Antidiabetic Agent- Insulin

INSULIN

Insulin is a polypeptide hormone of complex structure, secreted by the beta cells of the pancreas. It plays key roles in the metabolism of carbohydrates, fats and proteins. There are differences in the amino acid sequences of animal and human insulin. Formerly, the source of commercially available insulin was from the pancreas of cows or pigs. Now a days recombinant DNA technology (using E. coli bacteria) is the main source of biosynthetic human insulin. However, there are still lots of bovine and porcine insulins, as well as natural or enzymatically modified semisynthetic human analogue insulin in the market.

Animal and semisynthetic insulins are to a greater or lesser extent immunogenic to man but resistance to insulin action is uncommon. Insulin is needed by all patients of Type-1 DM regardless of age, those with ketoacidosis, and most of those with rapid onset of symptoms or weight loss. Almost all children with diabetes require it. Type-2 DM cases where other methods fail or with frequent acute infection, tuberculosis, hepatitis, during surgery and with other complications like nephropathy and retinopathy also need insulin. It is also indispensable in acute metabolic decompensated states in Type-2 DM (like diabetic ketoacidosis, hyperon-molar nonketotic coma, lactic acidosis, etc.). Insulin in Type-2 DM is also used as a combination therapy with OHA. The subcutaneous route is ideal in most cases. The dose of insulin is adjusted on an individual basis, by gradually increasing the dose but carefully avoiding hypoglycemic reactions. Based on the onset and duration of action, insulin preparations are of various types.

Short-acting insulins (e.g. soluble insulin; insulin lispro) have relatively rapid onset of action (about 30-60 minutes) and duration of action up to 8 hours (peak 24 hours). Human insulin has a faster onset and shorter duration of action. With insulin lispro (a human insulin analogue), fasting and preprandial blood glucose is a little lower and hypoglycemia occur less frequently. By the intravenous route, only the soluble insulin can be used, not the other types.

Intermediate-acting insulin (e.g. isophane insulin and insulin zinc suspension) has duration of action of about 24 hours. Long-acting insulin (e.g. crystalline insulin zinc suspension) has long duration of action about 28 hours and slower onset of action after about 4 hours.

Biphasic or Premixed insulin contains a combination of a short acting and intermediate-acting insulin in a standard proportion.

Side effects of insulin therapy include hypoglycemia, allergy, immunologic reaction, insulin edema and lipodystrophy. Patient should be shown the bottle and explained about the type and source of insulin to ensure that the version dispensed is actually the one the patient was expecting.

EXAMPLES OF INSULIN REGIMENS
An appropriate regimen of insulin therapy must be individualized. Usual regimens are one injection a day, two injections a day, multiple (3 to 7) injections a day and insulin pump.

One injection a day: One injection of intermediate acting insulin is given either in morning or evening pre-meal time. It serves, as supplement/basal secretion. It may be effective in Type-2 DM as monotherapy or in combination with other oral hypoglycemic agents (OHA).

Two injections a day: This is the most commonly used regimen. It can be used in type-1 DM and type-2 DM. A short-acting and an intermediate acting-insulin are mixed in proportion that is adjusted by trial and injected before breakfast and dinner. Alternatively, each injection can be either intermediate-acting insulin or biphasic insulin.

Multiple injections: As many as 3 to 7 injections per day may be needed where there is difficulty in achieving optimal control with other regimes. A dose of short-acting insulin is given before each meal, intermediate-acting insulin is given before bedtime and sometimes before breakfast as basal dose. This is very flexible and suitable for those who are very active and cannot comply with a rigid meal plan.

Insulin pump: Insulin pumps are available in two forms-open or closed loop (Artificial Pancreas). The open loop system is composed of two parts a battery-operated pump and a computer programmed system for insulin delivery. The closed loop consists of three parts-a battery-operated pump, a computer controlled insulin delivery system and a glucose sensor giving feedback to the computer. These are portable and designed to deliver basal amount of regular insulin throughout the day as well as meal related boluses.

