DIURETICS and

ANTIDIURETICS

Nafrialdi & Vivian Soetikno

Department of Pharmacology
Faculty of Medicine
Universitas Indonesia

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 Introduction
• Nephron is the functional unit of the kidney
• There are about 1,000,000 nephron in each
kidney
• Process of urine formation:
– Filtration by glomerulus
– Reabsorption by tubules
– Secretion by tubules
• Glomeruli receive 25% of cardiac output
– Filtration rate: 100-120 ml/minute
• Tubules:
– Reabsorption of 99% of glomerular filtrate à thus
only + 1 ml/min. excreted as urine

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 Introduction
• Proximal tubule:
– Reabsorption of 65% Na+
– Permeable to water à isotonic urine
• Loop of Henle
– Descending thin limb: most active water reabsorption
– Ascending thin limb: water impermeable
– Thick ascending limb:
• Reabsorption of 25% Na+,
• Water impermeable à diluting segment
• Distal convoluted tubules :
– Na+ reabsorption
– Water impermeable à diluting segment
• Collecting duct system
– Tubular fluid depends on antidiuretic hormone (ADH) 3
 Diuretic drugs
• DRUG THAT CAN INDUCE THE INCREASE
OF URINE VOLUME & increase of Na+-Cl-
excretion
• Main Indications:
– Hypertension
– Congestive heart failure
– Other conditions with water retention:
• Edema, Ascites
– Others :
• Cerebral edema, Glaucoma, Etc ...

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 Site and Mechanisms of Diuretics
Drug Site of Action Mechanism
1.Osmotic Diuretic 1. Proximal tubules Inhibition of water and Na+
2. Loop of Henle reabsorption
3. Collecting duct

2. Carbonic Proximal tubules Inhibition of bicarbonate

Anhydrase reabsorption
Inhibitor (CA-I)
3. Thiazides Early distal tubule Inhibition of Na+/Cl- co-
transport
4. Loop Diuretic Loop of Henle Inhibition of Na+/K+/Cl- co-
(thick ascending limb) transport
5. Potassium Late distal tubule Inhibition of Na+ reabsorption
sparing diuretics Collecting duct and K+ secretion
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Nephron sites of action of diuretics

Goodman & Gilman’s, 12th ed., p. 697

 Osmotic Diuretics
•Glycerin, Isosorbid, Mannitol, Urea
•Properties of osmotic diuretics:
–Freely filtered by glomerulus
–Limit reabsorption by renal tubule
–Relatively inert pharmacologically
•MoA:
–increases osmotic pressure in tubular lumen à
prevent reabsorption of electrolytes and water à
water excretion ↑
•Almost all electrolytes are excreted: Na+, K+, Ca++,
Mg++, HCO3-, phosphate

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 Osmotic Diuretics
Pharmacokinetics
• Glycerin & isosorbid à orally
• Mannitol & urea à intravenously
• Distribute in the extracellular fluid à
extract intracellular fluid à é extracellular
fluid volume
• Metabolism:
– mannitol 20% metabolized
• Excretion: renal
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 Osmotic Diuretics

Indications
• Brain edema
• mannitol is given before and after brain surgery
• Glaucoma (rare)
• Disequilibrium syndrome after hemodialysis
• Prophylaxis of ATN (acute tubular necrosis)
due to contrast media, surgery, and trauma.

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 Osmotic Diuretics
Adverse Effects
• Initial increase of plasma volume (due to
relatively large volume of mannitol) à potentially
dangerous in heart failure and lung edema
• Hyponatremia à headache, nausea, vomitus
• Hypovolemia
• Hypersensitivity reaction
• Vein thrombosis, pain if extravasation (urea)
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 Osmotic Diuretics

Contraindications
• Renal failure with anuria
• Lung edema
• Dehydration
• Intracranial hemorrhage, except before
craniotomy

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 CARBONIC ANHYDRASE INHIBITOR
(Acetazolamide, Dichlorphenamide, Metazolamide)

Mechanism of Action
• In tubular cell, CA-I inhibits conversion of CO2 +
H2O à HCO3- + H+
• In tubular lumen, CA-I inhibits conversion of HCO3-
à H2O + CO2
• Na-H exchange is inhibited à Na is combined with
HCO3- à NaHCO3 à then, excreted in urine along
with H2O
• In the eye: CA-I inhibits formation of aqueos humor
à decrease intraocular pressure
Mechanism of Action of CA-I

