vaptanes para mia 2011

8/4/2019 Vaptanes Para mia 2011

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NorthesternUniversity MedicalSchool, Division of Endocrinology,303 East Superior Tarry15–755, Chicago,IL 60611, USA.glr388@ northestern.edu

Vapta f th tatmt f hpatmaGary L. Robertson

Abtat | The vaptans constitute a ne class of pharmaceuticals developed for the treatment of the

hypervolemic and euvolemic forms of hyponatremia. These agents are nonpeptide vasopressin antagonists

that interfere ith the antidiuretic effect of the hormone by competitively binding to V2receptors in the kidney.

This blockade results in ater diuresis (aquaresis) that, if not offset by increased fluid intake, reduces body

ater content and raises plasma sodium levels. Probably as a result of this rise in plasma sodium, thirst and

plasma vasopressin concentration increase, potentionally limiting the effects of the vasopressin antagonists.

Nonetheless, vaptans are particularly useful to treat hypervolemic hyponatremia associated ith severe

congestive heart failure or chronic liver failure, as the only other treatments currently available, such as fluid

restriction and diuretics, are slo-acting and minimally effective. Vaptans are also useful for treating euvolemic

hyponatremia associated ith the syndrome of inappropriate antidiuretic hormone (SIADH), at least hen it

is chronic and/or minimally symptomatic. Hoever, because their effects vary unpredictably from patient topatient, vaptans are less useful than hypertonic saline infusion in cases of acute, severe and symptomatic

hyponatremia. Vaptan therapy is absolutely contraindicated in hypovolemic hyponatremia (in hich total body

ater is reduced) and is ineffective in the vasopressin-independent form of inappropriate antidiuresis caused

by constitutive activating mutations of V2receptors.

Robertson, G. L. Nat. Rev. Endocrinol. 7, 151–161 (2011); published online 1 February 2011; doi:10.1038/nrendo.2010.229

Introduction

o h p 20 y, h dp f ppd, p v

2cp g f h f

hyp h y xpdd. th c f phcc, k ccy p, c

y gz h dc ffc f pby cpy bdg v

2cp h kdy.

th bckd c xc h f cy (q) d, cpd fby c fd k, dc bdy c d p d cc.

th r z h d h ph cgy d cc ffc f h f dff p dy dd hhy dd d ph hyp. i dc c xpd chcc f h dg hy ffc h f p dd p dff cd h f p h

d hd f g h ypf hyp. H, p b d cp h hpc ffccy fy f df f p, bc h d pbhd d y ch dg, p c d d y p b cc. id, ph b g h b, ch fd k d hdyg phphygy h y fc ffccy.

Osmoregulation

i hhy d, p y d pc p d, h cc f d d , y d h g

cmpt ttThe author, the journal Chief Editor Vicky Heath and the CMEquestions author C. P. Vega declare no competing interests.

Continuing Medical Education online

This activity has been planned and implemented in accordance

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for Continuing Medical Education through the joint sponsorship of

Medscape, LLC and Nature Publishing Group. Medscape, LLC is

accredited by the ACCME to provide continuing medical educationfor physicians.

Medscape, LLC designates this Journal-based CME for a maximum

of 1 AMA PrA cat 1 ctTM. Physicians should claim only

the credit commensurate ith their participation in the activity.

All other clinicians completing this activity ill be issued a

certificate of participation. To participate in this journal CME

activity: (1) revie the learning objectives and author disclosures;

(2) study the education content; (3) take the post-test and/or

complete the evaluation at http://www.mapm.m/

jua/; (4) vie/print certificate.

Released: 1 February 2011; Expires: 1 February 2012

la bjtv

Upon completion of this activity, participants should be able to:

1 Identify different forms of hyponatremia

2 Evaluate traditional management of hyponatremia

3 Analyze the efficacy and safety of vaptans in hyponatremia

4 Describe the efficacy and safety of vaptans in the

management of the syndrome of inappropriate antidiuretic

hormone specifically

REVIEwS

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275–295 / d 135–145 /, pcy.th ccy chd by pdy g g

bdy cp f chg dk d p g bgy, b(p f k d g) d y f . th dj bdy c dby ppg hyphc h gh d c f h dc h g p (Fg 1).1 ech fck hhd p g, h h f h ghy hgh h h f p c(Fg 2). th g b py, h d d , b h

Key points

Vaptans are nonpeptide agents that antagonize the antidiuretic effect of ■

vasopressin by competing ith it for binding to V2

receptors in the kidney

Vaptans increase solute-free ater excretion, reduce body ater content and■

raise the plasma sodium level by reducing urine concentration, unless the

aquaresis is offset by increased fluid intake

The vaptan-induced rise in plasma sodium often stimulates thirst and/or■

vasopressin secretion, hich, in turn, may feed back to increase fluid intakeand/or overcome blockade of the V2

receptor

In conjunction ith modest restriction of fluid intake, vaptans have proven safe■

and effective in treating chronic hypervolemic and euvolemic hyponatremia

The use of vaptans to treat acute, symptomatic forms of hyponatremia is still■

debatable, because their effects on plasma sodium vary unpredictably from

patient to patient

Vaptan therapy is contraindicated in hypovolemic hyponatremia, a disorder■

associated ith decreased total body ater and sodium levels, and is ineffective

in a form of inappropriate antidiuresis that is independent of vasopressin

hhd d h h d k d p d cc b h hch h cg ffcf p x.

