The lecture is more useful to UG and PG Pharma and Medical Students

1. Pharmacology of
Antidiabetic drugs
Lecture by
Dr. T.S. Mohamed Saleem M.Pharm., Ph.D
Assistant Professor & Head, Department of Pharmacology
Annamacharya College of Pharmacy, Rajampet
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2. Introduction
 The endocrine pancreas - 1 million islets of Langerhans
 Four hormone-producing cells are present
 Insulin - the storage and anabolic hormone of the body;
 Islet amyloid polypeptide (IAPP, or amylin) - modulates
appetite, gastric emptying, and glucagon and insulin secretion;
 Glucagon - hyperglycemic factor that mobilizes glycogen
stores;
 Somatostatin - a universal inhibitor of secretory cells;
 gastrin, which stimulates gastric acid secretion; and pancreatic
peptide
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3. Diabetes mellitus
• An elevated blood glucose associated with
• absent or inadequate pancreatic insulin secretion,
• With or without concurrent impairment of insulin
action
• Classified into four categories:
• type 1, insulin-dependent diabetes;
• type 2, non–insulin-dependent diabetes;
• type 3, other; MODY
• type 4, gestational diabetes mellitus
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4. Type 1 Diabetes Mellitus
• The hallmark of type 1 diabetes is selective beta cell (B
cell) destruction and severe or absolute insulin
deficiency.
• Type 1 diabetes is further subdivided into immune and
idiopathic causes.
• The immune form is the most common form of type 1
diabetes.
• Susceptibility appears to involve a multifactorial genetic
linkage, but only 10–15% of patients have a positive
family history.
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5. Type 1
• For persons with type 1 diabetes, insulin replacement
therapy is necessary to sustain life.
• Interruption of the insulin replacement therapy can be
life-threatening and can result in diabetic ketoacidosis
or death.
• Diabetic ketoacidosis is caused by insufficient or absent
insulin and results from excess release of fatty acids and
subsequent formation of toxic levels of ketoacids.
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6. Type 2 Diabetes Mellitus
• Tissue resistance to the action of insulin combined with a
relative deficiency in insulin secretion.
• Insulin is produced by the beta cells in these patients, it
is inadequate to overcome the resistance, and the blood
glucose rises.
• The impaired insulin action also affects fat metabolism,
resulting in increased free fatty acid flux and triglyceride
levels and reciprocally low levels of high-density
lipoprotein (HDL).
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7. Type II
• Individuals with type 2 diabetes may not require insulin to
survive, but 30% or more will benefit from insulin therapy to
control blood glucose.
• It is likely that 10–20% of individuals in whom type 2 diabetes
was initially diagnosed actually have both type 1 and type 2 or
a slowly progressing type 1 called latent autoimmune diabetes
of adults (LADA), and they ultimately require full insulin
replacement.
• Dehydration in individuals with untreated or poorly controlled
type 2 diabetes can lead to a life-threatening condition called
nonketotic hyperosmolar coma .
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8. Type 3 Diabetes mellitus
• The type 3 designation refers to multiple other specific
causes of an elevated blood glucose:
• Pancreatectomy,
• Pancreatitis,
• Nonpancreatic diseases,
• Drug therapy, etc.
• MODY
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9. Type 4 Diabetes Mellitus
• Gestational diabetes (GDM) is defined as any abnormality in
glucose levels noted for the first time during pregnancy.
• Gestational diabetes is diagnosed in approximately 7% of all
pregnancies in the USA.
• During pregnancy, the placenta and placental hormones create
an insulin resistance that is most pronounced in the last
trimester.
• Risk assessment for diabetes is suggested starting at the first
prenatal visit.
• High-risk women should be screened immediately.
• Screening may be deferred in lower-risk women until the 24th
to 28th week of gestation.
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10. INSULIN
• Insulin is a small protein with a molecular weight in
humans of 5808.
• It contains 51 amino acids arranged in two chains (A and
B) linked by disulfide bridges
• Proinsulin, a long single-chain protein molecule, is
processed within the Golgi apparatus of beta cells and
packaged into granules, where it is hydrolyzed into
insulin and a residual connecting segment called C-
peptide by removal of four amino acids
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11. Insulin is shown as the shaded (orange color) peptide chains, A and B. Differences in the A and B chains and
amino acid modifications for the rapid-acting insulin analogs (aspart, lispro, and glulisine) and long-acting insulin
analogs (glargine and detemir) are discussed in the text.
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Structureofhumanproinsulin(C-peptideplusAandBchains)andinsulin

12. • Insulin and C-peptide are secreted in equimolar amounts
in response to all insulin secretagogues
• Granules within the beta cells store the insulin in the form
of crystals consisting of two atoms of zinc and six
molecules of insulin.
