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<h2 style="text-align: center;" class="art-PostHeader">Dipirona: modo de
a��o analg�sica</h2>
<p>Publicado em 25 de agosto de 2000 | �ltima atualiza��o: 5 de dezembro
de 2015</p>
<div style="text-align: justify;">
<div style="text-align: justify;"><span style="font-weight: bold;">1 -
INTRODU��O<br>
<br>
</span></div>
Analgesia por analg�sicos e anti-inflat�rios n�o esteroidais (AINEs) �
explicada pela a��o inibit�ria da s�ntese local de prostaglandina-2
(PGE2) (Vane, 1971). Essa a��o previne o desenvolvimento da
hiperalgesia , isto �, a sensibiliza��o dos receptores de dor
para est�mulos qu�micos e f�sicos. </div>
<p style="text-align: justify;">Dipirona � um analg�sico e antipir�tico
muito utilizado em diversos pa�ses onde sua propaganda � permitida.</p>
<p style="text-align: justify;">Existe uma impress�o entre os m�dicos de
que a dipirona tem um efeito cl�nico diferente dos AINEs. Existem
muitos artigos e estudos na literatura mostrando que a dipirona tem
efeito analg�sico maior que aspirina, que � um antiinflamat�rio
inibidor de COX cl�ssico (Mukherjee et Sudha, 1980; Petrova et al.
1980) ou paracetamol (Daftary et al, 1980), um analg�sico do grupo da
anilina, e por isso o perfil do efeito farmacol�gico da dipirona �
certamente diferente do que dos AINEs e tamb�m dos analg�sicos de a��o
central (Nikolova et al, 1980; Nikolov et al., 1980). No entanto, esse
s�tio de a��o analg�sica � um mecanismo controverso. A a��o central
foi proposta por Von Tomek (1955) e n�o confirmada por Lorenzetti
(1999) que, ao aplicar dipirona intra-cerebroventricular de rato, n�o
conseguiu inibir a hiperalgesia induzida por prostaglandina em pata
trazeira de rato.</p>
<div style="text-align: justify;"></div>
<p style="text-align: justify; font-weight: bold;">2 � O QUE � DIPIRONA</p>
<p style="text-align: justify;">Dipirona � o nome gen�rico de �cido
[(2,3-dihidro-1,5-dimetil-3-oxo-2-fenil-1H-pirazol-4-il)metilamino]metanossulf�nico,
tamb�m
chamado de
1-fenil-2,3-dimetil-5-pirazolona-4-metilaminometanossulfonato de s�dio
(ou de magn�sio), e ainda denominado de metamizol, um segundo nome
gen�rico e muito encontrado na literatura farmacol�gica
norte-americana e europ�ia</p>
<p style="text-align: center;"> <img style="width: 367px; height: 151px;"
title="Dipirona" src="../img/dipirona.jpg" alt="Dipirona"></p>
<p style="text-align: justify;">Com peso molecular de 351,36 e uma
distribui��o relativa de 44,44% de carbono, 5,16% de hidrog�nio,
11,96% de nitrog�nio, 6,54% de s�dio (7,26% se for magn�sio), 22,77%
de oxig�nio e 9,13% de enxofre, apresenta f�rmula emp�rica
C13H16N3NaO4S.H2O (ou C26H32MgN6O8S2. Na dipirona magnesiana ligam-se
duas mol�culas de dipirona ao c�tion magn�sio). � preparada a partir
da metila��o do grupo amino da sulfamipirina, tratada com alde�do
metan�ico (formalde�do ou formol), em solu��o de bissulfito de s�dio.