Hyponatremia

cafat a pathphHypc hyp hg ddh f fdy dff ypf d d bc. i dff f h hyp cd by hypgyc h p y p d d cd by cb f pd xc d xc k h xc f bdy . th b k d xcc h df f c d b cd h dff dbc d bc. th, hypchyp ddd h yp dpdg hh xc fd d d cd (hypc), dcd (hypc) y (c) (tb 1).2

Hypervolemic hyponatremia

Hypc hyp d xc f d d, y f cg hf ch. th dd bd c dc ‘ffc’ bd fg p hdc g f; c bpf d d h px b;3 dcdy f f d dg ; c p cy d d; d h d/ p , pbby by g h f

H2O

Urine

LumenRenal collecting tubules

Vasopressin

Desmopressin

Plasmaosmolarity

Osmoreceptors

Blood vessel

Cells

cAMPAVP

Neurohypophysis

Desmopressin

“Thirst”

GutHypothalamus

H2O

H2O

H2O

H2O

H2O

H2O

H2O

H2O

H2O

H2O

H2O

Control Production Transport Action

Increased uid intake

Figure 1 | Principal elements of the osmoregulatory system. Vasopressin reduces urine output and raises urineconcentration (osmolarity) by increasing the reabsorption of solute-free ater in collecting tubules of the kidney.45 Thisantidiuretic effect is mediated via the V

2receptor that acts via adenyl cyclase to insert preformed aquaporin 2 ater

channels into the luminal surface of the cell,46 thereby permitting solute-free ater to diffuse passively from the lumen andthrough the cell along the osmotic pressure gradient created by the hypertonic renal medulla. In the absence of V

2receptor

stimulation, dilute filtrate passes unmodified through the collecting ducts to be excreted as urine ith an osmolarity<90 mosmol/l and a flo rate as high as 900 ml/h. As output of this magnitude can compensate for all but the mostpathologically excessive rates of ater intake, the threshold or set point of the vasopressin osmostat effectivelydetermines the loest level to hich plasma osmolarity and sodium can be depressed, provided glomerular filtration andsolute excretion are normal. Abbreviations: AVP, arginine vasopressin; cAMP, cyclic AMP.

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h f p4 d pby h. th ffc g c bdy h d

g hyp d gzd d, h g f xp.

Hypovolemic hyponatremia

Hypc hyp cd by xc f d cy f h g c kdy, y f dh bf dc dg. th hyp dcg f; c dp f d h px ph; dc dy f f d dg g; d c p cy d d c. l f,hypc hyp c f py

hypd add d (py dffccy), hch c p d cc pppy . i h c, hyp h d/ p cby g h hhd f h .5 th c k d dy xc p y cc h dfccy b d cch d dfccy, hch hyp dp g f xc dp.

Euvolemic hyponatremia

ec hyp cd by py dfc y d hch, f cbd h xc

k, xpd d d bdy fd. if g gh,h xp f bdy fd pp p cy d d d gg (y xc f d). th ph h hyp b dc xc ,hby g g f hyp. thdfc d y g b y h g f p. s hby cdy fc by cgzdd ccb c , ch , dg cdy d ffccy.6 H, f f cpc p c(f ) pc p c (f

h hypphy) h bc f y dcb dy ccb . th dd cy

fd h yd f ppp dch c (siaDH) d c b cd by dff b g.2

th fq by pp b d g f h . th c k by b b p f h bgy y.th h f h g c fc p p (yp a) c k f h h (yp B) d ffcdby chg p d . ifqy, hppp d b p dpd. th dd f pdy d h y db b

y p p .2 i p, hppp d h f ccg f h v

2cp7 h c ffc

hzyg hzyg .8 thc f h xc k p h c hyp , y b g cd by h g f hb c b pychgc gc (f xp,cd by d f fd).

dffta ath yp f hyp c b dd f hcc hy dd phyc d b

y g f (tb 1).9 Hypchyp cc p h cgh f ch. i p h phyc g f cdc f c, gzd d dby b c h dcd pf (f xp, p z).

Hypc hyp ypcy cc p h hy h dc f d h, dc b add d. i dd, cd h phyc d/ by gf xc dp, ch p hyp, chycd d p z.Hypk y b p, h c

10 –

8 –

6 –

4 –

2 –

0 –

– 5

– 4

– 3

– 2

– 1

– 0

130 135 140 145

Serum sodium (mmol/l)

AVP

Thirst

P l a s m a

v a s o p r e s s i n ( p g / m l )

T h i r s t ( m m )

150

a 1,500 –

1,200 –

900 –

600 –

300 –

0 –

– 1,000

– 800

– 600

– 400

– 200

– 0

130 135 140 145

Plasma vasopressin (pg/ml)

Thirst (mm)

Uosm

Uow

Intake

U r i n e o s m o l a r i t y ( m o s m / l )

U r i n e o w

o r w a t e r i n t a k e ( m l / h )

150

b

Figure 2 | Osmoregulation of ater balance in healthy adults. a | Relation of plasma vasopressin levels and thirst toplasma sodium concentration. b | Relation of urine osmolarity (U

osm), urine flo (U

flo) to plasma vasopressin and of ater

intake to thirst. Based on data in Robertson, G. L. et al.25 and Zerbe, R. L. et al.26. Abbreviation: AVP, arginine vasopressin.

