1、Diuretics,Yanna Wu Ph.D., M.D. Associate Professor Department of Pharmacology School of Basic Medicine Tianjin Medical University Email: ,1,introduction,Diuretics act on renal tubules, promote the production of urine are used to treat edema and unedema diseases (hypertension, heart failure, renal fa
2、ilure, and cirrhosis),2,Physiology of Kidneys,Process of urine formation,180 L filtrate,1-2 L final urine,99%,nephron,renal corpuscle,3,Reabsorption of tubules and collecting tubes,Proximal convoluted tubules NaHCO3 (Na+, HCO3-) are reabsorbed epithelium is permeable to ions and water, and permit pa
3、ssive flow in either direction - Na+ reabsorption is accompanied by passive absorption of water Carbonic anhydrase inhibitors (acetazolamide) reduce Na+-H+ exchange, in turn, sodium reabsorption is decreased,4,Na+-K+-ATPase,Na+-H+-exchanger,Carbonic anhydrase,diffuses,Na+-HCO3- symporter,basolateral
4、 membrane,apical membrane,bicarbonate,Carbonic acid,Carbon dioxide,5,Reabsorption of tubules and collecting tubes,thick ascending limb of Henles Loop Na+/K+/2Cl- cotransport system water is impermeable at this segment, tubular fluid is hypotonic with respect to plasma as it enters the distal convolu
5、ted tubule (diluted) inhibitors of Na+/K+/2Cl- symporter block its function, increase excretion of Na+, K+, Cl-, Mg2+, Ca2+,6,apical membrane,Basolateral membrane,Na+/K+/2Cl- cotransport system,lumen-positive electrical potential,Na+-K+-ATPase,interstitial fluid,7,dilution function and concentration
6、 function,In the thick ascending limb, large amount of ions are reabsorbed, but water is impermeable at this segment, as a result, the tubular fluid becomes dilutedilution function At the same time, the reabsorption of ions at this limb produces a hypertonic renal medulla. When the urine pass throug
7、h the collecting duct, the hypertonic interstitial fluid sucks water out of the tubules, thereby the tubular fluid becomes concentrationconcentration function,8,Reabsorption of tubules and collecting tubes,Distal convoluted tubule Na+/Cl- symporter both parathormone and calcitriol increase Ca2+ reab
8、sorption further diluted this segment is in the cortical part, the hypertonic state of renal medulla is not affected,9,Cl-,apical membrane,Basolateral membrane,interstitial fluid,Parathormone calcitriol,Na+/Cl- symporter,10,Reabsorption of tubules and collecting tubes,late distal tubules and collect
9、ing tubules 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 water modulates the concentration of final urine,11,lumen-negative electrical potential,
10、all these agents are K+-sparing diuretics,12,Classification of Diuretics,High efficacy diuretics Moderate efficacy diuretics Low efficacy diuretics,13,Classification of Diuretics,High efficacy diuretics Moderate efficacy diuretics Low efficacy diuretics,14,High efficacy diuretics,Furosemide, bumetan
11、ide, ethacrynic acid have their major action on the ascending limb of the loop of Henle loop diuretics,15,Pharmacokinetics,absorbed rapidly by oral administration. Bioavailability is 50-70%. If given iv, the effects of furosemide response within 5 mins, duration time 2-3 hrs. 50-60 L of urine excret
12、ion within 24 hours after using large doses of furosemide. Protein binding rate is 95%. t1/2 1 hr, which may be prolonged to 10 hr in renal dysfunction.,16,Mechanism of action,inhibit the Na+/K+/2Cl- cotransporter in the thick ascending limb of the loop of Henle reabsorption of Na+, Cl-, Ca2+ and Mg
13、2+ are decreased secretion of K+ is increased the most efficacious of the diuretic drugs the ascending limb accounts for the reabsorption of 25%-30% of filtered NaCl downstream sites are not able to compensate for this increased Na+ load,17,apical membrane,Basolateral membrane,Na+/K+/2Cl- cotranspor
14、t system,lumen-positive electrical potential,Na+-K+-ATPase,interstitial fluid,18,Pharmacological effects,Diuretic activity Diuretic activity is rapid, strong and short Large amounts of Na+, Cl-, K+, Ca2+ and Mg2+ are excreted and Cl- loss is more than Na+ in urine,Relative changes in the composition
