Diuretics

Ravish Yadav
Anatomy and Physiology of Renal
system
► Remember the nephron is the most important part of the
kidney that regulates fluid and electrolytes.

► Urine formation:
1. Glomerular filtration rate = 180L/day
2. Tubular re-absorption (around 98%)
3. Tubular secretion
► How could urine output be increased ?
↑ Glomerular filtration Vs ↓ Tubular reabsorption (the
most important clinically)
o If you increase the glomerular filtration  increase
tubular reabsorption (so you cant use glomerular
filtration)

► Purpose of Using Diuretics

1. To maintain urine volume ( e.g.: renal failure)

2. To mobilize edema fluid (e.g.: heart failure, liver failure,

nephrotic syndrome)

3. To control high blood pressure.

►Percentage of reabsorption in each segment:
• Proximal convoluted tubule 60-70%

• Thick portion of ascending limb of the loop of Henle. 25%

• Distal convoluted tubule 5-10%

• Cortical collecting tubule 5% (Aldosterone and ADH)

Physiology of tubular reabsorption

The filtrate
here is
isotonic

The filtrate here

is hypertonic
 Classification of Diuretics
► The best way to classify diuretics is to look for their Site of
action in the nephron

Site 1 Diuretics that inhibit transport in the Proximal

Convoluted Tubule ( Osmotic diuretics, Carbonic Anhydrase
Inhibitors)
Site 2 Diuretics that inhibit transport in the Medullary
Ascending Limb of the Loop of Henle ( Loop diuretics) or High
ceiling Diuretics
Site 3 Diuretics that inhibit transport in the Distal Convoluted
Tubule( Thiazides : Indapamide , Metolazone)
Site 4 Diuretics Diuretics that inhibit transport in the Cortical
Collecting Tubule (Potassium sparing diuretics)
A. Diuretics that inhibit transport in the
Convoluted Proximal Tubule
1. Osmotic Diuretics (e.g.: Mannitol)

IUPAC: (2R,3R,4R,5R)-
Hexane-1,2,3,4,5,6-hexol

MOA: They are hydrophilic compounds that are easily filtered

through the glomerulus with little re-absorption and thus
increase urinary output via osmosis.
PK: Given parentrally. If given orally it will cause osmotic
diarrhea.
ISOSORBIDE

IUPAC: (3S,3aR,6R,6aR)-2,3,3a,5,6,6a-hexahydrofuro[3,2-b]furan-3,6-diol
2. Carbonic Anhydrase Inhibitors (Acetazolamide (Oral) ;
Dorzolamide (Ocular) ; Brinzolamide (Ocular)
Mechanism of action Simply inhibit reabsorption of sodium and
bicarbonate.

It prevents the
reabsorption of
HCO3 and Na

•Inhibition of HCO3 reabsorption  metabolic acidosis.

•HCO3 depletion  enhance reabsorption of Na and Cl  hyperchloremea.

•Reabsorption of Na  ↑ negative charge inside the lumen  ↑K secretion

ACETAZOLAMIDE

IUPAC: N-(5-sulfamoyl-1,3,4-thiadiazol-2-yl)acetamide
•Weak diuretic : because depletion of HCO3  enhance reabsorption of Na and Cl

•In glaucoma :
The ciliary process absorbs HCO3 from the blood.
 ↑HCO3  ↑aqueous humor.
Carbonic anhydrase inhibitors prevent absorption of HCO3 from the blood.

•Urinary alkalinization : to increase renal excretion of weak acids e.g.cystin and uric acid.

•In metabolic alkalosis.

•Epilepsy : because acidosis results in ↓seizures.

•Acute mountain sickness (Altitude sickness).

•Benign intracranial hyper tension.