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hypd add d, hch c p cc y hgh.

ec hyp cc y dffcc g, f xp, k, p gcy; h, h yp f hyp c b dphc.9 Dg gy d hb f xc, d phyc g f xc xp cc p, hgh bd f g d ccd f pby g gh xp. th p dpd f f c hyp bddd by h pc bc f k, ccb , ch

cdy d ffccy. m f p p f dgc xcp dff siaDH f h yd f pp p d (siaD). i h , hghfy hy d y f h v

2cp g y

b f.i c, h dc y b f f

h dff dg, pc (tb 1).P cy y hgh hypcd hypc hyp b chyp, h cd by cdy d ffccy. if d ffccy pcd cc gd (f xp, hypc hyp

h hypk c hyph hypgyc), bf g gcy gc ccd hpy, p hd b ccd c h d cf xcf h dg. i hy, h f y d xc ( p ) hd b f h dff dg f hyp. ipcc, h, h y d d y hh, cdby dpdg hfc, cdg h dp ph f h y d. th cc f d (/) gf f dff dg, bc gy fc f h f d.

Tata tatmt a maamtth f hyp dpdg h yp, d, y d cc ffc (tb 2).syp, hch g f hdch d d c f c d c, y cc f hhyp dp pdy 24–48 h d/ (p d <125 /). th yp bb cd c pcd by cy d hf f bc.10 H, b g d ypy dh f f dy f hypp, pby bc y ddc cd (xcd k p

g c), hch dffbck h xc pc. a h g, hyp , hyp hd b c cd y, bc pd cc k b jy by c dyz.11 th f cc qd d h k c b gy hgh b <12 / 24 h. H, f h hyp ypc d f y hd (24–48 h), hd b ccd ppy, h k f dy, ch c, c d dhf h f h b, y b g h h k f c dyz. i c, cc f hyp h yp f h,

hgh cp cy f c z y k 1 dy g.

Hypc hyp hd b d by dc f bdy , by cg h f bdy d. rcg fd k 500 pdy h h y p ffc, b y (h f p d y xcd 1–3 / p dy) d dffc , pcy by b. n b f fd k dc bdy h x p bc h z d f p dpdg h f dd k. e f p y

Table 1 | Differential diagnosis of hyponatremia

chaatt Hpvm* Hpvm* euvm (siAdH)* euvm (siAd)‡

cHF ch daha dutabu

Pmaaa fau

naua saaa fau

oth§ nph ipath

Edema Yes Yes No No No No No No No No

Blood pressure Variable Variable Lo|| Lo Lo Variable Lo Normal Normal Normal

BUN High Variable High High High Variable Variable Lo Lo Lo

Serum potassium Lo Lo Lo Lo High Variable Normal Normal Normal Normal

PRA High High High High High Normal Variable Lo Lo Lo

Aldosterone High High High High Lo Variable Normal Normal Normal Normal

Cortisol Normal Normal Normal Normal Lo Variable Lo Normal Normal Normal

Vasopressin Yes Yes Yes Yes Yes Yes Yes Yes No No

V2

receptormutation

No No No No No No No No Yes No

*Partially or completely vasopressin-dependent. ‡Vasopressin-independent.§Other common causes refers to the many different illnesses or drugs thought to cause SIADH by unknon oruncertain mechanisms. ||It is vir tually impossible to put specific numbers on lab results associated ith the different types of hyponatremia, because firstly, the reference ranges for testsvary from lab to lab and are alays (or alays should be) shon on the report alongside the patient values, making it easy to conclude if it is high, lo or ithin normal limits; and secondly, themagnitude of the lab abnormality (high or lo) varies markedly from patient to patient depending on the severity or duration of each type of hyponatremia. Abbreviations: BUN, blood ureanitrogen; CHF, congestive heart failure; PRA, plasma renin activity.

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b cpy cc b y b

h chg bdy gh f djg c dd q. if h hyp d ypc, cp c (xcp f cchp f h x) hd b d bf h f p d. th p dc f d c d xc, bh p p d d d fccpd by hypk. th cyc bcdccyc, hch y c xcby cg b phgc db pd, cdcd p h cg h fd ch g h k f phxcy. th, c y f g hypc hyp

p, d b y f pg xc dd h cd.

Hypc hyp hd b d by cg bdy d d, by dc g h f bdy . uy, hd b c cd ppy, f c d ypcd p k hdyc fc. th y by f f (0.9%) hypc (3.0%) . ipc f h d, h c p d hd b d cy (b y 2–4 h) dcd by djg h f , bc d c dp, hby ccg h f

p d , bf h hyp fy ccd.

ec hyp c b d by dc g bdy c, cg bdy d bh. if h yp f hyp cd by pcd cdy d ffccy, pcp f c f c y ffc hb p c, c xc d p d . i cypc siaDH siaD, h hyp c bccd ppy d pdcby c f fd k d f f hypc ( f b 0.05 /kg bdy gh/). th f

ph h d dfccy d dc bdy

by pdcg c d.th ffc p d cc hd bd cy, d h f f djd cy h ppy yph h k f c dyz. th ‘f’ c d pbby dpd x h b, b pd g p ppxy 2 / 4 h. H, f h hyp chc d/ y ypc, h c d pbby hd b gd ( h b 1–2 / 4 h). t ch b, fdc, dccyc y ffc b c h db d

ffc, ch hypk, hyp, p, z d phy. Bc f kd d ffc, ch g d hypcc,h g cdd f h f hyp. thf, p, f y f cg xc p d ccd b f siaDH d siaD.

