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Prepared by:
  Huzaifa Hamid Ahmad
Shanyar Kadir Hama-Karim
Shkar Dilshad Abdulkarim
Overview
   The pancreas is both an endocrine gland
    that produces the peptide hormones
    insulin, glucagon, and somatostatin and
    an exocrine gland that produces digestive
    enzymes. The peptide hormones are
    secreted from cells located in the islets of
    Langerhans (β cells produce insulin, α cells
    produce glucagon, and δ cells produce
    somatostatin). These hormones play an
    important role in regulating the metabolic
    activities of the body, particularly the
    homeostasis of blood glucose.
Overview
   Hyperinsulinemia (due, for example, to an
    insulinoma)     can       cause       severe
    hypoglycemia. More commonly, a relative
    or absolute lack of insulin, such as in
    diabetes mellitus, can cause serious
    hyperglycemia, which, if left untreated, can
    result                                     in
    retinopathy, nephropathy, neuropathy, and
    cardiovascular                complications.
    Administration of insulin preparations or
    oral hypoglycemic agents can prevent
    morbidity and reduce mortality associated
    with diabetes.
Overview
 Anti-diabetic medications treat diabetes
  mellitus by lowering glucose levels in the
  blood. With the exceptions of
  insulin, exenatide, and pramlintide, all
  are administered orally and are thus also
  called oral hypoglycemic agents or oral
  antihyperglycemic agents. There are
  different classes of anti-diabetic drugs, and
  their selection depends on:
 Nature of the diabetes
 Age and situation of the person
 Other factors.
Diabetes Mellitus Type I
   Type 1 diabetes most commonly afflicts individuals in
    puberty or early adulthood, but some latent forms can
    occur later in life. The disease is characterized by an
    absolute deficiency of insulin caused by massive β-cell
    necrosis. Loss of β-cell function is usually ascribed to
    autoimmune-mediated processes directed against the β-
    cell, and it may be triggered by an invasion of viruses or
    the action of chemical toxins. As a result of the destruction
    of these cells, the pancreas fails to respond to
    glucose, and the Type 1 diabetic shows classic symptoms
    of insulin deficiency (polydipsia, polyphagia, polyuria, and
    weight loss). Type 1 diabetics require exogenous insulin
    to avoid the catabolic state that results from and is
    characterized by hyperglycemia and life-threatening
    ketoacidosis.
Diabetes Mellitus Type II
   Most diabetics are Type 2. The disease is
    influenced              by          genetic
    factors, aging, obesity, and peripheral
    insulin   resistance      rather than   by
    autoimmune processes or viruses. The
    metabolic alterations observed are milder
    than those described for Type 1 (for
    example, Type 2 patients typically are not
    ketotic), but the long-term clinical
    consequences can be just as devastating
    (for example, vascular complications and
    subsequent      infection    can  lead   to
    amputation of the lower limbs).
Types of DM
 Diabetes mellitus type 1 is a disease
  caused by the lack of insulin. Insulin must
  be used in Type I, which must be injected.
 Diabetes mellitus type 2 is a disease of
  insulin resistance by cells. Treatments
  include:
     agents that increase the amount of insulin
      secreted by the pancreas
     agents that increase the sensitivity of target
      organs to insulin
     agents that decrease the rate at which glucose
      is absorbed from the gastrointestinal tract.
Types of DM
                         Type 1                     Type 2
Age of onset             Usually during childhood   Frequently over age 35
                         or puberty
Nutritional status at    Frequently                 Obesity usually present
time of onset            undernourished
Prevalence               5 to 10 % of diagnosed     90 to 95 % of diagnosed
                         diabetics                  diabetics
Genetic predisposition   Moderate                   Very strong
Defect or deficiency     B cells are destroyed,     Inability of B cells to
                         eliminating the            produce appropriate
                         production of insulin      quantities of insulin;
                                                    insulin resistance; other
                                                    defects
Insulin forms
Kinetics (in Hours) of Insulin Forms with Subcutaneous Injection
Form                Onset                Peak Effect         Duration
Lispro*             0.3 – 0.5            1–2                 3–4
Regular*            0.5 – 1              2–4                 5–7
Glargine            1                    No peak

* Only forms that can be used intravenously; peak action in 2 to 4 min
Symptoms of Hypoglycemia
DRUG GROUPS
                                  OHA



                                                           Dipeptidyl
    Insulin           Insulin             α-glucosidase
                                                          Peptidase-IV
secretagogues       sensitizers             inhibitors
                                                           inhibitors



    Sulfonylureas       Biguanides




     Meglitinide     Thiazolidinediones
     analogue              (TZD)
Adverse effects of OHAs
Meglitinide
Sulfonylureas                        Biguanides                Thiazolidinediones




Hypoglycemia                          Nausea                Risk of hepatotoxicity


                                                  Sulfonylureas
                Biguanides
                                                  Meglitinides
                α-Glucosidase inhibitors
                                                  Thiazolidinediones




                GI disturbance                     Weight gain
1) Insulin secretagogues
 Useful in the treatment of patients who
  have Type 2 diabetes but who cannot be
  managed by diet alone.
