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Sulfonylureas

The authors make no claims of the accuracy of the information contained herein; and these suggested doses and/or guidelines are not a substitute for clinical judgment. Neither GlobalRPh Inc. nor any other party involved in the preparation of this document shall be liable for any special, consequential, or exemplary damages resulting in whole or part from any user's use of or reliance upon this material.    PLEASE READ THE DISCLAIMER CAREFULLY BEFORE ACCESSING OR USING THIS SITE. BY ACCESSING OR USING THIS SITE, YOU AGREE TO BE BOUND BY THE TERMS AND CONDITIONS SET FORTH IN THE DISCLAIMER.

Diabetes:  Drug Class Navigation

Secretagogues

Insulin sensitizers

Alpha-glucosidase inh

Sulfonylurea's   Biguanides e.g. Metformin Alpha-glucosidase Inhibitors
 Meglitinides (e.g. Prandin) Glitazones - Thiazolidinediones  

Peptide analogs

AMYLIN AGONISTS -Anti-hyper glycemic Synthetic Analogs DPP-4 INHIBITORS -  Dipeptidyl peptidase-4 inhibitor -Gliptins Glucagon-like peptide-1 (GLP-1) AGONIST - Incretin Mimetics

Drug Monographs   top of page

First-generation agents

Chlorpropamide (Diabinese ®) Tolazamide (Tolinase ®)
Tolbutamide (Orinase ®)    acetohexamide (Dymelor)

Second-generation agents

glimepiride (Amaryl ®) glyburide (Micronase ®, Diabeta ®)
glipizide (Glucotrol ®) -----------------------

Typical reductions in A1C values - 2nd gen sulfonylureas:

 

1.0 - 2.0%.
Background


Chlorpropamide (Diabinese ®):  top of page

Dosing (Adults):
Oral: The dosage of chlorpropamide is variable and should be individualized based upon the patient's response
Initial dose: --------------
Adults: 250 mg/day in mild to moderate diabetes in middle-aged, stable diabetic
Elderly: 100-125 mg/day in older patients

Subsequent dosages may be increased or decreased by 50-125 mg/day at 3- to 5-day intervals
Maintenance dose: 100-250 mg/day; severe diabetics may require 500 mg/day; avoid doses >750 mg/day.

Dosing adjustment/comments in renal impairment:
Clcr<50 mL/minute: Avoid use.
Hemodialysis: Removed with hemoperfusion.
Peritoneal dialysis: Supplemental dose is not necessary

Dosing adjustment in hepatic impairment: Dosage reduction is recommended. Conservative initial and maintenance doses are recommended in patients with liver impairment because chlorpropamide undergoes extensive hepatic metabolism.

Supplied
Tablet: 100 mg, 250 mg

glimepiride (Amaryl ®):  top of page

Mechanism of Action
The primary mechanism of action of glimepiride in lowering blood glucose appears to be dependent on stimulating the release of insulin from functioning pancreatic beta cells. In addition, extrapancreatic effects may also play a role in the activity of sulfonylureas such as glimepiride. This is supported by both preclinical and clinical studies demonstrating that glimepiride administration can lead to increased sensitivity of peripheral tissues to insulin. These findings are consistent with the results of a long-term, randomized, placebo-controlled trial in which AMARYL therapy improved postprandial insulin/C-peptide responses and overall glycemic control without producing clinically meaningful increases in fasting insulin/C-peptide levels. However, as with other sulfonylureas, the mechanism by which glimepiride lowers blood glucose during long-term administration has not been clearly established.

AMARYL is effective as initial drug therapy. In patients where monotherapy with AMARYL or metformin has not produced adequate glycemic control, the combination of AMARYL and metformin may have a synergistic effect, since both agents act to improve glucose tolerance by different primary mechanisms of action. This complementary effect has been observed with metformin and other sulfonylureas, in multiple studies

INDICATIONS AND USAGE
AMARYL is indicated as an adjunct to diet and exercise to lower the blood glucose in patients with noninsulin-dependent (Type 2) diabetes mellitus (NIDDM) whose hyperglycemia cannot be controlled by diet and exercise alone. AMARYL may be used concomitantly with metformin when diet, exercise, and AMARYL or metformin alone do not result in adequate glycemic control.

AMARYL is also indicated for use in combination with insulin to lower blood glucose in patients whose hyperglycemia cannot be controlled by diet and exercise in conjunction with an oral hypoglycemic agent. Combined use of glimepiride and insulin may increase the potential for hypoglycemia.

