Oral drugs in non-insulin dependent diabetes (NIDDM)                                          Content        Next
	Historical review     Oral hypoglycemic agents are a boon to diabetic patients (NIDDM). More than 70-80% of NIDDM are controlled fairly well with OHA. Prior to OHA only insulin was available. Synthalin was the first oral hypoglycemia agent introduced in 1918. It is a guanidine derivative. Frank and Fuchs in 1954 introduced Carbutamide (B255) as a first sluphonylurea. The above two drugs were stopped from clinical use after the incidence of severe toxic effects including hepatotoxicity. In 1955 other sluphonylurea drugs namely tolbutamide, chlorpropamide and acetohexamide were introduced. In 1950 reputation of biguanides became tarnished by the association of phenformin induced lactic acidosis and phenformin was withdrawn in several countries. Clinical studies showed merformin to be safer.                                                            Classification of OHA   a) Sulphonylureas 1st Generation IInd Generation Tolbutamide Chlorpropamide Glipizide Gliburide Gliclamide Gliburonide Glisoxepide Glibenclamide   b)Biguanides Phenformin Metformin Buformin   c) Other agents              1) Alter nutrient entry through GIT                  Alpha glucosidase inhibitors -                                                                        Acarbose –Miglitol              2) Increase quantity or rapidity                  of Insulin secretion -                      Lingolride Midaglizole              3) Decrease hepatic glucose production                  1) By inhibiting fatty acid oxidation                   Hydrazines - M&B 3989A                  (Inhibit glucagon synthesis)              4) Increased peripheral uptake of glucose by potentiating                  insulin action - Ciglitizone.             5) Increased peripheral uptake of glucose through non-insulin dependent                               mechanism. Inhibitors of fatty acid oxidation (Methyl Palmoxirate) Mechanism of action of Sulphonylureas       1. Pancreatic - Increase insulin release. Effect mediated by Camp which increases the level of calcium in cytosol by decreasing mitochondrial uptake of calcium. This calcium increase is responsible for secretion of insulin by exocytosis. It increases somatostatin level which inhibits secretion of growth hormone, glucagon and insulin.   2. Extrapancreatic effects         i) Increased tissue sensitivity (receptor sensitivity) to insulin through inhibiting glucose            toxicity effects,        ii) Reduced hepatic clearance of insulin        iii) Gliclazide reduces platelet adhesiveness and platelet aggregation. Glipizide and            Gliclazide may be able to increase the fibrinolytic activity. Chlorpropamide is            associated with low fibrinolytic activity,        iv) Glipizide reverted the increased basement membrane thickness.   Difference among Sulphonyl ureas     Glibenclamide and Glipizide are more potent than Chlorpropamide and Tolbutamide. Diversity in potency does not signify, difference in clinical efficacy.   Sulphonylurea Sensitivity Test     In fasting state administer 1 gm of tolbutamide or 10 mgm of Glibenclamide. A fall in blood glucose by 30% in 4 hrs. indicates that the patient is likely to respond to oral sulphonylureas.   When not to use a particular OHA      1. Tolbutamide is not useful if fasting blood sugar is above 200 mgm%      2. Chlorpropamide not preferred in elderly with nephropathy, CCF, cirrhosis of liver and in          alcoholics. May produce protracted hypoglycemia.      3. Glibenclamide can cause dangerous hypoglycemia in elderly or if FBS is not high.      4. Biguanides not used with hepatic and renal disease with DM, in low blood pressure i.e.          systolic B.P. less than 90 mmHg and in hypoxia, due to danger of lactic acidosis.      5. Not to be used in IDDM, in pregnancy with diabetes and stressful situations like          infection or surgery.   When to use a particular OHA       a. Elderly mild diabetic - a short acting OHA like tolbutamide is suitable, if age is over 40 years, duration less than 10 years and insulin need less than 20-30 units.       b. In obese diabetic with no complication, when diet fail biguanides can be tried.       c. In young diabetics without complications chlorprop amide isused,       d. In secondary failure to OHA second generation OHA like Glibenclamide, Glipizide or          Gliclazide are used.   