Oral Hypoglycemics

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Oral Hypoglycemics

  1. 1. Hypoglycemic Agents By: Dr. Amit G. Nerkar, B.Pharm, CDD, M.Pharm (Medi.Chem), PhD Asst. Prof in Pharma.and Medicinal Chemistry, Smt. Kashibai Navale College Of Pharmacy, Kondhwa (BK), Pune-48
  2. 2. Hyperglycemia ≥ 7.0 (≥126) ≥ 11.1 (≥200) Diabetes mellitus <7.0 (<126) ≥ 7.8 (≥140) Impaired glucose tolerance ≥ 6.1(≥110) & <7.0(<126) <7.8 (<140) Impaired fasting glycaemia <6.1 (<110) <7.8 (<140) Normal mmol/l(mg/dl) mmol/l(mg/dl) Fasting glucose 2 hour glucose Condition 1999 WHO Diabetes criteria [10]
  3. 3. Microscopic structure of Pancreas
  4. 4. Microscopic Structure of Pancreas <ul><li>The islets of Langerhans are the regions of the pancreas that contain its endocrine (i.e., hormone-producing) cells. Discovered in 1869 by German pathological anatomist Paul Langerhans at the age of 22, the islets of Langerhans constitute approximately 1 to 2% of the mass of the pancreas. There are about one million islets in a healthy adult human pancreas, which are distributed throughout the organ; their combined mass is 1 to 1.5 grams. </li></ul>
  5. 5. Microscopic Structure of Pancreas <ul><li>Cell types </li></ul><ul><li>Hormones produced in the islets of Langerhans are secreted directly into the blood flow by (at least) five different types of cells. In rat islets, endocrine cell subsets are distributed as follows: [1] </li></ul><ul><li>Alpha cells producing glucagon (15-20% of total islet cells) </li></ul><ul><li>Beta cells producing insulin and amylin (65-80%) </li></ul><ul><li>Delta cells producing somatostatin (3-10%) </li></ul><ul><li>PP cells producing pancreatic polypeptide (3-5%) </li></ul><ul><li>Epsilon cells producing ghrelin (<1%) </li></ul><ul><li>It has been recognized that the cytoarchitecture of pancreatic islets differs between species.In particular, while rodent islets are characterized by a predominant proportion of insulin-producing beta cells in the core of the cluster and by scarse alpha, delta and PP cells in the periphery, human islets display alpha and beta cells in close relationship with each other throughout the cluster. </li></ul><ul><li>Islets can influence each other through paracrine and autocrine communication, and beta cells are coupled electrically to other beta cells (but not to other cell types). </li></ul>
  6. 6. Paracrine Feedback <ul><li>Paracrine feedback </li></ul><ul><li>The paracrine feedback system of the islets of Langerhans has the following structure: [5] </li></ul><ul><li>Insulin: activates beta cells and inhibits alpha cells </li></ul><ul><li>Glucagon: activates alpha cells which activates beta cells and delta cells </li></ul><ul><li>Somatostatin: inhibits alpha cells and beta cells </li></ul>
  7. 7. Interconversion of Carbohydrate, Protein and Fat
  8. 9. DIABETES Cardiovascular disease Diabetic comas :    •  Diabetic hypoglycemia    •  Diabetic ketoacidosis    •  Nonketotic hyperosmolar Diabetic myonecrosis Diabetic nephropathy Diabetic neuropathy Diabetic retinopathy Diabetes and pregnancy Complications Diabetic diet Anti-diabetic drugs Insulin therapy Glossary of diabetes Diabetes management Blood sugar Glycosylated hemoglobin Glucose tolerance test Fructosamine Blood tests Prediabetes :    •  Impaired fasting glycaemia    •  Impaired glucose tolerance Diabetes mellitus type 1 Diabetes mellitus type 2 Gestational diabetes Types of diabetes Diabetes mellitus Related articles
  9. 10. <ul><li>Diabetes mellitus type 1 (Type 1 diabetes, IDDM, or juvenile diabetes) is a form of diabetes mellitus that results from autoimmune destruction of insulin producing beta cells of the pancreas . [2] The subsequent lack of insulin leads to increased blood and urine glucose. The classical symptoms of polyuria (frequent urination), polydipsia (increased thirst), polyphagia (increased hunger), and weight loss result. [3] </li></ul><ul><li>Type 1 diabetes is fatal unless treated with insulin . Injection is the most common method of administering insulin; insulin pumps and inhaled insulin has been available at various times. Pancreas transplants have been used to treat type 1 diabetes however is still in experimental trials. [4] </li></ul><ul><li>There is no preventive measure against developing type 1 diabetes. Most people who develop type 1 are otherwise healthy. [5] Although the cause of type 1 diabetes is still not fully understood it is believed to be of immunological origin. Type 1 can be distinguished from type 2 diabetes via a C-peptide assay, which measures endogenous insulin production. </li></ul><ul><li>Type 1 treatment must be continued indefinitely in all cases. Treatment need not significantly impair normal activities, if sufficient patient training, awareness, appropriate care, discipline in testing and dosing of insulin is taken. However, treatment is burdensome for many people. Complications may be associated with both low blood sugar and high blood sugar. Low blood sugar may lead to seizures or episodes of unconsciousness and requires emergency treatment. High blood sugar may lead to increased tiredness and can also result in long term damage to other organs such as eyes and joints. </li></ul>
