Oral Hypoglycemic Agents (OHA)

The groups of oral agents i~scd to lowcr blood glucose arc :IS l'ollows:

1) Insulin secrelogogues:

a)Sulpl~onylureas (SU)

2) Biguanides

3) I~lsulin sensitizers (Thinzolidenediones)

4) a-glucosidase inhibitors.

1) Insulin Secretogogues 

Mechanism of action
 

The drugs in this class incrcasc the secretion ol endogenous insulin heom the beta cell of the pancreas. The dsug attaches itsclf Lo a receptor on the membrane of the beta cell, causing a closing of the ATP- sensitive potassiiun channel. This then results in opening of a Ca ++ channel which allows Calcium ions to enter the beta cell. This triggers the movement of the insulin granule to the cell surface where it's contents 01' insulin and c-peptidc are elc cased into Lhe circulation.

a)Sulphonylureas

Thus the role of sulphonylureas is lo increase insulin oulput l'orin tllc beta cell. There has been some research to postulate that theses drugs also increase the sensitivity of insulin on other tissues such as adipose [issue and the ~n~lscle.However, this is not a rnajor effecl.The drugs in this class are listed in the table (on page 36) with tlleir special characleristics.

First Generation SU

The firs1 generation SU's are no longer in general use as they do not olfer any advantages over the second generation drugs, except for the fact that tolbutalnide has the shortest half-life and therefore in patients with renal insufficiency and in the elderly, it is an ideal oral drug.

SecondGeneration SU

There is no specific advantage of' one drug over the other despite claims ol' the plicumaceutical agencies. The only reason to prefer one drug over the other are the special clinical pharmacological and cost reasons in special situations.Glibeilclarnide has been in use for the last 30 years and has been proven to be highly effective and safe. The onset of action is short (three hours), so patients with rliild diabetes nlay experience hypoglycemic synlptonls before lunch if the dose was trtken at breakfast. The duration of action however is long and therel'ore this drug should be given with caution, or preferably replaced by a shorter acting d r ~ in ~ g renal failure.

This is the cheapest SU available today.Glipizide has alrnost the same properties as glibenclainide except that it has a slightly shorter duration of action.Gliclazide has a shorter duration of action than the above two, and is generally prefei~ed in the elderly and in rean1 hilure; however, it is co~nyaratively more expensive and therefore it's use is limited.

Third Genzeration SU

Glimeperide is a new SU with slightly different additional properties to the older SU"s. In addition to insulin secreting properties, it has a signil'icant extra-pancreatic efFect by which insulin sensitivity is e~ihanced. It is thought to act on intracellular glucose transporter (GLUT 4) to bring about this effect. These glucose transporters are located within cellular organelles, and unless activated are unable to reach the surface of the cell membrane to which insulin binds. Under the action of Glimiyiride,GLUT 4 is allowed to reach the cell membrane resulting in, insulin internalization.~ o s i n ~ At : lower doses the drug can be given as a  single dose before breakfast, but at higher doses twice daily dosing is preferable.

b) Non-sulphonylurea Secretogogues

This is a recently available group of drugs which acts by attaching itself to a smaller sub-unit of the Sulphonyl receptor (K+ sensitive ATPase receptor), while the SU group of druge attach themselves to a larger sub-unit.The action is very short and therefore this drug is effective to reduce post-pmndial hyperglycemia. Hypoglyceinia is rare with this drug and therefore is quite safe in the elderly and in renal failure; however, it is expensive. This drug should not be combined with a suphonyl urea because the two diugs act on the same receptors.

Metformin is the only d n ~ of g this class which is in use today; phenforn~in has becn removed form the market. The nlenchanisnl of action include all of the following:

1) Glucose output from the liver is reduced.

2) Increased utilizaton of glucose by peripheral tissues.

3) Reduced gluconeogenesis.

4) Decreased absorption if glucose form the gut.

5) Reduced appetite.

It's principal mode of action is not clearly defined: it is an effective drug especitllly in obesity. It can be contbined well with SU drugs its well as with 'Thiazolidendiones.It has the potential to cause lactic acidosis cspccially in patients with cill-ditlc, hepatic or renal failure. It is therefore contrnindicatcd in these situations.

3) Instllin Sensitizers (Thiszolidenediones)
This is a new class of drugs which came into general clinic:tl usage in 2000-2001. The mode of action is cssenti;llly that it illlows irlcreased sensitivity of cells to the action of insulin. They ttct on an enzyme P P or Y whicli is ~niiinly present in adipocytes.There is a marked reduction of circuli~ting triglyccridcs arid free fatty acids.The first drug released in this class. Troglitazonc was withtirawn when hepi~t~-toxicity was cliscove~-ed.Thereafter two drugs, pioglitazone and rosiglitau)ne is in general clinical use. Though they have a potential for hepatotoxicity they have becn proved to be quite safe. They should not he used as the lirst line of trealrnent for a new diabetic,since the SU and biguanidcs have a long tradition of safety and efficacy. However,they can be added to the above drugs when glucose control is n d iidequi~tc with them alone.

4) Alpha Glucosidase Inhibitors

This class of drugs acts by preventing the alpha glucosidasc enzyrile in the srnall intestine from digesting the complex carkhydratcs and hcrefore preventing it's absorption. The drug in common usagc in this group is aearhose. Tile tablets must be. taken as the meal is started. The starting dose is 25 n ~ g s with each meal, increascct to 50 mgs thrice a day. A troubling side cffcct for some people is bloating and gaseousness, at time necessitating stoppage of the drug.hypoglycemic efyect is weak, and it does not cause hypoglycemia. It is relatively cxpcnsive, It is safe in the elderly and in renal failure.