Treatment of diabetes Life style modification o Insulin

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

Life style modification Diet control o Exercise o Smoking cessation o

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

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

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

DIET CONTROL Carbohydrate content should be in o 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 → 50 - 55% o Fat→ 30 -35% o Protein → 10 - 15% o

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

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

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

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

Biguanides Mode of actiono 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. n n

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

Biguanides Pharmacokinetics: Metformin is well absorbed n from small intestine, stable, does not bind to plasma proteins, excreted unchanged in urine. Half life of Metformin is 1. 5 - n 4. 5 hours, taken in three doses with meals

Biguanides Side effects: occur in 20 -25 % of patients. o include. . Diarrhea, abdominal o discomfort, nausea, metallic taste and decreased absorption of vitamin B 12.

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

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

SULFONYLUREAS Types: o First generation, n Chlorpropamide (Pamidin) p Tolbutamide (Diamol) p Second generation, Gliclazide (Diamicron) p Glibenclamide (Daonil) p Glipizide (Minidiab) p Third generation, Glimepiride (Diabride) (Amaryl) p n n

SULFONYLUREAS Mechanism of action: o Pancreatic effect n Extra-pancreatic effect n

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

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

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

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

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

SULFONYLUREAS Adverse Reactions : Very few adverse reactions [4 %] in o the first generation and rare in the 2 nd and 3 rd generation. SUs may induce hypoglycemia especially o 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 o 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 o suppress the actions of sulfonylureas Either by affecting: Their metabolism and excretion n The concentration of free n sulfonylureas in plasma through competing them on plasma proteins.

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

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

α Glucosidase Inhibititor Acarbose (Glucobay) Indicated for type 2 diabetes In addition with diet p In addition with other anti-p diabetic therapies n

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

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

Thiazolidenedione Rosiglitazone (Avandia) Pioglitazone (Actos)

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

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

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

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

Repaglinide, Novonorm Clinical efficacy: o Improves postprandial glycemia Less effective in decreasing fasting blood glucose levels and Hb. A 1 C n n drawbacks: o 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? n n n