 Best response to OHA is seen in one who
  develops diabetes after age 40 and has
  had diabetes less than 5 years.
 Patients with long-standing disease may
  require a combination of hypoglycemic
  drugs with or without insulin to control their
  hyperglycemia.
 Oral hypoglycemic agents should NOT be
  given to patients with Type 1 diabetes.
A. Sulfonylureas
   These agents are classified as insulin
    secretagogues, because they promote
    insulin release from the β cells of the
    pancreas. The primary drugs used today
    are tolbutamide and the second-
    generation
    derivatives, glyburide, glipizide, and
    glimepiride.
A. Sulfonylureas
  Mechanism of action:
1) stimulation of insulin release from the β
   cells of the pancreas by blocking the
   ATP-dependent K+ channels, resulting
   in depolarization and Ca2+ influx
2) reduction in hepatic glucose production
3) increase in peripheral insulin sensitivity.
Oral Hypoglycemic Agents
A. Sulfonylureas
 Pharmacokinetics:
 Given orally, these drugs bind to serum
  proteins
 Metabolized by the liver
 Excreted by the liver or kidney
 Tolbutamide has the shortest duration
  of action (6-12 hours), whereas the
  second-generation agents last about 24
  hours
A. Sulfonylureas
   Adverse Effects:
   Weight gain
   Hyperinsulinemia
   Hypoglycemia
   These drugs should be used with caution in patients with
    hepatic or renal insufficiency, because delayed excretion of
    the drug-resulting in its accumulation-may cause
    hypoglycemia.
   Renal impairment is a particular problem in the case of
    those agents that are metabolized to active
    compounds, such as glyburide.
   Glyburide has minimal transfer across the placenta and
    may be a reasonably safe alternative to insulin therapy
    for diabetes in pregnancy.
B. Meglitinide analogs
   This   class   of   agents    includes
    repaglinide and nateglinide. Although
    they are not sulfonylureas, they have
    common actions.
B. Meglitinide analogs
   Mechanism of action:
   Their action is dependent on functioning pancreatic β
    cells.
   They bind to a distinct site on the sulfonylurea receptor
    of ATP-sensitive potassium channels, thereby
    initiating a series of reactions culminating in the release
    of insulin.
   However, in contrast to the sulfonylureas, the
    meglitinides have a rapid onset and a short duration
    of action.
   They are are categorized as postprandial glucose
    regulators.
   Meglitinides should not be used in combination with
    sulfonylureas due to overlapping mechanisms of action.
B. Meglitinide analogs
 Pharmacokinetics:
 These drugs are well absorbed orally
  after being taken 1 to 30 minutes before
  meals.
 Both meglitinides are metabolized to
  inactive products by CYP3A4 in the
  liver.
 Excreted through the bile.
B. Meglitinide analogs
 Adverse Effects:
 Incidence of hypoglycemia is lower than that
  of the sulfonylureas.
 Repaglinide has been reported to cause
  severe hypoglycemia in patients who are
  also taking the lipid-lowering drug
  gemfibrozil.
 Weight gain is less of a problem with the
  meglitinides than with the sulfonylureas.
 Must be used with caution in patients with
  hepatic impairment.
2) Insulin sensitizers
 Two classes of oral agents-the
  biguanides and thiazolidinediones
  improve insulin action. These agents
  lower blood sugar by improving target-
  cell response to insulin without
  increasing pancreatic insulin secretion.
 They address the core problem in Type
  II diabetes—insulin resistance.
