medicatia diuretica -...
TRANSCRIPT
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Medicatia diuretica
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Introducere Medicamente care cresc fluxul urinar
In principal – cresc rata de eliminare a Na+ si Cl-
Diuretice natriuretice
Efect specific la nivelul unor proteine
transportoare membranare,
Actiune asupra unor receptori pentru hormoni,
asupra reabsorbtiei apei, inhibarea unor enzime
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Nefronul Unitatea morfo-functionala a rinichiului
Responsabil de formarea urinii
Localizare in corticala, unele segmente trec in medulara
Capsula Bowman - filtrare glomerulara – urina primara
Tub renal – reabsorbtia si secretia tubulara – Na+ si apa
Diureza finala – 1,5 l/24 de ore
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Reabsorbtia Na+ Trecerea Na+ si apa din lumenul tubular in interstitiul
peritubular
Mecanisme active si pasive
Mecanisme simport sau antiport
2 etape
Lumen tubular – citoplasma celulei tubulare (mai multe mecanisme)
Citoplasma celulei – interstitiu (ATP-aza Na+/K+)
Spatiu intercelular – mica importanta
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Reabsorbtia Na+
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Reabsorbtia Na+
Tub contort proximal – 70% din
totalul Na+
1. Pasiv – gradient electrochimic
transmembranar
Atragere echivalenta – Cl- si
apa
Reabsorbtie izoosmotica
2. schimb cu H- -
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mecansim simport
cuplati cu anionii
organici, glucoza,
anion fosfat
Reabsorbtia Na+
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Reabsorbtia Na+ Ansa Henle – portiune ascendenta – 25%
2 mecanisme simport
Reabsorbtia Na +, K +, 2 Cl-
Reabsorbtia Na + si Cl- - in portiunea terminala
Epiteliul ansei – impermeabil pentru apa
Concentrarea si diluarea urinii
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Reabsorbtia Na+
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Reabsorbtia Na+ Tub contort distal si tub colector – 5% din totalul
Na+
Schimb cu K+ si H+
Controlul aldosteronului
H+ - disocierea acidului carbonic (bioxid de carbon
si apa)
Intensitatea procesului – direct proportionala cu
concentratia Na din lumen
Urina - tubul colector – reabsorbtia apei fara sare
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Medicatia diuretica Cresterea diurezei – 2 mecanisme
Cresterea filtrarii glomerulare – diureza apoasa
Ingestie de apa, vd
Scaderea reabsorbtiei tubulare – eliminarea sarii
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CLASIFICARE Tiazide si compusi asemanatori
Furosemid, acid etacrinic
Diuretice antialdosteronice – spironolactona, triamteren
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CLASIFICARE Aminofilina - putin folosita, creste circulatia
renala
Manitol – diuretic osmotic
Mercuriale – active, nu mai sunt utilizate din cauza toxicitatii mari, ineficiente pe cale orala
Inhibitori de carboanhidraza – acetazolamida
Nu se mai utilizeaza – eficacitate redusa, risc de dezechilibre hidroelectrolitice mare
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DIURETICE TIAZIDICE
Reprezentant principal : hidroclorotiazida (HCT), Indapamida, Clortalidona
Se administreaza oral
Se metabolizeaza diferit
Hidroclorotiazida
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Mecanism de actiune Inhiba mecanismul co-
transportor la nivelul tubului contort distal pentru Na+– efect saluretic modest
Doze excesive – inhiba anhidraza carbonica cu alcalinizarea urinii
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Diuretice cu actiune moderata, durabila (8-24 ore)
Eliminarea unei urini cu
volum mare
Conc - Na+, Cl-, K+, Mg+
Conc - Ca2+
Doze mari – urina alcalina
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Stimuleaza sistemul co-transportor pentru calciu la niv tubului contort distal – reabsorbtia Ca
Pot masca hipercalcemia datorata altor cauze(hiperparatiroidism, carcinoame, sarcoidoza)
Utile in tratamentul calculilor renali prinhipercalciurie
Efectul - depinde partial de productia renala de PG
AINS pot reduce efectul lor
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nu influenţează fluxul plasmatic renal – nu sunt eficiente în condiţiile unui clearance al creatininei sub 30 ml/min.
efect vasodilatator musculotrop - în tratamentul cronic al HTA şi insuficienţă cardiacă
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FARMACOCINETICA Absorbtie intestinala – efect dupa 1 ora
Distributie uniforma in spatiul extracelular
Traverseaza bariera placentara
Legare de proteine plasmatice, T1/2 – variabile
Eliminare renala – prin filtrare glomerulara si secretie tubulara proximala, sub forma neschimbata
Compusi putin solubili (clorotiazida, hidroclorotiazida)–eliminare rapida, efect 8-12 h
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INDICATII
RETENTIE HIDROSALINA MODERATA
ICC, ciroza hepatica, boli renale cronice
Edeme rebele la tratament – asociere tiazida +
furosemid – efect sinergic
2. HTA
Actioneaza prin cresterea diurezei + vd (?)
