cap27 diureticos

7/24/2019 cap27 diureticos

1/26

Print Preview

Chapter 27

Diuretics

Gary O. Rankin

Introduction

Diuret ics are chemicals that increase the rate of ur ine format ion ( 1) . By increas ing the ur ine f low rate,

d iuret ic usage leads to increased excret ion of e lect ro ly tes (especia l ly sodium and c h lor ide ions) and water

f rom the body wi thout a f fect ing prote in , v i tamin, g lucose, or amino a c id reabsorpt ion. These

pharmacologica l proper t ies have led to the use of d iuret ics in th e t reatment o f edematous condi t ions

resul t ing f rom a var ie ty of causes (e.g. , congest ive hear t fa i lure, nephrot ic syndrome, and chronic l iver

d isease) and in the management of hyper tens ion. Diuret ic drugs a l so are usefu l as the so le agent or as

adjunct therapy in the t reatment o f a wide range o f c l in ica l condi t ions, inc lud ing hypercalcemia, d iabetes

ins ip idus, acute mounta in s ickness, pr imary hypera ldosteronism, and g laucoma.

The pr imary target organ for d iuret ics is the k idney, where th ese drugs in ter fere wi th the reabsorpt ion of

sodium and other ions f rom the lumina of the nephrons, which are the funct ional un i ts o f the k idney. Theamount o f ions and accompanying water that are excreted as ur ine fo l lowing admin is t ra t ion of a d iuret ic ,

however , is determined by many factors , inc lud ing the chemical s t ructure of the d iuret ic , the s i te or s i tes of

act ion of the agent , the sa l t in take of the pa t ient , and the amount o f ext racel lu lar f lu id present . In addi t ion

to the d i rect e f fect o f d iuret ics to impai r so lute and w ater reabsorpt ion f rom the nephron, d iuret ics a lso can

t r igger compensatory phys io log ica l events that have an impact on e i ther the magni tude or the durat ion of

the d iuret ic response. Thus, i t is impor tant to be aware of the normal mechanisms of ur ine format ion and

renal cont ro l mechanisms to understand c lear ly the abi l i ty o f chemicals to induce a d iures is .

Normal Physiology of Urine Formation

Two impor tant funct ions of the k idney are 1) to m ainta in a homeostat ic ba lance of e lect ro ly tes and water

and 2) to excrete water -so lub le end products of me tabol ism. The k idney accompl ishes these funct ions

through the format ion of ur ine by the nephrons ( F ig. 27.1) . Each k idney conta ins approx imate ly 1 mi l l ion

nephrons and is capable of forming ur ine independent ly . The nephrons are composed of a spec ia l ized

capi l lary bed ca l led the g lomerulus and a long tubule d iv ided anatomical ly and funct ional ly in to the prox imal

tubule, loop of Henle, and d is ta l tubule. Each component o f the nephron contr ibutes to the normal funct ions

of the k idney in a un ique manner ; thus, a l l are targets for d i f ferent c lasses of d iuret ic agents .

Ur ine format ion begins wi th the f i l t ra t ion of b lood at the g lomerulus. Approx imate ly 1,200 mL of b lood per

minute f lows through both k idneys and reaches the n ephron by way of a f ferent ar ter io les. Approx imate ly

20% of the b lood enter ing the g lomerulus is f i l tered in to Bowman's capsule to form the g lomerular f i l t ra te.

The g lomerular f i l t ra te is composed of b lood components wi th a molecular weight less than that o f a lbumin

(~69,000 dal tons) and not bound to p lasma prote ins. The g lomerular f i l t ra t ion rate (GFR) averages 125

mL/min in humans but can vary widely even in normal funct ional s ta tes.

The g lomerular f i l t ra te leaves the Bowman's capsule and enters th e prox imal convoluted tubule (S1, S2

segments, F ig 27.1) , where the major i ty (5060%) of f i l tered sodium is reabsorbed osmot ica l ly . Sodium

reabsorpt ion is coupled e lect rogenet ica l ly wi th the reabsorpt ion of

g lucose, phosphate, and amino ac ids and nonelect rogenet ica l ly wi th b icarbonate reabsorpt ion. Gluc ose and

amino ac ids are complete ly reabsorbed in th is por t ion of the nephron, whereas phosphate reabsorpt ion is

between 80 and 90% complete. The ear ly prox imal convoluted tubule a lso is the pr imary s i te of b icarbonate

reabsorpt ion (8090%), a process that is main ly sodium depende nt and coupled to hydrogen ion secret ion.

The reabsorpt ion of sodium and b icarbonate is fac i l i ta ted by the e nzyme carbonic anhydrase, which is

present in prox imal tubular ce l ls and cata lyzes the format ion of carbonic ac id f rom water and carbon

diox ide. The carbonic ac id prov ides the hydrogen ion, which dr ives the reabsorpt ion of sodium b icarbonate.

Chlor ide ions are reabsorbed pass ive ly in the prox imal tubule, where they fo l low act ive ly t ranspor ted

sodium ions in to tubular ce l ls .

P.723

Pgina 1 de 26

27/05/2010http://pt.wkhealth.com/pt/re/9780781768795/bookContentPane_frame.01329153-6th_...


2/26

Clinical Signif icance

I t is impor tant for the c l in ic ian to understand the medic ina l chemist ry of the d iuret ics to appropr ia te ly

use them in ind iv idual pat ients . Th is d iverse group of medicat ions is c lass i f ied in many ways:

mechanism of act ion, s i te of act ion, chemical c lass, and e f fect on ur ine contents . Knowledge of

s t ructureact iv i ty re la t ionships helps to predic t ind icat ions, poss ib le of f - label uses, magni tude of

d iures is , potency, and s ide ef fect prof i le .

Consequent ly , d iuret ics have a var ie ty of uses. Thiaz ide d iuret ics may be used e i ther a lone or in

combinat ion wi th other pharmacotherapy for the t reatment o f hyper tens ion. Loop d iuret ics can prov ide

immediate d iures is and are used for hear t fa i lure and in l ieu of th iaz ides in pat ients wi th compromised

renal funct ion. In addi t ion to more t rad i t ional uses, cer ta in potass ium-spar ing d iuret ics prov ide added

benef i t to o ther pharmacotherapy in pat ients wi th pr imary hypera ldosteronism, hear t fa i lure, o r post

acute myocard ia l in farc t ion. Carbonic anhydrase inh ib i tors have l imi ted use for d iures is ; how ever , they

may be used to reduce in t raocular pressure and t rea t acute mounta in s ickness.

A thorough understanding of the medic ina l chemist ry , mechanisms of act ion, and pharmacokinet ics

helps the c l in ic ian to use avai lab le d iuret ics appropr ia te ly . As new me dicat ions are developed, the

c l in ic ian wi l l re ly on these bas ic concepts to cont inue ta i lor ing therapy to the ind iv idual pat ient wi th the

goals to maximize outcomes, improve qual i ty o f l i fe , and min imize adverse events .

Kimber ly B i r tcher Pharm.D.

Cl in ica l Ass is tant Professor , Depar tment o f Cl in ica l Sc iences and Admin is t ra t ion, Univers i ty o f Houston

Col lege of Pharmacy

The reabsorpt ion of e lect ro ly tes and water a lso occurs isosmot ica l ly in the p rox imal s t ra ight tubule or pars

recta (S3 segment , F ig. 27.1) . By the end of the s t ra ight segment , b etween 65 and 70% of water and

sodium, ch lor ide, and ca lc ium ions; 80 to 90% of b icarbonate and phosphate; and essent ia l ly 100% of

g lucose, amino ac ids, v i tamins, and prote in have been reabsorbed f rom the g lomerular f i l t ra te. The prox imal

tubule a lso is the s i te for act ive secret ion of weakly ac id ic and weakly bas ic organic compounds. Thus,

many of the d iuret ics can enter luminal f lu id not o n ly by f i l t ra t ion at the g lomerulus but a lso by act ive

secret ion.

The descending l imb of the loop of Henle is impermeable to ions, but water can f ree ly move f rom the

luminal f lu id in to the surrounding medul lary in ters t i t ium, where the h igher osmola l i ty draws water in to the

inters t i t ia l space and concentrates luminal f lu id . Luminal f lu id cont inues to concentrate as i t descends to

the deepest por t ion of the loop of Henle, wh ere the f lu id becomes the most concentrated. The hyper ton ic

luminal f lu id next enters the water - impermeable, th ick ascending l imb of the loop of Henle. In th is segment

of the nephron, approx imate ly 20 to 25% of the f i l tered sodium and ch lor ide ions are reabsorbed v ia a

cot ranspor t system (Na +/K +/2 Cl - ) on the luminal membrane. Reabsorpt ion of sodium and ch lor ide in the

medul lary por t ion of the th ick ascending l imb is impor tant for mainta in ing the medul lary in ters t i t ia lconcentrat ion gradient . Reabsorpt ion of sodium chlor ide in the cor t ica l component o f the th ick ascending

l imb of the loop of Henle and the ear ly d is ta l convoluted tubule cont r ibutes to ur inary d i lu t ion, and as a

View Figure

Fig. 27.1.The nephron. BC, Bowman'scapsule; G, glomerulus; PCT, proximalconvoluted tubule; PST, proximal straight

tubule; DLH, descending limb of the Loopof Henle; TALH, thick ascending limb ofthe loop of Henle; DCT, distal convolutedtubule; CD, collecting duct.

