1、Chapter 10 Diuretics and Synthetic Hypoglycemic Drugs Section 1 Hypoglycemic Drugs Section 2 Diuretics Section 1 Hypoglycemic Drugs The classic triad of symptoms in diabetes is polyphagia, polydypsia (thirst), and polyuria (excess urine). All three result directly from excessive serum glucose levels
2、. Type 1 diabetes usually develops in an acute manner, although the destructive autoimmune process may have been underway for some time. Type 2 diabetes has a more insidious, often asymptomatic onset and its presence is usually detected by routine medical examinations. Definitions Type I Diabetes. I
3、nsulin-dependent diabetes mellitus (IDDM), this condition occurs when the - cells of the pancreatic islets of Langerhans are destroyed, probably by an autoimmune process, such that insulin production is deficient. Type 2 Diabetes. Noninsulin-dependent diabetes mellitus (NIDDM) is very frequently ass
4、ociated with obesity in its mainly adult victims. Serum insulin levels are normal or elevated, so in essence this is a disease of insulin resistance. Biochemistry and Pathogenesis of Diabetes Classifications First Generation Sulfonylureas: tolbutamide. Second Generation Sulfonylureas: glibenclamide.
5、 Third Generation Sulfonylureas: glimepiride, repaglinide. Biguanides: metformin. - Glucosidase Inhibitors: Acarbose, Miglitol. Mechanism of Action Sulfonylureas interact with receptors on pancreatic -cells to block ATP-sensitive potassium channels. This in turn leads to opening of voltage-sensitive
6、 calcium channels which produces an influx of calcium; the influx of calcium results in -cells production of insulin. An additional effect of sulfonylureas is suppression of gluconeogenesis in the liver. Physical-Chemical Properties Sulfonylureas are weak acids due to the marked delocalization of th
7、e nitrogen lone electron pair by the sulfonyl group. Their pKas cluster around 5.0 and they are strongly protein bound. Structure-activity Relationships l There must be reasonable bulk on the urea nitrogen; methyl and ethyl compounds are not active. l Usually, there is only one (normally substituent
8、 para) on the sulfonyl aromatic ring. Many simple substituents on the sulfonyl aromatic ring are active. The p-(-arylcarboxamidoethyl) grouping seen in second generation compounds is consistent with high potency. It is thought that the spatial relationship between the amide nitrogen of the substitue
9、nt and the sulfonamide nitrogen is important. Tolbutamide l N-(Butylamino)carbonyl-4-methylbenzene sulfonamide l Butyl group on the urea nitrogen; l Para-methylbenzene on the sulfonyl group. Properties Tolbutamide have sulfonylurea structure with weak acid, and this property may be used for assay. I
10、nstability: Tolbutamide is hydrolyzed to para- toluene sulfonamide by acids. Heating of its filtrate with sodium hydroxide solution produces n -butylamine odour. Metabolism Tolbutamide is metabolized in the liver to p- hydroxyl tolbutamide, retaining about 35% of the activity of the parent compound.
11、 it is converted very rapidly to the inactive tolbutamide 4-carboxylic acid. Glibenclamide 5-Chloro-N-2-4-(cyclohexylamino)carbonyl aminosulfonylphenyl-2-methoxybenzamide Introduction of cyclohexane on the urea nitrogen; Introduction of side chain on the sulfonyl aromatic ring. Properties It is not
12、stable to moisture and is hydrolyzed to sulfamide derivate. Metabolism Glibenclamide affords trans-4-hydroxy-glyburide as the major product. The 3-hydroxy metabolite retains about 15% of the activity of the parent compound. Therapeutic Application In general, the effects of the first- and second- ge
13、neration sulfonylureas are similar. All produce reliable hypoglycemia in type 2 diabetics. These agents work best in patients whose type 2 diabetes is relatively mild. Synthetic Route Third-generation sulfonylurea Glimepiride is a sulfonylurea with a quick onset of action and a long duration of acti
14、on. It may bind to a different protein in the putative sulfonylurea receptor than earlier drugs, and may exert its hypoglycemic effect with less secretion of insulin. Metformin hydrochloride l N,N-Dimethylimidodicarbonimidic diamide hydrochloride l Metformin, Biguanides, has been in use throughout t
15、he world, with the exception of the U.S., for decades. Mechanism of Action Metformin is usually said to be an antihyperglycemic rather than a hypoglycemic agent. Overall, the drug appears to increase glucose utilization. Inhibition of gluconeogenesis appears to be an important component of the drugs
16、 activity. Actions and Uses Unlike sulfonylureas, Metformin is not protein bound, is not metabolized, and is rapidly eliminated by the kidney. It is widely used as monotherapy or in combination with a sulfonylurea in type 2 diabetes, particularly when the patient is obese and insulin- resistant. - G
17、lucosidase Inhibitors To be absorbed from the gastrointestinal tract into the bloodstream, the complex carbohydrates we ingest as part of our diet must first be hydrolyzed to monosaccharides. The rationale for the-glucosidase inhibitor is that by preventing the hydrolysis of carbohydrates their abso
