Antidiabetic Agent- Insulin

INSULIN

Insulin is a polypeptide hormone of complex structure, secreted by the beta cells of the pancreas. It plays key roles in the metabolism of carbohydrates, fats and proteins. There are differences in the amino acid sequences of animal and human insulin. Formerly, the source of commercially available insulin was from the pancreas of cows or pigs. Now a days recombinant DNA technology (using E. coli bacteria) is the main source of biosynthetic human insulin. However, there are still lots of bovine and porcine insulins, as well as natural or enzymatically modified semisynthetic human analogue insulin in the market.

Animal and semisynthetic insulins are to a greater or lesser extent immunogenic to man but resistance to insulin action is uncommon. Insulin is needed by all patients of Type-1 DM regardless of age, those with ketoacidosis, and most of those with rapid onset of symptoms or weight loss. Almost all children with diabetes require it. Type-2 DM cases where other methods fail or with frequent acute infection, tuberculosis, hepatitis, during surgery and with other complications like nephropathy and retinopathy also need insulin. It is also indispensable in acute metabolic decompensated states in Type-2 DM (like diabetic ketoacidosis, hyperon-molar nonketotic coma, lactic acidosis, etc.). Insulin in Type-2 DM is also used as a combination therapy with OHA. The subcutaneous route is ideal in most cases. The dose of insulin is adjusted on an individual basis, by gradually increasing the dose but carefully avoiding hypoglycemic reactions. Based on the onset and duration of action, insulin preparations are of various types.

Short-acting insulins (e.g. soluble insulin; insulin lispro) have relatively rapid onset of action (about 30-60 minutes) and duration of action up to 8 hours (peak 24 hours). Human insulin has a faster onset and shorter duration of action. With insulin lispro (a human insulin analogue), fasting and preprandial blood glucose is a little lower and hypoglycemia occur less frequently. By the intravenous route, only the soluble insulin can be used, not the other types.

Intermediate-acting insulin (e.g. isophane insulin and insulin zinc suspension) has duration of action of about 24 hours. Long-acting insulin (e.g. crystalline insulin zinc suspension) has long duration of action about 28 hours and slower onset of action after about 4 hours.

Biphasic or Premixed insulin contains a combination of a short acting and intermediate-acting insulin in a standard proportion.

Side effects of insulin therapy include hypoglycemia, allergy, immunologic reaction, insulin edema and lipodystrophy. Patient should be shown the bottle and explained about the type and source of insulin to ensure that the version dispensed is actually the one the patient was expecting.

EXAMPLES OF INSULIN REGIMENS
An appropriate regimen of insulin therapy must be individualized. Usual regimens are one injection a day, two injections a day, multiple (3 to 7) injections a day and insulin pump.

One injection a day: One injection of intermediate acting insulin is given either in morning or evening pre-meal time. It serves, as supplement/basal secretion. It may be effective in Type-2 DM as monotherapy or in combination with other oral hypoglycemic agents (OHA).

Two injections a day: This is the most commonly used regimen. It can be used in type-1 DM and type-2 DM. A short-acting and an intermediate acting-insulin are mixed in proportion that is adjusted by trial and injected before breakfast and dinner. Alternatively, each injection can be either intermediate-acting insulin or biphasic insulin.

Multiple injections: As many as 3 to 7 injections per day may be needed where there is difficulty in achieving optimal control with other regimes. A dose of short-acting insulin is given before each meal, intermediate-acting insulin is given before bedtime and sometimes before breakfast as basal dose. This is very flexible and suitable for those who are very active and cannot comply with a rigid meal plan.

Insulin pump: Insulin pumps are available in two forms-open or closed loop (Artificial Pancreas). The open loop system is composed of two parts a battery-operated pump and a computer programmed system for insulin delivery. The closed loop consists of three parts-a battery-operated pump, a computer controlled insulin delivery system and a glucose sensor giving feedback to the computer. These are portable and designed to deliver basal amount of regular insulin throughout the day as well as meal related boluses.

