DIURETICS

Dr Sindwa Kanyimba

Lecturer, Pharmacology
DIURETICS

INTRODUCTION:
• The kidneys are responsible for urine production
• Urine is produced through filtration, reabsorption and
secretion
• The working units of the kidney are known as nephrons
• The nephrons secrete hydrogen ions, potassium ions, and
weak acids and bases to regulate acid-base balance of the
body
• Diuretics are drugs that increase excretion of sodium and
water from the body by an action on the kidney
• Diuretics accelerate the rate of urine formation
DIURETICS
LEARNING OBJECTIVES:
• To classify diuretic agents
• To describe the mechanisms of actions, clinical uses
and unwanted effects of the various diuretic agents
CLASSES OF DIURETICS

Diuretics are generally classified according to their mode of

action or site of action:
1. Carbonic anhydrase inhibitors (act on proximal convoluted
tubule)
2.Loop diuretics (act on loop of Henle)
3.Thiazide and thiazide-like diuretics (act on distal convoluted
tubule)
4.Potassium-sparing diuretics (act on collecting tubule and
duct): (1) competitive inhibitors of aldosterone e.g.
spironolactone (2) sodium channel blockers
5. Osmotic diuretics (act on entire tubule)
GENERAL PROPERTIES OF DIURETICS

• All diuretics (except osmotic diuretics) are organic

acids
• All diuretics (except osmotic diuretics) are secreted
by the proximal convoluted tubule secretory
mechanism
• Diuretics attain higher concentrations within the
tubule than blood
• Diuretics exert their effects from within tubule
ACTIONS OF DIURETICS

• Many diuretics act to block the re-absorption of

sodium from the tubule [except osmotic diuretics]
• Sodium is a solute and as such exerts an osmotic
effect which reduces the rate of water re-
absorption from the tubule
• Consequently if the rate of re-absorption of sodium
chloride is reduced the volume of urine produced
increases
ACTIONS OF DIURETICS …. CONT’D

• Except for K+-sparing diuretics, all diuretics not

only increase Na+ excretion, but also cause increase
K+ excretion
• Any diuretic which acts before the collecting tubule
will result in K+ loss
• Diuretics which block Na+ reabsorption at the
collecting tubule will prevent the Na+/K+ exchange
that occurs there. Hence, these diuretics will not
cause loss of K+.
DRUGS ACTING AT THE PROXIMAL
CONVOLUTED TUBULE (PCT)
At the PCT, there is:
• Reabsorption of Na+, Cl-, HCO3-, K+ and H2O
• Na+/H+ exchange – Na+ is absorbed while H+ is
excreted (Na+ is exchanged for H+ via carbonic
anhydrase)
• Carbonic anhydrase (CA) catalyzes the following
reaction: HCO3- + H+ ↔ H2O + CO2 in tubular
lumen (CA can catalyze reaction in either direction
depending on relative concentration of substrates)
DRUGS ACTING AT THE PROXIMAL
CONVOLUTED TUBULE …. CONT’D
• CO2 diffuses into the cell and CA catalyzes CO2 +
H2O → HCO3- + H+
• CA thus helps to make H+ ions available for
exchange with Na+ and HCO3- (H2O follows Na+) in
the proximal tubules
• Example of a diuretic acting at the PCT include
acetazolamide, dichlorphenamide and
methazolamide (carbonic anhydrase inhibitors)
CARBONIC ANHYDRASE (CA) INHIBITORS

• CA is involved in the reabsorption of HCO3-, Na+ and Cl- at

the PCT
• CA inhibitors reduce the reabsorption of HCO3- and Na+
• They are low efficacy diuretics because all the sites distal to
the proximal tubule will be able to compensate for the excess
Na+ they are receiving, and reabsorb it, so that in the end,
the amount of Na+ lost is minimal
• CA inhibitors block not only renal CA, but also CA in the
ciliary body in the eye (CA is required for production of
aqueous humor) and in the brain (inhibition of CA facilitates
GABA synthesis in the brain; GABA is an inhibitory
neurotransmitter)
CA INHIBITORS …. CONT’D

Uses
• Rarely used as diuretics
• Mainly used for treatment of glaucoma (reduces production
of aqueous humour)
• Other uses: (1) treatment of epilepsy (2) to increase
alkalinity of tubular urine so as to facilitate excretion of
cysteine in cystinuria
Adverse effects
Drowsiness, headache, GI distress, metabolic acidosis,
hyponatremia and hypokalemia
Contraindications
Contraindicated in hepatic cirrhosis
LOOP OF HENLE