Muito sol�vel em �gua (1g/1,5ml), � pouco sol�vel em etanol e
praticamente insol�vel em �ter, acetona, benzeno e clorof�rmio, sendo
um complicador quando � necess�rio fazer uma cromatografia de camada
delgada para diferencia��o da dipirona de outros t�xicos e
barbit�ricos em processos jucidiais onde � pedido a identifica��o
toxicol�gica com fins forenses, pois os melhores carreadores de
mol�culas em cromatografia de camada delgada s�o justamente o benzeno,
o �ter, o etanol, o hexano e a acetona, sendo o metanol muito pouco
utilizado devido � sua toxicidade e a �gua n�o ser usada por dissolver
a camada de s�lica da placa.</p>
<p style="text-align: justify;">Observando a mol�cula da dipirona, �
poss�vel identificar duas estruturas ligantes que tem pap�is
importantes no mecanismo de a��o deste f�rmaco. O primeiro � o
grupamento benzoil, que tem atividade anest�sica comprovada, tanto que
a maior contribui��o da coca�na para a farmacol�gia foi a
identifica��o dos componentes de sua f�rmula estrutural e a descoberta
de que, retirando-se o radical benzoil, a coca�na perdia sua a��o
anest�sica (Cavazzani, 1994).</p>
<p style="margin: 0cm 0cm 0.0001pt; text-align: justify; text-indent: 36pt; line-height: 150%;"><span
style="font-family: "Arial","sans-serif"; color: black;"> <o:p></o:p></span></p>
<div style="text-align: center;"><img style="width: 108px; height: 84px;"
title="Benzoil (benzil ou fenil)" src="../img/benzoil.jpg" alt="Benzoil (benzil ou fenil)"><span
style="font-family: "Arial","sans-serif"; color: black;"></span><br>
<span style="font-family: "Arial","sans-serif"; color: black;">
</span></div>
<div style="text-align: justify;"><span style="font-family: "Arial","sans-serif"; color: black;"><br>
</span>Outro ligante de import�ncia na estrutura da dipirona � o
grupamento sulfato, respons�vel por sua alta solubilidade em �gua e
pela sua facilidade de absor��o, � potencilamente agressivo para a
medula �ssea, podendo causar desde neutropenias, agranilocitoses, at�
aplasia de medula �ssea, uma patologia hematopoi�tica muito severa que
s� tem um tratamento, o transplante de medula �ssea que, se n�o
realizado em tempo, pode levar o indiv�duo ao �bito.</div>
<div style="text-align: center;"><img style="width: 104px; height: 120px;"
title="Sulfato" src="../img/sulfato.jpg" alt="Sulfato"><br>
</div>
<br>
<p style="text-align: justify;">Foi patentetada sob n� 254, pelo
Laborat�rio Hoechst em 1911, na Alemanha com o nome de Metamizol� que
hoje acabou virando nome gen�rico, como aconteceu com a Aspirina�, que
� marca registrada de �cido acetilsalic�lico, desenvolvido pela Bayer
e que se consagrou, tornando-se um nome gen�rico.</p>
<p style="text-align: justify; font-weight: bold;">3 � MECANISMO DE A��O</p>
<p style="text-align: justify;">Apesar de todas as pesquisas j�
realizadas apontarem para uma a��o bloqueadora da hiperalgesia
exercida pela liga��o a um receptor perif�rico, combinado com a��o
espinal da dipirona e com poucos efeitos antiedematosos e/ou
antiiflmat�rios, alguns bancos de dados insistem em continuar
afirmando que a a��o da dipirona atua unicamente por inibi��o de
cicloxigenase, inibindo a s�ntese de prostaglandinas (Abbate et al,
1990; Anon, 1973; Reynolds, 1994; Gladtke, 1983; Arellano et
Sacristan, 1990).</p>
<p style="text-align: justify;">No volume 116, de setembro de 2000 do
banco de dados Drugdex (Micromedex) aparece a cita��o feita no
par�grafo anteiror, ignorando os trabalhos realizados entre 1996 e
1999 por Aleksander Zampronio, Berenice B. Lorenzetti e S�rgio H.
Ferreira, que apontam para a a��o perif�rica da dipirona sobre um
receptor sin�ptico com estimula��o epinhal via ativa��o da
arginina/cGMP em neur�nios sensoriais prim�rios.</p>
<p style="text-align: justify;">Em 2014 um grupo de pesquisadores do
Departamento de Biologia Estrutural e Funcional do Instituto de
Biologia da Universidade de Campinas (UNICAMP) publicou um estudo
demonstrando que a dipirona atua sobre um receptor canabinoide da
classe 1, chamado de CB1 (SANTOS et al., 2014) e praticamente
corroborou os resultados do grupo de Ribeir�o Preto acerca do
mecanismo de ativa��o antinociceptiva sobre um neur�nio sensorial
prim�rio e indicou o receptor canabin�ide da classe 1, designado na
literatura como CB1, integrante da fam�lia de receptores acoplados �
prote�na G, inibidores da adenilciclase e de canais de c�lcio (Ca2+)
operados por voltagem como o respons�vel pela liga��o ao f�rmaco e seu
efeito antinociceptivo. <br>
<br>
O grupo da UNICAMP trabalhou com inibi��o da express�o dos receptores
CB1 atrav�s da aplica��o de inje�es intratecais de sequ�ncias
