Oral Hypoglycemic agents- Others

Biguanides
History
Metformin (GLUCOPHAGE) and phenformin were introduced in 1957, and buformin was introduced in 1958. The latter was of limited use, but metformin and phenformin were widely used. Phenformin was withdrawn in many countries during the 1970s because of an association with lactic acidosis. Metformin has been associated only rarely with that complication, and has been widely used in Europe and Canada; it became available in the United States in 1995. Metformin given alone or in combination with a sulfonyl-urea improves glycemic control and lipid concentrations in patients who respond poorly to diet or to a sulfonylurea alone (DeFronzo et al., 1995).
ADME
Metformin is absorbed mainly from the small intestine. The drug is stable, does not bind to plasma proteins, and is excreted unchanged in the urine. It has a half-life of 1.3 to 4.5 hours (see Bailey, 1992). The maximum recommended daily dose of metformin is 3 g, taken in three doses with meals.
Mechanism of action
The main causes of reduced glucose levels during metformin therapy appear to be an increase in insulin action in peripheral tissues (see Bailey, 1992) and reduced hepatic glucose output due to inhibition of gluconeogenesis (Stumvoll et al., 1995). Metformin also may decrease plasma glucose by reducing the absorption of glucose from the intestine, but this action has not been shown to have clinical relevance.
Therapeutic uses
Metformin hydrochloride has been most often prescribed for patients with refractory obesity whose hypoglycemia is due to ineffective insulin action, i.e., “insulin resistance syndrome”. Because metformin is an insulin-sparing agent and does not increase weight or provoke hypoglycemia, it offers obvious advantages over insulin or sulfonylureas in treating hyperglycemia in such patients. Another indication for its use is in combination with sulfonylureas in non-insulin-dependent diabetics in whom sulfonylurea therapy alone is inadequate.
Contraindications
Patients with renal impairment should not receive metformin. Hepatic disease, a past history of lactic acidosis (of any cause), cardiac failure, or chronic hypoxic lung disease also are contraindications to the use of the drug. These conditions all predispose to increased lactate production and hence to the fatal complications of lactic acidosis. The reported incidence of lactic acidosis during metformin treatment is lower than 0.1 case per 1000 patient years, and the mortality risk is even lower.
Side effects
Acute side effects of metformin, which occur in up to 20% of patients, include diarrhea, abdominal discomfort, nausea, metallic taste, and anorexia. These are usually minimized by increasing the dosage of the drug slowly and taking it with meals. Intestinal absorption of vitamin B12 and folate often is decreased during chronic metformin therapy.
Consideration should be given to stopping treatment with metformin if the plasma lactate level exceeds 3 mM. Similarly, decreased renal or hepatic function also may be a strong indication for withholding treatment. It also would be prudent to stop metformin if a patient is undergoing a prolonged fast or is treated with a very low calorie diet. Myocardial infarction or septicemia mandate stopping the drug immediately. Metformin often is given in combination with sulfonylureas (Hermann et al., 1994).

Other Oral Hypoglycemic Agents
Thiazolidinediones
Ciglitazone, Pioglitazone are thiazolidinediones. They are antihyperglycemic in a variety of insulin-resistant and diabetic animal models. Like biguanides, they do not cause hypoglycemia in diabetic or normal persons. Ciglitazone reduces plasma glucose, insulin, and lipid concentrations after oral administration in several insulin-resistant animal models. The reduction in plasma insulin levels follows a fall in plasma glucose concentration, which is thought to be due to an effect of the drug to decrease insulin resistance in liver, skeletal muscle, and adipose tissue. The administration of these agents to normal animals does not potentiate insulin effects. Thiazolidinediones appear to augment insulin action in insulin-resistant animals by increasing the number of glucose transporters. These compounds, along with several other newer analogs, are currently undergoing phase I or II clinical trials.

α-Glucosidase Inhibitors
α-Glucosidase inhibitors such as acarbose reduce intestinal absorption of starch, dextrin, and disaccharides by inhibiting the action of intestinal brush border α-glucosidase. Inhibition of this enzyme slows the absorption of carbohydrates; the postprandial rise in plasma glucose is blunted in both normal and diabetic subjects.
Acarbose also competitively inhibits glucoamylase and sucrase but has weak effects on pancreatic α-amylase. It reduces postprandial plasma glucose levels in IDDM and NIDDM subjects. However, only small improvements in hemoglobin A1C values have been reported. The drug is poorly absorbed.
Acarbose results in dose-related malabsorption, flatulence, and abdominal bloating. Doses of 50 to 100 mg given with each meal are usually well tolerated. Smaller doses are given with snacks. Acarbose is most effective when given with a starchy, high-fiber diet with restricted amounts of glucose and sucrose (Bressler and Johnson, 1992).

