chlorpropamide
Diabinese, Novo-Propamide ◆

Pharmacologic classification: sulfonylurea
Therapeutic classification: antidiabetic, antidiuretic
Pregnancy risk category C


Available forms
Available by prescription only
Tablets: 100 mg, 250 mg

Indications and dosages
 Adjunct to diet to lower blood glucose levels in patients with type 2 diabetes mellitus. Adults: 250 mg P.O. daily with breakfast or in divided doses if GI disturbances occur. First dosage increase may be made after 5 to 7 days because of extended duration of action, then dosage may be increased q 3 to 5 days by 50 to 125 mg, if needed, to a maximum of 750 mg daily.
≡ Dosage adjustment. For adults older than age 65, initial dose should be 100 to 125 mg daily. Debilitated or malnourished patients and those with impaired renal or hepatic function usually require a lower initial dosage.
 To change from insulin to oral therapy. Adults: If insulin dosage is less than 40 units daily, insulin may be stopped and oral therapy started as above. If insulin dosage is 40 units or more daily, start oral therapy as above, with insulin dose reduced 50% the first few days. Further insulin reductions should be made based on patient response.

Pharmacodynamics
Antidiabetic action: Chlorpropamide lowers blood glucose levels by stimulating insulin release from beta cells in the pancreas. After prolonged administration, it produces hypoglycemic effects through extrapancreatic mechanisms, including reduced basal hepatic glucose production and enhanced peripheral sensitivity to insulin; the latter may result either from an increased number of insulin receptors or from changes in events that follow insulin binding.
Antidiuretic action: Drug appears to potentiate the effects of vasopressin, an antidiuretic hormone within the renal tubules.

Pharmacokinetics
Absorption: Absorbed readily from the GI tract. Maximum decrease in serum glucose levels at 3 to 6 hours.
Distribution: Distribution isn’t fully understood, but is probably similar to that of the other sulfonylureas. It’s highly protein-bound.
Metabolism: About 80% of drug is metabolized by the liver. Whether the metabolites have hypoglycemic activity is unknown.
Excretion: Excreted in urine. Rate of excretion depends on urinary pH; it increases in alkaline urine and decreases in acidic urine. Duration of action is up to 60 hours; half-life is 36 hours.

Route Onset Peak Duration
P.O. 1 hr 2-4 hr 24 hr


Contraindications and precautions
Contraindicated for treating type 1 diabetes or diabetes that can be adequately controlled by diet. Also contraindicated in pregnant women, breast-feeding women, patients hypersensitive to drug, and patients with type 2 diabetes complicated by ketosis, acidosis, diabetic coma, major surgery, severe infections, or severe trauma.
  Use cautiously in geriatric, debilitated, or malnourished patients and in those with porphyria or impaired renal or hepatic function.

Interactions
Drug-drug. Anticoagulants: May increase plasma levels of both drugs and, after continued therapy, may reduce plasma levels and anticoagulant effects. Monitor patient closely.
Beta blockers: May increase risk of hypoglycemia. Monitor patient closely.
Calcium channel blockers, corticosteroids, estrogens, hormonal contraceptives, isoniazid, nicotinic acid, phenothiazines, phenytoin, sympathomimetics, thiazides, thyroid drugs: May cause hyperglycemia and loss of control. Monitor blood glucose level closely.
Chloramphenicol, guanethidine, insulin, MAO inhibitors, probenecid, salicylates, sulfonamides: May enhance hypoglycemic effects by displacing chlorpropamide from its protein-binding sites. Avoid use together.
Drug-herb. Bitter melon (karela), ginkgo biloba: May increase risk of hypoglycemia. Discourage use together.
Drug-lifestyle. Alcohol use: May produce disulfiram-like reaction. Discourage alcohol use.
Smoking: Increases corticosteroid release. May require higher dosages of chlorpropamide. Discourage smoking.

Adverse reactions
CNS: paresthesia, fatigue, dizziness, vertigo, malaise, headache.
GI: nausea, heartburn, epigastric distress.
GU: tea-colored urine, altered urine phenyl ketone level.
Hematologic: leukopenia, thrombocytopenia, aplastic anemia, agranulocytosis, hemolytic anemia.
Metabolic: prolonged hypoglycemia; dilutional hyponatremia; altered cholesterol, porphyrin, and protein levels; altered cephalin flocculation.
Skin: rash, pruritus, erythema, urticaria.
Other: hypersensitivity reactions.

Effects on lab test results
• May increase BUN, creatinine, alkaline phosphatase, bilirubin, AST, LDH, and cholesterol levels. May decrease glucose and sodium levels.
• May decrease hemoglobin and WBC, platelet, and granulocyte counts.

Overdose and treatment
Signs and symptoms of overdose include low blood glucose levels, tingling of lips and tongue, hunger, nausea, decreased cerebral function (lethargy, yawning, confusion, agitation, and nervousness), increased sympathetic activity (tachycardia, sweating, and tremor), and ultimately seizures, stupor, and coma.
 Mild hypoglycemia (without loss of consciousness or neurologic findings) can be treated with oral glucose and dosage adjustments. If patient loses consciousness or experiences neurologic symptoms, he should receive rapid injection of D50W, followed by a continuous infusion of D10W at a rate to maintain blood glucose levels greater than 100 mg/dl. Because of chlorpropamide’s long half-life, monitor patient for 3 to 5 days.

Special considerations
• To avoid GI intolerance in patients who require daily doses of 250 mg or more and to improve control of hyperglycemia, divided doses are recommended. These are given before the morning and evening meals.
• Because of the long duration of action of the drug, adverse reactions, especially hypoglycemia, may be more frequent or severe than with some other sulfonylureas.
• Patients with severe diabetes who don’t respond to 500 mg usually won’t respond to higher doses.
• Oral hypoglycemics have been linked to an increased risk of CV mortality compared with diet or diet and insulin.
• Drug may accumulate in patients with renal insufficiency. Observe patient for signs such as dysuria, anuria, and hematuria.
• Patients switching from chlorpropamide to another sulfonylurea should be monitored closely for 1 week because of chlorpropamide’s prolonged retention in the body.
• Chlorpropamide may potentiate antidiuretic effects of vasopressin. Monitor patient for drowsiness, muscle cramps, seizures, unconsciousness, water retention, and weakness.
Breast-feeding patients
• Drug appears in breast milk and shouldn’t be given to breast-feeding women.
Pediatric patients
• Safety and effectiveness in children haven’t been established.
Geriatric patients
• Elderly patients may be more sensitive to the effects of drug because of reduced metabolism and elimination. They’re more likely to develop neurologic symptoms of hypoglycemia.
• Avoid drug in elderly patients because of its longer duration of action.
• Elderly patients usually require a lower initial dosage.

Patient education
• Emphasize importance of following prescribed diet, as well as the exercise and medical regimen.
• Instruct patient to take drug at the same time each day. If a dose is missed, it should be taken immediately, unless it’s almost time for the next dose. Patient should never double the dose.
• Encourage patient to wear a medical identification bracelet or necklace.
• Instruct patient to take drug with food if it causes GI upset.
• Teach patient how to monitor blood glucose, urine glucose, and ketone levels, as needed.
• Teach patient to recognize the signs and symptoms of hypoglycemia and hyperglycemia and what to do if they occur.

Reactions may be common, uncommon, life-threatening, or COMMON AND LIFE THREATENING.
◆ Canada only
◇ Unlabeled clinical use