antisense de oligo-deoxinucleot�deos, isoladas atrav�s de
sequenciamento (ORTU�O et al., 2013) do genoma dos animais
experimentais utilizados (ratos), que parece ter elucidado o receptor
da dipirona, mas n�o identificado pelo grupo de Ribeir�o Preto que,
conforme a literatura farmacol�gica, receptores CB1 s�o abundantes no
sistema nervoso central, enquanto os CB2, a outra isoforma de
receptores canabin�ides, predominam nos tecidos perif�ricos (KATZUNG,
2017) e c�lulas do sistema imunol�gico (RANG, H.P, DALE, M. M.,
RITTER, 2016).</p>
<p style="text-align: justify;">At� pouco tempo atr�s a a��o antit�rmica
da dipirona podia ser explicada pelo antagonismo direto de cininas
pirog�nicas em receptores do centro termo-regulador, localizado no
t�lamo, mas em 2015 surgiu um novo estudo corroborando os resultados
do grupo UNICAMP, mas apontando para um efeito antipir�tico da
dipirona quando ligada aos receptores CB1 e n�o demonstrando efeito
analg�sico (CRUNFLI, et al., 2015). O efeito antipir�tico produzido
pela liga��o da dipirona com o receptor CB1 � compat�vel com a
hipotermia produzida pelo tetra-hidrocanabinol da maconha e pode
explicar o efeito antipir�tico da dipirona, podendo esta liga��o
acontecer em tecidos perif�ricos e n�o no sistema nervoso central.</p>
<p style="text-align: justify;"><br>
</p>
<p style="text-align: justify; font-weight: bold;">4 � FARMACOCIN�TICA</p>
<p style="text-align: justify;">4.1 � IN�CIO DA A��O</p>
<p style="text-align: justify;">Na hipertermia (febre), ap�s
administra��o oral, o efeito hipotermiante come�a a aparecer entre 30
minutos e no m�ximo em uma hora (Ajgaonkar et al, 1988; Giovannini et
al, 1986; Reiner et al, 1984). O pico m�ximo de resposta ficam entre 4
e 6 horas (Ajgaonkar et al, 1988; Giovannini et al, 1986; Reiner et
al, 1984).</p>
<p style="text-align: justify;">4.2 � N�VEL M�XIMO DE CONCENTRA��O
PLASM�TICA</p>
<p style="text-align: justify;">Ap�s administra��o oral, pode ser
encontrado um n�vel m�ximo de concentra��o ap�s 1 a 2 horas (Vlahov et
al, 1990; Flusser et al, 1988; Volz et Kellner, 1980). O n�vel m�ximo
de concentra��o plasm�tica do metab�lito ativo 4-MAA encontrado foi de
11, 21 e 41 mcg/ml, ap�s administra��o oral de 750, 1500 e 3000mg de
dipirona, respectivamente (Vlahov et al, 1990). Na realidade e
dipirona � uma pro-droga que � metabolizada no trato intestinal em
4-metilaminoantipirina (4-MAA), o metab�lito ativo (Vlahov et al,
1990; Flusser et al, 1988; Brune, 1988; Levy, 1986; Volz et Kellner,
1980). O 4-MAA � metabolizado no f�gado em 4-aminoantipirina (4-AA),
um segundo metab�lito ativo (Brune, 1988; Flusser et al, 1988).</p>
<p style="text-align: justify;">A dipirona n�o apresenta intera�es
conhecidas com alimentos ou ent�o s�o clinicametne insignificantes
(Levy et al, 1995; Flusser et al, 1988).</p>
<p style="text-align: justify;">4.3 � S�TIOS DE DISTRIBUI��O</p>
<p style="text-align: justify;">Cerca de 58% do 4-MAA e 48% do 4-AA s�o
distribuidos ligados �s prote�nas plasm�ticas (Zylber-Katz et al,
1985). Os metab�litos da dipirona tem sido encontrados no l�quido
c�falo-raquidiano. Em estudo controlado, 28 pacientes com indica��o
terap�utica de dipirona, tomando 1g por via oral (dois comprimidos de
500mg) em tempos diversos (6 em 6 horas) foram submetidos a pun��o
lombar em v�rios intervalos de tempo e colhido cerca de 2ml de l�quor
sendo detectada a presen�a dos metab�litos em concentra��o menor que
no plasma, mas guardando uma propor��o l�quor/plasma de ambos os
metab�litos (Cohen et al, 1998).</p>
<p style="text-align: justify;">4.4 � VOLUME DE DISTRIBUI��O</p>
<p style="text-align: justify;">O volume de distribui��o do 4-MAA � de
40 litros (Vlahov et al, 1990).</p>
<p style="text-align: justify;">4.5 � METABOLISMO</p>
<p style="text-align: justify;">4.5.1 � PAREDE INTESTINAL</p>
<p style="text-align: justify;">A metaboliza��o da dipirona na parede
intestinal � extensa (Vlahov et al, 1990; Flusser et al, 1988; Brune,
1988; Levy, 1986; Volz et Kellner, 1980).</p>
<p style="text-align: justify;">O metabolismo � feito monoenzimaticamene
por hidr�lise no trato intestinal formando o 4-MAA, um dos seus
metab�litos ativos (Vlahov et al, 1990; Flusser et al, 1988; Brune,
1988; Levy, 1986; Volz et Kellner, 1980).</p>
<p style="text-align: justify;">4.5.2 � F�GADO</p>
<p style="text-align: justify;">No f�gado o metabolismo tamb�m � grande
(Flusser et al, 1988; Brune, 1988; Volz et Kellner, 1980). O 4-MAA �
transformado em 4-AA (Brune, 1988; Flusser et al, 1988; Volz et
Kellner, 1980) e outros metab�litos inativos e de pouca import�ncia.
