1、1,Chapter 10 Diuretics and Synthetic Hypoglycemic Drugs,Pei Yu College of pharmacy Jinan University,2,Synthetic Hypoglycemic Agents (降血糖藥),Definitions A key indicator of diabetes is persistent fasting blood glucose levels above 11.1 mmol/L which arise from defective conversion of glucose into energy

2、.,The plasma levels of FPG7.0mmol/L or PPG 11.1mmol/L,3,Diabetes,Hyperglycemia result in widespread damage in the body that can lead to hypertension, heart disease, stroke, impaired circulation, nerve dysfunction, pain, infection, or organ failure. Clinical diabetes mellitus（糖尿病）occurs in two forms,

3、 Type 1 and Type 2 , with different causes and methods of therapy.,4,Type 1 Diabetes (insulin-dependent),Formerly known as insulin-dependent diabetes mellitus (IDDM, 胰島素依賴性糖尿病). The cells of the pancreatic islets of Langerhans (胰島) are destroyed, probably by an autoimmune process, such that insulin

4、production is grossly deficient（嚴(yán)重缺乏）. There exists only a weak genetic link in the etiology(病原學(xué))of this form of diabetes. Type 1 diabetes is invariably treated with insulin.,5,6,Type 2 Diabetes (noninsulin-dependent),Formerly known as noninsulin-dependent diabetes mellitus (NIDDM). Frequently assoc

5、iated with obesity(肥胖癥)in its mainly adult victims. Serum insulin levels are normal or elevated, so in essence this is a disease of insulin resistance. There is a strong genetic link in the etiology（病原學(xué)）of the condition, and insulin therapy is not always required.,7,8,9,Hypoglycemic Drugs,Treatments

6、 of Type 2 diabetes include： (1) agents which increase the amount of insulin secreted by the pancreas (2) agents which increase the sensitivity of target organs to insulin (3) agents which decrease the rate at which glucose is absorbed from the gastrointestinal tract.,10,Classification of Hypoglycem

7、ic Drug,Sulfonylureas (磺酰脲類) Biguanides (雙胍類) -Glucosidase inhibitors (-葡萄糖苷酶抑制劑) Thiazolindiones (噻唑烷二酮類),11,The hypoglycemic(降血糖)effect of salicylates(水楊酸鹽)has been known for 100 years. Clinical use of salicylates was not feasible, since the very large doses required produced intolerable side effe

8、cts. The hypoglycemic effects of the thiadiazole sulfonamide known as IPTD, used to treat typhoid (傷寒癥)fever in the 1940s. This drug produced many deaths which were subsequently attributed to prolonged drug-induced hypoglycemia.,Sulfonylureas(磺酰脲類),12,Sulfonylureas,At same time these effects were no

9、ted, the synthesis of sulfonylurea such as Carbutamide, so far active as hypoglycemic agents, was reported. Since then, about 12, 000 sulfonylureas have been tested, and about 10 are currently on the market.,13,Sulfonylureas,Tolbutamide 甲苯磺丁脲 Chlorpropamide 氯磺丙脲 Acetohexamide 醋磺己脲 Tolazamide 妥拉磺脲 Gl

10、iclazide 格列齊特 Glibornuride 格列波脲 Glibenclamide 格列本脲 Glipizide 格列吡嗪 Gliquidone 格列喹酮 Glimepiride 格列美脲,1st generation,2nd generation,3rd generation,14,First and second generation sulfonylureas,15,Tolbutamide (甲苯磺丁脲 ),1-Butyl-3-(p-tolylsulfonyl)urea N-(butylamino)carbonyl-4-methylbenzenesulfonamide White

11、, crystalline powder, insoluble in water, soluble in alcohol or aqueous alkali. It is stable in air.,16,Acidic property,Tolbutamide shows acidic property，it can be dissolved in base.,17,Unstable under acidic condition.,odour,18,Metabolism of Tolbutamide,Tolbutamide is absorbed rapidly in responsive

12、diabetic patients. The blood sugar level reaches a minimum after 5-8 h. It is oxidized rapidly in vivo to derivative with hydroxyl group (I) or derivative with carboxyl group (II), which are inactive.,19,Synthesis of Tolbutamide,20,Glibenclamide(格列本脲 ),1-p-2-(5-chloro-o-anisamido)ethyl-phenylsulfony