Dorzolamde and brinzolamide are mixed with β blockers

(Timolol) to treat glaucoma (as topical drops)
►Side Effects of Acetazolamide:
Sedation and drowsiness; Hypersensitivity reaction (because it
contains sulfur) Acidosis (because of decreased absorption of
HCO3 ) ; Renal stone (because of alkaline urine); Hyperchloremia,
hyponatremia and hypokalemia
METHAZOLAMIDE

IUPAC: N-(3-methyl-5-sulfamoyl-1,3,4-thiadiazol-2-ylidene)acetamide

A carbonic anhydrase inhibitor that is used as a diuretic and in the

treatment of glaucoma
 BRINZOLAMIDE

IUPAC: (4R)-4-(ethylamino)-2-(3-methoxypropyl)-1,1-dioxo-3,4-
dihydrothieno[3,2-e]thiazine-6-sulfonamide
 ETHOXZOLAMIDE

IUPAC: 6-ethoxy-1,3-benzothiazole-2-sulfonamide

Ethoxzolamide is a carbonic anhydrase inhibitor used as diuretic and

in glaucoma. It may cause hypokalemia
 SITE I
DRUGS
 B. Diuretics Acting on the Thick Ascending Loop
of Henle (loop diuretics) High ceiling (most efficacious)
► e.g. Furosemide (LasixR), Torsemide, Bumetanide
(BumexR), Ethacrynic acid.
1) Mechanism of Action : Simply inhibit the coupled
Na/K/2Cl cotransporter in the loop of Henle. Also,
they have potent pulmonary vasodilating effects (via
prostaglandins).
2) They eliminate more water than Na.
3) They induce the synthesis of prostaglandins in kidney
and NSAIDs interfere with this action.

They are the best diuretics for 2 reasons:

1- they act on thick ascending limb which has large capacity of reabsorption.
2- action of these drugs is not limited by acidosis
In loop diuretics and
thiazides :
The body senses the loss of So the body will
Na in the tubule. increase synthesis of
aldosterone leading
This lead to compensatory to :
mechanism (the body will try 1- increase Na
to reabsorb Na as much as absorption
possible) 2- hypokalemia
3- alkalosis
2. Side effects:.
Ototoxicity; Hypokalemic metabolic alkalosis; hypocalcemia and
hypomagnesemia; hypochloremia; Hypovolemia; hyperuricemia
(the drugs are secreted in proximal convoluted tubule so they
compete with uric acid’s secretion) hypersensitivity
reactions(contain sulfur)

3. Therapeutic Uses
a) Edema (in heart failure, liver cirrhosis, nephrotic syndrome)
b) Acute renal failure
c) Hyperkalemia
d) Hypercalcemia
Dosage of loop diuretics:
Furosemide 20-80 mg
Torsemide 2.5-20 mg
Bumetanide 0.5-2.0 mg
FUROSEMIDE/FRUSEMIDE

IUPAC: 4-chloro-2-(furan-2-ylmethylamino)-5-
sulfamoylbenzoic acid

Furosemide is a benzoic-sulfonamide-furan. It is a diuretic with

fast onset and short duration that is used for EDEMA and
chronic Renal insufficiency.
 2,4-Dichloro 5 sulfamoyl benzoic acid

2,4-Dichloro benzoic acid H2N

O

Furosemide
AZOSEMIDE

IUPAC: 2-chloro-5-(2H-tetrazol-5-yl)-4-(thiophen-2-
ylmethylamino) benzenesulfonamide

Azosemide is a monosulfamyl belonging to the class of High

Ceiling loop diuretics. 
Azosemide inhibits sodium and chloride reabsorption
throughout the thick ascending limb of the loop of Henle.
BUMETANIDE (Phenoxybenzoic acid der.)
Bumetanide is a Loop Diuretic. The physiologic effect
of bumetanide is by means of Increased Diuresis at Loop of
Henle.

IUPAC: 3-(Aminosulfonyl)-5-(butylamino)-4-phenoxybenzoic acid

 ETHACRYNIC ACID (Phenoxyacetic acid der.)

It inhibits symport of sodium, potassium, and chloride primarily in the

ascending limb of Henle, but also in the proximal and distal tubules. This
pharmacological action results in excretion of these ions, increased urinary
output, and reduction in extracellular fluid. This compound has been
classified as a loop or high ceiling diuretic.

