Sulfonylureas are a group of medications called oral hypoglycemic agents. That is, they reduce blood glucose values and for this reason they are used in the treatment of adult diabetes mellitus that is not dependent on insulin. They are given orally.
Diabetes mellitus is a disease in which failure occurs in the production of insulin or in the receptors for this hormone. Glucose needs insulin to enter many tissues, for example, skeletal muscles. When insulin fails, glucose cannot enter and accumulates in the bloodstream.
Blood sugar regulation scheme (Source: Rhcastilhos via Wikimedia Commons)
As a result, blood glucose values increase, but the availability of glucose to tissues decreases. This creates a feeling of tiredness, hunger, thirst, increased urine output and, in many cases, weight loss.
There are two types of diabetes, type I and type II. Type I diabetes can only be treated with insulin (insulin-dependent) because the body no longer produces it. It is also called juvenile diabetes because it usually appears early in life.
Type II diabetes or adult diabetes is caused by a decrease in insulin secretion or by problems with insulin receptors. This type of diabetes is what can be treated with sulfonylureas.
What are they for
Sulfonylureas are used to lower blood glucose levels, that is, they are hypoglycemic drugs. This effect is achieved by increasing insulin levels. It is used in patients with type II diabetes or adult diabetes.
They are drugs that are well absorbed in the gastrointestinal tract, so they are administered orally. All sulfonylureas are metabolized in the liver and the end products of this metabolism are excreted in the urine.
The hypoglycemic effect of sulfonylureas was discovered in 1942 by accident in experimental animals. Subsequently, their use as oral hypoglycemic agents was extended and the first drug of this group that was used for this purpose was carbutamide.
Carbutamide was discontinued due to its harmful effects on the bone marrow, but it allowed the development of a large group of so-called “first-generation” sulfonylureas. Since then, more than 20 drugs in this group have been developed and their use has spread throughout the world.
Currently, there are two major groups of sulfonylureas: 1) the first generation sulfonylureas and 2) the second generation sulfonylureas. In their hypoglycemic effects, the latter are approximately 100 times more powerful than the first generation.
Mechanism of action
The mechanism of action of these drugs consists in stimulating the secretion of insulin (hormone) from the β cells of the pancreas (endocrine portion of the pancreas). While this increases plasma insulin levels, these drugs also decrease liver metabolism of the hormone.
These effects are recorded as the short-term (acute) effect of the drug, however, with chronic use of these drugs, the stimulatory effect of the pancreatic cells decreases markedly, but the effect on the reduction of the levels of blood glucose.
The explanation for this phenomenon has not been fully elucidated. For one thing, insulin is believed to have a greater effect on your target organs. On the other hand, chronic hyperglycemia reduces insulin secretion due to a toxic effect, and lowering blood glucose reduces this effect.
The acute effect of sulfonylureas on the β cells of the pancreas occurs because they bind and block an ATP-sensitive potassium channel. This depolarizes the cell (excites) and increases the input of calcium through voltage-gated channels and initiates insulin secretion.
The effect of chronic use of sulfonylureas appears to be accompanied by down-regulation of these pancreatic β-cell surface receptors. If chronic administration is stopped, the acute response of β cells to sulfonylureas is restored.
Increased levels of insulin receptors have been observed in monocytes (blood cells), adipocytes (fat cells), and erythrocytes (red blood cells) in type II diabetes patients using sulfonylureas. A decrease in hepatic gluconeogenesis has also been reported.
Hepatic gluconeogenesis is the synthesis of glucose by the liver from non-glycosidic substances.
Side effects
Currently, side effects from the administration of sulfonylureas are not very frequent. They have an approximate incidence of 4% in those patients who use first-generation sulfonylureas and slightly lower in those who use second-generation ones.
Sulfonylureas can cause hypoglycemia, including hypoglycemic coma. This can occur especially in elderly patients with poor liver and kidney function and with the use of long-acting sulfonylureas.
Sulfonylureas can be classified according to their half-life in order to reduce the risk of hypoglycemia. The shorter the half-life, the lower the risk of hypoglycemia and vice versa. Emergencies for this cause are treated with intravenous infusion of glucose solutions.
The concomitant use of sulfonylureas with sulfonamides, dicoumarol, salicylates, ethanol, phenylbutazone or clofibrate, potentiates the effect of sulfonylureas and increases the risk of hypoglycemia.
Other side effects that can accompany the use of sulfonylureas are:
- Nausea and Vomiting
-Yellow tint of the mucous membranes
-Agranulocytosis (significant decrease in white blood cell counts)
-Hemolytic or aplastic anemias (decrease in red blood cells due to destruction or lack of production respectively)
-Hypersensitivity (allergic) reactions
-Dermatological reactions (skin problems)
Tradenames
Sulfonylureas are classified into two large groups: the first and second generation. The most important and most used members of each group are listed below. Their trade names are listed in parentheses in the attached list for each component of each group.
Gibenclamide, a second generation sulfonylurea (Source: Fvasconcellos 21:27, 16 April 2007 (UTC) via Wikimedia Commons)
First-generation sulfonylureas include tolbutamide, acetohexamide, tolazamide, and chloropropamide. The second-generation, which are more potent, include glyburide or glibenclamide, glipizide, gliclazide, and glimepiride.
First generation sulfonylureas
Some trade names are included. The generic name is included in bold and italic type.
Gliburide or Glibenclamide (MICRONASE and DIABETA 1.25, 2.5 and 5 mg tablets, GLYNASE 1.5, 3 and 6mg tablets)
Glipizide (GLUCOTROL, SINGLOBEN 5 AND 10 mg tablets)
Gliclazide (DIAMICRON 60 mg)
Glimepiride (AMARYL 2 and 4 mg)
There are commercial presentations that combine some sulfonylurea with other oral antidiabetics that were not included in this list.
References
- Ashcroft, FM, & Gribble, FM (2000). Sulfonylurea stimulation of insulin secretion: lessons from studies of cloned channels. J Diabetes Complications.
- Best and Taylor's Physiological Basis of Medical Practice, 12th ed, (1998) William and Wilkins.
- Ganong, WF, & Barrett, KE (2012). Ganong's review of medical physiology. McGraw-Hill Medical.
- Goodman and Gilman, A. (2001). The pharmacological basis of therapeutics. Tenth edition. McGraw-Hill
- Meyers, FH, Jawetz, E., Goldfien, A., & Schaubert, LV (1978). Review of medical pharmacology. Lange Medical Publications.