Diuretics: Pharmacology, Indications and

UsesPresenter: Dr. Suresh PradhanModerator: Prof. UC Sharma

General organization of the kidneys and the urinary system

Section of kidney showing the major vessels that supply the

blood flow to the kidney

Nephron• Functional unit of Kidney• Each kidney contains about 1million nephrons• Contains six anatomical and functional divisions• the renal corpuscle,• the proximal convoluted tubule,• the loop of Henle,• the distal renal tubule,• the collecting tubule, and • the juxtaglomerular apparatus

Basic tubular segments of the nephron

Juxtraglomerular Apparatus

Schematic of the microcirculation of nephron

Physiology• Involves• Glomerular Filtration• Tubular Secretion• Tubular Reabsorption

• Micturation

Mechanisms of tubular secretion and reabsorption

Transport proteins involved in the movement of Na+ and Cl– across the

apical membranes of renal tubular cells

Functions of Kidneysthe kidneys serve many important homeostatic functions:⌐ Excretion of metabolic waste products and foreign

chemicals⌐ Regulation of water and electrolyte balances⌐ Regulation of body fluid osmolality and electrolyte

concentrations ⌐ Regulation of arterial pressure

⌐ Regulation of acid-base balance⌐ Regulation of erythrocyte production⌐ Secretion, metabolism, and excretion of hormones⌐ Gluconeogenesis

Overview• are drugs that increase the volume of urine

excreted• most diuretic agents are inhibitors of renal ion

transporters that decrease the reabsorption of Na+ at different sites in the nephron• Na+ and other ions, such as Cl−, enter the urine in

greater than normal amounts along with water

• increase the volume of urine, often change its pH• alter the ionic composition of the urine and blood• diuretic effect of the different classes of diuretics

varies considerably• with the increase in Na+ secretion varying from

less than 2% for the weak potassium-sparing diuretics to over 20% for the potent loop diuretics

• in addition to the ion transport inhibitors, other types of diuretics include osmotic diuretics, aldosterone antagonists, and carbonic anhydrase inhibitors• are most commonly used for management of

· abnormal fluid retention (edema) or · treatment of hypertension

Classification

Thiazide Diuretics• are most often administered for long-term

treatment of essential hypertension where diuresis, natriuresis, and vasodilation are synergistic• Includes hydrochlorothiazide and thiazide-like

drugs, such as chlorthalidone and indapamide• Hydrochlorothiazide is the second most frequently

prescribed antihypertensive medication

• are usually administered in combination with other antihypertensives• may also be used to mobilize edema fluid

associated with renal, hepatic, or cardiac dysfunction• less common uses of thiazide diuretics include

management of diabetes insipidus and treatment of hypercalcemia

Pharmacokinetics and Pharmacodynamics

• inhibit the Na+-Cl− cotransporter in the cortical portion of the ascending loop of Henle and the DCT, inhibiting reabsorption of 5% to 10% of the filtered sodium• enhanced distal delivery of Na+ results in increased

excretion of potassium into the renal tubules• resulting in an increase in the urinary excretion of

sodium, chloride, and potassium ions• also stimulate the reabsorption of calcium in the DCT

• readily absorbed when administered orally• extensively protein-bound• eliminated unchanged in the kidney; indapamide-

metabolized by the liver• thiazides’ effectiveness markedly decreases in

patients with renal insufficiency

• thiazide diuretics have a long half-life of 8 to 12 hours, allowing for a convenient once-a-day dosing• Indapamide, xipamide, and metolazone are

structurally related to furosemide but share a thiazide-like mechanism of action with differences in their clinical effects

