{"id":4682,"date":"2000-06-19T11:08:24","date_gmt":"2000-06-19T11:08:24","guid":{"rendered":"http:\/\/antonini.med.br\/blog\/?p=4682"},"modified":"2024-09-22T16:34:21","modified_gmt":"2024-09-22T16:34:21","slug":"dipirona","status":"publish","type":"post","link":"https:\/\/antonini.psc.br\/?p=4682","title":{"rendered":"Dipirona: modo de a\u00e7\u00e3o analg\u00e9sica"},"content":{"rendered":"

INTRODU\u00c7\u00c3O
\nAnalgesia por AINEs \u00e9 explicada pela a\u00e7\u00e3o inibit\u00f3ria da s\u00edntese local de PGE2 (Vane, 1971). Essa a\u00e7\u00e3o previne o desenvolvimento da hiperalgesia , isto \u00e9, a  sensibiliza\u00e7\u00e3o dos receptores de dor para est\u00edmulos qu\u00edmicos e f\u00edsicos.<\/p>\n

Dipirona \u00e9 um analg\u00e9sico e antipir\u00e9tico muito utilizado em diversos pa\u00edses onde sua propaganda \u00e9 permitida.<\/p>\n

Existe uma impress\u00e3o entre os m\u00e9dicos de que a dipirona tem um efeito cl\u00ednico diferente dos AINEs. Existem muitos artigos e estudos na literatura mostrando que a dipirona tem efeito analg\u00e9sico maior que aspirina, que \u00e9 um antiinflamat\u00f3rio inibidor de COX cl\u00e1ssico (Mukherjee et Sudha, 1980; Petrova et al. 1980) ou paracetamol (Daftary et al, 1980), um analg\u00e9sico do grupo da anilina, e por isso o perfil do efeito farmacol\u00f3gico da dipirona \u00e9 certamente diferente do que dos AINEs e tamb\u00e9m dos analg\u00e9sicos de a\u00e7\u00e3o central (Nikolova et al, 1980; Nikolov et al., 1980). No entanto, esse s\u00edtio de a\u00e7\u00e3o analg\u00e9sica \u00e9 um mecanismo controverso. A a\u00e7\u00e3o central foi proposta por Von Tomek (1955) e n\u00e3o confirmada por Lorenzetti (1999) que, ao aplicar dipirona intra-cerebroventricular de rato, n\u00e3o conseguiu inibir a hiperalgesia induzida por prostaglandina em pata trazeira de rato.<\/p>\n

2 \u2013 O QUE \u00c9 DIPIRONA<\/p>\n

Dipirona \u00e9 o nome gen\u00e9rico de \u00e1cido [(2,3-dihidro-1,5-dimetil-3-oxo-2-fenil-1H-pirazol-4-il)metilamino]metanossulf\u00f4nico, tamb\u00e9m chamado de 1-fenil-2,3-dimetil-5-pirazolona-4-metilaminometanossulfonato de s\u00f3dio (ou de magn\u00e9sio), e ainda denominado de metamizol, um segundo nome gen\u00e9rico e muito encontrado na literatura farmacol\u00f3gica norte-americana e europ\u00e9ia.<\/p>\n

\"\"<\/p>\n

Com peso molecular de 351,36 e uma distribui\u00e7\u00e3o relativa de 44,44% de carbono, 5,16% de hidrog\u00eanio, 11,96% de nitrog\u00eanio, 6,54% de s\u00f3dio (7,26% se for magn\u00e9sio), 22,77% de oxig\u00eanio e 9,13% de enxofre, apresenta f\u00f3rmula emp\u00edrica C13H16N3NaO4S.H2O (ou C26H32MgN6O8S2. Na dipirona magnesiana ligam-se duas mol\u00e9culas de dipirona ao c\u00e1tion magn\u00e9sio). \u00c9 preparada a partir da metila\u00e7\u00e3o do grupo amino da sulfamipirina, tratada com alde\u00eddo metan\u00f3ico (formalde\u00eddo ou formol), em solu\u00e7\u00e3o de bissulfito de s\u00f3dio. Muito sol\u00favel em \u00e1gua (1g\/1,5ml), \u00e9 pouco sol\u00favel em etanol e praticamente insol\u00favel em \u00e9ter, acetona, benzeno e clorof\u00f3rmio, sendo um complicador quando \u00e9 necess\u00e1rio fazer uma cromatografia de camada delgada para diferencia\u00e7\u00e3o da dipirona de outros t\u00f3xicos e barbit\u00faricos em processos jucidiais onde \u00e9 pedido a identifica\u00e7\u00e3o toxicol\u00f3gica com fins forenses, pois os melhores carreadores de mol\u00e9culas em cromatografia de camada delgada s\u00e3o justamente o benzeno, o \u00e9ter, o etanol, o hexano e a acetona, sendo o metanol muito pouco utilizado devido \u00e0 sua toxicidade e a \u00e1gua n\u00e3o ser usada por dissolver a camada de s\u00edlica da placa.<\/p>\n

Observando a mol\u00e9cula da dipirona, \u00e9 poss\u00edvel identificar duas estruturas ligantes que tem pap\u00e9is importantes no mecanismo de a\u00e7\u00e3o deste f\u00e1rmaco. O primeiro \u00e9 o grupamento benzoil, que tem atividade anest\u00e9sica comprovada, tanto que a maior contribui\u00e7\u00e3o da coca\u00edna para a farmacol\u00f3gia foi a identifica\u00e7\u00e3o dos componentes de sua f\u00f3rmula estrutural e a descoberta de que, retirando-se o radical benzoil, a coca\u00edna perdia sua a\u00e7\u00e3o anest\u00e9sica (Cavazzani, 1994).<\/p>\n

\"\"<\/p>\n

Outro ligante de import\u00e2ncia na estrutura da dipirona \u00e9 o grupamento sulfato, respons\u00e1vel por sua alta solubilidade em \u00e1gua e pela sua facilidade de absor\u00e7\u00e3o, \u00e9 potencilamente agressivo para a medula \u00f3ssea, podendo causar desde neutropenias, agranilocitoses, at\u00e9 aplasia de medula \u00f3ssea, uma patologia hematopoi\u00e9tica muito severa que s\u00f3 tem um tratamento, o transplante de medula \u00f3ssea que, se n\u00e3o realizado em tempo, pode levar o indiv\u00edduo ao \u00f3bito.<\/p>\n

Grupamento sulfato:<\/p>\n

\"\"<\/p>\n

Foi patentetada sob n\u00ba 254, pelo Laborat\u00f3rio Hoechst em 1911, na Alemanha com o nome de Metamizol\u00ae que hoje acabou virando nome gen\u00e9rico, como aconteceu com a Aspirina\u00ae, que \u00e9 marca registrada de \u00e1cido acetilsalic\u00edlico, desenvolvido pela Bayer e que se consagrou, tornando-se um nome gen\u00e9rico.<\/p>\n

3 \u2013 MECANISMO DE A\u00c7\u00c3O<\/p>\n

Apesar de todas as pesquisas j\u00e1 realizadas apontarem para uma a\u00e7\u00e3o bloqueadora da hiperalgesia exercida pela liga\u00e7\u00e3o a um receptor perif\u00e9rico, combinado com a\u00e7\u00e3o espinal da dipirona e com poucos efeitos antiedematosos e\/ou antiiflmat\u00f3rios, alguns bancos de dados insistem em continuar afirmando que a a\u00e7\u00e3o da dipirona atua unicamente por inibi\u00e7\u00e3o de cicloxigenase, inibindo a s\u00edntese de prostaglandinas (Abbate et al, 1990; Anon, 1973; Reynolds, 1994; Gladtke, 1983; Arellano et Sacristan, 1990).<\/p>\n

No volume 116, de setembro de 2000 do banco de dados Drugdex (Micromedex) aparece a cita\u00e7\u00e3o feita no par\u00e1grafo anteiror, ignorando os trabalhos realizados entre 1996 e 1999 por Aleksander Zampronio, Berenice B. Lorenzetti e S\u00e9rgio H. Ferreira, que apontam para a a\u00e7\u00e3o perif\u00e9rica da dipirona sobre um receptor sin\u00e1ptico com estimula\u00e7\u00e3o epinhal via ativa\u00e7\u00e3o da arginina\/cGMP em neur\u00f4nios sensoriais prim\u00e1rios.<\/p>\n

A a\u00e7\u00e3o antit\u00e9rmica da dipirona pode ser explicada pelo antagonismo direto de cininas pirog\u00eanicas em receptores do centro termo-regulador, localizado no t\u00e1lamo.<\/p>\n

4 \u2013 FARMACOCIN\u00c9TICA<\/p>\n

4.1 \u2013 IN\u00cdCIO DA A\u00c7\u00c3O<\/p>\n

Na hipertermia (febre), ap\u00f3s administra\u00e7\u00e3o oral, o efeito hipotermiante come\u00e7a a aparecer entre 30 minutos e no m\u00e1ximo em uma hora (Ajgaonkar et al, 1988; Giovannini et al, 1986; Reiner et al, 1984). O pico m\u00e1ximo de resposta ficam entre 4 e 6 horas (Ajgaonkar et al, 1988; Giovannini et al, 1986; Reiner et al, 1984).<\/p>\n

4.2 \u2013 N\u00cdVEL M\u00c1XIMO DE CONCENTRA\u00c7\u00c3O PLASM\u00c1TICA<\/p>\n