SHORT ACTING INSULIN
Soluble insulin is a short acting form of insulin. It is the only form of insulin that can be used subcutaneously intramuscularly, as well as intravenously. For maintenance regimens it is injected subcutaneously 15 to 30 minute prior to a meal. When injected subcutaneously, soluble insulin has a rapid onset of action (after 30-60 minutes), a peak action between 2 and 4 hours, and duration of action up to 8 hours.
Intravenous route is used during diabetic emergencies and also during major surgery. When injected intravenously, soluble insulin has a very short half-life of only about 5 minutes and its effect disappears within 30 minutes.
The human insulin analogue insulin lispro has a shorter duration of action than soluble insulin and also rapid onset of action; so subcutaneous injection of insulin lispro may be given close to meal.

SOLUBLE INSULIN
(Other names: Insulin Injection; Neutral Insulin)
A sterile solution of insulin (i.e. bovine or porcine) or of human insulin; pH 6.6-8.0
Indications: diabetes mellitus, diabetic ketoacidosis
Cautions: see notes above; reduce dose in renal impairment
Interactions: see Appendix-2
Side effects: see notes above; local reactions and fat hypertrophy at injection site; over dose causes hypoglycemia Dose:- by subcutaneous, intramuscular or intravenous injection or intravenous infusion, according to patient's requirement and response
Proprietary Preparations
Acrapid Novolet I" (Novo Nordisk), Inj. 1001U/ml, Tk.512.26/3ml;
Humulin-R I) (Eli Lilly), Inj.40 IlUlml Tk. 266.88/10ml; Inj. 100 IIJ/ml. Tk. 630/10 ml Insulin Acrapid (1I (Novo Nordisk), Inj. 10010/ml, Tk.554.95/10ml;
Insulin Acrapid HM I') (Novo Nordisk), Inj. 1 OOIU/rnl, Tk.554.95/10ml; 4010/ml, Tk. 292.03/1 ml; Pen-filled syringe, 1 ODIU/ml, Tk.313.66/vial.
Insuman Rapid (Aventis), Inj. 100 lUlml. Tk 259.69/10 ml

INSULIN LISPRO
(Other name: Recombinant human insulin analogue)
Indications: diabetes mellitus
Cautions: see under Soluble Insulin; use in children if benefit as good as with Soluble Insulin
Side effects: see under Soluble Insulin Interactions: see Appendix-2
Dose: by subcutaneous injection according to the patient's requirement and response
Generic Preparation Injection, 100 IU/ml

INTERMEDIATE AND LONG ACTING INSULIN
When injected subcutaneously, an intermedediate and long-acting insulin have an onset of action of approximately 1-2 hours, a maximal effect at 4-12 hours, and duration of action of 16-35 hours. Some are used twice daily in conjunction with soluble form and other only once (see insulin regimens above). Various types are available. Isophane Insulin is a suspension of insulin with protamine. They are suitable for twice daily regime either as split mixed (mixing with soluble insulin) or pre/ready-mixed preparations. Insulin Zinc Suspension (amorphous) has an inter-mediate duration of action, and Insulin Zinc suspension (Crystalline) a more prolonged duration of action. These preparations may be used independently or as pre-mixed Insulin Zinc suspension (30% amorphous, 70% crystalline). Protamine Zinc Insulin is usually given once daily in conjunction with soluble insulin. It has the drawback of binding with soluble insulin when mixed in the same syringe.

ISOPHANE INSULIN
(Other names: Isophane Insulin; Isophane Protamine Insulin; Isophane Insulin-NPH).
A sterile suspension of bovine or porcine insulin or of human insulin in the form of a complex obtained by the addition of protamine sulphate.
Indications: diabetes mellitus (for intermediate action)
Cautions; Side effects: see under soluble insulin; protamine may cause allergic reactions
Interactions: see Appendix-2
Dose: by subcutaneous injection, according to the patient's response Proprietary Preparations
Humulin N ti (Eli Lilly), Inj. 40 IU/ml, Tk.266.88/1 Oml;l 0011J, Tk.630/10ml
Insulated Novolet (') (NovoNordisk) Inj. 1001U,Tk.512.26/3mi
Insulin Insularated HM (') (NovoNordisk), Inj. 401U/ml, Tk. 292.03/1 Oml vial; 100 U/ml, Tk. 554.95/10ml vial;
Insuman basal (') (Aventis), Inj. 100 IU/Ml, Tk. 259.69/10 ml