  10. 11. <ul><li>Signs and symptoms: </li></ul><ul><li>The classical symptoms of type 1 diabetes include: polyuria (frequent urination), polydipsia (increased thirst), polyphagia (increased hunger), and weight loss. [6] </li></ul>
  11. 12. <ul><li>Cause: </li></ul><ul><li>Environment </li></ul><ul><li>Environmental factors can strongly influence expression of type 1. A study showed that for identical twins, when one twin had type 1 diabetes, the other twin only had type 1 30%–50% of the time. Despite having the exact same genome, one twin had the disease, where the other did not; this suggests that environmental factors, in addition to genetic factors, can influence disease prevalence. [7] </li></ul><ul><li>Genetics </li></ul><ul><li>Type 1 diabetes is a polygenic disease, meaning many different genes contribute to its expression. Depending on locus or combination of loci, it can be dominant, recessive, or somewhere in between. The strongest gene, IDDM1, is located in the MHC Class II region on chromosome 6, at staining region 6p21. This is believed to be responsible for the histocompatibility disorder characteristic of type 1: Insulin-producing pancreas cells ( beta cells ) display improper antigens to T cells . This eventually leads to the production of antibodies that attack these beta cells. Weaker genes are also located on chromosomes 11 and 18. </li></ul>
  12. 13. <ul><li>Pathophysiology </li></ul><ul><li>The cause of type 1 diabetes is not fully understood. Some theorize that type 1 diabetes is a virally triggered autoimmune response in which the immune system's attack virus infected cells along with the beta cells in the pancreas. The Coxsackie virus family or German measles is implicated, although the evidence is inconclusive. In type 1, pancreatic beta cells in the Islets of Langerhans are destroyed decreasing endogenous insulin production. This distinguishes type 1's origin from type 2 DM. The type of diabetes a patient has is determined only by the cause—fundamentally by whether the patient is insulin resistant (type 2) or insulin deficient without insulin resistance (type 1). </li></ul><ul><li>This vulnerability is not shared by everyone, for not everyone infected by the suspected organisms develops type 1 diabetes. This has suggested presence of a genetic vulnerability [8] and there is indeed an observed inherited tendency to develop type 1. It has been traced to particular HLA genotypes, though the connection between them and the triggering of an auto-immune reaction is still poorly understood. </li></ul><ul><li>Some researchers believe that the autoimmune response is influenced by antibodies against cow's milk proteins. [9] A large retrospective controlled study published in 2006 strongly suggests that infants who were never breastfed had a risk for developing type 1 diabetes twice that of infants who were breastfed for at least three months.[ citation needed ] The mechanism is not fully understood. No connection has been established between autoantibodies , antibodies to cow's milk proteins, and type 1 diabetes. A subtype of type 1 (identifiable by the presence of antibodies against beta cells) typically develops slowly and so is often confused with type 2. In addition, a small proportion of type 2 cases manifest a genetic form of the disease called maturity onset diabetes of the young (MODY). </li></ul><ul><li>Vitamin D in doses of 2000 IU per day given during the first year of a child's life has been connected in one study in Northern Finland (where intrinsic production of Vitamin D is low due to low natural light levels) with an 80% reduction in the risk of getting type 1 diabetes later in life. The causal connection, if any, is obscure. </li></ul><ul><li>Type 1 diabetes was previously known as juvenile diabetes because it is one of the most frequent chronic diseases in children; however, the majority of new-onset type 1 diabetes is seen in adults. Scientific studies that use antibody testing (glutamic acid decarboxylase antibodies (GADA), islet cell antibodies (ICA), and insulinoma-associated (IA-2) autoantibodies) to distinguish between type 1 and type 2 diabetes demonstrate that most new-onset type 1 diabetes is seen in adults. A 2008 book, “Type 1 Diabetes in Adults: Principles and Practice” (Informa Healthcare, 2008) says that adult-onset type 1 autoimmune diabetes is two to three times more common than classic childhood-onset autoimmune diabetes (p. 27). In type 1 diabetes, the body does not produce insulin. Insulin is a hormone that is needed to convert sugar (glucose), starches and other food into energy needed for daily life. </li></ul>