Pgina 2 de 26



3/26

resul t , these two nephron sect ions somet imes are ca l led the cor t ica l d i lu t ing segment of the nephron.

Luminal f lu id leav ing the ear ly d is ta l tubule next passes through the la te d is ta l tubule and cor t ica l co l lect ing

tubule (co l lect ing duct ) , where sodium is reabsorbed in exchange for hydrogen and potass ium ions. This

process is par t ia l ly cont ro l led by minera locor t ico ids (e.g. , a ldosterone) and accounts for the reabsorpt ion o f

between 2 and 3% of f i l tered sodium ions. A l though the reabsorpt ion of sodium ions f rom these segments of

the nephron is not large, th is sodium/potass ium/hydrogen ion exchange system determines the f ina l ac id i ty

and potass ium content o f ur ine. Severa l factors , however , can in f luence the act iv i ty o f th is exchangesystem, inc lud ing the amount o f sodium ions del ivered to th ese segments, the s tatus of the ac id-base

balance in the body, and the levels of c i rcu lat ing a ldosterone.

The ur ine formed dur ing th is process represents on ly approx imate ly 1 to 2% of the or ig ina l g lomeru lar

f i l t ra te, wi th more than 98% of e lect ro ly tes and water f i l tered at the g lomerulus being reabsorbed dur ing

passage through the nephron. Thus, a change in u r ine output o f on ly 1 to 2% could double ur ine vo lume.

Ur ine leaves the k idney through the ureters and t ravels to the b ladder , where i t is s tored unt i l ur inat ion

removes the i t f rom the body.

Normal Regulation of Urine Formation

The body conta ins severa l cont ro l mechanisms that regulate the vo l ume and contents of ur ine. These

systems are act ivated by changes in so lute or water content o f the body, by changes in systemic or renal

b lood pressure, and by a var ie ty of o ther s t imul i . Act ivat ion o f one or more of these systems by d iuret ic

drugs can modi fy the ef fect iveness of these drugs to produce the i r therapeut ic response and may requi re

addi t ional therapeut ic measures to ensure a maximal response.

The k idney has the abi l i ty to respond to changes in the GFR through the act ion of spe c ia l ized d is ta l tubular

epi the l ia l ce l ls ca l led the macula densa. These ce l ls are in c lose contact wi th the g lomerular apparatus of

the same nephron and detect changes in the rate of ur ine f low and luminal sodium chlor ide concentrat ion.

An increase in the ur ine f low rate at th is s i te (as can occur wi th the use of some d iuret ics) act ivates the

macula densa ce l ls to communicate wi th the granular ce l ls a nd vascular segments of the juxtag lomerular

apparatus. St imulat ion of the juxtag lomerular apparatus causes ren in to be r e leased, which leads to the

format ion of angiotens in I I and subsequent renal vasoconst r ic t ion. Renal vasoconst r ic t ion leads to a

decrease in GFR and, poss ib ly , a decrease in the ef fect iveness of the d iuret ic . Renin re lease a lso can be

st imulated by factors other than d iuret ics , inc lud ing decreased renal per fus ion pressure, increased

sympathet ic tone, and decreased b lood vo lume.

Another impor tant regulatory mechanism for ur ine format ion is ant id iuret ic hormone (ADH), a lso known as

vasopress in, which is re leased f rom the poster ior p i tu i tary in response to reduced b lood pressure and

elevated p lasma osmola l i ty . In the k idney, ADH acts on th e co l lect ing tubule to increase water permeabi l i ty

and reabsorpt ion. As a resul t , the ur ine becomes mo re concentrated, and water is conserved in the

presence of ADH.

Disease States

The d iuret ic drugs are used pr imar i ly to t reat two m edica l ly impor tant condi t ions, edema and hyper tens ion.

Both condi t ions are common, a l though some pat ients exhib i t re f ractory d isease s tates that requi re

addi t ional modi f icat ion of the drug reg imen to inc lude a l ternat ive d iuret ics or ad di t ion of nondiuret ic drugs.

Edema (excess ive ext racel lu lar f lu id) normal ly resul ts f rom d isease to the hear t , k idney, or l iver . Decreased

card iac funct ion (e.g. , congest ive hear t d isease) can resul t in decreased per fus ion o f a l l organs (e.g. ,

k idney) and l imbs and an accumulat ion of edema f l u id in the ext remi t ies, par t icu lar ly around the ank les and

in the hands. Lef t -s ided hear t fa i lure can lead to the development of acute pulmonary edema, which is a

medica l emergency. Right -s ided hear t fa i lure sh i f ts ext racel lu lar f lu id vo lume f rom the ar ter ia l c i rcu lat ion to

the venous c i rcu lat ion, which leads to genera l edema format ion.

Kidney dysfunct ion can lead to edema format ion as a resul t o f decreased format ion of ur ine and the

subsequent imbalance of water and e lect ro ly te (e .g. , sodium ion) homeostas is . Retent ion of sa l t and water

resul ts in an expansion of the ext racel lu lar f lu id vo lume and, th us, edema format ion. Thus, when sa l t in take

exceeds sa l t excret ion, edema can form. Edema format ion a lso is assoc iated wi th deceased prote in leve ls

in b lood, as seen in nephrot ic syndrome and l iver d isease. Ci r rhos is of the l iver leads to increased lymph in

the space of Disse. Eventual ly , the increased lymph vo lume r esul ts in movement of f lu id in to the per i toneal

cav i ty and asc i tes develops.

Hyper tens ion develops f rom many causes and wi l l be d iscussed in more deta i l e lsewhere (see Chapter 29) .

In genera l , hyper tens ion occurs when b lood pressure is susta ined a t greater than 140/90 mm Hg. At th is

b lood pressure leve l , pat ients are at increased r isk for developing card iovascular d isease. One key e lement

in cont ro l l ing b lood pressure is sodium ion, and ear ly ant ihyper tens ive ef fects of d iuret ics are re la ted to

P.724

Pgina 3 de 26



4/26

increased sa l t and water excret ion. Addi t ional ly , however , d iuret ics have long- term ef fects resu l t ing in

decreased vascular res is tance that cont r ibute to b lood pressure cont ro l . A l though ef fects o n vascular

ca lc ium-act ivated potass ium channels have been proposed as cont r ibut ing to the chronic ant ihyper tens ive

ef fects of th iaz ide d iuret ics , the exact mechanisms of long term ef fe cts remain to be determined.

Diuret ics a lso are usefu l in t reat ing a number of o ther condi t ions inc lud ing increased crania l ( t rauma or

surgery) or in t raocular (g laucoma) pressure ( i .e . , osmot ic d iuret ics) , d iabetes ins ip idus ( i .e . , th iaz ides) ,

hypercalcemia ( i .e . , loop d iuret ics) , acute mounta in s ickness ( i .e . ,

carbonic anhydrase inh ib i tors) , pr imary hypera ldosteronism ( i .e . , a ldosterone antagonis ts) , and

osteoporos is ( i .e . , th iaz ides) .

General Therapeutic Approaches

Diuret ic drugs may be admin is tered acute ly or chronica l ly to t reat ed ematous s tates. When immediate

act ion to reduce edema (e.g. , acute pulmonary edema) is needed, in t ravenous admin is t ra t ion of a loop

diuret ic o f ten is the approach of choice. Thiaz ide or loop d iuret ics normal ly are admin is tered ora l ly to t reat

nonemergency edematous s tates. The magni tude of the d iuret ic response is d i rect ly propor t ional to the

amount o f edema f lu id that is present . As the vo lume of edema decreases, so does the m agni tude of the

diuret ic response wi th each dose. I f concern ex is ts about d iuret ic - induced h ypokalemia developing, then a

potass ium supplement or potass ium-spar ing d iuret ic may be added to th e drug reg imen. The development of

hypokalemia is par t icu lar ly impor tant for pat ients wi th congest ive hear t fa i lure who a lso are tak ing card iac

glycos ides, such as d ig i ta l is . D ig i ta l is has a narrow therapeut ic index, and developing hypokalemia can

potent ia te d ig i ta l is - induced card iac ef fects wi th potent ia l ly fa ta l resul ts .

Diuret ic drugs ( th iaz ide and loop d iuret ics) are admin is tered ora l ly to he lp cont ro l b lood pressure in the

t reatment o f hyper tens ion. Diuret ics of ten are the f i rs t drugs used to t r eat hyper tens ion, and they a lso may

be added to other drug therapies used to cont ro l b lood pressure wi th benef ic ia l e f fects .

Diuretic Drug C lasses

History

Compounds that increase the ur ine f low rate have bee n known for centur ies. One of the ear l ies t substances

known to induce d iures is is water , an inh ib i tor o f ADH re lease. Calomel (mercurous ch lor ide) was used as

ear ly as the 16th century as a d iuret ic , but because of poor absorpt ion f rom the gast ro in test ina l t ract and

tox ic i ty , ca lomel was rep laced c l in ica l ly by the organomercur ia ls (e .g. , ch lormerodr in) . The

organomercur ia ls represented the f i rs t group of h igh ly ef f icac ious d iuret ics avai lab le for c l in ica l use. Th e

need to admin is ter these drugs parentera l ly , the poss ib i l i ty o f to lerance, and the i r potent ia l tox ic i ty ,

however , soon led to the search for newer , less tox ic d iuret ics . Today, the organomercur ia ls are no longer

used as d iuret ics , but the i r d iscovery began the search for many of the d iuret ics used today. Other

compounds prev ious ly used as d iuret ics inc lude the ac id- forming sa l ts (ammonium chlor ide) and

methy lxanth ines ( theophyl l ine) .