INSULIN ZINC SUSPENSION
(Other names: Insulin Zinc suspension [Mixed]; I.Z.S.)
A sterile neutral suspension of bovine and/or porcine insulin or of human insulin in the form of a complex obtained by the addition of a zinc salt; may be amorphous or microcrystalline consisting of rhombohedral crystals.
Indications: diabetes mellitus (long acting) Cautions; Side effects: see umb-i soluble insulin
Interactions: see Appendix-2
Dose: by subcutaneous injection, according to the patient's response
Proprietary Preparation Insulin lente (Novo Nordisk)"' Inj. 100 IU/ml Tk. 450/amp; Inj. 401U/ml;Tk.221 A5/10ml

PROTAMINE ZINC INSULIN
(Other name: Insulin P.Z)
A sterile suspension of insulin in the form of a complex obtained by the addition of protamine and zinc chloride.
Indications: diabetes mellitus (long-acting)
Cautions; Side effects: see under soluble insulin notes above; protamine may cause allergic reactions. Interactions: see Appendix-2
Dose: by subcutaneous injection, according to the patient's response
Generic Preparation Injection. 40 IU/ml.

BIPHASIC INSULINS
(Other name: Biphasic Isophane Insulin)
A sterile buffered suspension of porcine insulin complexed with protamine sulphate in a solution of porcine insulin or a sterile buffered suspension of human insulin complexed with protamine sul-phate in a solution of human insulin.
Indications: diabetes mellitus
Cautions; Side effects: see under soluble insulin; protamine may cause allergic reactions. Should be dispensed under prescription only
Dose: by subcutaneous injection, according to the patient's response
Proprietary Preparations
Humulin 70/30 ('~ (Eli Lilly), Inj. 100 U/ml.
Tk. 641.95/1 Oml vial, 40 IU/ml. Tk.266.88/1 Ot i il Insulin Mixtard 30 HM (1) (Novo Nordisk), In]. 100 IU/ml.Tk.313.66/10m1 vial; 401U/ml. Tk.292.03/10ml vial

Insulin Mixtard 50 HM(') (Novo Nordisk), lnj. 100 IU/ml.Tk.562.86; Pen-filled syrnge.100IU/ml.Tk.313.66/3ml syringe. Insulin Mixtard 30 Novolet (') (Novo Nordisk), lnj. 100 IU/mI.Tk.512.26/3ml vial;
Insulin Mixtard 50 Novolet (') (Novo Nordisk), Inj. 100 IU/rnI.Tk.512.26/3ml vial;

INSULIN GLARGINE
Indications: diabetes mellitus Cautions; Side effects: see under soluble insulin. Dose: by subcutaneous injection, ADUL and CHILD over 6years, according to requirements. Note; sustained 24 hour duration of action allows dosing independently of meals. Proprietary Preparations Lantus")(Aventis),iniA 001U/mi, Tk.1,025.74/3ml carlidge.

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.

Anemia

বি. ফার্ম (সম্মান) পার্ট-১ এর সিলেবাস অনুযায়ী প্রণিতঃ

Falling the count of RBC and Hb percentage below normal. Normally, red cell production and destruction has a delicate balance. Deviation of this balance leads to anemia.

