Oral Hypoglycemic agents
History
In contrast to the systematic studies that led to the isolation of insulin, the sulfonylureas were discovered accidentally. In 1942, Janbon and colleagues noted that some sulfonamides caused hypoglycemia in experimental animals. These observations were soon extended, and 1-butyl-3-sulfonylurea (carbutamide) became the first clinically useful sulfonylurea for the treatment of diabetes. This compound was later withdrawn because of adverse effects on the bone marrow, but it led to the development of the entire class of sulfonylureas.
Sulfonylureas
Chemistry
The sulfonylureas are divided traditionally into two groups or generations of agents. Their structural relationships are shown in Table.
All members of this class of drugs are substituted arylsulfonylureas. They differ by substitutions at the para position on the benzene ring and at one nitrogen residue of the urea moiety. The first group of sulfonylureas includes tolbutamide, acetohexamide, tolazamide, and chlorpropamide.
A second generation of hypoglycemic sulfonylureas has emerged. These drugs (glibenclamide, glipizide, and gliclazide) are considerably more potent than the earlier agents.
History
In contrast to the systematic studies that led to the isolation of insulin, the sulfonylureas were discovered accidentally. In 1942, Janbon and colleagues noted that some sulfonamides caused hypoglycemia in experimental animals. These observations were soon extended, and 1-butyl-3-sulfonylurea (carbutamide) became the first clinically useful sulfonylurea for the treatment of diabetes. This compound was later withdrawn because of adverse effects on the bone marrow, but it led to the development of the entire class of sulfonylureas.
Sulfonylureas
Chemistry
The sulfonylureas are divided traditionally into two groups or generations of agents. Their structural relationships are shown in Table.
All members of this class of drugs are substituted arylsulfonylureas. They differ by substitutions at the para position on the benzene ring and at one nitrogen residue of the urea moiety. The first group of sulfonylureas includes tolbutamide, acetohexamide, tolazamide, and chlorpropamide.
A second generation of hypoglycemic sulfonylureas has emerged. These drugs (glibenclamide, glipizide, and gliclazide) are considerably more potent than the earlier agents.
Structure - Activity Relationships
The benzene ring should contain one substituent, preferably in the para position. The substituents that seem to enhance hypoglycemic activity are methyl, amino, acetyl, chloro, bromo, methylthio, and trifluoromethyl groups.
Compounds with p-(-β-arylcarboxamidoethyl) substituents (the second generation agents) are orders of magnitude better than the first generation agents. It is believed that this is because of a specific distance between the nitrogen atom of the substituent and the sulfonamide nitrogen atom.
The group attached to the terminal nitrogen should be of certain size and should impart lipophilic properties to the molecule. The N-methyl are inactive, N-ethyl have low activity, while N-propyl to N-hexyl are most active. Activity is lost if N-substituent contains 12 or more carbons.
Mechanism of Action
The principal action of the sulphonylureas is on the β-cells of the islets. Stimulating insulin secretion and thus reducing plasma glucose concentration.
High affinity receptors of sulfonlyreas are present on the ATP-sensitive K+ channels in β-cell plasma membranes and the binding of various sulphonylureas parallels their potency in stimulating insulin release. Glibenclamide reduces the potassium permeability of β-cell by blocking the ATP-sensitive potassium channels, causing depolarization, Ca2+ entry and hence insulin secretion.
Basal insulin secretion and the secretory response to various stimuli are enhanced in the first few days of treatment with sulphonylurea drugs. With longer treatment, insulin secretion continues to be augmented and tissue sensitivity to insulin also improves, by an unknown mechanism.
Absorption, Fate, and Excretion
The sulfonylureas have similar spectra of activities; thus, their pharmacokinetic properties are their most distinctive characteristics. Although there are differences in the rates of absorption of the different sulfonylureas, all are effectively absorbed from the gastrointestinal tract. However, food and hyperglycemia can reduce the absorption of sulfonylureas. (Hyperglycemia per se inhibits gastric and intestinal motility and thus can retard the absorption of many drugs.) In view of the time required to reach an optimal concentration in plasma, sulfonylureas with short half lives may be more effective when given 30 minutes before eating.
Sulfonylureas in plasma are largely (90% to 99%) bound to protein, especially albumin; plasma protein binding is least for chlorpropamide and greatest for glibenclamide. The volumes of distribution of most of the sulfonylureas are about 0.2 liter/kg.
The first-generation sulfonylureas vary considerably in their half-lives and extents of metabolism. Chlorpropamide has a long half-life (24 to 48 hours). The second-generation agents are approximately 100 times more potent than are those in the first group (Lebovitz and Feinglos, 1983). Although their half-lives are short (1.5 to 5 hours), their hypoglycemic effects are evident for 12 to 24 hours, and it is often possible to administer them once daily. The reason for the discrepancy between the half-life and duration of action of these drugs is not clear.