Diuretice de prima alegere
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INDICATII3. Diabet insipid nefrogen, rezistent la vasopresina
pot atenua poliuria si polidipsia
4. Litiaza renala prin hipercalciurie idiopatica – scad
eliminarea de calciu, reduc tendinta de formare a
calculilor
5. Intoxicatia cu bromuri – competitie pentru
sistemele de eliminare
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REACTII ADVERSE Hipokaliemie – doze mari, tratament prelungit
Hiposodemie – (datorita ADH prin hipovolemie,
↓ capacitatea de concentrare renala, senzatiei de
sete)
Alcaloza hpocloremica, hipomagneziemica – mai
rara
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REACTII ADVERSE
Tulburari metabolice:
hiperglicemie: se corecteaza partial prin corectarea hipopotesemiei (datorata alterarii eliberarii insulinei si a utilizarii ei periferice)
hiperuricemie,
hipercolesterolemie (LDL si Colesterolul total)
Agravare IR si IH
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Reactii alergice – purpura, fotosensibilizare,
mai rar anemie hemolitica, trombocitopenie, icter colestatic, pancreatita acuta necrozanta – rara
Alergia la tiazide – incrucisata cu cea la alte sulfonamide
Hipercalcemie si hipofosfatemie – rar
Tulburari GI
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CONTRAINDICATII Absolute
IR grava
Intoleranta la tiazide
Sarcina – tulburari hematologice grave la NN si mame
Relative - diabet zaharat, hiperuricemie, guta
Prudenta - IR moderata, ciroza hepatica, cardiaci
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INTERACTIUNI MEDICAMENTOASE Antidiabetice – reduc eficacitatea tiazidelor
Litiu – cresc cardio- si neurotoxicitatea Li
Gcc – pierdere crescuta de K+
Doze mari – cresc toxicitatea digitalicelor (aritmii)
AntiHTA, psihotrope – risc de hTA
AINS – scad efectul diuretic al tiazidelor
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HIDROCLOROTIAZIDA Diuretic larg folosit
Efect dupa 1 ora, maxim la 2-4 ore, durata 8-12 ore
T1/2=2,5 ore, crescut in IC si IR
Eliminare urinara – 95%, neschimbata
Doza = 25-50 mg, o data/zi, la inceput zilnic, apoi de 3 ori/sapt
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2. Ciclopentiazida – efect asemanator, 0,25-1 mg/zi
3. Meclotiazida – efect 12-24 ore, 2,5-10 mg/zi
4. Ciclotiazida, Politiazida – efect>24 ore, 1-6 mg/zi
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Indapamida
Clortalidona, Clorexolona, Metolazona, Clopamida, Indapamida, Xipamida
Sulfonamide heterociclice, diferite structural de tiazide
Efecte similare cu tiazidele
Durata lunga de actiune – peste 24 de ore
Folosite ca antiHTA
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DIURETICE DE ANSA Compusi cu nucleu
sulfonamidbenzoic – furosemid,
bumetanida, piretanida
Compusi cu nucleu ariloxiacetic
– acid etacrinic, indacrinona
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Mecanism de actiune Diuretice cu prag inalt –
efect de intensitate mare
Actioneaza preponderent
la nivelul ansei Henle,
portiunea ascendenta
Inhiba sistemul simport
Na+, K+, 2 Cl-
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Efecte farmacologice Provoaca saliureza, inhiba procesul de diluare si
concentrare a urinii
Cresc eliminarea Ca2+ si Mg2+
Efect diuretic
Dependent de doza
Durata scurta
Cresc fluxul sangvin renal
Risc de dezechilibre hidroelectrolitice - mare
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FARMACOCINETICA Absorbtie rapida, biodisponibilitate medie
Legare de proteinele plasmatice – 99%
Distributie in lichidul extracelular
Eliminare rapida
Renal - prin filtrare glomerulara si secretie tubulara, nemodificat
Prin scaun – 25%
T1/2 = 92 minute
IR, IC, ciroza –creste t1/2
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INDICATII
Toate tipurile de edeme – IC, ciroza, IR
De electie – in edemele grave, rezistente la tiazide
Se pot asocia cu tiazidele - creste eficienta
Sunt eficiente si in situatiile cu FG
IC - reduc congestia venoasă şi cea pulmonară
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INDICATII 2. HTA – monoterapie, in asociere cu alte antiHTA
3. IRA cu oligurie – inlatura oliguria, nu
influenteaza evolutia IR