Oral Hypoglycemic agents- Sulfonylureas

Oral Hypoglycemic agents

History
In contrast to the systematic studies that led to the isolation of insulin, the sulfonylureas were discovered accidentally. In 1942, Janbon and colleagues noted that some sulfonamides caused hypoglycemia in experimental animals. These observations were soon extended, and 1-butyl-3-sulfonylurea (carbutamide) became the first clinically useful sulfonylurea for the treatment of diabetes. This compound was later withdrawn because of adverse effects on the bone marrow, but it led to the development of the entire class of sulfonylureas.

Sulfonylureas
Chemistry
The sulfonylureas are divided traditionally into two groups or generations of agents. Their structural relationships are shown in Table.
All members of this class of drugs are substituted arylsulfonylureas. They differ by substitutions at the para position on the benzene ring and at one nitrogen residue of the urea moiety. The first group of sulfonylureas includes tolbutamide, acetohexamide, tolazamide, and chlorpropamide.
A second generation of hypoglycemic sulfonylureas has emerged. These drugs (glibenclamide, glipizide, and gliclazide) are considerably more potent than the earlier agents.

Structure - Activity Relationships

The benzene ring should contain one substituent, preferably in the para position. The substituents that seem to enhance hypoglycemic activity are methyl, amino, acetyl, chloro, bromo, methylthio, and trifluoromethyl groups.
Compounds with p-(-β-arylcarboxamidoethyl) substituents (the second generation agents) are orders of magnitude better than the first generation agents. It is believed that this is because of a specific distance between the nitrogen atom of the substituent and the sulfonamide nitrogen atom.
The group attached to the terminal nitrogen should be of certain size and should impart lipophilic properties to the molecule. The N-methyl are inactive, N-ethyl have low activity, while N-propyl to N-hexyl are most active. Activity is lost if N-substituent contains 12 or more carbons.

Mechanism of Action
The principal action of the sulphonylureas is on the β-cells of the islets. Stimulating insulin secretion and thus reducing plasma glucose concentration.
High affinity receptors of sulfonlyreas are present on the ATP-sensitive K+ channels in β-cell plasma membranes and the binding of various sulphonylureas parallels their potency in stimulating insulin release. Glibenclamide reduces the potassium permeability of β-cell by blocking the ATP-sensitive potassium channels, causing depolarization, Ca2+ entry and hence insulin secretion.
Basal insulin secretion and the secretory response to various stimuli are enhanced in the first few days of treatment with sulphonylurea drugs. With longer treatment, insulin secretion continues to be augmented and tissue sensitivity to insulin also improves, by an unknown mechanism.
Absorption, Fate, and Excretion
The sulfonylureas have similar spectra of activities; thus, their pharmacokinetic properties are their most distinctive characteristics. Although there are differences in the rates of absorption of the different sulfonylureas, all are effectively absorbed from the gastrointestinal tract. However, food and hyperglycemia can reduce the absorption of sulfonylureas. (Hyperglycemia per se inhibits gastric and intestinal motility and thus can retard the absorption of many drugs.) In view of the time required to reach an optimal concentration in plasma, sulfonylureas with short half lives may be more effective when given 30 minutes before eating.
Sulfonylureas in plasma are largely (90% to 99%) bound to protein, especially albumin; plasma protein binding is least for chlorpropamide and greatest for glibenclamide. The volumes of distribution of most of the sulfonylureas are about 0.2 liter/kg.
The first-generation sulfonylureas vary considerably in their half-lives and extents of metabolism. Chlorpropamide has a long half-life (24 to 48 hours). The second-generation agents are approximately 100 times more potent than are those in the first group (Lebovitz and Feinglos, 1983). Although their half-lives are short (1.5 to 5 hours), their hypoglycemic effects are evident for 12 to 24 hours, and it is often possible to administer them once daily. The reason for the discrepancy between the half-life and duration of action of these drugs is not clear.
All of the sulfonylureas are metabolized by the liver, and the metabolites are excreted in the urine. Metabolism of chlorpropamide is incomplete, and about 20% of the drug is excreted unchanged. Thus, sulfonylureas should be administered with caution to patients with either renal or hepatic insufficiency.
Adverse Reactions
Adverse effects of the sulfonylureas are infrequent, occurring in about 4% of patients taking first-generation drugs and perhaps slightly less often in patients receiving second-generation agents (Paice et al., 1985). Not unexpectedly, sulfonylureas may cause hypoglycemic reactions, including coma (Ferner and Neil, 1988; Seltzer, 1989). This is a particular problem in elderly patients with impaired hepatic or renal function who are taking longer-acting sulfonylureas. Sulfonylureas can be ranked in order of decreasing risk of causing hypoglycemia based on their half-lives. The longer the half-life, the more likely an agent will induce hypoglycemia. Severe hypoglycemia in the elderly can present as an acute neurologic emergency that may mimic a cerebrovascular accident. Thus, it is important to check the plasma glucose of any elderly patient presenting with acute neurologic symptoms. Owing to the long half life of some sulfonylureas, it may be necessary to treat an elderly hypoglycemic patient for 24 to 48 hours with an intravenous glucose infusion.
Other side effects of sulfonylureas include nausea and vomiting, cholestatic jaundice, agranulocytosis, aplastic and hemolytic anemias, generalized hypersensitivity reactions, and dermatological reactions. About 10% to 15% of patients who receive these drugs, particularly chlorpropamide, develop an alcohol-induced flush similar to that caused by disulfiram. Sulfonylureas, especially chlorpropamide, also may induce hyponatremia by potentiating the effects of antidiuretic hormone on the renal collecting duct (Paice et al., 1985). This undesirable side effect occurs in up to 5% of all patients; it is less frequent with glibenclamide and glipizide.
Drug interactions (Rang 1999)
Several compounds augment the hypoglycemic effect of the sulfonylureas and several such interactions are potentially clinically important. Non-steroidal anti-inflammatory drugs (including azapropazone, phenylbutazone and salicylates), alcohol, monoamine oxidase inhibitors, some antibacterial (including sulphonamides, trimethoprime chloramphenicol), some antifungal drugs (including miconazole and possibly fluconazole) have all been reported to produce severe hypoglycemia when given with the sulfonylureas. The probable basis of the interaction is competition for the metabolizing enzymes but interference with plasma protein binding or with excretion may play a part. Agents that decrease the action of the sulphonylureas include diuretics (thiazides and loop diuretics) and corticosteroids.