Classification:
A) According to variation in size and Hb content:1. Microcytic anemias (Hypochromic or normochromic type)i. Cause- Iron deficiency
ii. Effect-RBC count low and decreased size leads to low Hb content
iii. Feature-
#Color index lower than normal
#Mean corpuscular Hb (MCH) < normal #MCH conc. (MCHC) < normal #Mean corpuscular volume (MCV) < normal #Cells pale, only colored at periphery
2. Macrocytic anemias (Hypochromic or normochromic type) i. Cause- Deficiency of folic acid and vit. B12. Special type is pernicious anemia.
ii. Effect- defect in maturation factors lead to defect in cell divisions and cell maturation, so the number of cell reduced and size is increased.
iii. Feature-
Þ Color index > normal, about 1.2 (% Hb/ % red cells)
Þ MCH > normal (29.5 micro microgm) (Hb gm/L blood ¸ red cells million/cu mm)
Þ MCHC > normal {(Hb gm/100 ml blood ¸ Vol. of packed RBC/100 ml blood)X 100}, 35%
Þ MCV > normal, -135 (Vol. of packed RBC ml/L blood ¸ red cells million/cu mm), 87 cu m (normal value)
Þ Cells deep red, larger in size, > normal size (8m)
Þ decrease fragility
Þ decrease leucocyte
Þ Bone marrow hyperplastic
Þ Pernicious anemia- subacute combined degeneration of nervous system

B) According to cause

1. Hemorrhagici. following sustained loss of blood- injury, ulcer, piles
ii. persistent hemorrhage- from g.i.t, hook worm infection

2. Dyshemopoietic- defective formation of RBC
i. Nutritional deficiencies-
a. Iron deficiencies-
b. Protein deficiencies-
c. Vit B12 deficiencies-
d. Folic acid deficiencies-
e. Vit C deficiencies-
ii. Absorption deficiencies due to g.i.t disorders-
iii. Lack of storage-
iv. Lack of release factor-
v. Excessive demand on part of the body-
vi. Endocrine deficiencies-

3. Hemolytic- excessive destruction of RBC
Normally RBC destroyed by RE cells- situated in liver, spleen and bone marrow.
i. abnormal formation of red cells as in spherocytosis, thalassemia and sickle cell anemia.
Þ Spherocytosis- RBC are small, spherical and fragile
Þ Thalassemia- RBC fragile, Hb of F-type instead of A-type
Þ Sickle cell anemia- RBC sickle shape, Hb of S-type
ii. due to circulating hemolysin, as in congenital hemolytic anemia & paroxysmal Hburia.
iii. incompatibilities of blood groups, mismatched transfusions, Rh incompatibilities
iv. specific parasitic infections- malaria
v. bacterial infections- septicemia
vi. chemical agents- arsphenamine, coal-tar derivatives, lead poisoning
vii. snake venoms cause acute anemia due to hemolysis
viii. drugs- cytotoxic drugs as phenyl hydrazine HCl, quinine in malaria

4. Aplastic or non-functioning of bone marrow
lack of utilization of hemopoietic factors by bone marrow. Drugs depress bone marrow- chloromycetin, benzol. Radium salts, radioactive materials, X-rays cause bone marrow hypoplasia. Severe infections also depress bone marrow.

Alpha-adrenergic blocking drugs

রাজশাহী বিশ্ববিদ্যালয়ের ফার্মেসী বিভাগের বি. ফার্ম (সম্মান) তৃতীয় বর্ষের সিলেবাস অনুযায়ী প্রণিতঃ

Syllabus
Drug Acting on ANS:
a) (i) Parasympathomimetic agents: Acetyl choline, Methacoline, Carbachol. (ii) Sympathomimetic drugs: Epinephrine, norepinephrine. (iii) Anticholinesterase agents: Physostigmine, Edrophonium. Organophosphorous compounds.
b) (i) Antimuscarinic Agents or Atropine Drugs: atropine sulfate, scopolamine hydrobromide, homatropine hydrobromide. (ii) Drugs inhibiting adrenergic nerves and structures innervated by them, Adrenergic blocking agents.
c) Ganglion Stimulating and Blocking Agents.

ADRENOCEPTORS
Drugs that produce responses by interacting with adrenoceptors are referred to as adrenoceptor agonistsor adrenergic agonists. Norepinephrine and isoproterenol are examples of such compounds. Agents that inhibit responses mediated by adrenoceptor activation are known as adrenoceptor antagonists, adrenergic antagonists, or adrenergic blocking agents. Prazosin and propranolol are examples of receptor-blocking drugs.