Ap\u00f3s administra\u00e7\u00e3o oral, pode ser encontrado um n\u00edvel m\u00e1ximo de concentra\u00e7\u00e3o ap\u00f3s 1 a 2 horas (Vlahov et al, 1990; Flusser et al, 1988; Volz et Kellner, 1980). O n\u00edvel m\u00e1ximo de concentra\u00e7\u00e3o plasm\u00e1tica do metab\u00f3lito ativo 4-MAA encontrado foi de 11, 21 e 41 mcg\/ml, ap\u00f3s administra\u00e7\u00e3o oral de 750, 1500 e 3000mg de dipirona, respectivamente (Vlahov et al, 1990). Na realidade e dipirona \u00e9 uma pro-droga que \u00e9 metabolizada no trato intestinal em 4-metilaminoantipirina (4-MAA), o metab\u00f3lito ativo (Vlahov et al, 1990; Flusser et al, 1988; Brune, 1988; Levy, 1986; Volz et Kellner, 1980). O 4-MAA \u00e9 metabolizado no f\u00edgado em 4-aminoantipirina (4-AA), um segundo metab\u00f3lito ativo (Brune, 1988; Flusser et al, 1988).<\/p>\n

A dipirona n\u00e3o apresenta intera\u00e7\u00f5es conhecidas com alimentos ou ent\u00e3o s\u00e3o clinicametne insignificantes (Levy et al, 1995; Flusser et al, 1988).<\/p>\n

4.3 \u2013 S\u00cdTIOS DE DISTRIBUI\u00c7\u00c3O<\/p>\n

Cerca de 58% do 4-MAA e 48% do 4-AA s\u00e3o distribuidos ligados \u00e0s prote\u00ednas plasm\u00e1ticas (Zylber-Katz et al, 1985). Os metab\u00f3litos da dipirona tem sido encontrados no l\u00edquido c\u00e9falo-raquidiano. Em estudo controlado, 28 pacientes com indica\u00e7\u00e3o terap\u00eautica de dipirona, tomando 1g por via oral (dois comprimidos de 500mg) em tempos diversos (6 em 6 horas) foram submetidos a pun\u00e7\u00e3o lombar em v\u00e1rios intervalos de tempo e colhido cerca de 2ml de l\u00edquor sendo detectada a presen\u00e7a dos metab\u00f3litos em concentra\u00e7\u00e3o menor que no plasma, mas guardando uma propor\u00e7\u00e3o l\u00edquor\/plasma de ambos os metab\u00f3litos (Cohen et al, 1998).<\/p>\n

4.4 \u2013 VOLUME DE DISTRIBUI\u00c7\u00c3O<\/p>\n

O volume de distribui\u00e7\u00e3o do 4-MAA \u00e9 de 40 litros (Vlahov et al, 1990).<\/p>\n

4.5 \u2013 METABOLISMO<\/p>\n

4.5.1 \u2013 PAREDE INTESTINAL<\/p>\n

A metaboliza\u00e7\u00e3o da dipirona na parede intestinal \u00e9 extensa (Vlahov et al, 1990; Flusser et al, 1988; Brune, 1988; Levy, 1986; Volz et Kellner, 1980).<\/p>\n

O metabolismo \u00e9 feito monoenzimaticamene por hidr\u00f3lise no trato intestinal formando o 4-MAA, um dos seus metab\u00f3litos ativos (Vlahov et al, 1990; Flusser et al, 1988; Brune, 1988; Levy, 1986; Volz et Kellner, 1980).<\/p>\n

4.5.2 \u2013 F\u00cdGADO<\/p>\n

No f\u00edgado o metabolismo tamb\u00e9m \u00e9 grande (Flusser et al, 1988; Brune, 1988; Volz et Kellner, 1980). O 4-MAA \u00e9 transformado em 4-AA (Brune, 1988; Flusser et al, 1988; Volz et Kellner, 1980) e outros metab\u00f3litos inativos e de pouca import\u00e2ncia. Em portadores assintom\u00e1ticos de hepatite B, com fun\u00e7\u00e3o hep\u00e1tica normal, testes demonstraram preju\u00edzo no metabolismo oxidativo da dipirona quando comparado com sujeitos n\u00e3o portadores (Levy et al, 1997).<\/p>\n

4.5.3 \u2013 METAB\u00d3LITOS<\/p>\n

1. 4-Metilaminoantipirina, \u00e9 um metab\u00f3lito ativo (Flusser et al, 1988; Brune, 1988).<\/p>\n

2. 4-Aminoantipirina, tamb\u00e9m \u00e9 um metab\u00f3lito ativo (Brune, 1988; Flusser et al, 1988; Volz et Kellner, 1980).<\/p>\n

3. 4-Formil-aminoantipirina (4-FAA), \u00e9 um metab\u00f3lito inativo (Vlahov et al, 1990; Volz et Kellner, 1980).<\/p>\n

4. 4-acetilaminoantipirina (4-AcAA), tamb\u00e9m \u00e9 inativo (Vlahov et al, 1990; Volz et Kellner, 1980).<\/p>\n

4.5.4 – EXCRE\u00c7\u00c3O<\/p>\n

4.5.4.1 \u2013 Leite Materno<\/p>\n

Os metab\u00f3litos ativos da dipirona, tanto o 4-MAA, quanto o 4-AA podem ser encontrados em altos n\u00edveis no leite materno. Est\u00e3o em concentra\u00e7\u00e3o igual ou at\u00e9 maior que no plasma. No entanto, os metab\u00f3litos foram encontrados no leite at\u00e9 48 horas ap\u00f3s administra\u00e7\u00e3o \u00fanica de dipirona por via oral , devendo o uso de dipirona ser evitado durante o aleitamento materno (Zylber-Katz et al, 1986).<\/p>\n

4.5.4.2 – Rins<\/p>\n

A excre\u00e7\u00e3o renal \u00e9 intensa, sendo a maior via de elimina\u00e7\u00e3o (Vlahov et al, 1990; Volz et Kellner, 1980). Os metab\u00f3litos 4-FAA e 4-AcAA s\u00e3o excretados primeiramente na urina (Vlahov et al, 1990; Volz et Kellner, 1980).<\/p>\n

4.5.5 \u2013 MEIA VIDA<\/p>\n

O metab\u00f3lito 4-MAA tem uma meia vida de 2 a 3 horas (Vlahov et al, 1990; Volz et Kellner, 1980). O tempo de elimina\u00e7\u00e3o m\u00e9dio do metab\u00f3lito 4-MAA \u00e9 significativamente aumentado nos portadores assintom\u00e1ticos de hepatite B, quando comparado com indiv\u00edduos sadios. (Levy et al, 1997), enquanto o tempo de meia-vida de elimina\u00e7\u00e3o do 4-FAA est\u00e1 significativamente diminuido em portadores de hepatite B em compara\u00e7\u00e3o com sujeitos n\u00e3o portadores. Os tempos de meia-vida de elimina\u00e7\u00e3o dos metab\u00f3litos 4-MAA e 4-AcAA n\u00e3o apresentam diferen\u00e7as estat\u00edsticas significantes entre os dois grupos. (Levy et al, 1997).<\/p>\n

O metab\u00f3lito 4-AA tem uma meia-vida de elimina\u00e7\u00e3o de 4 a 5 hoas (Vlahov et al, 1990; Volz et Kellner, 1980).<\/p>\n

5 – Dilui\u00e7\u00e3o e Estabilidade<\/p>\n

A Dipirona \u00e9 compat\u00edvel com solu\u00e7\u00e3o glicosada a 5%, solu\u00e7\u00e3o de NaCl a 0,9%
\ne Ringer lactato*.
\nA administra\u00e7\u00e3o deve ser imediata em “bolus” (ou em bolo) j\u00e1 que a estabilidade \u00e9 limitada nas
\ntr\u00eas solu\u00e7\u00f5es, devendo ser evitada a infus\u00e3o cont\u00ednua*.<\/p>\n

* Informa\u00e7\u00f5es do fabricante Aventispharma  (fabricante da Novalgina\u00ae).
\n6 \u2013 RESTRI\u00c7\u00d5ES AO USO<\/p>\n

6.1 \u2013 CONTRA-INDICA\u00c7\u00d5ES<\/p>\n

Discrasias sangu\u00edneas ou depress\u00e3o da medula \u00f3ssea, hipersensibilidade, rinite, urtic\u00e1ria, asma e rea\u00e7\u00f5es al\u00e9rgicas \u00e0 aspirina ou outros agentes antiinflamat\u00f3rios.<\/p>\n

6.2 \u2013 PRECAU\u00c7\u00d5ES<\/p>\n

Hist\u00f3ria de \u00falceras gastrointestinais, hemorragias g\u00e1stricas ou perfura\u00e7\u00f5es da mucosa; disfu\u00e7\u00f5es renais; hipertens\u00e3o card\u00edaca (sobrecarga ventricular esquerda) ou disfun\u00e7\u00f5es card\u00edacas agravadas por reten\u00e7\u00e3o de fluidos e edema; disfu\u00e7\u00e3o hep\u00e1tica; infec\u00e7\u00f5es pr\u00e9-existentes; porf\u00edria; deficiencia de glicose-6-fosfato desidrogenase e uso concomitante com clorpormazina.<\/p>\n

6.3 \u2013 REA\u00c7\u00d5ES ADVERSAS<\/p>\n

Anemia hemol\u00edtica e aplasia de medula \u00f3ssea tem sido reportada durante o uso de dipirona (Anon, 1986; Sansone et al, 1984; Lay, 1966). Agranulocitose \u00e9 a ocorr\u00eancia mais frequente durante a administra\u00e7\u00e3o 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\u00eancia da indu\u00e7\u00e3o de agranulocitose tem varia\u00e7\u00e3o geogr\u00e1fica. Aparece em altas frequ\u00eancias em Barcelona e Berlim e em pequnos \u00edndices 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\u00e7as regionais s\u00e3o muito provavelmente relatadas pela avalia\u00e7\u00e3o e uso em modelos em v\u00e1rios pa\u00edses. A incid\u00eancia de agranulocitose varia em 1,1 por milh\u00e3o, durante a primeira semana de administra\u00e7\u00e3o (Anon, 1986) e um caso para cada 3000 usu\u00e1rios (Bottiger et Westerholm, 1973). Calculos baseados em dados levantados, sugerem que o uso da dipirona est\u00e1 associado a menos de 7000 casos por ano no mundo todo (Kiatboonsri et Richter, 1989).<\/p>\n