13、l -3-cyclohexylurea. Second-generation oral hypoglycemic agent. The drug has a half-life elimination of 10h, but its hypoglycemic effect remains for up to 24h.,21,Hydrolysis of Glibenclamide,22,Glimepiride(格列美脲),1-p-2-(3-ethyl-4-methyl-2-oxo-3-pyrroline-1-carboxamido)ethyl phenylsulfonyl-3-(trans-4-

14、methylcyclohexyl)urea. The third-generation oral hypoglycemic agent. Instead of the benzene ring found in Glibenclamide, Glimepiride contains a pyrrolidine system. It is metabolized primarily through oxidation of the alkyl side chain of the pyrrolidine, with a minor metabolic route involving acetyla

15、tion of the amine.,23,Other Antidiabetic drugs:,Biguanide: (雙胍) The most commonly used oral drug for type 2 diabetes. Increasing insulin sensitivity. Decreasing the absorption of glucose from the gastroinestinal tract.,24,Discovery,The guanidine derivatives（胍衍生物）Synthalin A and B were introduced int

16、o therapy in the 1920s, but chronic toxicity forced their abandonment in the 1930s. The widely used biguanides(雙胍) Phenformin and Metformin were prepared in the 1950s, and the latter is still in widespread use.,25,Metformin Hydrochloride（鹽酸二甲雙胍）,N，N-Dimethylimidodicarbonimidic diamide hydrochloride,

17、26,Metformin,Metformin was discovered in 1957，it was not approved by the FDA until 1994 for the treatment of type 2 diabetes. It is to lower blood glucose and to reduce cardiovascular complications（并發(fā)癥）. Over 6 million people were treated by it annually.,27,-Glucosidase inhibitorsMiglitol (米格列醇),1-(

18、2-Hydroxyethyl)-2-(hydroxymethyl)piperidine-3,4,5-triol,pyranose,28,Miglitol,White to pale-yellow powder is soluble in water, and exhibits a pKa 5.9. In chemical structure, this agent is very simliar to a pyranose sugar (吡喃糖), with a nitrogen atom replacing the oxygen isosterically. -Glucosidase tak

19、es it in as a substrate and is thereby competitively inhibited. The end result is a delay in the absorption of complex carbohydrates from the gastrointestinal tract.,29,Thiazolindiones (噻唑烷二酮類)Rosiglitazone Maleate (馬來酸羅格列酮),Chemical Name: (5-4-2-methyl-2-pyridinylamino)ethoxyphenylmethyl -2,4-thiaz

20、olidinedione maleate,30,Function of Rosiglitazone Maleate,Rosiglitazone maleate is not chemically or functionally related to the sulfonylureas, the biguanides, or the alpha-glucosidase inhibitors. It is an oral antidiabetic agent which acts primarily by increasing insulin sensitivity. It sales 3.6-3

21、.8 billion USD in 2008.,Avandia 文迪雅,31,Side Effects,It is reported in May 2007 that the use of rosiglitazone was associated with a significantly increased risk of heart attack, and an even higher risk of death from all cardiovascular diseases. The FDA issued an alert on May 21, 2007. In 2009 the stu

22、dy found that there was no increase in cardiovascular hospitalisation or death with rosiglitazone compared to metformin plus sulfonylurea, but the rate of heart failure causing admission to hospital or death was significantly increased.,32,33,Diuretics(利尿劑),Definition: Diuretics are drugs that incre

23、ase the rate of urine formation. More commonly known as “water pills”.,Some people use diuretics as a weight loss aid. This is not a healthy way to lose weight. Abusing diuretics can lead to dehydration and sometimes severe potassium deficiencies.,34,Diuretics increase the rate of urine formation by

24、 interfering with the re-absorption of sodium by the nephron (腎元). There are four major anatomical(解剖)sites along the nephron that are responsible for the bulk of Na+ re-absorption.,35,Sodium Reabsorption Sites in the Nephron,Proximal Tubule近端小管,Distal Tubule遠(yuǎn)端小管,30%,5%,1-4%,Loop of Helen細(xì)尿管袢,Collec

25、ting Tubule集合小管,Glomerulus腎小球,1,4,2,3,65%,36,Four major anatomical(解剖學(xué))sites,Site 1: the convoluted and straight portions of the proximal tubule(近端小管); Site 2: the thick ascending limb(升支)of Helens loop; Site 3: the distal convoluted tubule(遠(yuǎn)曲小管); Site 4: the connecting tubule(集合小管) and the cortical