In initiating treatment for noninsulin-dependent diabetes, diet and exercise should be emphasized as the primary form of treatment. Caloric restriction, weight loss, and exercise are essential in the obese diabetic patient. Proper dietary management and exercise alone may be effective in controlling the blood glucose and symptoms of hyperglycemia. In addition to regular physical activity, cardiovascular risk factors should be identified and corrective measures taken where possible.

If this treatment program fails to reduce symptoms and/or blood glucose, the use of an oral sulfonylurea or insulin should be considered. Use of AMARYL must be viewed by both the physician and patient as a treatment in addition to diet and exercise and not as a substitute for diet and exercise or as a convenient mechanism for avoiding dietary restraint. Furthermore, loss of blood glucose control on diet and exercise alone may be transient, thus requiring only short-term administration of AMARYL.

During maintenance programs, AMARYL monotherapy should be discontinued if satisfactory lowering of blood glucose is no longer achieved. Judgments should be based on regular clinical and laboratory evaluations. Secondary failures to AMARYL monotherapy can be treated with AMARYL-insulin combination therapy.

In considering the use of AMARYL in asymptomatic patients, it should be recognized that blood glucose control in Type 2 diabetes has not definitely been established to be effective in preventing the long-term cardiovascular and neural complications of diabetes. However, the Diabetes Control and Complications Trial (DCCT) demonstrated that control of HbA1c and glucose was associated with a decrease in retinopathy, neuropathy, and nephropathy for insulin-dependent diabetic (IDDM) patients.


CONTRAINDICATIONS
AMARYL is contraindicated in patients with

1) Known hypersensitivity to the drug.
2) Diabetic ketoacidosis, with or without coma. This condition should be treated with insulin

Dosing (Adults): Oral (allow several days between dose titrations):
Adults: Initial: 1-2 mg once daily, administered with breakfast or the first main meal; usual maintenance dose: 1-4 mg once daily; after a dose of 2 mg once daily, increase in increments of 2 mg at 1- to 2-week intervals based upon the patient's blood glucose response to a maximum of 8 mg once daily

Combination with insulin therapy (fasting glucose level for instituting combination therapy is in the range of >150 mg/dL in plasma or serum depending on the patient): initial recommended dose: 8 mg once daily with the first main meal.

After starting with low-dose insulin, upward adjustments of insulin can be done approximately weekly as guided by frequent measurements of fasting blood glucose. Once stable, combination-therapy patients should monitor their capillary blood glucose on an ongoing basis, preferably daily.


Elderly: Initial: 1 mg/day; dose titration and maintenance dosing should be conservative to avoid hypoglycemia

Dosing adjustment/comments in renal impairment:
Clcr<22 mL/minute: Initial starting dose should be 1 mg and dosage increments should be based on fasting blood glucose levels

Supplied
Tablet: 1 mg, 2 mg, 4 mg

glyburide (Micronase ®, Diabeta ®):  top of page

CLINICAL PHARMACOLOGY
Diabetaeta appears to lower the blood glucose acutely by stimulating the release of insulin from the pancreas, an effect dependent upon functioning beta cells in the pancreatic islets. The mechanism by which Diabetaeta lowers blood glucose during long-term administration has not been clearly established.

With chronic administration in Type II diabetic patients, the blood glucose lowering effect persists despite a gradual decline in the insulin secretory response to the drug. Extrapancreatic effects may play a part in the mechanism of action of oral sulfonylurea hypoglycemic drugs.

In addition to its blood glucose lowering actions, Diabetaeta produces a mild diuresis by enhancement of renal free water clearance. Clinical experience to date indicates an extremely low incidence of disulfiram-like reactions in patients while taking Diabetaeta

INDICATIONS AND USAGE
Diabetaeta is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus.

CONTRAINDICATIONS
Diabetaeta is contraindicated in patients:

-With known hypersensitivity to the drug or any of its excipients.
-With type I diabetes mellitus, diabetic ketoacidosis, with or without coma. This condition should be treated with insulin.
-Treated with bosentan.
-With severely impaired renal and/or hepatic function: The metabolism and excretion may be slowed in patients with severely impaired renal and/or hepatic function. If hypoglycemia should occur in such patients, it may be prolonged and appropriate management should be instituted

Dosing (Adults)
Oral
:
Initial: 2.5 to 5 mg/day, administered with breakfast or the first main meal of the day. In patients who are more sensitive to hypoglycemic drugs, start at 1.25 mg/day.

Increase in increments of no more than 2.5 mg/day at weekly intervals based on the patient's blood glucose response

Maintenance: 1.25 to 20 mg/day given as single or divided doses; maximum: 20 mg/day.

Administer with meals at the same time each day. Patients who are anorexic or NPO may need to have their dose held to avoid hypoglycemia.