• Na+ is reabsorbed in the ascending limb by a co-transport

system, the Na+/K+/2Cl- co-transport
• The absorptive process involves co-transport of Na+ and K+
and 2Cl-
• There is secondary reabsorption of Mg2+ and Ca2+ at the
loop of Henle
• The reabsorption of Na+ establishes an osmotic gradient
and water follows
• The most effective diuretics act here because there is not
much opportunity distal to the loop of Henle for
compensatory reabsorption of the excess Na+
LOOP DIURETICS

• The diuretics acting at the Loop of Henle are loop diuretics

• Examples include frusemide (most important), torsemide,
bumetanide and ethacrynic acid
• Act directly on the ascending limb of the loop of Henle to
inhibit chloride and sodium reabsorption
• Act by inhibiting the Na+/K+/2Cl- co-transporter in the thick
ascending limb of the loop of Henle
• They also interfere with the re-absorption of K+, Ca2+ and
Mg2+ in the loop
• Also induce renal synthesis of prostaglandins, which result
in the dilatation of blood vessels and reduced peripheral
vascular resistance
LOOP DIURETICS …. CONT’D

Effects of loop diuretics

• Diuresis and subsequent loss of water, and potassium
and sodium depletion
• Reduced pulmonary vascular resistance
• Reduced systemic vascular resistance
• Reduced central venous pressure
• Reduced left ventricular end-diastolic pressure
LOOP DIURETICS: CLINICAL USES

• Hypertension, in patients with impaired renal function and

in hypertensive crises
• Congestive heart failure (moderate to severe)
• Acute pulmonary edema
• Acute renal failure and chronic renal failure
• Nephrotic syndrome
• Hypercalcaemia
• Hyperkalemia
• Chemical intoxication (to increase urine flow and facilitate
excretion of the toxicant)
LOOP DIURETICS: CLINICAL USES ….
CONT’D
• Loop diuretics are the preferred diuretics in the treatment of
sodium and water retention where there is renal dysfunction
and in severe heart failure
• All loop diuretics are effective at low GFR
• They are useful in all forms of heart failure
• In patients with refractory heart failure, the action of loop
diuretics may be potentiated by intravenous administration,
and by the addition of other diuretics, i.e., thiazides,
metozalone, and the potassium-sparing diuretics
• Route of administration: oral and IV infusion
LOOP DIURETICS: ADVERSE EFFECTS

• Hypovolaemia
• Electrolyte imbalances: hypokalemia, metabolic alkalosis,
hypocalcemia, hypomagnesemia
• Central nervous system: ototoxicity, dizziness, headache,
tinnitus, blurred vision
• Other adverse effects: hyperglycaemia, hyperuricemia (the
drugs are secreted in proximal convoluted tubule so they
compete with secretion of uric acid), blood dyscrasias and
hypersensitivity reactions
DISTAL CONVOLUTED TUBULES (DCT)

• There is reabsorption of sodium and chloride

• Sodium and chloride are reabsorbed by a Na+/Cl- co-
transport
• The distal tubule is relatively impermeable to water
• Diuretics which act here are medium efficacy diuretics
• Thiazide diuretics and thiazide-like drugs act at the DCT –
inhibit the Na/Cl co-transport
• Examples of thiazides: chlorothiazide, hydrochlorothiazide,
bendroflumethiazide and cyclothiazide
• Examples of thiazide-like diuretics: chlorthalidone ,
indapamide and metolazone
THIAZIDE AND THIAZIDE-LIKE DIURETICS

• MOA: inhibit sodium transport in the distal convoluted tubule,

causing loss of sodium and water. They exert their diuretic
effect by inhibiting the Na+-Cl- co-transport in the early distal
convoluted tubules.
• They elicit a weaker diuretic response compared to the loop
diuretics
• Increase the loss of K+ and Mg2+, but reduce Ca2+ excretion by
increasing parathyroid hormone secretion (may cause
hypercalcemia)
• There is loss of action in renal failure (GFR < 25ml/min)
• Metolazone is effective even at low GFR and is synergistic with
loop diuretics; therefore used with loop diuretics in resistant
oedema
THIAZIDE AND THIAZIDE-LIKE DIURETICS:
CLINICAL USES
• Mild to moderate hypertension
• Mild heart failure
• Renal calculi (calcium stones)
• Chronic renal failure (as an adjunct to loop diuretic)
• Severe resistant oedema (metolazone in combination with
loop diuretic)
• Nephrogenic diabetes insipidus: they prevent the urine from
being diluted further in the distal convoluted tubules
(increase synthesis of aquaporins)
• Idiopathic hypercalciuria
THIAZIDE AND THIAZIDE-LIKE DIURETICS:
ADVERSE EFFECTS