Structure Classification

The d iuret ics current ly in use today ( Table 27.1) are c lass i f ied by the i r chemical c lass ( th iaz ides) ,

mechanism of act ion (carbonic anhydrase inh ib i tors and osmot ics) , s i te o f ac t ion ( loop d iuret ics) , or e f fects

on ur ine contents (potass ium-spar ing d iuret ics) . These drugs vary widely in the i r e f f icacy ( i .e . , the i r ab i l i ty

to increase the rate of ur ine format ion) and the i r s i te o f act ion wi th in the nephron. Ef f icacy of ten is

measured as the abi l i ty o f the d iuret ic to increase the excret ion of sodium ions f i l tered at the g lomerulus

( i .e . , the f i l tered load of sodium) and should not be confused wi th potency, which is the amount o f the

diuret ic requi red to produce a spec i f ic d iuret ic response.

Ef f icacy is determined, in par t , by the s i te of act ion of the d iuret ic . Drugs (e.g. , carbonic anhydrase

inhib i tors) that act pr imar i ly on the prox imal convoluted tubule to induce d iures is are weak d iuret ics

because of the abi l i ty o f the nephron to reabsorb a s ign i f icant por t ion of the luminal contents in la t ter

por t ions of the nephron. L ikewise, drugs (potass ium-spar ing d iuret ics) that act a t the more d is ta l segments

of the nephron are weak d iuret ics ,

because most o f the g lomerular f i l t ra te has a l ready been rea bsorbed in the prox imal tubule and ascending

l imb of the loop of Henle before reaching the d is ta l tubule. Thus, the most e f f icac ious d iuret ics d iscoveredso far , the h igh-ce i l ing or loop d iuret ics , in ter fere wi th sodium chlor ide reabsorpt ion at the ascending l imb

of the loop of Henle, which is s i tuated af ter the prox imal tubule but before the d is ta l por t ions of the nephron

and co l lect ing tubule.

P.725

P.726

Pgina 4 de 26



5/26

Osmotic Diuretics

Mechanism of Action

Osmot ic d iuret ics are low-molecular -weight compounds that are f ree ly f i l tered through the Bowman 's

capsule in to the renal tubules, are nonreabsorbable so lutes, and are not extens ive ly metabol ized except for

Table 27.1. Diuretics: Sites and Mechanisms of Action

Class ofDiuretic Site of Action Mechanism of Action

Osmotics Proximal tubule Osmotic effects decrease

sodium and water reabsorption

Loop of Henle Increases medullary blood flowto decrease medullaryhypertonicity and reducesodium and water reabsorption

Collecting tubule Sodium and waterreabsorption decreasesbecause of reduced medullaryhypertonicity and elevatedurinary flow rate

Carbonicanhydraseinhibitors

Proximalconvolutedtubule

Inhibition of renal carbonicanhydrase decreases sodiumbicarbonate reabsorption

Thiazidesand thiazide-

like

Cortical portionof the thick

ascending limbof loop of Henleand distal tubule

Inhibition of Na+/Cl-symporter

Loop orhigh-ceiling

Thick ascendinglimb of the loopof Henle

Inhibition of the luminal

Na+/K+/2Cl-transport system

Potassium-sparing

Distal tubule andcollecting duct

Inhibition of sodium and waterreabsorption by: Competitiveinhibition of aldosterone(spironolactone) Blockade ofsodium channel at the luminalmembrane (triamterene andamiloride)

Pgina 5 de 26



6/26

glycer in and urea (see Table 27.2) for the i r pharmacokinet ic proper t ies) . Once in the renal tubule, osmot ic

d iuret ics have a l imi ted reabsorpt ion because of the i r h igh water so lub i l i ty . When admin is tered as a

hyper ton ic (hyperosmolar ) so lut ion, these agents increase in t ra luminal osmot ic pressure, caus ing water to

pass f rom the body in to the tubule. S ince the osmot ic agent and assoc iated water are not reabsorbed f rom

the nephron, a d iuret ic e f fect is observed. Osmot ic d iuret ics increase the vo lume of ur ine and the excret ion

of water and a lmost a l l o f the e lect ro ly tes.

Polyo ls , such as manni to l , sorb i to l , and isosorb ide, prov ide th is e f fect . Sugars, such as g lucose and

sucrose, a lso can have a d iuret ic e f fect by th is me chanism. Al though not a po lyo l , urea has a s im i larosmot ic e f fect and has been used in the past as an osmot ic d iuret ic .

Therapeutic Applications

Osmot ic d iuret ics are not f requent ly used in medic ine today except in the prophylax is o f acute renal fa i lure,

in which these drugs inh ib i t water reabsorpt ion and mainta in

ur ine f low. They a lso may be helpfu l in mainta in ing ur in e f low in cases where ur inary output is d imin ished

because of severe b leeding or t raumat ic surg ica l exper iences. The osmot ic d iuret ics a lso have been used to

acute ly reduce increased in t racrania l or in t raocular pressure. They are not cons idered to be pr imary

diuret ic agents in t reat ing ord inary edemas, because osmot ic d iuret ics can exp and ext racel lu lar f lu id

volume.

P.727

Table 27.2. Pharmacokinetic Properties of the Nonthiazide Diure

Drug Trade NameRelativePotency

OralAbsorption(%)

PeakPlasma

Durationof EffectHalf-life

Osmotic diuretics

Glycerin >80 1 1.5h

46h

0.50.75 h

Isosorbide >80 NA NA 59.5h

Pgina 6 de 26



7/26


8/26

Adverse Effects

Osmot ic d iuret ics induce few adverse ef fects , but expansion of the ext racel lu lar f lu id vo lume can occur , as

noted above. A l terat ion of b lood sodium levels can be seen, and these drugs should not be used in anur ic

or unresponsive pat ients . I f c ran ia l b leeding is present , manni to l or urea s hould not be used.

Specific Drugs

Mannitol

Manni to l is the agent most commonly used as an osmot ic d iuret ic . Sorb i to l a lso can be used for s imi lar

reasons. These compounds can be prepared by the e lect ro ly t ic reduct ion of g lucose or sucrose.

Manni to l is admin is tered in t ravenously in so lut ions of 5 to 50% at a ra te of admin is t ra t ion that is ad justed to

mainta in the ur inary output a t 30 to 50 ml /hour . Manni to l is f i l tered at the g lomerulus and is poor ly

reabsorbed by the k idney tubule. The osmot ic e f fect o f m anni to l in the tubule inh ib i ts the reabsorpt ion of

water , and the rate of ur ine f low can be mainta ined. I t a lso is used to reduce in t racrania l pressure by

reducing cerebra l in t ravascular vo lume.

Isosorbide

Isosorb ide is bas ica l ly a b icyc l ic form of sorb i to l that is used o ra l ly to cause a reduct ion in in t raocular

pressure in g laucoma cases. A l though a d iuret ic e f fect is noted, i ts ophthalmologic proper t ies are i ts

pr imary va lue.

Carbonic Anhydrase Inhibitors

Triameterene Dyrenium 0.1 >70 2 4 h

>24h

23 h

Aldosterone antagonists; potassium-sparing diuretics (mineralocorticoid reantagonists)

Spironolactone Aldactone >90c 12 h

23d

13 h

Canrenone NA 13 24 h

34 h

(7-thiospironolactone) active metabolite

aFood affects bioavailability.

bIn patients with renal insufficiency.

cFormulation affects bioavailability.

Data from McEvoy GK, ed. AHFS 2000 Drug Information. Bethesda, MD: AmericHealth-System Pharmacists, 2000.NA, no data available.

Pgina 8 de 26



9/26

Mechanism of Action

In 1937, i t was proposed that the normal ac id i f icat ion o f ur ine was caused by secret ion of hydrogen ions by

the tubular ce l ls o f the k idney. These ions were p rov ided by the act ion of the enzyme carbonic anh ydrase,

which cata lyzes the format ion of carbonic ac id (H 2CO 3 ) f rom carbon d iox ide and water .

I t a lso was observed that su l fan i lamide rendered the ur ine of dogs a lka l ine because of the inh ib i t ion of

carbonic anhydrase. This inh ib i t ion of carbonic anhydrase resul ted in a lesser exchange of hydrogen ions

for sodium ions in the k idney tubule. Sodium ions, a long wi th b icarbonate ions, and assoc iated water

molecules were then excreted, and a d iuret ic e f fect was noted. The large doses requi red and the s ide

ef fects of su l fan i lamide prompted a search for more ef fect ive carbonic a nhydrase inh ib i tors as d iuret ic

drugs.

I t was soon learned that the su l fonamide por t ion of an act ive d iuret ic molecule could not be

monosubst i tu ted or d isubst i tu ted. I t was reasoned that a more ac id ic su l fonamide would b ind more t ight ly to

the carbonic anhydrase enzyme. Synthes is of more ac id ic su l fonamides produced compounds more than

2,500- fo ld more act ive than su l fan i lamide. Acetazolamide was in t roduced in 1953 as an ora l ly e f fect ive

diuret ic drug. Before that t ime, the organic mercur ia ls , which commonly requi red in t ramuscular in ject ion,

were the pr inc ipa l d iuret ics avai lab le.

