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This document discusses the classification, mechanisms of action, pharmacokinetics, clinical uses, and side effects of various classes of oral hypoglycemic drugs used to treat type 2 diabetes. It covers insulin secretagogues like sulfonylureas and meglitinides, insulin sensitizers like biguanides and thiazolidinediones, alpha-glucosidase inhibitors, incretin mimetics, and dipeptidyl peptidase-4 inhibitors. The goal is for students to understand how each class of drug works to lower blood glucose levels and their proper uses and adverse effect profiles.
This document discusses the classification, mechanisms of action, pharmacokinetics, clinical uses, and side effects of various classes of oral hypoglycemic drugs used to treat type 2 diabetes. It covers insulin secretagogues like sulfonylureas and meglitinides, insulin sensitizers like biguanides and thiazolidinediones, alpha-glucosidase inhibitors, incretin mimetics, and dipeptidyl peptidase-4 inhibitors. The goal is for students to understand how each class of drug works to lower blood glucose levels and their proper uses and adverse effect profiles.
This document discusses the classification, mechanisms of action, pharmacokinetics, clinical uses, and side effects of various classes of oral hypoglycemic drugs used to treat type 2 diabetes. It covers insulin secretagogues like sulfonylureas and meglitinides, insulin sensitizers like biguanides and thiazolidinediones, alpha-glucosidase inhibitors, incretin mimetics, and dipeptidyl peptidase-4 inhibitors. The goal is for students to understand how each class of drug works to lower blood glucose levels and their proper uses and adverse effect profiles.
By the end of this lecture, students should be able to:
Classify different categories of oral hypoglycemic drugs. Identify mechanism of action, pharmacokinetics and pharmacodynamics of each class oral hypoglycemic drugs. Identify the clinical uses of hypoglycemic drugs Know the side effects, contraindications of each class of oral hypoglycemic drugs.
Types of diabetes mellitus Type I due to autoimmune or viral diseases Type II due to obesity, genetic factors Pts with Type 11 diabetes have two physiological defects:
1. Abnormal insulin secretion.
2. Resistance to insulin action in target tissues associated with decreased number of insulin receptors. Drugs used for treatment of Type-2 diabetes 1. Sulfonylurea drugs 2. Meglitinide analogues 3. Biguanides 4. Thiazolidinediones. 5.Alpha-glucosidase inhibitors. 6. Dipeptidyl peptidase-4(DPP-4) inhibitors Insulin secretagogues Sulfonylurea drugs Meglitinide analogues Insulin sensitizers Biguanides Thiazolidinediones Oral hypoglycemic drugs Others Alpha glucosidase inhibitors Dipeptidyl peptidase-4(DPP-4) inhibitors Insulin secretagogues Are drugs which increase the amount of insulin secreted by the pancreas
Include: Sulfonylureas Meglitinides
Classification of sulfonylureas Tolbutamide
Acetohexamide Tolazamide Chlorpropamide
Glipizide Glyburide (Glibenclamide) Glimepiride First generation Long acting Short acting second generation Short acting Intermediate acting Long acting Stimulate insulin release from functioning B cells by blocking of ATP-sensitive K channels resulting in depolarization and calcium influx(Hence, not effective in totally insulin-deficient pts type-1). Potentiation of insulin action on target tissues. Reduction of serum glucagon concentration. Mechanism of action of sulfonylureas: Mechanisms of Insulin Release Pharmacokinetics of sulfonylureas: Orally, well absorbed. Reach peak concentration after 2-4 hr. All are highly bound to plasma proteins. Duration of action is variable. Second generation has longer duration than first generation. Metabolized in liver excreted in urine Cross placenta, stimulate fetal B cells to release insulin hypoglycemia at birth.
Chlorpropa mide long- acting Absorption Well Well Slow Well Metabolism Yes Yes Yes Yes Metabolites Inactive Active Active Inactive Half-life 4 - 5 hrs 6 8 hrs 7 hrs 24 40 hrs Duration of action Short (6 8 hrs) Intermediate (12 20 hrs) Intermediate (12 18 hrs) Long ( 20 60 hrs) Excretion Urine Urine Urine Urine First generation sulfonylurea Tolbutamide: safe for old diabetic patients or pts with renal impairment. First generation sulfonylureas Glipizide Glibenclamide (Glyburide) Glimepiride
Absorption Well Well Well Metabolism Yes Yes Yes Metabolites Inactive Moderate activity Moderate activity Half-life 2 4 hrs Less than 3 hrs 5 - 9 hrs Duration of 10 16 hrs 12 24 hrs 12 24 hrs action short long long Doses Divided doses 30 min before meals Single dose Single dose 1 mg
Excretion Urine Urine Urine SECOND GENERATION SULPHONYLUREA Type II diabetes: monotherapy or in combination with other antidiabetic drugs.