• Hypokalaemia • Hyperglycemia (due to

• Hyponatremia both impaired pancreatic
release of insulin and
• Orthostatic hypotension diminished utilization of
• Hyperlipidemia glucose)
• Hyperuricemia • GI distress
• Metabolic alkalosis • Headache
• Hypercalcemia due to • Muscle spasms or cramps
↑parathyroid hormone
COLLECTING TUBULE & DUCT

• 2 – 5% of the sodium filtered at the glomerulus is reabsorbed

through sodium channels
• Na+ is re-absorbed without Cl-. This results in a net buildup
of negative charges in the tubule lumen. To balance out this
negative charge, K+ or H+ is secreted
• The amount of K+ or H+ secreted depends on volume flow,
anion present, availability of K+ and H+ and the potential
difference created by the Na+ re-absorption
• Water is reabsorbed through water channels (aquaporins)
• Drugs acting here are aldosterone antagonists (e.g.
spironolactone) and sodium channel blockers (triamterene
and amiloride)
COLLECTING TUBULE & DUCT …. CONT’D

Sodium and water reabsorption in this part of the tubule is

controlled physiologically by two hormones:
1. Aldosterone
2. Vasopressin (anti-diuretic hormone)
Vasopressin
Secreted from the posterior pituitary
Binds on vasopressin V2 receptors present in the collecting
tubule and duct, and increases the number of water channels
(aquaporins) through which water is reabsorbed
COLLECTING TUBULE & DUCT …. CONT’D

Aldosterone
A hormone secreted by the adrenal cortex
Increases sodium re-absorption and potassium excretion
Mechanism of action
• Stimulates the Na+/H+ exchanger
• Increases synthesis of a mediator protein that activates
sodium channels
• Increases the number of sodium pumps (Na+/K+ ATPase).
The Na+/K+ ATPase exchanges 3Na+ for 2K+. It takes up Na+
and secretes K+ into the lumen.
POTASSIUM SPARING DIURETICS

• Include sodium channel blockers (amiloride and

triamterene) and aldosterone antagonists
(spironolactone and eplerenone)
• They are low efficacy diuretics that exert their action
mainly on the collecting ducts (most of the Na + has
already been reabsorbed in the more proximal parts of
the nephron)
• Potassium sparing diuretics enhance diuretic effects of
loop and/or thiazide diuretics
ALDOSTERONE ANTAGONISTS

• Include spironolactone and eplerenone

• They are competitive antagonists to aldosterone:
compete with aldosterone for receptor sites in the
collecting tubules and ducts
• Eplerenone is more selective for aldosterone
receptors while spironolactone binds to other
nuclear receptors such as androgen receptors
ALDOSTERONE ANTAGONISTS: ACTIONS

• Interfere with Na+/K+ exchange in collecting

tubules and ducts
• Prevent K+ from being pumped into the tubule, thus
preventing its secretion
• The actions result in decreased Na+ re-absorption
thereby promoting Na+ and water loss
• Decreased Na+ re-absorption is balanced by K+ and
H+ retention
ALDOSTERONE ANTAGONISTS: CLINICAL
USES
1. To prevent hypokalemia induced by loop or thiazide
diuretics
2. Secondary hyperaldosteronism due to hepatic cirrhosis &
ascites
3. Primary hyperaldosteronism (Conn's syndrome)
4. Congestive heart failure
Generally given with loop or thiazide diuretics
Are slow acting (take 2-3 days to reach maximum diuretic
effect)
Spironolactone has been shown to improve survival in heart
failure when given as an adjunct to ACE inhibitor and loop
diuretic
ALDOSTERONE ANTAGONISTS: ADVERSE
EFFECTS
• Spironolactone & eplerenone: hyperkalemia,
hyperchloremic metabolic acidosis and arrhythmias
• Spironolactone: anti-androgenic effects (e.g.
gynecomastia and impotence) and menstrual
abnormalities in women
Contraindicated in renal insufficiency
Use with caution in hepatic disease
SODIUM CHANNEL BLOCKERS

• Include amiloride and triamterene

• Are Na+ channel blockers in the collecting tubule and
duct: block entry of Na+ into tubule cells across
luminal membrane
• Decrease availability of Na+ to Na+-K+-ATPase at basal
cell membrane
• Similar effect to aldosterone antagonists by reducing
Na+ absorption and H+/K+ secretion but the actions are
independent of aldosterone
• Produce effects in 2-4 hours of being administered
SODIUM CHANNEL BLOCKERS …. USES

Clinical uses
• Have mild diuretic effect
• Used in conjunction with potassium losing diuretics to
reduce the K+ loss they cause
Adverse effects
• Triamterene and amiloride: nausea and vomiting,
diarrhea, hyperkalemia, metabolic acidosis and
ventricular arrhythmias
• Triamterene causes kidney stones
• Both are contra-indicated in renal insufficiency
MANNITOL

