Oral hypoglycaemic Agents - PowerPoint Presentation

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Oral hypoglycaemic Agents

By: Akash Saxena

KLE

College of Pharmacy,

Belagavi

A constituent Unit of KLE Academy of Higher Education and Research

Nehru Nagar,

Belagavi

–

590 010, Karnataka, India

Phone:

0831-2471399;

Fax:

0831-2472387;

Web:

http

://

www.klepharm.edu

E

-mail:

principal@klepharm.edu

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ObjectivesBy the end of the chapter you will be able to know:Diabetes, its etiology and clinical implicationsOral hypoglycaemic agents and their classificationMechanism of action of anti diabetic agents

SAR, drug structure and uses of the drugs in the course content.

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IntroductionDiabetes also referred to as diabetic mellitus is a chronic disorder characterised by insulin deficiency or insulin resistance. As a result of which body fails to utilise the proximate nutrients like carbohydrate, fats and proteins and there will be reduced production of energy in the form of Adenosine triphosphate

.

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Symptoms of diabetesPolydypsia --------- Increased thirstPolyphasia--------- Increased hungerPolu Urea --------- Increased urine

exceretionPoor wound healingFatigue etc…

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Types of diabetes Insulin dependent diabetes mellitus: Its type-1 diabetes in which Beta cells of pancreas can no longer make insulin because the body’s immune system has attacked and destroyed them. Exogenous administration of insulin is the only method to decrease the blood glucose levels.

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Type -2 Diabetes NIDDMIt was formerly called as adult onset diabetes and is the most common form of diabetes. People can develop it at any age, even during childhood , but mostly occurs over the age of forty.It begins with insulin resistance .The disease can be well balanced by strict dietary restrictions and exercise.

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Oral hypoglycaemic agentsReferred to as “Anti-diabetic medication”. Drugs used in the treatment of diabetes mellitus by lowering the blood glucose level.

These are administered orally and are thus also called as oral hypoglycemic agents or oral ant hyperglycemic agents.

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CLASSIFICATION OF ORAL HYPOGLYCAEMIC AGENTSSULPHONYLUREASNON-SULPHONYLUREAS (MEGLITINIDES)

THIAZOLIDINEDIONESBIGUANIDEALPHA-GLUCOSIDASE INHIBITORS

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SULFONYL UREAS Contain sulphonyl and urea group

The sulphonyl portion is very water soluble, it has an acidic amine and oxygen atoms for good hydrogen bondingR1 and R2 are very lipophilic and account for differences in overall potency, metabolism,duration and routes of eliminationOverall drugs tend to be lipophilic

and ionised at body pH They are weak acids with a pKa equivalent 5-6Second generation much more lipophilic

than the first and hence more potent They stimulate secretion of insulin from the functioning β-cells of the intact pancreasSulphonyl

ureas are similar in chemistry to the sulphonamides and thus potentially share toxicities and allergies.

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SAR OF SULFONYL UREASSAR:-  R1

Must be lipophilic Must have an aromatic ring next to the sulfoxide groups have a phenyl ringShould have a substitutent at the

para position. Methyl, amino, acetyl, chloro, bromo, metyithio and trifluorometyl

enhance hypoglycemic activity.The larger, more complex, para

substituents comprise the 2nd generation. The ethylcarboxamide appears to be very potent in these drugs which may be due to the distance from the carboxamide nitrogen to the sulfonamide nitrogen and how its binds to the receptor. R2Must be

lipophilic

 

Has some size constraints: N-

metyl

is inactive, N-ethyl is low active, N-

dodecyl

and above are inactive

N-

propyl

to N-

hexyl

are the most potent

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Examples of sulfonyl ureas

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Contd…….

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In general these are eliminated in the urine as some parent compound plus metabolites.Tolbutamide is one of the least potent oral hypoglycemics with short duration due

to rapid hydroxylationof para methyl substituents followed by oxidation to the acid.In Chlorpropamide

the para chloro protect from oxidation and thus has a longer duration than tolbutamide. Also increases lipid solubility to increase potency.

Tolazamide has a cyclic substituents that makes it approximately equal to

chlorpropamide in potency even though the para substituents is the same as tolbutamide. Oxidized quickly as with tolbutamde, but the alcohol formed has reasonable activity (active metabolite) so its overall duration is longer than tolbutamide and shorter than

chlorpropamide

.

Acetohexamide

possesses

ketone

group that is rapidly reduced to the alcohol but

this is more active than the parent compound and has a longer half-life. The 4

th

position on the hexane ring is also

hydroxylated

. Duration is similar to

tolazamide

.

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2nd GenerationDue to their larger molecular size, biliary excretion becomes important.

Glyburide and Glipizide are hydroxylated at the 3rd and 4th position on the cyclohexyl

ring. Some metabolites are active so duration is longer than parent compound.Glimepride, sometimes referred to as 3rd generation, is most potent of all sulfonylureas

. The cyclohexyl metyl is hydroxylated

then oxidized to the acid.

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NON SULFONYL UREASThe meglitinide are nonsulfonylurease

oral hypoglycemic agents used in the management of type 2 diabetes (NIDDM).These agents tends to have rapid onset and short duration of action.Mechanism of action is similar to that of sulfonylurease.There are two major difference between these two classes

Meglitinide cause must faster insulin production than sulfonylureaseEffects of metaglinides do not last as long as the effect of

sulfonylureaseThe effect of these class appear to last less than one hrs while sulfonylurease

continue to stimulate insulin productin for several hrs.As a result meglitinide should be taken 5 to 10 mins before meal.There is less risk of hypoglycemia due to short duration of action.Repaglinide

excreted less than 0.2% by kidney which may be advantage for elderly patient who are

renally

impaired.

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EXAMPLES OF NON SULFONYL UREAS

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THIAZOLINDIONEThe thiazolindione represent a novel nonsulfonylurease class of hypoglycemic agents for the treatment of NIDDM.

Much like the sulfonylurease, the use of these agents requires a functioning pancreas that can successful secrete insulin from β-cell.The thiazolindindione are highly selective agonist for the peroxisome proliferator

–activated receptor-gamma(PPARG), which is responsible for improving glycemic control, primarily through the improvement of insulin sensitivity in muscle and adipose tissue.

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MECHANISM OF ACTION OF THIAZOLIDINEDIONE

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EXAMPLES OF THIAZOLINDIONE ROSIGLITAZONE

PIOGLITAZONE

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insulin

USES: It is used in the treatment of Type-I diabetes

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METFORMINMetformin

 is used with a proper diet and exercise program and possibly with other medicationsto control high blood sugar. It is used in patients with type 2 diabetes. 

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GLICLAZIDEGliclazide

belongs to the class of medications known as oral hypoglycemics.It is used for the control of blood glucose in people with type 2 diabetes. It is used when diet, exercise, and weight reduction have not been found to control blood glucose well enough without medication. Gliclazide increases the amount of insulin released by the pancreas and helps the body use insulin more efficiently.

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NATEGLINIDEStarlix

(nateglinide) is an oral diabetes medicine that helps control blood sugar levels. This medicine helps your body respond better to insulin produced by your pancreas.Starlix is used together with diet and exercise to improve blood sugar control in adults with type 2 diabetes mellitus. This medicine is not for treating type 1 diabetes.

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PIOGLITAZONEPioglitazone

 is a diabetes drug (thiazolidinedione-type, also called "glitazones") used along with a proper diet and exercise program to control high blood sugar in patients with 

type 2 diabetes. It works by helping to restore your body's proper response to insulin, thereby lowering your blood sugar.

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