oral hypoglycemic agents

Oral hypoglycemic agents Biguanides Sulfonylureas α- glucosidase inhibitors Thiazolidinediones Prandial glucose regulator

Biguanides Biguanides are derivatives of the antimalarial agent Chloroguanide. Which is found to have hypoglycemic action. The most commonly used member of biguanides is Metformin.

Biguanides Indication: Type 2 diabetes failed on diet Metformin can be given alone or in combination with sulfonylureas or Insulin

Biguanides Mode of action Biguanides [Metformin] is an Antihyperglycemic and not Hypoglycemic agent. It does not stimulate pancreas to secrete insulin and does not cause hypoglycemia (as a side effect) even in large doses. Also it has no effect on secretion of Glucagon or Somatostatin.

Biguanides Mode of action: Decreases the intestinal absorption of CHO Increases glucose uptake (GLUT 4) Increases glucose utilization (glycogensynthase) Increases glycolysis via anaerobic pathway (lactic acidosis)

Biguanides Pharmacokinetics: Metformin is well absorbed from small intestine, stable, does not bind to plasma proteins, excreted unchanged in urine. Half life of Metformin is 1.5 - 4.5 hours, taken in three doses with meals

Biguanides Side effects: occur in 20-25 % of patients. include.. Diarrhea, abdominal discomfort, nausea, metallic taste and decreased absorption of vitamin B12.

Biguanides Contraindications Patients with renal or hepatic impairment. Past history of lactic acidosis. Heart failure, Chronic lung disease. .. These conditions predispose to increased lactate production which causes lactic acidosis which is fatal.

SULFONYLUREAS SUs., have been discovered during the 2nd. World war (sulfonamide). SUs are drugs that used orally to control blood glucose levels of type 2 diabetes.

SULFONYLUREAS Types: First generation, Second generation, Chlorpropamide Tolbutamide Second generation, Gliclazide Glibenclamide Glipizide Third generation, Glimepiride

SULFONYLUREAS Mechanism of action: Pancreatic effect Extra-pancreatic effect

SULFONYLUREAS Pancreatic effect: Increase insulin release from pancreas Suppress secretions of Glucagon

SULFONYLUREAS Extra pancreatic effect: Increases the number of insulin receptors Increases post-receptor insulin sensitivity Increases glucolysis Increases glycogen storage in muscle and liver Decreases the hepatic output of glucose

SULFONYLUREAS Pharmacokinetics: They are effectively absorbed from gastrointestinal tract. Food can reduce the absorption of sulfonylurea. Sulfonylureas are more effective when given 30 minutes before eating. Plasma protein binding is high 90 – 99 % .. mainly bind to albumen.

SULFONYLUREAS 1st generation members have short half lives. Pharmacokinetics: 1st generation members have short half lives. 2nd generation is administered once, twice or several times daily. 3rd generation is administered once daily.

SULFONYLUREAS Pharmacokinetics: All sulfonylurea are metabolized by liver and their metabolites are excreted in urine with about 20 % excreted unchanged. Sulfonylurea should be administered with caution to patients with either renal or hepatic insufficiency.

SULFONYLUREAS Adverse Reactions : Very few adverse reactions [4 %] in the first generation and rare in the 2nd and 3rd generation. SUs may induce hypoglycemia especially in elderly patients with impaired hepatic or renal functions-These cases of hypoglycemia are treated by I/V glucose infusion.

SULFONYLUREAS Adverse Reactions : First generation may induce other side effects as …nausea and vomiting & dermatological reactions …These side effects are fewer in the 2nd generation and rare in the 3rd generation.

SULFONYLUREAS Drug interactions: Some drugs may enhance or suppress the actions of sulfonylureas Either by affecting: Their metabolism and excretion The concentration of free sulfonylureas in plasma through competing them on plasma proteins.

Drug – Drug interaction NSAIDs Salicylates Sulfonamide ß-blockers Chloramphenicol Diazepam MAOI Barbiturates Thiazide and loop diuretics Sympathomimetics Corticosteroids Oestrogen / Progesterone combinations

SULFONYLUREAS Contraindications : Type 1 DM Pregnancy and Lactation. Significant hepatic or renal failure.

α Glucosidase Inhibititor Acarbose Indicated for type 2 diabetes In addition with diet In addition with other anti-diabetic therapies

Acarbose (Glucobay) Mode of action: Dose: Poorly absorbed 1% (act locally in G.I.T.) Inhibits α glucosidase, so inhibits CHO degradation Dose: 50mg to 100mg 3 times daily before meals

Acarbose (Glucobay) Side effects: Flatulence (77%) Diarrhea Abdominal pain (21%) Decreased iron absorption

Thiazolidenedione Rosiglitazone Pioglitazone

Thiazolidenedione Mode of action: Insulin sensitizer (increase insulin sensitivity in muscle, adipose tissue & liver) They are not insulin secretagogues (Not insulin releasers)

Thiazolidenedione Drawbacks: Side effects: They are not effective alone in case of severe insulin deficiency and should be combined with sulfonylurea or metformin or both Side effects: Hepatotoxicity weight gain Dyslipidaemia (increases LDL)

Prandial glucose regulators (Meglitinide) Example: Repaglinide Rational: Fast acting, short duration non-sulfonylurea Designed to minimize mealtime blood glucose peaks

Repaglinide Mechanism of action: Stimulation of pancreatic insulin release by closing ß-cells KATP channels Very rapid onset of action and short duration (TMAX = 1 hour, metabolized by liver T1/2 = 70 minutes) No hypoglycemic metabolites

Repaglinide Clinical efficacy: drawbacks: Improves postprandial glycemia Less effective in decreasing fasting blood glucose levels and HbA1C drawbacks: Fails to provides a stable 24 hours blood glucose control Complicated dosage style (3-8 tablets/daily) How to adapt the dosage to the meal volume?