DIURETICS

REAGAN KABUKA
(B.PHARM, MPH, MSc Pharmacology PG2)
INTRODUCTION
• Diuretics are drugs that cause a net loss of sodium and
water from the body resulting in contraction of the
extracellular fluid.
• They include:
- Loop diuretics:
- Thiazide diuretics
- Potassium sparing diuretics
- Osmotic Diuretics
- Carbonic anhydrase inhibitors
 GENERAL PRINCIPLES
• Diuretics act by different mechanisms and at different sites along the
nephron
• Osmotic diuretics reach their site of action by glomerular filtration
while others diuretics are renal secreted to reach the nephron
• Diuretics have to reach their sites of action in order to exert
pharmacological action
• Diuretics acting at different sites or by different mechanisms of action
have a synergistic effect if they are combined together
• Diuretics act only if sodium reaches their site of action. Thus, more
distally acting diuretics lose their effectiveness if proximal sodium
reabsorption is increased e.g. edematous states due to renal
hypotension
• Therefore, any impairment of delivery of diuretics to their site of
action will result in diminished diuretic response (e.g. in renal
impairment)
Mechanisms of action
LOOP DIURETICS
• The most effective diuretics available

• Referred to as high ceiling diuretics

• Examples are Frusemide, Bumetanide, Torsemide, Ethacrynic

acid.
MECHANISM OF ACTION
1) Act on the thick ascending loop of Henle blocking the 2Cl-Na-K
reabsorption pump resulting in:
✓Excretion of 20% of filtered Na+
✓ Interference with medullary hypertonicity causing failure of water
conservation by medulla causing excretion of free water in excess of
Na+.
✓Also inhibits reabsorption of Mg and Calcium
2) They release prostaglandins (PGs) that increase glomerular filtration
and intensify their action at the loop of Henle by inhibiting Na+
reabsorption
✓Indomethacin inhibits PGs synthesis and therefore interferes with
action of Loop diuretics).
PHARMACOLOGICAL EFFECTS

• ↑ urinary excretion of Na+ and K+

• ↑ urine volume
• ↑ urinary excretion Ca++ and Mg ++
• ↑ renal blood flow
• ↑ renal H+ and K+ Excretion in distal tubule in exchange for
Na+ due to aldosterone effect
PHARMACOKINETICS OF LOOP DIURETICS
• Given orally or I. V

• Have fast onset of action (suitable for emergency)

• Have short duration of action

• Excreted by active tubular secretion of weak acids into urine

• Interfere with uric acid secretion (hyperuricemia)

INDICATIONS
1. Hypertension, congestive heart failure
2. Oedema associated with CCF, nephrotic syndrome, and Hepatic disease
3. Acute renal failure: -They decrease energy requirement and preserve
cellular integrity by blocking active Na+ transport and increase GFR by
increasing renal Prostaglandins
4. Treatment of hypercalcemia: - They interfere with Ca++ reabsorption in
the loop of Henle increasing Ca++ excretion
5. Treatment of hyperkalemia: - Loop diuretics inhibit reabsorption of K+ in
the loop of Henle and enhance K+ excretion in distal tubule in exchange
with Na+.
6. Treatment of acidosis: - Loop diuretics increase H+ excretion in exchange
of Na+ at the distal tubule hence correcting the acidosis
SIDE EFFECTS
1. Hypovolemia, Hypotension, Collapse due to intensive diuresis within a short time
2. Hypokalemia, Hypomagnesemia and Alkalosis: - Increased delivery of Na+ to the
distal tubules stimulates the excretion of K+ and H+ in exchange for Na+ under the
effect of Aldosterone. Spironolactone, the Aldosterone antagonist prevents these
effects
3. Hypocalcemia due to interference with Ca++ reabsorption in the loop of Henle
4. Ototoxicity especially with aminoglycosides
5. Interstitial nephritis with cephalosporins
6. Hypersensitivity reactions as skin rash
7. Myalgia with Bumetanide
8. Severe G.I.T upsets with Ethacrynic acid
9. Hyperglycemia- Disrupts potassium levels, impacting insulin release and reducing
glucose uptake in cells
10. Hyperuricemia- inhibits voltage driven drug efflux transporter NPT4 in proximal
tubules
THIAZIDE DIURETICS
• They have moderately powerful diuretic effect.
• Mechanism of action
- Inhibit active NaCl reabsorption in early distal tubule causing
excretion of 5-10% of filtered Na+
- Inhibit carbonic anhydrase enzyme at high doses
• Examples; Chlorothiazides, Hydrochlorothiazide,
Chlorthalidone, and Indapamide
PHARMACOLOGICAL EFFECTS
• Increased urinary Na-CL excretion
• Increased urinary K excretion (Hypokalemia)
• Increased urinary magnesium excretion
• Increased re-absorption of calcium (hypercalcemia)
PHARMACOKINETICS
• Given orally, slow of onset
• long duration of action
• are secreted by active tubular secretory system of the
kidney
• may interfere with uric acid secretion and cause
hyperuricemia
INDICATIONS
1. Treatment of Hypertension:- Antihypertensive effect due to its
diuretic action decreasing blood volume
2. Mild edema especially of heart failure. They are non-effective in
renal insufficiency due to low excretion of Na+
3. Hypercalcuria (Calcium in urine) and calcium stones. The
decreased glomerular filtration induced by chronic use of Thiazides
increases Ca++ reabsorption at the proximal tubules resulting in
decreased Ca++ excretion
4. Nephrogenic diabetes insipidus: - Chronic Thiazide therapy
paradoxically decreases urine output in nephrogenic diabetes
insipidus by decreasing glomerular filtration;
Thiazides inhibit NaCl reabsorption, thus, they increase NaCl at macula
densa which interferes with tubulo-glomerular balance leading to
decreased glomerular filtration and urine volume
SIDE EFFECTS
• Hypokalemia and Metabolic acidosis; Due to enhancement of K+ and
H+ excretion in exchange with Na+ at more distal nephron sites
• Glucose intolerance: Thiazides induce hypokalemia with increased
cellular outflux of K+ and causes membrane hyperpolarization. This
inhibits Ca++ influx and insulin release
• Dyslipidemia and increases risk of coronary atherosclerosis
• Hyperuricemia - interfere with uric acid excretion
• Hypersensitivity reactions
• Pancreatitis
• Impotence
• Hepatic encephalopathy in patients with liver impairment
POTASSIUM SPARING DIURETICS
• They are weak diuretics as they excrete only 5% of filtered Na+
• Mechanism: - Inhibit Na/K/H exchange at the distal tubule by two different
mechanisms;
a) Spironolactone and eplerenone antagonizes Aldosterone receptor-
binding, reducing the synthesis of a specific protein that stimulates the
Na+ pump (This mechanisms of action explains the delayed onset of
action of Spironolactone- 3-4 days)
b) Triamterene and Amiloride act independent of Aldosterone to block Na+
channels directly
INDICATIONS
1. Oedema of Hyperaldosteronism: -(liver cirrhosis, nephrotic syndrome,
C.H.F)
· This oedema is usually resistant to other diuretics because the Na+ lost by
these diuretics is reabsorbed again by the excess Aldosterone at the distal
tubule
· Spironolactone is also safer, in liver cirrhosis, than other diuretics which
cause alkalosis with increased risk of hepatic encephalopathy
2. Hypokalemia and Hypomagnesaemia
· The direct acting drugs; Triamterene and Amiloride, are preferable to
Spironolactone due to their short action making daily dose adjustment
possible
· These agents are more effective in maintaining K+ and Mg++
concentrations than the exogenous supplement of these ions
SIDE EFFECTS
1) Hyperkalemia and metabolic acidosis: - patients with renal
insufficiency or diabetes mellitus more susceptible
2) Gynecomastia: - due to the anti-androgen effect of Spironolactone
OSMOTIC DIURETICS
• Mechanism: - Mannitol, isosorbide, Glycerol- freely filtered
at the glomerulus with limited reabsorption by the renal tubules
resulting in:
1) Increase in osmotic pressure of tubular filtrate with
retention of water and increased urine volume
2) The high osmotic pressure of the tubular filtrate that opposes
plasma osmotic pressure inhibiting sodium reabsorption
throughout the nephron
INDICATIONS
1) Rapid reduction of intracranial tension in cerebral oedema caused
by head injury or brain surgery
2) Rapid reduction of intraocular tension in acute congestive glaucoma
3) Prophylaxis in acute renal failure following surgery or trauma
4) Prevents concentration of toxic agents which
cause renal damage by maintaining high rate of urine flow