• An osmotic diuretic
• Filtered by glomerulus but not reabsorbed by renal
tubules, creating an osmotic gradient which results in
water being drawn into the renal tubule causing a
diuresis
• Its diuretic effect is not related to inhibition of sodium
reabsorption
• Uses: (1) Acute renal failure (early, oliguric phase) (2)
Cerebral edema (3) Increase urine flow to help excrete
toxic substances (4) Reduce preoperative intraocular
or intracranial pressure
MANNITOL …. CONT’D

• Given as IV bolus doses

• Adverse effects: convulsions, thrombophlebitis,
pulmonary congestion nausea, dizziness, headache,
fever and chills, hypernatremia
• Contra-indications: edema from cardiac failure,
pulmonary edema and intracranial bleeding
CLINICAL USES OF DIURETICS
Uses of diuretics

Oedematous states Non-oedematous states

• Heart failure • Hypertension

• Kidney disease • Nephrolithiasis

• Liver cirrhosis • Hypercalcaemia

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Heart failure

• Diuretics relieve the symptoms of heart failure

• Thiazide diuretics are used in mild heart failure while loop
diuretics are used in moderate to severe heart failure
• Loop diuretics are the drug of choice for reducing the acute
pulmonary odema of congestive heart failure
• Loop diuretics have a rapid onset of action and therefore useful
in emergency situations
• Spironolactone is beneficial in heart failure (reduces mortality)
• In refractory oedema a loop diuretic is combined with
metolazone (± spironolactone)

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Kidney disease

• Diuretics are used in nephrotic syndrome and acute renal

failure (ARF)
• Diuretics are given in ARF to make management of fluid and
electrolyte balance easier
• Loop diuretics increase renal blood flow and are the diuretics
of choice in ARF
• Loop diuretics are more effective with less adverse effects
when given by continuous IV infusion in acute renal failure
than as intermittent bolus doses

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 Kidney disease …. cont’d

• Mannitol is used in the treatment of patients in the early, oliguric

phase of ARF (given as IV bolus). Should not be given when there
is anuria.
• In nephrotic syndrome, loop diuretic is combined with
spironolactone and/or metolazone
• Avoid potassium sparing diuretics and acetazolamide in renal
disease (exacerbates acidosis)
• Thiazide diuretics are generally ineffective when glomerular
filtration falls below 30ml/min and are contra-indicated in renal
failure (metolazone is effective even when GFR is below
30ml/min)
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Liver cirrhosis
• Liver disease is often associated with oedema and ascites
• Secondary hyperaldosteronism plays a role in the pathogenesis of
oedema in patients with cirrhosis
• Oedema due to liver cirrhosis is very responsive to aldosterone
antagonists
• Patients with liver cirrhosis are often resistant to loop diuretics because
of decreased secretion of the drugs into the renal tubular fluid and
because of high aldosterone levels
• An aldosterone antagonist should be combined with a loop diuretic (or
thiazide diuretic if creatinine clearance is > 50ml/min)
• Excessive use of loop diuretics in patients with liver cirrhosis can lead to
hepato-renal syndrome and hepatic encephalopathy
• Hypokalaemia induced by loop diuretics can precipitate hepatic
encephalopathy
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Hypertension

• Thiazide diuretics are first line treatment in the management

of mild to moderate hypertension
• In patients with adequate renal function (GRF > 30ml/min),
thiazide diuretics are more effective anti-hypertensive agents
than loop diuretics
• Loop diuretics are useful when there is associated renal
insufficiency or heart failure and in hypertensive crises
• Diuretics enhance the efficacy of other anti-hypertensive
drugs

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Nephrolithiasis
• About 2/3 of kidney stones contain calcium phosphate or calcium
oxalate
• Many patients with such kidney stones have impaired calcium re-
absorption in the proximal tubule and thus develop hypercalciuria
• Thiazide diuretics enhance calcium re-absorption in the distal
convoluted tubule and thus reduce the urinary calcium
concentration
Hypercalcaemia
• Loop diuretics are used in the treatment of hypercalcaemia because
they reduce calcium reabsorption and promote calcium diuresis
• Saline should be administered simultaneously with loop diuretics to
maintain effective calcium diuresis (calcium reabsorption in the PCT
is enhanced when there is reduced plasma volume which can occur
with loop diuretics)
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LEARNING OUTCOMES
Students must be able to comprehend:
• Classification of diuretic agents
• Mechanisms of actions, clinical uses and
unwanted effects of the various diuretic agents
 END
Thanks for listening