15、 of urine induced by loop diuretics,19,Pharmacological effects,Decrease renal vascular resistance, increase renal blood flow redistribution of blood flow within the renal cortex Increase renin release large volume depletion reflexly activate the sympathetic nervous system and stimulate the intrarena
16、l baroreceptor mechanism induces renal prostaglandins synthesis in the kidney,20,Pharmacological effects,Relieve pulmonary congestion and reduce left ventricular filling pressures increase systemic venous capacitance in congestive heart failure patient Inhibit electrolyte transport in inner ear alte
17、rnate the electrolyte composition of endolymph, contribute to drug induced ototoxity,21,Clinical Uses,emergency situations acute pulmonary edema and brain edema bumetanide or furosemide is first choice Serious edema edema of nephrotic syndrome, nephrosis; ascites of liver cirrhosis edema patients wh
18、o do not respond to salt restrictions or thiazides Chronic congestive heart failure to minimize venous and pulmonary congestion,22,Clinical Uses,Hyperkalemia Acute or chronic renal failure increase the rates of urine flow and enhance K+ excretion in acute renal failure convert oliguric renal failure
19、 to nonoliguric failure Acute hypercalcemia Hypertension crisis Detoxication,23,Side effects,Electrolyte disturbance hypokalemia, hyponatremia, hypomagnesemia, hypochloremic metabolic alkalosis induce cardiac arrhythmias potassium-sparing diuretics or dietary supplementation with potassium Ototoxici
20、ty hearing loss or deafness which can be potentiated by renal dysfunction or combined with another ototoxic drugs (eg, aminoglycoside antibiotics),24,Side effects,Hyperuricemia hypovolemia-associated enhancement of uric acid reabsorption in the proximal tubule Others Hyperglycemia increase LDL-C and
21、 decrease HDL-C in plasma,25,Interaction,first or second generation of cephalosporins potentiates ototoxicity of loop diuetics NSAIDs reduce Na+ excretion by inhibiting PGs synthesis in the kidney warfarin is capable of competitive binding plasma protein with loop diuretics,26,Classification of Diur
22、etics,High efficacy diuretics (loop diuretics) Moderate efficacy diuretics Low efficacy diuretics,27,Moderate efficacy diuretics,classification thiazides Hydrochlorothiazide Chlorothiazide Cyclopenthiazide thiazide-like diuretics Chlorthalidone the most widely used diuretic drugs affect the distal t
23、ubule,28,Pharmacokinetics,All thiazides are absorbed when given orally They are excreted unchanged in the urine and are not effective when renal function is severely impaired Hydrochlorothiazide Its renal excretion competes with uric acid,29,Mechanism of action,act mainly in the distal tubule to dec
24、rease the reabsorption of Na+ by inhibition 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,30,Cl-,apical membrane,Basolateral membrane,interstitial fluid,Parathormone calcitriol,Na+/Cl- symporte
25、r,31,Pharmacological effects,Diuretic activity 10% 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 tu
26、bule,32,Pharmacological effects,Relative changes in the composition of urine induced by thiazide diuretics,33,Pharmacological effects,Hypotensive effect initial hypotensive effects decrease in blood volume and therefore a decrease in cardiac output continued hypotensive effects Na+ excretion - inter
27、cellular 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,34,Clinical Uses,Edema mild and moderate cardiac edema (CHF) Hypertension either us
28、es alone or in combination with other antihypertensive drugs Nephrolithiasis due to idiopathic hypercalciuria; osteoporosis decrease Ca2+ in tubular fluid increase Ca2+ in plasma,35,Clinical Uses,Diabetes insipidus Used for the palliation of nephrogenic and pituitary diabetes insipidus. Typical symp
