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ChlorproPAMIDE


Pronunciation

 (klor PROE pa mide)


U.S. Brand Names

 Diabinese®


Generic Available

 Yes


Canadian Brand Names

 Apo-Chlorpropamide®; Novo-Propamide


Use

 Management of blood sugar in type 2 diabetes mellitus (noninsulin dependent, NIDDM)


Use - Unlabeled/Investigational

 Neurogenic diabetes insipidus


Pregnancy Risk Factor

 C


Pregnancy Implications

 Crosses the placenta. Hypoglycemia; ear defects reported; other malformations reported but may have been secondary to poor maternal glucose control/diabetes. Insulin is the drug of choice for the control of diabetes mellitus during pregnancy. Prolonged hypoglycemia has been reported in neonates born to mothers who were receiving sulfonylureas (particularly long-acting drugs).


Lactation

 Enters breast milk/contraindicated


Contraindications

 Hypersensitivity to sulfonylureas, sulfonamides, or any component of the formulation; do not use with type 1 diabetes mellitus (insulin dependent, IDDM) or with severe renal, hepatic, thyroid, or other endocrine disease


Warnings/Precautions

 Patients should be properly instructed in the early detection and treatment of hypoglycemia; long half-life may complicate recovery from excess effects. Because of chlorpropamide's long half-life, duration of action, and the increased risk for hypoglycemia, it is not considered a hypoglycemic agent of choice in the elderly.

Chemical similarities are present among sulfonamides, sulfonylureas, carbonic anhydrase inhibitors, thiazides, and loop diuretics (except ethacrynic acid). Use in patients with sulfonylurea or sulfonamide allergy is specifically contraindicated in product labeling, however, a risk of cross-reaction exists in patients with allergy to any of these compounds; avoid use when previous reaction has been severe.

Product labeling states oral hypoglycemic drugs may be associated with an increased cardiovascular mortality as compared to treatment with diet alone or diet plus insulin. Data to support this association are limited, and several studies, including a large prospective trial (UKPDS) have not supported an association.


Adverse Reactions

>10%:

Central nervous system: Headache, dizziness

Gastrointestinal: Anorexia, constipation, heartburn, epigastric fullness, nausea, vomiting, diarrhea

1% to 10%: Dermatologic: Skin rash, urticaria, photosensitivity

<1%: Agranulocytosis, aplastic anemia, bone marrow suppression, cholestatic jaundice, disulfiram reaction, edema, eosinophilia, erythema multiforme, exfoliative dermatitis, hemolytic anemia, hypoglycemia, hyponatremia, leukopenia, porphyria cutanea tarda, proctocolitis, SIADH, thrombocytopenia


Overdosage/Toxicology

Symptoms of overdose include low blood glucose levels, tingling of lips and tongue, tachycardia, convulsions, stupor, coma

Antidote is glucose; intoxications with sulfonylureas can cause hypoglycemia and are best managed with glucose administration (oral for milder hypoglycemia or by injection in more severe forms); prolonged effects lasting up to 1 week may occur with this agent


Drug Interactions

 Substrate of CYP2C8/9 (minor)

Thiazides may decrease effectiveness of chlorpropamide

Possible interaction between chlorpropamide and fluoroquinolone antibiotics has been reported resulting in a potentiation of hypoglycemic action of chlorpropamide

Since this agent is highly protein bound, the toxic potential is increased when given concomitantly with other highly protein bound drugs (ie, phenylbutazone, oral anticoagulants, hydantoins, salicylates, NSAIDs, beta-blockers, sulfonamides) - increase hypoglycemic effect.

Ethanol increases disulfiram reactions.

Phenylbutazone can increase hypoglycemic effects.

Certain drugs tend to produce hyperglycemia and may lead to loss of control (ie, thiazides and other diuretics, corticosteroids, phenothiazines, thyroid products, estrogens, oral contraceptives, phenytoin, nicotinic acid, sympathomimetics, calcium channel blocking drugs, and isoniazid).

Possible interactions between chlorpropamide and coumarin derivatives have been reported that may either potentiate or weaken the effects of coumarin derivatives.


Ethanol/Nutrition/Herb Interactions

 Ethanol: Avoid ethanol (possible disulfiram-like reaction may occur).