18、rption could be reduced. Metabolism of complex carbohydrades Section 2 Diuretics Diuretics are chemicals that increase the rate of urine formation. Diuretic usage leads to the increased excretion of electrolytes (especially sodium and chloride ions) and water from the body without affecting protein,
19、 vitamin, glucose or amino acid reabsorption. Structure Classification The diuretics currently in use today are classified as follows: Thiazides (by their chemical classes); Carbonic anhydrase inhibitors, osmotics (by mechanism of action); Loop diuretics (by site of action); Potassium-sparing diuret
20、ics (by effects on urine contents). Furosemide 5-(Aminosulfonyl)-4-chloro-2-(2-furanylmethyl) amino benzoic acid Furosemide is an example of a high-ceiling diuretic and may be regarded as a derivative of anthranilic acids. Structure-activity Relationships The chlorine and sulfonamide substitutions a
21、re features of this class drugs. Furosemide is a stronger acid than the thiazide diuretics (pKa 3.9). This drug is excreted primarily unchanged. A small amount of metabolism, however, can take place on the furan ring. Therapeutic Applications Furosemide has a saluretic effect 8-10 times that of the
22、thiazide diuretics, however, it has a shorter duration of action, about 6-8 hours. It is effective for the treatment of edemas connected with cardiac, hepatic, and renal sites. Clinical toxicity of furosemide involves abnormalities of fluid and electrolyte balance. Hydrochlorothiazide 6-Chloro-3,4-d
23、ihydro-2H-1,2,4-benzothiadiazine- 7-sulfonamide 1,1-dioxide The thiazide diuretics are weakly acidic with a benzothiadiaze 1,1-dioxide nucleus. Mechanism of Action The major site of action of these compounds is in the distal tubule, where these drugs compete for the chloride binding site of the Na+-
24、C1- symporter and inhibit the reabsorption of sodium and chloride ions. They also inhibit the reabsorption of potassium and bicarbonate ions but to a lesser degree. Structure-activity Relationship The hydrogen atom at the 2-N is the most acidic. These acidic protons make possible the formation of a
25、water-soluble sodium salt. An electron-withdrawing group is necessary at position 6 for diuretic activity. Replacement or removal of the sulfonamide at position 7 yields compounds with little or no diuretic activity. Saturation of the double bond to give a 3, 4 dihydro derivative produces a diuretic
26、 that is 10 times more than the unsaturated derivative. Substitution lipophilic group at position 3 gives a marked in the diuretic potency with a longer duration of action. Alkyl substitution on the 2-N position also decreases the polarity and increases the duration of diuretic action. Therapeutic A
27、pplications Hydrochlorothiazide is indicated in the management of hypertension either as the sole therapeutic agent, or in combination with other antihypertensives. Acetazolamide l N-5-(Aminosulfonyl)1,3,4-thiadiazol-2-yl acetamide l Acetazolamide was the first of the carbonic anhydrase inhibitors w
28、ith a diuretic effect that lasts about 8-12 hours. It is used primarily for the treatment of glaucoma and absence seizures. Mechanism of Action The action of the enzyme carbonic anhydrase catalyzes the formation of carbonic acid from carbon dioxide and water. Carbonic anhydrase inhibitors induce diu
29、resis by inhibiting the formation of carbonic acid within proximal and distal tubular cells to limit the number of hydrogen ions available to promote sodium reabsorption. Spironolactone l The adrenal (7-17)-7(Acetylthio)-17-hydroxy-3- oxopregn-4ene-21-carboxylic acid -lactone l Spironolactone is a c
30、ompetitive antagonist to the mineralocorticoids such as aldosterone. Mechanism of Action The adrenal cortex secretes a potent mineralocorticoid called aldosterone which promotes salt and water retention and potassium and hydrogen ion excretion. Spironolactone inhibits reabsorption of sodium and chlo
31、ride ion and increased potassium ion excretion. Metabolism Spironolactone is significantly metabolized in liver to its major active metabolite, canrenone, which is interconvertible with its canrenoate anion. Canrenone is an antagonist to aldosterone and it has been suggested as the active form of sp
32、ironolactone. The canrenoate anion is not active per se but acts as aldosterone antagonist because of its conversion to canrenone. The most serious side effect of spironolactone is hyperkalemia because it has a potassium- sparing effect. Triamterene 6-Phenyl-2,4,7-pteridinetriamine The diuretic effe
33、ct of triamterene occurs rapidly, in 30 minutes, and reaches a peak plasma concentration in 2-4 hours, with a duration of action of more than 24 hours. Structural Modification Activity is retained if an amine group is replaced with a lower alkylamine group. Introduction of a para-methyl group on the
34、 phenyl ring decreases the activity about one- half. Introduction of a para-hydroxyl group on the phenyl ring yields a compound that is essentially inactive as a diuretic. 重点内容 掌握磺酰脲类的作用机制、构效关系。 掌握甲苯磺丁脲、格列本脲、盐酸二甲双胍的结 构、性质、代谢和用途。 掌握呋塞米、氢氯噻嗪、乙酰唑胺、螺内酯、氨 苯蝶啶的结构和用途。 熟悉各类利尿药的 作用机制、构效关系。 熟悉 格列本脲和 氨苯蝶啶的合成。