Table No.l: Pharmacology and Pharmacokinetic Difference between Sulphonylureas   S.No. Drug/ Commercially available as Metabolism Route of Elimination Half Life Mrs. Duration of action Hrs. Dose Range Dose per day1 1. Tolbutamide (Rastinon) Hepatic renal 7(4-25) Short acting 6-10 1-3 gm 2-3 2. Chlorpro-pamide (Diabenase) Hepatic renal 36(25-60) Long acting 24-72 100-500 mgm single 3. Glibencla mide (Daonil) Hepatic renal 10(6-12) Medium acting 16+ 2.5-20 mgm 1-2 4. Glipizide (Glynase) Hepatic renal 4(3-7) Short acting 6+ 2.5-20 mg 1-2 5. Gliclazide (Diabend) Hepatic renal Unknown Medium acting 6-12 80- 240mg 1-2                                                   Table No.2: Side Effects of OHA   Drug/cornmer-cially available as Hypoglycemia GIT Skin side effects Haematological Other Tolbutamide (Rastinon)  Low + + Photosensitivity  leucopenia Thrombocytop- enia Haemolytic anaemia   Chlorpropamide (Diabenase) More in Elderly Cholestatic Jaundice Exfoliative dermatitis Anlidiuretic effect Agranulocytosis Haemolytic anaemia Goitre Disulfiram like reaction with Alcohol   Glibenclamide (Daonil) Prominent + Skin rash Rare - Glipizide(Glynase) Most common + - -   Gliclazide (Diabend) + - + Rare - 1st generation sulphonylureas have less than 2% incidence of side effects.                                           Table No.3: Drug Interactions with OHA     Drugs Effects Comments 1. Ethanol Decrease gluconeogenesis. Inhibit tolbutamide metabolism Hypoglycemic attacks in fasting state cutaneous flushing with chlorpropamide 2. Salicylates PAS Decrease protein binding Increase insulin release Hypoglycemia 3. Suiphonamide Decrease protein binding Potentiates Hypoglycemia 4. Coumarin Decrease Hepatic metabolism Potentiates Hypoglycemia 5. Beta blockers Decrease Gluconeogenesis. Block symptoms of hypoglycemia. Decrease hepatic metabolism. Propranolol may decrease insulin release Sweating due to Hypoglycemia not blocked. Net effect potentiation of hypoglycemia 6. MAO inhibitors Increase insulin secretion. Decrease hepatic gluconeogenesis. Hypoglycemic effect enhanced. 7. Clonidine Guanethidine Reserpine Block symptoms of hypoglycemia Decrease protein binding —— 8. Clofibrate Oxytetracycline Decrease protein binding (Displace from protein bound siie) Peripheral response to insulin                                             Drugs reducing Hypoglycemic effect of OHA     Drugs Mechanism 1. Thiazides Decrease insulin release 2. Furosemide Potassium depletion 3. Diazoxide Cause insulin resistance 4. Corticosteroid Intrinsic hyperglycemic effect 5. Rifampicin Increase metabolism of Tolbutamide 6. Phenobarbitone Increase hepatic metabolism 7. Beta agonists Increase gluconeogenesis and glycogenolysis 8. Oral contraceptives Increase glycogenolysis                (Net effect will be hyperglycemia. Increase OHA dosage).   When to stop use of OHA     1. Presence of severe and persistent side effects.     2. During intercurrent infections and foot lesions which are infected.     3. Underweight and hyperglycemic in spite of OHA     4. During pregnancy and prior to surgery stop OHA and start insulin.   OHA failure Primary failure            No response with maximum dose of OHA even after four week? trial.   Secondary failure     Initially well responds to OHA. Euglycemia achieved but after a month time no response or poor response. Incidence 5-10% per year. In OHA failure try to exclude.     1) Dietary indiscretion 2) Inadequate dosage 3) Occult infection like UTI or PTB 4) Look for diabetogenic drug usage e.g., Furosernide, steroids. 5) Thyrotoxicosis or other endocrinopathies associated with diabetes. Mechanism of action of Biguanides    1) Reduced absorption of glucose from gut.    2) Facilitates entry of glucose by anaerobic glycolysis in extra hepatic tissues.    3) Inhibits gluconeogenesis    4) Inhibit oxidative phosphorylation Indications for using Biguanides    1) Obese NIDDM when diet fails    2) As a combination therapy in secondary failure cases with sulphonylureas    3) In patients having allergy to sulphonylureas, Pharmacokinetics     One third is eliminated as metabolite. Two thirds is eliminated in urine in five hrs. 90% excreted in 24hrs.   Contraindications for Biguanides     1) Renal and hepatic insufficiency     2) In alcoholics     3) In patients with propensity for hypoxia      4) In patients using barbiturates, salicylates, phenothiazines     5) In septicemia with DM and advanced age. In all these states chances of developing         lactic acidosis is high.         Dosage: 500 mg to 3 gm daily.   Adverse Reactions     Metallic taste, nausea, vomiting, abdominal discomfort, diarrhoea, impaired B12 absorption, skin allergy, lactic acidosis-less common with metformin in contrast to Phenformin. Hypoglycemia due to biguanides alone is practically unknown. When to stop Biguanides    When plasma lactate is more than 3 mmol. Classification of Biguanides     Drug Tablet Strength Dose in 24 Mrs. Duration of Action Peak Time Half Life Clinical Effect upto 1.Metformin 500 mgm 1000-3000 Short acting 2 Mrs. 4 Mrs. 8 Mrs. 2.Phenformin 25-50 mgm 50-150 Short acting 2Hrs. 4 Mrs. 8 Mrs.      Lactic acidosis is rare in Indian patients as compared to Western countries. This is because of usage of high carbohydrate diet and less alcohol consumption compared to western patients. 1. Prevention of Post Prandial Glucose rise     Alpha glucosidase inhibitors act by inhibiting alpha glucosidase enzyme which is present in the intestinal brush border and which is required for absorption of starch, dextran and disaccharides. The agents belonging to this group are acarbose and desoxynosirimycin inhibitors. Acarbose is most widely studied. It is minimally absorbed from GIT, when 50-100 mgm is given with each meal. In IDDM and NIDDM it causes fall in post prandial rise in blood sugar. It is more effective with high fibre. Side effects include flatulence and abdominal distention. Clinical effect is dose-dependent. No significant malabsorption is produced.       