IUPAC: 2-[2,3-dichloro-4-(2-methylidenebutanoyl) phenoxy]acetic acid

 C. Diuretics that Inhibit Transport in the Distal
Convoluted Tubule (e.g.: Thiazides and
Thiazide-like (Indapamide; Metolazone)
►Pharmacodynamics:
Mechanism of action: Inhibit Na+ via inhibition of Na+/Cl- cotransporter.
They have natriuretic action.

►Side Effects: No ototoxicity; hypercalcemia due to ↑PTH,

more hyponatremia; hyperglycemia (due to both impaired
pancreatic release of insulin and diminished utilization of
glucose) hyperlipidemia and hyperurecemia ; hypokalemic
metabloic alkalosis.
► Clinical uses:

 Hypertension Drug of Choice (Hydrochlorthiazide; Indapamide

(NatrilexR)

 Refractory Edema (doesn’t respond well to ordinary treatment)

together with the Loop diuretics (Metolazone).

 Nephrolithiasis (Renal stone) due to idiopathic hypercalciuria

 Hypocalcemia.

 Nephrogenic Diabetes Insipidus. (it decreases flow of urine 

more reabsorption)
 CHLORTHIAZIDE

IUPAC: 6-chloro-7-Sulfamoyl-2H-1,2,4-benzothiadiazine 1,1-dioxide

HYDROCHLORTHIAZIDE

IUPAC: 6-chloro-1,1-dioxo-3,4-dihydro-2H-1,2,4-benzothiadiazine-7-
sulfonamide
BENZTHIAZIDE

IUPAC: 3-((Benzylthio)methyl)-6-chloro-7-sulfamoyl-2H-
benzo-1,2,4-thiadiazine 1,1-dioxide
 METHYCLOTHIAZIDE

Methyclothiazide is a thiazide diuretic with properties similar to

those of hydrochlorothiazide.

IUPAC: 6-chloro-3-(chloromethyl)-2-methyl-1,1-dioxo-3,4-
dihydro-1,2,4-benzothiadiazine-7-sulfonamide
 TRICHLORMETHIAZIDE
Trichlormethiazide is a thiazide diuretic with
properties similar to those of hydrochlorothiazide

IUPAC: 6-chloro-3-(dichloromethyl)-1,1-dioxo-3,4-dihydro-
2H-1,2,4-benzothiadiazine-7-sulfonamide
CHLORTHALIDONE
A benzenesulfonamide-phthalimidine that tautomerizes to a
benzophenones form.
It is considered a thiazide-like diuretic.

IUPAC: 1-keto-3-(3'-Sulfamyl-4'-chlorophenyl)-3-hydroxyisoindoline
METOLAZONE
A quinazoline-sulfonamide that is considered a thiazide-like
diuretic which is long-acting so useful in chronic renal failure. It
also tends to lower blood pressure and increase potassium loss. 

IUPAC: 7-chloro-2-methyl-3-(2-methylphenyl)-4-oxo-1,2-
dihydroquinazoline-6-sulfonamide.
QUINETHIZONE
Quinethazone is a thiazide diuretic used to treat hypertension.
Common side effects include dizziness, dry mouth, nausea, and
low potassium levels.

IUPAC: 7-chloro-2-ethyl-4-oxo-2,3-dihydro-1H-quinazoline-6-
sulfonamide
INDAPAMIDE
A benzamide-sulfonamide-indole. It is called a thiazide-like
diuretic but structure is different enough (lacking the thiazo-
ring) so it is not clear that the mechanism is comparable.

IUPAC: 4-chloro-N-(2-methyl-2,3-dihydro-1H-indol-1-yl)-3-
sulfamoylbenzamide
D. Diuretics that inhibit transport in the Cortical Collecting Tubule (e.g.
potassium sparing diuretics).