Os efeitos cardiovasculares incluem hipotens\u00e3o de moderada at\u00e9 severa (Hoigne et al, 1986; Sanahuja et al, 1990). Evidencias de hipotens\u00e3o com doses orais tamb\u00e9m tem sido descritas (Giovannini et al, 1986; Paeile et Gallardo, 1974).<\/p>\n

Efeitos centrais mais significativos s\u00e3o sonol\u00eancia, astenia e cefal\u00e9ia (Lehtonen et al, 1983; Paeile et Gallardo, 1974).<\/p>\n

Efeitos gastrointestinais incluem n\u00e1usea, v\u00f4mitos, irrita\u00e7\u00e3o g\u00e1strica e xerotomia, que tem sido relatadas com a administra\u00e7\u00e3o parenteral de dipirona (Marthak et al, 1991; Lehtonen et al, 1983; Paeile et Gallardo, 1974; von Szeged et Michos, 1986).<\/p>\n

Broncoespasmo tamb\u00e9m tem sido descrito em administra\u00e7\u00f5es cont\u00ednuas de dipirona (Arellano et Sacristan, 1990).<\/p>\n

Entre as rea\u00e7\u00f5es cut\u00e2neas pode ser encontrado necrose epidermal t\u00f3xica, urtic\u00e1ria, “rash” cut\u00e2neo (Anon, 1973; Arellano et Sacristan, 1990; Pandhi et al, 1984; Pasricha, 1979; Lehtonen et al, 1983; Saban et al, 1991).<\/p>\n

Choque anafil\u00e1tico tamb\u00e9m pode acontecer, com uma incid\u00eancia de 1 caso em 5000 administra\u00e7\u00f5es (Fosseus et Straughan, 1983; Arellano et Sacristan, 1990; Kiatboonsri et Richter, 1988).<\/p>\n

6.4 \u2013 TERATOG\u00caNESE<\/p>\n

Em estudo controlado, com administra\u00e7\u00e3o 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\u00f3stico foi de 41,1 meses. As m\u00e3es foram questionadas sobre o uso de medicamentos durante a gravidez para se determinar a correla\u00e7\u00e3o 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 \u00e0 droga. Sem dados de estudos prospectivos, o aumento na indicencia de tumor de Wilms em crian\u00e7as expostas \u00e0 dipirona n\u00e3o pode ser atribuida definitivamente ao f\u00e1rmaco, no entanto, baseado nesses estudos o uso de dipirona durante a gravidez deve ser evitado (Sharpe et Franco, 1996).<\/p>\n

6.5 \u2013 INTERA\u00c7\u00d5ES MEDICAMENTOSAS<\/p>\n

6.5.1 \u2013 ACENOCOUMAROL<\/p>\n

N\u00e3o foram observados efeitos significantes nos tempos de coagula\u00e7\u00e3o durante uso concomitante com a dipirona (Zylber-Katz et al, 1985), por\u00e9m sempre \u00e9 indicado o m\u00e1ximo de cuidado e monitoriza\u00e7\u00e3o do paciente em uso concomitante de dipirona com anticoagulantes orais, especialmente se houver necessidade da adi\u00e7\u00e3o de um antiinflamat\u00f3rio n\u00e3o ester\u00f3ide ao tratamento. O efeito adverso mais comum \u00e9 o aumento do risco de hemorragias.<\/p>\n

6.5.2 \u2013 ALENDRONATO<\/p>\n

Durante tr\u00eas anos de estudo cl\u00ednico controlado, envolvendo 2027 pacientes que recebiam antiinflamat\u00f3rios n\u00e3o esteroidais, a incid\u00eancia 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\u00e7\u00e3o g\u00e1strica, efeito tamb\u00e9m observado com a dipirona (Prod Info Fosamax\u00d2 , 1999).<\/p>\n

6.5.3 \u2013 INIBIDORES DA ECA<\/p>\n

\u00c9 conhecida a intera\u00e7\u00e3o entre os inibidores da ECA e a dipirona, podendo surgir bradicardia, frequentemente induzida por hipercalemia (Shionori, 1993). Esse dist\u00farbio pode levar a paradas card\u00edacas (Kurata et al, 1999).<\/p>\n

6.5.4 \u2013 BLOQUEADORES BETA-ADREN\u00c9RGICOS<\/p>\n

Em uso concomitante de dipirona com beta-bloqueadores, tem sido reportado aumento na tens\u00e3o arterial e interfer\u00eancia no controle da press\u00e3o sangu\u00ednea (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>\n

6.5.5 \u2013 BLOQUEADORES DE CANAIS DE C\u00c1LCIO<\/p>\n

O uso de dipirona com bloqueadores de canais de c\u00e1lcio (nifedipina), aumenta o risco de hemorragia gastrintestinal (Pahor et al, 1996).
\n7 \u2013 EFIC\u00c1CIA COMPARATIVA<\/p>\n

7.1 – ACETAMINOFENO (Paracetamol)<\/p>\n

7.1.1 \u2013 FEBRE<\/p>\n

Dipirona na dose de 0,5g oral demonstrou efeitos antipir\u00e9ticos mais acentuados que o paracetamol na mesma dose em pacientes com febre tif\u00f3ide e estudo controlado. A redu\u00e7\u00e3o da temperatura retal foi muito mais significativa com dipirona do que com paracetamol at\u00e9 uma ou duas horas ap\u00f3s a administra\u00e7\u00e3o. Existe uma tend\u00eancia da dipirona para um efeito prolongado, em torno de 6 horas ou mais (Ajgaonkar et al, 1988).<\/p>\n

7.2 \u2013 \u00c1CIDO ACETILSALIC\u00cdLICO (Aspirina)<\/p>\n

7.2.1 \u2013 FEBRE<\/p>\n

Em um estudo pequeno, duplo-cego, o efeito de 500mg de dipirona “per-\u00f3s” foi superior \u00e0 mesma dose de \u00e1cido acetilsalic\u00edlico no tratamento de febre (Reiner et al, 1984).<\/p>\n

7.2.2 \u2013 DOR P\u00d3S-OPERAT\u00d3RIA<\/p>\n

O efeito de 500mg de dipirona 500mg “per-\u00f3s” \u00e9 consideravelmente superior ao do \u00e1cido acetilsalic\u00edlico na mesma dose no tratamento de dor, em estudo controlado (Arellano et Sacristan, 1990).<\/p>\n

7.3 \u2013 N-METIL-BUTIL-ESCOPOLAMINA (Hioscina)<\/p>\n

7.3.1 \u2013 NA C\u00d3LICA RENAL<\/p>\n

Em estudo controlado com n=96 pacientes com c\u00f3lica renal, a hioscina em dose 20mg intravenosa foi inefetiva na remiss\u00e3o 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\u00e7\u00e3o conjunta de analg\u00e9sicos narc\u00f3ticos (petidina, nalbufina, tramadol ou morfina) para controlar a dor, enquanto 17% e 0%, respectivamente, dos pacientes em uso de dipirona precisaram da adi\u00e7\u00e3o de analg\u00e9sico opi\u00f3ide (Lloret et al, 1987).<\/p>\n

7.4 \u2013 CLONIXINA<\/p>\n

7.4.1 \u2013 DOR NA P\u00d3S-HISTERECTOMIA<\/p>\n

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\u00f3s a cirurgia, ou 660mg de dipirona em bolus antes e 330mg ap\u00f3s a histerectomia. 4,4% das pacientes tratadas com dipirona necessitaram de doses adicionais de dipirina para controlar a dor no p\u00f3s-operat\u00f3rio contra 11% das pacientes tratadas com clonixina (Rodriguez et al, 1993).<\/p>\n

7.5 \u2013 DEXTROCETOPROFENO<\/p>\n

7.5.1 \u2013 DOR NO P\u00d3S-OPERAT\u00d3RIO ODONTOL\u00d3GICO<\/p>\n

A dipirona \u00e9 t\u00e3o eficaz quanto do cetoprofeno em analgesia no p\u00f3s-operat\u00f3rio odontol\u00f3gico (Bagan et al, 1998).<\/p>\n

7.6 \u2013 DICLOFENACO<\/p>\n

7.6.1 \u2013 NA C\u00d3LICA RENAL<\/p>\n

inje\u00e7\u00e3o intravenosa de 2,5 gramas de dipirona combinada com pitofenona (um espasmol\u00edtico semelhante \u00e0 atropina) e fempiverinium (um espasmol\u00edtico hom\u00f3logo da papaverina) tem efeito similar ao diclofenaco na dose 75mg por via intramuscular. Ou seja, o diclofenaco em monoterapia \u00e9 mais efetivo que a dipirona em monoterapia (Sanahuja et al, 1990).<\/p>\n

7.6.2 \u2013 NA CIATALGIA<\/p>\n

No tratamento da ciatalgia (dor do nervo ci\u00e1tico), 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\u00edcio do efeito ap\u00f3s uma hora da aplica\u00e7\u00e3o e prolongando-se por cerca de 48 horas (Babej-Dolle et al, 1994).<\/p>\n

7.7 \u2013 IBUPROFENO<\/p>\n

7.7.1 \u2013 NA DOR P\u00d3S-CIR\u00daRGICA<\/p>\n

Em estudo comparado entre dipirona magnesiana intramuscular, ibuprofeno e placebo por via oral, a espectro analg\u00e9sico e o tempo de dura\u00e7\u00e3o da a\u00e7\u00e3o entre a dipirona e o ibuprofeno foram semelhantes e superiores ao placebo (de Miguel Rivero et al, 1997).<\/p>\n

7.8 \u2013 INDOMETACINA<\/p>\n

7.8.1 \u2013 NA C\u00d3LICA RENAL<\/p>\n

Inje\u00e7\u00e3o intravenosa de 2,5g de dipirona tem mostrado efeito maior que 50mg de indometacina pela mesma via, no tratamento da c\u00f3lica ureteral em lit\u00edases (c\u00e1lculos) renais (Lehtonen et al, 1983).<\/p>\n

