothiazide
- potassium sparing diuretics e.g.
spironolactone, amiloride and triamterene
Loop Diuretics, Thiazide Diuretics and
Potassium Sparing Diuretics
• Inhibit the reabsorption (reuptake) of
sodium at different sites in the renal
tubules (cause more sodium to be excreted
- natriuretic effect)
• Increase osmotic pressure in the renal
tubules and reduce the passive
reabsorption of water
• The amount of diuresis produced depends
primarily on the amount of sodium
reabsorption inhibited
Furosemide is the same as frusemide

Lehne RA – Pharmacology for Nursing Care, 3rd Edition

 Loop Diuretics
• Example is frusemide
• Inhibit the Na+/K+/2Cl-
cotransporter in the thick
ascending limb of the loop of
Henle by combining with its
Cl- binding site
• Inhibit the reabsorption of
sodium and chloride
• Name (loop diuretics) refers
to their geographic site of
action in the nephron Lehne RA , Pharmacology for Nursing Care,
WB Saunders Company
 Loop Diuretics
• Potent diuretics because
- 20 to 25% of Na+ is
reabsorbed in the thick
ascending limb of the loop
of Henle
- sites distal to the thick
ascending limb of the loop
of Henle do not have the
re-absorptive capacity to
compensate for the
Lehne RA , Pharmacology for Nursing Care,
increased Na+ load WB Saunders Company
 Loop Diuretics
• May produce electrolyte
disturbances e.g.
hypokalaemia and
hyponatraemia
• May increase blood uric acid
levels (hyperuricaemia) and
precipitate gout
• May increase blood glucose
levels (hyperglycaemia)
• May produce urinary
frequency and urgency Lehne RA , Pharmacology for Nursing Care,
WB Saunders Company
 Thiazide Diuretics
• Example is
hydrochlorothiazide
-
• Inhibit the +
Na /Cl
transporter in the early
distal convoluted
tubule by combining
with its Cl- binding site
• Inhibit the reabsorption
of sodium and chloride
Lehne RA , Pharmacology for Nursing Care,
WB Saunders Company
 Thiazide Diuretics
• Less potent
diuretics than the
loop diuretics
• Only 5-10% of Na+
is reabsorbed in the
early distal
convoluted tubule of
the nephron
Lehne RA , Pharmacology for Nursing Care,
WB Saunders Company
 Thiazide Diuretics
• May produce electrolyte
disturbances e.g.
hypokalaemia and
hyponatraemia
• May increase blood uric
acid levels (hyperuricaemia)
and precipitate gout
• May increase blood glucose
levels (hyperglycaemia)
• May produce urinary
frequency and urgency
Lehne RA , Pharmacology for Nursing Care,
WB Saunders Company
 Uric Acid
• Uric acid is the end product
of purine metabolism in
humans (e.g. DNA, RNA,
ATP and food)
• Humans cannot breakdown
uric acid, and it is excreted
unchanged
• Hyperuricaemia may lead to
gout
• Virtually all other mammals
have an enzyme called
urate oxidase (uricase)
which can break down uric Clinical Review, www.medicalobserver.com.au; Roddy E (2011). Journal

acid to allantoin of Foot and Ankle Research 2011, 4:13

www.inspiration seek.com
Purine Metabolism in Humans
Purines e.g. DNA, RNA, ATP, food

Hypoxanthine
Xanthine oxidase

Xanthine
Xanthine oxidase

Uric acid
Purine Metabolism in Most Mammals
Purines

Hypoxanthine
Xanthine oxidase
Xanthine
Xanthine oxidase
Uric acid
Uricase (not in humans)

Allantoin
 Uric Acid Excretion
• Around 30% of uric acid excretion is via
the gastrointestinal tract, and 70% is
via the kidney
• Renal excretion of uric acid consists of
- glomerular filtration

- tubular reabsorption

- tubular secretion
www.medscape.org
Loop and Thiazide Diuretics May Produce Hyperuricaemia
Competition
between loop and
thiazide diuretics
with uric acid for
the uric acid
transporters in the
proximal tubules
may result in a net
increase in urate
reabsorption
(decrease in uric
acid excretion)
Organic Anion Transporter 1 (OAT1)
Urate/Anion Transporter 1 (URAT1)

http://www.ebmconsult.com/articles/hydrochlorothiazide-hctz-hyperuricemia
Loop and Thiazide Diuretics May
Produce Hyperglycaemia
• Loop and thiazide diuretics may increase
blood glucose levels (hyperglycaemia)
• May precipitate diabetes
• Mechanism is not fully understood
- decreased insulin release (due to
hypokalaemia?)
- reduced insulin effect (insulin resistance)
Luna B & Feinglos CM 2001, JAMA 286(16) 1945-1948
Mandal AK & Hiebert LM (2012) Journal of Diabetes Research & Clinical Metabolism
Chatterjee R et al (2011) Expert Rev Endocrinol Metab. Sep; 6(5): 665–672.
Glucose uptake by
GLUT4 into skeletal
muscle and adipose
tissue

https://www.quora.com/How-do- http://www.austincc.edu/apreview/EmphasisIte
muscles-consume-glucose ms/Glucose_regulation.html
 Insulin Resistance
• Reduced signaling following insulin/receptor combination?
• Defect in GLUT4 translocation and activity?