Classification of Potassium Sparing Diuretics:

A)Direct antagonist of mineralocorticoid receptors
(Aldosterone Antagonists e.g spironolactone
(AldactoneR) or
B) Indirect via inhibition of Na+ influx in the luminal
membrane (e.g. Amiloride, Triametrene)
Spironolactone (AldactoneR)

►Synthetic steroid acts as a competitive antagonist of aldosterone

with a slow onset of action.
► Mechanism of action: Aldosterone cause ↑K
and H+ secretion and ↑Na reabsorption.
►The action of spironolactone is the opposite
Clinical Uses of K+ sparing Diuretics:

• In states of primary aldosteronism (e.g. Conn’s syndrome, ectopic ACTH

production) of secondary aldosteronism (e.g. heart failure, hepatic cirrhosis,
nephrotic syndrome)
• To overcome the hypokalemic action of diuretics
• Hirsutism (the condensation and elongation of female facial hair) because it is an
antiandrogenic drug.
Side effects:
► Hyperkalemia (some times it’s useful other wise it’s a side
effect).
► Hyperchloremic (it has nothing to do with Cl) metabolic
acidosis
► Antiandrognic effects (e.g. gynecomastia: breast
enlargement in males, impotence) by spironolactone.
►Triametrene causes kidney stones.
► Diuretics Combination preparations
these are anti-hypertensive drugs:
DyazideR = Triametrene 50 mg + Hydrochlorothiazide HCT 25 mg
AldactazideR= Spironolactone 25 mg + HCT 25 mg
ModureticR = Amiloride 5 mg + HCT 50 mg
► Note : HCT to decrease hypertension and K sparing
diuretics to overcome the hypokalemic effect of HCT
►Contraindications: Oral K administration and using of ACE inhibitors
SPIRONOLACTONE
Spironolactone is a synthetic 17-lactone steroid which is a renal competitive
aldosterone antagonist in a class of pharmaceuticals called potassium-sparing
diuretics.
It is used mainly in the treatment of refractory edema in patients with
congestive heart failure, nephrotic syndrome, or hepatic cirrhosis. Its effects
on the endocrine system are utilized in the treatments of hirsutism and acne
but they can lead to adverse effects.

IUPAC: S-[(7R,8R,9S,10R,13S,14S,17R)-10,13-dimethyl-3,5'-
dioxospiro[2,6,7,8,9,11,12,14,15,16-decahydro-1H-
cyclopenta[a]phenanthrene-17,2'-oxolane]-7-yl] ethanethioate
EPLERENONE
Eplerenone is a selective aldosterone receptor antagonist. Eplerenone binds to the
mineralocorticoid receptor and blocks the binding of aldosterone, thereby
decreasing sodium resorption and subsequently increasing water outflow. This
leads to a decrease in blood pressure. Eplerenone is used in the treatment of
hypertension and congestive heart failure.

IUPAC: methyl (1'R,2R,2'S,9'R,10'R,11'S,15'S,17'R)-2',15'-dimethyl-5,5'-dioxo-18'-

oxaspiro[oxolane-2,14'-pentacyclo[8.8.0.0¹,¹⁷.0²,⁷.0¹¹,¹⁵]octadecan]-6'-ene-9'-
carboxylate
TRIAMTERENE
Triamterene is a pteridine derivative with potassium-sparing diuretic
property. Triamterene blocks the sodium-potassium exchange pump (Na-K-
ATPase) in the luminal membrane of principal cells in the late distal tubule,
cortical collecting tubule and collecting duct in the kidney. This reversible
inhibition of the electrogenic sodium transport decreases the lumen-negative
transepithelial potential difference and thus reduces the driving force for K+
movement into the tubular lumen resulting in the inhibition
of sodium reabsorption in exchange for K+ and H+.

IUPAC: 6-phenylpteridine-2,4,7-triamine
 AMILORIDE
A pyrazine compound inhibiting sodium reabsorption through sodium
channels in renal epithelial cells. This inhibition creates a negative potential
in the luminal membranes of principal cells, located in the distal convoluted
tubule and collecting duct. Negative potential reduces secretion of
potassium and hydrogen ions. Amiloride is used in conjunction with
diuretics to spare potassium loss.

IUPAC: 3,5-Diamino-N-carbamimidoyl-6-chloropyrazine-2-
carboxamide