Vaptans

s dff p (zp, cp, p, p, xp d rwJ351647) hb dpd d d h.12–24 a f hdg cp g f p cp

h dcb g cy. H, hpcfcy f h p cp dffghy. Cp bd y v

1d v

2cp

, h h h p y pcfc fv

2cp; h, p d x

y p phygc phphygc ffc h v

1cp. th y xcp y b h h

xy hgh p p pdcd by ( f f g d f p) y c c cc h pbf h p h cc h g.

a p c b k y, hgh cpc b dd y. D h

Table 2 | Therapy for hyponatremia

Thap Tta ha rat Hpvm(cau f na+ a H

2o a)

Hpvm(cau f wattt )

euvm(Vap-pt)

euvm(Vap-pt)

na+ H2o cHF clF ra gi Aa emt Aa siAdH V2r ?

Fluid restriction Slo Yes No No Yes No Yes Yes Yes Yes Yes

Isotonic saline Slo No No Yes Yes Yes Yes Yes Yes Yes Yes

3% saline Fast No No Yes Yes Maybe Maybe Maybe Yes Yes Yes

Fludrocortisone Slo No No No No Yes No No Yes* Yes* Yes*

Demeclocycline Slo No No No No No No No Yes* ?* ?*

Urea Slo No No No No No No No Yes* Yes* Yes*

Cortisol Slo No No No No Yes No Yes No No No

Antiemetic Slo No No No No No Yes No No No No

Vaptan Fast Yes Yes No No No Maybe No Yes* No ?

*Hyponatremia is chronic or asymptomatic. Abbreviations: , increased; , decreased; , severely decreased; , unchanged; ?, unknon; CHF, congestive heart failure; CLF, chronic liverfailure ith cirrhosis; GI, gastrointestinal; NA+, sodium; SIADH, syndrome of inappropriate antidiuretic hormone; V2R, activating mutation of vasopressin V2 receptor.

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phckc d phcdyc pp d, b h g dff y ghy f bby, pk p cc , pk y ffc d cc hf f d. H, dd h pp g. i dd, f h b d hb f cych P450 3a4(CYP3a4) d hd b d h h dgk b bzd by h y, ch k cz, chyc d . t p— cp d p—hb ppd f h f ccy gf c c d hypc hyp hpzd p.

efft hath vuath ffc f p bc xpfd by dy y hydd hhy d.15 l h1 h f d f cp, y f by 50% d f y dbd.th chg x 2 h, h d

b h x 6–12 h. th c p cd y by q, y xc dd c. th ck f ffc xc b chcc f p dc h h f dc c, ch fd, hch c xc f d dh cy.13

th p dcd q dcd bdy c by g f b 1.5 h f 6 h,bc h c p b2.4 , h fd k cd 900 (150 /h) dg h pd. a f hdc bdy , p y by

g f b 7 /. th d cd by f p p, dcd by h sD f b 5 /. th c p y, , d h d p pcc. Bh phygcy pppp h dc bdy d p d d q cp hhy d. th ffc cc hhy d d h zp12–14 d p hhyp d h h p ( b).

th c f h d p c dg p hpy y b cq, hp cd ‘fd bck’ dc ffccy. th

p cd dh h hqc ffc f h p by bg h h cp ffcy f bdg v

2cp.

if , cd pfy dd dffc qc ffc, h p p c gy f p p,25 ppy h b f gyp.26 th fccd cb h y g dddffc h f p d cc hhy d f d f zp13,14 cp.15 By cg fd k, h cd ff h ffc f q bdy cd p y. th pc f h b

h by h dy hch fd k cd f y 2 h f d f f df f d f p (60–240 g) hhy dy pcp.18 H, 24 h p cd pp h d b dd c h h p d h chg k.H, dd chg p d c c dd c h chg bc, ccd h dffc b 24 h fdk d p. th, k p cd f h chg p dcc h p hpy.

efft hpvm hpatmaCongestive heart failure

sx pcb cd cc f p hpy cdd p h cg h f c h, dd h c hyp .27–32 a f h d fd h ppdcd b c p d pd h gp h, d d

d p g d yp f cg h f. H, p g y hpz dd. ap f yp f h d py , cc h d cp, dg d d d, hgh h d f p xcddh cdd d h k f cdyz. H, f h d pdh fdg p h hypc hypf h h h yp f hyp. th, hy d p cc b pb dffc ffccy fy h f dffc h

phphygy f pd xc.F h p fcd xcy p h

cg h f.33–36 th d ccdpy h h ffc f p hdycfc d cdd f p h hyp.nh, hy pd f f b hffc f p bc d p d cg cdc f. o dy cpdh ffc f pcb d h dff d f p f p 23 dy 254 p.33 th dy pcp d dk ad libitum d h , cdg fd. o hf dy f p hpy, d dpd f

24 h y d p ccd.H, h d fd k cd, h c cd dc bc d bdy gh d, d p d by y b 2.5–3.5 / h h d gp. thchg cd h dc pd db p h p’ qy f f c.th c p d cc fh f d f p b f 20 p hhyp ghy g (5 /) h hgp h33 d h bd hhy d g h d f p dd dk ad libitum.18 th dffc

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y b ccy gfc d c b xpdy, b gh fc dffc dg bp cc, h, fd k d/ p pcc h cd.

