內(nèi)容說明講稿mbbs-diuretics

1、Department of PharmacologyZhongShan Medical collegeSun Yat-sen UniversityDiureticsMingming Ma馬明明 The concept of diureticsDiuretics are drugs that increase the rate of urine flowClinically useful diuretics also increase the rate of excretion of Na+ (natriuresis) and of an panying anion, usually Cl-An

2、 aquaretic causes an increase excretion of solute-free waterBecause natriuretics almost always increase water excretion, they are usually called diuretics.Formation of urineUltrafiltrate 120ml/min (180L/d)Urine 1 ml/min (1-2L/d) 99% ultrafiltrate is reabsorbednephronBasic unitEfficiency of Na+ excre

3、tion (H, I, L)Mechanism and targetsK+-sparing or notClassification of diureticsCarbonic anhydrase inhibitors (L)Osmotic diureticsLoop diuretics (H)Thiazides / Thiazides-like diuretics (I)Aldosterone antagonists (L)Antidiuretic hormone (ADH) antagonists65% NaSixtypesCarbonic anhydrase inhibitors Carb

4、onic anhydrase inhibitorsCarbonic anhydrase inhibitorsProximal convoluted tubule (PCT)Na+/H+ exchanger (NHE3)Carbonic anhydrase (CA)Na+-K+-ATPaseUrinary excretion of HCO3-, K+ and water Carbonic anhydrase inhibitorsAcetazolamide 乙酰唑胺 a: reduce aqueous humor formation and decrease the intraocular pre

5、ssure Acute mountain sickness: decrease cerebrospinal fluid formation and the pH of the cerebrospinal fluid and brainUrinary alkalinization: prevent uric acid and cystine calculi, but can lead to calcium and phosphoric stone formationMetabolic alkalosis: especially useful in correcting the alkalosis

6、 which is due to excessive use of diuretics in patients with severe heart failure【Therapeutic Uses 】Carbonic anhydrase inhibitorsHyperchloremic metabolic acidosis: chronic reduction of body HCO3- stores by CA inhibitors Renal stones: phosphaturia and hypercalciuriaRenal potassium wasting: the increa

7、sed Na+ presented to the collecting tubule is partially reabsorbed, enhancing K+ secretionOther toxicities: nervous system toxicity (drowsiness, paresthesias), hypersensitivity reactions (fever, rashes, bone marrow suppression, and interstitial nephritis)【Toxicity 】LowOsmoticHighOsmoticOsmotic diure

8、ticsCarbonic anhydrase inhibitors【Clinical uses】Increase urine volume: increase water excretion in preference to sodium excretionReduction of intracranial and intraocular pressure【Toxicity】Extracellular volume expansion: due to increase in extracellular osmotic pressure Dehydration, hyperkalemia, an

9、d hypernatremia: excessive use of manitol without water replacementHyponatremia: in patients with severe renal impairmentOsmotic diuretics Mannitol 甘露醇, sorbitol 山梨醇, glucose 葡萄糖 (iv. not po.)25% NaSixtypesLoop diureticsCarbonic anhydrase inhibitorsLoop diureticsThick ascending limb (TAL)Na+/K+/2Cl-

10、 cotransporter (NKCC2, NK2Cl)Na+-K+-ATPaseUrinary excretion of Na+ , K+ , Cl-, water, Mg2+ 【Pharmacokinetics】 The loop diuretics are rapidly absorbed and eliminated by the kidney by glomerular filtration and tubular secretion.Plasma protein binding rate is 95%, their diuretic activity correlates wit

11、h their secretion by the proximal tubule.Reduction in the secretion of loop diuretics may result from simultaneous administration of agents such as NSAIDs or probenecid, which compete for weak acid secretion in the proximal tubule.Loop diureticsthe high efficacious diuretic agents【Clinical Uses】Edem

12、atous condition: heart failure, chronic renal failure, hepatic cirrhosisHypercalcemia: reduce Ca2+ reabsorptionHyperkalemia: enhance urinary excretion of K+Acute renal failure: increase the rate of urine flow and enhance K+ excretion in acute renal failureAnion overdose: useful in treating toxic ing

