The antidiabetics are used to control diabetes mellitus, a disease in which there is total or partial failure of beta-cells within pancreas to secrete enough insulin, one of hormones concerned with handling of glucose. In some cases there is evidence to show that disease results from presence of factors that oppose activity of insulin.
With insufficient insulin, body tissues are unable to take up and utilise glucose that is in circulation in blood. Because of this, glucose, which is derived largely from digestion of food, and which would normally be removed and stored in tissues throughout body, accumulates and boosts glucose in blood to such grossly elevated proportions that kidney is unable to cope with such a load and glucose appears in urine. Raised blood glucose levels (hyperglycaemia) with glucose and ketone bodies in urine (glycosuria and ketonuria) are among manifestations of a serious disturbance in metabolic chemistry of body, which, if untreated, can lead to development of diabetic coma and death.
There are two main types of diabetes: one develops early in life and occurs when ability of pancreas suddenly, and often almost totally, fails to produce insulin. This type is called type 1,juvenile, or insulin-dependent diabetes (IDDM), and requires insulin replacement therapy. The other form is type 2,maturity-onset, or non-insulin dependent diabetes mellitus (NIDDM), which is most often seen in those over 40 years old. This occurs when pancreas gradually loses ability to produce insulin over a period of months or years and/or resistance to action of insulin develops. It is often associated with being overweight and can sometimes be satisfactorily controlled simply by losing weight and adhering to an appropriate diet. This may then be augmented with oral antidiabetic drugs,and eventually insulin. A classification of antidiabetics is given in table 1 below,.
Modes of action of antidiabetics
Pramlintide is a synthetic analogue of amylin,a pancreatic hormone involved in glucose homoeostasis. It slows rate of gastric emptying and reduces appetite. It is given subcutaneously immediately prior to meals,and is used in patients already receiving insulin.
Exenatide is an incretin mimetic that acts as a glucagon-like peptide-1 (GLP-1) receptor agonist. This increases insulin secretion when glucose levels are high. It is given subcutaneously as an adjunct in type 2 diabetes in patients already receiving metformin,a sulphonylurea, or both.
Insulin extracted from pancreatic tissue of pigs and cattle is so similar to human insulin that it can be used as a replacement. However,human insulin, manufactured by genetically engineered microorganisms, is more commonly used. Insulin is usually given by injection in order to bypass enzymes of gut, which would digest and destroy it like any other protein. The onset and duration of action of insulin may be prolonged by complexing with zinc or protamine. More recently,various insulin analogues have been developed, which have specific pharmacokinetic profiles. Insulin aspart and lispro have a faster onset and shorter duration of action than soluble insulin. Insulin glargine and detemir both have a prolonged duration of action.
Epalrestat inhibits enzyme aldose reductase, which converts glucose to sorbitol. The accumulation of sorbitol may play a role in some diabetic complications.
Acarbose, miglitol and voglibose act against alpha glucosidases and specifically against sucrase in gut to delay digestion and absorption of monosaccharides from starch and sucrose.
The mode of action of biguanides, such as metformin, is obscure, but they do not stimulate pancreas like sulphonylureas to release insulin, but appear to facilitate uptake and utilisation of glucose by cells in some way. Their use is restricted to type 2 diabetes because they are not effective unless insulin is present.
The meglitinides (e.g. repaglinide) increase endogenous insulin secretion,and so are used in type 2 diabetes.
The sulphonylurea and other sulfonamide-related compounds such as chlorpropamide and tolbutamide were first synthetic compounds used in medicine as antidiabetics. Among their actions they stimulate remaining beta-cells of pancreas to grow and secrete insulin which, with a restricted diet, controls blood glucose levels and permits normal metabolism to occur. Clearly they can only be effective in those diabetics whose pancreas still has capacity to produce some insulin, so their use is confined to type 2 diabetes.
Outside orthodox Western medicine,there are herbal preparations which are used to treat diabetes and which can be given by mouth. Blueberries were traditionally used by Alpine peasants, and bitter gourd or karela (Momordica charantia) is an established part of herbal treatment in Indian subcontinent and elsewhere. Traditional Chinese medicine also has herbal medicines for diabetes. As yet it is not known how these herbal medicines act and their efficacy awaits formal clinical evaluation.
The commonest interactions with antidiabetic drugs are those that result in a rise or fall in blood glucose levels, thereby disturbing control of diabetes. These are detailed in this section. Other interactions where anti-diabetic drug is affecting drug are described elsewhere.
1 Drugs used in management of diabetes
Insulin zinc suspension,Isophane insulin, Protamine zinc insulin
Insulin aspart,Insulin glulisine, Insulin lispro
Insulin aspart protamine,Insulin detemir, Insulin glargine, Insulin lispro protamine
Acarbose,Miglitol, Voglibose
Buformin,Metformin, Phenformin
Nateglinide,Repaglinide
Acetohexamide,Carbutamide, Chlorpropamide, Glibenclamide (Glyburide), Glibornuride, Gliclazide, Glimepiride, Glipizide, Gliquidone, Glisentide, Glisolamide, Glisoxepide, Glycyclamide, Tolazamide, Tolbutamide
Pioglitazone,Rosiglitazone
| Table 1 Drugs used in the management of diabetes | ||
|---|---|---|
| Group | Drugs | |
| Parenteral antidiabetics | ||
| Amylin analogues | Pramlintide | |
| Incretin mimetics (Glucagon like peptide-1 (GLP-1) receptor agonist) | Exenatide | |
| Insulins | Short-acting | Soluble insulin |
| Intermediate- and long-acting | Insulin zinc suspension, Isophane insulin, Protamine zinc insulin | |
| Short-acting analogues | Insulin aspart, Insulin glulisine, Insulin lispro | |
| Intermediate to long-acting analogues | Insulin aspart protamine, Insulin detemir, Insulin glargine, Insulin lispro protamine | |
| Oral antidiabetics | ||
| Aldose reductase inhibitors | Epalrestat | |
| Alpha glucosidase inhibitors | Acarbose, Miglitol, Voglibose | |
| Biguanides | Buformin, Metformin, Phenformin | |
| Meglitinides | Nateglinide, Repaglinide | |
| Sulphonylureas | Acetohexamide, Carbutamide, Chlorpropamide, Glibenclamide (Glyburide), Glibornuride, Gliclazide, Glimepiride, Glipizide, Gliquidone, Glisentide, Glisolamide, Glisoxepide, Glycyclamide, Tolazamide, Tolbutamide | |
| Thiazolidinediones (Gamma-PPAR (peroxisome proliferator-activated receptor) agonists) | Pioglitazone, Rosiglitazone | |
| Other drugs | Guar gum | |