  13. 14. Management of Diabetes (Type-I) <ul><li>Type 1 is treated with insulin replacement therapy—usually by insulin injection or insulin pump , along with attention to dietary management, typically including carbohydrate tracking, and careful monitoring of blood glucose levels using glucose meters . Today the most common insulins are biosynthetic products produced using genetic recombination techniques; formerly, cattle or pig insulins were used, and even sometimes insulin from fish. Major global suppliers include Eli Lilly and Company , Novo Nordisk , and Sanofi-Aventis . A more recent trend, from several suppliers, is insulin analogs which are slightly modified insulins which have different onset of action times or duration of action times. </li></ul><ul><li>Untreated type 1 diabetes commonly leads to coma , often from diabetic ketoacidosis , which is fatal if untreated. Continuous glucose monitors have been developed and marketed which can alert patients to the presence of dangerously high or low blood sugar levels, but technical limitations have limited the impact these devices have had on clinical practice so far. </li></ul><ul><li>In more extreme cases, a pancreas transplant can restore proper glucose regulation. However, the surgery and accompanying immunosuppression required is considered by many physicians to be more dangerous than continued insulin replacement therapy, and is therefore often used only as a last resort (such as when a kidney must also be transplanted, or in cases where the patient's blood glucose levels are extremely volatile). Experimental replacement of beta cells (by transplant or from stem cells) is being investigated in </li></ul>
  14. 15. <ul><li>Some suggest that deficiency of Vitamin D3 (one of several related chemicals with Vitamin D activity) may be an important pathogenic factor in type 1 diabetes independent of geographical latitude, and so of available sun intensity. </li></ul><ul><li>Some chemicals and drugs preferentially destroy pancreatic cells. Pyrinuron (Vacor, N-3-pyridylmethyl-N'-p-nitrophenyl urea), a rodenticide introduced in the United States in 1976, selectively destroys pancreatic beta cells, resulting in type 1 diabetes after accidental or intentional ingestion. Vacor was withdrawn from the U.S. market in 1979, but is still used in some countries. Zanosar is the trade name for streptozotocin , an antibiotic and antineoplastic agent used in chemotherapy for pancreatic cancer ; it also kills beta cells, resulting in loss of insulin production. Other pancreatic problems, including trauma, pancreatitis or tumors (either malignant or benign), can also lead to loss of insulin production. </li></ul><ul><li>The exact cause(s) of type 1 diabetes are not yet fully understood, and research on those mentioned, and others, continues several research programs. Thus far, beta cell replacement has only been performed on patients over age 18, and with tantalizing successes amidst nearly universal failure. </li></ul>
  15. 16. Diabetes Type-II <ul><li>Diabetes mellitus type 2 or type 2 diabetes (formerly called non- insulin -dependent diabetes mellitus (NIDDM), or adult-onset diabetes ) is a disorder that is characterized by high blood glucose in the context of insulin resistance and relative insulin deficiency. [1] While it is often initially managed by increasing exercise and dietary modification , medications are typically needed as the disease progresses. There are an estimated 23.6 million people in the U.S. (7.8% of the population) with diabetes with 17.9 million being diagnosed, [2] 90% of whom are type 2. [3] With prevalence rates doubling between 1990 and 2005, CDC has characterized the increase as an epidemic . [4] </li></ul><ul><li>Traditionally considered a disease of adults, type 2 diabetes is increasingly diagnosed in children in parallel to rising obesity rates [5] due to alterations in dietary patterns as well as in life styles during childhood. [6] </li></ul><ul><li>Unlike type 1 diabetes , there is very little tendency toward ketoacidosis in type 2 diabetes, though it is not unknown. [7] One effect that can occur is nonketonic hyperglycemia which also is quite dangerous, though it must be treated very differently. Complex and multifactorial metabolic changes very often lead to damage and function impairment of many organs , most importantly the cardiovascular system in both types. This leads to substantially increased morbidity and mortality in both type 1 and type 2 patients, but the two have quite different origins and treatments despite the similarity in complications .[ citation needed </li></ul>
  16. 17. <ul><li>Signs and symptoms </li></ul><ul><li>Early symptoms may be nothing more than chronic fatigue, generalised weakness and malaise (feeling of unease) </li></ul><ul><li>Excessive urine production </li></ul><ul><li>Excessive thirst and increased fluid intake </li></ul><ul><li>Blurred vision (typically from lens shape alterations, due to osmotic effects, e.g., high blood glucose levels) </li></ul><ul><li>Unexplained weight loss </li></ul><ul><li>Lethargy </li></ul><ul><li>Itching of external genitalia </li></ul><ul><li>Excessive bowel movements </li></ul>