7.9 \u2013 KETORALAC<\/p>\n

7.9.1 \u2013 EM ANALGESIA<\/p>\n

Em estudo randomizado, comparando aplica\u00e7\u00e3o 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 \u00e0 moderada ap\u00f3s cirurgia ortop\u00e9dica, encontrou-se uma efic\u00e1cia similar entre o ketorolac e a dipirona no controle da dor nas primeiras 6 horas do p\u00f3s-operat\u00f3rio. Ap\u00f3s os tr\u00eas dias seguintes, a redu\u00e7\u00e3o da intensidade da dor foi melhor conseguida com o ketorolac, demonstrando uma efic\u00e1cia maior deste analg\u00e9sico em rela\u00e7\u00e3o \u00e0 dipirona (Fernandez-Sabate et al, 1991).<\/p>\n

7.10 \u2013 MEPERIDINA (Petidina)<\/p>\n

7.10.1 \u2013 NA DOR P\u00d3S-CIR\u00daRGICA<\/p>\n

Dipirona na dose 2,5g intramuscular ou intravenosa tem sido t\u00e3o efetivo quanto 50 ou 100mg de petidina intravenosa no tratamento da dor p\u00f3s-cir\u00fargica (Patel et al, 1980; Lal et al, 1973; Arellano et Sacristan, 1990).<\/p>\n

7.10.2 \u2013 NA C\u00d3LICA RENAL<\/p>\n

Doses de 2,5g de dipirona intravenosa tem se mostrado t\u00e3o efetivo quanto 50mg de petidina intravenosa no tratamento da c\u00f3lica renal em c\u00f3lica ureteral em um estudo randomizado (Lehtonen et al, 1983).<\/p>\n

7.11 \u2013 NIMESULIDE<\/p>\n

7.11.1 \u2013 NA FEBRE<\/p>\n

Em um pequeno estudo duplo-cego, 500mg de dipirona por via oral foi comparada em efic\u00e1cia 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 \u00e1cido acetilsalic\u00edlico, que tamb\u00e9m foi utilizado no estudo, em efeito (Reiner et al, 1984).<\/p>\n

7.11.2 \u2013 NA DOR P\u00d3S-CIR\u00daRGICA<\/p>\n

Em estudo duplo-cego em crian\u00e7as com dor p\u00f3s-operat\u00f3ria foram utilizados suposit\u00f3rios de 100mg de nimesulide e 300mg de dipirona a cada 6 horas e ambas as drogas apresentaram a mesma efic\u00e1cia no tratamento da dor inflamat\u00f3rio no p\u00f3s-operat\u00f3rio das crian\u00e7as (Scharli et al, 1990).<\/p>\n

7.12 \u2013 PENTAZOCINE<\/p>\n

7.12.1 \u2013 NA DOR DO P\u00d3S-CIR\u00daRGICO BUCO-MAXILO-FACIL<\/p>\n

Administra\u00e7\u00f5es orais de dipirona na dose 300mg e pentazocine na dose 50mg a cada 4 horas mostraram efic\u00e1cia semelhante em tratamento da dor no p\u00f3s-cir\u00fargico de procedimentos bucais, maxilares e faciais, em estudo duplo-cego. Neste estudo encontrou-se efeitos adversos maiores causados pelo pentazocine em rela\u00e7\u00e3o \u00e0 dipirona (Paeile et Gallardo, 1974).<\/p>\n

7.13 \u2013 SUPROFENO<\/p>\n

7.13.1 \u2013 NEURALGIAS CR\u00d4NICAS<\/p>\n

Suprofeno oral na dose 200mg 3 \u00e0 4 vezes ao dia foi t\u00e3o 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>\n

7.14 \u2013 TRAMADOL<\/p>\n

7.14.1 \u2013 NA C\u00d3LICA BILIAR AGUDA<\/p>\n

Um estudo multic\u00eantrico e randomizado, um grupo de 74 pacientes com c\u00f3lica aguda severa de ves\u00edcula biliar, induzida por lit\u00edase biliar, foram comparados dipirona, 2,5g, hioscina 20mg e tramadol 100mg, todos por via intravenosa. O temp in\u00edcio da redu\u00e7\u00e3o da dor foi significativamente menor com a dipirona (10,9 minutos), em compara\u00e7\u00e3o 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\u00f3s 20 minutos, enquanto no grupo da hioscina 8 pacientes necessitaram de outra dose do f\u00e1rmaco e no grupo tratado com tramadol apenas 1 paciente necessitou de outra dose do analg\u00e9sico (Schmieder et al, 1993).<\/p>\n

7.14.2 \u2013 NAS ODONTALGIAS<\/p>\n

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\u00edduos sadios (Rohdewald et al, 1988).<\/p>\n

7.14.3 \u2013 NA DOR P\u00d3S-CIR\u00daRGICA<\/p>\n

A efic\u00e1cia do efeito analg\u00e9sico do tramado (100mg intramuscular) foi comparado com uma associa\u00e7\u00e3o de dipirona 500mg com difenidramina 12,5mg, drofenina 25mg e benzetilio 2,5mg, para o tratamento da dor p\u00f3s-operat\u00f3ria 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\u00f3s a primeria dose e durante os tr\u00eas 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>\n