Mechanism of Action

 Stimulates insulin release from the pancreatic beta cells; reduces glucose output from the liver; insulin sensitivity is increased at peripheral target sites


Pharmacodynamics/Kinetics

Onset of action: Peak effect: ~6-8 hours

Distribution: Vd: 0.13-0.23 L/kg; enters breast milk

Protein binding: 60% to 90%

Metabolism: Extensively hepatic (~80%)

Half-life elimination: 30-42 hours; prolonged in elderly or with renal impairment

End-stage renal disease: 50-200 hours

Time to peak, serum: 3-4 hours

Excretion: Urine (10% to 30% as unchanged drug)


Dosage

 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.


Monitoring Parameters

 Fasting blood glucose, normal Hgb A1c or fructosamine levels; monitor for signs and symptoms of hypoglycemia (fatigue, sweating, numbness of extremities); monitor urine for glucose and ketones


Reference Range

 Target range: Adults:

Fasting blood glucose: <120 mg/dL

Glycosylated hemoglobin: <7%


Dietary Considerations

 Dietary modification based on ADA recommendations is a part of therapy. Decreases blood glucose concentration. Hypoglycemia may occur. Must be able to recognize symptoms of hypoglycemia (palpitations, sweaty palms, lightheadedness). May cause GI upset; take with food. Take at the same time each day; eat regularly and do not skip meals.


Patient Education

 This medication is used to control diabetes; it is not a cure. Other components of treatment plan are important: follow prescribed diet, medication, and exercise regimen. Take exactly as directed, at the same time each day. Do not change dose or discontinue without consulting prescriber. Avoid alcohol while taking this medication; could cause severe reaction. Inform prescriber of all other prescription or OTC medications you are taking; do not introduce new medication without consulting prescriber. If you experience hypoglycemic reaction, contact prescriber immediately. Maintain regular dietary intake and exercise routine and always carry quick source of sugar with you. You may experience side effects during first weeks of therapy (headache, constipation or diarrhea, bloating or loss of appetite); consult prescriber if these persist. Report severe or persistent side effects, including fever, extended vomiting or flu-like symptoms, skin rash, easy bruising or bleeding, or change in color of urine or stool. Pregnancy/breast-feeding precautions: Inform prescriber if you are or intend to become pregnant. Do not breast-feed.


Nursing Implications

Patients who are anorexic or NPO may need to hold the dose to avoid hypoglycemia

Monitor fasting blood glucose, normal Hgb A1c, or fructosamine levels; monitor for signs and symptoms of hypoglycemia (fatigue, sweating, numbness of extremities); monitor urine for glucose and ketones


Anesthesia and Critical Care Concerns/Other Considerations

 Long half-life may complicate recovery from excess effects. Patients previously maintained on insulin at <40 units/day may be directly changed to chlorpropamide. Patients previously receiving larger insulin doses should have their insulin doses decreased by 50% daily for the first few days, then gradually reduced further as necessary.

The possibility of higher doses of sulfonylureas eliciting an increase in cardiovascular events, because of their effects on blocking potassium sensitive ATP channels, has been raised. However, there are presently only limited data to support this premise, particularly with newer generation agents.


Cardiovascular Considerations

 The possibility of higher doses of sulfonylureas eliciting an increase in cardiovascular events, because of their effects on blocking potassium sensitive ATP channels, has been raised. However, there are presently only limited data to support this premise, particularly with newer generation agents. An early study suggested poor cardiovascular outcomes in diabetic patients treated with tolbutamide. Retrospective studies evaluating cardiovascular outcomes following angioplasty and acute myocardial infarction in diabetic patients receiving newer sulfonylureas are inconsistent. Longer-term prospective trials of sulfonylurea therapy, such as the UKPDS, do not reveal any increased cardiovascular mortality.


Dental Health: Effects on Dental Treatment

 Chlorpropamide-dependent diabetics (noninsulin dependent, Type 2) should be appointed for dental treatment in morning in order to minimize chance of stress-induced hypoglycemia.


Dental Health: Vasoconstrictor/Local Anesthetic Precautions

 No information available to require special precautions


Mental Health: Effects on Mental Status

 Dizziness is common


Mental Health: Effects on Psychiatric Treatment

 Rare reports of agranulocytosis; use caution with clozapine and carbamazepine


Dosage Forms

 Tablet: 100 mg, 250 mg


References

Alexander RW, "Prolonged Hypoglycemia Following Acetohexamide Administration," Diabetes , 1966, 15(5):362-4.