ADRENERGIC BLOCKING AGENTS
1. Classification of adrenoceptors
Main pharmacological classification into α and β subtypes, based originally on order of potency among agonists, later on selective antagonists.
Adrenoceptor subtypes:
two main α-receptor subtypes, α1 and α2, each divided into three further subtypes
three β-adrenoceptor subtypes (β1, β2, β3)
all belong to the superfamily of G-protein-coupled receptors.
Second messengers:
· α1-receptors activate phospholipase C, producing inositol trisphosphate and diacylglycerol as second messengers
· α2-receptors inhibit adenylate cyclase, decreasing cAMP formation
· all types of β-receptor stimulate adenylyl cyclase.

The main effects of receptor activation are as follows.
α1-receptors: vasoconstriction, relaxation of gastrointestinal smooth muscle, salivary secretion and hepatic glycogenolysis
α2-receptors: inhibition of transmitter release (including noradrenaline and acetylcholine release from autonomic nerves), platelet aggregation, contraction of vascular smooth muscle, inhibition of insulin release
β1-receptors: increased cardiac rate and force
β2-receptors: bronchodilatation, vasodilatation, relaxation of visceral smooth muscle, hepatic glycogenolysis and muscle tremor
β3-receptors: lipolysis.

2. α-Adrenoceptor antagonists
The clinically important α-blockers fall primarily into three chemical groups:
Ø the haloalkylamines (e.g., phenoxybenzamine)
Ø the imidazolines (e.g., phentolamine), and
Ø the quinazoline derivatives (e.g., prazosin).
Of these three classes of α-adrenoceptor antagonists, the quinazoline compounds are of greatest clinical utility and are much emphasized. The use of the haloalkylamines and imidazolines has diminished in recent years because they lack selectivity for α1- and α2-receptors.
The main groups of α-adrenoceptor antagonists based on their selectivity are:
# non-selective α-receptor antagonists (e.g. phenoxybenzamine, phentolamine)
# α1-selective antagonists (e.g. prazosin, doxazosin, terazosin)
# α2-selective antagonists (e.g. yohimbine, idazoxan)

Non-selective α-adrenoceptor antagonists
Phenoxybenzamine is not specific for α-receptors, and also antagonises the actions of acetylcholine, histamine and 5-HT. It is long-lasting because it binds covalently to the receptor. Phentolamine is more selective, but it binds reversibly and its action is short-lasting. In humans, these drugs cause a fall in arterial pressure (because of block of α-receptor-mediated vasoconstriction) and postural hypotension. The cardiac output and heart rate are increased. This is a reflex response to the fall in arterial pressure, mediated through β-receptors. The concomitant block of α2-receptors tends to increase noradrenaline release, which has the effect of enhancing the reflex tachycardia that occurs with any blood pressure-lowering agent. Phenoxybenzamine retains a niche (but vital) use in preparing patients with phaeochromocytoma for surgery; its irreversible antagonism and the resultant depression in the maximum of the agonist dose -response are desirable in a situation where surgical manipulation of the tumour may release a large bolus of pressor amine into the circulation.

Selective α1 antagonists
Prazosin was the first α1-selective antagonist. Similar drugs with longer half-lives (e.g. doxazosin, terazosin), which have the advantage of allowing once-daily dosing, are now available. They are highly selective for α1-adrenoceptors and cause vasodilatation and fall in arterial pressure, but less tachycardia than occurs with non-selective α-receptor antagonists, presumably because they do not increase noradrenaline release from sympathetic nerve terminals. Some postural hypotension may occur.
The α1-receptor antagonists cause relaxation of the smooth muscle of the bladder neck and prostate capsule, and inhibit hypertrophy of these tissues, and are therefore useful in treating urinary retention associated with benign prostatic hypertrophy. Tamsulosin, an α1A-receptor antagonist, shows some selectivity for the bladder, and causes less hypotension than drugs such as prazosin, which act on α1B-receptors to control vascular tone.
It is believed that α1A-receptors play a part in the pathological hypertrophy not only of prostatic and vascular smooth muscle, but also in the cardiac hypertrophy that occurs in hypertension, and the use of selective α1A-receptor antagonists to treat these chronic conditions is under investigation.