Em portadores assintom�ticos de hepatite B, com fun��o hep�tica
normal, testes demonstraram preju�zo no metabolismo oxidativo da
dipirona quando comparado com sujeitos n�o portadores (Levy et al,
1997).</p>
<p style="text-align: justify;">4.5.3 � METAB�LITOS</p>
<p style="text-align: justify;">1. 4-Metilaminoantipirina, � um
metab�lito ativo (Flusser et al, 1988; Brune, 1988).</p>
<p style="text-align: justify;">2. 4-Aminoantipirina, tamb�m � um
metab�lito ativo (Brune, 1988; Flusser et al, 1988; Volz et Kellner,
1980).</p>
<p style="text-align: justify;">3. 4-Formil-aminoantipirina (4-FAA), �
um metab�lito inativo (Vlahov et al, 1990; Volz et Kellner, 1980).</p>
<p style="text-align: justify;">4. 4-acetilaminoantipirina (4-AcAA),
tamb�m � inativo (Vlahov et al, 1990; Volz et Kellner, 1980).</p>
<p style="text-align: justify;">4.5.4 � EXCRE��O</p>
<p style="text-align: justify;">4.5.4.1 � Leite Materno</p>
<p style="text-align: justify;">Os metab�litos ativos da dipirona, tanto
o 4-MAA, quanto o 4-AA podem ser encontrados em altos n�veis no leite
materno. Est�o em concentra��o igual ou at� maior que no plasma. No
entanto, os metab�litos foram encontrados no leite at� 48 horas ap�s
administra��o �nica de dipirona por via oral , devendo o uso de
dipirona ser evitado durante o aleitamento materno (Zylber-Katz et al,
1986).</p>
<p style="text-align: justify;">4.5.4.2 � Rins</p>
<p style="text-align: justify;">A excre��o renal � intensa, sendo a
maior via de elimina��o (Vlahov et al, 1990; Volz et Kellner, 1980).
Os metab�litos 4-FAA e 4-AcAA s�o excretados primeiramente na urina
(Vlahov et al, 1990; Volz et Kellner, 1980).</p>
<p style="text-align: justify;">4.5.5 � MEIA VIDA</p>
<p style="text-align: justify;">O metab�lito 4-MAA tem uma meia vida de
2 a 3 horas (Vlahov et al, 1990; Volz et Kellner, 1980). O tempo de
elimina��o m�dio do metab�lito 4-MAA � significativamente aumentado
nos portadores assintom�ticos de hepatite B, quando comparado com
indiv�duos sadios. (Levy et al, 1997), enquanto o tempo de meia-vida
de elimina��o do 4-FAA est� significativamente diminuido em portadores
de hepatite B em compara��o com sujeitos n�o portadores. Os tempos de
meia-vida de elimina��o dos metab�litos 4-MAA e 4-AcAA n�o apresentam
diferen�as estat�sticas significantes entre os dois grupos. (Levy et
al, 1997).</p>
<p style="text-align: justify;">O metab�lito 4-AA tem uma meia-vida de
elimina��o de 4 a 5 hoas (Vlahov et al, 1990; Volz et Kellner, 1980).</p>
<p style="text-align: justify; font-weight: bold;">5 � DILUI��O E
ESTABILIDADE</p>
<p style="text-align: justify;">A Dipirona � compat�vel com solu��o
glicosada a 5%, solu��o de NaCl a 0,9%<br>
e Ringer lactato*.<br>
A administra��o deve ser imediata em �bolus� (ou em bolo) j� que a
estabilidade � limitada nas<br>
tr�s solu�es, devendo ser evitada a infus�o cont�nua*.</p>
<p style="text-align: justify;">* Informa�es do fabricante
Aventispharma (fabricante da Novalgina�).<br>
</p>
<p style="text-align: justify; font-weight: bold;">6 � RESTRI��ES AO USO</p>
<p style="text-align: justify;">6.1 � CONTRA-INDICA��ES</p>
<p style="text-align: justify;">Discrasias sangu�neas ou depress�o da
medula �ssea, hipersensibilidade, rinite, urtic�ria, asma e rea�es
al�rgicas � aspirina ou outros agentes antiinflamat�rios.</p>
<p style="text-align: justify;">6.2 � PRECAU��ES</p>
<p style="text-align: justify;">Hist�ria de �lceras gastrointestinais,
hemorragias g�stricas ou perfura�es da mucosa; disfu�es renais;
hipertens�o card�aca (sobrecarga ventricular esquerda) ou disfun�es
card�acas agravadas por reten��o de fluidos e edema; disfu��o
hep�tica; infec�es pr�-existentes; porf�ria; deficiencia de
glicose-6-fosfato desidrogenase e uso concomitante com clorpormazina.</p>
<p style="text-align: justify;">6.3 � REA��ES ADVERSAS</p>
<p style="text-align: justify;">Anemia hemol�tica e aplasia de medula
�ssea tem sido reportada durante o uso de dipirona (Anon, 1986;