• The entire human pancreas contains up to 8 mg of
insulin, representing approximately 200 biologic units.
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13. Insulin Secretion
• Insulin is released at a low basal rate and at a much
higher stimulated rate in response to a variety of stimuli,
especially glucose.
• Other stimulants such as other sugars (eg, mannose),
amino acids (especially gluconeogenic amino acids, eg,
leucine, arginine), hormones such as glucagon-like
polypeptide-1 (GLP-1), glucose-dependent insulinotropic
polypeptide (GIP), glucagon, cholecystokinin, high
concentrations of fatty acids, and β-adrenergic
sympathetic activity are recognized.
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14. • Stimulatory drugs are sulfonylureas, meglitinide and
nateglinide, isoproterenol, and acetylcholine.
• Inhibitory signals are hormones including insulin itself
and leptin, α-adrenergic sympathetic activity, chronically
elevated glucose, and low concentrations of fatty acids.
Inhibitory drugs include diazoxide, phenytoin, vinblastine,
and colchicine.
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15. figure
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17. Insulin Degradation
• The liver and kidney are the two main organs that remove
insulin from the circulation.
• Liver normally clears - 60% of the insulin
• Kidney removing 35–40%
• Subcutaneous insulin injections, this ratio is reversed
• Liver normally clears - 60% of the insulin
• Kidney removing 35–40%
• The half-life of circulating insulin is 3–5 minutes.
• Basal insulin values of 5–15 μU/mL (30–90 pmol/L) are found
in normal humans, with a peak rise to 60–90 μU/mL (360–540
pmol/L) during meals.
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18. The Insulin Receptor
• Identified in the primary target tissues, ie,
liver, muscle, and adipose tissue
• High specificity and affinity in the
picomolar range
• Increase in glucose uptake;
• increased glycogen synthase activity
• increased glycogen formation;
• multiple effects on protein synthesis,
lipolysis, and lipogenesis;
• activation of transcription factors that
enhance DNA synthesis and cell growth
and division
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Translocation of glucose transporter (GLUT 4)

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20. Insulin Preparations
• Rapidacting, with very fast onset and short duration;
• Short-acting, with rapid onset of action;
• Clear solutions at neutral pH and contain small amounts of zinc
to improve their stability and shelf life.
• Intermediate-acting;
• turbid suspension at neutral pH with protamine in phosphate
buffer (neutral protamine Hagedorn [NPH] insulin)
• Long-acting, with slow onset of action
• Insulin glargine and insulin detemir are clear, soluble long-
acting insulins
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22. Rapid-acting and short-acting
insulin preparations
• Modification of the amino acid sequence of regular insulin
produces analogs that are rapid-acting insulins.
• Insulin lispro - lysine and proline at positions 28 and 29 in the
B chain are reversed.
• Peak levels - 30 to 90 minutes, as compared with 50 to 120
minutes for regular insulin.
• Mimic the prandial (mealtime) release of insulin and to control
postprandial glucose.
• Administered in the 15 minutes proceeding a meal or within 15
to 20 minutes after starting a meal
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23. Intermediate-acting insulin
• Neutral protamine Hagedorn (NPH) insulin - addition of
zinc and protamine to regular insulin.
• insulin isophane
• less soluble, resulting in delayed absorption and a longer
duration of action
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24. Long-acting insulin
• Lower isoelectric point leading to formation of a
precipitate at the injection site
• slower onset and a flat, prolonged hypoglycemic effect
with no peak
• Insulin detemir has a fatty acid side chain that enhances
association to albumin
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25. Pharmacokinetics and fate
• Human insulin is produced by recombinant DNA technology
• Modification of the amino acid sequence of human insulin
produces insulins with different pharmacokinetic properties.
• Insulin preparations vary primarily in their onset and duration of
activity.
• Dose, injection site, blood supply, temperature, and physical
activity can also affect the onset and duration of various insulin
preparations.
• Because insulin is a polypeptide generally administered by
subcutaneous injection.
• Continuous subcutaneous insulin infusion (also called the insulin
pump) is another method of insulin delivery.
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26. Adverse reactions to insulin
• Hypoglycemia
• Weight gain,
• Local injection site reactions
• Lipodystrophy
• Diabetics with renal insufficiency may require a decrease
in insulin dose.
