1、Diuretics Yanna Wu Ph.D.,M.D.Associate ProfessorDepartment of PharmacologySchool of Basic MedicineTianjin Medical UniversityEmail:1introductionuDiuretics uact on renal tubules,promote the production ofurine uare used to treat edema and unedema diseases(hypertension,heart failure,renal failure,and ci
2、rrhosis)2glomerulus Proximal convoluted tubule Distal convoluted tubule collecting duct Loop of HenleThick ascending limbThin descending limbfiltrationsecretionexcretionreabsorptionPhysiology of KidneysProcess of urine formation180 L filtrate1-2 L final urine99%nephronrenal corpuscle 3Reabsorption o
3、f tubules and collecting tubesuProximal convoluted tubules uNaHCO3(Na+,HCO3-)are reabsorbed uepithelium is permeable to ions and water,and permit passive flow in either direction-Na+reabsorption is accompanied by passive absorption of wateruCarbonic anhydrase inhibitors(acetazolamide)reduce Na+-H+ex
4、change,in turn,sodium reabsorption is decreased 4interstitial fluidproximal tubule epithelial cell tubular lumen 1234567Carbonic anhydrase inhibitors(acetazolamide)Na+-K+-ATPaseNa+-H+-exchangerCarbonic anhydrasediffuses Na+-HCO3-symporterbasolateral membraneapical membranebicarbonateCarbonic acidCar
5、bon dioxide5Reabsorption of tubules and collecting tubesuthick ascending limb of Henles Loop uNa+/K+/2Cl-cotransport system uwater is impermeable at this segment,tubular fluid is hypotonic with respect to plasma as it enters the distal convoluted tubule(diluted)uinhibitors of Na+/K+/2Cl-symporter bl
6、ock its function,increase excretion of Na+,K+,Cl-,Mg2+,Ca2+612453apical membraneBasolateral membrane Na+/K+/2Cl-cotransport system lumen-positive electrical potential H2OdilutedLoop diuretics(furosemide)Na+-K+-ATPaseinterstitial fluid dilution function and concentration functionuIn the thick ascendi
7、ng limb,large amount of ions are reabsorbed,but water is impermeable at this segment,as a result,the tubular fluid becomes dilutedilution functionuAt the same time,the reabsorption of ions at this limb produces a hypertonic renal medulla.When the urine pass through the collecting duct,the hypertonic
8、 interstitial fluid sucks water out of the tubules,thereby the tubular fluid becomes concentrationconcentration function8Reabsorption of tubules and collecting tubesuDistal convoluted tubuleuNa+/Cl-symporteruboth parathormone and calcitriol increase Ca2+reabsorption ufurther diluteduthis segment is
9、in the cortical part,the hypertonic state of renal medulla is not affected 9Cl-thiazidesapical membraneBasolateral membraneinterstitial fluid H2OdilutedParathormonecalcitriolNa+/Cl-symporter10Reabsorption of tubules and collecting tubesulate distal tubules and collecting tubules uNa+/K+exchange urea
10、bsorption of Na+and its coupled secretion of K+is regulated by aldosterone uabsorption of water is regulated by antidiuretic hormone(ADH)uPromotes collecting tubules permeable to waterumodulates the concentration of final urine11spironolactoneTriamtereneamiloridelumen-negative electrical potential u
11、all these agents are K+-sparing diuretics12Classification of Diuretics uHigh efficacy diureticsuModerate efficacy diuretics uLow efficacy diuretics13Classification of Diuretics uHigh efficacy diureticsuModerate efficacy diuretics uLow efficacy diuretics14High efficacy diuretics uFurosemide,bumetanid
12、e,ethacrynic acid uhave their major action on the ascending limb of the loop of Henle loop diuretics15Pharmacokineticsuabsorbed rapidly by oral administration.Bioavailability is 50-70%.uIf given iv,the effects of furosemide response within 5 mins,duration time 2-3 hrs.u50-60 L of urine excretion wit
13、hin 24 hours after using large doses of furosemide.uProtein binding rate is 95%.ut1/2 1 hr,which may be prolonged to 10 hr in renal dysfunction.16Mechanism of actionuinhibit the Na+/K+/2Cl-cotransporter in the thick ascending limb of the loop of Henle ureabsorption of Na+,Cl-,Ca2+and Mg2+are decreas
14、edusecretion of K+is increaseduthe most efficacious of the diuretic drugs uthe ascending limb accounts for the reabsorption of 25%-30%of filtered NaCludownstream sites are not able to compensate for this increased Na+load 1712453apical membraneBasolateral membrane Na+/K+/2Cl-cotransport system lumen