Therapeutic Uses
Sulfonylureas are used to control hyperglycemia in NIDDM patients who cannot achieve appropriate control with changes in diet alone. In all patients, however, continued dietary restrictions are essential to maximize the efficacy of the sulfonylureas. Some physicians still consider treatment with insulin to be the preferred approach in such patients.
Dosage and administration
The usual initial daily dose of tolbutamide is 500 mg, while 3000 mg is the maximally effective total dose.
Chlorpropamide are usually administered in a daily dose of 100 to 250 mg, while 750 to 1000 mg is maximal.
The initial daily dose of glibenclamide is 2.5 to 5 mg, while daily doses of more than 20 mg are not recommended.
Therapy with glipizide is usually initiated with 5 mg given once daily. The maximal recommended daily dose is 40 mg; daily doses of more than 15 mg should be divided. The starting dose of gliclazide is 40 to 80 mg per day, and the maximal daily dose is 320 mg. Treatment with the sulfonylureas must be guided by the individual patient's response, which must be monitored frequently.

Diabetes Mellitus

রাজশাহী বিশ্ববিদ্যালয়

ফার্মেসী বিভাগ

বি. ফার্ম (সম্মান) পার্ট-III এর সিলেবাস অনুযায়ী প্রণিতঃ

Introduction

The diabetic population has reached the 100 million mark. Decreased physical activity, increasing obesity, stress and changing food consumption are responsible for the increasing prevalence in the past two decades. As the incidence continues to grow diabetes is being projected to be the world’s primary killer in the next 25 years.
3.2 million deaths can be attributed to diabetes each year according to a new publication released by the world health organization (WHO) and International Diabetes Federation (IDF). Updated estimates suggest that six deaths can be attributed to diabetes or related conditions somewhere in the world every minute (WHO and IDF 2004).
In most developing counties at least one in ten deaths in adults aged 35 to 64 is attributable to diabetes, and in some the figure is as high as one in five. Diabetes has become one of the major causes of premature illness and death in most countries, mainly through the increased risk of cardiovascular disease (CVD).