Sansone et al, 1984; Lay, 1966). Agranulocitose � a ocorr�ncia mais
frequente durante a administra��o de dipirona e pode ser fatal
(Arellano et Sacristan, 1990; Hargis et al, 1989; Kiatboonsri et
Richter, 1989; Anon, 1986; Gladtke, 1983; Anon, 1973; Bottiger et
Westerholm, 1973; Sadusk, 1965; Huguley, 1964), tendo muitos casos
acontecidos durante 20 anos de uso de dipirona na Holanda (van der
Klauw et al, 1998). A incid�ncia da indu��o de agranulocitose tem
varia��o geogr�fica. Aparece em altas frequ�ncias em Barcelona e
Berlim e em pequnos �ndices em Budapest, Tel-Aviv e Sofia (Anon, 1986;
Arellano et Sacristan, 1990; Anon, 1973; Vlahov et Bacracheva, 1989) e
varia de estudo para estudo. Diferen�as regionais s�o muito
provavelmente relatadas pela avalia��o e uso em modelos em v�rios
pa�ses. A incid�ncia de agranulocitose varia em 1,1 por milh�o,
durante a primeira semana de administra��o (Anon, 1986) e um caso para
cada 3000 usu�rios (Bottiger et Westerholm, 1973). Calculos baseados
em dados levantados, sugerem que o uso da dipirona est� associado a
menos de 7000 casos por ano no mundo todo (Kiatboonsri et Richter,
1989).</p>
<p style="text-align: justify;">Os efeitos cardiovasculares incluem
hipotens�o de moderada at� severa (Hoigne et al, 1986; Sanahuja et al,
1990). Evidencias de hipotens�o com doses orais tamb�m tem sido
descritas (Giovannini et al, 1986; Paeile et Gallardo, 1974).</p>
<p style="text-align: justify;">Efeitos centrais mais significativos s�o
sonol�ncia, astenia e cefal�ia (Lehtonen et al, 1983; Paeile et
Gallardo, 1974).</p>
<p style="text-align: justify;">Efeitos gastrointestinais incluem
n�usea, v�mitos, irrita��o g�strica e xerotomia, que tem sido
relatadas com a administra��o parenteral de dipirona (Marthak et al,
1991; Lehtonen et al, 1983; Paeile et Gallardo, 1974; von Szeged et
Michos, 1986).</p>
<p style="text-align: justify;">Broncoespasmo tamb�m tem sido descrito
em administra�es cont�nuas de dipirona (Arellano et Sacristan, 1990).</p>
<p style="text-align: justify;">Entre as rea�es cut�neas pode ser
encontrado necrose epidermal t�xica, urtic�ria, �rash� cut�neo (Anon,
1973; Arellano et Sacristan, 1990; Pandhi et al, 1984; Pasricha, 1979;
Lehtonen et al, 1983; Saban et al, 1991).</p>
<p style="text-align: justify;">Choque anafil�tico tamb�m pode
acontecer, com uma incid�ncia de 1 caso em 5000 administra�es
(Fosseus et Straughan, 1983; Arellano et Sacristan, 1990; Kiatboonsri
et Richter, 1988).</p>
<p style="text-align: justify;">6.4 � TERATOG�NESE</p>
<p style="text-align: justify;">Em estudo controlado, com administra��o
de dipirona via oral durante a gravidez, mostrou que o desenvolvimento
de tumor de Wilms foi da ordem de 10,9% (com p<0,05). Esse estudo
incluiu 109 casos de tumor de Wilms e 218 controles. A idade
significante dos casos ao tempo do diagn�stico foi de 41,1 meses. As
m�es foram questionadas sobre o uso de medicamentos durante a gravidez
para se determinar a correla��o do desenvolvimento do tumor e o uso de
medicamentos e a dipirona foi a mais utilizada durante a gravidez de
mulheres cujos filhos apresentaram o tumor, possivelmente devido a
facilidade de acesso � droga. Sem dados de estudos prospectivos, o
aumento na indicencia de tumor de Wilms em crian�as expostas �
dipirona n�o pode ser atribuida definitivamente ao f�rmaco, no
entanto, baseado nesses estudos o uso de dipirona durante a gravidez
deve ser evitado (Sharpe et Franco, 1996).</p>
<p style="text-align: justify;">6.5 � INTERA��ES MEDICAMENTOSAS</p>
<p style="text-align: justify;">6.5.1 � ACENOCOUMAROL</p>
<p style="text-align: justify;">N�o foram observados efeitos
significantes nos tempos de coagula��o durante uso concomitante com a
dipirona (Zylber-Katz et al, 1985), por�m sempre � indicado o m�ximo
de cuidado e monitoriza��o do paciente em uso concomitante de dipirona
com anticoagulantes orais, especialmente se houver necessidade da