wh p hpy xdd f 25 dy c p h cg h f,h chg y, bdy ghd p d dcd y h gp h.33 th f h dc c, bd h b f hypc ph cg h f.33 th dffc ggh g dc ffccy h cgp cd by g c h, fd kd/ p c h pbby d fh hgh b b f p d hc h h hypc gp. ap fh, dg d d bd, hgh h p d fp xcdd h cdd, f .

a cd dy d h c ffc f f df f d (10–400 g) f xp p h

n Yk H ac c iii cg hf d d .34 thdy fd h, cpd h pcb, d f xp >10 g pdcd b c f d f cc, 2–4 h f . ahgh d (150–400 g), h cd xc cd h cy gfc f d (f pcfd gd) dp p. th ffc hypc yp , f y, pd. n d kd pcfcy h .

t dd d ccd y hh ffc f p cdc fc d

p h cg h f. i dy,35 45f 68 hpzd p h hyp cdh p d by 2 / dg h 30 g, 60 g 90 g d f p.th p hd y (11%)60 dy f dchg h dd p h hyp dd p (22%). th fdg ggh cc f hyp cg fp h p c h hch hcd. i h h dy,36 h 30 gdy f p f 60 dy d p d d pd cdy f cdcfc p h c h f d

p d cc b dd ffcy bdy cpd h pcb. th, hj bf f p hpy b d p h hyp.

Cirrhosis

s pcb cd f p x p hpy h cdd p h ch, h yp f hypc c hyp .30–32 o pd h gd f4 25 dy, g fd h p pdcd b b cy gfc c p, f cc d d

h dg d d yph h h. H, h fdg p hch pd py, kg p b d f hy pd y h hcg cdc f c hyp.

F d h fcd xcy h ffcf p p h ch. o dy c pd h qc ffc f g d f z p d fxd f fd k 24 h xhhy d d gh p h ch, f h c.37 th hd h g 30 g d pdy dcd y dcd bh gp h f 2 h f, b h chg p h ch h h hhy dd. th fdg xpd b c h h ccp hpd xc ch d py p dpd ch, ch dcdd dy f f. igy, h dy fd h p p h dbd bh gp, hgh c p

d ccd, pby bc k y dy cd d fc dxc ghy hhy dd. th fdg h pby h h p f p by c ch. th ffc h d h p.

ah dy,23 cpd h phckcd phcdyc f f dff d (25 g,50 g, 100 g, 200 g d 300 g) f xp p h hd ch d c, b h y c. Fd k phbd fh f 4 h f b cd h f. th hd h xp pdcd

pd, d dpd f y d p d f cc h pkd b 2 h, h dcd gdy b hx 22 h. a h hgh d, 24 h pgd 4.6 , b d gy f p p, gg f 1.2–12.2 dy. sp fdk cd, b gy h p. th, bc g d pd by ( ± sD) 1.2 ± 1.0 /,2.7 ± 1.5 /, 4.0 ± 2.6 /, 4.3 ± 3.2 / d5.0 ± 3.0 / f 12 h ch f h f d gp.P p fd hfdf d f h hgh p d. th

c p d cc ghy gd d by hpdcd by h hgh d f p ph cg h f, f h c.33 idd f gd bd f cp p h hyp cd by c h.38 i h c, h pbby dd f dd dffc bby b pby f p cc , fd k p p, f hch pd.

a hd p h ch hd gh h f ffccy dg p dg.39 rch

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d 110 pcp h ch d hyp( b p d 127 ± 5 /) dh fd c (1.5 p dy) p pcb hfxd d f p (5.0 g, 12.5 g 25.0 gc dy) f p 14 dy. o h f dy, pdcd bdy gh d cd p d by g f 3–5 /, chg hpdcd by xp c p hch d by p c ph cg cdc f. o h x 4 dy f , h, h chg pd cdghy h p h h c (± sD) p d 4.5 ± 3.5 /, 4.5 ± 4.8 /d 6.6 ± 4.3 / h h gp d h p. a dcd by h sD c, dd g h . i fc, y 54–64%f p zd p d cc cd h by >5 /, d p (2.3%)dpd hyp, b h gcq. n dg d d , h hcd h hch d d, ccd.

o dd 9 dy f , h ffc f p d gy dd h qc ffc d. th hypc p h ch dff f hgd bd dg p hpy f c p h cg h f;h, h fdg h cd ffcf p p d cc hyp c p h cg h f.33 th,h ffc p d b f gd hypc h c ppby bc f h dffc b f c f h, fd k d/

p c pdcd by . i c h, h d f p c cd b gg dcd hpc cc. th phc kc f xp c ch hb pd,23 b y f 24 h pd, d cp d f hhy d hypc ph ch b.

efft uvm hpatmaSyndrome of inappropriate antidiuresis

P h ffd h c f c hyp cdd h h h hd hyp c hyp f pcb cd

f p hpy.27–32 H, h pdd pd h dc h yp f hyp. t h 40,41 fcd xcy p h c hyp. th p cgzd hg siaDH, b h ppf dd h y h hd h p dpd p dpd c f ppp d c b dd fh d pdd.