A. Biguanides
 Metformin (glucophage), the only
  currently available biguanide
 it increases glucose uptake and utilization
  by target tissues, thereby decreasing
  insulin resistance.
 Requires insulin for its action, but it does
  not promote insulin secretion.
 Hyperinsulinemia is not a problem. Thus,
  the risk of hypoglycemia is far less than
  that with sulfonylureas
A. Biguanides
   Mechanism of action:
   reduction of hepatic glucose output, largely
    by inhibiting hepatic gluconeogenesis.
   Slowing intestinal absorption of sugars
   Improves peripheral glucose uptake and
    utilization.
   Metformin may be used alone or in
    combination with one of the other
    agents, as well as with insulin.
   Hypoglycemia       has     occurred    when
    metformin was taken in combination.
A. Biguanides
 Pharmacokinetics:
 Metformin is well absorbed orally, is not
  bound to serum proteins
 It is not metabolized
 Excretion is via the urine.
A. Biguanides
   Adverse effects:
   These are largely gastrointestinal.
   Contraindicated in diabetics with renal and/or
    hepatic     disease,      acute      myocardial
    infarction, severe infection, or diabetic
    ketoacidosis.
   It should be used with caution in patients
    greater than 80 years of age or in those with a
    history of congestive heart failure or alcohol
    abuse.
   Long-term use may interfere with vitamin B12
    absorption.
B. Thiazolidinediones
   Another group of agents that are insulin
    sensitizers are the thiazolidinediones (TZDs)
    or, more familiarly the glitazones.
   Although insulin is required for their
    action, these drugs do not promote its release
    from       the       pancreatic     β    cells;
    thus, hyperinsulinemia does not result.
   Troglitazone was the first of these to be
    approved for the treatment of Type 2
    diabetic, but was withdrawn after a number of
    deaths due to hepatotoxicity were reported.
    Presently, two members of this class are
    available, pioglitazone and rosiglitazone.
B. Thiazolidinediones
 Mechanism of action:
 Exact mechanism by which the TZDs lower
  insulin resistance remains to be elucidated
 They are known to target the peroxisome
  proliferator-activated receptor-γ (PPARγ)-α
  nuclear hormone receptor. Ligands for
  PPARγ regulate adipocyte production and
  secretion of fatty acids as well as glucose
  metabolism, resulting in increased insulin
  sensitivity in adipose tissue, liver, and
  skeletal muscle.
B. Thiazolidinediones
   Pharmacokinetics:
   Both pioglitazone and rosiglitazone are absorbed
    very well after oral administration and are extensively
    bound to serum albumin.
   Both undergo extensive metabolism by different
    cytochrome P450 isozymes.
   Pioglitazone:
   Renal elimination is negligible, with the majority of
    the active drug and metabolites excreted in the bile
    and eliminated in the feces.
   Rosiglitazone:
   The metabolites are primarily excreted in the urine.
B. Thiazolidinediones
   Adverse Effects:
   Very few cases of liver toxicity have been
    reported with rosiglitazone or pioglitazone.
   Weight increase can occur, possibly through the
    ability of TZDs to increase subcutaneous fat or
    due to fluid retention.
   Glitazones have been associated with
    osteopenia and increased fracture risk.
   Other adverse effects include headache and
    anemia.
3) α-glucosidase inhibitors
   Alpha-glucosidase inhibitors are oral anti-
    diabetic drugs used for diabetes mellitus
    type 2 that work by preventing the
    digestion of carbohydrates (such as
    starch and table sugar). Carbohydrates are
    normally converted into simple sugars
    (monosaccharides),      which    can      be
    absorbed      through     the     intestine.
    Hence, alpha-glucosidase inhibitors reduce
    the impact of carbohydrates on blood
    sugar.
α-glucosidase inhibitors
   Acarbose and miglitol are orally active
    drugs used for the treatment of patients
    with Type 2 diabetes.
α-glucosidase inhibitors
   Mechanism of action:
   These drugs are taken at the beginning of meals. They
    act by delaying the digestion of carbohydrates, thereby
    resulting in lower postprandial glucose levels. Both drugs
    exert their effects by reversibly inhibiting membrane-
    bound α-glucosidase in the intestinal brush border. This
    enzyme is responsible for the hydrolysis of
    oligosaccharides to glucose and other sugars.