Carbonic anhydrase inh ib i tors induce d iures is by inh ib i t ing the format ion of carbonic ac id wi th in prox imal

(prox imal convoluted tubule; S2) and d is ta l tubular ce l ls to l imi t the n umber of hydrogen ions avai lab le to

promote sodium reabsorpt ion. For a d iuret ic response to be observed, more than 99% of the carbonic

anhydrase must be inh ib i ted. A l though carbonic anhydrase act iv i ty in the p rox imal tubule regulates the

reabsorpt ion of approx imate ly 20 to 25% of the f i l tered load of sodium, the carbonic anhydrase inh ib i tors

are not h igh ly ef f icac ious d iuret ics . An increased excret ion of on ly 2 to 5% of the f i l tered load of sodium is

seen wi th carbonic anhydrase inh ib i tors because of increased reabsorpt ion of s odium ions by the ascending

l imb of the loop of Henle and more d is ta l nephron segments.

Therapeutic ApplicationsWith pro longed use of the carbonic anhydrase inh ib i tor d iuret ics , the ur ine becomes more a lka l ine, and the

blood becomes more ac id ic . When ac idos is occurs, the carbonic anhydrase inh ib i tors lose the i r

e f fect iveness as d iuret ics . They remain inef fect ive unt i l normal ac id-base balance in the body has been

regained. For th is reason, th is c lass of compounds is l imi ted in i ts d iuret ic use. Today, they are most

commonly used in the t reatment o f g laucoma, in wh ich they reduce the rate of aqueous humor format ion

and, subsequent ly , reduce the in t raocular pressure. These compounds a lso h ave found some l imi ted use in

the t reatment o f absence se izures, to a lka l in ize the ur ine, to t reat fami l ia l per iod ic para lys is , to reduce

metabol ic a lka los is , and prophylact ica l ly , to reduce acute mounta in s ickness.

Specific Drugs

AcetazolamideAcetazolamide was the f i rs t o f the carbonic anhydrase inh ib i tors to be in t roduced as an ora l ly e f fect ive

diuret ic , w i th a d iuret ic e f fect that las ts approx imate ly 8 to 12 h ours (see Table 27.2for i ts pharmacokinet ic

proper t ies) . As ment ioned ear l ier , i ts d iuret ic act ion is l imi ted because of the systemic ac idos is i t produces.

Pgina 9 de 26



10/26

Acetazolamide reduces the rate of aqueous humor format ion and is used pr imar i ly for reduc ing in t raocular

pressure in the t reatment o f g laucoma. The dose is 250 mg to 1 g per day.

Glaucoma

The fo l lowing carbonic anhydrase inh ib i tors are used ora l ly in the t reatment o f g laucoma.

Methazolamide

Methazolamide is a der ivat ive of acetazolamide in which one o f the act ive hydrogens has been rep laced by

a methy l group. This decreases the polar i ty and permi ts a greater penetrat ion in to the ocular f lu id , where i t

acts as a carbonic anhydrase inh ib i tor , reduc ing in t raocular pressure. I ts dose for g laucoma is 50 to 100 mg

two to three t imes a day.

Ethoxzolamide and dichlorphenamide

Ethoxzolamide is another carbonic anhydrase inh ib i tor wi th proper t ies and uses resemb l ing those of

acetazolamide. Dich lorphenamide is a d isu l fonamide der ivat ive that shares the same ph armacologica l

proper t ies and c l in ica l uses as the prev ious ly d iscussed compounds. The dose of d ich lorphenamide is 25 to

100 mg one to three t imes a da y.

Benzothiadiazine or Thiazide Diuretics

Fur ther s tudy of the benzene d isu l fonamide der ivat ives was under taken to f ind more ef f icac ious carbonic

anhydrase inh ib i tors . These s tud ies prov ided some compounds wi th a h igh degree of d iuret ic act iv i ty .

Chloro and amino subst i tu t ion gave compounds wi th increased act iv i ty , bu t these compounds were weak

carbonic anhydrase inh ib i tors . When the amino group was acy lated, an unexpected r ing c losure took p lace.

These compounds possessed a d iuret ic act iv i ty independent o f the carbonic anhydrase inh ib i tory act iv i ty ,

and a new ser ies of d iuret ics ca l led the benzoth iad iaz ines w as d iscovered.

Mechanism of Action

The mechanism of act ion of the benzoth iad iaz ine d iuret ics is p r imar i ly re la ted to the i r ab i l i ty to inh ib i t the

Na+/C l - sympor ter located in the d is ta l convoluted tubule. These d iuret ics are act ive ly secreted in the

prox imal tubule and are carr ied to the loop of Henle and to the d is ta l tubule. The major s i te of act ion of

these compounds is in the d is ta l tubule, where these drugs compete for the ch lor ide b ind ing s i te of the

Na+/C l - sympor ter and inh ib i t the reabsorpt ion of sodium and c h lor ide ions. For th is reason, they are

refer red to as sa luret ics . They a lso inh ib i t the reabsorpt ion of potass ium a nd b icarbonate ions, but to a

lesser degree.

StructureActivity Relationship

P.728

Pgina 10 de 26



11/26

The th iaz ide d iuret ics are weakly ac id ic (see Appendix A for the i r pKa va lues ) , w i th a benzoth iad iaz ine 1,1-

d iox ide nuc leus. The s t ructure for the th iaz ide d iuret ics , re la t ive act iv i t ies , and pharmacokinet ic proper t ies

for the th iaz ides are shown in Table 27.3 . Chloroth iaz ide is the s implest member of th is ser ies, hav ing a

pK a o f 6 .7 and 9.5. The hydrogen a tom at the 2-N is the most ac id ic because o f the e lect ron-wi thdrawing

ef fects of the neighbor ing su l fone group. The su l fonamide group that is subst i tu ted at C-7 prov ides an

addi t ional po int o f ac id i ty in the molecule but is less a c id ic than the 2-N proton. These ac id ic protons make

poss ib le the format ion of a water -so lub le sodium sal t that can be used for in t ravenous admin is t ra t ion of the

diuret ics .

An e lect ron-wi thdrawing group is necessary at pos i t ion 6 for d iuret ic act iv i ty . L i t t le d iuret ic act iv i ty is seen

wi th a hydrogen atom at pos i t ion 6, whereas c ompounds wi th a ch loro or t r i f luoromethy l subst i tu t ion are

high ly act ive. The t r i f luoromethy l -subst i tu ted d iuret ics are more l ip id-so lub le and have a longer d urat ion of

act ion than the i r ch loro-subst i tu ted analogues. When e lect ron-re leas ing groups, such as methy l or

methoxy l , are p laced at pos i t ion 6, the d iuret ic act iv i ty is markedly reduced.

Replacement or removal o f the su l fonamide group at pos i t ion 7 y ie lds compounds wi th l i t t le or no d iuret ic

act iv i ty . Saturat ion of the double bond to g ive a 3,4 -d ihydro der ivat ive produces a d iuret ic that is 10- fo ld

more act ive than the unsaturated der ivat ive. Subst i tu t ion wi th a l ipophi l ic group a t pos i t ion 3 g ives a

marked increase in the d iuret ic potency. Haloalky l , ara lky l , or th ioether subst i tu t ion increases the l ip id

solub i l i ty o f the molecule and y ie lds compounds wi th a longer durat ion of act ion. A lky l subst i tu t ion on the 2-

N pos i t ion a lso decreases the polar i ty and increases the d urat ion of d iuret ic act ion. A l though these

compounds do have carbonic anhydrase act iv i ty , there is no c orre la t ion of th is act iv i ty wi th the i r sa luret ic

act iv i ty (excret ion of sodium and ch lor ide ions) .


The th iaz ide d iuret ics are admin is tered once a day or in d iv ided dai ly doses. Some have a durat ion of

act ion that permi ts admin is t ra t ion of a dose every other day. Some of these compounds are rap id ly

absorbed ora l ly and can show the i r d iuret ic e f fect in an hour (Table 27.3) . These compounds are not

extens ive ly metabol ized and are pr imar i ly

P.729

P.730

Pgina 11 de 26



12/26

excreted unchanged in the ur ine. Thiaz ide d iuret ics are used to t reat edemas caused by card iac

decompensat ion as wel l as in hepat ic or renal d isease. They a lso commonly are used in the t reatment o f

hyper tens ion. Thei r e f fect may be at t r ibuted to a reduct ion in b lood vo lume and a d i rect re laxat ion of

vascular smooth muscle.