i dy f 56 p h c hyp ( b p d ppxy 125 /),38 h cb f d fd c (<2 dy) d cp (40 g

80 g p dy) d d by gf b 3 / d 5 /, pcy, h f12 h d by b 6–7 / f 24 h. th ffc ccpd by kd c f c c. o h x 24–72 h, h, cd ff cp pdcd fh c p d cc d f ccdcd b. Bh f h ffc chczd by y g dd .a d f h sem d b f p ch gp, h (± sD) c f c c h f 24 h f hpy h h d f cp ppxy 950 (± 1,870) d 2,000(± 2,300) , pcy, h h c pd f 48 h 5.7 ± 4 / d 6.4 ± 4 /,pcy— by h bd dg f hypc hyp h p.H, f h p dpd hyp cd p d cc f hh cdd . th ffc h d p p pd, b h

f fd k dc cd q by p cp hpy, h hghd. th ffc h yp pd,b cd cdc f dg d d ,y phb h f , ccd.

th () f h g dd p d p h dy f siaDH c h h bd h hypc ff hyp. Dffc fd k cd hpyd p, p y h xcdd hdd c f h 2 p dy. th kd xc cd h cbd,b h pc f h pb c

b d bc h hp b h h b pd. th c() f h kddffc qc ffc () qy c; c b bd dd df fc dgbby, cp g y.Dffc h f dg cc cd py p, hgh g dd df fc bd h f dy f , d p h ffccy hb f CYP3a4 xcdd. a pbb xp f h by qy b fc h h ffccy f h pd g dd dffc p pcc. vp pd h

dy b h b k y gy f p p h siaDH bh bf d dg f hyp2. m, f y f h p hd hc yp f siaDH h dg f h , h p d cd hpdcd c p p cc ffc cc h g f h p,g h bd dc q f hf 24 h f .

th pp f f h g c p d/ p d f ph c hyp y gfy h hppp d p dpd 2

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d, hf, ffcd by p. Fh dy ckg d g dd dffc p p, dg d f cc dg p hpy y h c f h by dgg y dc .

th ffc f p41 c hyp bd siaDH b dc h f cp. wh c bd h fd c (1.5 p dy), bh 25 gd 50 g f p pdcd c f cc d p d dy 1 h xcdd hchg h pcb d gp d g h pdcd by 40 g d 80 g f cp. H, c cp hpy, p d cd gdy,d h q dcd y ghy dg h x72 h f p . th y bbd py h dff f d ( ) d/ f cc f h p. H, hy cd fc c p p h p

dy. i p h hgh p d, h p p cc hghy bb d (2.6 ± 6.7 pg/), hgh hcc c p d gdy 16 /.41 th dpy cd gfy h y hgh pp f h p h gphd h yp a yp B gy dfc.2 thp ffccy f p d p b f p f 23 dy 12 h hchzd pd cc f hyp dy pcp.41

th h ffc f p p dp d d f p p ch,

, h ffc f cp hd b d. ab 20% f p d h phd c p d cc,h b 10% hd c g h 12 / h f 24 h. t p h d cpgd d hyp h yp f , g d cf, hch d hq. a h h d, h ffc f h b d h yp dcbd, dh f h dffc cpy d. i p, h ck f d c b d p dkg, cd h g q. i h, h, h b

d y h b gy bd dffc qc ffc, g h h f fd c h g dd p f p.

nby, h g c p d c c pdcd by cp d p p h siaDH ghy g h h p dcd h hypc f f hyp. thfdg cd b h f dffc xp dg h v

2bdg ffy f dff p.

H, cd fc dffc h c()f h pd xc, bc, p hhypc hyp, h ph d

y p c b dcd dy f f h d ph, p dpddfc. th gh b cfd by py yzg d h cpg h d bd f hdff gp dd h g ’xd’ .

Psychogenic polydipsia.

th hyp h cc p hpychgc pydp b cd by bchg p c d/ c hp h by pdy xc h hg f gd.42 a pcb cd f phpy h fd c p h dhyp d pd y d h hh p ppy cd p d by b7 / d d h f h df (30 dy).43 th cf h xc h f b dfc h p p f p c d hpy p cc f h p.

Nephrogenic syndrome of inappropriate antidiuresis

th p dpd f f pppd cd by cg f h v

2

cp ffcd by p p.44 id b hh d h f h dfccc d hh h f f ppp d h pp b p dpd(siaD) fcy p.

Av fftth fy pf f h p gd h cd ffc h h h. H, cp c c f f d

p h b cd h cd cdcf g bdg p h dd hd b d h c d y f by cy p h h cd.

occy, p h b b d p d f hgh h c dd d c dyz, b h p cpc bd y pd d. nh, cc h ffc h d cc d g h f fd c h p hpy, dg h f 24 h, hghh c d ffc d cd fdk y ff ch f h dd ffc p

d . i y c, h ffc p dcc hd b d cy dg d d gd dj fd k dcd dg.

Conclusions

th ppd p g k cc y p b f h g f c yp f hyp, hy pdc p d h c dc bdy d c h cc f d p dxc fd. idpd f h d, h qc ffc bg qcky, pk h

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f h d gy bd h 12–24 h. th p d p h q d pb by fcd hcd by cc c f fd k. H, dd qd p d p h dg y g. th c f h c b y dffc bby d cc f h p, ffg ffc f cd h d p c. F k , h ffc f h p p d d/ p dc h cd byd24–72 h; h, h cc y,f y, h b p d cc . th ph ppy d h y f p f g f ph hyp.

vp b f h f hyp c hyp, h dd by hpc ffc f d cc, dcc f h hyp y h ddbf f g . vp f

p h bc chc f f siaDH,cdg p h pychgc pydp. H,h f p g c, ypc f f hyp siaDH c

bc f f hypc (3%) j f d chp, d h ffc pdc b d c. vp hd b d p h hypc hyp, hdd h g dfc d d hcp hdyc by d fc.vp cy d hd b d h yp f c hyp cd by c cdy d ffccy, dhy ffc h p dpd ff siaD cd by cg f h v

2cp

d pby h ch. F d hdcd h c f h pdcb by ff ccy h pc h f dg p d p dpd chf d.

