Treatment of Diabetes Mellitus

Dr. Salman IftikharDepartment of PharmacologyUHS

Diabetes Mellitus

• Type 1 (IDDM):– Early onset– Loss of pancreatic B cells absolute

dependence on insulin– Ketoacidosis – prone

• Type 2 (NIDDM)– Usually adult onset response to insulin– Not Ketoacidosis – prone

Insulin

Oral Hypoglycemic Agents

Sulfonylureas

Sulfonylureas

• Mechanism– The acute action of sulfonylureas is to

block K+ channels depolarization insulin release

• Effects of increased insulin glucagon release from pancreatic cells

Sulfonylureas

• Acetohexamide (active metabolite, dose in renal dysfunction)

• Tolbutamide (appropriate in renal dysfunction)

• Chlorpropamide (long acting, SIADH/disulfiram reaction)

• Glipizide ( dose in hepatic dysfunction)• Glyburide (active metabolite, dose in renal

dysfunction)

Sulfonylureas

• Adverse effects:– Hypoglycemia– Weight gain– Hypersensitivity (possible cross allergy

with sulfonamides)– Drug interactions mainly with first-

generation drugs hypoglycemia with cemetidine, insulin, sulfonamides, salicylates

Metformin

• “Euglycemic”, postprandial glucose levels but does not cause hypoglycemia or weight gain

• May involve tissue sensitivity to insulin and/or hepatic gluconeogenesis

• Adverse effects: possible lactic acidosis; gastrointestinal distress is common

Acarbose

• No hypoglycemia• Mechanisms: inhibits glucosidase in

brush borders of small intestine formation of absorbable carbohydrate postprandial glucose demand for insulin

• Adverse effects: GI discomforts, flatulence and diarrhea; recent concerns over potential hepatotoxicity

Thiazolidinediones

Pioglitazone & Rosiglitazone

• Mechanism:– Bind to nuclear peroxisome proliferator-activating

receptors (PPARs) involved in transcription of insulin responsive genes sensitization of tissues to insulin, plus in hepatic gluconeogenesis and triglycerides and insulin receptor numbers

– Adverse effects: less hypoglycemia than sulfonylureas, but weight gain and edema reported

BLOOD

New Drugs

PRAMLINTIDE

• Synthetic analog of amylin• Injectable: modulates postprandial glucose

levels• Suppresses glucagon release via

undetermined mechanisms, delays gastric emptying, and has central nervous system-mediated anorectic effects

• Administered in addition to insulin in those who are unable to achieve their target postprandial blood sugars

• Renal metabolism and excretion

• Always be injected by itself with a separate syringe; it cannot be mixed with insulin

• Adverse effects: hypoglycemia and gastrointestinal symptoms including nausea, vomiting, and anorexia.

PRAMLINTIDE

EXENATIDE

• A synthetic analog of glucagon-like-polypeptide 1 (GLP-1), exenatide is the first incretin therapy to become available for the treatment of diabetes

• Approved as an injectable, adjunctive therapy in persons with type 2 diabetes treated with metformin or metformin plus sulfonylureas who still have suboptimal glycemic control

• Multiple actions– potentiation of glucose-mediated insulin secretion– Suppression of postprandial glucagon release through as-

yet unknown mechanisms– slowed gastric emptying, and a central loss of appetite– The increased insulin secretion is speculated to be due in

part to an increase in beta-cell mass

• Adverse effects are nausea (about 44% of users) and vomiting and diarrhea. The nausea decreases with ongoing exenatide usage

• Weight loss is reported in some users, presumably because of the nausea and anorectic effects. A serious and, in some cases, fatal adverse effect of exenatide is necrotizing and hemorrhagic pancreatitis.

• Safety issues, however, may deter future use.

EXENATIDE

SITAGLIPTIN• Inhibitor of dipeptidyl peptidase-4 (DPP-4), the enzyme

that degrades incretin and other GLP-1-like molecules• Its major action is to increase circulating levels of GLP-

1 and GIP.

• Decreases postprandial glucose excursions by increasing glucose-mediated insulin secretion and decreasing glucagon levels

• Adverse effects include – nasopharyngitis, upper respiratory infections, and

headaches. Rarely, severe allergic reactions

• Dosage should be reduced in patients with renal impairment. Sitagliptin can be given as monotherapy or combined with metformin or Tzds.