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166 Diuretics

Diuretics of the Sulfonamide Type

These drugs contain the sulfonamide group –SO2NH2 and are suitable for oral administration. In addition to being filtered at the glomerulus, they are subject to tubular secretion. Their concentration in urine is higher than in blood. They act on the tubule cells from the luminal side. Loop diuretics have the highest ef cacy. Thiazides are most frequently used. The carbonic anhydrase inhibitors no longer serve as diuretics but have important other therapeutic uses; accordingly,theirmodeofactionisconsideredhere.

Acetazolamide is a carbonic anhydrase

(CAH) inhibitor that acts predominantly in the proximal convoluted tubules. Its mechanismofaction canbe summarizedasfollows. Reabsorption of Na+ is decreased because fewer H+ ions are available for the Na+/H+ antiporter. As a result, excretion of Na+ and H2O increases. CAH accelerates attainment of equilibrium of CO2 hydration/dehydration reactions:

(1)(2)

H+ + HCO3– H2CO3 H2O + CO2 Cytoplasmic enzyme is used in tubulus cells to generate H+ (reaction 1), which issecreted into the tubular fluid in exchange for Na+. There, H+ captures HCO3. CAH localized in the luminal membrane catalyzes reaction 2 (dehydration) to yield again H2O and CO2, which can easily permeate through the cell membrane. In the tubulus cell, H+ and HCO3are regenerated. When the enzyme is inhibited, these reactions occur too slowly, so that less Na+, HCO3and water are reabsorbed from the fast-flowing tubular fluid. Loss of HCO3leads to acidosis. The diuretic effectiveness of CAH inhibitors decreases with prolonged use. CAH is also involved in the production of ocular aqueous humor. Present indications for drugs in this class include: acute glaucoma, acute mountain sickness, and epilepsy.

Dorzolamide can be applied topically to the eye tolower intraocular pressurein glaucoma (p.346).

Loop diuretics include furosemide (frusemide), piretanide, and others. After oral administration of furosemide, a strong diuresis occurs within 1 hour but persists for only about 4 hours. The site of action of these agents is the thick ascending limb of Henle’s loop, where they inhibit Na+/K+/2Clcotransport. As a result, these electrolytes, together with water, are excreted in larger amounts. Excretion of Ca2+ and Mg2+ also increases. Special adverse effects include (reversible) hearing loss and enhanced sensitivitytonephrotoxicagents. Indications:pulmonary edema (added advantage of i.v. injection in left ventricular failure: immediate dilation of venous capacitance vessels, † preload reduction); refractoriness to thiazide diuretics; e.g., in renal failure with creatinine clearance reduction (< 30 ml/min); prophylaxis of acute renal hypovolemic failure. Ethacrynic acid is classed in this group although it is not a sulfonamide.

Thiazide diuretics (benzothiadiazines) include hydrochlorothiazide, trichlormethiazide and butizide. Chlorthalidone is a longacting analogue. These drugsaffect the distal convoluted tubules, where they inhibit Na+/ Clcotransport in the luminal membrane of tubulus cells. Thus, reabsorption of NaCl and water is inhibited. Renal excretion of Ca2+ decreases, that of Mg2+ increases. Indications are hypertension, congestive heart failure, and mobilization of edema. Frequently, they are combined with the K+ sparing diuretics triamterene or amiloride (p.168)

Unwanted effects of sulfonamide-type diuretics: (a) hypokalemia is a consequence of an increased secretion of K+ in the connecting tubule and the collecting duct because more Na+ becomes available for exchange against K+; (b) hyperglycemia; (c) increase in serum urate levels (hyperuricemia), which may precipitate gout in predisposed patients. Sulfonamide diuretics compete with urate for the tubular organic anion secretory system.

Luellmann, Color Atlas of Pharmacology © 2005 Thieme

All rights reserved. Usage subject to terms and conditions of license.