Table 27.3. Pharmacological and Pharmacokinetic Pro

Generic Name Trade Name StructureRelativePotencya

CarboAnhydInhibit

Chlorothiazide Diuril Structure I: R1= H 0.8 2 1

6

Benzthiazide Exna 1.3 ~10-

Hydrochlorothiazide HydroDiurilEsidrixOretic

Structure II: R1= H

R2= Cl; R3= H

1.4 2 15

Trichloromethiazide DiureseMetahydrinNaqua

Structure II: R1=

CHCl2

R2= Cl; R3= H

1.7 6 15

Methyclothiazide EnduronAquatensen

Structure II: R1=

CH2Cl

R2= Cl; R3= CH3

1.8

Polythiazide Renese Structure II: R1=

CH2-S-CH2-CF3

R2= Cl; R3= CH3

2.0 5 17

Hydroflumethiazide SaluronDiucardin

Structure II: R1= H

R2= CF3; R3= H

1.3 2 14

Bendroflumethiazide Naturetin Structure II: R1= 1.8 3 1

Pgina 12 de 26



13/26

Adverse Effects

Thiaz ide d iuret ics may induce a number of adverse ef fects , inc lud ing hypersensi t iv i ty react ions, gast r ic

i r r i ta t ion, nausea, and e lect ro ly te imbalances, such as hyponatremia, hypokalemia, hypomagnesemia,

hypochloremic a lka los is , hypercalcemia, and hyperur icemia. Ind iv iduals who exhib i t hypersensi t iv i ty

react ions to one th iaz ide are l ike ly to have a hypersensi t iv i ty react ion to other th iaz ides and su l famoyl -

conta in ing d iuret ics (e .g. , th iaz ide- l ike and some h igh-ce i l ing d iuret ics) . Potass ium and magnesium

supplements may be admin is tered to t reat hypokalemia or hypomagnesemi a, but the i r use is not a lways

ind icated. These supplements usual ly are admin is tered as potass ium chlor ide, potass ium g luconate,

potass ium c i t ra te, magnesium ox ide, or magnesium lactate. The sa l ts are admin is tered as so lut ions,

tab lets , or t imed-re lease tab lets . Genera l ly , approx imate ly 20 mEq of potass ium is g iven dai ly . In cases of

hypokalemia, 40 to 100 mEq/day may be a dmin is tered. Potass ium-spar ing d iuret ics (e .g. , t r iamterene or

ami lor ide) a lso may be used to prevent hypokalemia. Combinat ion preparat ion of hydrochloroth iaz ide or a

potass ium-spar ing d iuret ic are avai lab le (e .g. , D iaz ide and Moduret ic ) .

Long- term use of th iaz ide d iuret ics a lso may resul t in d ecreased g lucose to lerance and increased b lood

l ip id ( low-densi ty l ipoprote in cholestero l , to ta l cholestero l , and to ta l t r ig lycer ide) content .

Quinazolinone DerivativesQuinethazone and Metolazone

Overview

The quinazol in-4-one molecule has been s t ructura l ly modi f ied in a ma nner s imi lar to the modi f icat ion of the

th iaz ide d iuret ics . Quinethazone and meto lazone (pK a = 9.7) are examples of th is c lass ( Table 27.4) . The

st ructura l d i f ference between the quinazol inone d iuret ics is the rep lacement of the 4-su l fone group (SO 2

) , w i th a 4-keto group (CO).

benzylR2= CF3; R3= H

4

aThe numerical values refer to potency ratios (in humans) with the natriuretic resgiven a value of one.b50% inhibition of carbonic anhydrase in vitro.

Data from AHFS 2000 Drug Information. Bethesda, MD: American Society of HeaInformation for the Health Care Professional, 20th Ed. Rockville, MD: U.S. PharmU, urine unchanged; M, metabolized; NA, data not available; Var, variables absor

Pgina 13 de 26



14/26

Because of the i r s imi lar s t ructures, i t is not surpr is ing that the q uinazol inones have a d iuret ic e f fect s imi lar

to that o f the th iaz ides.

Mechanism of Action and Therapeutic Applications

The pharmacokinet ic proper t ies for the quinazol inone d iuret ics are l is ted in Table 27.4 . They have a long

durat ion of act ion, usual ly as a resul t o f prote in b ind ing. A l though ch loroth iaz ide has a durat ion of act ion of

6 to 12

hours, qu inethazone a durat ion of 18 to 24 hours, and meto lazone a durat ion of 12 to 24 hours. Meto lazone

has a b ioavai lab i l i ty o f 65% (Zaroxolyn) and a pro longed onset to reach peak p lasma concentrat ions of

act ion ranging f rom 8 to 12 hours. When reformulated as for Mykrox, however , meto lazone is a lmost

complete ly absorbed, wi th peak p lasma concentrat ions reached in 2 to 4 hours. Thus, o ther vers ions of

meto lazone cannot be in terchanged wi th Mykrox. Approx imate ly 50 to 7 0% of meto lazone is bound to

carbonic anhydrase in the ery throcytes. Meto lazone a lso has an increased potency, and the mode of act ion

for both compounds is s imi lar to that o f the th iaz ide der ivat ives. In cont rast to th iaz ide d iuret ics ,

meto lazone may be ef fect ive as a d iuret ic when the GFR fa l ls be low 40 mL/min. The dose of qu inethazone

is 50 to 100 mg dai ly and that o f meto lazone 2.5 to 20 mg g iven as a s ing le ora l dose. S ide ef fects are

s imi lar to adverse ef fects induced by the th iaz ide d iuret ics .

Phthalimidine DerivativesChlorthalidone

Overview

Chlor tha l idone (pK a = 9.4) is an example of a d iuret ic in th is c lass of compounds that bears a s t ructura l

analogy to the quinazol inones ( Table 27.4 ) . Th is compound may be named as a 1-oxo- iso indol ine or a

phthal imid ine. A l though the molecule ex is ts pr imar i ly in the phthal imid ine form, the r ing may be opened to

form a benzophenone der ivat ive.

The benzophenone form i l lus t ra tes the re la t ionship to the quinazol inone ser ies of d iuret ics . I t may beregarded as an open r ing var ia t ion.

P.731

View Table

Table 27.4. PharmacokineticProperties for the Thiazide-LikeDiuretics

Pgina 14 de 26



15/26

Therapeutic Application

Chlor tha l idone has a long durat ion of act ion (4872 hou rs) (see Table 27.3for i ts o ther pharmacokinet ic

proper t ies) . A l though quinethazone and meto lazone are admin is tered dai ly , ch lor tha l idone may b e

admin is tered in doses of 25 to 100 mg three t imes a week. When ch lor tha l idone is formulated wi th th eexc ip ient pov idone, the product , Thal i tone, has greater b ioavai lab i l i ty (>90%) and reaches peak p lasma

concentrat ions in a shor ter t ime compared wi th i ts o ther products . S imi lar to the quinazol inones, i t a lso is

extens ive ly bound to carbonic anhydrase in the ery throcytes. Chlor tha l idone- induced ef fects on ur ine

content and s ide ef fects are s imi lar to those induced b y th iaz ide d iuret ics .

IndolinesIndapamide

Mechanism of Action

The prototyp ic indol ine d iuret ic is indapamide, which was repor ted as a d iuret ic in 1984. Indapamide

conta ins a po lar ch lorobenzamide moiety and a nonpolar l ipophi l ic m ethy l indol ine group. In cont rast to the

th iaz ides, indapamide does not conta in a th iaz ide r ing, and only one su l fonamide group is present wi th in

the molecular s t ructure (pK a = 8.8) . I t is rap id ly and complete ly absorbed f rom the gast ro in test ina l t ract andreaches i ts peak p lasma level in 2 to 3 hours, wi th a durat ion of act ion of up to 8 weeks. This pro longed

durat ion of act ion is assoc iated wi th i ts extens ive b ind ing to carbo nic anhydrase in the ery throcytes. I t

exh ib i ts b iphas ic k inet ics , wi th a ha l f - l i fe o f 14 to 18 ho urs and an e l iminat ion hal f - l i fe o f 24 hours.

Indapamide is extens ive ly metabol ized, wi th 60 to 70% of the ora l dose being e l iminated in the ur ine as

glucuronide and su l fa te metabol i tes and less than 10% being excreted unchanged. The remain ing 20 to 30%

is e l iminated v ia ext rahepat ic cyc l ing.

Therapeutic Application

Uses of indapamide inc lude the t reatment o f essent ia l hyper tens ion a nd edema resul t ing f rom congest ive

hear t fa i lure. L ike meto lazone, indapamide is an ef fect ive d iuret ic drug when GFR fa l ls be low 40 mL/min.

The durat ion of act ion is approx imate ly 24 hours, wi th the normal ora l adul t dosage s tar t ing at 2 .5 mg g iven

each morn ing. The dose may be increased to 5.0 mg/day, but doses beyond th is leve l do not appear toprov ide addi t ional resul ts . Ef fects on ur ine content and s ide ef fects are s imi lar to ef fects induced by

th iaz ide d iuret ics .

High-Ceiling or Loop Diuretics

Mechanism of Action

This c lass of drugs is character ized more by i ts pha rmacologica l s imi lar i t ies than by i ts chemical

s imi lar i t ies . These d iuret ics produce a peak d iures is much greater than th at observed wi th the other

commonly used d iuret ics , hence the name h igh-ce i l ing d iuret ics . Thei r main s i te of act ion is be l ieved to be

on the th ick ascending l imb of the loop o f Henle, where they inh ib i t the luminal Na +/K +/2 C l - sympor ter .

These d iuret ics are commonly re fer red to as loop d iuret ics . Addi t ional e f fects on the prox imal and d is ta l

tubules a lso are poss ib le . High-ce i l ing d iuret ics are character ized by a quick on set and shor t durat ion ofact iv i ty . Thei r d iuret ic e f fect appears in approx imate ly 30 minutes and lasts fo r approx imate ly 6 hours. The

pharmacokinet ic proper t ies for the loop d iuret ics are l is ted in Table 27.2.

Specific Drugs

Furosemide

Pgina 15 de 26



16/26

StructureActivity Relationships

Furosemide is an example of a h igh-ce i l ing d iuret ic and may be regarded as a der ivat ive of anthrani l ic ac id

or o-aminobenzoic ac id .