adi��o de um antiinflamat�rio n�o ester�ide ao tratamento. O efeito
adverso mais comum � o aumento do risco de hemorragias.</p>
<p style="text-align: justify;">6.5.2 � ALENDRONATO</p>
<p style="text-align: justify;">Durante tr�s anos de estudo cl�nico
controlado, envolvendo 2027 pacientes que recebiam antiinflamat�rios
n�o esteroidais, a incid�ncia de efeitos adversos gastrointestinais
foi similar entre os pacientes recebendo alendronato e pacientes
recebendo placebo. No entanto, quando administrado alendronato com
AINEs, e dipirona, a incidencia aumentava, especialmente a irrita��o
g�strica, efeito tamb�m observado com a dipirona (Prod Info Fosamax� ,
1999).</p>
<p style="text-align: justify;">6.5.3 � INIBIDORES DA ECA</p>
<p style="text-align: justify;">� conhecida a intera��o entre os
inibidores da ECA e a dipirona, podendo surgir bradicardia,
frequentemente induzida por hipercalemia (Shionori, 1993). Esse
dist�rbio pode levar a paradas card�acas (Kurata et al, 1999).</p>
<p style="text-align: justify;">6.5.4 � BLOQUEADORES BETA-ADREN�RGICOS</p>
<p style="text-align: justify;">Em uso concomitante de dipirona com
beta-bloqueadores, tem sido reportado aumento na tens�o arterial e
interfer�ncia no controle da press�o sangu�nea (Radack et al, 1987;
Webster et al, 1984; Abate et al, 1990; Chalmers et al, 1984; Durao et
al, 1977; Salvetti et al, 1984; Watkins et al, 1980).</p>
<p style="text-align: justify;">6.5.5 � BLOQUEADORES DE CANAIS DE C�LCIO</p>
<p style="text-align: justify;">O uso de dipirona com bloqueadores de
canais de c�lcio (nifedipina), aumenta o risco de hemorragia
gastrintestinal (Pahor et al, 1996).<br>
</p>
<p style="text-align: justify; font-weight: bold;">7 � EFIC�CIA
COMPARATIVA (ANTONINI et al, 2012)</p>
<p style="text-align: justify;">7.1 � ACETAMINOFENO (Paracetamol)</p>
<p style="text-align: justify;">7.1.1 � FEBRE</p>
<p style="text-align: justify;">Dipirona na dose de 0,5g oral demonstrou
efeitos antipir�ticos mais acentuados que o paracetamol na mesma dose
em pacientes com febre tif�ide e estudo controlado. A redu��o da
temperatura retal foi muito mais significativa com dipirona do que com
paracetamol at� uma ou duas horas ap�s a administra��o. Existe uma
tend�ncia da dipirona para um efeito prolongado, em torno de 6 horas
ou mais (Ajgaonkar et al, 1988).</p>
<p style="text-align: justify;">7.2 � �CIDO ACETILSALIC�LICO (Aspirina)</p>
<p style="text-align: justify;">7.2.1 � FEBRE</p>
<p style="text-align: justify;">Em um estudo pequeno, duplo-cego, o
efeito de 500mg de dipirona �per-�s� foi superior � mesma dose de
�cido acetilsalic�lico no tratamento de febre (Reiner et al, 1984).</p>
<p style="text-align: justify;">7.2.2 � DOR P�S-OPERAT�RIA</p>
<p style="text-align: justify;">O efeito de 500mg de dipirona 500mg
�per-�s� � consideravelmente superior ao do �cido acetilsalic�lico na
mesma dose no tratamento de dor, em estudo controlado (Arellano et
Sacristan, 1990).</p>
<p style="text-align: justify;">7.3 � N-METIL-BUTIL-ESCOPOLAMINA
(Hioscina)</p>
<p style="text-align: justify;">7.3.1 � NA C�LICA RENAL</p>
<p style="text-align: justify;">Em estudo controlado com n=96 pacientes
com c�lica renal, a hioscina em dose 20mg intravenosa foi inefetiva na
remiss�o dos sintomas dolorosos, enquanto a dipirona na dose de 1
grama intravenosa apresentou efeito menor que 2,5 gramas pela mesma
via. 61% dos pacientes tratados com hioscina precisaram da
adminstra��o conjunta de analg�sicos narc�ticos (petidina, nalbufina,
tramadol ou morfina) para controlar a dor, enquanto 17% e 0%,
respectivamente, dos pacientes em uso de dipirona precisaram da adi��o
de analg�sico opi�ide (Lloret et al, 1987).</p>
<p style="text-align: justify;">7.4 � CLONIXINA</p>
<p style="text-align: justify;">7.4.1 � DOR NA P�S-HISTERECTOMIA</p>
<p style="text-align: justify;">Em estudo randomizado, duplo-cego com
n=160 pacientes divididos em 4 grupos de 40 pacientes cada, foi