4. EPA – iv
5. Edem cerebral –
6. Intoxicatii acute medicamentoase – intoxicatii cu
bromuri, ioduri, floruri
7. hipercalcemie si hiponatriemie severa – in
asociere cu solutii saline izo sau hipertone
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REACTII ADVERSE Dezechilibre hidroelectrolitice
Risc mai mare decat la tiazide
Scaderea - Na+, K+ cu sau fara alcaloza, Mg2+
2. Scaderea marcata a TA
3. Deshidratare si hiperazotemie – tratament prelungit cu doze mari, dieta hiposodata stricta
4. Hiperuricemie
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REACTII ADVERSE5. Hiperglicemie, agravarea diabetului
6. Hipercolesterolemie
7. Tulburari digestive
8. Rar – pancreatita, nefrita interstitiala, eruptii cutanate, leucopenie, trombocitopenie,
9. Surditate – trecatoare sau definitiva
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CONTRAINDICATII Hipokaliemie, hiponatriemie marcate
Hipovolemie cu deshidratare
Ciroza decompensata
Intoxicatia digitalica
Prudenta – IC severa, DZ, guta, obstacol pe caile urinare, sarcina trim I
Necesar – controlul electrolitilor, uree, creatinina serica
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INTERACTIUNI MEDICAMENTOASE 1. Asocierea cu tiazide - in edemele refractare
efect sinergic cu reducerea toxicitatii furosemidului
2. AINS, indometacin – reduc efectul diuretic (reduc sinteza de PG la nivel renal)
3. Aminoglicozide
risc de oto- si nefrotoxicitate
4. Cefaloridina – risc de nefrotoxicitate
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INTERACTIUNI MEDICAMENTOASE
5. Cisplatina – risc de ototoxicitate
6. Tratament cu Li – monitorizarea Li, poate creste
7. Nu se amesteca cu alte medicamente si cu
solutii acide in aceeasi seringa
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FUROSEMID Derivat sulfonamidbenzoic
Efect diuretic
po– 20-60 min, max. la 2-3 h, durata 4-6 h
Iv – 3-15 min, max. 15-30 min, durata 2-5 h
Cresterea diurezei – evidenta si in conditiile unei
filtrari glomerulare scazute (<15 ml)
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MOD DE ADMINISTRARE Oral
40-80 mg/zi,
se poate creste la 6 ore pana la obtinerea
raspunsului, sau pana la doza de 240 mg/zi (1-
3 doze)
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2. Injectabil – in cazuri severe, urgente
20-40 mg in 2 min, se poate repeta la 3 ore pana
la maxim 240 mg/zi
IR – doze mari, injectate lent (4 mg/min)
Ulterior se trece la administrare orala
Controlul debitului urinar si al electrolitilor
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Torasemid
Bumetanida
TORASEMID, AZOSEMID
Proprietati similare
Torasemid – fara ototoxicitate, poate favoriza ischemia miocardica si cerebrala, aritmii
PIRETANIDA, BUMETANIDA
Potenta superioara
Piretanida – 3-6 mg/zi
Bumetanida – 1 mg/zi
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ACIDUL ETACRINIC
Derivat de acid fenoxiacetic
Actiune diuretica intensa, de scurta durata
Efect prezent pentru FG redus
Inhiba reabsorbtia sarii fara apa la nivelul
portiunii ascendente a ansei Henle
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MOD DE ADMINISTRARE Po 50 mg, se creste progresiv pana la obtinerea
efectului sau pana la 150 mg/zi
Tratament de intretinere – intermitent 50-100
mg la 2 zile sau de 2-4 ori/sapt
Urgente – iv edecrinat de sodiu 50 mg (0,5-1
mg/kg)
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REACTII ADVERSE similar cu furosemid
Tulburari digestive mai frecvente - anorexie, dureri
abdominale, disfagie, greata, voma, hemoragii
intestinale
Risc de dezechilibre hidroelectrolitice – mare
Nu se asociaza cu medicamente ototoxice,
Nu se administreaza in sarcina
Risc de surditate – mai mare decat la furosemid
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Diuretice care economisesc potasiul1. Antagonisti competitivi
ai receptorilor pentru aldosteron –spironolactona
2. Actiune contrara aldosteronului – prin blocarea canalelor de Na+ de la nivelul epiteliului renal –triamteren, amilorid
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Diuretice care economisesc potasiul
Creste eliminarea de sare si retinerea potasiului in organism
