Hypoglycemic Drugs

Thianti Sylviningrum

Learning Objectives
By the end of this lecture,students will be able to : a. Explain the physiology of glucose circulation b. Classify Diabetes Mellitus c. Explain hypoglycemic drugs classification and how they work d. Explain insulin and how it works e. Explain the side effects of hypoglycemic drugs and insulin f. Make a therapy plan for diabetic patients

Introduction
Maintenance of blood glucose homeostasis is critical for the function of many organs Rising blood glucose concentrations stimulate insulin release from the -cells on the pancreatic islets of Langerhans The effect of insulin : to coordinate tissue glucose uptake, glycogen synthesis, fatty acid storage, and protein synthesis

 a. b. c.

Decreases in plasma glucose concentrations pancreatic glucagon release sympathetic nervous system activation hypothalamicpituitaryadrenal release of growth hormone, cortisol, and epinephrine The prodromal symptoms of hypoglycemia : are caused by adrenergic stimulation (nervousness, tachycardia, tremor, sweating)

Type 1 diabetes mellitus

syndrome of absolute insulin deficiency It is characterized by predisposition to recurrent ketoacidosis in the absence of insulin therapy most cases are due to autoimmune destruction of pancreatic -cells. Most type 1 diabetics are diagnosed before the age of 35 Therapy : insulin

Type 2 diabetes mellitus

maturity onset diabetes of the young (MODY) can present with acute hyperglycemia and ketoacidosis in teenagers, but may be managed by diet and oral agents for many years without recurrent ketoacidosis.

Gestational diabetes mellitus (GDM

The occurrence of impaired glucose tolerance during pregnancy in a woman without a previous history of diabetes is termed gestational diabetes mellitus (GDM) Associated with an increased risk of fetal abnormalities, adverse birth outcomes, and increased lifelong maternal risk of chronic diabetes.

Contd..
Glucose tolerance is most impaired during the third trimester The treatment of GDM focuses on tight control of blood glucose to improve perinatal outcomes, as well as behavioral interventions to minimize the risk of type 2 diabetes later in life

Therapeutic Guidelines
Type 1 diabetic patients are usually treated with insulin following their initial presentation the initial therapy for all patients with type 2 diabetes mellitus is a program that combines dietary modification and exercise. If patients are asymptomatic and have glucose values <300 mg/dL : a period of 36 months of dietary intervention should be undertaken before pharmacologic therapy is considered however, for symptomatic patients or patients with glucose values >300 mg/dL, initiating drug therapy concurrently with dietary intervention is warranted. Exercise is an important adjunct to dietary treatment and is associated with improvements in glucose control independent of changes in body weight in both type 1 and type 2 diabetes.

 a. b. c. d.

The goal for glycemic control in both type I and type II diabetes : preprandial blood glucose of 80120 mg/dL postprandial (1.52 hours) blood glucose <180 mg/dL bedtime blood glucose of 100140 mg/dL Treatment of blood pressure >140/90 mm Hg to achieve blood pressure <130/85 mm Hg reduces the incidence of diabetes-related morbidity and mortality Angiotensin-converting enzyme (ACE)-inhibitor therapy in patients who have elevated urinary albumin on at least two occasions (by timed collection or urinary albumin/creatinine ratio) reduces the progression of diabetic nephropathy in type 1 diabetes and the progression of proteinuria in type 2 diabetes Cardiovascular disease : smoking, hypertension, dyslipidemia is warranted

Insulin Pharmacology
Human insulin is a protein containing 51 amino acids; it consists of A and B chains linked by disulfide bonds The two chains are produced along with C-peptide from a single proinsulin molecule. A large portion of the insulin in the portal circulation is degraded in the liver The rate of absorption of subcutaneously administered insulin is modified by : a. The physical properties of the insulin b. species of insulin c. volume of injection d. site of injection e. concentration of the dose

 Systemically administered insulin is degraded by proteases in the kidney and liver, and by receptormediated clearance at sites of insulin action