8 – REFERENCIAS BIBLIOGR\u00c1FICAS <\/strong><\/p>\n

    \n
  1. Abate MA, Layne RD, Neely JL et al. Effect of naproxen and sulindac on blood pressure response to atenolol.<\/strong> Drug Intell Clin Pharm 1990; 24:810-813.<\/li>\n
  2. Abate MA, Neely JL, Layne RD et al. Interaction of indomethacin and sulindac with labetolol<\/strong>. Br J Clin Pharmacol 1991; 31:363-366.<\/li>\n
  3. Abbate R, Gori AM, Pinto S et al. Cyclooxygenase and lipoxygenase metabolite synthesis by polymorphonuclear neutrophils: in vitro effect of dipyrone<\/strong>.      Prostagl Leukotr Ess Fatty Acids 1990;
    \n41:89-93.<\/li>\n
  4. Agar JW. Cyclosporine A and mefenamic acid in a renal transplant patient<\/strong>. Aust N Z J Med 1991; 21:784-785.<\/li>\n
  5. Ahmad S. Indomethacin-enalapril interaction: an alert (letter). <\/strong>South Med J 1991; 84:411-412.<\/li>\n
  6. Ajgaonkar VS, Marathe SN et Virani AR. Dipyrone versus paracetamol: a double-blind study in typhoid fever<\/strong>. J Int Med Res 1988;
    \n16:225-230.<\/li>\n
  7. Ajgaonkar VS et Pinto Pereira LM. Patient study of antipyretic drug efficacy<\/strong>. Curr Ther Res 1985; 33:440-445.<\/li>\n
  8. Altman RD, Perez GO et Sfakianakis GN. Interaction of cyclosporine A and nonsteroidal anti-inflammatory drugs on renal function in patients with rheumatoid arthritis<\/strong>. Am J Med 1992; 93:396-402.<\/li>\n
  9. Anon. Comparative study of the efficacy of dipyrone, diclofenac sodium and pethidine in acute renal colic<\/strong>. Eur J Clin Pharmacol 1991; 40:543-546.<\/li>\n
  10. Anon. Dipyrone and aminopyrine – for relief of fever<\/strong>. Med Lett Drugs Ther 1973; 15:4.<\/li>\n
  11. Anon. Dipyrone as a cause of drug rashes: an epidemiologic study<\/strong>. A report from the Boston Collaborative Drug Surveillance Program. Int J Epidemiol 1973a; 2:167-170.<\/li>\n
  12. Anon. Reports prompt new warnings on LMW heparin, heparinoids<\/strong>. Am J Health Syst Pharm 1998; 55:210.<\/li>\n
  13. Anon. Risks of agranulocytosis and aplastic anemia: a first report of their relation to drug use with special reference to analgesics<\/strong>. JAMA 1986; 256:1749-1757.<\/li>\n
  14. ANTONINI, V, MARAMA, N, SERATICUK, J. C. Anu\u00e1rio Estat\u00edstico do Servi\u00e7o de Farm\u00e1cia Hospitalar \u2013 1999. <\/strong>Curitiba : Servi\u00e7o de Farm\u00e1cia Hospitalar do HC-UFPR, 2000.<\/li>\n
  15. Arellano F et Sacristan J\u00c1. Metamizole: reassessment of its therapeutic role<\/strong>. Eur J Clin Pharmacol 1990; 38:617-619.<\/li>\n
  16. Babej-Dolle R, Freytag S, Eckmeyer J et al. Parenteral dipyrone versus diclofenac and placebo in patients with acute lumbago or sciatic pain: randomized observer-blind multicenter study<\/strong>. Int J Clin Pharmacol Ther Toxicol 1994; 32:204-209.<\/li>\n
  17. Bagan JV, Arranz JSL, Valencia E et al. Clinical comparison of dexketoprofen trometamol and dipyrone in postoperative dental pain<\/strong>. JClin Pharmacol 1998; 38:55S-64S.<\/li>\n
  18. Bagan JV, Lopez Arranz S, Valencia E et al. Clinical comparison of dexketoprofen trometamol and dipyrone in postoperative dental pain<\/strong>. JClin Pharmacol 1998; 38(suppl):55S-64S.<\/li>\n
  19. Bahrt KM, Korman LY et Nashel DJ. Significance of a positive test for occult blood in stools of patients taking anti-inflammatory drugs<\/strong>. Arch Intern Med 1984; 144:2165-2166.<\/li>\n
  20. Bloch B, Smythe E et Weeks R. Analgesics for pain relief after gynaecological surgery<\/strong>. S Afr Med J 1985; 67:325-329.<\/li>\n
  21. Bottiger LE et Westerholm B. Drug-induced blood dyscrasias in Sweden<\/strong>. Br Med J 1973; 3:339-343.<\/li>\n
  22. Branthwaite JP et Nicholls A. Cyclosporine and diclofenac interaction in rheumatoid arthritis <\/strong>(letter). Lancet 1991; 337:252.<\/li>\n
  23. Brenner S, Bialy-Golan A et Crost N. Dipyrone in the induction of pemphigus<\/strong>. J Amer Acad Dermatol 1997; 36:488- 490.<\/li>\n
  24. Brune K. The pharmacological profile of non-opioid (OTC) analgesics: aspirin, paracetamol (acetaminophen), ibuprofen, and phenazones<\/strong>. Agents Actions 1988; 25(suppl):9-19.<\/li>\n
  25. Canepa G, DiSomma C, Ghia M et al. Post-operative analgesia with tramadol: a controlled clinical study compared with analgesic combination<\/strong>. Int J Clin Pharm Res 1993; 13:43-51.<\/li>\n
  26. Cassano WF. Serious methotrexate toxicity caused by interaction with ibuprofen <\/strong>(letter). Am J Pediatr Hematol Oncol 1989; 11:481-482.<\/li>\n
  27. Chalmers JP, West MJ, Wing LM et al. Effects of indomethacin, sulindac, naproxen, aspirin, and paracetamol in treated hypertensive patients<\/strong>. Clin Exp Hypertens 1984; 6:1077-1093.<\/li>\n
  28. Chennavasin P, Seiwell R et Brater DC. Pharmacokinetic-dynamic analysis of the indomethacin-furosemide interaction in man<\/strong>. J Pharmacol Exp Ther 1980; 215:77-81.<\/li>\n
  29. Chlud K et Kaik VB. Clinical studies of the interaction between tolmetin and glibenclamide<\/strong>. Int J Clin Pharmacol 1977; 15:409-410.<\/li>\n
  30. Cohen O, Zylber-Katz E, Caraco Y et al. Cerebrospinal fluid and plasma concentrations of dipyrone metabolites after a single oral dose of dipyrone<\/strong>. Eur J Clin Pharmacol 1998; 54:549-553.<\/li>\n
  31. Collins CL, DeTullio PL, Berardi RR et al. Comparison of home occult blood tests and interaction of tests with ibuprofen<\/strong>. Clin Pharm 1989; 8:501-504.<\/li>\n
  32. Constantopoulos A. Colitis induced by interaction of cyclosporine A and non-steroidal anti-inflammatory drugs<\/strong>. Pediatr Intl 1999; 41:184-186.<\/li>\n
  33. Daly H, Boyle J, Roberts C et al: Interaction between methotrexate and non-steroidal anti-inflammatory drugs<\/strong>. Lancet 1986; 1:559.<\/li>\n
  34. Das UN: Modification of anti-hypertensive action of verapamil by inhibition of endogenous prostaglandin synthesis<\/strong>. Prostaglandins Leukot Med 1982; 9:167-169.<\/li>\n
  35. Davis A, Day RO et Begg EJ: Interactions between non-steroidal anti-inflammatory drugs and antihypertensives and diuretics<\/strong>. Aust N Z J Med 1986; 16:537-546.<\/li>\n
  36. Day RO, Geisslinger G, Paull P et al: The effect of tenoxicam on tolbutamide pharmacokinetics and glucose concentrations in healthy volunteers<\/strong>. Int J Clin Pharmacol Ther 1995; 33:308-310.<\/li>\n
  37. de Miguel Rivero C, Araujo CG, Sousa MM et al: Comparative efficacy of oral ibuprofen-arginine, intramuscular magnetic dipyrone and placebo in patients with postoperative pain following total hip replacement<\/strong>. Clin Drug Invest 1997; 14:276-285.<\/li>\n
  38. Deray G, Le Hoang P, Aupetit B et al: Enhancement of cyclosporine A nephrotoxicity by diclofenac <\/strong>(letter). Clin Nephrol 1987; 27:213-214.<\/li>\n
  39. Dixey JJ, Noormohamed FH, Lant AF et al: The effects of naproxen and sulindac on renal function and their interaction with hydrochlorothiazide and piretanide in man<\/strong>. Br J Clin Pharmacol 1987; 23:55-63.<\/li>\n
  40. Dupuis LL, Shore A, Silverman ED et al: Methotrexate-nonsteroidal antiinflammatory drug interaction in children with arthritis. <\/strong>J Rheumatol 1990; 17:1469-1473.<\/li>\n
  41. Durao V, Prata MM et Goncalves LM: Modification of antihypertensive effect of beta-adrenoreceptor blocking agents by inhibition of endogenous prostaglandin synthesis<\/strong>. Lancet 1977; 2:1005-1007.<\/li>\n
  42. Ebel DL, Rhymer AR, Stahl E et al: Effect of Clinoril (sulindac, MSD), piroxicam and placebo on the hypotensive effect or propranolol in patients with mild to moderate essential hypertension<\/strong>. Scand J Rheumatol 1986; 62(suppl):41S-49S.<\/li>\n
  43. Fairley KF, Woo KT, Birch DF et al: Triamterene-induced crystalluria and cylinduria: clinical and experimental studies<\/strong>. Clin Nephrol 1986; 26:169-173.<\/li>\n
  44. Fauno P, Petersen KD et Husted SE: Increased blood loss after preoperative NSAID. <\/strong>Acta Orthop Scand 1993; 64:522-524.<\/li>\n
  45. Favre L, Glasson P, Riondel A et al: Interaction of diuretics and non-steroidal anti-inflammatory drugs in man<\/strong>. Clin Sci 1983; 64:407-415.<\/li>\n
  46. Favre L, Glasson P et Vallotton MB: Reversible acute renal failure from combined triamterene and indomethacin<\/strong>. Ann Intern Med 1982;
    \n96:317-320. Fernandez-Sabate A, Roca-Burniol J, Roca-Barbera A et al: Ketorolac, a new nonopioid analgesic, in a single-blind trial versus metamizole in orthopedic surgery pain. <\/strong>Curr Ther Res 1991; 49:1016-1024.<\/li>\n
  47. Fleming JL, Ahlquist DA, McGill DB et al: Influence of aspirin and ethanol on fecal blood levels as determined by using the HemoQuant assay<\/strong>. Mayo Clin Proc 1987; 62:159-163.<\/li>\n
  48. Flusser D, Zylber-Katz E, Granit L et al: Influence of food on the pharmacokinetics of dipyrone. <\/strong>Eur J Clin Pharmacol 1988; 34:105-107.<\/li>\n
  49. Fosseus CG et Straughan H: Sudden death due to intravenous avapyrazone and dipyrone<\/strong>. S Afr Med J 1983; 64:81.<\/li>\n
  50. Frolich JC, Rupp WA, Zapf RM et al: The effects of metamizol on prostaglandin synthesis in man<\/strong>. Agents Actions Suppl 1986; 19:155-166<\/li>\n
  51. Furst DE: Clinically important interactions of nonsteroidal antiinflammatory drugs with other medications<\/strong>. J Rheumatol Suppl 1988; 17:58-62.<\/li>\n
  52. Furst DE, Herman RA, Koehnke R et al: Effect of aspirin and sulindac on methotrexate clearance. <\/strong>J Pharm Sci 1990; 79:782-786.<\/li>\n
  53. Giovannini M, Longhi R, Besana R et al: Clinical experience and results of treatment with suprofen in pediatrics. 5th communication: a single-blind study on antipyretic effect and tolerability of suprofen syrup versus metamizole drops in pediatric patients<\/strong>. Arzneimittelforschung 1986; 36:959-964.<\/li>\n
  54. Gladtke E: Use of antipyretic analgesics in the pediatric patient<\/strong>. Am J Med 1983; Symposium Nov. 14:121-126.<\/li>\n
  55. Greer IA, Gibson JL, Young A et al: Effect of ketorolac and low-molecular-weight heparing individually and in combination on haemostasis<\/strong>. Blood Coagul Fibrinolysis 1999; 10:367-373.<\/li>\n
  56. Greer IA, Gibson JL, Young A et al: Effect of ketorolac and low-molecular-weight heparin individually and in combination on haemostasis<\/strong>. Blood Coagul Fibrinolysis 1999; 10:367-373.<\/li>\n
  57. Hardy BG, Bartle WR, Myers M et al: Effect of indomethacin on the pharmacokinetics and pharmacodynamics of felodipine<\/strong>. Br J Clin Pharmacol 1986; 26:719-720.<\/li>\n
  58. Hargis JB, LaRussa VF, Redmond J et al: Agranulocytosis associated with “Mexican aspirin” (dipyrone): evidence for an autoimmune mechanism affecting multipotential hematopoietic progenitors<\/strong>. Am J Hematol 1989; 31:213-215.<\/li>\n
  59. Harris KP, Jenkins D et Walls J: Nonsteroidal antiinflammatory drugs and cyclosporine: a potentially serious adverse interaction<\/strong>. Transplantation 1988; 46:598-599.<\/li>\n
  60. Harvey PJ, Wing LM, Beilby J et al: Effect of indomethacin on blood pressure control during treatment with nitrendipine<\/strong>. Blood Press 1995; 4:307-312.<\/li>\n
  61. Heerdink ER, Leufkens HG, Herings RMC et al: NSAIDs associated with increased risk of congestive heart failure in elderly patients taking diuretics<\/strong>. Arch Intern Med 1998; 158:1108-1112.<\/li>\n