Efect operant in caz de hiperaldosteronism
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SPIRONOLACTONA
Compus 17-spirolactosteroidic, inrudit cu aldosteronul
Actiune diuretica relativ slaba
Creste eliminarea de apa si NaCl
Ionii H, K, NH4 – cantitate scazuta in urina
Urina alcalina, plus de bicarbonati
Efectul diuretic – conditionat de prezenta ALD
Intensitatea efectului – dependenta de conc hormonului
Raspuns minim- dupa 3-4 zile, se mentine 2-3 zile dupa oprirea tratamentului
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Actiune de tip competitiv
Legare de receptorii citoplasmici specifici pt
mineralocorticoizi impiedica translocarea
complexului agonist-receptor in nucleu
blocarea activitatii genelor care regleaza sinteza
proteinelor induse de aldosteron
Scade influxul Na din urina in celulele tubulare
Scade secretia K si H in lumenul tubular
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actiune de tip metabolic – posibila
Inhiba 5 alfa reductaza – inhiba formarea
metabolitilor activi ai aldosteronului
efect antiaritmic - blocare a genelor care codifică canalele de K+ de tip HERG
afinitate mare pentru receptorii specifici ai progesteronului şi androgenilor - efectele adverse endocrine.
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FARMACOCINETICA Utilizata in forma cristalina - absorbtie buna
Biodisponibilitate redusa – primul pasaj hepatic
T1/2=14 ore
Metabolizare hepatica – canrenona, acid canrenonic – activi
Mod de administrare – po 10-50 mgx4/zi.
apoi 10-25 mgx1-4/zi
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INDICATII1. Edeme cu hiperaldosteronism secundar rezistente la
alte diuretice
Cardiaci, in ciroza, sindrom nefrotic
Asociata tiazidelor si furosemidului
2. Hiperaldosteronism primar - formele inoperabile
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3. Insuficienta cardiaca
Impiedica consecintele negative ale stimularii RAA
Favorizeaza efectele benefice ale ANP
Asociere IEC-spironolactona – risc crescut de hiperK+ -emie
Efect cardioprotector – inhiba fibroza miocardica
4. Situatii clinice in care se doreste cresterea K+ in organism:
Paralizie familiala, miastenia gravis, ileus, aritmii ectopice prin hipoK+ -emie
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EFECTE ADVERSE Cresterea K+ -emiei – risc crescut la cei cu IR
hipoNa+ -emie – hTa
Ginecomastie – la doze mari,
Impotenta sexuala – la barbati
Amenoree, hirsutism – la femei
Tulburari digestive
Eruptii cutanate
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CONTRAINDICATII. INTERACTIUNI MEDICAMENTOASE Hiperpotasemie
IRA si IH grava
Prudenta – IRC, DZ,
Asocierea cu alte diuretice care economisesc K sau administrare de KCl – risc de hiperpotasemie
Asocierea cu IEC – controlul K-emiei
AINS – reduc efectul spironolactonei
Creste efectul antiHTA
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Eplerenona analog de spironolactonă
inhiba receptorii pentru aldosteron
biodisponibilitate crescută dupa administrare orală, T1/2=5 ore
metabolizare hepatica - CYP3A4
Indicatii
Similar cu spironolactona
HTA, IMA cu disfunctie ventriculara stanga
afinitate mai mică pentru receptorii androgenilor şi progesteronului
25-50 mg/zi
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AMILORID Efect diuretic asemanator spironolactonei
Efectul - apare la 2 ore, se mentine 24 ore
Actiune contrara aldosteronului – blocheaza
canalele de sodiu din membrana luminala a
celulelor la nivelul tubului contort distal si colector
T1/2=21 ore
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INDICATII Hiperaldosteronism secundar – in asociere cu
tiazida si furosemid
Sdr. Liddle – hiperreactivitate la aldosteron a epiteliului tubular
Fibroza chistica – aerosoli, amelioreaza clearance-ul mucociliar
Diabet insipid nefrogenic
produs de Li
Administrare – po 15-20 mg/zi
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TRIAMTEREN Compus pteridinic
Efect in 2 ore, durata 7-10 ore
Acelasi mecanism de actiune ca si pentru amilorid
Biodisponibilitate medie, T1/2=4,2 ore
Epurare prin metabolizare si eliminare urinara
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TRIAMTEREN Oral – 100 mgx3/zi, se poate creste pana la 600