15、-positive electrical potential H2OdilutedLoop diuretics(furosemide)Na+-K+-ATPaseinterstitial fluid Pharmacological effectsuDiuretic activity uDiuretic activity is rapid,strong and shortuLarge amounts of Na+,Cl-,K+,Ca2+and Mg2+are excreted and Cl-loss is more than Na+in urine Relative changes in the
16、composition of urine induced by loop diuretics19Pharmacological effectsuDecrease renal vascular resistance,increase renal blood flow uredistribution of blood flow within the renal cortex uIncrease renin release ularge volume depletion reflexly activate the sympathetic nervous system and stimulate th
17、e intrarenal baroreceptor mechanism uinduces renal prostaglandins synthesis in the kidney 20Pharmacological effectsuRelieve pulmonary congestion and reduce left ventricular filling pressures uincrease systemic venous capacitance in congestive heart failure patient uInhibit electrolyte transport in i
18、nner ear ualternate the electrolyte composition of endolymph,contribute to drug induced ototoxity 21Clinical Usesuemergency situationsuacute pulmonary edema and brain edemaubumetanide or furosemide is first choice uSerious edema uedema of nephrotic syndrome,nephrosis;ascites of liver cirrhosis uedem
19、a patients who do not respond to salt restrictions or thiazidesuChronic congestive heart failure to minimize venous and pulmonary congestion22Clinical UsesuHyperkalemia uAcute or chronic renal failure uincrease the rates of urine flow and enhance K+excretion in acute renal failureuconvert oliguric r
20、enal failure to nonoliguric failureuAcute hypercalcemia uHypertension crisis uDetoxication 23Side effectsuElectrolyte disturbanceuhypokalemia,hyponatremia,hypomagnesemia,hypochloremic metabolic alkalosisuinduce cardiac arrhythmias upotassium-sparing diuretics or dietary supplementation with potassiu
21、m uOtotoxicity uhearing loss or deafness which can be potentiated by renal dysfunction or combined with another ototoxic drugs(eg,aminoglycoside antibiotics)24Side effectsuHyperuricemia uhypovolemia-associated enhancement of uric acid reabsorption in the proximal tubule uOthersuHyperglycemiauincreas
22、e LDL-C and decrease HDL-C in plasma 25Interactionufirst or second generation of cephalosporins potentiates ototoxicity of loop diuetics uNSAIDs reduce Na+excretion by inhibiting PGs synthesis in the kidneyuwarfarin is capable of competitive binding plasma protein with loop diuretics26Classification
23、 of Diuretics uHigh efficacy diuretics(loop diuretics)uModerate efficacy diuretics uLow efficacy diuretics27Moderate efficacy diureticsuclassification uthiazidesuHydrochlorothiazideuChlorothiazideuCyclopenthiazide uthiazide-like diureticsuChlorthalidone uthe most widely used diuretic drugs uaffect t
24、he distal tubule 28Pharmacokinetics uAll thiazides are absorbed when given orallyuThey are excreted unchanged in the urine and are not effective when renal function is severely impaired uHydrochlorothiazideuIts renal excretion competes with uric acid29Mechanism of actionuact mainly in the distal tub
25、ule to decrease the reabsorption of Na+by inhibition of Na+/Cl-cotransporter on the luminal membrane uincrease the concentration of Na+and Cl-in the tubule fluid uacid-base balance is not usually affected 30Cl-thiazidesapical membraneBasolateral membraneinterstitial fluid H2OdilutedParathormonecalci
26、triolNa+/Cl-symporter31Pharmacological effectsuDiuretic activityu10%of filtered sodium is excreted uPromote potassium excretion uincrease the Na+in the filtrate arriving at the distal tubule umore potassium is exchanged for sodium uEnhance Ca2+reabsorption udecrease Ca2+excretion from urine in the d
27、istal convoluted tubule32Pharmacological effectsRelative changes in the composition of urine induced by thiazide diuretics33Pharmacological effectsuHypotensive effect uinitial hypotensive effectsudecrease in blood volume and therefore a decrease in cardiac output ucontinued hypotensive effectsuNa+ex
28、cretion-intercellular Na+concentration-Na+/Ca2+exchange-intercellular Ca2+concentration-sensitivity of blood vessel response to NA-reduced peripheral vascular resistance caused by relaxation of arteriolar smooth muscle 34Clinical UsesuEdemaumild and moderate cardiac edema(CHF)uHypertensionueither us
29、es alone or in combination with other antihypertensive drugs uNephrolithiasis due to idiopathic hypercalciuria;osteoporosisudecrease Ca2+in tubular fluiduincrease Ca2+in plasma35Clinical UsesuDiabetes insipidusuUsed for the palliation of nephrogenic and pituitary diabetes insipidus.uTypical symptoms