26、 collecting tubule(皮質(zhì)部集合小管).,37,acetazolamide,acetazolamide,hydrochlorothiazide,Triamterene,Spironolactone,sfuf,fu,furosemide,1,2,3,4,38,Potency and efficacy of Diuretics,Class 1, CA inhibitor: Inhibit the reabsorption of Na+/HCO3-at site 1.,Diuretic efficacy has increased with the corresponding cha

27、nges in the site of action of each of three classes of diuretics:,Class 2, Thiazide and thiazide-like diuretics: Inhibit the reabsorption of Na+/Cl- at site 3.,Class 3, High-ceiling diuretics: Block Na+/Cl-/K+/Ca+/Mg2+ reabsorption at site 2.,Stronger,Weaker,39,Shortly after its introduction for the

28、 treatment of bacterial infections, sulfanilamide was observed to produce a mild diuresis characterized by presence of urinary Na+ and a substantial amount of HCO3-. It induced this effect through inhibition of renal carbonic anhydrase (碳酸酐酶，CA). It was a relatively weak inhibitor of renal CA, and t

29、he dose needed to exert adequate diuresis was associated with severe adverse effects.,Class 1: Carbonic Anhydrase Inhibitors,40,To improve on the CA-inhibitory property of sulfanilamide, many sulfamoyl-containing compounds (-SO2NH2) were synthesized. Two groups of CA inhibitors emerged: simple heter

30、ocyclic sulfonamides and meta- disulfamoylbenzene derivatives.,CA inhibitor,41,Two groups of CA inhibitors,42,Common CA inhibitor,43,Acetazolamide,Name: （Diamox) N-5-(aminosulfony)-1,3,4-thiadiazol-2-ylacetamide. White needle crystal, m.p. 258-259 C, soluble in basic solution (NH3.H2O).,44,Acetazola

31、mide,It was introduced in 1953 as the first orally effective, non-mercurial diuretic available to the physician. It has a relatively restricted use today because of its limited efficacy and the refractoriness (失效) that develops to its diuretic action within the first week of continuous therapy.,45,M

32、echanism of action,Similar structure,46,Uses,The major use of the CA inhibitors is in the treatment of glaucoma (青光眼). CA is a functionally important enzyme in the eye, where it plays a key role in the formation of aqueous humor (眼球的水狀體). As adjuvants(佐藥)for the treatment of epilepsy(癲癇). Create an

33、alkaline urine in an attempt to hasten the renal excretion of certain noxious weak acids (uric acid). CA inhibitors have been used prophylactically(預(yù)防) to counteract (抵抗) acute mountain sickness(急性高山病).,急性高山反應(yīng)：由于在高海拔人呼吸急促，血液里氧氣不足導(dǎo)致了碳酸過多，碳酸過多引起輕微腦部水腫，結(jié)果是頭疼和心。,47,Class 2: Thiazide and Thiazide-like di

34、uretics,48,Chloraminophenamide became a key intermediate in the development of diuretics that lack the undesirable properties of the CA inhibitors (?). When Chloraminophenamide was treated with acylating agents, cyclization resulted in the formation of Thiazides. The use of aldehydes or ketones in p

35、lace of the acylating reagents yielded the corresponding dihydro derivatives. The products of these reactions became known as thiazides and hydrothiazides, respectively. The thiazides were the first orally effective saluretic agents（促尿食鹽排泄藥）whose diuretic activity was not influenced by the patients

36、acid-base status.,49,Hydrochlorothiazide,Name：6-Chloro-3,4-dihydro-2H-1,2,4-benzothiadiazine-7-sulfonamide,1,1-dioxide It can be hydrolyzed in water.,50,Synthesis of Hydrochlorothiazide,51,Class 3: High-ceiling or loop diuretics(髓袢利尿劑),Results from structure-activity relationship studies that led to the development of furosemide.,52,Furosemide,Name: 5-(Aminosulfonyl)-4-chloro-2-(2-furanylmethyl）amino benzoic acid,速尿,53,54,Chemical property of Furosemide,Acidic，pKa 3.9,Most effective, Strongest diuretic!,55,Metabolism,The bioavailability of furosemide (o