Review criteria

A search for original articles published beteen 1990

and 2010 as performed in MEDLINE and PubMed. The

search terms used ere “vaptan” and “hyponatremia”.All articles identified ere English-language, full-text

papers. The author also searched the reference lists of

identified articles and other revies for further papers.

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2. Robertson, G. L. Regulation of argininevasopressin in the syndrome of inappropriateantidiuresis. Am. J. Med. 119 (Suppl. 1),S36–S42 (2006).

3. Schrier, R. w. water and sodium retention inedematous disorders: role of vasopressin and

aldosterone. Am. J. Med. 119 (Suppl. 1),S47–S53 (2006).4. Pruszczynski, w., Vahanian, A., Ardaillou, R. &

Acar, J. Role of antidiuretic hormone in impairedater excretion of patients ith congestive heartfailure. J. Clin. Endocrinol. Metab. 58, 599–605(1984).

5. Robertson, G. L. The use of vasopressin assaysin physiology and pathophysiology. Semin.

Nephrol. 14, 368–383 (1994).6. Oelkers, w. Hyponatremia and inappropriate

secretion of vasopressin (antidiuretic hormone)in patients ith hypopituitarism. N. Engl. J. Med. 321, 492–496 (1989).

7. Gitelman, S. E., Feldman, B. J. &Rosenthal, S. M. Nephrogenic syndrome of inappropriate antidiuresis: a novel disorder in

ater balance in pediatric patients. Am. J.

Med.

119 (Suppl. 1), S54–S58 (2006).8. Decaux, G. et al. Nephrogenic syndrome of

inappropriate antidiuresis in adults: highphenotypic variability in men and omen from alarge pedigree. J. Am. Soc. Nephrol. 18, 606–612(2007).

9. Robertson, G. L. Antidiuretic hormone. Normaland disordered function. Endocrinol. Metab. Clin. North Am. 30, 671–694 (2001).

10. Pasantes-Morales, H., Lezama, R. A.,Ramos-Mandujano, G. & Tuz, K. L.Mechanisms of cell volume regulation inhypo-osmolality. Am. J. Med. 119 (Suppl. 1),S4–S11 (2006).

11. Sterns, R. H. & Silver, S. M. Brain volumeregulation in response to hypo-osmolality and its

correction. Am. J. Med. 119 (Suppl. 1), S12–S16(2006).

12. Shimizu, K. Aquaretic effects of thenonpeptide V2 antagonist OPC-31260 inhydropenic humans. Kidney Int. 48, 220–226(1995).

13. Ohnishi, A. et al. Potent aquaretic agent. A novelnonpeptide selective vasopressin 2 antagonist(OPC-31260) in men. J. Clin. Invest. 92,

2653–2659 (1993).14. Ohnishi, A. et al. Aquaretic effect of a potent,orally active, non-peptide V2 antagonist in men.

J. Pharmacol. Exp. Ther. 272, 546–551 (1995).15. Burnier, M., Fricker, A. F., Hayoz, D.,

Nussberger, J. & Brunner, H. R. Pharmacokineticand pharmacodynamic effects of YM087, acombined V1/V2 vasopressin receptorantagonist in normal subjects. Eur. J. Clin. Pharmacol. 55, 633–637 (1999).

16. Mao, Z. L., Stalker, D. & Keirns, J.Pharmacokinetics of conivaptan hydrochloride,a Vasopressin V1a/V2-receptor antagonist, inpatients ith euvolemic or hypervolemichyponatremia and ith or ithout congestiveheart failure from a prospective, 4-day open-label study. Clin. Ther. 31, 1542–1550 (2009).

17. Matsuhisa, A., Taniguchi, N., Koshio, H., Yatsu, T.& Tanaka, A. Nonpeptide arginine vasopressinantagonists for both V1A and V2 receptors:synthesis and pharmacological properties of 4-(1,4,5,6-tetrahydroimidazo[4,5-d][1]benzoazepine-6-carbonyl)benzanili de derivativesand 4'-(5,6-dihydro-4H-thiazolo[5,4-d][1]benzoazepine-6-carbonyl)benzanilid e derivatives.Chem. Pharm. Bull. (Tokyo) 48, 21–31 (2000).

18. Shoaf, S. E., wang, Z., Bricmont, P. &Mallikaarjun, S. Pharmacokinetics,pharmacodynamics, and safety of tolvaptan, anonpeptide AVP antagonist, during ascendingsingle-dose studies in healthy subjects. J. Clin. Pharmacol. 47, 1498–1507 (2007).

19. Serradei l-Le Gal, C. An overvie of SR121463, aselective, non-peptide vasopressin V(2) receptor

antagonist. Cardiovasc. Drug Rev. 19, 201–214(2001).

20. Albright, J. D. et al. 5-Fluoro-2-methyl-N-[4-(5H-pyrrolo[2,1-c]-[1, 4]benzodiazepin-10(11H)-ylcarbonyl)-3-chlorophenyl]benzamide (VPA-985):an orally active arginine vasopressin antagonistith selectivity for V2 receptors. J. Med. Chem. 41, 2442–2444 (1998).

