Food

increases

AUC. Highly

protein bound

A1C, glycosylated hemoglobin; BID, 2 times a day; Cmax

, maximal concentration; CrCl, creatinine clearance;

CYP, cytochrome P-450; DM, diabetes mellitus; DPP-4, dipeptidyl peptidase-4; F, bioavailability; FPG, fasting

plasma glucose; GI, gastrointestinal; GLP-1, glucagon-like peptide-1; HF, heart failure; N/A, not available; QID, 4

times a day; SC, subcutaneously; TG, triglycerides; TID, 3 times a day.

MECHANISM OF ACTION

Sulfonylureas stimulate the release of insulin from pancreatic β-cells and enhance βcell sensitivity to glucose. A specific sulfonylurea receptor closely linked to the

ATP-sensitive potassium ion channel exists on the β-cell. Sulfonylureas inhibit this

potassium ion channel, thus blocking the efflux of potassium and lowering the

membrane potential to cause depolarization. The voltage-dependent calcium channels

then open, increasing intracellular calcium concentration. The increased intracellular

concentration of calcium ultimately stimulates preformed insulin secretion.

Additionally, sulfonylureas can normalize hepatic glucose production and enhance

peripheral glucose disposal.

63,175

PHARMACOKINETICS

The duration of hypoglycemic activity is related to the half-life of these compounds

only in very general terms and may correlate poorly in some cases.

176 All

sulfonylureas are highly protein bound (90%–100%), mainly to albumin. Binding

characteristics, however, vary among individual sulfonylureas. Food does not impair

the extent of drug absorption, but may delay the time to peak levels of some agents.

The relationship between sulfonylurea doses and their BG-lowering effect remains

unclear. Studies of glyburide and glipizide suggest that these agents may operate

within a narrow range of plasma concentrations that may be achieved with low (10

mg/day) doses.

177–179 The maximal recommended daily doses of 40 mg for glipizide

and 20 mg for glyburide may therefore not be more effective and may decrease β-cell

function.

179

Glipizide is an intermediate-acting second-generation agent with a half-life of 2 to

4 hours, but a duration of action of 12 to 24 hours. Patients receiving less than 20

mg/day may require only once-daily dosing. Food delays its rate of absorption, but

not its bioavailability. Glipizide should be taken 30 minutes before meals. The onset

of action occurs in 90 minutes, and the maximum decrease in serum glucose occurs

within 2 to 3 hours. Glipizide is extensively metabolized by the liver to inactive

products that are eliminated primarily by the kidney.

176 An extended-release

formulation of glipizide also is available.

Glyburide is a longer-acting second-generation agent similar to glipizide. The

half-life is approximately 1.5 to 4 hours after single-dose studies and up to 13.7

hours when chronically administered.

180 Nevertheless, as with glipizide, the duration

of action can last for up to 24 hours in many patients, allowing for once-daily dosing

with small-to-intermediate doses (<15 mg). Food does not delay the rate or extent of

absorption. The onset of action is 2 hours, and the maximum decrease in serum

glucose occurs within 3 to 4 hours. Glyburide is metabolized completely by the liver

to two weakly active metabolites, half of which are excreted in the urine and feces. A

micronized formulation is available (e.g., Glynase PresTab), but it is not

bioequivalent to the conventionally formulated tablets. Thus, patients switched

between the conventional form and the micronized product must be carefully

monitored and the dose titrated again.

Glimepiride is a long-acting second-generation sulfonylurea. Its half-life is 9 hours

and its duration of action is 24 hours, allowing for once-daily dosing.

181 The

administration of glimepiride with food slightly decreases the AUC and slightly

increases the time to peak concentration. Its peak effect on plasma glucose

concentrations is observed 2 to 3 hours after each dose. Glimepiride is completely

metabolized by the liver, and its principal metabolite has 30% of the activity of the

parent drug. Metabolites are excreted in feces and urine. Interestingly, research

suggests that the sulfonylureas may close ATP-sensitive potassium channels in

cardiac tissue, similar to their action at the β-cell. In the heart, this effect could

prevent vasodilation during an ischemic episode (i.e., ischemic preconditioning).