Research on 5-su l famoylanthrani l ic ac ids at the Hoechst Laborator ies in Germany showed them to be

ef fect ive d iuret ics . The most act ive of a ser ies of var ious ly subst i tu ted der ivat ives w as furosemide.

The ch lor ine and su l fonamide subst i tu t ions are features a lso seen in prev ious ly d iscussed d iuret ics .

Because the molecule possesses a f ree carboxy l group, furosemide is a s t ronger ac id than the th iaz ide

diuret ics (pKa = 3.9) . Th is drug is excreted pr imar i ly unchanged. A smal l amount o f metabol ism, however ,

can take p lace on the furan r ing, which is subst i tu ted on the aromat ic amino group (see Table 27.2 for i ts

other pharmacokinet ic proper t ies) .


Furosemide has a sa luret ic e f fect 8- to 10- fo ld that o f the th iaz ide d iuret ics ; however , i t has a shor ter

durat ion of act ion (~68 hours) . Furosemide causes a marked e xcret ion of sodium, ch lor ide, potass ium,

calc ium, magnesium, and b icarbonate ions, wi th as much as 25% of the f i l tered load of sodium excreted in

response to in i t ia l t reatment . I t is e f fect ive for the t reatment o f e demas connected wi th card iac, hepat ic ,

and renal s i tes. Because i t lowers the b lood pressure s imi lar to the th iaz ide der ivat ives, one of i ts uses is

in the t reatment o f hyper tens ion.

Furosemide is ora l ly e f fect ive but may be used parentera l ly when a more prompt d iuret ic e f fect is des i red,

such as in the t reatment o f acute pulmonary edema. The dosage of furosemide, 2080 mg/day, ma y be

given in d iv ided doses because of the shor t durat ion of act ion of the drug and carefu l ly increased up to a

maximum of 600 mg/day.

Adverse Effects

Cl in ica l tox ic i ty o f furosemide and other loop d iuret ics pr imar i ly invo lves abnormal i t ies of f lu id a nd

elect ro ly te ba lance. As wi th the th iaz ide d iuret ics , hypokalemia is an impor tant adverse ef fect that can be

prevented or t reated wi th potass ium supplements or coadmin is t ra t ion of potass ium-spar ing d iuret ics .

Increased ca lc ium ion excret ion can be a problem for postmenopausal osteopenic women, and furosemide

genera l ly should not be used in these ind iv iduals . Hyperur icemia, g lucose i n to lerance, increased seruml ip id leve ls , o totox ic i ty , and gast ro in test ina l s ide ef fects might be observed as wel l . Hype rsensi t iv i ty

react ions a lso are poss ib le wi th furosemide (a su l fonamide-based drug) , and cross -react iv i ty wi th other

su l fonamide conta in ing drugs is poss ib le .

Bumetanide

P.732

Pgina 16 de 26



17/26


A diuret ic s t ructura l ly re la ted to furosemide is bumetanide. This compound a lso funct ions as a h igh-ce i l ing

diuret ic in the ascending l imb of the loop of H enle. I t has a durat ion of act ion of approx imate ly 4 hours. The

uses of th is compound are s imi lar to those descr ibed fo r furosemide. The dose of bumetanide is 0 .5 to 2

mg/day g iven as a s ing le dose. Adverse ef fects are s imi lar to those induced by furosemide.

StructureActivity Relationships

For bumetanide, a phenoxy group has rep laced the customary ch loro or t r i f luoromethy l subst i tu t ions seen in

other d iuret ic molecules. The phenoxy group is an e lect ron-wi thdrawing g roup s imi lar to the ch loro or

t r i f luoromethy l subst i tu t ions. The amine group customar i ly seen at pos i t ion 6 has b een moved to pos i t ion 5.

These minor var ia t ions f rom furosemide produced a compound w i th a mode of act ion s imi lar to that o f

furosemide, but wi th a marked increase in d iuret ic potency. The shor t durat ion of act iv i ty is s imi lar , but the

compound is approx imate ly 50- fo ld more potent . Replacement of the phenoxy group at pos i t ion 4 wi th a

C6H5NH- or C 6H5S- group a lso g ives compounds wi th a favorable act iv i ty . When the buty l group on the C-5

amine is rep laced wi th a furany lmethy l group, such as i n furosemide; however , the resul ts are not

favorable.

Torsemide

Fur ther modi f icat ion of furosemide- l ike s t ructures has led to the development of torsemide. Instead of the

sul fonamide group found in furosemide and bumetanide, torsemide conta ins a su l fony lurea moiety . S imi lar

to other h igh-ce i l ing d iuret ics , torsemide inh ib i ts the luminal Na 1/K 1/2 C l - sympor ter in the ascending l imb of

the loop of Henle to promote the excret ion of sodium, potass ium, ch lor ide, ca lc ium, and magnesium ions

and water . An addi t ional e f fect on the per i tubular s ide at ch lor ide channels may enhance the luminal e f fects

of torsemide. In cont rast to furosemide and bumetanide, however , torsemide does not act a t the prox imaltubule and, therefore, does not increase phosphate or b icarbonate ex cret ion. Peak d iures is is observed 1 to

2 hours fo l lowing ora l or in t ravenous admin is t ra t ion, wi th a durat ion of act ion of approx imate ly 6 hours.

Torsemide is ind icated for the t reatment o f edema resul t ing f rom congest ive hear t fa i lure and for the

Pgina 17 de 26



18/26

t reatment o f hyper tens ion. In pat ients wi th c i r rhos is and asc i tes, Torsemide should be used wi th caut ion.

Adverse ef fects are s imi lar to those induced by furosemide.

Ethacrynic acid

Mechanism of Action

Another major c lass of h igh-ce i l ing d iuret ics is the phenoxyacet ic ac id der ivat ives, o f which ethacryn ic ac id

is the prototyp ica l agent . These compounds were developed a t about the same t ime as furosemide but w ere

designed to act mechanis t ica l ly s imi lar to the organomercur ia ls ( i .e . , v ia inh ib i t ion of su l fhydry l -conta in ing

enzymes involved in so lute reabsorpt ion) . The mechanism of act ion of e thacryn ic ac id appears to be more

complex than the s imple addi t ion of su l fhydry l groups of the enzyme to the drug molecule. When the d ouble

bond of e thacryn ic ac id is reduced, the resul tant compound i s s t i l l ac t ive, a l though the d iuret ic act iv i ty is

d imin ished. The su l fhydry l groups of the enzyme would not be expected to add to the drug molec ule in the

absence of the , -unsaturated ketone. The pharmacokinet ic proper t ies for e thacryn ic ac id are l is ted in

Table 27.2 .

In 1984, a new ser ies of d iuret ics was repor ted (2,3) . The fo l lowing substance is representat ive of th is

ser ies:

These compounds are potent h igh-ce i l ing d iuret ics that resemble ethacryn ic ac id in the i r mechanism of

act ion. The ethy l ester group represents a pro-drug that can be eas i ly hydro lyzed to the f ree carboxy l

group. As in ethacryn ic ac id , a 2,3-d ich loro subst i tu t ion is necessary. In addi t ion, a para-hydroxy l group

and an unsubst i tu ted aminomethy l group on the benzene r ing are h igh ly benef ic ia l . The carbonyl group can

be rep laced wi th an ether or su l f ide group. These compounds have no abi l i ty to add the su l fhydry l g roups of

the k idney enzymes. The complete mechanism of act ion of these compounds remains in doubt .

S imi lar to the other h igh-ce i l ing d iuret ics , e thacryn ic ac id inh ib i ts the Na 1/K 1/2 Cl - sympor ter in the

P.733

Pgina 18 de 26



19/26

ascending l imb of the loop of Henle to p romote a marked d iures is . Sodium, ch lor ide, potass ium, and

calc ium excret ion are increased fo l lowing ora l or in t ravenous admin is t ra t ion of e thacryn ic ac id . Ora l

admin is t ra t ion of e thacryn ic ac id resul ts in d iures is wi th in 1 hour and a durat ion of act ion of 6 to 8 hours.

Tox ic i ty induced by ethacryn ic ac id is s imi lar to that induced by furosemide and bumetanide. Ethacryn ic

ac id is not widely used, however , because i t induces a greater inc idence of o totox ic i ty and more ser ious

gast ro in test ina l e f fects than those of furosemide or bumetanide.

StructureActivity RelationshipOpt imal d iuret ic act iv i ty was obta ined when an oxyacet ic ac id group was pos i t ioned para to an , -

unsaturated carbonyl (or o ther su l fhydry l - react ive group) and ch loro or methy l groups were p laced at the 2-

or 3-pos i t ion of the phenyl r ing. In addi t ion, hydrogen atoms on the terminal a lkene carbon a lso prov ided

maximum react iv i ty . Thus, a molecule wi th a weakly ac id ic g roup to d i rect the drug to the k idney and an

alky la t ing moiety to react wi th su l fhydry l groups and l ipophi l ic groups seemed to prov ide the best

combinat ion for a d iuret ic in th is c lass. These features led to the development of e thacryn ic ac id as the

prototyp ic agent in th is c lass.

New drugs

Four addi t ional h igh-ce i l ing d iuret ics are azosemide, muzol imine, p i re tan ide, and t r ipamide. Azosemide has

low ora l b ioavai lab i l i ty (~1015%) because of h igh f i rs t -pass metabol ism in the l iver , whe reas p i re tan ide

has comparable pharmacokinet ics to bumetanide.