Side Effects• thiazide diuretic–induced hypokalemic,

hypochloremic, metabolic alkalosis is a common side effect However, these side effects are usually well tolerated at low doses• hypokalemia may manifest as skeletal muscle

weakness and gastrointestinal ileus and may increase the risk of developing digitalis toxicity• depletion of sodium and magnesium ions may

accompany kaliuresis

• cardiac dysrhythmias may occur as the result of diuretic-induced hypokalemia or hypomagnesemia• hypercalcemia may result, especially in patients

receiving calcium supplements or vitamin D therapy• can potentiate non-depolarizing neuromuscular

blockade by producing hypokalemia• effectiveness of thiazides is decreased in patients

receiving nonsteroidal anti-inflammatory drugs

• may promote lithium reabsorption in the proximal tubule by a compensatory mechanism, thereby potentiating toxicity in patients on lithium therapy• Inhibition of renal tubular secretion of urate by

thiazide diuretics can result in hyperuricemia in 50% of treated patients, and a small percentage of patients might develop clinical gout• glucose intolerance and aggravate glucose control

in diabetic patients, especially when used in combination with β blockers

• thiazide-induced hypokalemia may be associated with glucose intolerance and treating the hypokalemia may protect from developing diabetes• may affect cholesterol and triglyceride levels,

aggravating hyperlipidemia• because of the structural similarities between

sulfonamide antibiotics and thiazide & loop diuretics, it has been suggested that patients with sulfa allergy may demonstrate cross-reactivity to these classes of diuretics

Loop Diuretics• inhibit reabsorption of sodium, potassium, and

chloride by impairing activity of the Na+-K+-2Cl− transport protein in the medullary portions of the thick ascending limb of the loop of Henle• Includes• Ethacrynic acid• Furosemide• Torasemide• Azosemide• Bumetanide

Pharmacokinetics and Pharmacodynamics

• effective when administered orally or intravenously (IV)• an average bioavailability of 50% (10-100%)• Protein binding is extensive, with approximately

90% of the drug bound to albumin• Glomerular filtration and renal tubular secretion--

50% to 60% of furosemide excretion• remaining 40% to 50% is conjugated to

glucuronide in the kidneys

• elimination half-life is 1 to 2 hours• a rapid onset, 5 to 10

minutes of administration• a peak effect at 30 minutes • duration of action of 2 to 6

hours

• Torasemide is twice as potent as furosemide and has a longer duration of action, with a plasma half-life of 3 to 4 hours allowing for a once a day dosing• Bumetanide has a bioavailability of 80% to 100% after

oral administration and is 40 times more potent than furosemide• Doses :

• I.V Furosemide 20-100mg (PO 0.75-3mg/kg,IV 0.1 -1.0mg/ kg)• Torsemide 10-100mg • Bumetanide 0.5-1mg

Clinical Uses• commonly used in patients with acute

exacerbation of heart failure-mobilization of edema fluid

• hypertension as adjuncts

• evaluation of acute oliguria

• conversion of oliguric renal failure to non oliguric renal failure

• treatment of hypercalcemia

• treatment of increased intracranial pressure

Side Effects• manifest as abnormalities of fluid and electrolyte

balance

• hypokalemia and increase the likelihood of digitalis toxicity

• may cause hyperuricemia

• Hyperglycemia

• braking phenomenon

• Hypotension may result in hypovolemic patients exacerbating renal ischemic injury and concentrating nephrotoxins in the renal tubules

• increases renal tissue concentrations of aminoglycosides and enhances the possible nephrotoxic effects of these antibiotics

• potentiate non-depolarizing neuromuscular blockade

• renal clearance of lithium is decreased and plasma concentrations of lithium may be increased

• Ototoxicity, either transient or permanent-rare, dose-dependent

Carbonic Anhydrase Inhibitors

• Acetazolamide• bind avidly to the enzyme carbonic anhydrase• produces noncompetitive inhibition of enzyme

activity, principally in the proximal renal tubules and the collecting ducts• Interfere with Na+ reabsorption and H+ secretion in

PCT• results in decreased reabsorption of Na+, HCO3

−, and water

Pharmacokinetics and Pharmacodynamics

• After oral administration, acetazolamide is excreted unchanged by the kidneys

• dose should be adjusted in patients with renal failure and the elderly

• increased excretion of HCO3− results in an alkaline

urine and metabolic acidosis

• Natriuresis associated with carbonic anhydrase inhibitors is modest

• increased delivery of Na+ to the distal tubules leads to potassium loss

• Most of the chloride is reabsorbed in the loop of Henle, leading to the excretion of an alkaline urine in the presence of hyperchloremic metabolic acidosis

