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.