Arrigoni L, Fundak G, Horn J, et al, "Chlorpropamide Pharmacokinetics in Young Healthy Adults and Older Diabetic Patients," Clin Pharm , 1987, 6(2):162-4.

"A Study of the Effects of Hypoglycemia Agents on Vascular Complications in Patients With Adult-onset Diabetes. VI. Supplementary Report on Nonfatal Events in Patients Treated With Tolbutamide. The University Group Diabetes Program," Diabetes , 1976, 25(12):1129-53.

Cowen DL, Burtis B, and Youmans J, "Prolonged Coma After Acetohexamide Ingestion," JAMA , 1967, 201(2):141-2.

"Effect of Intensive Blood-Glucose Control With Metformin on Complications in Overweight Patients With Type 2 Diabetes (UKPDS 34). UK Prospective Diabetes Study (UKPDS) Group," Lancet , 1998, 352(9131):854-65.

Erickson T, Arora A, Lebby TI, et al, "Acute Oral Hypoglycemic Ingestions," Vet Hum Toxicol , 1991, 33(3):256-8.

Forrest JAH, "Chlorpropamide Overdosage: Delayed and Prolonged Hypoglycemia," Clin Toxicol , 1974, 7(1):19-24.

Garratt KN, Brady PA, Hassinger NL, et al, "Sulfonylurea Drugs Increase Early Mortality in Patients With Diabetes Mellitus After Direct Angioplasty for Acute Myocardial Infarction," J Am Coll Cardiol , 1999, 33(1):119-24.

Gordon MR, Flockhart D, Zawadzki JK, et al, "Hypoglycemia Due to Inadvertent Dispensing of Chlorpropamide," Am J Med , 1988, 85(2):271-2.

Graw RG and Clarke RR, "Chlorpropamide Intoxication - Treatment With Peritoneal Dialysis," Pediatrics , 1970, 45(1):106-8.

"Intensive Blood-Glucose Control With Sulphonylureas or Insulin Compared With Conventional Treatment and Risk of Complications in Patients With Type 2 Diabetes (UKPDS 33) UK Prospective Diabetes Study (UKPDS) Group," Lancet , 1998, 352(9131):837-53.

Klamann A, Sarfert P, Launhardt V, et al, "Myocardial Infarction in Diabetic vs Nondiabetic Subjects. Survival and Infarct Size Following Therapy With Sulfonylureas (Glibenclamide), Eur Heart J , 2000, 21(3):220-9.

Meinert CL, Knatterud GL, Prout TE, et al, "A Study of the Effects of Hypoglycemic Agents on Vascular Complications in Patients With Adult-Onset Diabetes. II. Mortality Results," Diabetes , 1970, 19:789-830.

O'Keefe JH, Blackstone EH, Sergeant P, et al, "The Optimal Mode of Coronary Revascularization for Diabetics. A Risk-Adjusted Long-Term Study Comparing Coronary Angioplasty and Coronary Bypass Surgery," Eur Heart J , 1998, 19(11):1696-703.

Seltzer HS, "Drug-Induced Hypoglycemia. A Review of 1418 Cases," Endocrinol Metab Clin North Am , 1989, 18(1):163-83.

"Standards of Medical Care for Patients With Diabetes Mellitus. American Diabetes Association," Diabetes Care , 1994, 17(6):616-23.


International Brand Names

 Abemide® (JP); Anti-D® (SG); Apo-Chlorpropamide® (CA); Chlorformin® (IN); Chlorpropamid® (CY, PL, RU); Chlorpropamide® (GB, SG); Clorpropamida® (CL); Clorpropamida L.CH.® (CL); Diabeedol® (TH); Diabemide® (IT); Diabinese® (AR, BE, BR, CL, DO, EG, ES, GB, HK, ID, IL, IT, LU, MX, PL, SG, SI, TH, TR, ZA); Diabitex® (IL); Dibecon® (TH); Diprometane® (AR); Glycemin® (TH); Hypomide® (ZA); Insogen® (MX); Meldian® (HR); Novo-Propamide (CA); Oral Gluc® (AR); Propamide® (SG, TH); Sucranase® (HK, JO, KW, LB, MT, MY, RO); Tesmel® (ID); Trane® (AR)


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