• dose 200mg – 500mg orally

Clinical Uses• Diuretic of choice in altitude sickness

• Correction of metabolic alkalosis in edematous patients

• Alkalinization of urine- enhance urinary excretion of weakly acidic compound such as uric acid

• Reduction of IOP

• Idiopathic intracranial hypertension

• Epilepsy : because acidosis results in decrease seizures

• Familial periodic paralysis- drug induced metabolic acidosis which increases the local concentration of K+ in skeletal muscles

Side Effects• high incidence of systemic side effects associated

with the use of acetazolamide• fatigue• decreased appetite• depression• paresthesias

• dose should be reduced in patients with chronic renal insufficiency and avoided in patients with severe chronic renal insufficiency because of the increased risk of metabolic acidosis

Osmotic Diuretics• are inert substances that do not undergo

metabolism and are filtered freely at the glomerulus • mannitol, urea, isosorbide, and glycerin• administration causes increased plasma and renal

tubular fluid osmolality, with resulting osmotic diuresis

• portions of the renal tubules that are highly permeable to water-the proximal renal tubules and more importantly, the loop of Henle, represent the principal site of action of osmotic diuretics

Mannitol• only osmotic diuretic in current use• mannitol is a six-carbon sugar alcohol that does not

undergo metabolism• is not absorbed from the gastrointestinal tract,

which necessitates its exclusive use by IV injection• does not enter cells, and only means of clearance

from the plasma is by glomerular filtration

Pharmacokinetics and Pharmacodynamics• is completely filtered at the glomeruli, and none of

the filtered drug is subsequently reabsorbed from the renal tubules

• by increasing tubular fluid osmolality, it decreases water reabsorption and promotes water diuresis

• sodium is diluted in the retained water in the renal tubules, leading to less reabsorption

• Hypernatremia may result from the water diuresis

• Onset-10 to 15 minutes, with a peak effect at 30 to 45 minutes and a duration of 6 hours

Clinical Uses• primarily in the acute management of elevated ICP

and in the treatment of glaucoma• to prevent perioperative kidney failure in the

setting of acute tubular necrosis• has free radical scavenging properties, which may

protect transplanted kidneys following reperfusion

Side Effects• increase in intravascular volume with the use of

mannitol may be poorly tolerated in patients with left ventricular dysfunction, leading to pulmonary edema• in patients with renal insufficiency, mannitol is not

filtered and will cause increase in the intravascular volume• prolonged use of mannitol may cause hypovolemia,

electrolyte disturbances with hypokalemic hypochloremic alkalosis, and plasma hyperosmolarity due to excessive excretion of water and sodium

Potassium-Sparing Diuretics

• act on the collecting ducts• grouped in two categories: pteridine analogs and

aldosterone receptor blockers

• Pteridine analogs-triamterene and amiloride• prevent Na+ reabsorption in the cortical

collecting duct by blocking the epithelial Na+ channels independent of aldosterone

• Aldosterone receptor blockers-spironolactone and eplerenone• prevent the synthesis and the activation of the

aldosterone-dependent basal cell Na+-K+-ATPase pump

• Both mechanisms result in decreased Na+ reabsorption without the increased K+ secretion• do not cause substantial diuresis and are not used

as single antihypertensive therapy• are used in conjunction with thiazide diuretics to

prevent the associated loss of potassium and magnesium

Pteridine AnalogsPharmacokinetics and Pharmacodynamics

• Oral absorption of amiloride and triamterene is limited (25% and 50%, respectively)• Amiloride is more potent than triamterene and is

not metabolized but excreted unchanged in the kidneys• Triamterene is a pteridine with a structural

resemblance to folic acid

• metabolism of triamterene by the liver is extensive, and its metabolite, secreted into the renal tubule, has diuretic activity• Accordingly, both kidney and liver disease will affect

the pharmacokinetics of triamterene• the elimination half-time for triamterene is 4 hours

and for amiloride is about 20 hours

Clinical Uses• are most often used in combination with loop

diuretics or thiazide diuretics to augment diuresis and limit renal loss of potassium• are rarely used as monotherapy• cystic fibrosis is associated with increased sodium

absorption across airway epithelium, aerosolized amiloride has been investigated in patients with cystic fibrosis