SHORT ACTING INSULIN
Soluble insulin is a short acting form of insulin. It is the only form of insulin that can be used subcutaneously intramuscularly, as well as intravenously. For maintenance regimens it is injected subcutaneously 15 to 30 minute prior to a meal. When injected subcutaneously, soluble insulin has a rapid onset of action (after 30-60 minutes), a peak action between 2 and 4 hours, and duration of action up to 8 hours.
Intravenous route is used during diabetic emergencies and also during major surgery. When injected intravenously, soluble insulin has a very short half-life of only about 5 minutes and its effect disappears within 30 minutes.
The human insulin analogue insulin lispro has a shorter duration of action than soluble insulin and also rapid onset of action; so subcutaneous injection of insulin lispro may be given close to meal.

SOLUBLE INSULIN
(Other names: Insulin Injection; Neutral Insulin)
A sterile solution of insulin (i.e. bovine or porcine) or of human insulin; pH 6.6-8.0
Indications: diabetes mellitus, diabetic ketoacidosis
Cautions: see notes above; reduce dose in renal impairment
Interactions: see Appendix-2
Side effects: see notes above; local reactions and fat hypertrophy at injection site; over dose causes hypoglycemia Dose:- by subcutaneous, intramuscular or intravenous injection or intravenous infusion, according to patient's requirement and response
Proprietary Preparations
Acrapid Novolet I" (Novo Nordisk), Inj. 1001U/ml, Tk.512.26/3ml;
Humulin-R I) (Eli Lilly), Inj.40 IlUlml Tk. 266.88/10ml; Inj. 100 IIJ/ml. Tk. 630/10 ml Insulin Acrapid (1I (Novo Nordisk), Inj. 10010/ml, Tk.554.95/10ml;
Insulin Acrapid HM I') (Novo Nordisk), Inj. 1 OOIU/rnl, Tk.554.95/10ml; 4010/ml, Tk. 292.03/1 ml; Pen-filled syringe, 1 ODIU/ml, Tk.313.66/vial.
Insuman Rapid (Aventis), Inj. 100 lUlml. Tk 259.69/10 ml

INSULIN LISPRO
(Other name: Recombinant human insulin analogue)
Indications: diabetes mellitus
Cautions: see under Soluble Insulin; use in children if benefit as good as with Soluble Insulin
Side effects: see under Soluble Insulin Interactions: see Appendix-2
Dose: by subcutaneous injection according to the patient's requirement and response
Generic Preparation Injection, 100 IU/ml

INTERMEDIATE AND LONG ACTING INSULIN
When injected subcutaneously, an intermedediate and long-acting insulin have an onset of action of approximately 1-2 hours, a maximal effect at 4-12 hours, and duration of action of 16-35 hours. Some are used twice daily in conjunction with soluble form and other only once (see insulin regimens above). Various types are available. Isophane Insulin is a suspension of insulin with protamine. They are suitable for twice daily regime either as split mixed (mixing with soluble insulin) or pre/ready-mixed preparations. Insulin Zinc Suspension (amorphous) has an inter-mediate duration of action, and Insulin Zinc suspension (Crystalline) a more prolonged duration of action. These preparations may be used independently or as pre-mixed Insulin Zinc suspension (30% amorphous, 70% crystalline). Protamine Zinc Insulin is usually given once daily in conjunction with soluble insulin. It has the drawback of binding with soluble insulin when mixed in the same syringe.

ISOPHANE INSULIN
(Other names: Isophane Insulin; Isophane Protamine Insulin; Isophane Insulin-NPH).
A sterile suspension of bovine or porcine insulin or of human insulin in the form of a complex obtained by the addition of protamine sulphate.
Indications: diabetes mellitus (for intermediate action)
Cautions; Side effects: see under soluble insulin; protamine may cause allergic reactions
Interactions: see Appendix-2
Dose: by subcutaneous injection, according to the patient's response Proprietary Preparations
Humulin N ti (Eli Lilly), Inj. 40 IU/ml, Tk.266.88/1 Oml;l 0011J, Tk.630/10ml
Insulated Novolet (') (NovoNordisk) Inj. 1001U,Tk.512.26/3mi
Insulin Insularated HM (') (NovoNordisk), Inj. 401U/ml, Tk. 292.03/1 Oml vial; 100 U/ml, Tk. 554.95/10ml vial;
Insuman basal (') (Aventis), Inj. 100 IU/Ml, Tk. 259.69/10 ml