    Consequently, the postprandial rise of blood glucose is
    blunted. Unlike the other oral hypoglycemic agents, these
    drugs do not stimulate insulin release, nor do they
    increase insulin action in target tissues. Thus, as
    monotherapy, they do not cause hypoglycemia.
    However, when used in combination with the
    sulfonylureas or with insulin, hypoglycemia may develop.
α-glucosidase inhibitors
 Pharmacokinetics:
 Acarbose is poorly absorbed. It is
  metabolized primarily by intestinal
  bacteria, and some of the metabolites
  are absorbed and excreted into the
  urine. On the other hand, miglitol is very
  well absorbed but has no systemic
  effects. It is excreted unchanged by the
  kidney.
α-glucosidase inhibitors
 Adverse effects:
 The      major    side   effects  are
  flatulence, diarrhea, and abdominal
  cramping. Patients with inflammatory
  bowel disease, colonic ulceration, or
  intestinal obstruction should not use
  these drugs.
4) Dipeptidyl peptidase-4
inhibitor
   DPP-4 inhibitors or gliptins, are a class of oral
    hypoglycemics that block DPP-4. They can be used
    to treat diabetes mellitus type 2.

   The first agent of the class - sitagliptin - was
    approved by the FDA in 2006.

   Glucagon increases blood glucose levels, and DPP-
    4 inhibitors reduce glucagon and blood glucose
    levels. The mechanism of DPP-4 inhibitors is to
    increase incretin levels (GLP-1 and GIP), which
    inhibit glucagon release, which in turn increases
    insulin secretion, decreases gastric emptying, and
    decreases blood glucose levels.
Dipeptidyl peptidase-4
inhibitor
   Sitagliptin is an orally active dipeptidyl
    peptidase-IV (DPP-IV) inhibitor used for
    the treatment of patients with Type 2
    diabetes. Other agents in this category
    are currently in development.
Sitagliptin
 Mechanism of action:
 Sitagliptin inhibits the enzyme DPP-
  IV, which is responsible for the inactivation
  of incretin hormones, such as glucagon-like
  peptide-1 (GLP-1). Prolonging the activity
  of incretin hormones results in increased
  insulin release in response to meals and a
  reduction in inappropriate secretion of
  glucagon. Sitagliptin may be used as
  monotherapy or in combination with a
  sulfonylurea, metformin or a glitazone.
Sitagliptin
 Pharmacokinetics:
 Sitagliptin is well absorbed after oral
  administration. Food does not affect the
  extent of absorption. The majority of
  sitagliptin is excreted unchanged in the
  urine.     Dosage      adjustments   are
  recommended for patients with renal
  dysfunction.
Sitagliptin
 Adverse Effects:
 In     general,    sitagliptin is   well
  tolerated, with the most common
  adverse effects being nasopharyngitis
  and headache. Rates of hypoglycemia
  are comparable to those with placebo
  when sitagliptin is used as monotherapy
  or in combination with metformin or
  pioglitazone.

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Oral Hypoglycemic Agents

  • 1. Prepared by: Huzaifa Hamid Ahmad Shanyar Kadir Hama-Karim Shkar Dilshad Abdulkarim
  • 2. Overview  The pancreas is both an endocrine gland that produces the peptide hormones insulin, glucagon, and somatostatin and an exocrine gland that produces digestive enzymes. The peptide hormones are secreted from cells located in the islets of Langerhans (β cells produce insulin, α cells produce glucagon, and δ cells produce somatostatin). These hormones play an important role in regulating the metabolic activities of the body, particularly the homeostasis of blood glucose.
  • 3. Overview  Hyperinsulinemia (due, for example, to an insulinoma) can cause severe hypoglycemia. More commonly, a relative or absolute lack of insulin, such as in diabetes mellitus, can cause serious hyperglycemia, which, if left untreated, can result in retinopathy, nephropathy, neuropathy, and cardiovascular complications. Administration of insulin preparations or oral hypoglycemic agents can prevent morbidity and reduce mortality associated with diabetes.
  • 4. Overview  Anti-diabetic medications treat diabetes mellitus by lowering glucose levels in the blood. With the exceptions of insulin, exenatide, and pramlintide, all are administered orally and are thus also called oral hypoglycemic agents or oral antihyperglycemic agents. There are different classes of anti-diabetic drugs, and their selection depends on:  Nature of the diabetes  Age and situation of the person  Other factors.