  62. Heinemeyer G, Gramm HJ, Roots I et al: The kinetics of metamizol and its metabolites in critical-care patients with acute renal dysfunction<\/strong>. Eur J Clin Pharmacol 1993; 45:445-450.<\/li>\n
  63. Hempel V: Pyrazolones in the treatment of postoperative pain. <\/strong>Agents Actions 1986; 19(suppl):331-337.<\/li>\n
  64. Hoigne R, Zoppi M, Sollberger J et al: Fall in systolic blood pressure due to metamizol (dipyrone, noramidopyrine, novaminsulfone)<\/strong>. Agents Actions 1986; 19(auppl):189-195.<\/li>\n
  65. Houston MC, Weir M, Gray J et al: The effects of nonsteroidal anti-inflammatory drugs on blood pressures of patients with hypertension controlled by verapamil<\/strong>. Arch Intern Med 1995; 155:1049-1054.<\/li>\n
  66. Huguley CH: Agranulocytosis induced by dipyrone, a hazardous antipyretic and analgesic<\/strong>. JAMA 1964; 189:938-941.<\/li>\n
  67. Kiatboonsri P et Richter J: Dipyrone trials in Thailand <\/strong>(letter). Lancet 1989; 2:107.<\/li>\n
  68. Kiatboonsri P et Richter J: Unethical trials of dipyrone in Thailand <\/strong>(letter). Lancet 1988; 2:1491.<\/li>\n
  69. Kirchner KA: Role of antidiuretic hormone in the attenuated furosemide response observed during indomethacin administration<\/strong>. J Lab Clin Med 1988; 111:237-243.<\/li>\n
  70. Klassen DK, Jane LH, Young DY et al: Assessment of blood pressure during naproxen therapy in hypertensive patients treated with nicardipine<\/strong>. Am J Hypertens 1995; 8:146-153.<\/li>\n
  71. Koopmans PP, Kateman WG, Tan Y et al: Effects of indomethacin and sulindac on hydrochlorothiazide kinetics<\/strong>. Clin Pharmacol Ther 1985; 37:625-628.<\/li>\n
  72. Koopmans PP, Thien T et Gribnau FWJ: The influence of ibuprofen, diclofenac and sulindac on the blood pressure lowering effect of hydrochlorothiazide<\/strong>. Eur J Clin Pharmacol 1987; 31:553-557.<\/li>\n
  73. Koopmans PP, Thien T, Thomas CM et al: The effects of sulindac and indomethacin on the anti-hypertensive and diuretic action of hydrochlorothiazide in patients with mild to moderate essential hypertension<\/strong>. Br J Clin Pharmacol 1986; 21:417-423.<\/li>\n
  74. Kovarik JM, Kurki P, Mueller E et al: Diclofenac combined with cyclosporine in treatment refractory rheumatoid arthritis: longitudinal safety assessment and evidence of a pharmacokinetic\/dynamic interaction<\/strong>. J Rheumatol 1996; 23:2033-2038.<\/li>\n
  75. Kulkarni RD, Bakhle DS, et Pinto Pereira LM: Objective evaluation of antipyretic activity in human volunteers<\/strong>. IRCS Med Sci 1985; 13;148-149.<\/li>\n
  76. Kurata C, Uehara A, Sugi T et al: Syncope caused by nonsteroidal anti-inflammatory drugs and angiotensin-converting enzyme inhibitors<\/strong>. Jpn Circ J 1999; 63:1002-1003.<\/li>\n
  77. Lal A, Pandey K, Chandra P et al: Dipyrone for treatment of post-operative pain. <\/strong>Anaesthesia 1973; 28:43-47.<\/li>\n
  78. Lay WH: Drug-induced haemolytic reactions to antibodies against the erythrocyte\/dipyrone complex<\/strong>. Vox Sang 1966; 11:601-610.<\/li>\n
  79. Lehtonen T, Kellokumpu I, Permi J et al: Intravenous indomethacin in the treatment of ureteric colic<\/strong>. Ann Clin Res 1983; 15:197-199.<\/li>\n
  80. Levy M, Leibowich I, Zylber-Katz E et al: Impairment of the metabolism of dipyrone in asymptomatic carriers of the hepatitis B virus<\/strong>. Clin Pharmacol Ther 1997; 62:6-14.<\/li>\n
  81. Levy M: Pharmacokinetics of metamizol metabolites<\/strong>. Agents Actions 1986; 19(suppl):199-204.<\/li>\n
  82. Levy M, Zylber-Katz E et Rosenkranz B: Clinical pharmacokinetics of dipyrone and its metabolites<\/strong>. Clin Pharmacokinet 1995; 28(3):216-234.<\/li>\n
  83. Lloret J, Munoz J, Mommany J et al: Treatment of renal colic with dipyrone<\/strong>. Curr Ther Res 1987; 42:1119-1128.<\/li>\n
  84. Maiche AG: Acute renal failure due to concomitant action of methotrexate and indomethacin <\/strong>(letter). Lancet 1986; 1:1390<\/li>\n
  85. Marthak KV, Gokarn AM, Rao AV et al: A multi-centre comparative study of diclofenac sodium and a dipyrone\/spasmolytic combination, and a single-centre comparative study of diclofenac sodium and pethidine in renal colic patients in India<\/strong>. Curr Med Res Opin 1991; 12:366-373.<\/li>\n
  86. Marthak KV, Gokarn AM, Rao AV et al: A multi-centre comparative study of diclofenac sodium and a dipyrone\/spasmolytic combination, and single-centre comparative study of diclofenac sodium and pethidine in renal colic patients in India<\/strong>. Curr Med Res Opin 1991; 12:366-373.<\/li>\n
  87. Mathews A et Baillie FR: Acute renal failure and hyperkalaemia associated with triamterene and indomethacin<\/strong>. Vet Hum Toxicol 1986; 28:224-225.<\/li>\n
  88. McCarthy JT, Torres VE, Romero JC et al: Acute intrinsic renal failure induced by indomethacin: role of prostaglandin synthetase inhibition<\/strong>. Mayo Clin Proc 1982; 57:289-296.<\/li>\n
  89. MICROMEDEX, Healthcare Series v. 116<\/strong>. Englewood, Colorado – USA : sept, 2000. (Banco de dados em farmacologia e terapeutica).<\/li>\n
  90. Mills EH, Whitworth JA, Andrews J et al: Non-steroidal anti-inflammatory drugs and blood pressure<\/strong>. Aust N Z J Med 1982; 12:478-482.<\/li>\n
  91. Minuz P, Pancera P, Ribul M et al: Amlodipine and haemodynamic effects of cyclo-oxygenase inhibition<\/strong>. Br J Clin Pharmacol 1995; 39:45-50.<\/li>\n
  92. Morgan T et Anderson A: Interaction of indomethacin with felodipine and enalapril<\/strong>. J Hypertens 1993; 11(suppl 5):338S-339S.<\/li>\n
  93. Mork NL et Robertson RP: Effects of nonsteroidal antiinflammatory drugs in conventional dosage on glucose homeostasis in patients with diabetes<\/strong>. West J Med 1983; 139:46-49.<\/li>\n
  94. Morrison PJ, Rogers HJ, Spector RG et al: Effect of pirprofen on glibenclamide kinetics and response<\/strong>. Br J Clin Pharmacol 1982; 14:123-126.<\/li>\n
  95. Mor R, Pitlik S et Rosenfeld JB: Indomethacin and Moduretic-induced hyperkalemia<\/strong>. Isr J Med Sci 1983; 19:535-537.<\/li>\n
  96. Muck W, Heine PR, Schmage N et al: Steady-state pharmacokinetics of nimodipine during chronic administration of indometacin in elderly healthy volunteers. <\/strong>Arzneimittelforschung 1995; 45:460-462.<\/li>\n
  97. Muck W, Heine PR, Schmage N et al: Steady-state pharmacokinetics of nimodipine during chronic administration of indomethacin in elderly healthy volunteers<\/strong>. Arzneimittelforschung 1995; 45:460-462.<\/li>\n
  98. Nies AS, Gal J, Fadul S et al: Indomethacin-furosemide interaction: the importance of renal blood flow<\/strong>. J Pharmacol Exp Ther 1983; 226:27-32.<\/li>\n
  99. Nies AS: Renal effects of nonsteroidal anti-inflammatory drugs<\/strong>. Agents Actions 1988; 24(suppl):95-106.<\/li>\n
  100. Norfleet RG: 1,300 mg of aspirin daily does not cause positive fecal hemoccult tests<\/strong>. J Clin Gastroenterol 1983; 5:123-125.<\/li>\n
  101. Okonek S: Intoxication with pyrazolones<\/strong>. Br J Clin Pharmacol 1980; 10:385S-390S.<\/li>\n
  102. Okonek S et Reinecke HJ: Acute toxicity of pyrazolones<\/strong>. Am J Med 1983; Symposium Nov 14:94-98.<\/li>\n
  103. Paeile C et Gallardo F: Analgesic activity of pentazocine and dipyrone in ambulatory oral surgery patients<\/strong>. J Oral Surg 1974; 32:191-194.<\/li>\n
  104. Pahor M, Gurainik JM, Furberg CD et al: Risk of gastrointestinal haemorrhage with calcium antagonists in hypertensive persons over 67 years old<\/strong>. Lancet 1996; 347:1061-1065.<\/li>\n
  105. Pancera P, Arosio E, Minuz P et al: Changes in peripheral hemodynamics and vasodilating prostaglandins after high-dose short-term ibuprofen in chronically treated hypertensive patients<\/strong>. Prostaglandins Leukot Essent Fatty Acids 1996; 54:217-222.<\/li>\n
  106. Pandhi RK, Kumar AS, Satish DA et al: Fixed drug eruptions on male genitalia: clinical and etiologic study<\/strong>. Sex Transm Dis 1984; 11:164-166.<\/li>\n
  107. Pasricha JS: Drugs causing fixed eruptions<\/strong>. Br J Dermatol 1979; 100:183-185.<\/li>\n
  108. Patel CV, Koppikar MG, Patel MS et al: Management of pain after abdominal surgery: dipyrone compared with pethidine<\/strong>. Br J Clin Pharmacol 1980; 10:351S-354S.<\/li>\n
  109. Pedrinelli R, Magagna A, Arzilli F et al: Influence of indomethacin on the natriuretic and renal-stimulating effect of bumetanide in essential hypertension<\/strong>. Clin Pharmacol Ther 1980; 28:722-730.<\/li>\n
  110. Peterson MS et al: Differential effects of naproxen and diclofenac on verapamil pharmacokinetics<\/strong>. Clin Pharmacol Ther 1991; 49:129.<\/li>\n
  111. Pilotto A, Leandro G, Franceschi M et al: Antagonism to calcium antagonists. <\/strong>Lancet 1996; 347:1761-1762.<\/li>\n
  112. Polonia J, Boaventura I, Gama G et al: Influence of non-steroidal anti-inflammatory drugs on renal function and 24h ambulatory blood pressure-reducing effects of enalapril and nifedipine gastrointestinal therapeutic system in hypertensive patients<\/strong>. J Hypertens 1995; 13:925-931.<\/li>\n
  113. Pond SM, Birkett DJ et Wade DN: Mechanisms of inhibition of tolbutamide metabolism: phenylbutazone, oxyphenbutazone, sulfaphenazole<\/strong>. Clin Pharmacol Ther 1977; 22:573-579.<\/li>\n
  114. Pond SM, Birkett DJ et Wade DN. Mechanisms of inhibition of tolbutamide metabolism: phenylbutazone, oxyphenbutazone, sulfaphenazole<\/strong>. Clin Pharmacol Ther 1977; 22(5 pt 1):573-579.<\/li>\n
  115. Porterfield WR et Wu CL. Epidural hematoma in an ambulatory surgical patient<\/strong>. J Clin Anesth 1997; 9:74-76.<\/li>\n
  116. Pritchard G, Lyons D, Webster J et al. Do trandolapril and indomethacin influence renal function and renal functional reserve in hypertensive patients. <\/strong>Br J Clin Pharmacol 1997; 44:145-149.<\/li>\n
  117. Product Information<\/strong>: Coumadin(R), warfarin sodium. DuPont Pharma, Wilmington, DE, 1999.<\/li>\n
  118. Product Information<\/strong>: Floxin(R), ofloxacin. Ortho Pharmaceutical Corporation, Raritan, NJ, 1995.<\/li>\n
  119. Product Information<\/strong>: Fosamax(R), alendronate sodium. Merck et Co., Inc., West Point, PA, 1999.<\/li>\n
  120. Product Information<\/strong>. Integrilin(R), eptifibatide. Key Pharmaceuticals, Inc., Kenilworth, NJ, 1999.<\/li>\n
  121. Product Information<\/strong>. Lovenox(R), enoxaparin sodium. Rhone-Poulenc Rorer Pharmaceuticals Inc., Collegeville, PA, 1999.<\/li>\n
  122. Product Information<\/strong>. Naprelan(TM), naproxen sodium. Wyeth-Ayerst Laboratories, Philadelphia, PA, 1996.<\/li>\n
  123. Product Information<\/strong>. Orgaran(TM), danaparoid sodium injection. Organan Inc., West Orange, NJ, 1998.<\/li>\n
  124. Product Information<\/strong>. Toradol(R), ketorolac tromethamine. Roche Laboratories Inc., Nutley, NJ, 1996.<\/li>\n
  125. Product Information<\/strong>. Voltaren(R), diclofenac sodium. Novartis Pharmaceuticals Corporation, East Hanover, NJ, 1996.<\/li>\n
  126. Pye G, Ballantyne KC, Armitage NC et al. Influence of non-steroidal anti-inflammatory drugs on the outcome of faecal occult blood tests in screening for colorectal cancer<\/strong>. Br Med J 1987; 294:1510-1511.<\/li>\n
  127. Radack KL, Deck CC et Bloomfield SS. Ibuprofen interferes with the efficacy of antihypertensive drugs. A randomized, double-blind, placebo-controlled trial of ibuprofen compared with acetaminophen<\/strong>. Ann Intern Med 1987; 107:628-635.<\/li>\n