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28. Drug classification
• Insulin secretagogues
• sulfonylureas, meglitinides, D-phenylalanine derivatives
• biguanides,
• thiazolidinediones,
• α-glucosidase inhibitors,
• incretin-based therapies,
• an amylin analog,
• a bile acidbinding sequestrant
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29. SULFONYLUREAS
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30. Mechanism of action
• Increase insulin release from the pancreas
• A reduction of serum glucagon levels
• Closure of potassium channels in extrapancreatic tissue
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31. Insulin Release from Pancreatic Beta
Cells Sulfonylureas
bind to a 140-kDa high-affinity sulfonylurea receptor
inhibits the efflux of potassium ions
depolarization.
opens a voltage-gated calcium channel
calcium influx
the release of preformed insulin.
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32. Pharmacokinetics and fate
• Given orally
• Bind to serum proteins,
• Metabolized by the liver
• Excreted in the urine and feces
• The duration of action ranges from 12 to 24 hours
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33. • Tolbutamide
• Well absorbed but rapidly metabolized in the liver.
• Its duration of effect is relatively short, with an elimination
half-life of 4–5 hours
• Dicumarol, phenylbutazone, some sulfonamides that inhibit
the metabolism of tolbutamide.
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34. • Chlorpropamide
• half-life of 32 hours
• Slowly metabolized in the liver
• 20–30% is excreted unchanged in the urine.
• contraindicated in patients with hepatic or renal insufficiency.
• Dosages higher than 500 mg daily increase the risk of jaundice.
• The average maintenance dosage is 250 mg daily,
• ADR
• Prolonged hypoglycemic reactions
• hyperemic flush after alcohol ingestion
• Dilutional hyponatremia.
• Hematologic toxicity (transient leukopenia, thrombocytopenia) occurs
in less than 1% of patients.
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35. • Tolazamide
• shorter duration of action.
• more slowly absorbed.
• Its half-life is about 7 hours.
• Metabolized to several compounds that retain hypoglycemic
effects.
• If more than 500 mg/d are required the dose should be
divided and given twice daily.
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36. • Glyburide
• Metabolized in the liver into products
• Very low hypoglycemic activity.
• starting dosage is 2.5 mg/d or less,
• maintenance dosage is 5–10 mg/d
• ADR
• hypoglycemia
• Flushing
• slightly enhances free water clearance
• contraindicated in the presence of hepatic impairment and in patients
with renal insufficiency.
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37. • Glipizide
• Shortest half-life (2–4 hours)
• ingested 30 minutes before breakfast
• starting dosage is 5 mg/d, with up to 15 mg/d
• 90% of glipizide is metabolized
• 10% is excreted unchanged in the urine
• Contraindicated in patients with significant hepatic or renal
impairment, who would be at high risk for hypoglycemia.
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38. • Glimepiride
• approved for once-daily use as monotherapy or in
combination with insulin.
• 1 mg has been shown to be effective, and the
recommended maximal daily dose is 8 mg.
• Long duration of effect with a half-life of 5 hours,
• Completely metabolized by the liver to metabolites with
weak or no activity.
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39. Other insulin secretagogues
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40. Repaglinide
• The first member of the meglitinide group
• Mechanism of action is similar to sulfonylureas
• Two binding sites in common with the sulfonylureas and
one unique binding site.
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41. Pharmacokinetics
• Very fast onset of action
• Peak effect within 1 h
• Duration of action is 4–7 hours
• Metabolism by CYP3A4
• Indicated for use in controlling postprandial glucose
excursions.
• Doses of 0.25–4 mg (maximum 16 mg/d);
• Hypoglycemia is a risk
• C/I in renal and hepatic impairment.
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42. Nateglinide
• a D-phenylalanine derivative
• Stimulates very rapid and transient release of insulin
from beta cells through closure of the ATP-sensitive K +
channel.
• Partially restores initial insulin release in response to an
intravenous glucose tolerance test
• Special role in the treatment of individuals with isolated
postprandial hyperglycemia, but it has minimal effect on
overnight or fasting glucose levels.
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43. Pharmacokinetics
• Ingested just before meals.
• It is absorbed within 20 minutes with a time to peak
concentration of less than 1 hour
• Metabolized in the liver by CYP2C9 and CYP3A4 with a
half-life of about 1 hour.
• The overall duration of action is about 4 hours.
• nateglinide has the advantage of being safe in those with
very reduced renal function.
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44. BIGUANIDES
• Metformin
• Insulin sensitizer.
• It increases glucose uptake and use by target tissues,
• decreasing insulin resistance.
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45. Mechanism of action
Metformin
Activate AMP activated
protein kinase (AMPA-PK)
Reduce hepatic glucose
production
Lower blood glucose level
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46. Actions
• impairment of renal gluconeogenesis,
• slowing of glucose absorption from the gastrointestinal
tract,
• increased glucose to lactate conversion by enterocytes,
• direct stimulation of glycolysis in tissues,
• increased glucose removal from blood,
• Reduction of plasma glucagon levels.