Uses of sulfonylureas Unwanted Effects: 1. Hyperinsulinemia & Hypoglycemia: 2. Weight gain due to increase in appetite
e.g. Repaglinide
Rapidly acting insulin secretagogues
Meglitinide analogues
Mechanism of Action:
Insulin secretagogue as sulfonylureas. Pharmacokinetics of Meglitinides Orally, well absorbed. Very fast onset of action, peak 1 h. short duration of action (4 h). Metabolized in the liver & excreted in bile. Type II diabetes: monotherapy or combined with other antidiabetic drugs.
Patients allergic to sulfonylurea Uses of Meglitinides
Hypoglycemia Weight gain. Adverse effects of Meglitinides 1. Biguanides, e.g. Metformin 2. Thiazolidinediones, e.g. pioglitazone
Insulin sensitizers
BIGUANIDES
E.g. Metformin
Does not stimulate insulin release. Increases liver ,muscle &adipose tissues sensitivity to insulin & increase peripheral glucose utilization. Inhibits gluconeogenesis. Impairs glucose absorption from GIT.
Mechanism of action of metformin orally. Not bound to serum protein. Not metabolized. t 3 hours. Excreted unchanged in urine Pharmacokinetics of metformin Obese patients with type II diabetes Monotherapy or in combination. Advantages: No risk of hyperinsulinemia or hypoglycemia or weight gain (anorexia). Uses of metformin Metallic taste in the mouth GIT disturbances: nausea, vomiting, diarrhea Lactic acidosis Long term use interferes with vitamin B 12
Contraindications of metformin Insulin sensitizers Thiazolidinediones (glitazones) Pioglitazone
Mechanism of action Increase sensitivity of target tissues to insulin. Increase glucose uptake and utilization in muscle and adipose tissue. Pharmacokinetics of pioglitazone Orally (once daily dose). Highly bound to plasma albumins (99%) Slow onset of activity Half life 3-4 h Metabolized in the liver Excreted in urine 64% & bile Type II diabetes with insulin resistance. Used either alone or combined with sulfonylurea, biguanides or insulin. No risk of hypoglycemia when used alone Uses of pioglitazone Hepatotoxicity ?? (liver function tests for 1st year of therapy). Fluid retention (Edema). Precipitate congestive heart failure Mild weight gain. Adverse effects of pioglitazone E.g. Acarbose, Meglitol Reversible inhibitors of intestinal - glucosidases in intestinal brush border responsible for degradation of oligosaccharides to monosaccharides.
-Glucosidase inhibitors
decrease carbohydrate digestion and absorption in small intestine. Decrease postprandial hyperglycemia. Taken just before meals. No hypoglycemia if used alone.
-Glucosidase inhibitors
37 -GLUCOSIDASE INHIBITORS (Contd.)
MECHANISM OF ACTION Acarbose Given orally, poorly absorbed. Metabolized by intestinal bacteria. Excreted in stool and urine.
Kinetics of -glucosidase inhibitors
GIT: Flatulence, diarrhea, abdominal pain. No hypoglycemia if used alone.
Adverse effects of -glucosidase inhibitors
Incretin mimetics e.g. Exenatide(GLP-1) Incretins are GI hormones secreted in response to food, carried through circulation to the beta cells to stimulate insulin secretion & decrease glucagon secretion. Incretins
Two main Incretin hormones: GLP-1 (glucagon-like peptide-1) GIP (gastric inhibitory peptide or glucose- dependent insulinotropic peptide)
Both are inactivated by dipeptidyl peptidase-4 (DPP-4). Incretin mimetics Exenatide is glucagon-like peptide-1 (GLP-1) agonist. given s.c. once or twice daily Therapy of patients with type 2 diabetes who are not controlled with oral medicine. Adverse efects Nausea & vomiting(most common)
Dipeptidyl peptidase-4 (DPP- 4 ) inhibitors
e.g. Sitagliptin Orally Given once daily half life 8-14 h Dose is reduced in pts with renal impairment
Mechanism of action of sitagliptin
Inhibit DPP-4 enzyme and leads to an increase in incretin hormones level. This results in an increase in insulin secretion & decrease in glucagon secretion. Mechanism of action Clinical uses Type 2 DM as an adjunct to diet & exercise as a monotherapy or in combination with other antidiabetic drugs. Adverse effects Nausea, abdominal pain, diarrhea Nasopharyngitis