21. Martinez-Castelao, A. Lixivaptan (American

Home Products). Curr. Opin. Investig. Drugs 2,525–530 (2001).22. Muralidharan, G. et al. Pharmacokinetics and

pharmacodynamics of a novel vasopressinreceptor antagonist, VPA-985, in healthysubjects. Clin. Pharmacol. Ther. 65, 189(1999).

23. Guyader, D., Patat, A., Ellis-Grosse, E. J. &Orczyk, G. P. Pharmacodynamic effects of anonpeptide antidiuretic hormone V2 antagonistin cirrhotic patients ith ascites. Hepatology 36,1197–1205 (2002).

24. Gunnet, J. w. et al. Characterization of RwJ-351647, a novel non-peptidevasopressin V2 receptor antagonist. Clin. Exper.

Pharmacol. Physiol. 33, 320–326 (2006).25. Robertson, G. L., Shelton, R. L. & Athar, S. The

osmoregulation of vasopressin.Kidney Int.

10,25–37 (1976).26. Zerbe, R. L., Miller, J. Z. & Robertson, G. L.

The reproducibility and heritability of individualdifferences in osmoregulatory function in normalhuman subjects. J. Lab. Clin. Med. 117, 51–59(1991).

27. Ghali, J. K. et al. Efficacy and safety of oralconivaptan: a V1A/V2 vasopressin receptorantagonist, assessed in a randomized, placebo-controlled trial in patients ith euvolemic orhypervolemic hyponatremia. J. Clin. Endocrinol. Metab. 91, 2145–2152 (2006).

28. Annane, D., Decaux, G. & Smith, N. Efficacy andsafety of oral conivaptan, a vasopressin-receptorantagonist, evaluated in a randomized,controlled trial in patients ith euvolemic or

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hypervolemic hyponatremia. Am. J. Med. Sci. 337, 28–36 (2009).

29. Zeltser, D., Rosansky, S., van Rensburg, H.,Verbalis, J. G. & Smith, N. Assessment of theefficacy and safety of intravenous conivaptan ineuvolemic and hypervolemic hyponatremia.

Am. J. Nephrol. 27, 447–457 (2007).30. Schrier, R. w. et al. Tolvaptan, a selective oral

vasopressin V2-receptor antagonist, forhyponatremia. N. Engl. J. Med. 355, 2099–2112

(2006).31. Gheorghiade, M. et al. Vasopressin v(2) receptorblockade ith tolvaptan versus fluid restrictionin the treatment of hyponatremia. Am. J. Cardiol. 97, 1064–1067 (2006).

32. wong, F., Blei, A. T., Blendis, L. M. &Thuluvath, P. J. A vasopressin receptorantagonist (VPA-985) improves serum sodiumconcentration in patients ith hyponatremia: amulticenter, randomized, placebo-controlled trial.Hepatology 37, 182–191 (2003).

33. Gheorghiade, M. et al. Vasopressin V2-receptorblockade ith tolvaptan in patients ith chronicheart failure: results from a double-blind,randomized trial. Circulation 107, 2690–2696(2003).

34. Abraham, w. T., Shamshirsaz, A. A., McFann, K.,

Oren, R. M. & Schrier, R. w. Aquaretic effect of lixivaptan, an oral, non-peptide, selective V2receptor vasopressin antagonist, in Ne YorkHeart Association functional class II and IIIchronic heart failure patients. J. Am. Coll. Cardiol. 47, 1615–1621 (2006).

35. Rossi, J. et al. Improvement in hyponatremiaduring hospitalization for orsening heart failureis associated ith improved outcomes: insightsfrom the Acute and Chronic Therapeutic Impactof a Vasopressin Antagonist in Chronic HeartFailure (ACTIV in CHF) trial. Acute Card. Care 9,82–86 (2007).

36. Konstam, M. A. et al. Effects of oral tolvaptan inpatients hospitalized for orsening heart failure:the EVEREST Outcome Trial. JAMA 297,

1319–1331 (2007).37. Inoue, T. et al. Therapeutic and diagnosticpotential of a vasopressin-2 antagonist forimpaired ater handling in cirrhosis. Clin. Pharmacol. Ther. 63, 561–570 (1998).

38. Ginès, P. et al. Effects of satavaptan, a selectivevasopressin V(2) receptor antagonist, on ascitesand serum sodium in cirrhosis ithhyponatremia: a randomized trial. Hepatology 48, 204–213 (2008).

39. Verbalis, J. G., Zeltser, D., Smith, N., Barve, A.& Andoh, M. Assessment of the efficacy andsafety of intravenous conivaptan in patients itheuvolaemic hyponatraemia: subgroup analysisof a randomized, controlled study. Clin.

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ith satavaptan (SR121463B), an orally activenonpeptide vasopressin V2-receptor antagonist.Clin. J. Am. Soc. Nephrol. 1, 1154–1160 (2006).

42. Goldman, M. B., Luchins, D. J. &Robertson, G. L. Mechanisms of altered atermetabolism in psychotic patients ith polydipsiaand hyponatremia. N. Engl. J. Med. 318,397–403 (1988).

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AkwmtC. P. Vega, University of California, Irvine, CA, is theauthor of and is solely responsible for the content of the learning objectives, questions and ansers of theMedscapeCME-accredited continuing medicaleducation activity associated ith this article.

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