(British Approved Name, rINN)

International Nonproprietary Names (INNs) in main languages (French, Latin, and Spanish): Chloropropamid; Chlorpropamid; Chlorpropamidas; Chlorpropamidum; Clorpropamida; Klooripropamidi; Klorpropamid

Pharmacopoeias. In China, Europe, Japan, and US. European Pharmacopoeia, 6th ed. (Chlorpropamide). A white or almost white, crystalline powder. It exhibits polymorphism. Practically insoluble in water soluble in alcohol freely soluble in acetone and in dichlo-romethane dissolves in dilute solutions of alkali hydroxides. Protect from light.

The United States Pharmacopeia 31, 2008 (Chlorpropamide). A white crystalline powder having a slight odour. Practically insoluble in water soluble in alcohol sparingly soluble in chloroform.

Adverse Effects and Treatment

As for sulfonylureas in general. Chlorpropamide may be more likely than other sulfonylureas to induce a syndrome of inappropriate secretion of antidiuretic hormone characterised by water retention, hyponatraemia, and CNS effects. Patients receiving chlorpropamide may develop facial flushing after drinking alcohol.

Precautions

As for sulfonylureas in general. Chlorpropamide should be avoided in the elderly and in renal or hepatic impairment because its long half-life increases the risk of hypoglycaemia. The antidiuretic effect of chlorpropamide may cause problems in patients with conditions associated with fluid retention.

Fasting. For the view that although some sulfonylurea antidiabetics may be able to be used with caution in fasting Muslim patients during Ramadan, chlorpropamide is contra-indicated, see under Precautions of Insulin.

Porphyria. Chlorpropamide has been associated with acute attacks of porphyria and is considered unsafe in porphyric patients.

Thyroid disorders. Some manufacturers recommend that chlorpropamide should not be used in patients with impaired thyroid function, but see under Sulfonylureas.

Interactions

As for sulfonylureas in general. Chlorpropamide may produce profound facial flushing associated with alcohol ingestion.

Pharmacokinetics

Chlorpropamide is readily absorbed from the gastrointestinal tract and is extensively bound to plasma proteins. The half-life is about 35 hours. About 80% of a dose is metabolised in the liver metabolites and unchanged drug are excreted in the urine. Chlorpropamide crosses the placenta and has been detected in breast milk.

Uses and Administration

Chlorpropamide is a sulfonylurea antidiabetic. It has a duration of action of at least 24 hours, and is given orally in the treatment of type 2 diabetes mellitus in an initial daily dose of 250 mg as a single dose with breakfast. After 5 to 7 days the dose may be adjusted, in steps of 50 to 125 mg at intervals of 3 to 5 days, to achieve an optimum maintenance dose which is usually in the range 100 to 500 mg daily. Increasing the dose above 500 mg daily is unlikely to produce further benefit, and doses above 750 mg daily should be avoided. Although a reduced dose range has been proposed for the elderly, use of chlorpropamide is inadvisable in this group.

Chlorpropamide, though not the other sulfonylureas, is also sometimes used in cranial diabetes insipidus. It has been reported to act by sensitising the renal tubules to antidiuretic hormone. The dose has to be carefully adjusted to minimise the risk of hypogly-caemia. An initial dose of 100 mg daily, adjusted if necessary to a maximum of 350 mg daily has been recommended, although doses of up to 500 mg daily have been used.

Diabetes mellitus. Patients with type 2 diabetes whose blood glucose is adequately controlled at first by sulfonylureas often eventually have treatment failure and loss of diabetic control. Results from the UK Prospective Diabetes Study have suggested that the 6-year failure rate was higher in patients treated with glibenclamide (48%) than in those given chlorpropamide (40%). This difference was equivalent to delaying the requirement for additional therapy for a year in chlorpropamide-treated patients.

Preparations

British Pharmacopoeia 2008: Chlorpropamide Tablets

The United States Pharmacopeia 31, 2008: Chlorpropamide Tablets.