Definition (WHO 1999)
The term diabetes mellitus describes a metabolic disorder of multiple etiologies, characterized by chronic hyperglycemia with disturbances of carbohydrate, fat and protein metabolism resulting from defects in insulin secretion, insulin action, or both. The effects of diabetes mellitus include long term damage, dysfunction and failure of various organs.
Clinically, it is characterized by high blood glucose concentration- hyperglycemia (fasting blood glucose>7.0 mmol/l, or plasma glucose>11.1 mmol/l two hours after meal). Hyperglycemia occurs because of uncontrolled hepatic glucose output and reduced uptake of glucose by skeletal muscle with reduced glycogen synthesis. When the renal threshold for glucose reabsorption is exceeded, glucose spills over into the urine (glycosuria) and causes an osmotic diuresis (polyuria), which inturn results in dehydration, thirst and increased drinking (Polydipsia).
Diabetes mellitus may present with characteristic symptoms-
> thirst
> polyuria
> blurring of vision and
> weight loss
In its most severe forms, ketoacidosis or a non-ketonic hyperosmolar state may develop and lead to stupor coma and, in absence of effective treatment, death.
The long-term effects of diabetes mellitus
-progressive development of the specific complications of retinopathy with potential blindness
-nephropathy that may lead to renal failure
-neuropathy with risk of foot ulcers
-amputation
-charcot joints and
-features of autonomic dysfunction- sexual dysfunction.
People with diabetes are at increased risk of cardiovascular, peripheral vascular and cerebrovascular disease.
Several pathogenetic processes are involved in the development of diabetes. These include processes which destroy the beta cells of the pancreas with consequent insulin deficiency, and others that result in resistance to insulin action. The abnormalities of carbohydrate, fat and protein metabolism are due to deficient action of insulin or target tissues resulting from insensitivity or lack of insulin.
A serious complication of intensive therapy was an increased incidence of severe hypoglycemia. Patients receiving intensive therapy had a threefold greater incidence of severe hypoglycemia (blood glucose below 2.8 mmol/l and needing external resuscitative assistance) and hypoglycemic coma than did conventionally treated subjects.

Classification
The first widely accepted classification of diabetes mellitus was published by WHO in 1980 and in modified form in 1985. The 1985 classification is widely accepted and is used internationally. It includes both staging of diabetes mellitus based on clinical descriptive criteria and a complementary etiological classification.

Type 1 diabetes mellitus
Type 1 indicates the processes of beta cell destruction that may ultimately lead to diabetes mellitus in which “insulin is required for survival” to prevent the development of ketoacidosis, coma and death. Previously known as insulin-dependent DM (IDDM).

Type 2 diabetes mellitus
Type 2 is the most common form of diabetes and is characterized by disorders of insulin action and insulin secretion either of which may be the predominant feature. By definition, the specific reasons for the development of these abnormalities are not yet known. Previously known as non-insulin-dependent DM (NIDDM).

Other specific types
Other specific types are currently less common causes of diabetes mellitus, but are those in which the underlying defect of disease process can be identified in a relatively specific manner they include, for example, fibrocalculous pancreatopathy, a form of diabetes which was formerly classified as one type of malnutrition-related diabetes mellitus (MRDM).
Impaired glucose regulation --- impaired glucose tolerance (IGT) and impaired fasting glycemia (IFG)
Impaired glucose regulation (IGT and IFG) refers to a metabolic state intermediate between normal glucose homeostasis and diabetes. It should be stated unequivocally, however, that IFG and IGT are not interchangeable and represent different abnormalities of glucose regulation one is the fasting state and one post-prandial.
Gestational diabetes
Gestational diabetes is carbohydrate intolerance resulting in hyperglycemia of variable severity with onset or first recognition during pregnancy. It does not exclude the possibility that the glucose intolerance may antedate pregnancy but has been previously unrecognized. The definition applies irrespective of whether or not insulin is used for treatment or the condition persists after pregnancy.

Treatment
Studies have shown that many complications of diabetes can be prevented or delayed through effective management. This includes lifestyle measures such as a healthy diet, physical activity, the avoidance of overweight and obesity, and not smoking. Preventative care need not involve costly treatment or medication. Education in good foot care as well as regular inspection is a good example of a low cost method of prevention.
Diabetes therapy is not only about lowering glucose, but also about the overall reduction in the risk factors for diabetic complications, which includes the control of blood pressure and blood lipids.
This requires lifelong care and management. Health systems that are able to deliver optimal care need to be designed around the needs of the person with the condition, as on a day to day basis most diabetes care is undertaken by the person with diabetes and not the health professional. Diabetes education plays a key role in empowering people with the knowledge and skills to manage their own condition effectively. In order to prevent or delay complications, people with diabetes may have to modify their lifestyle.
People with type 2 diabetes often require oral drugs, and sometimes insulin to control their blood glucose levels. People with type 1 diabetes require insulin to survive. Although insulin has been designated an essential drug by WHO, it is not yet universally accessible to all those who need it in the majority of countries of the world. Continuous access to insulin remains a major problem in many developing countries especially those in sub- Saharan Africa. In some of these countries people with diabetes die because they cannot get the insulin they need to survive.