Selective α2 antagonists
Yohimbine is a naturally occurring alkaloid; various synthetic analogues have been made, such as idazoxan. These drugs are used experimentally to analyse α-receptor subtypes, and yohimbine, probably by virtue of its vasodilator effect, historically enjoyed notoriety as an aphrodisiac, but they are not used therapeutically.

PRAZOSIN

Mechanism of Action
The α-antagonism produced by prazosin and the other quinazoline derivatives is of the equilibrium-competitive type. The drugs are selective for α1-adrenoceptors, so that at usual therapeutic concentrations there is little or negligible antagonism of α2-adrenoceptors. However, selectivity is only relative and can be lost with high drug concentrations. While most of the pharmacological effects of prazosin are directly attributable to α1-antagonism, at high doses the drug can cause vasodilation by a direct effect on smooth muscle independent of α-receptors. This action appears to be related to an inhibition of phosphodiesterases that results in an enhancement of intracellular levels of cyclic nucleotides (like cGMP).

Absorption, Metabolism, Excretion
Prazosin is readily absorbed after oral administration, peak serum levels occur approximately 2 hours after a single oral dose, and the antihypertensive effect of prazosin persists for up to 10 hours.
Distribution- * Plasma half-life- 2.5 to 4 hours
* Elimination from plasma follows first-order kinetics.
* 97% bound to plasma proteins.
Biotransformation- Hepatic O-dealkylation and glucuronide formation.
Excretion- 10% of orally administered prazosin is excreted in the urine. Plasma levels of prazosin are increased in patients with renal failure; the nature of this interaction is unknown.

Pharmacological Actions
The most important pharmacological effect of prazosin is its ability to antagonize vascular smooth muscle contraction that is caused by either sympathetic nervous activity or the action of adrenomimetics. Hemodynamically, the effects of prazosin differ from those of phenoxybenzamine and phentolamine in that venous smooth muscle is not as much affected by prazosin. Postural hypotension during chronic treatment is also less of a problem. Also, increases in heart rate, contractile force, and plasma renin activity, which normally occur after the use of vasodilators and α-blockers, are much less prominent following chronic treatment with prazosin. Prazosin blocks responses mediated by postsynaptic α1-receptors but has no effect on the presynaptic α2-receptors. Thus, stimulation of the heart and renin release is less prominent with this drug.

Clinical Uses
Hypertension- Prazosin is effective in reducing all grades of hypertension. The drug can be administered alone in mild and (in some instances) moderate hypertension. When the hypertension is moderate or severe, prazosin generally is given in combination with a thiazide diuretic and a β-blocker. The antihypertensive actions of prazosin are considerably potentiated by coadministration of thiazides or other types of antihypertensive drugs.
Prazosin may be particularly useful when patients cannot tolerate other classes of antihypertensive drugs or when blood pressure is not well controlled by other drugs. Since prazosin does not significantly influence blood uric acid or glucose levels, it can be used in hypertensive patients whose condition is complicated by diabetes mellitus or gout.
Prostatic hypertrophy- Prazosin and other α-antagonists find use in the management of benign prostatic obstruction, especially in patients who are not candidates for surgery. Blockade of α-adrenoceptors in the base of the bladder and in the prostate apparently reduces the symptoms of obstruction and the urinary urgency that occurs at night.

Adverse Effects
Although less of a problem than with phenoxybenzamine or phentolamine, symptoms of postural hypotension, such as dizziness and light-headedness, are the most commonly reported side effects associated with prazosin therapy. These effects occur most frequently during initial treatment and when the dosage is sharply increased. Postural hypotension seems to be more pronounced during Na+ deficiency, as may occur in patients on a low-salt diet or being treated with diuretics, α- blockers, or both.