Proprietary Preparations:

Argentina: Diabinese Idle † Trane

Belgium: Diabinesef

Brazil: Clorpromini † Clorzin † Diabecontrol Diabinese Glicoben Glicorp Pramiclalin

Canada: Novo-Propamide

Chile: Diabinese

Greece: Diabinese

Hong Kong: Diabinese

India: Copamidef

Indonesia: Diabinese

Israel: Diabinese † Diabitex

Italy: Diabemide

Malaysia: Anti-D † Diabinese † Propamide

Mexico: Ap-oprod Diabiclor Diabinese Insogen

Philippines: Diabinese

South Africa: Diabinese Hypomide

Singapore: Anti-D Chlomide † Diabinese † Propamide

Spain: Diabinese

Thailand: Diabeedol Diabinese Dibecon Glycemin Propamide

Turkey: Diabinese

USA: Diabinese

Venezuela: Dabinese.

Multi-ingredient:

India: Chlorformin †

Italy: Bidiabe Pleiamide

Mexico: Insogen Plus Mellitron Obinese

Switzerland: Diabiformine

The symbol † denotes a preparation no longer actively marketed.

Sulfonylureas: First-Generation

Sulfonylureas consists of two groups or generations of agents. The first-generation agents are now less commonly used because second-generation agents are as effective and have fewer side effects. Two first-generation agents, chlorpropamide and tolbutamide are still popular with some physicians. This group also contains tolazamide and acetohexa-mide; both are rarely used today.

Chlorpropamide. Brand Name Drug: Diabinese. Chlorpropamide is administered once daily in a 100 mg or 250 mg tablet. Its half-life is extremely long, with effects lasting up to >48 hours. The principal disadvantage of this agent is that it is excreted almost entirely renally. Therefore, the risk of hypoglycemia makes this drug relatively contraindicated in the elderly and absolutely contraindicated in those with renal insufficiency. Chlorpropamide also enhances the effects of vasopressin, at times resulting in the syndrome of inappropriate antidiuretic hormone (SIADH). With the introduction of more potent agents that have a much shorter half-life and fewer side effects, today there is little reason to use chlorpropamide.

Tolbutamide. Brand Name Drug: Orinase. Tolbutamide has a much shorter duration of action (6-10 hours) and is metabolized primarily by the liver. It is a safer agent than chlorpropamide; however, it is relatively weak in its antidiabetic activity.

Sulfonylureas: Second-Generation

Second-generation sulfonylureas are the most commonly prescribed agents for treating type 2 diabetes. As a group, they are at least 100 times more potent than tolbutamide. They include glyburide, glipizide, and the newest agent, glimepiride. Glyburide and glipizide, when used as monotherapy, have proven effective in lowering HgbA₁C 1% to 2% in most studies.

Glyburide. Brand Names: Diabeta, Glycron, Glynase, Micronase. Glyburide is metabolized in the liver to metabolites with reduced hypoglycemic activity. These metabolites are then excreted renally. Therefore, in the elderly and patients with compromised renal function, glyburide is relatively contraindicated because of the risk of hypoglycemia. Even in normal subjects it is not unusual to see persistence of glyburide’s effects for up to 24 hours. In the United Kingdom Prospective Diabetes Study (UKPDS), a multicenter trial of >5000 patients with type 2 diabetes mellitus, the incidence of hypoglycemia with glyburide was similar to that seen with chlorpropamide. Patients usually are started on a 2.5-mg or 5-mg tablet in the morning before the first meal of the day. The dose can be escalated gradually to a maximum of 20 mg/day. However, it is rare to see further improvement in efficacy with doses > 10 mg/day. Again, this agent should be used with caution in the elderly population and in those with renal insufficiency.

There also is a micronized form of glyburide. However, it has been difficult to find exactly equivalent dosages between the two forms, which can lead to confusion for the patient and physician. The micronized agents have not been shown to have a higher bio availability or greater efficacy than regular glyburide.