Diuretics of the Sulfonamide Type

167

A. Diuretics of the sulfonamide type

 

 

 

 

 

 

 

 

 

 

Na+

 

 

Sulfonamide

 

 

 

 

 

 

K+

Normal

 

 

 

 

 

 

 

state

 

diuretics

 

 

 

 

 

 

 

 

 

 

 

 

 

Na+

 

 

 

 

 

 

 

 

 

 

 

 

Anion

 

 

 

 

 

 

 

 

 

secretory

 

 

 

 

 

Na+

K+loss

 

system

 

 

 

 

 

 

 

 

 

 

 

 

K+

induced

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Na+

 

by

 

 

 

 

 

 

 

 

diuretic

 

 

 

 

 

 

 

 

 

 

Uric acid

 

 

 

 

 

 

 

Collecting

 

 

 

 

 

 

 

 

duct

 

 

 

 

 

 

 

Thiazides

 

 

Gout

 

 

 

 

 

Na+

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Cl-

 

 

 

 

 

 

 

 

 

e.g., hydrochlorothiazide

 

 

 

 

 

 

 

H

 

Cl

 

 

 

 

 

 

 

N

 

 

 

 

 

 

 

 

HN S

 

O

 

 

 

 

 

 

 

 

S NH2

 

 

 

 

 

 

O

O

O

 

 

 

 

 

 

 

 

 

 

Carbonic anhydrase inhibitors

Loop diuretics

 

 

Na+

 

 

 

 

Na+

 

 

 

 

H+

H+

HCO-3

 

HCO-3

Na+

 

 

 

HCO-3

CAH

 

 

 

 

K+

 

 

 

H2O

CO2 H2O

 

 

2 Cl

 

 

 

CO2

 

 

 

 

 

 

 

 

 

e.g., acetazolamide

 

 

e.g., furosemide

 

 

 

CH3

N

N

O

 

CH2

NH

Cl

 

 

 

 

 

 

O

 

O

 

O

N

S

 

S

NH2

 

 

 

HOOC

S

NH2

 

H

 

 

O

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

O

 

 

 

 

 

 

 

 

 

 

Luellmann, Color Atlas of Pharmacology © 2005 Thieme

All rights reserved. Usage subject to terms and conditions of license.

168 Diuretics

Potassium-sparing Diuretics (A)

These agents act in the connecting tubules and the proximal part of the collecting ducts where Na+ is reabsorbed and K+ is secreted. Their diuretic effectiveness is relatively minor. In contrast to sulfonamide diuretics (p.166), there is no increase in K+ secretion; rather, there is a risk of hyperkalemia. These drugs are suitable for oral administration.

aTriamterene and amiloride, in addition to glomerular filtration, undergo secretion in the proximal tubule. They act on cortical collecting tubule cells from the luminal side. Both inhibit the entry of Na+ into the cell, whereby K+ secretion is diminished. They are mostly used in combination with thiazide diuretics, e.g., hydrochlorothiazide, because the opposing effects on K+ excretion cancel each other, while the effects on secretion of NaCl and water complement each other.

bAldosterone antagonists. The mineralocorticoid aldosterone increases synthesis of Na-channel proteins and Na+/K+-ATPases in principal cells of the connecting tubules and the cortical collecting ducts, thereby promoting the reabsorption of Na+ (Cl

and H2O follow), and simultaneously enhancing secretion of K+. Spironolactone, as well as its metabolite canrenone, are antagonists at the aldosterone receptor and attenuate the effect of the hormone. The diuretic effect of spironolactone develops fully only with continuous administration for several days. Two possible explanations are: (1) the conversion of spironolactone into and accumulation of the more slowly eliminated metabolite canrenone;

(2)an inhibition of aldosterone-stimu- lated protein synthesis would become noticeable only if existing proteins had become nonfunctional and needed to be re-

placed by de-novo synthesis.

A particular adverse effect results from interference with gonadal hormones, as evidenced by the development of gynecomastia. Clinical uses include conditions of

increased aldosterone secretion (e.g., liver cirrhosis with ascites) and congestive heart failure.

