利尿劑英文課件

1、Diuretics Yanna Wu Ph.D., M.D.Associate ProfessorDepartment of PharmacologySchool of Basic MedicineTianjin Medical UniversityEmail: 1introductionDiuretics act on renal tubules, promote the production ofurine are used to treat edema and unedema diseases (hypertension, heart failure, renal failure, an

2、d cirrhosis)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 3Reabsorpti

3、on of tubules and collecting tubesProximal convoluted tubules NaHCO3 (Na+, HCO3-) are reabsorbed epithelium is permeable to ions and water, and permit passive flow in either direction - Na+ reabsorption is accompanied by passive absorption of waterCarbonic anhydrase inhibitors (acetazolamide) reduce

4、 Na+-H+ exchange, 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 membranebicarbonateC

5、arbonic acidCarbon dioxide512453apical membraneBasolateral membrane Na+/K+/2Cl- cotransport system lumen-positive electrical potential H2OdilutedLoop diuretics (furosemide)Na+-K+-ATPaseinterstitial fluid 7dilution function and concentration functionIn the thick ascending limb, large amount of ions a

6、re reabsorbed, but water is impermeable at this segment, as a result, the tubular fluid becomes dilutedilution functionAt 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 interstitial fluid sucks

7、 water out of the tubules, thereby the tubular fluid becomes concentrationconcentration function8Cl-thiazidesapical membraneBasolateral membraneinterstitial fluid H2OdilutedParathormonecalcitriolNa+/Cl- symporter10Reabsorption of tubules and collecting tubeslate distal tubules and collecting tubules

8、 Na+/K+ exchange reabsorption of Na+ and its coupled secretion of K+ is regulated by aldosterone absorption of water is regulated by antidiuretic hormone (ADH)Promotes collecting tubules permeable to watermodulates the concentration of final urine11spironolactoneTriamtereneamiloridelumen-negative el

9、ectrical potential all these agents are K+-sparing diuretics12Classification of Diuretics High efficacy diureticsModerate efficacy diuretics Low efficacy diuretics14High efficacy diuretics Furosemide, bumetanide, ethacrynic acid have their major action on the ascending limb of the loop of Henle loop

10、 diuretics15Mechanism of actioninhibit the Na+/K+/2Cl- cotransporter in the thick ascending limb of the loop of Henle reabsorption of Na+, Cl-, Ca2+ and Mg2+ are decreasedsecretion of K+ is increasedthe most efficacious of the diuretic drugs the ascending limb accounts for the reabsorption of 25%-30

11、% of filtered NaCldownstream sites are not able to compensate for this increased Na+ load 1712453apical membraneBasolateral membrane Na+/K+/2Cl- cotransport system lumen-positive electrical potential H2OdilutedLoop diuretics (furosemide)Na+-K+-ATPaseinterstitial fluid 18Pharmacological effectsDiuret

12、ic activity Diuretic activity is rapid, strong and shortLarge amounts of Na+, Cl-, K+, Ca2+ and Mg2+ are excreted and Cl- loss is more than Na+ in urine Relative changes in the composition of urine induced by loop diuretics19Pharmacological effectsDecrease renal vascular resistance, increase renal b

13、lood flow redistribution of blood flow within the renal cortex Increase renin release large volume depletion reflexly activate the sympathetic nervous system and stimulate the intrarenal baroreceptor mechanism induces renal prostaglandins synthesis in the kidney 20Pharmacological effectsRelieve pulm

14、onary congestion and reduce left ventricular filling pressures increase systemic venous capacitance in congestive heart failure patient Inhibit electrolyte transport in inner ear alternate the electrolyte composition of endolymph, contribute to drug induced ototoxity 21Clinical Usesemergency situati

15、onsacute pulmonary edema and brain edemabumetanide or furosemide is first choice Serious edema edema of nephrotic syndrome, nephrosis; ascites of liver cirrhosis edema patients who do not respond to salt restrictions or thiazidesChronic congestive heart failure to minimize venous and pulmonary conge

16、stion22Side effectsElectrolyte disturbancehypokalemia, hyponatremia, hypomagnesemia, hypochloremic metabolic alkalosisinduce cardiac arrhythmias potassium-sparing diuretics or dietary supplementation with potassium Ototoxicity hearing loss or deafness which can be potentiated by renal dysfunction or

17、 combined with another ototoxic drugs (eg, aminoglycoside antibiotics)24Side effectsHyperuricemia hypovolemia-associated enhancement of uric acid reabsorption in the proximal tubule OthersHyperglycemiaincrease LDL-C and decrease HDL-C in plasma 25Classification of Diuretics High efficacy diuretics (

18、loop diuretics) Moderate efficacy diuretics Low efficacy diuretics27Moderate efficacy diureticsclassification thiazidesHydrochlorothiazideChlorothiazideCyclopenthiazide thiazide-like diureticsChlorthalidone the most widely used diuretic drugs affect the distal tubule 28Pharmacokinetics All thiazides