Glipizide. Brand Name Drug: Glucotrol. Glipizide is completely metabolized in the liver and excreted primarily by the kidneys. However, it is not as potent as glyburide at raising basal insulin levels and therefore is the preferred sulfonylurea in elderly patients or those with renal insufficiency. It usually is started with 5 mg orally 30 minutes prior to breakfast. If the dose exceeds 15 mg/day, then it is best to divide the doses by giving it before breakfast and before dinner. The maximum recommended dose is 40 mg/day, although it is rare to see additional efficacy with doses >20 mg/day. There is also an extended release form of glipizide, which allows for once a day dosing.

Glimepiride. Brand Name Drug: Amaryl. In 1996, a new sulfonylurea, glimepiride, was approved for use in the treatment of type 2 diabetes. It is the most potent of the sulfonylureas to date, requiring a 1-, 2-, or 4-mg dose once daily. It is completely metabolized in the liver, making it safe in the elderly and in those with renal insufficiency. The maximal recommended dose is 6 mg/day, and this agent is of equal efficacy whether given once or twice daily. Like the other sulfonylureas, glimepiride acts as an insulin secretagogue, but in comparative trials, it caused fewer episodes of hypoglycemia. Other data from comparative trials show that glimepiride provides greater postprandial insulin secretion, but fasting glucose control and HgbA₁C lowering is similar to that of glyburide. Glimepiride has been shown to have extrapancreat-ic in vitro effects on glucose uptake, but the clinical significance of these effects is still to be determined.

Oral antidiabetic drugs fall into several classes (Table 5). Of particular interest are the insulin sensitizers because they specifically target insulin resistance. Other agents address different aspects of glycemic control.

Insulin secretion stimulators (secretagogues)

For more than 40 years, sulfonylureas have been the first line of therapy for individuals with type 2 diabetes. These agents directly stimulate pancreatic b-cells to produce insulin by increasing the influx of calcium. Sulfonylureas increase circulating insulin and reduce both fasting and postprandial glucose, but they are not insulin sensitizers and therefore do not address the problem of insulin resistance. Sulfonylureas lower A1C an average of 1% to 2% and offer effective glycemic control in up to 75% of patients; however, efficacy lapses over time, with about 5-10% of patients per year failing to maintain the initial glycemic control. Primary adverse effects include hypoglycemia and weight gain (typically 2-5 kg). Glimepiride (Amaryl) is emerging as the sulfonylurea of choice due to its once-a-day dosing, extrapancreatic effect, and the fact that it causes less weight gain and hypoglycemia and is priced as low as generic glyburide.

Another class of secretagogues, derivatives of meglitinide or phenylalanine, also stimulate insulin but act at a different site on pancreatic beta-cells than the sulfonylureas. Because these agents have a very short onset of action and short half-life, they must be taken immediately before every meal (compared to once-daily dosing for sulfonylureas), so treatment adherence may be an issue for some patients. They have a side effect profile similar to the sulfonylureas; however, because meglitinides are shorter-acting agents, they carry a lower risk of sustained hypoglycemia. Efficacy is similar to that of sulfonylureas. The two products currently available are nateglinide (Starlix) and repaglinide (Prandin).

Alpha-glucosidase inhibitors

Drugs in this group produce mild reductions in postprandial hyperglycemia by inhibiting the enzyme responsible for metabolizing complex carbohydrates in the small intestine. Taken right before a meal, these agents reduce glucose levels by slowing absorption of carbohydrates and delaying entry of glucose into liver and muscle tissue. Gastrointestinal side effects (ie, abdominal pain, diarrhea, and flatulence) are the most common reactions to alpha-glucosidase inhibitors (reported in up to 75% of patients), leading some patients to discontinue therapy with these drugs. Available agents include acarbose (Precose) and miglitol (Glyset). Gastrointestinal side effects can be greatly reduced if low doses are started and then gradually titrated over 10-12 weeks to the maximum and effective doses. At present, these agents are seldom used in the United States.

