INTRO

Hehehehehehehe ……………..The one thing which has made a substitute for INSULIN…………….the only drug of choice for a early diagnosed and well diet controlled patient with Non insulin diabetes mellitus  ……….

Oral hypoglycemic agents commonly are referred to as sulfonylureas, a class of compounds. Sulfonylurea compounds are among the most widely prescribed medications in the world. The drugs are frequently used to treat patients with type II diabetes. Wide availability of these medications increases potential for either intentional or unintentional overdose in pediatric and adult populations.

First-generation sulfonylurea compounds became widely available in 1955. They are acetohexamide, chlorpropamide, tolazamide, and tolbutamide. First-generation agents have longer half-lives (eg, 49 hours for chlorpropamide). Second-generation sulfonylureas were introduced in 1984. Known as glipizide, glyburide, and glimepiride, second-generation sulfonylureas are more potent and have shorter half-lives than the first-generation sulfonylureas.

Other agents besides sulfonylureas are used to treat type II diabetes, including biguanides, alpha-glucosidase inhibitors, and troglitazone. Metformin (Glucophage in the United States) is one such agent. Even in excessive dosage, these agents do not decrease serum glucose below euglycemia; consequently, they are referred to appropriately as antihyperglycemic agents rather than hypoglycemic agents.

The Joslin Diabetes Center released a clinical guideline for the pharmacological management of type II diabetes in 2007.

CLASSIFICATION OF DRUGS

1. SULFONYL UREA’S
2. BIGUANIDES
3. ALPHA GLUCOSIDASE INHIBHITORS
4. MEGLITINIDES
5. THIAZOLINEDIONES

SULFONYLUREA’S

Sulfonylureas work primarily by stimulating pancreatic insulin secretion, which in turn reduces hepatic glucose output and increases peripheral glucose disposal.

The sulfonylureas are often classified as belonging to the first or second generation.

The First generation sulfonylureas:

• Acetohexamide
• Chlorpropamide
• Tolazamide
• Tolbutamide.

The Second generation sulfonylureas :

• Glibenclamide
• Glyburide
• Glipizide
• Glicazide
• Glimepiride

The first generation sulfonylureas are rarely used now.

NEWER DRUGS ARE Glimipiride (Amaryl) and Glicazide MR and XR ………Nowadays new medicine is used vastly in the practice of longterm NIDDM cases (Non insulin dependant Diabetes Mellitus)……..

The SU class of oral hypoglycemic agents (insulin secretagogues) has been in existence since tolbutamide was introduced in 1956.

The sulfonylurea drugs have effects which are still not completely understood. Initially, they work primarily by stimulating pancreatic insulin secretion, which in turn reduces hepatic glucose output and increases peripheral glucose disposal. They are potassium channel blockers whose effect on the pancreatic beta-islet cells is to allow an influx of calcium into the cell, which causes an increase in the release of insulin.

However, after several months, blood levels of insulin return to pre-medication levels, yet blood glucose levels remain reduced. Clearly, the sulfonylurea drugs must have other effects. Several have been identified, among them: sulfonylurea medications slow the rate at which the liver releases glucose into the bloodstream, and they increase the number of insulin receptors on cell membranes, thus increasing insulin efficiency.

The efficacy of the first- and second-generation sulfonylureas is similar, although second-generation agents are better formulated and, although costlier than the older sulfonylureas, have some advantages. Second-generation sulfonylureas:

Are more potent on a per milligram basis
Tend to produce fewer side effects
In addition, the pharmacokinetics of these second-generation agents allows for more effective once-a-day dosing, which enhances compliance.

Although some consider SUs to be dated compared with the newer oral hypoglycemic drugs, there remains a large number of patients that will continue to benefit from them.

BIGUANIDES

Two drugs in this category are phenformin and metformin.

Biguanides work mainly by

• Suppressing excessive hepatic glucose production
• Increasing glucose utilization in peripheral tissues to a lesser degree.
• Possibly reduce food intake and thus reduce intestinal glucose absorption

As the biguanides do not stimulate endogenous insulin secretion, hypoglycemia does not occur when they are used alone and therefore they are sometimes called anti-hyperglycemic agents rather hypoglycemic agents.

The use of phenformin has decreased considerably and it is usually metformin that is now used when a biguanide is prescribed.

The biguanides were introduced in 1957. Both phenformin and metformin have been widely used here, although in recent times, the use of phenformin has decreased significantly and most people now use metformin when a biguanide is to be used.

Metformin works mainly by suppressing excessive hepatic glucose production, although it may increase glucose utilization in peripheral tissues to a lesser degree, by decreasing insulin resistance in muscle cells. Metformin may also improve glucose levels by reducing intestinal glucose absorption.