  17. 18. <ul><li>Cause </li></ul><ul><li>Medical conditions </li></ul><ul><li>Although its incidence is far from universal, type 2 diabetes can arise from and be exacerbated by obesity, hypertension , elevated cholesterol ( combined hyperlipidemia ), and with the condition often termed Metabolic syndrome (it is also known as Syndrome X, Reavan's syndrome, or CHAOS). Other causes include acromegaly , Cushing's syndrome , thyrotoxicosis , pheochromocytoma , chronic pancreatitis, cancer and drugs. Additional factors found to increase the risk of type 2 diabetes include aging, [8] high-fat diets [9] and a less active lifestyle. [10] </li></ul><ul><li>Genetics </li></ul><ul><li>There is also a strong inheritable genetic connection in type 2 diabetes: having relatives (especially first degree) with type 2 increases risks of developing type 2 diabetes very substantially. In addition, there is also a mutation to the Islet Amyloid Polypeptide gene that results in an earlier onset, more severe, form of diabetes. [11] [12] About 55 percent of type 2 are obese [13] —chronic obesity leads to increased insulin resistance that can develop into diabetes, most likely because adipose tissue (especially that in the abdomen around internal organs) is a (recently identified) source of several chemical signals to other tissues (hormones and cytokines ). Other research shows that type 2 diabetes causes obesity as an effect of the changes in metabolism and other deranged cell behavior attendant on insulin resistance. [14] However, genetics play a relatively small role in the widespread occurrence of type 2 diabetes. This can be logically deduced from the huge increase in the occurrence of type 2 diabetes which has correlated with the significant change in western lifestyle. [15] </li></ul><ul><li>Medications </li></ul><ul><li>Drug induced hyperglycemia:[ citation needed ] </li></ul><ul><li>Atypical Antipsychotics - Alter receptor binding characteristics, leading to increased insulin resistance. </li></ul><ul><li>Beta-blockers - Inhibit insulin secretion. </li></ul><ul><li>Calcium Channel Blockers - Inhibits secretion of insulin by interfering with cytosolic calcium release. </li></ul><ul><li>Corticosteroids - Cause peripheral insulin resistance and gluconeogensis. </li></ul><ul><li>Fluoroquinolones - Inhibits insulin secretion by blocking ATP sensitive potassium channels. </li></ul><ul><li>Niacin - causes increased insulin resistance due to increased free fatty acid mobilization. </li></ul><ul><li>Phenothiazines - Inhibit insulin secretion. </li></ul><ul><li>Protease Inhibitors - Inhibit the conversion of proinsulin to insulin. </li></ul><ul><li>Somatropin - May decrease sensitivity to insulin, especially in those susceptible. </li></ul><ul><li>Thiazide Diuretics - Inhibit insulin secretion due to hypokalemia. They also cause increased insulin resistance due to increased free fatty acid mobilization. </li></ul>
  18. 19. <ul><li>Pathophysiology </li></ul><ul><li>Insulin resistance means that body cells do not respond appropriately when insulin is present. Unlike type 1 diabetes mellitus, insulin resistance is generally &quot;post-receptor&quot;, meaning it is a problem with the cells that respond to insulin rather than a problem with the production of insulin. </li></ul><ul><li>Other important contributing factors:[ citation needed ] </li></ul><ul><li>increased hepatic glucose production (e.g., from glycogen -> glucose conversion), especially at inappropriate times (typical cause is deranged insulin levels, as those levels control this function in liver cells) </li></ul><ul><li>decreased insulin-mediated glucose transport in (primarily) muscle and adipose tissues (receptor and post-receptor defects) </li></ul><ul><li>impaired beta-cell function—loss of early phase of insulin release in response to hyperglycemic stimuli </li></ul><ul><li>This is a more complex problem than type 1, but is sometimes easier to treat, especially in the early years when insulin is often still being produced internally. Type 2 may go unnoticed for years before diagnosis, since symptoms are typically milder (eg, no ketoacidosis, coma, etc) and can be sporadic.[ citation needed ] However, severe complications can result from improperly managed type 2 diabetes, including renal failure , erectile dysfunction , blindness, slow healing wounds (including surgical incisions), and arterial disease, including coronary artery disease . The onset of type 2 has been most common in middle age and later life , although it is being more frequently seen in adolescents and young adults due to an increase in child obesity and inactivity. A type of diabetes called MODY is increasingly seen in adolescents, but this is classified as a diabetes due to a specific cause and not as type 2 diabetes. </li></ul><ul><li>Diabetes mellitus with a known etiology, such as secondary to other diseases, known gene defects , trauma or surgery, or the effects of drugs, is more appropriately called secondary diabetes mellitus or diabetes due to a specific cause. Examples include diabetes mellitus such as MODY or those caused by hemochromatosis , pancreatic insufficiencies, or certain types of medications (e.g., long-term steroid use). </li></ul>
