hypoglicemic drugs 2009

8/13/2019 Hypoglicemic Drugs 2009

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Hypoglycemic Drugs

Thianti Sylviningrum


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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 howthey work

d. Explain insulin and how it works

e. Explain the side effects of hypoglycemic drugs and

insulinf. Make a therapy plan for diabetic patients


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Introduction

Maintenance of blood glucose homeostasis iscritical for the function of many organs

Rising blood glucose concentrationsstimulateinsulin release from the -cells on the pancreaticislets of Langerhans

The effect of insulin : to coordinate tissue glucose

uptake, glycogen synthesis, fatty acid storage, andprotein synthesis


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Decreases in plasma glucose concentrations

a. pancreatic glucagon release

b. sympathetic nervous system activationc. hypothalamicpituitaryadrenal release of

growth hormone, cortisol, and epinephrine

The prodromal symptoms of hypoglycemia : are

caused by adrenergic stimulation (nervousness,tachycardia, tremor, sweating)


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Type 1 diabetes mellitus

syndrome of absolute insulin deficiency

It is characterized by predisposition to recurrentketoacidosis in the absence of insulin therapy

most cases are due to autoimmune destruction ofpancreatic -cells.

Most type 1 diabetics are diagnosed before the

age of 35 Therapy : insulin


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Type 2 diabetes mellitus

maturity onset diabetes of the young (MODY)

can present with acute hyperglycemia and

ketoacidosis in teenagers, but may be managed bydiet and oral agents for many years without

recurrent ketoacidosis.


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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 chronicdiabetes.


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Contd..

Glucose tolerance is most impaired during the

third trimester

The treatment of GDM focuses on tight control ofblood glucose to improve perinatal outcomes, as

well as behavioral interventions to minimize the

risk of type 2 diabetes later in life


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Therapeutic Guidelines

Type 1 diabetic patients are usually treated with insulin following their initialpresentation

the initial therapy for all patients with type 2 diabetes mellitus is a program thatcombines dietary modification and exercise.

If patients are asymptomatic and have 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 withimprovements in glucose control independent of changes in body weight in bothtype 1 and type 2 diabetes.


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The goal for glycemic control in both type I and type II diabetes :

a. preprandial blood glucose of 80120 mg/dL

b. postprandial (1.52 hours) blood glucose 140/90 mm Hg to achieve blood pressure


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Insulin Pharmacology

Human insulin is a protein containing 51 amino acids; it consists of A and Bchains linked by disulfide bonds

The two chains are produced along with C-peptide from a single proinsulinmolecule.

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


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Systemically administered insulin is degraded by

proteases in the kidney and liver, and by receptor-

mediated clearance at sites of insulin action


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Formulations

Regular insulin : short acting

Monomeric insulin analogs

Zinc-protamine insulin suspension or isophaneinsulin suspension (NPH) : intermediate acting

Zinc crystallized intermediate insulin suspension(Lente)

Long-acting insulin (Ultralente) Insulin mixtures


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Sulfonylureas (Insulin Secretagogues)


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The first used therapeutically were tolbutamide and

chlorpropamide .

Consequently, it can cause severe hypoglycaemia,

especially in elderly patients in whom renal functiondeclines

Second-generation sulfonylureas : glibenclamide,

glipizide ; are more potent (on a milligram basis), but

their maximum hypoglycaemic effect is no greater andcontrol of blood glucose no better than with tolbutamide


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Unwanted effects

Hypoglycaemia(the highest incidence occurring with

chlorpropamide and glibenclamide and the lowest with

tolbutamide )

Glibenclamide is best avoided in the elderly and inpatients 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


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Drug interactions

Non-steroidal anti-inflammatory drugs, coumarins, someuricosuric drugs (e.g. sulfinpyrazone ), alcohol,monoamine oxidase inhibitors, some antibacterial drugs

(including sulfonamides, trimethoprim andchloramphenicol ) and some imidazole antifungal drugshave all been reported to produce severe hypoglycaemiawhen given with a sulfonylurea

Agents that decrease the action of sulfonylureas on blood

glucose include high doses of thiazide diuretics andcorticosteroids.


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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.


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Other drugs that stimulate insulin

secretion

Thiazolidinediones (glitazones)

The effect : slow in onset, the maximum effect being achievedafter only 1-2 months of treatment

Thiazolidinediones reduce hepatic glucose output and increase

glucose uptake into muscle, enhancing the effectiveness ofendogenous insulin and reducing the amount of exogenous insulin

The reduction in blood glucose is often accompanied byreductions in circulating insulin and free fatty acids

Triglycerides may decline, while LDL and high-density lipoprotein

(HDL) are either unchanged or slightly increased, with littlealteration in LDL:HDL ratio.


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Thiazolidinediones bind to a nuclear receptor

called theperoxisome 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 insulinsignalling


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Unwanted effects

hepatotoxicity

weight gain and fluid retention

headache, fatigue and gastrointestinaldisturbances

contraindicated in pregnant or breast-feeding

women and in children


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-Glucosidase inhibitors

Acarbose for type 2 patients whose diabetes isinadequately controlled by diet with or without otheragents

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 obesetype 2 patients, and it can be coadministered withmetformin


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Biguanides

Metformin

Biguanides lower blood glucose by mechanisms that arecomplex and incompletely understood

They increase glucose uptake and utilisation in skeletalmuscle (thereby reducing insulin resistance) and reducehepatic glucose production (gluconeogenesis)

Metformin, while preventing hyperglycaemia, does notcause hypoglycaemia

It also reduces low-density and very low-densitylipoproteins (LDL and VLDL, respectively).


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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, andmetformin should not be given to patients with renal or hepaticdisease, 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 notstimulate appetite and is consequently the drug of first choice inthe 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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hypoglicemic drugs 2009

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