Metformin is not metabolized and is excreted unchanged by the kidneys.

Metformin has many characteristics that are ideal for treating type 2 diabetes, including weight loss, insulin sensitization, positive lipid effect, mild hypotensive effect, and low or no incidence of hypoglycemia.

Because metformin does not stimulate endogenous insulin secretion, hypoglycemia does not occur when this dose is used alone, although hypoglycemia may occur if metformin is taken with insulin, a sulfonylurea, or an excessive amount of alcohol.

Treatment with metformin has beneficial effects on plasma lipids (it lowers triglyceride and low-density lipoprotein [LDL] cholesterol levels while increasing high-density lipoprotein [HDL] cholesterol) that are greater than expected from improved glucose control alone.

In addition, metformin therapy has been associated with weight loss or no weight gain. This may be particularly helpful in obese patients with type II diabetes.

Metformin is effective as monotherapy or in combination with sulfonylureas, alpha-glucosidase inhibitors, and insulin. The combination of metformin and troglitazone has also been shown to be safe and effective, although this combination is not an USA FDA- approved indication and extensive published data on this combination is lacking.

ALFA GLUCOSIDASE INHIBHITORS

There are Acarbose and Miglitol. Acarbose (Precose) is an alpha-glucosidase inhibitor that slows down the breakdown of disaccharides and polysaccharides and other complex carbohydrates into monosaccharides. The enzymatic generation and subsequent absorption of glucose is delayed and the postprandial blood glucose values, which are characteristically high in patients with type II diabetes, are reduced with acarbose. AGIs do not prevent the absorption of carbohydrates and complex sugars, but they do delay their absorption.

Delaying the absorption of carbohydrates is a unique mechanism among oral diabetic medications for lowering HgbA1c levels. The effectiveness of this mechanism is one of the physiologic characteristics of type 2 diabetes. Patients with type 2 diabetes demonstrate a delayed or sluggish insulin response from the pancreas to a glucose (a meal) load. By delaying the absorption of glucose, the insulin response is more matched to the serum glucose, resulting in less postprandial hyperglycemia and a lowering of the HbA1c. The AGIs also demonstrate a lowering of total insulin output of the pancreas, increased insulin sensitivity, a variable but mild decrease in triglycerides, with no effect on patient weight.

One disadvantage with the use of acarbose is that it is to be taken along with the first bite of a meal. Moreover, it has to be taken three times daily with meals. These factors often lead to non compliance and a decrease in the efficacy of the drug.

MEGLITINIDES +AMINOACID DERIVATIVES

A very recent addition to the OHA group. It is a ultra short acting drug which acts directly on the the beta cells of the pancreas and increases the secretion of insulin. It also corrects the problems with the pulsatile release of insulin which is seen in Type II diabetes.

Repaglinide from the meglitinide drug class, acts like an extremely short-acting SU (an insulin secretagogue) and is potentially useful as a SU replacement. The effect of repaglinide on the pancreas is very similar to that of the SUs. Repaglinide, like the SUs, blocks the potassium channels on the pancreatic islet beta-cells, which causes an influx of calcium into the cell and increasing the secretion of insulin. There appears to be 2 similar potassium channels on islet beta-cells, one of which is predominantly affected by repaglinide and the other is predominantly affected by SUs.

The repaglinide-affected potassium channel appears to be glucose dependent, which may partially explain why repaglinide is associated with a much lower incidence of hypoglycemia.

What makes repaglinide clinically different from the SUs is its ultra-short half-life (1 hour). Repaglinide is taken just before or with meals, and the stimulation of the pancreas is limited only to a brief time around meals. Because of the short duration, the patient does not have continuous high levels of insulin and the resulting adverse effects.

Its biggest advantage over the other oral hypoglycemic medications is that it allows for flexible timing and missed meals.

Repaglinide has been approved for use with metformin, and the combination appears to be a very effective. There are no clinical trials of repaglinide with the alpha-glucosidase inhibitors, and of the TZD class, only 1 clinical trial with troglitazone has been reported. There are theoretical interactions between repaglinide and the TZDs through their common metabolism in the P450 pathway, so more clinical trials are clearly needed.

THIAZOLIDINEDIONES

Thiazolidinediones are a new class of oral antidiabetic agents (commercially known as glitazones) that enhance insulin sensitivity in peripheral tissues. Troglitazone was the first glitazone introduced to the market, and though widely used, it has now been withdrawn from the market as its use has been linked with hepatocellular injury and death secondary to liver failure.