  19. 20. <ul><li>Medications </li></ul><ul><li>Main article: Anti-diabetic drug </li></ul><ul><li>Metformin 500mg tablets </li></ul><ul><li>There are several drugs available for type 2 diabetics—most are unsuitable or even dangerous for use by type 1 diabetics. They fall into several classes and are not equivalent, nor can they be simply substituted one for another.[ citation needed ] All are prescription drugs. </li></ul><ul><li>One of the most widely used drugs now used for type 2 diabetes is the biguanide metformin ; it works primarily by reducing liver release of blood glucose from glycogen stores and secondarily by provoking some increase in cellular uptake of glucose in body tissues. Both historically, and currently, the most commonly used drugs are in the Sulfonylurea group, of which several members (including glibenclamide and gliclazide ) are widely used; these increase glucose stimulated insulin secretion by the pancreas and so lower blood glucose even in the face of insulin resistance.[ citation needed ] </li></ul><ul><li>Newer drug classes include:[ citation needed ] </li></ul><ul><li>Thiazolidinediones ( TZDs ) ( rosiglitazone , pioglitazone , and troglitazone -- the last, as Rezulin, was withdrawn from the US market because of an increased risk of systemic acidosis). These increase tissue insulin sensitivity by affecting gene expression </li></ul><ul><li>α-glucosidase inhibitors ( acarbose and miglitol ) which interfere with absorption of some glucose containing nutrients, reducing (or at least slowing) the amount of glucose absorbed </li></ul><ul><li>Meglitinides which stimulate insulin release ( nateglinide , repaglinide , and their analogs) quickly; they can be taken with food, unlike the sulfonylureas which must be taken prior to food (sometimes some hours before, depending on the drug) </li></ul><ul><li>Peptide analogs which work in a variety of ways: </li></ul><ul><ul><li>Incretin mimetics which increase insulin output from the beta cells among other effects. These includes the Glucagon-like peptide (GLP) analog exenatide , sometimes referred to as lizard spit as it was first identified in Gila monster saliva </li></ul></ul><ul><ul><li>Dipeptidyl peptidase-4 (DPP-4) inhibitors increase Incretin levels ( sitagliptin ) by decreasing their deactivation rates </li></ul></ul><ul><ul><li>Amylin agonist analog, which slows gastric emptying and suppresses glucagon ( pramlintide ) </li></ul></ul>
  20. 21. Oral hypoglycemic agents can serve the purpose Insulin therapy is the only answer 8   Characterized by increased secretion of glucagon Characterized by decrease secretion of Insulin 7 The mass of beta , D and PP cells remains unchanged The mass of alpha, D and PP cells remains unchanged 6 Females are more affected than males Equally affects male and female 5 May be from Hereditary Origin May be of Viral Origin 4 Obesity is the general contributing factor Obesity not a common Factor 3 Occurs in the people usually over the age of forty Occurs at an early age 2 Can synthesize and release insulin but not enough to meet the requirement Lack of ability to synthesize and release insulin due to destruction of some Beta Cells 1 NIDDM IDDM Sr. No. DIFFERENTIATION BETWEEN NIDDM AND IDDM
  21. 22. Classification of Drugs (Clinical and Chemical) <ul><li>Insulin </li></ul><ul><li>2 Secretagogues </li></ul><ul><ul><li>2.1 Sulfonylureas </li></ul></ul><ul><ul><li>2.2 Meglitinides </li></ul></ul><ul><li>3 Sensitizers </li></ul><ul><ul><li>3.1 Biguanides </li></ul></ul><ul><ul><li>3.2 Thiazolidinediones </li></ul></ul><ul><li>4 Alpha- glucosidase inhibitors </li></ul><ul><li>5 Peptide analogs </li></ul><ul><ul><li>5.1 Incretin mimetics </li></ul></ul><ul><ul><ul><li>5.1.1 Glucagon -like peptide (GLP) analogs and agonists </li></ul></ul></ul><ul><ul><ul><li>5.1.2 Gastric inhibitory peptide (GIP) analogs </li></ul></ul></ul><ul><ul><li>5.2 DPP-4 inhibitors </li></ul></ul><ul><ul><li>5.3 Amylin analogues </li></ul></ul><ul><li>6 Experimental agents </li></ul><ul><li>7 Alternative medicine </li></ul>
  22. 23. Insulin <ul><li>Insulin therapy is the treatment of diabetes by administration of exogenous insulin . </li></ul><ul><li>Insulin is used medically to treat some forms of diabetes mellitus. Patients with Type 1 diabetes mellitus depend on external insulin (most commonly injected subcutaneously ) for their survival because the hormone is no longer produced internally. Patients with Type 2 diabetes mellitus are insulin resistant , have relatively low insulin production, or both; certain patients with Type 2 diabetes, on rare occasions, may eventually require insulin if other medications fail to control blood glucose levels adequately. </li></ul>
  23. 24. <ul><li>Principles </li></ul><ul><li>Insulin is required for all animal life (excluding certain insects). Its mechanism of action is almost identical in nematode worms (e.g. C . elegans ), fish, and mammals, and it is a protein that has been highly conserved across evolutionary time. Insulin must be administered to patients who experience such a deprivation. Clinically, this condition is called diabetes mellitus type 1 . </li></ul><ul><li>The initial sources of insulin for clinical use in humans were cow , horse , pig or fish pancreases. Insulin from these sources is effective in humans as it is nearly identical to human insulin (three amino acid difference in bovine insulin, one amino acid difference in porcine). Differences in suitability of beef-, pork-, or fish-derived insulin for individual patients have historically been due to lower preparation purity resulting in allergic reactions to the presence of non-insulin substances. Though purity has improved steadily since the 1920s ultimately reaching purity of 99% by the mid-1970s thanks to high-pressure liquid chromatography (HPLC) methods, but minor allergic reactions still occur occasionally, although the same types of allergic reactions have also been known to occur in response to synthetic &quot;human&quot; insulin varieties. Insulin production from animal pancreases was widespread for decades, but very few patients today rely on insulin from animal sources, largely because few pharmaceutical companies sell it anymore. </li></ul><ul><li>Biosynthetic &quot;human&quot; insulin is now manufactured for widespread clinical use using genetic engineering techniques using recombinant DNA technology, which the manufacturers claim reduces the presence of many impurities, although there is no clinical evidence to substantiate this claim. Eli Lilly marketed the first such insulin, Humulin, in 1982. Humulin was the first medication produced using modern genetic engineering techniques in which actual human DNA is inserted into a host cell ( E. coli in this case). The host cells are then allowed to grow and reproduce normally, and due to the inserted human DNA, they produce a synthetic version of human insulin. However, the clinical preparations prepared from such insulins differ from endogenous human insulin in several important respects; an example is the absence of C-peptide which has in recent years been shown to have systemic effects itself. </li></ul>
  24. 25. <ul><li>Genentech developed the technique Lilly used to produce Humulin, although the company never commercially marketed the product themselves. Novo Nordisk has also developed a genetically engineered insulin independently. According to a survey that the International Diabetes Federation conducted in 2002 on the access to and availability of insulin in its member countries, approximately 70% of the insulin that is currently sold in the world is recombinant, biosynthetic 'human' insulin. [1] A majority of insulin used clinically today is produced this way, although the clinical evidence has provided conflicting evidence on whether these insulins are any less likely to produce an allergic reaction. Also, the International Diabetes Federation's position statement is very clear in stating that &quot;there is NO overwhelming evidence to prefer one species of insulin over another&quot; and &quot;[modern, highly-purified] animal insulins remain a perfectly acceptable alternative.&quot; [2] </li></ul><ul><li>Since January 2006, all insulins distributed in the U.S. and some other countries are synthetic &quot;human&quot; insulins or their analogues. A special FDA importation process is required to obtain bovine or porcine derived insulin for use in the U.S., although there may be some remaining stocks of porcine insulin made by Lilly in 2005 or earlier, and porcine insulin is also sold and marketed under the brand name Vetsulin(SM) in the U.S. for veterinary usage in the treatment of companion animals with diabetes. </li></ul>
  25. 26. <ul><li>Slight variations of the human insulin molecule are called insulin analogues , (technically &quot;insulin receptor ligands &quot;) so named because they are not technically insulin, rather they are analogues which retain the hormone's glucose management functionality. They have absorption and activity characteristics not currently possible with subcutaneously injected insulin proper. They are either absorbed rapidly in an attempt to mimic real beta cell insulin (as with Lilly's lispro , Novo Nordisk 's aspart and Sanofi Aventis' glulisine ), or steadily absorbed after injection instead of having a 'peak' followed by a more or less rapid decline in insulin action (as with Novo Nordisk's version Insulin detemir and Sanofi Aventis 's Insulin glargine ), all while retaining insulin's glucose-lowering action in the human body. However, a number of meta-analyses , including those done by the Cochrane Collaboration in the United Kingdom in 2002, [3] Germany's Institute for Quality and Cost Effectiveness in the Health Care Sector [IQWiG] released in 2007, [4] and the Canadian Agency for Drugs and Technology in Health (CADTH) [5] also released in 2007 have shown no unequivocal advantages in clinical use of insulin analogs over more conventional insulin types. </li></ul><ul><li>Choosing insulin type and dosage/timing should be done by an experienced medical professional working closely with the diabetic patient. </li></ul><ul><li>The commonly used types of insulin are: </li></ul><ul><li>Rapid-acting types are presently insulin analogues, such as the insulin analogues aspart or lispro . these begin to work within 5 to 15 minutes and are active for 3 to 4 hours. Most insulins form &quot;clumps&quot; which delay entry into the blood in active form; these analog insulins do not, but have normal insulin activity. Newer varieties are in now in Phase II clinical trials which are designed to work rapidly, but retain the same genetic structure as regular human insulin. [6] </li></ul><ul><li>Short-acting , such as regular insulin – starts working within 30 minutes and is active about 5 to 8 hours. </li></ul><ul><li>Intermediate-acting, such as NPH – starts working in 1 to 3 hours and is active 16 to 24 hours. </li></ul><ul><li>Long-acting, such as ultralente insulin – starts working in 4 to 6 hours, and is active well beyond 32 hours. </li></ul><ul><li>Insulin glargine and Insulin detemir – both insulin analogs which start working within 1 to 2 hours and continue to be active, without major peaks or dips, for about 24 hours, although this varies in many individuals. </li></ul><ul><li>A mixture of NPH and regular insulin – starts working in 30 minutes and is active 16 to 24 hours. There are several variations with different proportions of the mixed insulins. </li></ul><ul><li>A mixture of Semilente and Ultralente (typically in the proportion 30% Semilente to 70% Ultralente), known as Lente , is typically active for an entire 24 hour period. Beef Lente, in particular, has a very 'flat' profile. </li></ul>
  26. 27. 2 units 9 units 2 units 9 units >300         [>16.7] 1 unit 8 units 1 unit 8 units 251-300     [14.0-16.7] 7 units 7 units 201-250     [11.2-13.9] 6 units 6 units 151-200     [8.4-11.1] 5 units 5 units 101-150     [5.6-8.3] 4 units 4 units 70-100       [3.9-5.5] regular insulin dose if fingerstick glucose is (mg/dl) [mmol/L]: 6 units 12 units NPH dose at bedtime before dinner before lunch before breakfast
  27. 28. 3 units 10 units 10 units 10 units >300         [>16.7] 2 units 9 units 9 units 9 units 251-300     [14.0-16.7] 1 unit 8 units 8 units 8 units 201-250     [11.2-13.9] 7 units 7 units 7 units 151-200     [8.4-11.1] 6 units 6 units 6 units 101-150     [5.6-8.3] 5 units 5 units 5 units 70-100       [3.9-5.5] at bedtime before dinner before lunch before breakfast if fingerstick glucose is (mg/dl) [mmol/L]:
  28. 29. Chemical Classification of Oral Hypoglycemic Agents <ul><li>Sulphonyl Ureas : Carbutamide, Tolbutamide </li></ul><ul><li>Biguanides: Phenformin, Metformin </li></ul><ul><li>Substituted Benzoic Acid Derivatives: Meglitinide </li></ul><ul><li>Thiazolidinones :Pioglitazone </li></ul><ul><li>Miscellaneous Agents: Linogliride </li></ul><ul><li>Glucagon </li></ul>
  29. 30. 1. Sulphonyl Ureas (FOR NIDDM Only) IST Generation II nd Generation
  30. 31. <ul><li>M.O.A: 1. Sulphonyl Ureas cause Hypoglcaemia by stimulating insulin release from pancreatic beta cells. </li></ul><ul><li>2. They bind to ATP-sensitive-K + channel. Reduced conductance causes membrane depolarization and in flux of Ca 2+ through voltage sensitive Ca 2+ channels. Increased entry of Ca 2+ and intracellualr binding to Calmodulin could activate kinases involved in exocytosis of secretory granules. Thus more insulin is released. </li></ul>
  31. 32. SAR OF SULPHONYL UREAS
  32. 33. Pharmacokinetics of Sulphonyl Ureas <ul><li>1. Extensively Metabolized in Liver </li></ul><ul><li>2.Tolbutamide : Mainly metabolized to Butylcarboxyphenyl sulphonylurea. </li></ul><ul><li>3.Tolbutamide is rapidly metabolized in other sulphonylUreas are relatively slow metabolized. </li></ul><ul><li>4.Acetohexamide: Undergoes Reduction to Hydroxyhexamide which shows antidiabetic activity.’ </li></ul><ul><li>5. Tolazamide shows weakly active metabolites. </li></ul><ul><li>6. Glypizide and Glyburide : Metablozed by Hydroxylation and then by conjugation to be excreted from Urine. </li></ul><ul><li>7.Chlorpropamide : Metabolized to unchanged form to be excreted from Urine. </li></ul>
  33. 34. Adverse Effects of Sulfonyl Ureas <ul><li>Overdoses for Long Period: Degranulation of beta Cells of Pnacreas. </li></ul><ul><li>Common Adverse Reactions: </li></ul><ul><li>1. Cutaneous Reactions. </li></ul><ul><li>2. GIT Reactions. </li></ul><ul><li>3. Cardiovascular Reactions. </li></ul><ul><li>Cutaneous Reactions: Skin rashes and Photosentivity. </li></ul><ul><li>GIT Reactions: Nausea Vomitting, anorexia, mild toxic Hepatitis with Jaundice </li></ul>
  34. 35. <ul><li>Haematological Reactions: Transient Leukpenia, Agranulocytosis, thrombocytopenia and fatal aplastic anemia </li></ul><ul><li>Cardiovascular Reactions: No significant Effects on Cardiovascular System. </li></ul><ul><li>Uses: 1. Used for strictly NIDDM patients. </li></ul><ul><li>2. Sometimes used to lower the dose of </li></ul><ul><li>Insulin. </li></ul>
  35. 36. 2. Biguanides
  36. 37. Biguanides <ul><li>In 1918 Gunidine was reported lower the blood glucose level.However it had high toxicities. </li></ul><ul><li>Phenformin was reported to have safe profile. </li></ul><ul><li>Metformin was the compound further reported to have lowering of Blood Sugar in pancreatomized animals and in absence of Islets cells of Pancreas. </li></ul><ul><li>M.O.A: </li></ul><ul><li>1. Biguanides do not cause insulin release from pancreas.They are antihyperglycaemic agents and not hypoglycaemic agents.They mainly cause reduction in hepatic glucose output by inhibition of gluconeogenesis. They also reduce plasma glucose uptake by reducing uptake of glucose from the intestine. </li></ul>
  37. 38. <ul><li>2. Biguanides inhibit oxidative phosphorylation by inhibiting such such oxidative enzymes such as Succinic Dehydrogenase. Respiratory inhibition results in cellular hypoxia subsequently glucose uptake by peripheral muscles increases followed by glycolysis. Also Lipogenesis is decrease as oxidation in adipose tissue decreases. </li></ul><ul><li>Possible Mechanism of actions: </li></ul><ul><li>Inhibition of Intestinal Transport and absorption of sugar. </li></ul><ul><li>Potentiation of action of insulin and absortion of Sugars. </li></ul><ul><li>Inhibition of Hepatic gluconeogensis. </li></ul><ul><li>Enhancement of oxidative phosphorylation and /or inhibition of oxidative phosphorylation in peripheral tissues. </li></ul><ul><li>Phenformin :It has side effect of Lactic Acidosis . </li></ul>
  38. 39. 3. Substituted Benzoic Acid Derivatives (Meglitinides) <ul><li>Similar in structure to sulphonyl ureas </li></ul><ul><li>Known as endogenous insuln secretagogues as they induce pancreatic release of endogenous insulin </li></ul><ul><li>Advantages is greater decrease in post prandial glucose and decrease risk of hypoglycemia </li></ul>
  39. 40. <ul><li>Mechanism of action: </li></ul><ul><li>Resemble sulphonyl ureas </li></ul><ul><li>Stimulate release of insulin from beta cells </li></ul><ul><li>Has effects on potassium conductance </li></ul><ul><li>Like sulphonyl ureas they has no direct effect on level of plasma lipids </li></ul>
  40. 41. Thiazolidindiones <ul><li>New class known as glitazone </li></ul><ul><li>Potent in reducing insulin resistance </li></ul><ul><li>They do not increase insulin secretion hence hypoglyceamia is not the risk </li></ul><ul><li>Have low effect on LDL and high on HDL </li></ul><ul><li>Safe in patient with impaired renal function </li></ul>
  41. 42. Thiazolidinediones (Giltazones)
  42. 43. Mechanism of action <ul><li>Reduces insulin resistance </li></ul><ul><li>Improves insulin sensitivity at the liver and muscle cells </li></ul><ul><li>Enchances glucose and lipid metabolism </li></ul><ul><li>Have effect on hepatic glucose uptake </li></ul><ul><li>Do not stimulate pancreas to produce more insulin </li></ul>
  43. 44. Glucagon <ul><li>Isolated from alpha cells of islets of langerhans </li></ul><ul><li>Single chain polypeptide </li></ul><ul><li>Molecular weight 3500 </li></ul><ul><li>Differs from insulin as it has no disulfide linkages </li></ul><ul><li>Physiological antagonist of insulin </li></ul>
  44. 45. Pharmacological action <ul><li>Opposite to insulin </li></ul><ul><li>Promote gluconeogenisis, ketogenisis and energy generation hence known as hormone of catabolism </li></ul><ul><li>Inhibit gastric acid secretion </li></ul><ul><li>Half life is 3-6 min </li></ul><ul><li>Inactivated in liver and kidney </li></ul>
  45. 46. Miscellaneous hypoglycemic agent <ul><li>1) Pirogliride: </li></ul><ul><li>Different hypoglycemic agent </li></ul><ul><li>Guanidine derivative </li></ul><ul><li>Enchances insulin secretion in presence of glucose only </li></ul><ul><li>2)Glycogen: </li></ul><ul><li>Peptide contaning 29 amino acid </li></ul><ul><li>Act through c-AMP </li></ul>
  46. 47. <ul><li>3)Isoxazole and pyrazoles: </li></ul><ul><li>Inhibit free fatty release </li></ul><ul><li>This decrease glucose level </li></ul><ul><li>4)Indole 2 Carboxylic acid: </li></ul><ul><li>Action due to inhibition of hepatic gluconeogenesis </li></ul><ul><li>Hydantoins: </li></ul><ul><li>only 3 substituted derivative possess acitivity </li></ul><ul><li>MOA is not known </li></ul><ul><li>Used in type 2 diabetes mellitus </li></ul>
  47. 48. <ul><li>7)Dichloracetate: </li></ul><ul><li>Lower plasma glucose level and free fatty acid </li></ul><ul><li>Prevent ketone bodies production </li></ul><ul><li>8)Natural substances: </li></ul><ul><li>Fruit of plant Blighia sapida contains hypoglycine A and B </li></ul>
  48. 49. <ul><li>Thank You… For your patience and Attention </li></ul>

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