INSULIN ZINC SUSPENSION
(Other names: Insulin Zinc suspension [Mixed]; I.Z.S.)
A sterile neutral suspension of bovine and/or porcine insulin or of human insulin in the form of a complex obtained by the addition of a zinc salt; may be amorphous or microcrystalline consisting of rhombohedral crystals.
Indications: diabetes mellitus (long acting) Cautions; Side effects: see umb-i soluble insulin
Interactions: see Appendix-2
Dose: by subcutaneous injection, according to the patient's response
Proprietary Preparation Insulin lente (Novo Nordisk)"' Inj. 100 IU/ml Tk. 450/amp; Inj. 401U/ml;Tk.221 A5/10ml

PROTAMINE ZINC INSULIN
(Other name: Insulin P.Z)
A sterile suspension of insulin in the form of a complex obtained by the addition of protamine and zinc chloride.
Indications: diabetes mellitus (long-acting)
Cautions; Side effects: see under soluble insulin notes above; protamine may cause allergic reactions. Interactions: see Appendix-2
Dose: by subcutaneous injection, according to the patient's response
Generic Preparation Injection. 40 IU/ml.

BIPHASIC INSULINS
(Other name: Biphasic Isophane Insulin)
A sterile buffered suspension of porcine insulin complexed with protamine sulphate in a solution of porcine insulin or a sterile buffered suspension of human insulin complexed with protamine sul-phate in a solution of human insulin.
Indications: diabetes mellitus
Cautions; Side effects: see under soluble insulin; protamine may cause allergic reactions. Should be dispensed under prescription only
Dose: by subcutaneous injection, according to the patient's response
Proprietary Preparations
Humulin 70/30 ('~ (Eli Lilly), Inj. 100 U/ml.
Tk. 641.95/1 Oml vial, 40 IU/ml. Tk.266.88/1 Ot i il Insulin Mixtard 30 HM (1) (Novo Nordisk), In]. 100 IU/ml.Tk.313.66/10m1 vial; 401U/ml. Tk.292.03/10ml vial

Insulin Mixtard 50 HM(') (Novo Nordisk), lnj. 100 IU/ml.Tk.562.86; Pen-filled syrnge.100IU/ml.Tk.313.66/3ml syringe. Insulin Mixtard 30 Novolet (') (Novo Nordisk), lnj. 100 IU/mI.Tk.512.26/3ml vial;
Insulin Mixtard 50 Novolet (') (Novo Nordisk), Inj. 100 IU/rnI.Tk.512.26/3ml vial;

INSULIN GLARGINE
Indications: diabetes mellitus Cautions; Side effects: see under soluble insulin. Dose: by subcutaneous injection, ADUL and CHILD over 6years, according to requirements. Note; sustained 24 hour duration of action allows dosing independently of meals. Proprietary Preparations Lantus")(Aventis),iniA 001U/mi, Tk.1,025.74/3ml carlidge.

