Basic Pharmacology of Diuretics

Photo: Scanning electron micrograph of the glomerulus in a human kidney.
From: Widmaier EP. Vander’s Human Physiology: The Mechanisms Of Body Function, 13th Ed. New York, NY: McGraw-Hill Companies, Inc., 2014: 490
Learning Objectives:
1. List major types of diuretics and relate them to their sites of action.
2. List the major applications, toxicities, and the efficacy of thiazides, loop
diuretics and potassium-sparing diuretics.
3. Describe two drugs that reduce potassium loss during diuresis.
4. Describe a therapy that will reduce calcium excretion in patients who have
recurrent urinary stones.
5. Discuss the principle of force diuresis.
6. Describe drugs for reducing urine volume in nephrogenic diabetes insipidus.
7. Understand the usefulness of altering urine pH by drugs.
8. Discuss the mechanisms by which drugs and chemicals damage the kidney.
9. Understand how to select and prescribe drugs for patients with renal
impairment.
Companion: Renal Pharmacology eNotes
Marc Imhotep Cray, M.D. 2
Some Relevant Drugs:
A. Carbonic Anhydrase D. Thiazides F. ADH antagonists
Inhibitors chlorthalidone demeclocycline
Acetazolamide chlorothiazide lithium
dichlorphenamide hydrochlorothiazide lixivaptan
methazolamide metolazone tolvaptan
dorzolamide indapamide conivaptan
B. Osmotic Diuretics E. Potassium-sparing
mannitol diuretics
C. Loop Diuretics spironolactone
furosemide eplerenone
bumetanide triamterene
torsemide amiloride
ethacrynic acid

Individual Diuretics
Topics Outline:
 Mercurial Diuretics
 Carbonic Anhydrase Inhibitors
 Thiazide Diuretics
 Potassium-Sparing Agents
 Loop (High-Ceiling) Diuretics
 Osmotic Agents

Mercurial Diuretics
Organomercurial agents inhibit active Cl− transport, especially in
ascending limb of the Henle loop
In acidic conditions, Hg2+ dissociates, binds to, and inhibits sulfhydryl
enzymes Na+ reabsorption is thus decreased; more Na+ and Cl− are
excreted
Because more Na+ is delivered to distal nephron during diuresis, K+ and

H+ excretion (sum of urinary NH4 + plus titratable acid − urinary
HCO3−) may increase
In alkaline conditions, Hg2+ does not dissociate, and patients become
refractory to mercurials
Mercurial Diuretics (2)
Mercurial diuretics (eg, mercaptomerin) are poorly absorbed
when taken orally, so an intramuscular route is required
 Because of this difficulty and their toxicity (eg, systemic
poisoning, cardiac toxicity, hypersensitivity, worsening of
renal insufficiency), mercurials are largely obsolete
They are sometimes used for CHF, cirrhosis, and portal

obstruction because they do not deplete K+

Mercurial
Diuretics (3)
Marc Imhotep Cray, M.D. Raff RB, Rawls SM, Beyzarov EP. Netter's Illustrated Pharmacology, Updated Edition. Saunders, 2014 7
Carbonic Anhydrase Inhibitors (CAIs) Capsule
Diuretic drugs such as acetazolamide (prototype),
dichlorphenamide, methazolamide and dorzolamide
inhibit carbonic anhydrase, particularly at proximal
convoluted tubule
 Carbonic anhydrase normally catalyzes dehydration of
carbonic acid (H2CO3)
o As a result of CAIs, H+ needed for Na+-H+ exchange
is reduced, HCO3− and Na+ reabsorption in
proximal tubules is suppressed, and diuresis is
promoted
Carbonic Anhydrase Inhibitors:
Mechanism of Action
The enzyme carbonic anhydrase normally helps to make H+
ions available for exchange with sodium and water in proximal
tubules
CAIs block action of carbonic anhydrase, thus preventing

exchange of H+ ions with sodium and water
these agents block formation of H+ and HCO3- from CO2 and

H2O  end result is that bicarbonate is excreted in urine

Mechanism of Action
Inhibition of carbonic anhydrase reduces H+ ion concentration in
renal tubules
As a result, there is increased excretion of bicarbonate, sodium,

water, and potassium
Reabsorption of water is decreased and urine volume is increased

CAIs: Therapeutic Uses
 Adjunct agents in long-term management of open-angle
glaucoma
 Used with miotics to lower intraocular pressure before ocular
surgery in certain cases
Also useful in treatment of:
 Glaucoma
 Edema
 Epilepsy
 High-altitude sickness
CAIs: Therapeutic Uses cont.
Acetazolamide is sometimes used in management of edema
secondary to CHF when other diuretics are not effective
CAIs are less potent diuretics than loop diuretics or thiazides
metabolic acidosis they induce reduces their diuretic effect in

2 to 4 days

Adverse Effects
 hyperchloremic metabolic acidosis (Because of decreased
reabsorption of Na+, Na+-K+ exchange increases in distal
convoluted tubules)
 Drowsiness
 Anorexia
 Paresthesias
 Hematuria
 Urticaria
 Photosensitivity
 Melena
CAIs MOA
Thiazide and Thiazide-Like Diuretics
hydrochlorothiazide (Esidrix, HydroDIURIL)
chlorothiazide (Diuril)
trichlormethiazide (Metahydrin)
chlorthalidone (Hygroton)
metolazone (Mykrox, Zaroxolyn)
indapamide

Thiazide Diuretics Capsule
 Thiazide (benzothiadiazide) diuretics inhibit Cl− reabsorption, especially in
distal portion of ascending limb of Henle loop and proximal portion of
distal convoluted tubule
 Excretion of Na+, K+, Cl−, and HCO3 − is increased
 refractoriness does not develop to diuretic effect
 Often used to treat chronic edema and essential hypertension and, less
often, nephrosis some forms of diabetes insipidus, and hypercalciuria
 Common adverse effects are hypokalemia (K+ supplements are
recommended) may lead to alkalosis, and hyperglycemia
 Extra caution is needed when these agents are used with digitalis for CHF
because of greater digitalis toxicity in conditions of low K+
 Because thiazides are excreted via glomerular filtration and tubular
secretion they compete with uric acid for tubular secretion result in
increase bld uric acid can precipitate gout in at risk persons
Thiazide and Thiazide-Like Diuretics:
Mechanism of Action
Inhibit tubular reabsorption of sodium and chloride ions
Action primarily in ascending loop of Henle and early distal tubule
Result: water, sodium, and chloride are excreted
Potassium is also excreted to a lesser extent
Dilate arterioles by direct relaxation

Drug Effects
 Lowered peripheral vascular resistance
 Depletion of sodium and water

Thiazide Diuretics:
Therapeutic Uses
Hypertension (one of most prescribed group of agents)
Edematous states
Idiopathic hypercalciuria
Diabetes insipidus
Adjunct agents in treatment of CHF and hepatic cirrhosis

Thiazide Diuretics:
Adverse Effects
Body System Effect
CNS Dizziness, headache,
blurred vision, paresthesias,
decreased libido
GI Anorexia, nausea, vomiting, diarrhea

Thiazide Diuretics:
Adverse Effects
Body System Effect
GU Impotence
Integumentary Urticaria, photosensitivity
Metabolic Hypokalemia, glycosuria,
Hyperglycemia, Hyperuricemia (gout)

Thiazide
Diuretics MOA
Potassium-Sparing Diuretics
Those in clinical use include:
 Epithelial sodium channel blockers:
 Amiloride
 Triamterene
Aldosterone antagonists:
 Spironolactone
 Eplerenone

Potassium-Sparing Agents Capsule
Two major categories of K+-sparing diuretic drugs are
1. Na+ channel antagonists (eg, amiloride, triamterene) and
2. Aldosterone receptor antagonists (eg, spironolactone)
Amiloride and triamterene inhibit active Na+ reuptake

Enhanced Na+ and Cl− excretion disrupts Na+ transport and
reduces K+ secretion
They moderately increase Na+, Cl−, and HCO3− excretion

when they are used with other diuretics, Na+ excretion
increases and K+ is retained
Reversible azotemia can occur

K+-Sparing Agents Capsule cont.
Triamterene can increase serum uric acid levels, so caution is
needed for its use in patients with gout
Spironolactone reduces aldosterone-mediated Na+-K+

exchange at distal convoluted tubule which increases Na+
loss while reducing K+ excretion
Adverse effects of both types of drugs include hyperkalemia

(especially when impaired renal function exists)
 Combination therapy with K+-sparing drugs is not advised, but

they are often used with other diuretics (eg, thiazides) that
Marcincrease K+ excretion to prevent hypoklemia
Imhotep Cray, M.D. 24
Potassium-Sparing Diuretics:
Mechanism of Action
Work in collecting ducts and distal convoluted tubules
Interfere with sodium-potassium exchange

 Competitively bind to aldosterone receptors
Block reabsorption of sodium and water usually induced by

aldosterone

Drug Effects
Prevent potassium from being pumped into tubule, thus
preventing its secretion
Competitively block aldosterone receptors and inhibit its action
Excretion of sodium and water is promoted

Therapeutic Uses
 spironolactone and triamterene
 Hyperaldosteronism
 Hypertension
 Reversing potassium loss caused by potassium-depleting
drugs (diuretics)
 amiloride
 Treatment of CHF

Adverse Effects
Body System Effect
CNS Dizziness, headache
GI Cramps, nausea,
vomiting, diarrhea
Other Urinary frequency,

weakness, hyperkalemia
 Spironolactone (also blocks androgenic receptors)
gynecomastia, amenorrhea, irregular menses
K+-Sparing
Diuretics MOA
Marc Imhotep Cray, M.D. Raff RB, Rawls SM, Beyzarov EP. Netter's Illustrated Pharmacology, Updated Edition. Saunders, 2014
29
Loop (High-Ceiling) Diuretics Capsule
 Bumetanide, ethacrynic acid, furosemide, torsemide acts
mainly on thick ascending limb of the Henle loop
 Because they elicit greatest diuresis possible, they are also

termed high-ceiling diuretics
 They act at luminal nephron surface and inhibit electrolyte

reabsorption, with resultant greater Na+, Cl−, K+, Mg2+, and
Ca2+ excretion
 Inhibition of NaCl reabsorption in Henle loop decreases strength

of countercurrent concentrating mechanism and causes greatly
increased
Marc Imhotep Cray, M.D. urine output 30
Loop Diuretics Capsule cont.
Pharmacologic Effects
 Bumetanide, furosemide, and torsemide are weak inhibitors of carbonic
anhydrase
 Ethacrynic acid, which is not a sulfonamide, does not inhibit this
enzyme
 Refractoriness does not occur
Clinical Use
Loop diuretics are used for acute pulmonary edema, edema associated
with CHF, cirrhosis, and renal disease
Adverse effects
 Fluid and electrolyte imbalances are most common adverse effects
 All increase Cl− more than Na+ excretion, which can lead to
hypochloremic alkalosis
Loop Diuretics:
Mechanism of Action
Act directly on ascending limb of loop of Henle to inhibit
sodium and chloride reabsorption
Increase renal prostaglandins, resulting in dilation of blood

vessels and reduced peripheral vascular resistance

Loop Diuretics:
Drug Effects
 Potent diuresis and subsequent loss of fluid
 Decreased fluid volume causes:
 Reduced BP
 Reduced pulmonary vascular resistance
 Reduced systemic vascular resistance
 Reduced central venous pressure
 Reduced left ventricular end-diastolic pressure
 Potassium depletion

Loop Diuretics:
Therapeutic Uses
 Edema associated with CHF or hepatic or renal disease
 Less commonly than thiazides, control of hypertension

Loop Diuretics:
Adverse Effects
Body System Effect
Nervous Dizziness
Headache
Ototoxicity (tinnitus)
Blurred vision
GI Nausea/vomiting, diarrhea

Loop Diuretics:
Adverse Effects
Body System Effect
Hematologic agranulocytosis,
neutropenia,
thrombocytopenia
Metabolic hypokalemia,
hyperglycemia,
hyperuricemia,
hypomagnesemia,
metabolic alkalosis

Loop Diuretics
MOA
Osmotic Diuretics Capsule
Osmotic diuretics (mannitol, glycerol, urea) enter nephron
through glomerulus but are poorly reabsorbed along nephron
because of their relatively large molecular size
Presence of unabsorbed molecules in tubule lumen creates a

concentration (osmotic) gradient across tubular membrane
In proximal convoluted tubule, reabsorption of Na+ and water

decreases, which produces diuresis without marked changes in
Na+ or Cl− excretion
Mannitol, agent used most often, is a hexacarbon sugar alcohol

that Cray,
Marc Imhotep is given
M.D. intravenously it is not metabolized 38
Osmotic Diuretics Capsule cont.
Osmotic diuretics are used to treat
 cerebral edema and glaucoma (by reducing cerebrospinal
or intraocular fluid pressure)
 oliguria and anuria, and
 certain phases of acute renal failure (as prophylaxis)
Because osmotic diuretics increase blood volume adverse

effects include decompensation in patients with CHF
Hyperosmolarity or hyponatremia can occur during therapy

of renal failure or cirrhosis

Osmotic Diuretics: Mannitol
Mechanism of Action
Work in proximal tubule
Nonabsorbable producing an osmotic effect
Pull water into blood vessels and nephrons from
surrounding tissues

Osmotic Diuretics:
Drug Effects
Reduced cellular edema
Increased urine production, causing diuresis
Rapid excretion of water, sodium, and other electrolytes, as well
as excretion of toxic substances from kidney
Reduces excessive intraocular pressure

Osmotic Diuretics:
Therapeutic Uses
Used in treatment of patients in early, oliguric phase of ARF
To promote excretion of toxic substances
Reduction of intracranial pressure
Treatment of cerebral edema