Formulations
Regular insulin : short acting Monomeric insulin analogs Zinc-protamine insulin suspension or isophane insulin suspension (NPH) : intermediate acting Zinc crystallized intermediate insulin suspension (Lente) Long-acting insulin (Ultralente) Insulin mixtures

Sulfonylureas (Insulin Secretagogues)

 The first used therapeutically were tolbutamide and chlorpropamide . Consequently, it can cause severe hypoglycaemia, especially in elderly patients in whom renal function declines Second-generation sulfonylureas : glibenclamide, glipizide ; are more potent (on a milligram basis), but their maximum hypoglycaemic effect is no greater and control of blood glucose no better than with tolbutamide

Unwanted effects
Hypoglycaemia(the highest incidence occurring with chlorpropamide and glibenclamide and the lowest with tolbutamide ) Glibenclamide is best avoided in the elderly and in patients with even mild renal impairment because of the risk of hypoglycaemia Stimulate appetite and often cause weight gain Allergic skin rashes can occur, and bone marrow damage

Drug interactions
Non-steroidal anti-inflammatory drugs, coumarins, some uricosuric drugs (e.g. sulfinpyrazone ), alcohol, monoamine oxidase inhibitors, some antibacterial drugs (including sulfonamides, trimethoprim and chloramphenicol ) and some imidazole antifungal drugs have all been reported to produce severe hypoglycaemia when given with a sulfonylurea Agents that decrease the action of sulfonylureas on blood glucose include high doses of thiazide diuretics and corticosteroids.

Clinical use
Sulfonylureas require functional B cells, so they are useful in the early stages of type 2 diabetes. They can be combined with metformin or with thiazolidinediones.

Other drugs that stimulate insulin secretion

Thiazolidinediones (glitazones) The effect : slow in onset, the maximum effect being achieved after only 1-2 months of treatment Thiazolidinediones reduce hepatic glucose output and increase glucose uptake into muscle, enhancing the effectiveness of endogenous insulin and reducing the amount of exogenous insulin The reduction in blood glucose is often accompanied by reductions in circulating insulin and free fatty acids Triglycerides may decline, while LDL and high-density lipoprotein (HDL) are either unchanged or slightly increased, with little alteration in LDL:HDL ratio.

 Thiazolidinediones bind to a nuclear receptor called the peroxisome proliferator-activated receptor- (PPAR), which is complexed with retinoid X receptor (RXR) Thiazolidinediones the PPAR-RXR complex to bind to DNA, promoting transcription of several genes with products that are important in insulin signalling

Unwanted effects
hepatotoxicity weight gain and fluid retention headache, fatigue and gastrointestinal disturbances contraindicated in pregnant or breast-feeding women and in children

-Glucosidase inhibitors
Acarbose for type 2 patients whose diabetes is inadequately controlled by diet with or without other agents It delays carbohydrate absorption, reducing the postprandial increase in blood glucose The commonest adverse effects are related to its main action and consist of flatulence, loose stools or diarrhoea, and abdominal pain and bloating Like metformin, it may be particularly helpful in obese type 2 patients, and it can be coadministered with metformin

Biguanides
Metformin Biguanides lower blood glucose by mechanisms that are complex and incompletely understood They increase glucose uptake and utilisation in skeletal muscle (thereby reducing insulin resistance) and reduce hepatic glucose production (gluconeogenesis) Metformin, while preventing hyperglycaemia, does not cause hypoglycaemia It also reduces low-density and very low-density lipoproteins (LDL and VLDL, respectively).

Unwanted effects
dose-related gastrointestinal disturbances (e.g. anorexia, diarrhoea, nausea), which are usually but not always transient Lactic acidosis is a rare but potentially fatal toxic effect, and metformin should not be given to patients with renal or hepatic disease, hypoxic pulmonary disease, heart failure or shock. contraindicated in pregnancy Long-term use may interfere with absorption of vitamin B12. Metformin is used to treat patients with type 2 diabetes. It does not stimulate appetite and is consequently the drug of first choice in the majority of type 2 patients who are obese and who fail treatment with diet alone It can be combined with sulfonylureas, glitazones or insulin.

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