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 Indications of CA-I
• Glaucoma (mainly)
• Treatment of metabolic alkalosis
• CNS:
• Anti epilepsi, limited usage
• acute mountain sickness
• Familial periodic paralysis
• Urinary alkalinization: preventing uric acid
and cystine stones
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Adverse effects
§ Metabolic acidosis
§ Renal stones (phosphate and calcium
stone)
§ Drowsiness, paresthesia, disorientation
Contraindication
§ Liver cirrhosis (CA-I inhibits conversion of
NH3 to NH4) à NH3 increased à hepatic
encephalopathy
§ Renal failure (↑ risk of metabolic acidosis)

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 Preparations
• Acetazolamide (Diamox®):
– Tablet 125 and 250 mg
– Doses: 250-1000 mg/day
• Dichlorphenamide: tablet 50 mg (1-4 times
daily)
• Metazolamide: tablet 25 and 50 mg (1-4
times daily)

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 THIAZIDES
• Site of action: distal tubules
• Mechanism of Actions
– Inhibitors of Na+/Cl- symport are sulfonamides
– Thiazides are secreted by proximal tubules
via organic acid secretory pathway but works
in distal convoluted tubules
– Inhibit reabsorption of Na+/Cl- from the lumen
to tubular cells à increase Na+ and Cl-
excretion (and water)
– Some thiazides have weak CA-I effect

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Mechanism of Action of Thiazides

Goodman & Gilman’s 12th ed. p. 689 18

 Thiazide
• Onset of anti hypertensive effect: 2-3 days
• Maximum effects: 2-4 weeks
• Drug of choice for mild to moderate HT, and HT
with low renin activity (elderly)
• Much less effective in renal insufficiency, except
Indapamide
• Frequently used in combination with other anti
HT drugs:
– Prevents water retention by other anti HT drugs
– Potentiation with other anti HT drugs

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 Effects on Electrolytes
and Adverse Effects
Ø Increases Na+ and Cl- excretion, (also K+ and
Mg2+)
à AE: hyponatremia, hypokalemia, hypomagnesemia,
hypochloremia
Ø Inhibits uric acid secretion (chronically)
à AE: hyper uricemia and gout
Ø Decreases Ca2+ excretion à tends to increase
plasma Ca2+ (hypercalcemia) à Delays
osteoporotic process

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Other adverse effects:
§ Hyperglycemia and hypercholesterolemia à
not very suitable for DM and dyslipidemia
(although not contraindicated)
§ (Indapamid has less effects on lipid and uric
acid)
§ Sexual dysfunction

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 Indications of Thiazides

Ø Hypertension (single drug or in combination)

Ø Common dose for hypertension: 25 mg/day HCT
Ø Initial therapy for uncomplicated hypertension
Ø Heart failure (chronic, mild)
Ø Edema (loop diuretic is preferable)
Ø Nephrogenic diabetes insipidus
Ø Idiopathic hypercalciuria

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 Drug Interactions
• Due to hypokalemia, thiazide may
increase the risk for arrhythmia when
combined with digitalis, quinidine and
other anti arrhythmias
• Probenecid reduce the efficacy of thiazide
• NSAIDs reduce the efficacy of thiazide
• Thiazides reduce the efficacy oral anti
diabetics, insulin, anticoagulants
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Thiazides & related diuretics

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 LOOP DIURETICS
Furosemide, torasemide, bumetanide, ethacrynic acid
Ø Site of action: thick ascending limb of Loop of Henle
Ø Mechanism:
§ Loop diuretic is secreted by proximal tubule via
organic acid secretory pathway into the lumen
§ Inhibits Na+-K+-2Cl- symport in the luminal side of
thick ascending limb of Loop of Henleà
increases the excretion of Na+, K+, Cl- and water
§ Ca2+ and Mg2+ are excreted

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Mechanism of action

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Goodman & Gilman’s 12th ed. p. 684
 Indications
Ø Congestive heart failure (first line drug)
Ø Acute pulmonary edema
Ø Other conditions with water retention: edema
due to renal failure, nephrotic syndrome,
ascites
Ø Hypercalcemia
Ø Severe hypertension
Ø Force diuresis during drug/chemical
intoxication (drug that excreted through the
kidney in active form)