30、:polydipsia and polyuria umechanismphosphodiesterase cAMP ADH action the secretion of NaCl plasma osmotic pressure less thirsty and desire to drink water 36Side effectsuElectrolyte disturbancesuhypokalemia,magnesium deficiency uHyperuricemia and induced gout uincreases absorption of uric acid and co
31、mpetes for the transport mechanism with uric aciduHyperglycemia and hyperlipidemia udecrease glucose tolerance,reduce insulin secretion and glucose utilization,aggravates preexisting diabetesuincreases plasma concentrations of LDL-cholesterol,triglyeride and total cholesterol37Side effectsuHypovolem
32、ia uover treatment,acute loss of excessive fluid leads to postural hypotension and dizzinessuOthersuphotosensitive,thrombocytopenia,agranulocytosis uThiazides binding with quinidine can lead to polymorphic ventricular tachycardia38Classification of Diuretics uHigh efficacy diuretics(loop diuretics)u
33、Moderate efficacy diuretics uLow efficacy diuretics(K+-sparing diuretics)39Low efficacy diureticsuact in the late distal tubules and collecting tubule to inhibit Na+reabsorption and K+secretionuThese drugs reduce potassium secretion,so term as K+retention diuretics or K+sparing diuretics uHigh effic
34、acy and moderate efficacy diuretics increase K+excretion,so term as K+lossing diureticsuMajor use is in combination with other diuretics to reduce sodium reabsorption and prevent potassium loss in the tubule.40SpironolactoneuMechanism of actionualdosterone regulate Na+reabsorption and K+secretion at
35、 late distal tubules and collecting ductuSpironolactone is a competitive antagonist to aldosteroneubind with cytoplasmic aldosterone receptorsupromotes Na+excretionublunt the K+secretion4142lumenapical membraneinterstitial fluid Collecting tubuleBasolateral membraneAIP:aldosterone-induced protein;SP
36、:spironolactone;ALD:aldosteroneTriamtereneamiloridespironolactonealdosterone42SpironolactoneuPharmacological effectsuless than 2-3%of the filtered sodium is excreted ueffective only in the increasing status of aldosterone and ineffective for total adrenoprival animal uthe higher the level of endogen
37、ous aldosterone,the greater the effects of spironolactone on urinary excretion 43Relative changes in the composition of urine induced by potassium-sparing diuretics44SpironolactoneuClinical UsesuEdema of primary hyperaldosteronism and refractory edema associated with secondary aldosteronism(cardiac
38、failure,hepatic cirrhosis,nephrotic syndrome,and severe ascites)uin combination with other diuretics to reduce sodium reabsorption and prevent potassium loss in the tubuleuinhibits renal excretion of digoxin,the dosages of digoxin need to be reduced if both drugs combined use45Triamterene and amilor
39、ide uPharmacological effectsudirectly block sodium ion channels in the late distal tubules and clollecing duct,inhibit Na+reabsorption and promote its excretion udo not block the aldosterone receptorustill effective for total adrenoprival animaluThe major use is in combination with other diuretics46
40、47lumenapical membraneinterstitial fluid Collecting tubuleBasolateral membraneAIP:aldosterone-induced protein;SP:spironolactone;ALD:aldosteroneTriamtereneamiloridespironolactonealdosterone474848Carbonic anhydraseOsmotic diuretics(mannitol,sorbitol,glucose,urea)49Osmotic diureticsuMechanism of action
41、uincrease the osmotic pressure of blood and renal filtrate uThe agents are filtered by the glomerulus,but are not reabsorbed or secreted by the renal tubulesuwork by expanding plasma volume,therefore increasing blood flow to thekidney uprevent the reabsorption of water at the segment of proximal tub
42、ule and desending limb of loop of Henle50Osmotic diureticsuPharmacodynamics and IndicationsuDehydrationureduction of intracranial and intraocular pressureuBrain edema,glaucomauDilate renal vascular,increase renal blood flow within the renal medulla,increase urine volumeuPrevent acute renal failureuE
43、liminate toxic substances from GI tract or promote removal of renal toxins51Osmotic diureticsuSide effectsuHyperkalemiaucontraindicated in upatients with hyperkalemia upatients at increased risk of developing hyperkalemiaupatients with renal failureupatients receiving other K+-sparing diuretics or taking angiotensin-converting enzyme inhibitors,or taking supplements K+52
