Antidiabetic Drugs

Dr Nagwa Nour EL DinAssistant Professor

Pharmacology

Diabetes Mellitus• Chronic disorder of carbohydrate metabolism• Results from inadequate production or

underutilization of insulin• Type 1: onset during childhood autoimmune

destruction of pancreatic B cells. • Type 2:increasing insulin resistance and

diminishing insulin secretory capacity. frequently associated with obesity and is much more common. usually has its onset in adulthood

Diabetes Mellitus

• Symptoms: Hyperglycemia (Fasting blood glucose 126mg/dl)glucosuria, polyuria, polydipsia and polyphagia.• Without intervention, significant complications

retinopathies, glaucoma, neuropathies, cardiovascular disease.PVD.

Anti-diabetic drugs • Insulin• Oral antidiabetic drugs

Effects of insulin (anabolic hormone)

• Decrease blood glucose level by:– Increase glucose uptake by muscle and adipose tissues – Increase glucose utilization – Increase glucose storage as glycogen in liver & muscle and inhibit glycogen

breakdown

• Increase lipid formation (lipogenesis )and inhibit lipid breakdown (lipolysis)

• Increase amino acid entry into the muscle and protein synthesis

Insulin Preparations Rapid-Actinginsulin lispro, insulin aspart, have rapid onsets and early peaks of activity that permit control of postprandial glucose levels. They are injected immediately before a meal. Short-ActingRegular insulin is used IV in emergencies or sc in maintenance regimens, alone or mixed with intermediate- or long-acting preparations. it requires administration 1 h or more before a meal. Intermediate-ActingNPH insulin exhibits a delayed onset and peak of action is often combined with regular and rapid-acting insulins. Long-ActingInsulin glargine provide a peakless basal insulin level lasting more than 20 h, which helps control basal glucose levels without producing hypoglycemia.

1 2 3 4 5 6 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24

Time (h)

Extent & duration of action of various types of insulin

Insulin lispro

Regular insulin

NPH insulinUltralente insulin

Insulin glargine

Up to 24hrs8-12hrs2hrsIntermediate –actingNPH Insulin

≥24hrs Peakless2hrsLong- actingInsulin glargine

8hrs2-4hrs30-45 minShort -acting Regular insulin

< 5hrs1 hr5-10min

Rapid acting1. Insulin Lispro2. Insulin aspart

Duration PeakOnset

0.6-0.7U/Kg/dayIn obese

2U/Kg/day

The daily dose of insulin includes:

WE use mixtures of Intermediate or long acting insulin to cover basal body needs

Regular, lispro or aspart insulin is added :1. They permit control of postprandial glucose levels2. Intermediate & long acting insulin require several hours to reach peak

therapeutic level

The most common regimen for insulin administration Split –mixed regimen

Involves the pre-breakfast(2/3dose) and pre-supper (1/3 dose) injection of a mixture of regular and intermediate acting insulin

Basal bolus regimen : rapid before meals + long acting once

Hazards of insulin use

1.Hypoglycemia

A. Excessive insulin effects

Conscious patients Sugar or candy by mouth

Unconscious patient: • IV infusion of 50ml of

50%glucose • Or Glucagon IM

2. Overeating & obesity

Tachycardia, sweating,Hunger pain, confusion, convulsion

and coma

B. Lipodystrophy at injection site

Indication for the use of insulin therapy

1. Patient with type I DM2. Pregnant women who already have

type II DM or acquire gestational diabetes during their pregnancy

3. Patients who have type II DM and require

intermittent insulin administration , such as during surgery or infection4. Ketoacidosis

Oral anti-diabetic drugsUsed for treatment of type II DM

Oral antidiabetics

Sulphonylureas

Secretogogues

Biguanides

endogenous glucose

production

Glitazones

tissue Sensitivity to

insulin

Acrabose

Slowing rate of Glucose

Absorption from GIT

1- Sulfonylureas• insulin release from pancreatic beta cells• 1st generation• 2nd generation Glyburide Glipizide Adverse effects:1- Hypoglycemia 2- ↑ appetite →↑body weight

2- Biguanides

Metformin1. hepatic Gluconeogenesis2. glucose uptake & oxidation3. glucose absorption from GIT4. plasma glucagon level Adverse effects: GIT distress

Biguanides Sulphonylureas

Metformin ↓endogenous G

productionNo (euglycemic)

↓

Obese type 2 diabetesGIT disturbances

Glyburide↑ release of

insulin

Yes

↑

Type 2 diabetesHypoglycemia-↑appetite

Example Mechanism

Risk of hypoglycemia

Appetite & weight

Use Adverse effects

3- Glitazones (Thiazolidinediones)

• Pioglitazone Mechanism of actionIncrease the sensitivity of liver, skeletal muscle & adipose tissue to insulin Adverse effects1. Fluid retention & Edema 2. Anemia3. CV risk (rosiglitazone)

4- Acarbose Glucosidase inhibitor act in the intestine • Slow digestion of starch & Delay absorption

of glucose so postprandial hyperglycemia is reduced No hypoglycemia

Complex-CHO

Glucose

glucosidase

Absorption

Adverse effects GIT distress : Flatulence and diarrhea

Glitazones

Sites of action of oral hypoglycemics