  128. Ragheb M, Ban TA, Buchanan D et al. Interaction of indomethacin and ibuprofen with lithium in manic patients under a steady-state lithium level. <\/strong>J Clin Psychiatry 1980; 41:397-398.<\/li>\n
  129. Rapeport WG, Grimwood VC, Hosie J et al: The effect of tenidap on the anti-hypertensive efficacy of ACE inhibitors in patients treated for mild to moderate hypertension<\/strong>. Br J Clin Pharmacol 1995; 39(suppl):57S-61S.<\/li>\n
  130. Rapeport WG, Grimwood VC, Korlipara K et al. The effect of tenidap on the anti-hypertensive efficacy of thiazide diuretics in patients treated for mild to moderate hypertension<\/strong>. Br J Clin Pharmacol 1995; 39(suppl1):51S-55S.<\/li>\n
  131. Ravic M, Johnston A et Turner P. Clinical pharmacological studies of some possible interactions of lornoxicam with other drugs<\/strong>. Postgrad Med J 1990; 66(suppl 4):S30-S34.<\/li>\n
  132. Reiner M, Massera E et Magni E. Nimesulide in the treatment of fever: a double-blind crossover clinical trial<\/strong>. J Int Med Res 1984; 12:102-107.<\/li>\n
  133. Reynolds JEF (ed). Martindale: The Extra Pharmacopoeia <\/strong>(electronic version). Micromedex, Inc, Denver, CO, 1992.<\/li>\n
  134. Ribera A, Monasterio J, Acebedo G et al. Dipyrone-induced immune haemolytic anaemia<\/strong>. Vox Sang 1981; 41:32-35.<\/li>\n
  135. Rodriguez M, Barutell C, Rull M et al. Efficacy and tolerance of oral dipyrone versus oral morphine for cancer pain<\/strong>. Eur J Cancer 1994; 30A(5):584-587.<\/li>\n
  136. Rodriguez MJ, de la Torre MR, Perez-Iraola P et al. Comparative study of tramadol versus NSAIDs as intravenous continuous infusion for managing postoperative pain<\/strong>. Curr Ther Res 1993; 54:375-383.<\/li>\n
  137. Rohdewald P, Granitzki HW et Neddermann E. Comparison of the analgesic efficacy of metamizole and tramadol in experimental pain<\/strong>. Pharmacology 1988; 37:209-217.<\/li>\n
  138. Roots I, Kampf D, Heinemeyer G et al. Changes in metamizol kinetics and metabolism during chronic and acute renal failure as compared to healthy volunteers<\/strong>. Arch Pharmacol 1985; 330(suppl):R81.<\/li>\n
  139. Ryan JR, Jain AK, McMahon G et al. On the question of an interaction between sulindac and tolbutamide in the control of diabetes<\/strong>. Clin Pharmacol Ther 1977; 21:231-233.<\/li>\n
  140. Saban J, Pais JR, Rodriguez JL et al. Sjogren-like pluriglandular exocrine insufficiency after drug-induced toxic epidermal necrolysis<\/strong>. Postgrad Med J 1991; 67:195-197.<\/li>\n
  141. Sadusk JF. The relationship of the Food and Drug Administration to the practice of medicine and the aminopyrine-dipyrone problem<\/strong>. South Med J 1965; 58:1508-1512.<\/li>\n
  142. Salvetti A, Arzilli F, Pedrinelli R et al. Interaction between oxprenolol and indomethacin on blood pressure in essential hypertensive patients<\/strong>. Eur J Clin Pharmacol 1982; 22:197-201.<\/li>\n
  143. Salvetti A, Pedrinelli R, Alberici P et al. The influence of indomethacin and sulindac on some pharmacological actions of atenolol in hypertensive patients<\/strong>. Br J Clin Pharmacol 1984; 17(suppl):108S-111S.<\/li>\n
  144. Sanahuja J, Corbera G, Garau J et al. Intramuscular diclofenac sodium versus intravenous Baralgin in the treatment of renal colic<\/strong>. DICP 1990; 24:361-364.<\/li>\n
  145. Sanahuja J, Corbera G, Garau J et al. Intramuscular diclofenac sodium versus intravenous Baralgin in the treatment of renal colic<\/strong>. DICP Ann Pharmacother 1990; 24:361-364.<\/li>\n
  146. Sansone G, Reali S, Sansone R et al. Acute hemolytic anemia induced by a pyrazolonic drug in a child with glucose-6-phosphate dehydrogenase deficiency<\/strong>. Acta Haematol 1984; 72:285-287.<\/li>\n
  147. Scharli AF, Brulhart K et Monti T. Pharmacokinetics and therapeutic study with nimesulide suppositories in children with post-operative pain and inflammation<\/strong>. J Int Med Res 1990; 18:315-321.<\/li>\n
  148. Schmieder G, Stankov G, Zerle G et al. Observer-blind study with metamizole versus tramadol and butylscopolamine in acute biliary colic pain<\/strong>. Arzneimittelforschung 1993; 43:1216-1221.<\/li>\n
  149. Schulz E, Koch K et Schmidt FH. Ursachen der potenzierung der hypoglykamischen wirkung von sulfonylharnstoff derivaten durch medikamente: II. Pharmakokinetik und metabolismus von glibenclamid (HB 419) in gegenwart von phenylbutazon<\/strong>. Eur J Clin Pharmacol 1971; 4:32-37.<\/li>\n
  150. Schuna AA, Vejraska BD, Hiatt JG et al. Lack of interaction between sulindac or naproxen and propranolol in hypertensive patients<\/strong>. J Clin Pharmacol 1989; 29:524-528.<\/li>\n
  151. Seltzer HS. Drug induced hypoglycemia<\/strong>. Endocrinol Metab Clin North Am 1989; 18:163-183.<\/li>\n
  152. Shah SJ, Bhadnardar SD et Satoskar RS. Drug interaction between chlorpropamide and nonsteroidal anti-inflamatory drugs, ibuprofen and phenylbutazone<\/strong>. Int J Clin Pharmacol Ther Toxicol 1984; 22:470-472.<\/li>\n
  153. Sharpe CR et Franco EL. Use of dipyrone during pregnancy and risk of Wilms’ tumor<\/strong>. Epidemiol 1996; 7:533-535.<\/li>\n
  154. Sheiner PA, Mor E, Chodoff L et al. Acute renal failure associated with the use of ibuprofen in two liver transplant recipients on FK506<\/strong>. Transplantation 1994; 57:1132-1133.<\/li>\n
  155. Shinar E et Hershko C. Causes of agranulocytosis in a hospital population: identification of dipyrone as an important causative agent<\/strong>. Israel J Med Sci 1983; 19:225-229.<\/li>\n
  156. Shionoiri H. Pharmacokinetic drug interactions with ACE inhibitors<\/strong>. Clin Pharmacokinet 1993; 25:20-58.<\/li>\n
  157. Singh RR, Malaviya AN, Pandey JN et al. Fatal interaction between methotrexate and naproxen <\/strong>(letter). Lancet 1986; 1:1390.<\/li>\n
  158. Skeith KJ, Russell AS, Jamali F et al. Lack of significant interaction between low dose methotrexate and ibuprofen or flurbiprofen in patients with arthritis<\/strong>. J Rheumatol 1990; 17:1008-1010.<\/li>\n
  159. Slavetti A, Pedrinelli R, Magagna A et al. Calcium antagonists: interactions in hypertension<\/strong>. Am J Nephrol 1986; 6(suppl 1):95-99.<\/li>\n
  160. Sommers DK, Kovarik JM, Meyer EC et al. Effects of diclofenac on isradipine pharmacokinetics and platelet aggregation in volunteers<\/strong>. Eur J Clin Pharmacol 1993; 44:391-393.<\/li>\n
  161. Stewart CF, Fleming RA, Arkin CR et al. Coadministration of naproxen and low-dose methotrexate in patients with rheumatoid arthritis<\/strong>. Clin Pharmacol Ther 1990; 47:540-546.<\/li>\n
  162. Stewart CF, Fleming RA, Germain BF et al. Aspirin alters methotrexate disposition in rheumatoid arthritis patients<\/strong>. Arthritis Rheum 1991; 34:1514-1520.<\/li>\n
  163. Sturrock NDC, Lang CC et Struthers AD. Indomethacin and cyclosporin together produce marked renal vasoconstriction in humans<\/strong>. J Hypertens 1994; 12:919-924.<\/li>\n
  164. Sturrock ND et Struthers AD. Non-steroidal anti-inflammatory drugs and angiotensive converting enzyme inhibitors: a commonly prescribed combination with variable effects on renal function<\/strong>. Br J Clin Pharmacol 1993; 35:343-348.<\/li>\n
  165. Tempel G, von Hundelshausen B et Reeker W. The opiate-sparing effect of dipyrone in post-operative pain therapy with morphine using a patient-controlled analgesic system<\/strong>. Intensive Care Med 1996; 22:1043-1047.<\/li>\n
  166. Tempero KF, Cirillo VJ et Steelman SL. Diflunisal: a review of pharmacokinetic and pharmacodynamic properties, drug interactions, and special tolerability studies in humans<\/strong>. Br J Clin Pharmacol 1977; 4(suppl 1):31S-36S.<\/li>\n
  167. Thyss A, Milano G, Kubar J et al. Clinical and pharmacokinetic evidence of a life-threatening interaction between methotrexate and ketoprofen<\/strong>. Lancet 1986; 1:256-258.<\/li>\n
  168. Tigerstedt I, Leander P et Tammisto T. Postoperative analgesics for superficial surgery: comparison of four analgesics<\/strong>. Acta Anaesth Scand 1981; 25:543-547.<\/li>\n
  169. Todd PA et Sorkin EM. Diclofenac: a reappraisal<\/strong>. Drugs 1988; 35:244-285.<\/li>\n
  170. Tracy TS, Worster T, Bradley JD et al: Methotrexate disposition following concomitant administration of ketoprofen, piroxicam and flurbiprofen in patients with rheumatoid arthritis<\/strong>. Br J Clin Pharmacol 1994; 37:453-456.<\/li>\n
  171. TRISSEL, Lawrence A. Handbook on injectable drugs<\/strong>. 10 ed. Houston, TX-USA: ASHP 1998.<\/li>\n
  172. Tugwell P, Ludwin D, Gent M et al. Interaction between cyclosporin A and nonsteroidal antiinflammatory drugs<\/strong>. J Rheumatol 1997; 24:1122-1125.<\/li>\n
  173. van der Klauw MM, Wilson JHP et Stricker BHC. Drug-associated agranulocytosis: 20 years of reporting in the netherlands (1974-1994)<\/strong>. Am J Hematol 1998; 57:206-211.<\/li>\n
  174. Vlahov V, Badian M, Verho M et al. Pharmacokinetics of metamizol metabolites in healthy subjects after a single oral dose of metamizol sodium<\/strong>. Eur J Clin Pharmacol 1990; 38:61-65.<\/li>\n
  175. Volz M et Kellner HM. Kinetics and metabolism of pyrazolones (propyphenazone, aminopyrine and dipyrone). <\/strong>Br J Clin Pharmacol 1980; 10:299S-308S.<\/li>\n
  176. von Szeged AV et Michos N. Controlled single-blind clinical study of suprofen syrup versus metamizole syrup<\/strong>. Arzneimittelforschung 1986; 36:1110-1112.<\/li>\n
  177. Walbridge DG et Bazire SR. An interaction between lithium carbonate and piroxicam presenting as lithium toxicity<\/strong>. Br J Psychiatry 1985; 145:206-207.<\/li>\n
  178. Watkins J, Abbott EC, Hensby CN et al. Attenuation of hypotensive effect of propranolol and thiazide diuretics by indomethacin. <\/strong>Br Med J 1980; 281:702-705.<\/li>\n
  179. Weale AE, Warwick DJ, Durant N et al. Is there a clinical interaction between low molecular weight heparin and non-steroidal analgesics after total hip replacement? <\/strong>Ann R Coll Surg Engl 1995; 77:35-37.<\/li>\n
  180. Webster J, Petrie JC, McLean I et al. Flurbiprofen interaction with single doses of atenolol and propranolol<\/strong>. Br J Clin Pharmacol 1984; 18:861-866.<\/li>\n
  181. Weinberg MS, Quigg RJ, Salant DJ et al. Anuric renal failure precipitated by indomethacin and triamterene<\/strong>. Nephron 1985; 40:216-218.<\/li>\n
  182. Whiting B, Williams RL, Lorenzi M et al. Effect of naproxen on glucose metabolism and tolbutamide kinetics and dynamics in maturity onset diabetes. <\/strong>Br J Clin Pharmacol 1981; 11:295-302.<\/li>\n
  183. Williams RL, Davies RO, Berman RS et al. Hydrochlorothiazide pharmacokinetics and pharmacologic effect: the influence of indomethacin<\/strong>. J Clin Pharmacol 1982; 22:32-41.<\/li>\n
  184. Wong DG, Spence JD, Lamki L et al. Effect of non-steroidal anti-inflammatory drugs on control of hypertension by beta-blockers and diuretics. <\/strong>Lancet 1986; 1:997-1001.<\/li>\n
  185. Wright JT, McKenney JM, Lehany AM et al. The effect of high-dose short-term ibuprofen on antihypertensive control with hydrochlorothiazide. <\/strong>Clin Pharmacol Ther 1989; 46:440-444.<\/li>\n
  186. Zylber-Katz E, Granit L et Levy M. Plasma protein binding of dipyrone metabolites in man<\/strong>. Eur J Clin Pharmacol 1985; 29:67-71.<\/li>\n
  187. Zylber-Katz E, Linder N, Granit L et al. Excretion of dipyrone metabolites in human breast milk<\/strong>. Eur J Clin Pharmacol 1986; 30:359-361.<\/li>\n<\/ol>\n

