Ethanol with sulfonylureas

Hypoglycemia Hypoglycemia does not occur in patients receiving metformin alone under usual circumstances, but could occur with deficient caloric intake, strenuous exercise not compensated by caloric supplementation, or during concomitant use with other glucose-lowering agents (such as sulfonylureas) or ethanol. 

Some populations, most notably East Asians, exhibit an unusual response after drinking ethanol. The symptoms include facial flushing, vasodilation, and tachycardia. These individuals apparently have a genetic deficiency of the enzyme aldehyde dehydrogenase, which leads to an accumulation of acetaldehyde even after they drink relatively small amounts of ethanol. If drugs such as metronidazole, griseofulvin, quinacrine, the hypoglycemic sulfonylureas, phenothiazines, and phenylbutazone are coadministered with ethanol, a similar accumulation of acetaldehyde may occur. 

Burge MR, Zeise TM, Sobhy TA, Rassam AG, Schade DS. Low-dose ethanol predisposes elderly fasted patients with type 2 diabetes to sulfonylurea-induced low blood glucose. Diabetes Care 1999 22(12) 2037-43. 

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). 

Ethanol induces hepatic metabolic enzymes and can. therefore, interfere with the actions of sulfonylureas by increasing the rate of metabolism. 

Other organ systems Ethanol, even at relatively low blood concentrations, significantly depresses the heart. Vascular smooth muscle is relaxed, which leads to vasodilation, sometimes with marked hypothermia. Ethanol relaxes uterine smooth muscle. The drug also enhances the hypoglycemic effects of sulfonylureas and the antiplatelet actions of aspirin. 

Only a few cephalosporins (eg, cefoperazone, cefotetan, moxalactam) cause disulfiram-Uke reactions with ethanol. Sulfonylureas used in type 2 diabetes may cause such reactions, and ethanol may enhance their hypoglycemic actions, especially in fasting patients. The answer is (A). 

Many commercial sulfonylureas contain an ortho ester, therefore, preparation of tied-back ester was of great interest. We could use the target intermediate monomethylamide 2 (Scheme X), as both a directing group for metallation and as the latent lactone group. The sulfonamide handle could be added via metallation and quenched with propyl disulfide. Sulfide 2Q can also be prepared via a nucleophilic displacement of the chlorobenzamide 21. A second metallation of 2Q gave the ethanol derivative 22. Base hydrolysis to the amide to the carboxylate, then lactonization under acidic conditions, gave the isocoumarin 22. Oxidative chlorination and amination proceeded without a problem. 

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