  • 5. Diabetes Mellitus Type I  Type 1 diabetes most commonly afflicts individuals in puberty or early adulthood, but some latent forms can occur later in life. The disease is characterized by an absolute deficiency of insulin caused by massive β-cell necrosis. Loss of β-cell function is usually ascribed to autoimmune-mediated processes directed against the β- cell, and it may be triggered by an invasion of viruses or the action of chemical toxins. As a result of the destruction of these cells, the pancreas fails to respond to glucose, and the Type 1 diabetic shows classic symptoms of insulin deficiency (polydipsia, polyphagia, polyuria, and weight loss). Type 1 diabetics require exogenous insulin to avoid the catabolic state that results from and is characterized by hyperglycemia and life-threatening ketoacidosis.
  • 6. Diabetes Mellitus Type II  Most diabetics are Type 2. The disease is influenced by genetic factors, aging, obesity, and peripheral insulin resistance rather than by autoimmune processes or viruses. The metabolic alterations observed are milder than those described for Type 1 (for example, Type 2 patients typically are not ketotic), but the long-term clinical consequences can be just as devastating (for example, vascular complications and subsequent infection can lead to amputation of the lower limbs).
  • 7. Types of DM  Diabetes mellitus type 1 is a disease caused by the lack of insulin. Insulin must be used in Type I, which must be injected.  Diabetes mellitus type 2 is a disease of insulin resistance by cells. Treatments include:  agents that increase the amount of insulin secreted by the pancreas  agents that increase the sensitivity of target organs to insulin  agents that decrease the rate at which glucose is absorbed from the gastrointestinal tract.
  • 8. Types of DM Type 1 Type 2 Age of onset Usually during childhood Frequently over age 35 or puberty Nutritional status at Frequently Obesity usually present time of onset undernourished Prevalence 5 to 10 % of diagnosed 90 to 95 % of diagnosed diabetics diabetics Genetic predisposition Moderate Very strong Defect or deficiency B cells are destroyed, Inability of B cells to eliminating the produce appropriate production of insulin quantities of insulin; insulin resistance; other defects
  • 9. Insulin forms Kinetics (in Hours) of Insulin Forms with Subcutaneous Injection Form Onset Peak Effect Duration Lispro* 0.3 – 0.5 1–2 3–4 Regular* 0.5 – 1 2–4 5–7 Glargine 1 No peak * Only forms that can be used intravenously; peak action in 2 to 4 min
  • 11. DRUG GROUPS OHA Dipeptidyl Insulin Insulin α-glucosidase Peptidase-IV secretagogues sensitizers inhibitors inhibitors Sulfonylureas Biguanides Meglitinide Thiazolidinediones analogue (TZD)
  • 12. Adverse effects of OHAs Meglitinide Sulfonylureas Biguanides Thiazolidinediones Hypoglycemia Nausea Risk of hepatotoxicity Sulfonylureas Biguanides Meglitinides α-Glucosidase inhibitors Thiazolidinediones GI disturbance Weight gain
  • 13. 1) Insulin secretagogues  Useful in the treatment of patients who have Type 2 diabetes but who cannot be managed by diet alone.  Best response to OHA is seen in one who develops diabetes after age 40 and has had diabetes less than 5 years.  Patients with long-standing disease may require a combination of hypoglycemic drugs with or without insulin to control their hyperglycemia.  Oral hypoglycemic agents should NOT be given to patients with Type 1 diabetes.
  • 14. A. Sulfonylureas  These agents are classified as insulin secretagogues, because they promote insulin release from the β cells of the pancreas. The primary drugs used today are tolbutamide and the second- generation derivatives, glyburide, glipizide, and glimepiride.
  • 15. A. Sulfonylureas  Mechanism of action: 1) stimulation of insulin release from the β cells of the pancreas by blocking the ATP-dependent K+ channels, resulting in depolarization and Ca2+ influx 2) reduction in hepatic glucose production 3) increase in peripheral insulin sensitivity.
