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Chapter: Modern Pharmacology with Clinical Applications: Insulin and Oral Drugs for Diabetes Mellitus

Sulfonylureas - Oral Agents For Treating Diabetes Mellitus

Sulfonylureas are the most widely prescribed drugs in the treatment of type II diabetes mellitus.



Sulfonylureas are the most widely prescribed drugs in the treatment of type II diabetes mellitus. The initial sulfonylureas were introduced nearly 50 years ago and were derivatives of the antibacterial sulfonamides. Although their structural similarities to the sulfon-amide antibacterial agents are readily apparent, the sul-fonylureas possess no antibacterial activity.

Mechanism of Action


The primary mechanism of action of the sulfonylureas is direct stimulation of insulin release from the pancreatic β-cells. In the presence of viable pancreatic β-cells, sul-fonylureas enhance the release of endogenous insulin, thereby reducing blood glucose levels. At higher doses, these drugs also decrease hepatic glucose production, and the second-generation sulfonylureas may possess additional extrapancreatic effects that increase insulin sensitivity, though the clinical significance of these phar-macological effects is unclear. These mechanisms are summarized in Table 67.3.


The sulfonylureas are ineffective for the manage-ment of type I and severe type II diabetes mellitus, since the number of viable β-cells in these forms of diabetes is small. Severely obese diabetics often respond poorly to the sulfonylureas, possibly because of the insulin re-sistance that often accompanies obesity.


The Sulfonylurea Receptor


The sulfonylurea receptor was identified as an adeno-sine triphosphate (ATP) sensitive potassium (KATP) channel that is present on the β-cell membrane surface. Closure of these KATP channels causes β-cell membrane depolarization and triggers the opening of voltage-dependent calcium channels. The influx of calcium into the β-cell triggers insulin granule fusion to the β-cell membrane and insulin release. The intracellular levels of ATP and adenosine diphosphate (ADP) modulate the activity of the KATP channel, depending on the avail-ability of glucose.


The activity of the KATP channels is modulated by the direct binding of sulfonylureas to a specific subunit of the KATP channel called SUR1. SUR1 is a member of the K+ inwardly rectifying (Kir) 6.0 subfamily of pro-teins and can bind nucleotides and sulfonylureas with high affinity. Four SUR1 subunits form a complex with four subunits from the Kir 6.2 subfamily and create the pore for K+ permeation in the pancreatic β-cell. Sulfonylurea binding to SUR1 directly promotes the closure of these KATP channels, lowering the threshold for glucose-dependent insulin release. Diazoxide also binds to SUR1 but keeps the KATP channels open, raising the threshold for glucose-stimulated insulin secretion and sometimes causing hyperglycemia in patients.



Absorption, Metabolism, and Excretion


Sulfonylureas are readily absorbed from the gastroin-testinal tract following oral administration but undergo varying degrees and rates of metabolism in the liver and/or kidney; some metabolites possess intrinsic hy-poglycemic activity. Thus, the biological half-lives of the sulfonylureas vary greatly, and a comparison of the drug half-life with the observed duration of action does not always show a good correlation. Sulfonylureas and their metabolites are excreted either renally or in the feces.



Clinical Uses


Sulfonylureas are generally effective in individuals with mild to moderate type II diabetes. The chance for suc-cessful glycemic control with sulfonylureas is poor in di-abetic patients requiring more than 40 units of insulin per day. When beginning therapy with one of these drugs, a low to intermediate dose is given initially and then gradually increased until the dosage results in nor-moglycemia. Once the maximum recommended dosage for a particular sulfonylurea is reached, further increas-ing the dose will not improve glycemic control.


Adverse Effects and Drug Interactions


The most common adverse effect associated with sul-fonylurea administration is hypoglycemia, which may be provoked by inadequate calorie intake (e.g., skipping a meal), or increased caloric needs (e.g., increased phys-ical activity). Collectively, sulfonylureas also tend to cause weight gain, which is undesirable in individuals

who already are obese. Some of this weight can be due to fluid retention and edema. Less common adverse re-actions include muscular weakness, ataxia, dizziness, mental confusion, skin rash, photosensitivity, blood dyscrasias, and cholestatic jaundice. Occasionally, per-sons who display drug sensitivities to sulfa-containing antibiotics show a cross-reactivity to the sulfonylureas. In this situation, a nonsulfonylurea insulin secretagogue can be used (if desired), such as repaglinide or nateglin-ide (discussed later). Sulfonylureas are not used in ges-tational diabetes, which is generally managed by a com-bination of intensive diet control and insulin.


Since diabetic patients with renal or hepatic disease are particularly vulnerable to hypoglycemia, the sul-fonylurea compounds should be avoided in these indi-viduals. A decrease in alcohol tolerance also has been observed in some patients taking sulfonylurea com-pounds. Since sulfonylureas are highly bound to plasma proteins and are extensively metabolized by microso-mal enzymes, coadministration of drugs capable of dis-placing them from their protein binding sites or inhibit-ing their metabolism (e.g., sulfonamide antibacterials, propranolol, salicylates, phenylbutazone, chlorampheni-col, probenecid, and alcohol) also may potentiate hypo-glycemia.



First-Generation Sulfonylureas


The first-generation sulfonylureas are not frequently used in the modern management of diabetes mellitus because of their relatively low specificity of action, de-lay in time of onset, occasional long duration of action, and a variety of side effects. They also tend to have more adverse drug interactions than the second-gener-ation sulfonylureas. They are occasionally used in pa-tients who have achieved previous adequate control with these agents.


Acetohexamide (Dymelor) is the only sulfonylurea with uricosuric activity, an action that may be of benefit in diabetic patients who also have gout.

Chlorpropamide (Diabinese) has a relatively slow onset of action, with its maximal hypoglycemic poten-tial often not reached for 1 or 2 weeks. Similarly, several weeks may be required to eliminate the drug after dis-continuation of therapy. This drug can cause flushing, particularly when taken with alcohol, and can also cause hyponatremia. This effect has been employed to treat some patients who have partial central diabetes in-sipidus, an unrelated condition due to a pituitary ADH deficiency.


Tolazamide (Tolinase) is an orally effective hypo-glycemic drug that causes less water retention than do the other compounds in this class.


Tolbutamide (Orinase) is a relatively short-acting compound that may be useful in patients who are prone to hypoglycemia.

Second-Generation Sulfonylureas


The second-generation sulfonylureas display a higher specificity and affinity for the sulfonylurea receptor and more predictable pharmacokinetics in terms of time of onset and duration of action, and they have fewer side effects. Second-generation sulfonylureas may also exert mild diuretic effects on the kidney and are highly protein bound, primarily through nonionic bind-ing (in contrast to the ionic binding observed with the first-generation compounds).


Glyburide (DiaBeta, Micronase, Glynase), also known as glibenclamide, is approximately 150 times as potent as tolbutamide on a molar basis and twice as potent as glipizide (discussed later). Glyburide is completely me-tabolized in the liver to two weakly active metabolites before excretion in the urine. Its average duration of ac-tion is 24 hours.


Glipizide (Glucotrol) is similar to glyburide, but it is metabolized by the liver to two inactive metabolites; these metabolites and glipizide are renally excreted.


Glimepiride (Amaryl) is metabolized to at least one active metabolite. It is quickly absorbed from the gas-trointestinal tract within an hour of oral administration and excreted in the urine and feces. Its half-life varies from 5 to 9 hours depending on the frequency of multi-ple dosing.


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