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 Adverse Effects
§ Hypo-K, hypo-Na, hypo-Cl, hypo-Mg,
hypo-Ca
§ Metabolic alkalosis,
§ Hypercholesterolemia, hyperuricemia,
hyperglycemia
§ Ototoxicity (especially ethacrynic acid if
given by rapid IV bolus)
§ Allergic reactions (sulfonamide derivative,
except ethacrynic acid)
 Interactions
Ø Increases the risk of arrhythmia when
combined w/ digitalis, quinidine and other
anti arrhythmias
Ø Concomitant use w/ aminoglycoside or
cisplatin increases the risk of
nephrotoxicity and ototoxicity
Ø NSAIDs reduce the effects of diuretics
Ø Probenecid reduce the effects of diuretics
Ø Loop diuretics reduce clearance of lithium
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Typical doses of loop diuretics

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 POTASSIUM (K+)-SPARING DIURETICS

Site of action: late distal tubule and collecting duct

MoA (2):
1. Na+ channel inhibitors (amiloride, triamterene)
§ Inhibit Na+-channel in the luminal membrane
§ Increases Na+ & Cl- excretion mildly (~2% of filtered load)
§ Both drugs are organic bases & transported by organic base
secretory mechanism in proximal tubule
2. Aldosterone antagonist (spironolactone, eplerenone)
§ Aldosterone induces Na+ reabsorption and K+ excretion
§ Spironolactone and eplerenone block aldosterone receptors à
thus, Na+ is excreted but K+ is retained

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K+-Sparing Diuretics
Late distal tubule & Collecting duct

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 K+-Sparing Diuretics
Ø K+-sparing diuretics have a weak diuretic
action
Ø Usually used in combination w/ other diuretics:
§ Potentiation with other diuretics
§ Prevent hypokalemia due to other diuretics that
increase K+ excretion (antikaliuretic)
Ø Longterm use of spironolactone for prevention
of myocardial remodeling (hypertrophy and
fibrosis)

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 Adverse Effects
§ Hyperkalemia
§ Anti androgenic effect (gynecomastia,
decrease of libido, impotency, menstrual
dysturbance): spironolactone
§ Megaloblastic anemia : Triamteren (a
folate antagonist)

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INDICATIONS
Ø Antihypertension:
§ In combination w/ other anti hypertensions
§ To increase the effect and to prevent hypokalemia of
other diuretics
Ø Heart failure: prevention of cardiac remodelling

Contraindications /Precautions
Ø Conditions that prone to hyperkalemia:
§ Renal failure
§ Concomitant use with ACE-inhibitor, ARB, NSAID, K+
supplementation (except in hypokalemic condition)

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ANTIDIURETIC HORMONES

Vasopresin, Arginine vasopressin (AVP),

Desmopressin (DDAVP, 1-deamino-8D-arginine
vasopressin)

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Mechanisms of Action
• Works on ascending limb of Henle’s loop
and collecting ducts
• 2 kind of receptors:
– V1: vascular smooth muscle à
vasoconstriction
– V2: kidney à increase water permeability of
tubular epithelium à water reabsorption

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Indications
• Neurogenic Diabetes Insipidus (central type)
(not for nephrogenic DI)
• DI due to head trauma or brain surgery
• GI bleeding due to portal hypertension:
vasoconstriction à reducing mesenteric blood
flow
• Von Willebrand disease (DDAVP stimulate
secretion of vWF in endothelial cells)

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Kinetics
• Not to be administered orally (rapid
degradation by trypsin)
• Administration: im, iv, sc, intranasal
• Half-life of ADH: 17-35 minutes
• Desmopresin (DDAVP): long half-life à
effective until 48-96 h after intranasal
administration.

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Adverse Effects

• Hypertension
• Abdominal colic due to increased peristalsis
• Coronary vasoconstriction à angina pectoris

Preparation:
– Pitressin for injection
– Vasopresin tanat for IM injection
– Intranasal powder
– Lipresin (lisine-vasopresin) nasal spray
– Desmopresin acetate (DDAVP): nasal drop

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