Anti-Diabetic Drugs

Presented byMahmudul Hasan TusharMd. KamrujjamanNajib Hasnain

Course instructorFarjana KhatunLecturerDpt. Of PharmacyEast west University

Pharmacology lll PHRM 413

Diabetes mellitus

A disease caused by elevated glucose levelsMajor causes: Body does not produce enough insulin Cells do not respond to the insulin that is produced

Anti Diabetic Drugs

Sulfonylureas: Stimulate beta cells to release more insulin.

Meglitinides: Nonsulfonylurea insulinotropic agent.

Biguanides: No effects on beta cells. 3 sites for work: peripheral tissue, liver, intestine.

• Thiazolidinediones: Decrease insulin resistance in peripheral target tissue.

• α-glucosidase inhibitor: Delay carbohydrate absorption from GI tract.

SulfonylureasThese agents promote the release of insulin from β-cellse.g. tolbutamide, glyburide, glipizide and glimepiride.

Mechanism: Require functioning β-cells, stimulate release by blocking ATP-

sensitive K+ channels resulting in depolarization with Ca2+ influx which promotes insulin secretion.

Reduce glucagon secretion and increase the binding of insulin to target tissues.

Increase the number of insulin receptors

Pharmacokinetics: Bind to plasma proteins Metabolized in the liver and excreted by the liver or kidney.

Mechanism of Action

Sulfonylureas

Adverse effects Weight gain Hyperinsulinemia Hypopglycemia

Onset and duration Short acting: tolbutamide Intermediate acting: tolazamide , glipizide , glyburide Long acting: chloropropamide, glimerpiride

Meglitinides

Mechanism: Binds to ATP sensitive K+channels like sulfonylureas acting in a

similar fashion to promote insulin secretion Onset and duration of action are much shorter. Particularly effective at mimicking the prandial and post-

prandial release of insulin. Used in combination with other oral agents they produce better

control than any monotherapy.

Pharmacokinetics: Reach effective plasma levels when taken 10-30 minutes before

meals. Metabolized to inactive products by CYP3A4 and excreted in

bile.

Meglitinides

Adverse Effects: Less hypoglycemia than sulfonylureas Drugs that inhibit CYP3A4 (ketoconozole, fluconazole,

erythromycin, etc.) prolong their duration of effect. Drugs that promote CYP3A4 (barbiturates,

carbamazepine and rifampin) decrease their effectiveness.

The combination of gemfibrozil and repaglinide has been reported to cause severe hypoglycemia.

BiguanidesMetformin is classified as an insulin sensitizer, it increases

glucose uptake and utilization by target tissues. It requires the presence of insulin to be effective. The risk of hypoglycemia is greatly reduced.

Mechanism: Inhibit hepatic gluconeogenesis Slows the intestinal absorption of sugars Reduces hyperlipidemia (↓LDL and VLDL cholesterol and

↑ HDL) Metformin also decreases appetite. It is the only oral

hypoglycemic shown to reduce cardiovascular mortality. It can be used in combination with other oral agents and

insulin.

Biguanides

Biguanides

Adverse effects: Hypoglycemia occurs only when combined with other

agents. Rarely severe lactic acidosis is associated with metformin

use particularly in diabetics with CHF. Drug interactions with cimetidine, furosemide, nifedipine

and others have been identified.

Thiazolidinediones

These agents are insulin sensitizers, they do not promote insulin secretion from β-cells but insulin is necessary for them to be effective. E.g. Pioglitazone and rosigglitazone.

Mechanism : Activate peroxisome proliferator-activated receptor-γ (PPAR-γ) Ligands for PPAR-γ regulate adipocyte production, secretion of

fatty acids and glucose metabolism. Agents binding to PPAR-γ result in increased insulin sensitivity

is adipocytes, hepatocytes and skeletal muscle. Hyperglycemia, hypertriglyceridemia and elevated HbA1c are

all improved. HDL levels are also elevated.

Thiazolidinediones

Thiazolidinediones

In the liver: ↓glucose outputIn muscle: ↑glucose uptakeIn adipose: ↑glucose uptake , ↓FA release

Pharmacokinetics: Extensively bound to albumin and undergo extensive P450

metabolism; metabolites are excreted in the urine the primary compound is excrete unchanged in the bile.

Adverse Effects: Fatal hepatotoxicityhepatic Oral contraceptives levels are decreased with

concomitant administration, this has resulted in some pregnancies.

α-Glucosidase Inhibitors

Mechanism of action: These agents are oligosaccharide derivatives taken at

the beginning of a meal delay carbohydrate digestion by competitively inhibiting α-glucosidase, a membrane bound enzyme of the intestinal brush border.

Pharmacokinetics: Acarbose is poorly absorbed remaining in the intestinal

lumen. Migitol is absorbed and excreted by the kidney. Both

agents exert their effect in the intestinal lumen.

α-Glucosidase Inhibitors

α-Glucosidase Inhibitors

Adverse Effects Flatulence, diarrhea, cramping Metformin bioavailability is severely decreased

when used concomitantly. These agents should not be used in diabetics with

intestinal pathology.

Thank You All

31st May 2013