29、toms: polydipsia and polyuria mechanism,36,Side effects,Electrolyte disturbances hypokalemia, magnesium deficiency Hyperuricemia and induced gout increases absorption of uric acid and competes for the transport mechanism with uric acid Hyperglycemia and hyperlipidemia decrease glucose tolerance, red
30、uce insulin secretion and glucose utilization, aggravates preexisting diabetes increases plasma concentrations of LDL-cholesterol, triglyeride and total cholesterol,37,Side effects,Hypovolemia over treatment, acute loss of excessive fluid leads to postural hypotension and dizziness Others photosensi
31、tive, thrombocytopenia, agranulocytosis Thiazides binding with quinidine can lead to polymorphic ventricular tachycardia,38,Classification of Diuretics,High efficacy diuretics (loop diuretics) Moderate efficacy diuretics Low efficacy diuretics (K+-sparing diuretics),39,Low efficacy diuretics,act in
32、the late distal tubules and collecting tubule to inhibit Na+ reabsorption and K+ secretion These drugs reduce potassium secretion, so term as K+ retention diuretics or K+ sparing diuretics High efficacy and moderate efficacy diuretics increase K+ excretion, so term as K+ lossing diuretics Major use
33、is in combination with other diuretics to reduce sodium reabsorption and prevent potassium loss in the tubule.,40,Spironolactone,Mechanism of action aldosterone regulate Na+ reabsorption and K+ secretion at late distal tubules and collecting duct Spironolactone is a competitive antagonist to aldoste
34、rone bind with cytoplasmic aldosterone receptors promotes Na+ excretion blunt the K+ secretion,41,42,lumen,apical membrane,interstitial fluid,Collecting tubule,Basolateral membrane,AIP: aldosterone-induced protein; SP: spironolactone; ALD: aldosterone,Triamterene amiloride,spironolactone,aldosterone
35、,42,Spironolactone,Pharmacological effects less 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 spironolactone on urinary excre
36、tion,43,Relative changes in the composition of urine induced by potassium-sparing diuretics,44,Spironolactone,Clinical Uses Edema of primary hyperaldosteronism and refractory edema associated with secondary aldosteronism (cardiac failure, hepatic cirrhosis , nephrotic syndrome, and severe ascites )
37、in combination with other diuretics to reduce sodium reabsorption and prevent potassium loss in the tubule inhibits renal excretion of digoxin, the dosages of digoxin need to be reduced if both drugs combined use,45,Triamterene and amiloride,Pharmacological effects directly block sodium ion channels
38、 in the late distal tubules and clollecing duct, inhibit Na+ reabsorption and promote its excretion do not block the aldosterone receptor still effective for total adrenoprival animal The major use is in combination with other diuretics,46,47,lumen,apical membrane,interstitial fluid,Collecting tubul
39、e,Basolateral membrane,AIP: aldosterone-induced protein; SP: spironolactone; ALD: aldosterone,Triamterene amiloride,spironolactone,aldosterone,47,48,48,Carbonic anhydrase,Osmotic diuretics,(mannitol, sorbitol, glucose, urea),49,Osmotic diuretics,Mechanism of action increase the osmotic pressure of b
40、lood and renal filtrate The agents are filtered by the glomerulus, but are not reabsorbed or secreted by the renal tubules work by expanding plasma volume, therefore increasing blood flow to the kidney prevent the reabsorption of water at the segment of proximal tubule and desending limb of loop of
41、Henle,50,Osmotic diuretics,Pharmacodynamics and Indications Dehydration reduction of intracranial and intraocular pressure Brain edema, glaucoma Dilate renal vascular, increase renal blood flow within the renal medulla, increase urine volume Prevent acute renal failure Eliminate toxic substances fro
42、m GI tract or promote removal of renal toxins,51,Osmotic diuretics,Side effects Hyperkalemia contraindicated in patients with hyperkalemia patients at increased risk of developing hyperkalemia patients with renal failure patients receiving other K+-sparing diuretics or taking angiotensin-converting enzyme inhibitors, or taking supplements K+,52,