13、estions of bromide, fluoride, and iodide Loop diureticsFurosemide 呋塞米 /Bumetanide 布美他尼/ Ethacrynic acid 依他尼酸【Toxicity】 Hypokalemic metabolic alkalosis: increase Na+ delivery to the collecting duct, which leads to increased secretion of K+ and H+ by the ductHypomagnesemia: rarely cause hypocalcemiaHy

14、peruricemia: precipitate attacks of goutOtotoxicity: dose-related hearing loss (aminoglycoside)Allergic & other reactions: skin rash, eosinophilia, interstitial nephritisLoop diureticsSixtypes10% NaThiazides diureticsCarbonic anhydrase inhibitorsThiazides diureticsDistal convoluted tubule (DCT)Na+ a

15、nd Cl- cotransporter (NCC)Na+-K+-ATPaseParathyroid hormone (PTH)Na+/Ca2+ exchangerCA inhibitorUrinary excretion of Na+ , Cl, water, K+ , Mg2+, HCO3- Ca2+【Pharmacokinetics】 Like carbonic anhydrase inhibitors and loop diuretic, all of the thiazides have an unsubstituted sulfonamideChlorothiazide is th

16、e only thiazide available for parenteral administrationHydrochlorothiazide is considerably more potent and should be used in much lower dosesAll thiazides are secreted by the organic acid secretory system in the proximal tubule and compete with the secretion of uric acid by that system. As a result,

17、 thiazide use may blunt uric acid secretion and elevate serum uric acid level.Thiazidesthe intermediate efficacious diuretic agents【Clinical Uses】Hypertension: hydrochlorothiazide is the most widely used diuretic for hypertension (first line) Heart failure: reduce salt and water retentionNephrolithi

18、asis: due to idiopathic hypercalciuriaNephrogenic diabetes insipidus: Diatary sodium restriction can potentiate the benefical effects ThiazidesHydrochlorothiazide (HCTZ) 氫氯噻嗪/ Chlorothiazide 氯噻嗪【Toxicity】 Hypokalemic metabolic alkalosis and hyperuricemia : similar to loop diureticsHyponatremia: caus

19、ed by a combination of hypovolemia-induced elevation of antidiuretic hormone (ADH)Impaired carbohydrate tolerance: impaired pancreatic release of insulin and diminished tissue utilization of glucose Hyperlipidemia : 515% increase in total serum cholesterol and low-density lipoproteins (LDLs)Allergic

20、 reactions : photosensitive or generalized dermatitisThiazides2-5% NaSixtypesK+-SparingdiureticsCarbonic anhydrase inhibitorsK+-sparing diureticsCollecting tubulePrincipal cellIntercalated cellEpithelial Na+ channel (ENaC)AldosteroneNa+-K+-ATPaseUrinary excretion of Na+, water K+, H+ Mineralocortico

21、id receptor aldosterone-induced proteinsIncrease the new synthesis of Na+ channel and K+ channel as well as fibrotic and inflammatory proteins【Pharmacokinetics】 Spironolactone is a synthetic steroid that may cause endocrine abnormalities by actions on other steroid receptors, which has a rather slow

22、 onset of action, requiring several days before full therapeutic effect is achieved.Eplerenone is a spironalactone analog with much greater selectivity for the mineralocorticoid receptor, therefore, eplerenone has considerably fewer adverse effects.Amiloride and triamterene are direct inhibitors of

23、Na+ infux in the CT.K+-sparing diureticsthe low efficacious diuretic agents【Clinical Uses】Hyperaldosteronism: primary (Conns syndrome) or secondary (evoked by heart failure, hepatic cirrhosis, nephrotic syndrome)Hypertension: combination with other diuretics (prevent K+ loss) Eplerenone: low dose of

24、 eplerenone may interfere with some of the fibrotic and inflammatory effects of aldosterone K+-sparing diureticsSpironolactone 螺內(nèi)酯/ eplerenone 依普利酮/ amiloride 阿米洛利/ triamterene 氨苯蝶啶【Toxicity】 Hyperkelemia: due to reduced urinary excretion of K+Hyperchloremic metabolic acidosis: due to reduced H+ secretion in parallel with K+ secretion astia : synthetic steroids may cause endocrine abnormalities by actions on other steroid receptors (spironolactone)Acute renal failure: caused by the combination of triamterene with indomethacinKidney stones : triamterene is only sli