All of the sulfonylureas are metabolized by the liver, and the metabolites are excreted in the urine. Metabolism of chlorpropamide is incomplete, and about 20% of the drug is excreted unchanged. Thus, sulfonylureas should be administered with caution to patients with either renal or hepatic insufficiency.
Adverse Reactions
Adverse effects of the sulfonylureas are infrequent, occurring in about 4% of patients taking first-generation drugs and perhaps slightly less often in patients receiving second-generation agents (Paice et al., 1985). Not unexpectedly, sulfonylureas may cause hypoglycemic reactions, including coma (Ferner and Neil, 1988; Seltzer, 1989). This is a particular problem in elderly patients with impaired hepatic or renal function who are taking longer-acting sulfonylureas. Sulfonylureas can be ranked in order of decreasing risk of causing hypoglycemia based on their half-lives. The longer the half-life, the more likely an agent will induce hypoglycemia. Severe hypoglycemia in the elderly can present as an acute neurologic emergency that may mimic a cerebrovascular accident. Thus, it is important to check the plasma glucose of any elderly patient presenting with acute neurologic symptoms. Owing to the long half life of some sulfonylureas, it may be necessary to treat an elderly hypoglycemic patient for 24 to 48 hours with an intravenous glucose infusion.
Other side effects of sulfonylureas include nausea and vomiting, cholestatic jaundice, agranulocytosis, aplastic and hemolytic anemias, generalized hypersensitivity reactions, and dermatological reactions. About 10% to 15% of patients who receive these drugs, particularly chlorpropamide, develop an alcohol-induced flush similar to that caused by disulfiram. Sulfonylureas, especially chlorpropamide, also may induce hyponatremia by potentiating the effects of antidiuretic hormone on the renal collecting duct (Paice et al., 1985). This undesirable side effect occurs in up to 5% of all patients; it is less frequent with glibenclamide and glipizide.
Drug interactions (Rang 1999)
Several compounds augment the hypoglycemic effect of the sulfonylureas and several such interactions are potentially clinically important. Non-steroidal anti-inflammatory drugs (including azapropazone, phenylbutazone and salicylates), alcohol, monoamine oxidase inhibitors, some antibacterial (including sulphonamides, trimethoprime chloramphenicol), some antifungal drugs (including miconazole and possibly fluconazole) have all been reported to produce severe hypoglycemia when given with the sulfonylureas. The probable basis of the interaction is competition for the metabolizing enzymes but interference with plasma protein binding or with excretion may play a part. Agents that decrease the action of the sulphonylureas include diuretics (thiazides and loop diuretics) and corticosteroids.
Therapeutic Uses
Sulfonylureas are used to control hyperglycemia in NIDDM patients who cannot achieve appropriate control with changes in diet alone. In all patients, however, continued dietary restrictions are essential to maximize the efficacy of the sulfonylureas. Some physicians still consider treatment with insulin to be the preferred approach in such patients.
Dosage and administration
The usual initial daily dose of tolbutamide is 500 mg, while 3000 mg is the maximally effective total dose.
Chlorpropamide are usually administered in a daily dose of 100 to 250 mg, while 750 to 1000 mg is maximal.
The initial daily dose of glibenclamide is 2.5 to 5 mg, while daily doses of more than 20 mg are not recommended.
Therapy with glipizide is usually initiated with 5 mg given once daily. The maximal recommended daily dose is 40 mg; daily doses of more than 15 mg should be divided. The starting dose of gliclazide is 40 to 80 mg per day, and the maximal daily dose is 320 mg. Treatment with the sulfonylureas must be guided by the individual patient's response, which must be monitored frequently.
Compounds with p-(-β-arylcarboxamidoethyl) substituents (the second generation agents) are orders of magnitude better than the first generation agents. It is believed that this is because of a specific distance between the nitrogen atom of the substituent and the sulfonamide nitrogen atom.
The group attached to the terminal nitrogen should be of certain size and should impart lipophilic properties to the molecule. The N-methyl are inactive, N-ethyl have low activity, while N-propyl to N-hexyl are most active. Activity is lost if N-substituent contains 12 or more carbons.
Mechanism of Action
The principal action of the sulphonylureas is on the β-cells of the islets. Stimulating insulin secretion and thus reducing plasma glucose concentration.
High affinity receptors of sulfonlyreas are present on the ATP-sensitive K+ channels in β-cell plasma membranes and the binding of various sulphonylureas parallels their potency in stimulating insulin release. Glibenclamide reduces the potassium permeability of β-cell by blocking the ATP-sensitive potassium channels, causing depolarization, Ca2+ entry and hence insulin secretion.
Basal insulin secretion and the secretory response to various stimuli are enhanced in the first few days of treatment with sulphonylurea drugs. With longer treatment, insulin secretion continues to be augmented and tissue sensitivity to insulin also improves, by an unknown mechanism.
