CHLORPROPAMIDE

Chemistry - An oral sulfonylurea antidiabetic agent, chlorpropamide occurs as a white, crystallinepowder having a slight odor. It is practically insoluble in water.

Storage, Stability, Compatibility

Chlorpropamide tablets should be stored in well-closed containers at room temperature.

Pharmacology - CHLORPROPAMIDE

Sulfonylureas lower blood glucose concentrations in both diabetic and non-diabetics. The exact mechanism of action is not known, but these agents are thought to exert the effect primarily by stimulating the beta cells in the pancreas to secrete additional endogenous insulin.
Ongoing use of the sulfonylureas appear to also enhance peripheral sensitivity to insulin and reducethe production of hepatic basal glucose. The mechanisms causing these effects are yet to be fullyexplained. Chlorpropamide also has antidiuretic activity, presumably by potentiating vasopressin'seffects on the renal tubules. It may also stimulate secretion of vasopressin.

Uses, Indications

While chlorpropamide could potentially be of benefit in the adjunctive treatment of diabetes mellitus in small animals, its use has been primarily for adjunctive therapy in diabetes insipidus in dogs and cats.

Pharmacokinetics - CHLORPROPAMIDE

Chlorpropamide is absorbed well from the GI tract. Its distribution characteristics have not been well described, but it is highly bound to plasma proteins and is excreted into milk. Elimination half lives have not been described in domestic animals, but in humans the elimination half life is about 36 hours. The drug is both metabolized in the liver and excreted unchanged. Elimination of chlorpropamide is enhanced in alkaline urine and decreased in acidic urine.

Contraindications, Precautions, Reproductive Safety

Oral antidiabetic agents are consideredcontraindicated with the following conditions: severe burns, severe trauma, severe infection, diabeticcoma or other hypoglycemic conditions, major surgery, ketosis, ketoacidosis or other significantacidotic conditions. Chlorpropamide should only be used when its potential benefits outweigh itsrisks during untreated adrenal or pituitary insufficiency; thyroid, cardiac, renal or hepatic functionimpairment; prolonged vomiting; high fever; malnourishment or debilitated condition; or when fluidretention is present.
Safe use during pregnancy has not been established.

Adverse Effects, Warnings

Hypoglycemia is the most common adverse effect noted with thisagent. Syndrome of inappropriate antidiuretic hormone (SIADH), anorexia, diarrhea, hepatotoxicity, lassitude or other CNS effects, and hematologic toxicity are all potentially possible, but except forthe GI disturbances are less likely to occur than hypoglycemia.

Overdosage, Acute Toxicity

Profound hypoglycemia is the greatest concern after an overdose.
Gut emptying protocols should be employed when warranted. Because of its long half life, bloodglucose monitoring and treatment with parenteral glucose may be required for several days.
Overdoses may also require additional monitoring (blood gases, serum electrolytes) and supportivetherapy.

Drug Interactions

A disulfiram-like reaction (anorexia, nausea, vomiting) has been reported inhumans who have ingested alcohol within 48-72 hours of receiving chlorpropamide.
The following drugs may displace chlorpropamide, or be displaced by chlorpropamide fromplasma proteins, thereby causing enhanced pharmacologic effects of the two drugs involved:chloramphenicol, furazolidone, non-steroidal anti-inflammatory agents, salicylates, sulfonamides, warfarin.
Beta adrenergic blocking agents (e.g., propranolol) may affect diabetes (mellitus) control.
Chlorpropamide may prolong the duration of action of barbiturates. Probenecid or monamineoxidase inhibitors may increase the hypoglycemic effects of chlorpropamide. Thiazide diuretics may exacerbate diabetes mellitus.
Because elimination of chlorpropamide is enhanced in alkaline urine and decreased in acidic urine.
Ammonium chloride or vitamin C may enhance the effects of chlorpropamide and sodiumbicarbonate or other urinary alkalinizers (citrate solutions) may reduce its effects.
Laboratory Considerations - Chlorpropamide may mildly increase values of liver enzymes,
BUN or serum creatinine.