ADVERSE EFFECTS
- Heart failure
- Dilutional hyponatremia (Water intoxication)
CARBONIC ANHYDRASE INHIBITORS
MECHANISM OF ACTION
- Inhibits Carbonic anhydrase enzyme responsible for H+ production
- This results in inhibition of the Na/H+ exchange at the proximal
tubules leading to decreased Na+ reabsorption
- with subsequent inhibition of NaHCO3 reabsorption. Loss of NaHCO3
in urine leads to:
a) Diuresis with alkaline urine
b) Decreased blood bicarbonate with metabolic acidosis
• They are weak diuretics because much of the sodium lost by these
diuretics is reabsorbed at more distal nephron sites
• Examples Dorzolamide, Methazolamide and acetazolamide
Pharmacological actions of CAI
• ↑ Mild increase in urine volume
• ↑ urinary excretion of sodium, potassium , bicarbonate (alkaline
urine)
• Metabolic acidosis
• ↑ Urinary phosphate excretion
• Promotes K+ excretion by ↑the load of Na+ delivered to the distal
tubules.
Acetazolamide
• Dose- 250mg three times daily
Indications
a) Oedema refractory to Loop diuretics: Acetazolamide with Loop diuretics
b) Alkalosis associated with emphysema and high-altitude sickness (by
inducing metabolic acidosis)
c) Epilepsy: suppress the irritable focus directly and by (↓PH)
d) Treatment of glaucoma by decreasing formation of aqueous humor (↓IOP)
e) Urinary alkalinisation to enhance renal excretion of acidic substances (uric
acid, methotrexate and cysteine)
Adverse reactions
• Drowsiness and disorientation due to metabolic acidosis
• Renal (Calcium and Phosphate) stones due to alkaline urine
• Hypersensitivity reactions as they are sulfonamide derivatives
Diuretic Site of action
Diuretics transporter Function segment

Carbonic anhydrase Na/H transporter, Re-absorption of 66% Proximal convoluted

inhibitors 2 Carbonic anhydrase Na, K, Ca, Mg, 100% tubules
enzyme glucose and amino
acids; 65% NaHCO3
Osmotic 6

Loop diuretics 10-15 Na/K/2Cl transporter Active reabsorption Thick ascending loop
25% Na, K, Cl
Secondary
reabsorptionCa, Mg
Thiazide diuretics 4 Na and Cl cotransporter Active tubular Distal convoluted
reabsorption of 5%Na, tubules
Cl, Ca
K-sparing diuretics 1 Na channels Na reabsorption Collecting tubules
K & H transporter K & H secretion
Classification based on efficacy
QUESTIONS???