As can be seen by these var ied s t ructures, the h igh-ce i l ing d iuret ics are character ized more by the i r

pharmacologica l s imi lar i t ies than by the i r chemical s imi lar i t ies .

Potassium-Sparing Diuretics (Mineralocorticoid ReceptorAntagonists)Antihormone Diuretics

Mechanism of Action

The adrenal cor tex secretes a potent minera locor t ico id ca l led a ldosterone, which promotes sa l t and water

retent ion and potass ium and hydrogen ion excret ion.

Pgina 19 de 26



20/26

Other minera locor t ico ids have an ef fect on the e lect ro ly t ic ba lance of the body, but a ldosterone is the most

potent . I ts ab i l i ty to cause increased reabsorpt ion of sodium and ch lor ide ion and increased potass ium ion

excret ion is approx imate ly 3,000- fo ld that o f hydrocor t isone. A substance that antagonizes the ef fects of

a ldosterone could conceivably be a good d iuret ic drug. Spi ronolactone is such an antagonis t .

Specific Drugs

Spironolactone

Spironolactone is a compet i t ive antagonis t to the minera locor t ico ids, such as a ldosterone. Th e

minera locor t ico id receptor is an in t racel lu lar prote in that can b ind a ldosterone. Spi ronolactone b inds to the

receptor and compet i t ive ly inh ib i ts a ldosterone b ind ing to the receptor . The inabi l i ty o f a ldosterone to b ind

to i ts receptor prevents reabsorpt ion of sodium and ch lor ide ions and the assoc iated water . The most

impor tant s i te of these receptors is in the la te d is ta l con voluted tubule and co l lect ing system (co l lect ing

duct ) .

Metabolism

On ora l admin is t ra t ion, approx imate ly 90% of the dose of s p i ronolactone is absorbed and is s ign i f icant ly

metabol ized dur ing i ts f i rs t passage through the l iver to i ts ma jor act ive metabol i te , canrenone (see Table

27.2for the i r pharmacokinet ic proper t ies) , which is in terconver t ib le wi th i ts canrenoate anion. C anrenone is

an antagonis t to a ldosterone.

P.734

Pgina 20 de 26



21/26

The canrenoate anion is not act ive per se but acts as an a ldosterone antagonis t because of i ts convers ion

to canrenone, which ex is ts in the lactone form. Canrenone h as been suggested to be the act ive form o f

sp i ronolactone as an a ldosterone antagonis t . The format ion of canrenone, ho wever , cannot fu l ly account for

the to ta l act iv i ty o f sp i ronolactone. Both canrenone and potass ium canrenoate are used as d iuret ics in o ther

countr ies, but they are not yet avai lab le in the U ni ted States.


Spironolactone is usefu l in t reat ing edema resul t ing f rom pr imary hypera ldosteronism and ref ractory edema

associated wi th secondary hypera ldosteronism. Spi ronolactone is cons idered to be the drug of choice for

t reat ing edema resul t ing f rom c i r rhos is of the l iver . The dose of sp i ronolactone is 100 mg/day g iven in

s ing le or d iv ided doses. Another use of sp i ronolactone is coadmin is t ra t ion wi th a potass ium-deplet ing

diuret ic (e .g. , a th iaz ide or loop d iuret ic ) to prevent or t reat d iuret ic - induced h ypokalemia. Spi ronolactone

can be admin is tered in a f ixed-dose combinat ion wi th hydrochloroth iaz ide for th is purpose, but opt imal

ind iv idual izat ion of the dose of each drug is recommended.

Adverse Effects

The pr imary concern wi th the use of sp i ronolactone is the development of hyperkalemia, which can be fa ta l .

Spi ronolactone may cause hypersensi t iv i ty react ions, gast ro in test ina l d is turbances, pept ic u lcer ,

gynecomast ia , decreased l ib ido, and impotence. I t a lso has been impl icated in tumor product ion dur ing

chronic tox ic i ty s tud ies in ra ts , but human r isk has not b een documented.

Eplerenone

Pgina 21 de 26



22/26

A newer drug, ep lerenone, has a s t ructure s imi lar to th at o f sp i ronolactone and a s imi lar mechanism of

act ion. I t was in i t ia l ly approved for use in the t reatment o f hyper tens ion but i t can now be used in the

t reatment o f pat ients wi th le f t vent r icu lar systo l ic dysfunct ion and congest ive hear t fa i lure af ter my ocard ia l

in farc t ion. I t has a hal f - l i fe o f approx imate ly 5 hours and undergoes hepat ic metabol ism to inact ive

metabol i tes as i ts main route of e l iminat ion. Cl in ica l exper ience wi th ep lerenone i s current ly l imi ted.

PteridinesTriamterene

Pter id ines have a marked potent ia l for in f luenc ing b io log ica l processes. Ear ly screening of p ter id ine

der ivat ives revealed that 2 ,4-d iamino-6,7-d imethy lpter id ine was a fa i r ly potent d iuret ic . Fur ther s t ructura l

modi f icat ion led to the development of t r iamterene.

Mechanism of action

Tr iamterene in ter feres wi th the process of cat ion ic exchange by b lock ing luminal sodium channels in the

late d is ta l convoluted tubule and co l lect ing duct . Sodium channel inh ib i tors b lock the reabsorpt ion of

sodium ion and inh ib i t the secret ion of potass ium ion. A ld osterone is not antagonized by t r iamterene. The

net resul t is increased sodium and ch lor ide ion excret ion

in the ur ine and a lmost no potass ium excret ion. Tr iamterene is more than 70% absorbed on ora l

admin is t ra t ion (see Table 27.2 for i ts o ther pharmacokinet ic proper t ies) . The d iuret ic e f fect occurs rap id ly

(~30 minutes) and reaches a peak p lasma concentrat ion in 2 to 4 hours, wi th a durat ion of act ion of m ore

than 24 hours. Tr iamterene is extens ive ly metabol ized, and some of the metabol i tes are act ive as d iuret ics .

Both the drug and i ts metabol i tes are excreted in the ur ine.

Structureactivity relationships

Modi f icat ions of the t r iamterene s t ructure are not usual ly benef ic ia l in terms of d iuret ic act iv i ty . Act iv i ty is

reta ined i f an amine group is rep laced wi th a lower a lky lamine group. In t roduct ion of a para-methy l group

P.735

Pgina 22 de 26



23/26

on the phenyl r ing decreases the act iv i ty by approx imate ly h a l f . In t roduct ion of a para-hydroxy l group on

the phenyl r ing y ie lds a compound that is essen t ia l ly inact ive as a d iuret ic .

Therapeutic applications

Tr iamterene is usefu l in combinat ion wi th a th iaz ide or loop d iuret ic in the t reatment o f edema or

hyper tens ion. L idd le 's syndrome a lso may be t reated wi th a sodium channel b lock ing drug, such as

t r iamterene. Tr iamterene is admin is tered in i t ia l ly in doses of 100 mg twice a day. A maintenance dose for

each pat ient should be ind iv idual ly determined. This dose may v ary f rom 100 mg a day to as low as 100 mg

every other day.

Adverse effects

The most ser ious s ide ef fect assoc iated wi th the use o f t r iamterene is hyperkalemia. For th is reason,

potass ium supplements are cont ra ind icated, and serum potass ium levels should be checked regular ly .

Tr iamterene a lso is used in combinat ion wi th hydrochloroth iaz ide. Here, the hypokalemic ef fect o f the

hydrochloroth iaz ide counters the hyperkalemic ef fect o f the t r iamterene. Other s ide ef fects that are seen

wi th the use of t r iamterene are nausea, vomi t ing, and headache.

AminopyrazinesAmiloride

Ami lor ide, another potass ium-spar ing d iuret ic , is an aminopyraz ine s t ructura l ly re la ted to t r iamterene as an

open-chain analogue. S imi lar to t r iamterene, i t in ter feres wi th the process of cat ion ic exchange in the d is ta l

convoluted tubule by b lock ing luminal sodium channels . I t b locks the reabsorpt ion of sodium ion and the

secret ion of potass ium ion. I t has no ef fect on the act ion of a ldosterone. Ora l ami lor ide is approx imate ly

50% absorbed (see Table 27.2 for i ts o ther pharmacokinet ic proper t ies) , w i th a durat ion of act ion of 10 to

12 hours, which is s l ight ly longer than that for t r iamterene. A l though t r iamterene is extens ive ly metabol ized,

approx imate ly 50% of ami lor ide is excreted unchanged. Renal impai rment can increase i ts e l iminat ion hal f -

l i fe . L ike t r iamterene, ami lor ide combined wi th a th iaz ide or loop d iuret ic is used to t reat edema or

hyper tens ion. Aerosol ized ami lor ide has shown some benef i t in improv ing mu coci l iary c learance in pat ientswi th cyst ic f ibros is . As wi th t r iamterene, the most ser ious s ide ef fect a ssoc iated wi th ami lor ide is

hyperkalemia, and i t a lso has the other s ide ef fects ass oc iated wi th t r iamterene. The dose of ami lor ide is 5

to 10 mg per day. Ami lor ide a lso is combined wi th hydrochloroth iaz ide in a f ixed-dose combinat ion.