Miglitol is a potent, short acting alpha glucosidase inhibitor given as 50 mgm three times daily. It may have potentiation of insulin effect or reduction in anti-insulin factors.                                    Criteria for evaluation of hypoglycemic agents   Relation to food Good Blood Sugar mg% Fair mg% Poor mg% Fasting 110 130   1 Hr. PC 150 ISO   2 Hr. PC 130 150 All other values 3Hr.PC 110 130   Alpha -Glucosidase Inhibitors     1) Acarbose     2) Miglitol     3) Emiglate     4) AO-128     5) Castanospermin     6) MDL-25, 637   2) Drugs which increase tissue sensitivity to Insulin: Thiazoli dine di one derivatives     1) Ciglitizone     2) Phoglitazone     3) Englitazone These are used in cases of DM with insulin resistance.   3) Drugs which reduce hepatic glucose output     These drugs act on pyruvate dehydrogenase enzyme, the rate limiting enzyme of aerobic glucose oxidation. Dichloroacetate increase the peripheral oxidation of alanine and lactate thereby interrupting the Cori's and alanine cycles, thereby reducing the availability of three carbon precursors for gluconeogenesis. The drugs also inhibit TGA cycle, cholesterol biosynthesis as well as ketonuria and lactonuria.   4) Drugs used to reduce hepatic gluconeogenesis      i) Etomoxir CoA     b) Hydroxyzomopropionic acid     The basal rate of long chain fatty acid oxidation (LCFAO) is a critical factor for gluconeogenesis. Etomoxir-CoA studied in rats is found to be effective as a regular of LCAT-1 malonyl CoA. Used in a dosage of 50-200 mgm. 5) Inhibitors of counter regulatory hormone release     Glucagon analogues antagonise the effect of glucagon on receptors. These are:     1. la Trinitrophenyl histidine     2. 12 Homo arginine glucagon   6) Anti obesity and Anti lipid lowering agents with anti diabetic activity.     Fenfluramin : Cause weight loss and have direct effect on insulin/glucose metabolic axis can produce.    Benfluorex : Pulmonary hypertension. Hence no panned   UGDP controversy (University Group Diabetic Programme)     12 clinical centres involving 823 patients were included in this prospective study continued for 9 years in USA. Newly diagnosed diabetics for the coming 5 years were included. Placebo, Tolbutamide 1.5 gm day, Insulin standard dose 10-16 unit/day, Insulin variable dose were of four therapeutic groups along with dietic regime to maintain optimum body weight. Results showed IVAR group had best control of diabetes. Mortality data were placebo 13.2% Tol.14.7, ISTD 9.5%, IVAR 8.6. Tol group had highest CVS mortality. On this basis it was recommended that diet should come first and insulin is preferred to other therapeutic agents. It carried great controversies and now the position is that OHA can be safely given provided it keeps euglycemia. Failure to control with OHA means that patient should be switched over to insulin therapy. Role of Herbal preparations and micronutrients in control of hyperglycemia     Zine, Cadmium Magnesium and chromivm improve glucose tolerance. Bittergaurd and Fenugreek have mild hypoglycemic effect. Hence indigenous drugs can be considered as an adjuvant to diet in diabetic management. They cannot take the role of OHA or insulin in treatment of DM. Hence, if a patient is already controlled well with OHA or insulin it is dangerous to try these modes of therapy. Conclusion     Oral hypoglycemic agents have an important role in control of hyperglycemia in NTDDM. Judicious use of OHA, proper dosage, avoiding hypoglycemia, avoiding drug interactions, compliance of therapy and diet will go long way in getting good control of diabetes. When sulphonylureas alone are not effective trial of combination therapy namely biguanides with sulphonylureas with high fibre diet may control the diabetic state in NIDDM. REFERENCES        1. K.D.Nihalani, S.N.Kulkarni: Newer oral hypoglycemic agents. Ind Jl., of the Diabetic            Association of India. Vol,34 No.3 Page 59-61,1994.        2. R.B. Phatak: Oral hypoglycemic agents. Ind Jl. of the diabetic association of India.            Vo.35 No.3 Page 64, 1995.        3. Oral hypoglycemic agents. Ashok Kumar Das. Special issue NIDDM. Guest Editor            Siddharth N.Shah, JAPI, Supplement I page 28, 1993.        4. Oral hypoglycemic agents: Siddharth Shah, Page 119 Novo Nordisk update            Proceeding 1992        5. Combination therapy in Diabetes mellitus Page 127, Novo Nordisk Proceeding 1992.        6. Bressler R. and Johnson D: New pharmological approaches to therapy of NIDDM.             Diabetes Care Vol.15 No.6 June 1992, 792-885.        7. UGDP - A study of the effects of hypoglycemic agents on vascular complications in            patients with adult onset diabetes. Part-I, Part-11. Diabetes 19 (Suppl-2) 745, 1970.