Rosiglitazone and Pioglitazone are now available for clinical use and are extremely potent in reducing peripheral insulin resistance.

The thiazolidinedione (TZD) class of oral hypoglycemics ( popularly known as glitazones) was developed in 1997 and offers a new mechanism for treatment of type 2 diabetes. The first, troglitazone was taken off the market in 1999 because of its association with hepatic toxicity. Rosiglitazone and pioglitazone have been available since 1999, and have recently been introduced in the Indian market.

The primary effect of TZDs is peripheral, with increasing insulin sensitivity and increased glucose uptake. The TZDs have some effect on hepatic glucose uptake and sensitivity to a lesser degree. They do not stimulate the pancreas to produce more insulin.

TZDs are hepatically metabolized and thus can be used safely in patients with renal dysfunction. They can be dosed once daily, although rosiglitazone works better with twice-daily dosing. Reports have suggested that rosiglitazone works better in women, but the reason for this is not known.

Both pioglitazone and rosiglitazone are approved for monotherapy and in combination with metformin, SUs, and insulin.

Besides their effect in lowering the blood glucose levels, both drugs also have notable effects on lipids. The current data show that pioglitazone has a minimal effect on low-density lipoprotein (LDL) cholesterol levels and a favorable effect on high-density lipoprotein (HDL) cholesterol and triglyceride levels. Rosiglitazone has a favorable effect on HDL cholesterol levels but a negative effect on LDL cholesterol levels.

With use of glitazones, patience is required. Blood sugar levels may show a significant reduction statistically in as little as two to four weeks, but the maximum effects are not seen until two or three months have passed.

CONCLUSION

So i dont have a conclusin yet……………………Postin it soon !!!!!!!!!!!!!!!!!!!!!!!!

INTRODUCTION

Sri krishna Hospital is at New Military Road, Avadi, Chennai -600062 . Dr.C.Jayapal BSc MD (CARDIOLOGY) has also recieved a lot a rewards from the Institute of Diabetology and has been very very sucessful in his diabetic practice and has been receiving a lot of good outcome from most of his patients …………………I was shell shocked the first day i joined there …that was 02/01/2010 ….a day that gave my life  a big big change ……..

ABT THE PRACTICE THERE

All patients there are interesting xcept for a few malingering cases ……………..the first case of my life was a TB patient at BH(Bombay hospital) a very well pronouned Hospital in the world ……………..but a lot of cases die out of poor patient care by the staff nurses ……bcoz the docs are trained better there and the nurses are not upto the mark…………………His name was Trilok /45/m from wadala(mumbai)…………..he was a businessman and suffered from TB ….Non smoker / Non drinker and also  a Vegeterian……….But he only survived of a very innate care take by Dr.K.Ramamoorthy MD the messiah of the Hospital………But here the story stands all behind the sucess of a single hero who has made his life so long in the history of medicine and who has dedicated himself to medicine ……………………..He is Dr.C.Jayapal MD from Krishna Hospital …..“Its like everyday learning hahahha ” the same words ……I just stole it from his mouth ….Looks nice to hear ….but more nicer  to xperience ………he always makes  a proper History taking and Xamines every single patient from hair to toe nail …….and also follows the course of the disease and treats according to the disease and not according to the symptom…….Bcoz it may cost him a lot of workin hours ……He is also a great devotee of Lord krishna and a life member of the ISKON trust ….and also has his own temple abt a 2 km   from Avadi. …..So he has a very good power on Speech and thought and learn like no 2 moro…..and teaches like the god krishna himself ,,,,,,,But the class he follows is very very simple …….he is like a 2nd yr MBBS student xaminig each case thoroughly very rarely missin any …….but his staffs are also not upto mark ……so his maintanence of inpatients has been not that sucessful compared to his blaring practice ….there are patients from even differents states and districts …….But his teaching has been a very good mark on my medical life ….Im very happy to inform u that he is my Chacha (chitappa, Kochuacchan, Fathers yunger brother )……

NEW IDEAS IN ME

This wondrful xperience of my life shud be shared by my frens and fellow viewers and also my dear readers and my patients and his patients too ….so plannin to write Blogs on Diabetes Mellitus ………………………………. and have to make a safe world and better country …………………………we are leading in oral cancers in the world 80% and next in DM 40 % and mostly in the developed states of the country ……….So there shud be proper education for the pople and the doctors to be well developed in their methods of proper learning abt the disease and the symptom…………………..understand its not the symptom creating the problem its the disease …………………same  way there is no proper treatment without necessary investigations and there is no proper treatment without management of the disease itself …………………………….

Regards

urs always DR.LOKKU (LOGARANGAN MUTHURANGAN)