Therapeutic Application of Diuretics

BD is a 67-year-old man who was admitted with a complaint of shor tness of breath that has

increased over the last few months. He also indicated that he has recently gained more than 12

pounds without changing his eat ing or exerc ise habi ts and that he often has trouble breathing

when c l imbing stairs at home. Physical examination reveals s igns and symptoms consis tent wi th

both r ight-s ided (systemic edema, hepatomegaly, neck vein dis tension) and left-s ided

(weakness, fat igue, ra les, cyanosis) heart fa i lure. A diagnosis of congestive heart fa i lure (CHF)

is establ ished, and a decis ion is made to l imit sodium intake ( low sodium diet) and to in i t iate

oral therapy with dig i ta l is to improve heart funct ion. A diuret ic a lso wi l l be added to help remove

edema f lu id and decrease the work load on the heart. What d iuret ics would be appropr iate to use

P.736

Pgina 23 de 26



24/26

in th is pat ient?

ANSWER:

Select ion of a diuret ic would be based on the drug's abil ity to mobilize edema f luid and to

help reduce the workload on the heart . Thiazide and loop (high-ceil ing) diuret ics are

effect ive in mobiliz ing edema f luid and could be used i n this pat ient. Osmotic diuret ics are

not effect ive at mobiliz ing edema f luid and will expand extracellular f luid, which would

worsen the workload on the heart . Carbonic anhydrase inhibitors are weak diuret ics and

would not provide adequate diuresis to effect ively reduce the workload on the heart .Potassium-sparing diuret ics also are less effect ive than thiazides or loop diuret ics in

mobiliz ing edema f luid and would not be a diuret ic of f irst choice in this pat ient.

Choosing between a thiazide or a loop diuret ic depends on many factors, including the

amount of edema present, severity of symptoms, and the patient 's renal function. Loop

diuret ics (e.g., furosemide and torsemide) are more eff icacious than thiazides and can

remove edema f luid faster than thiazides can, thus providing quicker relief . Loop diuret ics

also have direct effects on the pulmonary venous system to help improve pulmonary

symptoms related to the fail ing heart . Addit ionally, however, loop diuret ics can cause

more dramatic imbalances in extracellular volume and electrolyte levels than thiazides

can, and loop diuret ics can alter these levels sooner than with thiazide use. Thus, loop

diuret ics should be employed when moderate to severe CHF is present, but thiazides may

be preferred when mild CHF is present. Because this pat ient has moderate to severe

symptoms, furosemide is chosen as the diuret ic to use in this pat ient.I f BD had been seen when his CHF was mi ld but h is renal funct ion was already impaired

(glomerular f i l t rat ion rate [GFR], 25 mL/min) , how would these c ircumstances affect your

select ion of a d iuret ic?

ANSWER:

Although a thiazide diuret ic normally would be the diuret ic of choice in treat ing mild CHF,

a thiazide generally is less effect ive in pat ients with renal insuff iciency. Thiazides can

reach their site of act ion ( the luminal sodium ionchloride ion transporter of the distal

convoluted tubule) following f i lt rat ion at the glomerulus. The amount of drug f i ltered at the

glomerulus depends on the extent of plasma protein binding for that drug. In addit ion,

because thiazides are weakly acidic drugs (pKa

, 7.09.0) , they are substrates for act ive

secret ion by the organic anion transport system of the proximal tubular cells. With the

exception of metolazone and indapamide, however, most thiazides are ineffect ive as

diuret ics when the GFR is 30 to 40 mL/min (normal GFR, 125 mL/min).

Loop diuret ics reach their site of act ion ( luminal sodium ionpotassium ion2 chloride ion

transporter of the ascending l imb of the loop of Henle) primarily via act ive secret ion by the

organic anion transport system of proximal tubular cells. As stronger organic acids than

thiazide diuret ics (e.g., pKa of furosemide 5 4.7) , loop diuret ics are good substrates for

secret ion. Extensive plasma protein binding by these drugs l imits their access to the

lumina of nephrons via f i lt rat ion. Thus, a marked reduction in GFR does not l imit access of

loop diuret ics to tubular lumina or markedly alter the therapeutic eff icacy of these drugs.

As a result , a loop diuret ic would st i l l be a preferred choice for treat ing BD if his CHF had

been mild but his renal function reduced.

Fol lowing 6 weeks on his low-sal t d iet and drug therapy, BD's condi t ion seems to be great ly

improved. His serum potass ium levels , however, have decreased from 4.2 to 3.1 mEq/L (normal

value, 3.85.6 mEq/L) . What caused his serum potass ium levels to decrease over t ime? Why isth is change a concern? What can be done to remedy th is problem?

Answer

One of the major side effects of using a loop diuret ic is excessive excret ion of

electrolytes, including potassium ions. Loss of potassium can eventually lead to

hypokalemia ( low blood potassium), and hypokalemia alone can lead to the development of

cardiac arrhythmias. Potassium loss, however, also potentiates the act ions of digitalis

(cardiac sodiumpotassiumadenosine tr iphosphatase inhibit ion) and can lead to digitalis-

induced cardiac arrhythmias as well. Hypokalemia can be treated/prevented by the use of

potassium supplements or the use of a potassium-sparing diuret ic (e.g., t r iamterene and

amiloride) . Because potassium-sparing diuret ics are weakly basic drugs, they do not alter

the act ive secret ion of loop diuret ics.

Case Study

Victoria F. Roche

Pgina 24 de 26



25/26

S. Will iam Zito

You often eat lunch with your favor i te grandma, who is 85 years old and g eneral ly in good heal th

except for infrequent bouts of gout. Dur ing the last few years when you meet w i th her , you have

noticed that she has been gaining weight around her middle and that her legs and a nkle seem to

be puffy . Dur ing your most recent lunch date, grandma shares with you a problem she has been

having at n ight. I t doesn' t happen every night, but every now and then she wakes gasping for

air , which requires her to get out of bed and open the window to get re l ief. She has taken to

propping hersel f up us ing two or three pi l lows to get back to s leep. The next day, you

accompany grandma to the fami ly doctor , who based on physical examination and a chest

radiograph makes a diagnosis of mi ld (New York Heart Associat ion [NYHA] Funct ional

Class i f icat ion of Class I I) congestive heart fa i lure (CHF). A recommendation is made to l imit

sodium intake, inst i tute a regimen of exerc ise and in i t iate diuret ic therapy to remove pulmonary

and pedal edema f lu id, and decrease the work load on grandma's heart. The doctor knows you

are a pharmacy student who l ikes medic inal chemistry and asks you to make an appropr iate

choice from structures 1 to 4.

1. Identi fy the therapeutic problem(s) in which the pharmacist 's intervention may benefi t the

patient.

2. Identi fy and pr iori t ize the pat ient-speci f ic factors that must be considered to achieve the

desired therapeutic outcomes.

3 . Conduc t a thorough and mechan is t ica l ly o r ien ted s t ructureac t iv i ty analys is o f a l l

therapeutic a l ternat ives prov ided in t he case.

4. Evaluate the structureact ivi ty re lat ionship f indings against the pat ient-speci f ic factors

and desired therapeutic outcomes, and make a therapeutic decis ion.

5 . C ou ns el yo ur pa ti en t.

References

1. Jackson EK. Diuret ics . In : Brunton L, Lazo JS, P arker KL, eds. Goodman and Gi lman's The

Pharmaco log ica l Basis o f Therapeu t i cs , 11 th Ed. New York , McGraw-Hi l l , 2006 , pp 757769.

P.737

Pgina 25 de 26



26/26

2. Lee CM, Plat tner JJ, Ours CW, et . a l . [ (Aminomethy l )ary loxy]acet ic ac id esters . A new c lass of

h igh-ce i l ing d iuret ics . 1 . Ef fects of n i t rogen and aromat ic nuc lear subst i tu t ion. J Med C hem

1 98 4; 27 :1 57 9 15 87 .

3. P lat tner JJ, Fung AK, Smi ta l JR, e t a l . [ (A minomethy l )ary loxy]acet ic ac id esters . A new c lass of

h igh-ce i l ing d iuret ics . 2 . Modi f icat ions of the oxyacet ic s ide chain. J Med Che m 1984;27:15871596.

Suggested Readings

Acara MA. Renal pharmacologydiuret ics . In : Smi th CM, Reynard AM , eds. Textbook of

Pharmacology. Phi ladelph ia, WB Saunders, 1992, pp 554588.

Fr iedman PA, Berndt , WO. Diuret ic drugs. In : Cra ig CR, St ize l RE, eds. Modern Pharmacology wi th

Cl in ica l Appl icat ions, 6 th Ed. Phi ladelph ia: L ipp incot t Wi l l iams & Wi lk ins, 2004; pp 239255.

Brenner BM, Rector FC Jr , eds. The K idney, 4 th Ed. Phi ladelph ia, WB Saunders, 1991.

Breyer J , Jacobson HR. Molecular mechanisms of d iuret ic agents . Annu Rev Med 1990;41:265275.

Kalantar in ia K, Okusa MD. Diuret ics : Drugs that increase the e xcret ion of water and e lect ro ly tes. In :

Minneman KP, Wecker L, eds. Brody 's Huma n Pharmacology; Molecular to Cl in ica l , 4 th Ed.

Phi ladelph ia: E lsev ier Mosby, 2005; pp 163182.

Jackson EK. Diuret ics . In : Brunton L, Lazo JS, P arker KL, eds. Goodman and Gi lman's The

Pharmacologica l Bas is of Therapeut ics , 11th Ed. New York: M cGraw-Hi l l , 2006; pp 737769.

[CrossRef ]

[CrossRef ]

[CrossRef ]

Pgina 26 de 26

Documents

cap27 diureticos