mg/zi
Tratament de intretinere – 100 mgx2/zi, la 2 zile
Indicat in – ciroza cu ascita si edeme, sindrom
nefrotic
Combinatii cu tiazide
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DIURETICE OSMOTICE - MANITOL Polialcool, derivat de manoza
Mecanism osmotic – filtreaza glomerular si
ramane in urina unde retine echivalentul osmotic
de apa eliminarea unei cantitati
mari de apa
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MANITOL Indicatii
Prevenirea anuriei – postinterventii
chirurgicale, soc, arsuri - Iv 50-200 g in solutie
5-25%
Fazele precoce ale IRA – impiedica evolutia
ischemiei renale
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Mobilizeaza apa din tesuturi
Edem cerebral
Criza de glaucom acut congestiv – 1,5-2 g/kg in solutie 10-25% in 30-60 minute
Reactii adverse, contraindicatii
Supraincarcare circulatorie – HTA, EPA
CI – anurie, IC decompensata
Soc – completarea volumului plasmatic
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Rezistenta la tratamentul diuretic Administrarea indelungata a tiazidelor si
diureticelor de ansa
Autolimitarea efectului diuretic
Dezvoltarea unui hiperaldosteronism secundar
Cresterea compensatorie a reabsorbtiei Na
Asocierea cu diuretice antialdosteronice
Administrarea discontinua – pauza 1-2 zile
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Combinatii ale diureticelorDiuretice de ansa + tiazide
Raspuns inadecvat la tratamentul cu doze terapeutice
Efect sinergic
Locul de actiune – diferit
Tiazidele – efect minim si la nivelul tubului contort proximal (natriureza)
Metolazona, clorotiazida
Diureza importanta – monitorizarea atenta a echilibrului hidric si acido-bazic
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Combinatii ale diureticelorEconomisitoare de potasiu + tiazide / diuretice de
ansa
Pentru a evita hipopotasemia indusa de tiazide/diuretice de ansa
Evitare – la pacientii cu IRC (hiperpotasemie)
Combinatii fixe
Diurex (50 mg spironolactona + 20 mg furosemid)
Ecodurex (50 mg hidroclorotiazida + 5 mg
triamteren)
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Medicatia antidiuretica Tratamentul diabetului insipid
Diureza apoasa excesiva si polidipsie
Vasopresina, alti hormoni
Utilitate redusa – tiazide, carbamazepina, clofibrat
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Vasopresina Nanopeptida secretata de neurohipofiza
Hormon antidiuretic
Secretia – stimulata de hiperosmolaritate, hipovolemie
Efecte
Actiune la nivel renal - reabsorbtia apei si concentrarea urinei
PG – inhibitia actiunii renale
Vasoconstrictie generalizata – ischemie, HTA
Cresterea peristaltismului intestinal – ileus postoperator
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Vasopresina Actiune la nivelul
receptorilor V (V1 si V2)
Administare – iv
Inactivare rapida la nivel renal – T1/2 = 20 minute
Hipersecretie – stimularea sistemului hipotalamo-hipofizar, sinteza ectopica (cancer pulmonar)
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Vasopresina Utilizare terapeutica – preparate naturale (extract
de hipofiza de bovine si porcine) sau de sinteza
Diabet insipid central cu evolutie cronica – 1,5 – 5 U
Reactii adverse
injectarea la intervale mici – intoxicatia cu apa
dureri abdominale, greata, tenesme
HTA, fenomene ischemice
Contraindicatii – cardiopatie ischemica severa, infarct miocardic, aritmii
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Desmopresina Analog al vasopresinei
Efect antidiuretic
selectiv (afinitate mare pentru RV2)
Intens de durata lunga
Instilatie nazala, spray nazal
Oral – copii cu enurezis
Reactii adverse – cefalee, greata, crampe abdominale, congestie nazala
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Medicamente care influenteaza pH-ul urinar Medicamente care cresc pH-ul urinar
Inhibitorii de anhidraza carbonica – alcalinizarea urinii (inhiba reabsorbtia bicarbonatului)
Citrat de sodiu si potasiu – transformare in ciclul Krebs, cu formare de bicarbonati
Eliminarea unor medicamente slab acide – sulfamide, sulfasalazina, salicilati, barbiturice
Inhiba formarea calculilor urinari
Bicarbonatul de sodiu – intoxicatia acuta cu salicilati