Oral Hypoglycemic agents- Others

Biguanides
History
Metformin (GLUCOPHAGE) and phenformin were introduced in 1957, and buformin was introduced in 1958. The latter was of limited use, but metformin and phenformin were widely used. Phenformin was withdrawn in many countries during the 1970s because of an association with lactic acidosis. Metformin has been associated only rarely with that complication, and has been widely used in Europe and Canada; it became available in the United States in 1995. Metformin given alone or in combination with a sulfonyl-urea improves glycemic control and lipid concentrations in patients who respond poorly to diet or to a sulfonylurea alone (DeFronzo et al., 1995).
ADME
Metformin is absorbed mainly from the small intestine. The drug is stable, does not bind to plasma proteins, and is excreted unchanged in the urine. It has a half-life of 1.3 to 4.5 hours (see Bailey, 1992). The maximum recommended daily dose of metformin is 3 g, taken in three doses with meals.
Mechanism of action
The main causes of reduced glucose levels during metformin therapy appear to be an increase in insulin action in peripheral tissues (see Bailey, 1992) and reduced hepatic glucose output due to inhibition of gluconeogenesis (Stumvoll et al., 1995). Metformin also may decrease plasma glucose by reducing the absorption of glucose from the intestine, but this action has not been shown to have clinical relevance.
Therapeutic uses
Metformin hydrochloride has been most often prescribed for patients with refractory obesity whose hypoglycemia is due to ineffective insulin action, i.e., “insulin resistance syndrome”. Because metformin is an insulin-sparing agent and does not increase weight or provoke hypoglycemia, it offers obvious advantages over insulin or sulfonylureas in treating hyperglycemia in such patients. Another indication for its use is in combination with sulfonylureas in non-insulin-dependent diabetics in whom sulfonylurea therapy alone is inadequate.
Contraindications
Patients with renal impairment should not receive metformin. Hepatic disease, a past history of lactic acidosis (of any cause), cardiac failure, or chronic hypoxic lung disease also are contraindications to the use of the drug. These conditions all predispose to increased lactate production and hence to the fatal complications of lactic acidosis. The reported incidence of lactic acidosis during metformin treatment is lower than 0.1 case per 1000 patient years, and the mortality risk is even lower.
Side effects
Acute side effects of metformin, which occur in up to 20% of patients, include diarrhea, abdominal discomfort, nausea, metallic taste, and anorexia. These are usually minimized by increasing the dosage of the drug slowly and taking it with meals. Intestinal absorption of vitamin B12 and folate often is decreased during chronic metformin therapy.
Consideration should be given to stopping treatment with metformin if the plasma lactate level exceeds 3 mM. Similarly, decreased renal or hepatic function also may be a strong indication for withholding treatment. It also would be prudent to stop metformin if a patient is undergoing a prolonged fast or is treated with a very low calorie diet. Myocardial infarction or septicemia mandate stopping the drug immediately. Metformin often is given in combination with sulfonylureas (Hermann et al., 1994).

Other Oral Hypoglycemic Agents
Thiazolidinediones
Ciglitazone, Pioglitazone are thiazolidinediones. They are antihyperglycemic in a variety of insulin-resistant and diabetic animal models. Like biguanides, they do not cause hypoglycemia in diabetic or normal persons. Ciglitazone reduces plasma glucose, insulin, and lipid concentrations after oral administration in several insulin-resistant animal models. The reduction in plasma insulin levels follows a fall in plasma glucose concentration, which is thought to be due to an effect of the drug to decrease insulin resistance in liver, skeletal muscle, and adipose tissue. The administration of these agents to normal animals does not potentiate insulin effects. Thiazolidinediones appear to augment insulin action in insulin-resistant animals by increasing the number of glucose transporters. These compounds, along with several other newer analogs, are currently undergoing phase I or II clinical trials.

α-Glucosidase Inhibitors
α-Glucosidase inhibitors such as acarbose reduce intestinal absorption of starch, dextrin, and disaccharides by inhibiting the action of intestinal brush border α-glucosidase. Inhibition of this enzyme slows the absorption of carbohydrates; the postprandial rise in plasma glucose is blunted in both normal and diabetic subjects.
Acarbose also competitively inhibits glucoamylase and sucrase but has weak effects on pancreatic α-amylase. It reduces postprandial plasma glucose levels in IDDM and NIDDM subjects. However, only small improvements in hemoglobin A1C values have been reported. The drug is poorly absorbed.
Acarbose results in dose-related malabsorption, flatulence, and abdominal bloating. Doses of 50 to 100 mg given with each meal are usually well tolerated. Smaller doses are given with snacks. Acarbose is most effective when given with a starchy, high-fiber diet with restricted amounts of glucose and sucrose (Bressler and Johnson, 1992).

Oral Hypoglycemic agents- Sulfonylureas

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.

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.