Hypoglycemic sulfonylureas

Gllmepirlde (Amaryl) Second generation Tablets 1, 2, 4 mg sulfonylurea Hypoglycemic... 

The sulfonylurea hypoglycemic agents, as noted in Chapter 2, also trace their ancestry to the sulfonamides. It is of interest that activity is retained when a substituted 2-amino-1,3,4-thiadiazole replaces the urea function. Reaction of isobutyryl chloride (123-1) with thiosemicarbazone (123-2) leads initially to the transient 1,2-diacyUiydrazine (123-3). This apparently cyclizes spontaneously to thiadiazine (123-4) under reaction conditions. Acylation with p-methoxysulfonyl chloride (123-5) affords the oral hypoglycemic agent isobuzole (123-6) [134]. 

All sulfonamides, including antimicrobial sulfas, diuretics, diazoxide, and the sulfonylurea hypoglycemic agents, have been considered to be partially cross-allergenic. Flowever, evidence for this is not extensive. The most common adverse effects are fever, skin rashes, exfoliative dermatitis, photosensitivity, urticaria, nausea, vomiting, diarrhea, and difficulties referable to the urinary tract (see below). Stevens-Johnson syndrome, although relatively uncommon (ie, < 1% of treatment courses), is a particularly serious and potentially fatal type of skin and mucous membrane eruption associated with sulfonamide use. Other unwanted effects include stomatitis, conjunctivitis, arthritis, hematopoietic disturbances (see below), hepatitis, and, rarely, polyarteritis nodosa and psychosis. 

Cleveland JC Jr, Meldrum DR, Cain BS, Banerjee A, Harken AH. Oral sulfonylurea hypoglycemic agents prevent ischemic preconditioning in human myocardium. Two paradoxes revisited Circulation 1997 96(l) 29-32. 

Comparison of Orally Administered Sulfonylurea Hypoglycemic Agents... 

Several other drugs, eg, metronidazole, certain cephalosporins, sulfonylurea hypoglycemic drugs, and chloral hydrate, have disulfiram-like effects on ethanol metabolism. Patients should be warned to avoid drinking ethanol while taking these drugs and for several days after they discontinue them. 

Sulfonylurea hypoglycemics [P] Increased hepatic metabolism of tolbutamide and probably other sulfonylureas metabolized by the liver (including chlorpropamide). 

On the other hand, therapy of essential arterial hypertension with dihydropyridine or calcium channel antagonists (felodipine, amlodipine or lercanidipine) for 10 weeks led to a significant increase of blood plasma TAC (by 42%) (D5). Therapy with gliclazide, a sulfonylurea hypoglycemic drug, enhanced blood plasma TAC (Ol). 

Fluconazole Fluconazole may increase the plasma concentration of phenytoin, sulfonylurea (hypoglycemic), cyclosporin, zidovudine, cisapride, and terfenadine. Coadministration of fluconazole with rifampicin results in the reduced plasma concentration of fluconazole. Griseofulvin may reduce the plasma concentration of salicylates, coumarin, anticoagulants, and oral contraceptives. 

A A female patient with non-insulin-dependent diabetes has been maintained on an oral sulfonylurea hypoglycemic agent. She becomes pregnant. The doctor switches her to insulin. This is necessary for all of the following reasons EXCEPT ... 

Associated with renal dysfunction (4 PGs) and hypoglycemia. Many drug interactions (ethanol T GI bleeding, T effects of sulfonylurea hypoglycemics, and warfarin, 4 effects of uricosurics). 

Answer A. Back to ANS pharmacology The release of insulin from the pancreas is stimulated by insulinogens (glucose), sulfonylurea hypoglycemics (glipizide), activators of beta, adrenoceptors (e.g., albuterol), and activators of muscarinic receptors (e.g., pilocarpine). The only receptor that, when activated, inhibits insulin release is the alpha2 receptor, which could be stimulated by clonidine or methyldopa. 

GI distress, rash, gallstones, hypokalemia, myositis potentiates warfarin and sulfonylurea hypoglycemics. jPuMA-hs... 

Hypersensitivity, mostly rashes, which can be severe (Stevens-Johnson syndrome). Assume complete cross-allergenicity between sulfonamides and possibly with sulfonylurea hypoglycemics. 

Ans C The sulfonylurea hypoglycemics release insulin from the pancreas,... 

TABLE 1 Comparison of Orally Administered Characteristics Tolbutamide Sulfonylurea Hypoglycemic Agents Acetohexamide Tolazamide Chlorpropamide Glipizide Glyburide... 

Following are structural formulas for two more widely used sulfonylurea hypoglycemic agents. 

Sulfonylurea3- Four sulfonylurea hypoglycemics are currently on the American market. A great deal of information has been published on the actions and uses of these compounds. Much of this information has been summarized in a recent symposium. The results of clinical studies with the sulfonylureas continue to be published " but little new information has been presented on their mechanisms of action. It is still generally felt that they act by stimulating pancreatic insulin release but the mechanism by which they accomplish this is poorly understood. 

Several studies on the synthesis and evaluation of new sulfonylurea hypoglycemic agents have been reported during the year. One such study involved the synthesis and testing of a series of N-benzyl-N -p-toluenesul-fonylureas related to I. Many of these compounds were found to be effective hypoglycemics in rats. Compound I was found to be the most active member of the series. It is comparable to tolbutamide in potency. 

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