Elderly: Initial: 1.25 to 2.5 mg/day, increase by 1.25-2.5 mg/day every 1-3 weeks


Micronized tablets (Glynase™ PresTab™):
Adults:
Initial: 1.5-3 mg/day, administered with breakfast or the first main meal of the day in patients who are more sensitive to hypoglycemic drugs, start at 0.75 mg/day. Increase in increments of no more than 1.5 mg/day in weekly intervals based on the patient's blood glucose response.

Maintenance: 0.75-12 mg/day given as a single dose or in divided doses. Some patients (especially those receiving >6 mg/day) may have a more satisfactory response with twice-daily dosing.


Dosing adjustment/comments in renal impairment:
Clcr<50 mL/minute: Not recommended

Dosing adjustment in hepatic impairment:
Use conservative initial and maintenance doses and avoid use in severe disease

Supplied
Tablet (Diabeta®, Micronase®): 1.25 mg, 2.5 mg, 5 mg
Tablet, micronized (Glynase® PresTab®): 1.5 mg, 3 mg, 6 mg

glipizide (Glucotrol ®):   top of page

Sulfonylurea.
Mechanism of Action
The primary mode of action of glipizide in experimental animals appears to be the stimulation of insulin secretion from the beta cells of pancreatic islet tissue and is thus dependent on functioning beta cells in the pancreatic islets. In humans glipizide appears to lower the blood glucose acutely by stimulating the release of insulin from the pancreas, an effect dependent upon functioning beta cells in the pancreatic islets. The mechanism by which glipizide lowers blood glucose during long-term administration has not been clearly established. In man, stimulation of insulin secretion by glipizide in response to a meal is undoubtedly of major importance. Fasting insulin levels are not elevated even on long-term glipizide administration, but the postprandial insulin response continues to be enhanced after at least 6 months of treatment. The insulinotropic response to a meal occurs within 30 minutes after an oral dose of glipizide in diabetic patients, but elevated insulin levels do not persist beyond the time of the meal challenge. Extrapancreatic effects may play a part in the mechanism of action of oral sulfonylurea hypoglycemic drugs.

Blood sugar control persists in some patients for up to 24 hours after a single dose of glipizide, even though plasma levels have declined to a small fraction of peak levels by that time.

Some patients fail to respond initially, or gradually lose their responsiveness to sulfonylurea drugs, including glipizide. Alternatively, glipizide maybe effective in some patients who have not responded or have ceased to respond to other sulfonylureas.

Other Effects
It has been shown that glipizide therapy was effective in controlling blood sugar without deleterious changes in the plasma lipoprotein profiles of patients treated for NIDDM.

In a placebo-controlled, crossover study in normal volunteers, glipizide had no anti-diuretic activity, and, in fact, led to a slight increase in free water clearance

INDICATIONS AND USAGE:
Glipizide tablets are indicated as an adjunct to diet for the control of hyperglycemia and its associated symptomatology in patients with non-insulin-dependent diabetes mellitus (NIDDM; type II), formerly known as maturity-onset diabetes, after an adequate trial of dietary therapy has proved unsatisfactory.

In initiating treatment for non-insulin-dependent diabetes, diet should be emphasized as the primary form of treatment. Caloric restriction and weight loss are essential in the obese diabetic patient. Proper dietary management alone may be effective in controlling the blood glucose and symptoms of hyperglycemia. The importance of regular physical activity should also be stressed, and cardiovascular risk factors should be identified, and corrective measures taken where possible.

If this treatment program fails to reduce symptoms and/or blood glucose, the use of an oral sulfonylurea or insulin should be considered. Use of glipizide must be viewed by both the physician and patient as a treatment in addition to diet, and not as a substitute for diet or as a convenient mechanism for avoiding dietary restraint. Furthermore, loss of blood glucose control on diet alone also may be transient, thus requiring only short-term administration of glipizide.

During maintenance programs, glipizide should be discontinued if satisfactory lowering of blood glucose is no longer achieved. Judgments should be based on regular clinical and laboratory evaluations.

In considering the use of glipizide in asymptomatic patients, it should be recognized that controlling blood glucose in non-insulin-dependent diabetes has not been definitely established to be effective in preventing the long-term cardiovascular or neural complications of diabetes.


CONTRAINDICATIONS
Glipizide is contraindicated in patients with:
-Known hypersensitivity to the drug.
-Diabetic ketoacidosis, with or without coma. This condition should be treated with insulin.