Insulin Resistance

http://www.entwellbeing.com.au/polycystic-ovary-syndrome-pcos/ https://www.pinterest.fr/jeffreyhealth/insulin-resistance/
 Indapamide
• Is a thiazide like diuretic
• Inhibits the Na+/Cl-
transporter in the early distal
convoluted tubule
• May produce hypokalaemia
and hyponatraemia
• May produce hyperglycaemia
• May produce hyperuricaemia
and precipitate gout
• May produce urinary
frequency and urgency Lehne RA , Pharmacology for Nursing Care,
WB Saunders Company
 Spironolactone
• Potassium sparing
diuretic
• Competes with
aldosterone for
aldosterone receptors
(nuclear receptors) and
inhibits the stimulant
effects of aldosterone
on the Na+/K+ exchange
in the late distal
convoluted tubule Lehne RA , Pharmacology for Nursing Care,
WB Saunders Company
 Aldosterone
• Increases the reabsorption
of sodium and water Na+ H20
(returned to the body)

• Increases the excretion of

potassium (excreted out of K+
the body)
 Spironolactone
• Aldosterone increases
the reabsorption of
sodium and water, and Na+ H20 K+
increases the excretion of
potassium
• Spironolactone inhibits
the effects of aldosterone
leading to increased
excretion of sodium and
Na+ H20 K+
water, and decresed
excretion of potassium
 Spironolactone
• Increases sodium excretion
and reduces potassium
excretion
• May produce hyperkalaemia
• Weak diuretic as only 1-5%
of sodium is reabsorbed in
the late distal tubule
• Also has anti-androgenic
activity which may produce
gynaecomastia in males
Lehne RA , Pharmacology for Nursing Care,
WB Saunders Company
 Amiloride and Triamterene
• Potassium sparing diuretics
• Block Na+ channels in the
Na+/K+ exchange in the late
distal tubule
• Increase sodium excretion
and reduce potassium
excretion
• May produce hyperkalaemia
• Weak diuretics as only 1-5%
of sodium is reabsorbed in the
late distal tubule Lehne RA , Pharmacology for Nursing Care,
WB Saunders Company
Why Do Loop Diuretics e.g. Frusemide
Cause Hypokalaemia?
• Inhibition of the Na+/K+/2Cl-
cotransporter results in more
sodium reaching the Na+/K+
exchange in the late distal
tubule
• This results in more sodium
being reabsorbed by the
Na+/K+ exchange, and more
potassium being excreted
(may result in hypokalaemia)
Lehne RA , Pharmacology for Nursing Care,
WB Saunders Company
 Why Do Thiazide Diuretics and
Indapamide Cause Hypokalaemia?
• Inhibition of the Na+/Cl-
transporter in the early distal
convoluted tubule results in
more sodium reaching the
Na+/K+ exchange in the late
distal tubule
• This results in more sodium
being reabsorbed by the
Na+/K+ exchange, and more
potassium being excreted
(may result in hypokalaemia)
Lehne RA , Pharmacology for Nursing Care,
WB Saunders Company
 Effect of Diuretics on Sodium
Excretion
• Loop diuretics e.g. frusemide increase
sodium excretion
• Thiazide diuretics e.g. hydrochlorothiazide
and indapamide increase sodium excretion
• Potassium sparing diuretics e.g.
spironolactone, amiloride and triamterene
increase sodium excretion
• All may produce hyponatraemia
Effect of Diuretics on Potassium
Excretion
• Loop diuretics e.g. frusemide increase
potassium excretion - may produce
hypokalaemia
• Thiazide diuretics e.g. hydrochlorothiazide and
indapamide increase potassium excretion - may
produce hypokalaemia
• Potassium sparing diuretics e.g. spironolactone,
amiloride and triamterene decrease potassium
excretion - may produce hyperkalaemia
 Diuretic Combinations
• To reduce the potential for
hypokalaemia, therapies are
available which combine a
thiazide diuretic with
amiloride or triamterene
- hydrochlorothiazide and
amiloride
- hydrochlorothiazide and
triamterene
• These combinations are not
widely used
Lehne RA , Pharmacology for Nursing Care,
WB Saunders Company