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47. ADME
• Orally well absorbed
• Half-life of 1.5–3 hours
• Excreted by the kidneys
• Impair the hepatic metabolism of lactic acid.
• Increase the risk of lactic acidosis
• The dosage of metformin is from 500 mg to a maximum
of 2.55 g daily, with the lowest effective dose being
recommended.
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48. ADR
• Gastrointestinal (20%)
• anorexia, nausea, vomiting, abdominal discomfort, and
diarrhea
• which occur in up to 20% of patients.
• Vitamin B12 deficiency
• Renal failure – lactic acidosis
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49. THIAZOLIDINEDIONES
• Pioglitazone and rosiglitazone
• Decrease insulin resistance.
• Ligands of peroxisome proliferator-activated receptor
gamma (PPAR-f),
• Found in muscle, fat, and liver.
• Modulate the expression of the genes involved in
• lipid and glucose metabolism,
• insulin signal transduction,
• adipocyte and other tissue differentiation.
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50. Mechanism of actions
Thiazolidinediones
Activates peroxisome proliferator–
activated receptor-γ (PPARγ)
Regulates the transcription of
several insulin responsive genes
increased insulin sensitivity
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51. ADME
• Pioglitazone
• Well absorbed orally
• Absorption is decreased with concomitant use of bile acid
sequestrants.
• Metabolized by CYP2C8 and CYP3A4
• starting dose is 15–30 mg/d, and the maximum is 45 mg/d.
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52. ADME
• Rosiglitazone
• rapidly absorbed and highly protein-bound.
• It is metabolized predominantly by CYP2C8 and to a
lesser extent by CYP2C9.
• It is administered once or twice daily;
• 2–8 mg is the usual total dose.
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53. ADR
• Liver toxicity
• Weight gain
• osteopenia and increased fracture risk
• increase the risk of bladder cancer
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54. α-Glucosidase inhibitors
• Acarbose
• miglitol
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55. Mechanism of action
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56. ADME
• Acarbose is poorly absorbed.
• It is metabolized primarily by intestinal bacteria,
• Excreted into the urine.
• Miglitol is very well absorbed
• No systemic effects.
• It is excreted unchanged by the kidney.
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57. ADR
• Flatulence,
• diarrhea,
• Abdominal cramping
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58. Amylin analogue
• Pramlintide
• Synthetic amylin anlaogue
• Injectable hypoglycemic agents
• Approved for preprandial use in type I and II diabetes
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59. Actions
• Suppress the release of glucagon
• Delay gastric emptying
• central nervous system mediated anorectic effects
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60. Pharmacokinetics
• Rapid absorption after S.C injection
• Most preferable site is abdomen and thigh
• Arm administration is less reliable
• Reach peak plasma concentration with in 20 min
• Duration of action up to 120 min
• Metabolized and excreted via kidney route
• Even in less creatinine clearance no change in
bioavailability efficacy
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61. Dose and administration
• Inject just before meal
• Type I - 15-60 mcg S.C
• Typer II – 60-120 mcg S.C
• Meal time insulin administration should be reduced 50%
because of hypoglycemic risk
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62. ADR
• Hypoglycemia
• Gastrointestinal symptoms
• Nausea,
• Vomiting
• Anorexia
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63. GLUCAGON-LIKE POLYPEPTIDE-1
(GLP-1) RECEPTOR AGONISTS
• Exenatide
• Liraglutide
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64. Action
• Restore GLP-1 activity
• Potentiate glucose mediate insulin secretion
• Suppress postprandial glucagon release
• Slow gastric emptying
• Central mediated loss of appitite
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65. Exenatide
• A derivative of the exendin-4 peptide in Gila monster
venom
• First incretin therapy available in market
• 53% homology with native GLP-1,
• Glycine substitution to reduce degradation by dipeptidyl
peptidase-4 (DPP-4)
• Recommended for suboptimal glycemic control
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66. Exenatide cont…..
• Availabe injection formulation
• Equal absorption from arm, abdomen and thigh
• Reach peak conc with in 2 h
• Duration of action is 10 h
• Dose adjustment is required in case of CrCl less than 30
mL/min
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67. ADR
• Nausea
• Vomiting
• Diarrohoea
• Necrotizing and hemorrhogic pancreatitis
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68. Liraglutide
• Long-acting synthetic GLP-1 analog with 97% homology
to native GLP-1
• Peak levels are obtained in 8–12 hours
• Elimination half-life is about 13 hours
• Prolonged half-life that permits once-daily dosing.
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69. Action
• Liraglutide interacts with the GLP-1 receptor
• Increase insulin release
• Decrease glucagon
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70. ADR
• Headache
• Nausea
• Diarrhea
• