Diuretics

7/22/2020
Diuretic Agents
By
Dr. Kalam Sirisha,
Associate Professor & Head,
Department of Pharmaceutical Chemistry,
Vaagdevi College of Pharmacy, Ramnagar,
Warangal, Telangana
E-mail: ragisirisha@yahoo.com

7/22/2020
Diuretic Agents
• Drugs that accelerate the rate of urine
formation.
• Result: removal of sodium and water
• They mostly act from the luminal site of
the tubules to block the ion transporting
molecules

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Sodium
• Where sodium goes, water follows.
• 20 to 25% of all sodium is reabsorbed
into the bloodstream in the loop of Henle,
5 to 10% in the distal tubules, and 3%
in collecting ducts.
• If it is not absorbed, it is excreted with
the urine.

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Diuretic Agents
• Carbonic anhydrase inhibitors
• Loop diuretics
• Osmotic diuretics
• Potassium-sparing diuretics
• Thiazide and thiazide-like diuretics
• Aquaretics (ADH-antagonists)

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Osmotic agents Mannitol Proximal tubule
Descending loop
Collecting duct
Carbonic
anydrase inhib.
Acetazolamide Proximal tubule
Thiazides Hydrochlorothia
zide
Distal convoluted
tubule
Loop diuretic Ethacrynic acid
Furosemide
Loop of Henle
K+ - sparing Spironolactone
Amiloride
Collecting tubule

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Acetazolamide
Osmotic diuretics
Loop diuretics - furosemide
Thiazides
Aldosterone antagonists
ADH antagonists
Functional description of the nephron
upraveno podle Katzung's Pharmacology: Examination and Board Review.
McGraw-Hill/Appleton & Lange; 6th edition (August 6, 2001)
50-65 %
15-25 %
4-8 %
2-5 %

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Summary of sites of renal reabsorption of
filtrate

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Carbonic Anhydrase Inhibitors (CAIs)
• Acetazolamide (Diamox)
• Methazolamide
• Dichlorphenamide

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Proximal tubule
Acetazolamide
Proximální
tubulus
Lumen

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Carbonic Anhydrase Inhibitors:
Mechanism of Action
• The enzyme carbonic anhydrase helps to make
H+ ions available for exchange with sodium and
water in the proximal tubules.
• CAIs block the action of carbonic anhydrase,
thus preventing the exchange of H+ ions with
sodium and water.

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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.
• Resorption of water is decreased and urine
volume is increased.

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Therapeutic Uses
• Adjunct agents in the long-term management
of open-angle glaucoma
• Used with miotics to lower intraocular pressure
before ocular surgery in certain cases
• Also useful in the treatment of:
– Edema
– Epilepsy
– High-altitude sickness

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Therapeutic Uses
• Acetazolamide is used in the management of
edema secondary to CHF when other diuretics
are not effective.
• CAIs are less potent diuretics than loop diuretics
or thiazides—the metabolic acidosis they induce
reduces their diuretic effect in 2 to 4 days.

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Side Effects
Metabolic acidosis Drowsiness
Anorexia Paresthesias
Hematuria Urticaria
Photosensitivity Melena

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Loop Diuretics
• Bumetanide (Bumex)
• Ethacrynic acid (Edecrin)
• Furosemide (Lasix)
• Torasemide
• Etoziline

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Synthesis of Furosemide

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Loop of Henle
Furosemid
Lumen Vzestupné raménko
Henleovy kličky

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Loop Diuretics:
Mechanism of Action
• Loop diuretics act on the Na+-K+-
2Cl− symporter (NKCC2) in the thick
ascending limb of the loop of Henle to inhibit
sodium, chloride and potassium reabsorption.
This is achieved by competing for the
Cl− binding site.
• Increase renal prostaglandins, resulting in the
dilation of blood vessels and reduced
peripheral vascular resistance.

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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

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Loop Diuretics:
Therapeutic Uses
• Edema associated with CHF or hepatic
or renal disease
• Control of hypertension

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Loop Diuretics: Side Effects
Body System Effect
CNS Dizziness, headache,
tinnitus, blurred
vision
GI Nausea, vomiting,
diarrhea

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Loop Diuretics: Side Effects
Body System Effect
Hematologic Agranulocytosis,
neutropenia,
thrombocytopenia
Metabolic Hypokalemia,
hyperglycemia,
hyperuricemia

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Osmotic Diuretics
• mannitol (Resectisol, Osmitrol)

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

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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 the kidney
• Reduces excessive intraocular pressure

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Osmotic Diuretics:
Therapeutic Uses
• Used in the treatment of patients in the
early phase of ARF (acute renal failure)
• To promote the excretion of toxic
substances
• Reduction of intracranial pressure
• Treatment of cerebral edema

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Osmotic Diuretics: Side Effects
• Convulsions
• Thrombophlebitis
• Pulmonary congestion
Also headaches, chest pains, tachycardia,
blurred vision, chills, and fever

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Potassium-Sparing Diuretics
• amiloride (Midamor)
• spironolactone (Aldactone)
• triamterene (Dyrenium)

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Collecting tubuleLumen
Amiloride
Triamterene
Spironolactone
Potassium-sparring diuretics

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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 the resorption of sodium and water
usually induced by aldosterone

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Spironolactone competitively inhibits aldosterone dependant
sodium potassium exchange channels in the distal convoluted
tubule. This action leads to increased sodium and water
excretion, but more potassium retention. The increased
excretion of water leads to diuretic and also antihypertensive
effects.
Amiloride works by directly blocking the epithelial sodium
channel (ENaC) with an IC50 around 0.1 μM, indicating potent
blockade. Antagonism of ENaC thereby inhibits sodium
reabsorption in the late distal convoluted tubules, connecting
tubules, and collecting ducts in the nephron.
Triamterene exerts a diuretic effect on the distal renal tubule
to inhibit the reabsorption of sodium ions in exchange for
potassium and hydrogen ions and its natriuretic activity is
limited by the amount of sodium reaching its site of action.

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

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Therapeutic Uses
spironolactone and triamterene
• Hyperaldosteronism
• Hypertension
• Reversing the potassium loss caused by
• potassium-losing drugs
amiloride
• Treatment of CHF

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Side Effects
Body System Effect
CNS Dizziness, headache
GI Cramps, nausea,
vomiting,
diarrhea
Other Urinary frequency,
weakness
**hyperkalemia

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Side Effects
spironolactone
• gynecomastia, amenorrhea, irregular menses

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Thiazide and Thiazide-Like
Diuretics
• hydrochlorothiazide (Esidrix, HydroDIURIL)
• chlorothiazide (Diuril)
• trichlormethiazide (Metahydrin)
• Thiazide-like
• chlorthalidone (Hygroton)
• metolazone (Mykrox, Zaroxolyn)

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Chlorthiazide Hydrochlorthiazide
Chlorothiazide is an organic
compound used as a diuretic and
as an antihypertensive. It is used
to manage excess fluid
associated with congestive heart
failure,cancer, liver disease, and
kidney disease.
Hydrochlorothiazide is a diuretic
medication often used to treat high blood
pressure and swelling due to fluid build up.
Other uses include diabetes insipidus,
renal tubular acidosis, and to decrease the
risk of kidney stones in those with a high
calcium level in the urine.

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Hydroflumethiazide is a benzothiadiazine
consisting of a 3,4-dihydro-HH-1,2,4-
benzothiadiazine bicyclic system dioxygenated
on sulfur and carrying trifluoromethyl and
aminosulfonyl groups at positions 6 and 7
respectively. A diuretic with actions and uses
similar to those of hydrochlorothiazide.
Cyclothiazide is 3,4-Dihydro-2H-1,2,4-
benzothiadiazine 1,1-dioxide substituted
at positions 3, 5 and 6 by a 2-norbornen-
5-yl group, chlorine, and a sulfonamide
group, respectively. A thiazide diuretic, it
has been used in the management of
hypertension and oedema.

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Distal tubule
Distal tubuleLumen
Thiazides
Accrding to Katzung's Pharmacology: Examination and Board Review.
Thiazide diuretics control
hypertension in part by
inhibiting reabsorption of
sodium (Na+) and chloride
(Cl−) ions from the distal
convoluted tubules in the
kidneys by blocking
the thiazide-sensitive
Na+-Cl− symporter.

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Diuretics: Mechanism of Action
• Inhibit tubular resorption of sodium and chloride
ions
• Action primarily in the ascending loop of Henle
and early distal tubule
• Result: water, sodium, and chloride are
excreted
• Potassium is also excreted to a lesser extent
• Dilate the arterioles by direct relaxation

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Diuretics: Drug Effects
• Lowered peripheral vascular resistance
• Depletion of sodium and water

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Diuretics: Therapeutic Uses
• Hypertension
(one of the most prescribed group of agents
for this)
• Edematous states
• Idiopathic hypercalciuria
• Diabetes insipidus
• Adjunct agents in treatment of CHF, hepatic
cirrhosis

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

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Diuretics: Side Effects
Body System Effect
GU Impotence
Integumentary Urticaria, photosensitivity
Metabolic Hypokalemia, glycosuria,
hyperglycemia

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General Background of
Diuretics
• Pattern of excretion of electrolytes (how
much of which type) depends on class of
diuretic agent
• Maximal response is limited by site of
action
• Effect of two or more diuretics from
different classes is additive or synergistic if
there sites or mechanisms of action are
different

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Osmotic diuretics
• No interaction with transport systems
• All activity depends on osmotic pressure
exerted in lumen
• Blocks water reabsorption in proximal
tubule, descending loop, collecting duct
• Results in large water loss, smaller
electrolyte loss  can result in
hypernatremia

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Carbonic anydrase inhibitors
• Block carbonic-anhydrase catalyzation of
CO2/ carbonic acid/carbonate equilibrium
• Useful for treating glaucoma and
metabolic alkalosis but can cause
hyperchloremic metabolic acidosis from
HCO3
- depletion

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Loop diuretics
• Generally cause greater diuresis than
thiazides; used when they are insuffficient
• Can enhance Ca2+ and Mg2+ excretion
• Enter tubular lumen via proximal tubular
secretion (unusual secretion segment)
because body treats them as a toxic drug
• Drugs that block this secretion (e.g.
probenecid) reduces efficacy

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Thiazide diuretics
• Developed to preferentially increase Cl-
excretion over HCO3
- excretion (as from
CAIs)
• Magnitude of effect is lower because work
on distal convoluted tubule (only recieves
15% of filtrate)
• Cause decreased Ca excretion 
hypercalcemia  reduce osteoporosis

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Comparison of loop and thiazide
diuretics

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Potassium-sparing diuretics
• Have most downstream site of action
(collecting tubule)
• Reduce K loss by inhibiting Na/K
exchange
• Not a strong diuretic because action is
furthest downstream
• Often used in combination with thiazide
diuretics to restrict K loss

Diuretics

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