Vasopressin and Derivatives (B)

Vasopressin (ADH), a nonapeptide, is released from the posterior pituitary gland and promotes reabsorption of water in the kidney. This response is mediated by vasopressin receptors of the V2 subtype. AVP enhances the permeability of connecting tubules and medullary collecting duct epithelium for H2O (but not electrolytes) in the following manner: H2O-channel proteins (type 2 aquaporins) are stored in tubulus cells within vesicles. When AVP binds to V2 receptors, these vesicles fuse with the luminal cell membrane, allowing influx of H2O along its osmotic gradient (the medullary zone is hyperosmolar). AVP thus causes urine volume to shrink from 15 l/day at this point of the nephron to the final 1.5 l/day. This aquaporin type can be reutilized after internalization into the cell. Nicotine augments (p.112) and ethanol decreases release of AVP. At concentrations above those required for antidiuresis, AVP stimulates smooth musculature, including that of blood vessels (“vasopressin”). The latter response is mediated by V1 receptors. Blood pressure rises; coronary vasoconstriction can precipitate angina pectoris.

Lypressin (8-L-lysine-vasopressin) acts like AVP. Other derivatives may display only one of the two actions.

Desmopressin is used for the therapy of diabetes insipidus (AVP deficiency), primary nocturnal enuresis and von Willebrand disease (p.152); it is given by injection or via the nasal mucosa (as “snuff”).

Felypressin and ornipressin serve as adjunctive vasoconstrictors in infiltration local anesthesia (p.204).

Luellmann, Color Atlas of Pharmacology © 2005 Thieme

All rights reserved. Usage subject to terms and conditions of license.

Potassium-sparing Diuretics and Vasopressin

169

A. Potassium-sparing diuretics

 

 

 

 

 

 

Na+

 

 

 

 

 

 

H2N N N NH2

 

O

CH2OH

 

 

 

N

HO

HC

C O

 

 

 

 

 

N

 

 

 

K+

 

 

 

 

 

 

NH2

 

 

 

 

 

 

 

 

Triamterene

 

 

O

Aldosterone

 

 

 

Na+

 

 

Aldosterone

 

 

 

 

 

 

antagonists

 

 

 

 

K+ or

 

 

 

 

 

 

H+

 

Canrenone

 

 

 

 

Protein synthesis

 

 

 

 

 

 

 

 

 

 

 

Transport capacity

 

 

 

 

 

 

 

O

Amiloride

 

 

Spironolactone

O

 

 

HN2 H

 

 

 

H2N

N

NH2

 

 

 

N

 

 

 

Cl

N

 

NH

 

6 7

CH3

 

 

O

S C

 

 

O

 

 

 

 

 

 

 

 

 

 

 

 

 

 

O

B. Antidiuretic hormone (ADH) and derivatives

 

 

 

 

 

 

 

 

 

 

 

Nicotine

 

 

 

 

 

Neuro-

 

 

 

 

 

 

 

 

 

 

hypophysis

 

 

 

Ethanol

 

 

Vasoconstriction

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

V2

 

 

 

Adiuretin = Vasopressin

 

 

V1

 

H2O

 

 

 

 

 

 

 

 

 

 

 

permeability

Cys

Tyr

Phe

Gln

Asn

Cys

Pro

Arg

Gly

NH2

 

of collecting

 

 

 

 

 

 

 

 

 

 

 

duct

 

 

 

 

 

 

 

 

 

 

Desmopressin

 

 

 

 

 

 

Ornipressin

 

 

 

 

 

 

 

 

 

 

 

 

 

Orn

CH2

C

 

 

 

D-Arg

 

 

Felypressin

 

 

CH2

O

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

S

 

 

 

 

 

 

 

Phe

 

Lys

Luellmann, Color Atlas of Pharmacology © 2005 Thieme

All rights reserved. Usage subject to terms and conditions of license.

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