  • 17. A. Sulfonylureas  Pharmacokinetics:  Given orally, these drugs bind to serum proteins  Metabolized by the liver  Excreted by the liver or kidney  Tolbutamide has the shortest duration of action (6-12 hours), whereas the second-generation agents last about 24 hours
  • 18. A. Sulfonylureas  Adverse Effects:  Weight gain  Hyperinsulinemia  Hypoglycemia  These drugs should be used with caution in patients with hepatic or renal insufficiency, because delayed excretion of the drug-resulting in its accumulation-may cause hypoglycemia.  Renal impairment is a particular problem in the case of those agents that are metabolized to active compounds, such as glyburide.  Glyburide has minimal transfer across the placenta and may be a reasonably safe alternative to insulin therapy for diabetes in pregnancy.
  • 19. B. Meglitinide analogs  This class of agents includes repaglinide and nateglinide. Although they are not sulfonylureas, they have common actions.
  • 20. B. Meglitinide analogs  Mechanism of action:  Their action is dependent on functioning pancreatic β cells.  They bind to a distinct site on the sulfonylurea receptor of ATP-sensitive potassium channels, thereby initiating a series of reactions culminating in the release of insulin.  However, in contrast to the sulfonylureas, the meglitinides have a rapid onset and a short duration of action.  They are are categorized as postprandial glucose regulators.  Meglitinides should not be used in combination with sulfonylureas due to overlapping mechanisms of action.
  • 21. B. Meglitinide analogs  Pharmacokinetics:  These drugs are well absorbed orally after being taken 1 to 30 minutes before meals.  Both meglitinides are metabolized to inactive products by CYP3A4 in the liver.  Excreted through the bile.
  • 22. B. Meglitinide analogs  Adverse Effects:  Incidence of hypoglycemia is lower than that of the sulfonylureas.  Repaglinide has been reported to cause severe hypoglycemia in patients who are also taking the lipid-lowering drug gemfibrozil.  Weight gain is less of a problem with the meglitinides than with the sulfonylureas.  Must be used with caution in patients with hepatic impairment.
  • 23. 2) Insulin sensitizers  Two classes of oral agents-the biguanides and thiazolidinediones improve insulin action. These agents lower blood sugar by improving target- cell response to insulin without increasing pancreatic insulin secretion.  They address the core problem in Type II diabetes—insulin resistance.
  • 24. A. Biguanides  Metformin (glucophage), the only currently available biguanide  it increases glucose uptake and utilization by target tissues, thereby decreasing insulin resistance.  Requires insulin for its action, but it does not promote insulin secretion.  Hyperinsulinemia is not a problem. Thus, the risk of hypoglycemia is far less than that with sulfonylureas
  • 25. A. Biguanides  Mechanism of action:  reduction of hepatic glucose output, largely by inhibiting hepatic gluconeogenesis.  Slowing intestinal absorption of sugars  Improves peripheral glucose uptake and utilization.  Metformin may be used alone or in combination with one of the other agents, as well as with insulin.  Hypoglycemia has occurred when metformin was taken in combination.
  • 26. A. Biguanides  Pharmacokinetics:  Metformin is well absorbed orally, is not bound to serum proteins  It is not metabolized  Excretion is via the urine.
  • 27. A. Biguanides  Adverse effects:  These are largely gastrointestinal.  Contraindicated in diabetics with renal and/or hepatic disease, acute myocardial infarction, severe infection, or diabetic ketoacidosis.  It should be used with caution in patients greater than 80 years of age or in those with a history of congestive heart failure or alcohol abuse.  Long-term use may interfere with vitamin B12 absorption.
  • 28. B. Thiazolidinediones  Another group of agents that are insulin sensitizers are the thiazolidinediones (TZDs) or, more familiarly the glitazones.  Although insulin is required for their action, these drugs do not promote its release from the pancreatic β cells; thus, hyperinsulinemia does not result.  Troglitazone was the first of these to be approved for the treatment of Type 2 diabetic, but was withdrawn after a number of deaths due to hepatotoxicity were reported. Presently, two members of this class are available, pioglitazone and rosiglitazone.
  • 29. B. Thiazolidinediones  Mechanism of action:  Exact mechanism by which the TZDs lower insulin resistance remains to be elucidated  They are known to target the peroxisome proliferator-activated receptor-γ (PPARγ)-α nuclear hormone receptor. Ligands for PPARγ regulate adipocyte production and secretion of fatty acids as well as glucose metabolism, resulting in increased insulin sensitivity in adipose tissue, liver, and skeletal muscle.
