Treatment of diabetes:  Life style modification  Insulin  Oral hypoglycemic agents

Life style modification  Diet control  Exercise  Smoking cessation

DIET CONTROL  All diabetic patients should be on diet control.  Diet control is a must either the patient is taking insulin or oral therapy.  Over weight should be reduced.

 Diet control should be tried at first before the next step [insulin or tablets] especially in obese patients, When diet fails drugs are indicated. DIET CONTROL

 The diet for a diabetic patient is not so different from the healthy diets for the whole population.  Simple sugars Carbohydrate [as sucrose], should be limited for the diet of diabetic patients. DIET CONTROL

 Carbohydrate content should be in a fiber-rich diet [for example fruits containing fibers as apples]. ….. because the fiber content of diet delays absorption of carbohydrates avoiding the rapid elevation of blood glucose levels. DIET CONTROL

Calories : Calories should be tailored to the need of the patient. Diet should contain :  Carbohydrates → %  Fat → 30-35%  Protein → % DIET CONTROL

Indication of Insulin  Type 1 diabetes  Unstable diabetes  Type 2 diabetes failed on SUs.  Pregnant diabetic patients  Surgery (all diabetic patients)  Diabetic coma

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 [Cidophage].

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 hours, taken in three doses with meals

Biguanides Side effects:  occur in % of patients.  include.. Diarrhea, abdominal discomfort, nausea, metallic taste and decreased absorption of vitamin B 12.

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.

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

 Types: First generation,  Chlorpropamide ( Pamidin )  Tolbutamide ( Diamol ) Second generation,  Gliclazide (Diamicron)  Glibenclamide (Daonil)  Glipizide (Minidiab) Third generation,  Glimepiride (Diabride) (Amaryl)

SULFONYLUREAS  Mechanism of action: Pancreatic effect Extra-pancreatic effect

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  Pharmacokinetics: 1 st generation members have short half lives. 2 nd generation is administered once, twice or several times daily. 3 rd 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 2 nd and 3 rd 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 2 nd generation and rare in the 3 rd 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 (Glucobay) Indicated for type 2 diabetes  In addition with diet  In addition with other anti- diabetic therapies

Acarbose (Glucobay)  Mode of action: 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 (Avandia) Pioglitazone (Actos)

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

Thiazolidenedione  Drawbacks: 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, Novonorm (NovoNordisk)  Rational: Fast acting, short duration non- sulfonylurea Designed to minimize mealtime blood glucose peaks

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

Repaglinide, Novonorm  Clinical efficacy: Improves postprandial glycemia Less effective in decreasing fasting blood glucose levels and HbA 1C  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?