19、 are absorbed when given orallyThey are excreted unchanged in the urine and are not effective when renal function is severely impaired HydrochlorothiazideIts renal excretion competes with uric acid29Mechanism of actionact mainly in the distal tubule to decrease the reabsorption of Na+ by inhibition

20、of Na+/Cl- cotransporter on the luminal membrane increase the concentration of Na+ and Cl- in the tubule fluid acid-base balance is not usually affected 30Cl-thiazidesapical membraneBasolateral membraneinterstitial fluid H2OdilutedParathormonecalcitriolNa+/Cl- symporter31Pharmacological effectsDiure

21、tic activity10% of filtered sodium is excreted Promote potassium excretion increase the Na+ in the filtrate arriving at the distal tubule more potassium is exchanged for sodium Enhance Ca2+ reabsorption decrease Ca2+ excretion from urine in the distal convoluted tubule32Pharmacological effectsRelati

22、ve changes in the composition of urine induced by thiazide diuretics33Pharmacological effectsHypotensive effect initial hypotensive effectsdecrease in blood volume and therefore a decrease in cardiac output continued hypotensive effectsNa+ excretion - intercellular Na+ concentration - Na+/Ca2+ excha

23、nge - intercellular Ca2+ concentration - sensitivity of blood vessel response to NA - reduced peripheral vascular resistance caused by relaxation of arteriolar smooth muscle 34Clinical UsesEdemamild and moderate cardiac edema (CHF) Hypertensioneither uses alone or in combination with other antihyper

24、tensive drugs Nephrolithiasis due to idiopathic hypercalciuria; osteoporosisdecrease Ca2+ in tubular fluidincrease Ca2+ in plasma35Clinical UsesDiabetes insipidusUsed for the palliation of nephrogenic and pituitary diabetes insipidus. Typical symptoms: polydipsia and polyuria mechanismphosphodiester

25、ase cAMP ADH action the secretion of NaCl plasma osmotic pressure less thirsty and desire to drink water 36Side effectsElectrolyte disturbanceshypokalemia, magnesium deficiency Hyperuricemia and induced gout increases absorption of uric acid and competes for the transport mechanism with uric acidHyp

26、erglycemia and hyperlipidemia decrease glucose tolerance, reduce insulin secretion and glucose utilization, aggravates preexisting diabetesincreases plasma concentrations of LDL-cholesterol, triglyeride and total cholesterol37Side effectsHypovolemia over treatment, acute loss of excessive fluid lead

27、s to postural hypotension and dizzinessOthersphotosensitive, thrombocytopenia, agranulocytosis Thiazides binding with quinidine can lead to polymorphic ventricular tachycardia38Classification of Diuretics High efficacy diuretics (loop diuretics) Moderate efficacy diuretics Low efficacy diuretics (K+

28、-sparing diuretics)39Low efficacy diureticsact in the late distal tubules and collecting tubule to inhibit Na+ reabsorption and K+ secretionThese drugs reduce potassium secretion, so term as K+ retention diuretics or K+ sparing diuretics High efficacy and moderate efficacy diuretics increase K+ excr

29、etion, so term as K+ lossing diureticsMajor use is in combination with other diuretics to reduce sodium reabsorption and prevent potassium loss in the tubule.40SpironolactoneMechanism of actionaldosterone regulate Na+ reabsorption and K+ secretion at late distal tubules and collecting ductSpironolac

30、tone is a competitive antagonist to aldosteronebind with cytoplasmic aldosterone receptorspromotes Na+ excretionblunt the K+ secretion4142lumenapical membraneinterstitial fluid Collecting tubuleBasolateral membraneAIP: aldosterone-induced protein; SP: spironolactone;ALD: aldosteroneTriamtereneamilor

31、idespironolactonealdosterone42SpironolactonePharmacological effectsless than 2-3% of the filtered sodium is excreted effective only in the increasing status of aldosterone and ineffective for total adrenoprival animal the higher the level of endogenous aldosterone, the greater the effects of spirono

32、lactone on urinary excretion 43Relative changes in the composition of urine induced by potassium-sparing diuretics44SpironolactoneClinical UsesEdema of primary hyperaldosteronism and refractory edema associated with secondary aldosteronism (cardiac failure, hepatic cirrhosis , nephrotic syndrome, an

33、d severe ascites )in combination with other diuretics to reduce sodium reabsorption and prevent potassium loss in the tubuleinhibits renal excretion of digoxin, the dosages of digoxin need to be reduced if both drugs combined use45Triamterene and amiloride Pharmacological effectsdirectly block sodiu

34、m ion channels in the late distal tubules and clollecing duct, inhibit Na+ reabsorption and promote its excretion do not block the aldosterone receptorstill effective for total adrenoprival animalThe major use is in combination with other diuretics4647lumenapical membraneinterstitial fluid Collecting tubuleBasolateral membraneAIP: aldosterone-induced protein; SP: spironolac