Antidiabetic Drugs

1. Antidiabetic Drugs Kaukab Azim, MBBS, PhD

2. Definition A syndrome characterized by hyperglycemia resulting from impaired insulin secretion and/or effectiveness, associated with risks for diabetic ketoacidosis (DKA) or non-ketotichyperglycemic-hyperosmolar coma (NKHHC), and a group of late complications including retinopathy, nephropathy, atherosclerotic coronary and peripheral arterial disease, and peripheral and autonomic neuropathies. Diabetes Mellitus

3. Different Types of Diabetes General Both genetic and environment factors are involved in causation of diabetes • Type I(formerly called insulin-dependent) • A serious form of diabetes characterized by destruction of pancreatic beta cells and by severe or absolute insulin deficiency. • Type II(formerly called non insulin-dependent) • A milder form of diabetes characterized by tissue resistance to the action of insulin combined with a relative deficiency of insulin secretion. Specific • Type III(also called secondary) • Diabetes secondary to other diseases (Cushing’s disease, acromegaly, chronic pancreatitis, genetic syndromes, etc.) or drug therapy. • Type IV(also called gestational diabetes) • Any abnormality in glucose level noted for the first time during pregnancy (it occurs in about 4% of all pregnancies in USA)

5. Insulin Therapy All available insulin preparations are either human insulin (produced by recombinant DNA techniques)o or human analog insulin (some amino acids in the molecule are substituted or changed in position) Main insulin preparations • Lispro(human insulin analog): two amino acids near the end chain have been reversed in position. • Aspart(human insulin analog): proline is substituted with aspartic acid at the B28 position. • Regular: crystalline insulin-zinc (IZ) salt solution.(used in diabetic coma) • NPH(Neutral Protamine Hagedorn): suspension of insulin in a complex with zinc and protamine. • Lente: suspension of large IZ particles. • Glargine:glycine is substituted for asparagine at the A21 position and two arginine molecules are attached to the B chain. • Ultralente: suspension of very large IZ particles.

6. Insulin Therapy Administration • Insulin is administered either IV, IM or SC. • Administration of insulin differs from physiological secretion of insulin because: • The kinetics does not reproduce the normal rapid rise and decline of insulin secretion in response of ingestion of nutrients. • The insulin diffuses into the peripheral circulation instead of being released into the portal circulation. Therefore the direct effects of insulin on hepatic metabolic processes are eliminated.

7. Insulin Therapy Factors affecting SC insulin absorption • The site of injection (absorption is most rapid from the abdominal wall, followed by the arm, buttock and thigh). • The deepness of injection (IM absorption is faster than SC absorption). • The type of insulin. • Subcutaneous blood flow (in the upright posture sc blood flow diminish considerably in the legs) • Regional muscular activity at the site of injection. • Volume and concentration of the injected insulin (a large volume can lead to an initial "lag(slow,delay) phase" of absorption)

8. Insulin Therapy The duration of action of insulin can be varied by: • Modification of the insulin molecule (by recombinant technology) • Conjugation of insulin with protamine in a low soluble complex. After injection proteolytic enzymes degrade protamine ,so allowing absorption of insulin. • Combination of insulin with zinc, to form zinc salts. After injection, the salt precipitates and insulin is slowly released.

10. Adverse Reactions to Insulin Hypoglycemia • It is the most common complication of insulin therapy. • It can be also due (in long-term diabetics) to an inadequate production of counter-regulatory hormones that normally provide an effective defense against hypoglycemia. Symptoms and signs They are first discerned at a plasma level of 60 to 80 mg/DL and include: • Signs of autonomic hyperactivity. Both sympathetic (tachycardia, sweating, tremulousness, anxiety) and parasympathetic (hunger, nausea) • Signs of impaired function of the central nervous system.They are also named neuroglycopenic symptoms (headache, mental confusion, weakness, dizziness, blurred vision, drowsiness, bizarre behavior, convulsions and coma). Therapy • Conscious patients: oral glucose • Unconscious patients: IV glucose or glucagon IM

11. Adverse Reactions to Insulin Immunological problems Allergic reactions • They are generally mediated by IgE antibodies and are often due to noninsulin protein contaminants. Immune insulinresistance • It is exceedingly rare with human purified insulin(preferred by physician). Local reactions at the injection sites • Hypertrophy of subcutaneous fatty tissue can occur after month of repeated injections on the same site (it remains a problem ,even with purified insulin) • Atrophy of subcutaneous fatty tissues (rare today). • Localized infections.

12. Interaction of Insulin with Other Drugs

13. Glycemic Control in Diabetes • The short-term benefits of tight blood glucose control in diabetics are well established. • Recent evidence (DCCT Research Group, 1993) indicates that meticulous blood glucose control can also dramatically reduce and slow the development of tissue complications in type 1 diabetes. • Patients receiving meticulous blood glucose control however have a threefold greater risk of severe hypoglycemic episodes. • The consensus of the ADA(American diabetic association) is that tight blood glucose control should become standard therapy in type I as well as in type II diabetes after the age of puberty. • BEWARE OF HYPOGLYCEMIA

14. Events Requiring an Increase in Dosage of Insulin in Diabetic Patients • Infections • High fever • Trauma, surgical operations • Myocardial infarction • Pregnancy • Hyperthyroidism • Diabeticketoacidosis(L.End)