Thiazolidinediones

The thiazolidinediones (TZDs or glitazones) are a relatively new class of agents that reduce insulin resistance. TZDs do not stimulate the secretion of insulin but rather enhance the effects of circulating insulin by improving insulin sensitivity in muscle and adipose tissue and by inhibiting hepatic gluconeogenesis. TZDs work by stimulating certain receptors (peroxisome proliferator-activated receptor gamma, or PPAR-gamma) in the nucleus of the cells. Activation of PPAR-gamma modulates the transcription of a number of insulin-responsive genes involved in the control of glucose and lipid metabolism. In response to thiazolidinediones stimulation, the genes produce a protein called GLUT-4. Insulin works by recruiting GLUT-4 to the cell’s outer membrane. This partnership, in turn, promotes transport of glucose across the membrane and into the cell’s interior.

Examples of insulin sensitizers include pioglitazone hydrochloride (Actos) and rosiglitazone maleate (Avandia). Another drug in this class, troglitazone (Rezulin), was removed from the market because it was linked to idiosyncratic cases of hepatotoxicity. In clinical trials, there has been no evidence of drug-induced hepatotoxicity with pioglitazone or rosiglitazone, but there have been rare postmarketing case reports of liver damage in patients receiving rosiglitazone and pioglitazone (causality not established). The safe use of these agents, therefore, requires careful monitoring of liver function: ALT enzyme levels should be measured at baseline and monitored every 2 months for 1 year and periodically thereafter. Patients with hepatic impairment should not be treated with thiazolidinediones.

In large placebo-controlled trials lasting up to 26 weeks, monotherapy with pioglitazone or rosiglitazoneproduced significant improvements in A1C and fasting blood glucose concentrations (Table 6). Pioglitazone also led to significant improvements in A1C and improvements in FPG when combined with a sulfonylurea, metformin, or insulin. Rosiglitazone resulted in significant decreases in A1C and FPG levels when combined with metformin or a sulfonylurea.

In addition to reducing insulin resistance, thiazolidinediones also have effects on lipids (Table 6). In a 26-week placebo-controlled study, pioglitazone was associated with decreases in triglycerides of 9.0%, 9.6%, and 9.3% in patients treated with 15-, 30-, and 45-mg, respectively, compared with baseline. HDL (“good”) cholesterol increased by 14%, 12%, and 19% in the 15-, 30-, and 45-mg groups, respectively. No consistent differences were reported for LDL (“bad”) cholesterol and total cholesterol in patients treated with pioglitazone versus placebo.

In a similar 26-week pla-cebo-controlled study, rosiglitazone raised HDL cholesterol by 11.4% and 14.2% in doses of 4- and 8-mg per day, respectively, compared to baseline, but the drug also raised LDL cholesterol by 14.1% and 18.6%, respectively. Changes in triglycerides were variable and generally not statistically significant compared to placebo controls. A recent retrospective review of type 2 diabetes patients treated with either pioglitazone (n=525) or rosiglitazone (n=590) suggested that pioglitazone provides a greater benefit in terms of blood lipid profile than does rosiglitazone.

Because TZDs do not affect insulin secretion, they do not induce hypoglycemia. Dose-related weight gain is seen with both pioglitazone (average increase 0.5 kg to 2.8 kg) and rosiglitazone (median increase 1.0 kg to 3.1 kg). Also, a small number of patients experience mild to moderate edema and anemia. TZDs can cause fluid retention, which may lead to or exacerbate heart failure; thus, patients should be observed for signs and symptoms of congestive heart failure, and TZDs should not be used in patients with class III or IV cardiac status. Studies are currently underway to determine whether thiazolidinediones may be effective in preventing progression of insulin resistance to full-blown type 2 diabetes.