administrado 30mg em bolus 15 minutos antes da cirurgia e 15mg em
bolus de clonixina ap�s a cirurgia, ou 660mg de dipirona em bolus
antes e 330mg ap�s a histerectomia. 4,4% das pacientes tratadas com
dipirona necessitaram de doses adicionais de dipirina para controlar a
dor no p�s-operat�rio contra 11% das pacientes tratadas com clonixina
(Rodriguez et al, 1993).</p>
<p style="text-align: justify;">7.5 � DEXTROCETOPROFENO</p>
<p style="text-align: justify;">7.5.1 � DOR NO P�S-OPERAT�RIO
ODONTOL�GICO</p>
<p style="text-align: justify;">A dipirona � t�o eficaz quanto do
cetoprofeno em analgesia no p�s-operat�rio odontol�gico (Bagan et al,
1998).</p>
<p style="text-align: justify;">7.6 � DICLOFENACO</p>
<p style="text-align: justify;">7.6.1 � NA C�LICA RENAL</p>
<p style="text-align: justify;">inje��o intravenosa de 2,5 gramas de
dipirona combinada com pitofenona (um espasmol�tico semelhante �
atropina) e fempiverinium (um espasmol�tico hom�logo da papaverina)
tem efeito similar ao diclofenaco na dose 75mg por via intramuscular.
Ou seja, o diclofenaco em monoterapia � mais efetivo que a dipirona em
monoterapia (Sanahuja et al, 1990).</p>
<p style="text-align: justify;">7.6.2 � NA CIATALGIA</p>
<p style="text-align: justify;">No tratamento da ciatalgia (dor do nervo
ci�tico), 2,5 gramas de dipirona intramuscular foi mais efetivo que 75
miligramas de diclofenaco pela mesma via em tratamento controlado,
randomizado, duplo-cego de 260 pacientes que receberam dipirona,
diclofenado ou placebo por via intramuscular. A dipirona foi mais
efetiva que o diclofenaco com in�cio do efeito ap�s uma hora da
aplica��o e prolongando-se por cerca de 48 horas (Babej-Dolle et al,
1994).</p>
<p style="text-align: justify;">7.7 � IBUPROFENO</p>
<p style="text-align: justify;">7.7.1 � NA DOR P�S-CIR�RGICA</p>
<p style="text-align: justify;">Em estudo comparado entre dipirona
magnesiana intramuscular, ibuprofeno e placebo por via oral, a
espectro analg�sico e o tempo de dura��o da a��o entre a dipirona e o
ibuprofeno foram semelhantes e superiores ao placebo (de Miguel Rivero
et al, 1997).</p>
<p style="text-align: justify;">7.8 � INDOMETACINA</p>
<p style="text-align: justify;">7.8.1 � NA C�LICA RENAL</p>
<p style="text-align: justify;">Inje��o intravenosa de 2,5g de dipirona
tem mostrado efeito maior que 50mg de indometacina pela mesma via, no
tratamento da c�lica ureteral em lit�ases (c�lculos) renais (Lehtonen
et al, 1983).</p>
<p style="text-align: justify;">7.9 � KETORALAC</p>
<p style="text-align: justify;">7.9.1 � EM ANALGESIA</p>
<p style="text-align: justify;">Em estudo randomizado, comparando
aplica��o de 30mg de ketorolac por via intramuscular (um AINE derivado
da pirazolona) com 2g de dipirona pela mesma via cada 12 horas em n=60
pacientes com dor de severa � moderada ap�s cirurgia ortop�dica,
encontrou-se uma efic�cia similar entre o ketorolac e a dipirona no
controle da dor nas primeiras 6 horas do p�s-operat�rio. Ap�s os tr�s
dias seguintes, a redu��o da intensidade da dor foi melhor conseguida
com o ketorolac, demonstrando uma efic�cia maior deste analg�sico em
rela��o � dipirona (Fernandez-Sabate et al, 1991).</p>
<p style="text-align: justify;">7.10 � MEPERIDINA (Petidina)</p>
<p style="text-align: justify;">7.10.1 � NA DOR P�S-CIR�RGICA</p>
<p style="text-align: justify;">Dipirona na dose 2,5g intramuscular ou
intravenosa tem sido t�o efetivo quanto 50 ou 100mg de petidina
intravenosa no tratamento da dor p�s-cir�rgica (Patel et al, 1980; Lal
et al, 1973; Arellano et Sacristan, 1990).</p>
<p style="text-align: justify;">7.10.2 � NA C�LICA RENAL</p>
<p style="text-align: justify;">Doses de 2,5g de dipirona intravenosa
tem se mostrado t�o efetivo quanto 50mg de petidina intravenosa no
tratamento da c�lica renal em c�lica ureteral em um estudo randomizado
(Lehtonen et al, 1983).</p>
<p style="text-align: justify;">7.11 � NIMESULIDE</p>