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    INTRODU\u00c7\u00c3O Analgesia por AINEs \u00e9 explicada pela a\u00e7\u00e3o inibit\u00f3ria da s\u00edntese local de PGE2 (Vane, 1971). Essa a\u00e7\u00e3o previne o desenvolvimento da hiperalgesia , isto \u00e9, a  sensibiliza\u00e7\u00e3o dos receptores de dor para est\u00edmulos qu\u00edmicos e f\u00edsicos. Dipirona \u00e9 um … Continue lendo →<\/span><\/a><\/p>\n","protected":false},"author":1,"featured_media":0,"comment_status":"open","ping_status":"open","sticky":false,"template":"","format":"standard","meta":{"footnotes":""},"categories":[14],"tags":[],"class_list":["post-4682","post","type-post","status-publish","format-standard","hentry","category-farmacologia"],"_links":{"self":[{"href":"https:\/\/antonini.psc.br\/index.php?rest_route=\/wp\/v2\/posts\/4682","targetHints":{"allow":["GET"]}}],"collection":[{"href":"https:\/\/antonini.psc.br\/index.php?rest_route=\/wp\/v2\/posts"}],"about":[{"href":"https:\/\/antonini.psc.br\/index.php?rest_route=\/wp\/v2\/types\/post"}],"author":[{"embeddable":true,"href":"https:\/\/antonini.psc.br\/index.php?rest_route=\/wp\/v2\/users\/1"}],"replies":[{"embeddable":true,"href":"https:\/\/antonini.psc.br\/index.php?rest_route=%2Fwp%2Fv2%2Fcomments&post=4682"}],"version-history":[{"count":10,"href":"https:\/\/antonini.psc.br\/index.php?rest_route=\/wp\/v2\/posts\/4682\/revisions"}],"predecessor-version":[{"id":33385,"href":"https:\/\/antonini.psc.br\/index.php?rest_route=\/wp\/v2\/posts\/4682\/revisions\/33385"}],"wp:attachment":[{"href":"https:\/\/antonini.psc.br\/index.php?rest_route=%2Fwp%2Fv2%2Fmedia&parent=4682"}],"wp:term":[{"taxonomy":"category","embeddable":true,"href":"https:\/\/antonini.psc.br\/index.php?rest_route=%2Fwp%2Fv2%2Fcategories&post=4682"},{"taxonomy":"post_tag","embeddable":true,"href":"https:\/\/antonini.psc.br\/index.php?rest_route=%2Fwp%2Fv2%2Ftags&post=4682"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}