182

ADVERSE EFFECTS

The primary side effects of the sulfonylureas are hypoglycemia (particularly for those

that are long-acting, see Case 53-16, Question 2, and Case 53-18, Question 6) and

weight gain (~2 kg).

114 Other adverse effects attributed to the sulfonylureas generally

are so infrequent and mild that fewer than 2% of patients discontinue these agents

because of them. In general, the type, incidence, and severity of reported side effects

are similar for all the sulfonylureas. An important exception is chlorpropamide,

which has several unique adverse effects (see following discussion). Adverse

reactions to the sulfonylureas include GI symptoms (nausea, fullness, bloating that

can be relieved if taken with meals), rare blood dyscrasias, allergic dermatologic

p. 1122

p. 1123

2.

5.

6.

1.

3.

4.

reactions and photosensitivity, hepatotoxicity, and hyponatremia (also see Case 53-

16).

161

A disulfiram (Antabuse-like) reaction occurs when patients take certain

sulfonylureas (primarily chlorpropamide, occurring in approximately one-third of

patients receiving it) and drink ethanol. The flushing reaction is rare with other

sulfonylureas.

The syndrome of inappropriate secretion of antidiuretic hormone can occur with

chlorpropamide and, to a lesser extent, with tolbutamide, but these agents are rarely

used in the United States anymore. If it occurs, the syndrome of inappropriate

secretion of antidiuretic hormone is a syndrome of enhanced secretion of vasopressin

from the pituitary. This results in an increase in the retention of free water by the

kidneys and a dilutional hyponatremia. In the UKPDS study, the increase in BP seen

in patients on chlorpropamide was likely attributable to water retention.

35

In contrast

to chlorpropamide and tolbutamide, glipizide, glyburide, tolazamide, and

acetohexamide have a very mild diuretic effect.

CONTRAINDICATIONS AND PRECAUTIONS

Contraindications to the use of sulfonylureas include the following:

Type 1 diabetes;

Pregnancy or breast-feeding, because these agents (except glyburide) can cross the

placental barrier and can be excreted into breast milk;

Documented hypersensitivity to sulfonylureas;

Severe hepatic or renal dysfunction;

Severe, acute intercurrent illness (e.g., infection, MI), surgery, or other stress that

can unduly affect BG control, in which case insulin therapy should be used; and

G6PD deficiency—Patients with this deficiency may be at risk for hemolytic

anemia if they take chlorpropamide—consider using a nonsulfonylurea medication

as an alternative.

DRUG INTERACTIONS

Drug interactions with sulfonylureas have a pharmacodynamic or pharmacokinetic

basis. Pharmacodynamic interactions are discussed later in this chapter in sections

addressing drug-induced hypoglycemia and hyperglycemia. Most of the reported

pharmacokinetic drug interactions with the sulfonylureas involve chlorpropamide and

tolbutamide. Because most of the clinically significant interactions occur with drugs

that alter liver metabolism or urinary excretion, possible interactions with all of the

sulfonylureas must be anticipated, even though the outcomes may be quite different.

Glipizide and glyburide also differ from the first-generation agents in that they are

highly bound to albumin at nonionic rather than ionic sites.

176 On this basis, these

agents are unlikely to interact with other highly protein-bound drugs, such as

phenylbutazone, salicylates, or certain sulfonamide antibiotics that have been

reported to enhance the effects of the first-generation sulfonylureas. These highly

protein-bound drugs, however, seem to interact with the sulfonylureas by altering

their hepatic metabolism as well. Therefore, glipizide and glyburide should be used

cautiously with drugs reported to interact with first-generation sulfonylureas.

Sulfonylureas are CYP 2C9 substrates; therefore, coadministration with a medication

that is an inhibitor or inducer of CPY 2C9 will increase or decrease levels of

sulfonylurea medications, respectively.

173

EFFICACY

Like metformin, the sulfonylureas decrease the A1C by 1.5% to 1.7% and the FPG by

50% to 70%. With time and increased duration of Type 2 diabetes, the pancreas may

respond less to a sulfonylurea. Whether sulfonylureas actually contribute to β-cell

dysfunction and decline remains to be clearly determined.

183