  • 30. B. Thiazolidinediones  Pharmacokinetics:  Both pioglitazone and rosiglitazone are absorbed very well after oral administration and are extensively bound to serum albumin.  Both undergo extensive metabolism by different cytochrome P450 isozymes.  Pioglitazone:  Renal elimination is negligible, with the majority of the active drug and metabolites excreted in the bile and eliminated in the feces.  Rosiglitazone:  The metabolites are primarily excreted in the urine.
  • 31. B. Thiazolidinediones  Adverse Effects:  Very few cases of liver toxicity have been reported with rosiglitazone or pioglitazone.  Weight increase can occur, possibly through the ability of TZDs to increase subcutaneous fat or due to fluid retention.  Glitazones have been associated with osteopenia and increased fracture risk.  Other adverse effects include headache and anemia.
  • 32. 3) α-glucosidase inhibitors  Alpha-glucosidase inhibitors are oral anti- diabetic drugs used for diabetes mellitus type 2 that work by preventing the digestion of carbohydrates (such as starch and table sugar). Carbohydrates are normally converted into simple sugars (monosaccharides), which can be absorbed through the intestine. Hence, alpha-glucosidase inhibitors reduce the impact of carbohydrates on blood sugar.
  • 33. α-glucosidase inhibitors  Acarbose and miglitol are orally active drugs used for the treatment of patients with Type 2 diabetes.
  • 34. α-glucosidase inhibitors  Mechanism of action:  These drugs are taken at the beginning of meals. They act by delaying the digestion of carbohydrates, thereby resulting in lower postprandial glucose levels. Both drugs exert their effects by reversibly inhibiting membrane- bound α-glucosidase in the intestinal brush border. This enzyme is responsible for the hydrolysis of oligosaccharides to glucose and other sugars. Consequently, the postprandial rise of blood glucose is blunted. Unlike the other oral hypoglycemic agents, these drugs do not stimulate insulin release, nor do they increase insulin action in target tissues. Thus, as monotherapy, they do not cause hypoglycemia. However, when used in combination with the sulfonylureas or with insulin, hypoglycemia may develop.
  • 35. α-glucosidase inhibitors  Pharmacokinetics:  Acarbose is poorly absorbed. It is metabolized primarily by intestinal bacteria, and some of the metabolites are absorbed and excreted into the urine. On the other hand, miglitol is very well absorbed but has no systemic effects. It is excreted unchanged by the kidney.
  • 36. α-glucosidase inhibitors  Adverse effects:  The major side effects are flatulence, diarrhea, and abdominal cramping. Patients with inflammatory bowel disease, colonic ulceration, or intestinal obstruction should not use these drugs.
  • 37. 4) Dipeptidyl peptidase-4 inhibitor  DPP-4 inhibitors or gliptins, are a class of oral hypoglycemics that block DPP-4. They can be used to treat diabetes mellitus type 2.  The first agent of the class - sitagliptin - was approved by the FDA in 2006.  Glucagon increases blood glucose levels, and DPP- 4 inhibitors reduce glucagon and blood glucose levels. The mechanism of DPP-4 inhibitors is to increase incretin levels (GLP-1 and GIP), which inhibit glucagon release, which in turn increases insulin secretion, decreases gastric emptying, and decreases blood glucose levels.
  • 38. Dipeptidyl peptidase-4 inhibitor  Sitagliptin is an orally active dipeptidyl peptidase-IV (DPP-IV) inhibitor used for the treatment of patients with Type 2 diabetes. Other agents in this category are currently in development.
  • 39. Sitagliptin  Mechanism of action:  Sitagliptin inhibits the enzyme DPP- IV, which is responsible for the inactivation of incretin hormones, such as glucagon-like peptide-1 (GLP-1). Prolonging the activity of incretin hormones results in increased insulin release in response to meals and a reduction in inappropriate secretion of glucagon. Sitagliptin may be used as monotherapy or in combination with a sulfonylurea, metformin or a glitazone.
  • 40. Sitagliptin  Pharmacokinetics:  Sitagliptin is well absorbed after oral administration. Food does not affect the extent of absorption. The majority of sitagliptin is excreted unchanged in the urine. Dosage adjustments are recommended for patients with renal dysfunction.
  • 41. Sitagliptin  Adverse Effects:  In general, sitagliptin is well tolerated, with the most common adverse effects being nasopharyngitis and headache. Rates of hypoglycemia are comparable to those with placebo when sitagliptin is used as monotherapy or in combination with metformin or pioglitazone.