<p style="text-align: justify;">7.11.1 � NA FEBRE</p>
<p style="text-align: justify;">Em um pequeno estudo duplo-cego, 500mg
de dipirona por via oral foi comparada em efic�cia com o nimesulide
(um novo AINE) na dose 100mg pela mesma via, no tratamento da febre
frequentemente produzida por diversos fatores. Ambas as drogas
apresentaram o mesmo escore de efetividade e foram superioras ao �cido
acetilsalic�lico, que tamb�m foi utilizado no estudo, em efeito
(Reiner et al, 1984).</p>
<p style="text-align: justify;">7.11.2 � NA DOR P�S-CIR�RGICA</p>
<p style="text-align: justify;">Em estudo duplo-cego em crian�as com dor
p�s-operat�ria foram utilizados suposit�rios de 100mg de nimesulide e
300mg de dipirona a cada 6 horas e ambas as drogas apresentaram a
mesma efic�cia no tratamento da dor inflamat�rio no p�s-operat�rio das
crian�as (Scharli et al, 1990).</p>
<p style="text-align: justify;">7.12 � PENTAZOCINE</p>
<p style="text-align: justify;">7.12.1 � NA DOR DO P�S-CIR�RGICO
BUCO-MAXILO-FACIL</p>
<p style="text-align: justify;">Administra�es orais de dipirona na dose
300mg e pentazocine na dose 50mg a cada 4 horas mostraram efic�cia
semelhante em tratamento da dor no p�s-cir�rgico de procedimentos
bucais, maxilares e faciais, em estudo duplo-cego. Neste estudo
encontrou-se efeitos adversos maiores causados pelo pentazocine em
rela��o � dipirona (Paeile et Gallardo, 1974).</p>
<p style="text-align: justify;">7.13 � SUPROFENO</p>
<p style="text-align: justify;">7.13.1 � NEURALGIAS CR�NICAS</p>
<p style="text-align: justify;">Suprofeno oral na dose 200mg 3 � 4 vezes
ao dia foi t�o efetivo quanto a dipirona na dose 500mg 3 a 4 vezes ao
dia no tratamento de neuralgias cronicas de moderada a severa em
estudo controlado envolvendo 60 pacientes hospitalizados (von Szeged
et Michos, 1986).</p>
<p style="text-align: justify;">7.14 � TRAMADOL</p>
<p style="text-align: justify;">7.14.1 � NA C�LICA BILIAR AGUDA</p>
<p style="text-align: justify;">Um estudo multic�ntrico e randomizado,
um grupo de 74 pacientes com c�lica aguda severa de ves�cula biliar,
induzida por lit�ase biliar, foram comparados dipirona, 2,5g, hioscina
20mg e tramadol 100mg, todos por via intravenosa. O temp in�cio da
redu��o da dor foi significativamente menor com a dipirona (10,9
minutos), em compara��o com o tramadol (15,8 minutos) e hioscina (25,6
minutos). No grupo tratado com dipirona, 3 pacientes necessitaram de
doses adicionais da droga ap�s 20 minutos, enquanto no grupo da
hioscina 8 pacientes necessitaram de outra dose do f�rmaco e no grupo
tratado com tramadol apenas 1 paciente necessitou de outra dose do
analg�sico (Schmieder et al, 1993).</p>
<p style="text-align: justify;">7.14.2 � NAS ODONTALGIAS</p>
<p style="text-align: justify;">Tramadol na dose 50mg por via oral e
dipirona na dose 100mg pela mesma via foram considerados equipotentes
no tratamento da dor de dente em tratamento experimental de dor
induzida, em estudo controlado envolvendo 10 indiv�duos sadios
(Rohdewald et al, 1988).</p>
<p style="text-align: justify;">7.14.3 � NA DOR P�S-CIR�RGICA</p>
<p style="text-align: justify;">A efic�cia do efeito analg�sico do
tramado (100mg intramuscular) foi comparado com uma associa��o de
dipirona 500mg com difenidramina 12,5mg, drofenina 25mg e benzetilio
2,5mg, para o tratamento da dor p�s-operat�ria em um estudo
controlado, randomizado com 60 pacientes que sofreram cirurgia
abdominal. Ambas as drogas foram administradas a cada 8 horas por 3
dias. A intensidade da dor foi reduzida mais efetivamente com tramadol
ap�s a primeria dose e durante os tr�s dias de tratamento (p<0,05)
e a qualidade do sono dos pacientes foi significativamente melhor com
o tramadol do que com a dipirona associada (p<0,001). Efeitos
adversos apareceram em 3 pacientes do grupo com tramadol e apenas em
um paciente no grupo com dipirona associada (Canepa et al, 1993).</p>
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