Dosing (Adults)
Oral (allow several days between dose titrations): Adults: Initial: 5 mg/day; adjust dosage at 2.5 to 5 mg daily increments as determined by blood glucose response at intervals of several days.
Immediate release tablet:
Maximum recommended once-daily dose: 15 mg;
maximum recommended total daily dose: 40 mg

Extended release tablet (Glucotrol® XL):
Maximum recommended dose: 20 mg

When transferring from insulin to glipizide:
Current insulin requirement leq 20 units: Discontinue insulin and initiate glipizide at usual dose

Current insulin requirement >20 units: Decrease insulin by 50% and initiate glipizide at usual dose; gradually decrease insulin dose based on patient response. Several days should elapse between dosage changes.


Administration:  Administer immediate release tablets 30 minutes before a meal to achieve greatest reduction in postprandial hyperglycemia. Extended release tablets should be given with breakfast. Patients who are NPO may need to have their dose held to avoid hypoglycemia.

Elderly: Initial: 2.5 mg/day; increase by 2.5 to 5 mg/day at 1- to 2-week intervals


Dosing adjustment/comments in renal impairment: Clcr<10 mL/minute: Some investigators recommend not using
Dosing adjustment in hepatic impairment: Initial dosage should be 2.5 mg/day


Supplied 
Tablet (Glucotrol®): 5 mg, 10 mg
Tablet, extended release: 5 mg, 10 mg
(Glucotrol® XL): 2.5 mg, 5 mg, 10 mg

Tolazamide (Tolinase ®):   top of page

Adult (usual):
Oral (doses >1000 mg/day normally do not improve diabetic control):

Initial: 100 to 250 mg/day with breakfast or the first main meal of the day
Fasting blood sugar <200 mg/dL: 100 mg/day
Fasting blood sugar >200 mg/dL: 250 mg/day

Patient is malnourished, underweight, elderly, or not eating properly: 100 mg/day

Adjust dose in increments of 100 to 250 mg/day at weekly intervals to response. If >500 mg/day is required, give in divided doses twice daily; maximum daily dose: 1 g (doses >1 g/day are not likely to improve control)
[Supplied  100 mg , 250 mg , 500 mg tablet]

Tolbutamide (Orinase ®):  top of page

Divided doses may improve gastrointestinal tolerance
Adults: Oral:
Initial
: 1-2 g/day as a single dose in the morning or in divided doses throughout the day. Total doses may be taken in the morning; however, divided doses may allow increased gastrointestinal tolerance. Maintenance dose: 0.25 to 3 g/day; however, a maintenance dose >2 g/day is seldom required.

Elderly: Oral: Initial: 250 mg 1-3 times/day; usual: 500-2000 mg; maximum: 3 g/day

[Supplied 500 mg tablet]

Background  top of page

Sulfonylureas were the first widely used oral anti-hyperglycemic medications. They are insulin secretagogues, triggering insulin release by direct action on the KATP channel of the pancreatic beta cells.   The primary mechanism of action of sulfonylureas in lowering blood glucose appears to be dependent on stimulating the release of insulin from functioning pancreatic beta cells. In addition, extrapancreatic effects may also play a role in the activity of sulfonylureas.  This is supported by both preclinical and clinical studies demonstrating that the administration of a sulfonylurea can lead to increased sensitivity of peripheral tissues to insulin. These findings are consistent with the results of a long-term, randomized, placebo-controlled trial in which sulfonylurea therapy improved postprandial insulin/C-peptide responses and overall glycemic control without producing clinically meaningful increases in fasting insulin/C-peptide levels. However, the mechanism by which sulfonylureas lower blood glucose during long-term administration has not been clearly established.

All may cause weight gain.

Sulfonylureas bind strongly to plasma proteins.

Sulfonylureas are only useful in Type II diabetes, as they work by stimulating endogenous release of insulin.

They work best with patients over 40 years old, who have had diabetes mellitus for under ten years.

They cannot be used with type I diabetes, or diabetes of pregnancy. They can be safely used with metformin or -glitazones.

The primary side effect is hypoglycemia. [source  and Package insert]

References  top of page

National Institutes of Health, U.S. National Library of Medicine, DailyMed Database.
Provides access to the latest drug monographs submitted to the Food and Drug Administration (FDA). Please review the latest applicable package insert for additional information and possible updates.  A local search option of this data can be found here.

Disclaimer

Listed dosages are for - Adult patients ONLY. PLEASE READ THE DISCLAIMER CAREFULLY BEFORE ACCESSING OR USING THIS SITE. BY ACCESSING OR USING THIS SITE, YOU AGREE TO BE BOUND BY THE TERMS AND CONDITIONS SET FORTH IN THE DISCLAIMER. GlobalRPH does not directly or indirectly practice medicine or provide medical services and therefore assumes no liability whatsoever of any kind for the information and data accessed through the Service or for any diagnosis or treatment made in reliance thereon.
David F. McAuley, Pharm.D., R.Ph.  GlobalRPh Inc.
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