Side Effects• Hyperkalemia is the principal side effect of therapy

with potassium-sparing diuretics• especially when combined with angiotensin-converting

enzyme inhibitors or angiotensin II receptor blockers or in presence of nonsteroidal anti-inflammatory drugs

• although triamterene is a weak folic acid antagonist, it rarely causes megaloblastic anemia except in patients already at risk for folic acid deficiency

Aldosterone Antagonists• synthetic steroid analog and a nonspecific

mineralocorticoid receptor antagonist• Spironolactone• binds to the cytoplasmic mineralocorticoid

receptors in the collecting ducts, preventing Na+ reabsorption via the Na+-K+ pump• Eplerenone-selective aldosterone receptor blocker,

has less affinity for other mineralocorticoid receptors, and is less potent than spironolactone

• previously believed that spironolactone effects were solely the result of competitive antagonism of aldosterone binding to the mineralocorticoid receptors--it has been shown to block the effects of other ligands, such as cortisol

Pharmacokinetics and Pharmacodynamics

• exert their effect on the aldosterone receptor of the tubular cell• reach the tubular cells from the plasma, not from

the tubular fluid• only diuretics that do not need to reach the renal

tubule to exert their effect

• competitive blockade of epithelial aldosterone receptors in the distal tubule and the collecting duct, preventing Na+-K+-ATPase activation and resulting in • decreased sodium reabsorption and in • decreased potassium excretion

• Oral absorption of spironolactone approaches 70% of the administered dose

• Spironolactone undergoes extensive hepatic first-pass metabolism with multiple active metabolites, which account for spironolactone’s long half-life of 20 hours• Spironolactone and its metabolites are extensively

bound to plasma proteins and excreted by the kidneys• Eplerenone undergoes hepatic metabolism and its

half-life is prolonged in the presence of CYTP3A4 inhibitors, such as ketoconazole and verapamil

Clinical Uses• treatment of essential hypertension, in combination

with thiazides, particularly in patients with a low renin state or patients with metabolic syndrome• used in patients with refractory hypertension• combination with a thiazide diuretic results in

improved diuresis and blood pressure control• used to promote diuresis in patients with edema and

fluid overload associated with hyperaldosteronism, such as liver cirrhosis, nephrotic syndrome, and heart failure

Side Effects• Hyperkalemia, especially in the presence of

impaired renal function• nonspecific mineralocorticoid receptor antagonist--

can block androgen and progesterone receptors, leading to gynecomastia and breast tenderness

Other Diuretics• Dopamine Receptor Agonists• dopamine and fenoldopam

• Natriuretic Peptides• nesiritide, a recombinant brain natriuretic peptide

• Vasopressin Receptor Antagonists (V2)• tolvaptan

• Neprilysin Antagonists• Aquaporin Modulators

THANK YOU!!!

Effects Of Diuretics On Urine Composition

Volume(ml/min) pH Na+

(mEq/L)K+

(mEq/L)Cl-

(mEq/L) HCO3-

No Drug 1 6.4 50 15 60 1Thiazide diuretics 13 7.4 150 25 150 25

Loop Diuretics 8 6.0 140 25 155 1Osmotic Diuretics 10 6.5 90 15 110 4

Potassium-sparing diuretics 3 7.2 130 10 120 15

Carbonic anhydrase Inhibitors 3 8.2 70 60 15 120

Reabsorption of filtered water and solutes from the tubular lumen across

the tubular epithelial cells