Absorption, Fate, and Excretion
The sulfonylureas have similar spectra of activities; thus, their pharmacokinetic properties are their most distinctive characteristics. Although there are differences in the rates of absorption of the different sulfonylureas, all are effectively absorbed from the gastrointestinal tract. However, food and hyperglycemia can reduce the absorption of sulfonylureas. (Hyperglycemia per se inhibits gastric and intestinal motility and thus can retard the absorption of many drugs.) In view of the time required to reach an optimal concentration in plasma, sulfonylureas with short half lives may be more effective when given 30 minutes before eating.
Sulfonylureas in plasma are largely (90% to 99%) bound to protein, especially albumin; plasma protein binding is least for chlorpropamide and greatest for glibenclamide. The volumes of distribution of most of the sulfonylureas are about 0.2 liter/kg.
The first-generation sulfonylureas vary considerably in their half-lives and extents of metabolism. Chlorpropamide has a long half-life (24 to 48 hours). The second-generation agents are approximately 100 times more potent than are those in the first group (Lebovitz and Feinglos, 1983). Although their half-lives are short (1.5 to 5 hours), their hypoglycemic effects are evident for 12 to 24 hours, and it is often possible to administer them once daily. The reason for the discrepancy between the half-life and duration of action of these drugs is not clear.
All of the sulfonylureas are metabolized by the liver, and the metabolites are excreted in the urine. Metabolism of chlorpropamide is incomplete, and about 20% of the drug is excreted unchanged. Thus, sulfonylureas should be administered with caution to patients with either renal or hepatic insufficiency.
Adverse Reactions
Adverse effects of the sulfonylureas are infrequent, occurring in about 4% of patients taking first-generation drugs and perhaps slightly less often in patients receiving second-generation agents (Paice et al., 1985). Not unexpectedly, sulfonylureas may cause hypoglycemic reactions, including coma (Ferner and Neil, 1988; Seltzer, 1989). This is a particular problem in elderly patients with impaired hepatic or renal function who are taking longer-acting sulfonylureas. Sulfonylureas can be ranked in order of decreasing risk of causing hypoglycemia based on their half-lives. The longer the half-life, the more likely an agent will induce hypoglycemia. Severe hypoglycemia in the elderly can present as an acute neurologic emergency that may mimic a cerebrovascular accident. Thus, it is important to check the plasma glucose of any elderly patient presenting with acute neurologic symptoms. Owing to the long half life of some sulfonylureas, it may be necessary to treat an elderly hypoglycemic patient for 24 to 48 hours with an intravenous glucose infusion.
Other side effects of sulfonylureas include nausea and vomiting, cholestatic jaundice, agranulocytosis, aplastic and hemolytic anemias, generalized hypersensitivity reactions, and dermatological reactions. About 10% to 15% of patients who receive these drugs, particularly chlorpropamide, develop an alcohol-induced flush similar to that caused by disulfiram. Sulfonylureas, especially chlorpropamide, also may induce hyponatremia by potentiating the effects of antidiuretic hormone on the renal collecting duct (Paice et al., 1985). This undesirable side effect occurs in up to 5% of all patients; it is less frequent with glibenclamide and glipizide.
Drug interactions (Rang 1999)
Several compounds augment the hypoglycemic effect of the sulfonylureas and several such interactions are potentially clinically important. Non-steroidal anti-inflammatory drugs (including azapropazone, phenylbutazone and salicylates), alcohol, monoamine oxidase inhibitors, some antibacterial (including sulphonamides, trimethoprime chloramphenicol), some antifungal drugs (including miconazole and possibly fluconazole) have all been reported to produce severe hypoglycemia when given with the sulfonylureas. The probable basis of the interaction is competition for the metabolizing enzymes but interference with plasma protein binding or with excretion may play a part. Agents that decrease the action of the sulphonylureas include diuretics (thiazides and loop diuretics) and corticosteroids.
Therapeutic Uses
Sulfonylureas are used to control hyperglycemia in NIDDM patients who cannot achieve appropriate control with changes in diet alone. In all patients, however, continued dietary restrictions are essential to maximize the efficacy of the sulfonylureas. Some physicians still consider treatment with insulin to be the preferred approach in such patients.
Dosage and administration
The usual initial daily dose of tolbutamide is 500 mg, while 3000 mg is the maximally effective total dose.
Chlorpropamide are usually administered in a daily dose of 100 to 250 mg, while 750 to 1000 mg is maximal.
The initial daily dose of glibenclamide is 2.5 to 5 mg, while daily doses of more than 20 mg are not recommended.
Therapy with glipizide is usually initiated with 5 mg given once daily. The maximal recommended daily dose is 40 mg; daily doses of more than 15 mg should be divided. The starting dose of gliclazide is 40 to 80 mg per day, and the maximal daily dose is 320 mg. Treatment with the sulfonylureas must be guided by the individual patient's response, which must be monitored frequently.