Osmotic Diuretics:
Adverse Effects
 Convulsions
 Thrombophlebitis
 Pulmonary congestion
Also
 headaches
 chest pains
 tachycardia
 blurred vision
 chills and fever
Illust. of where of diuretics act, and how

Katzung, Masters, Trevor. Basic and Clinical Pharmacology, 12th ed. New York: McGraw-Hill, 2012
See next slide for sources and links to additional study tools and resources.
Sources and further study:
eLearning
Renal cloud folder tools and resources
MedPharm Guidebook:
Unit 9 Drugs Used to Affect Renal Function
Renal Pharmacology eNotes
Clinical Pharmacology Cases 7, 8, & 55 (Learning Triggers)
Textbooks
Brunton LL, Chabner BA , Knollmann BC (Eds.). Goodman and Gilman’s The Pharmacological
Basis of Therapeutics. 12th ed. New York: McGraw-Hill, 2011
Katzung, Masters, Trevor. Basic and Clinical Pharmacology, 12th ed. New York: McGraw-Hill,
2012
Mulroney SE. and Myers AK. Netter's Essential Physiology. Philadelphia: Saunders, 2009
Raff RB, Rawls SM, Beyzarov EP. Netter's Illustrated Pharmacology, Updated Edition.
Philadelphia: Sanders, 2014
Toy E C. et.al. Case Files-Pharmacology Lange 3rd ed. New York: McGraw-Hill 2014.

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Photo: Scanning electron micrograph of the glomerulus in a human kidney.

Marc Imhotep Cray, M.D. 3

Marc Imhotep Cray, M.D. 4

Because more Na+ is delivered to distal nephron during diuresis, K+ and

They are sometimes used for CHF, cirrhosis, and portal

Marc Imhotep Cray, M.D. 6

CAIs block action of carbonic anhydrase, thus preventing

these agents block formation of H+ and HCO3- from CO2 and

Marc Imhotep Cray, M.D. 9

As a result, there is increased excretion of bicarbonate, sodium,

Reabsorption of water is decreased and urine volume is increased

Marc Imhotep Cray, M.D. 10

CAIs are less potent diuretics than loop diuretics or thiazides

metabolic acidosis they induce reduces their diuretic effect in

Marc Imhotep Cray, M.D. 12

metolazone (Mykrox, Zaroxolyn)

Marc Imhotep Cray, M.D. 15

Action primarily in ascending loop of Henle and early distal tubule

Result: water, sodium, and chloride are excreted

Potassium is also excreted to a lesser extent

Dilate arterioles by direct relaxation

 Depletion of sodium and water

Adjunct agents in treatment of CHF and hepatic cirrhosis

Marc Imhotep Cray, M.D. 18

Marc Imhotep Cray, M.D. 19

Marc Imhotep Cray, M.D. 20

Marc Imhotep Cray, M.D. 22

Amiloride and triamterene inhibit active Na+ reuptake

They moderately increase Na+, Cl−, and HCO3− excretion

Reversible azotemia can occur

Spironolactone reduces aldosterone-mediated Na+-K+

Adverse effects of both types of drugs include hyperkalemia

 Combination therapy with K+-sparing drugs is not advised, but

Interfere with sodium-potassium exchange

Block reabsorption of sodium and water usually induced by

Marc Imhotep Cray, M.D. 25

Competitively block aldosterone receptors and inhibit its action

Excretion of sodium and water is promoted

Marc Imhotep Cray, M.D. 26

Marc Imhotep Cray, M.D. 27

CNS Dizziness, headache

Other Urinary frequency,

 Because they elicit greatest diuresis possible, they are also

 They act at luminal nephron surface and inhibit electrolyte

 Inhibition of NaCl reabsorption in Henle loop decreases strength

Increase renal prostaglandins, resulting in dilation of blood

Marc Imhotep Cray, M.D. 32

Marc Imhotep Cray, M.D. 33

Marc Imhotep Cray, M.D. 34

Marc Imhotep Cray, M.D. 35

Marc Imhotep Cray, M.D. 36

Presence of unabsorbed molecules in tubule lumen creates a

In proximal convoluted tubule, reabsorption of Na+ and water

Mannitol, agent used most often, is a hexacarbon sugar alcohol

Because osmotic diuretics increase blood volume adverse

Hyperosmolarity or hyponatremia can occur during therapy

Marc Imhotep Cray, M.D. 39

Marc Imhotep Cray, M.D. 40

Marc Imhotep Cray, M.D. 41

Marc Imhotep Cray, M.D. 42

Marc Imhotep Cray, M.D. 44

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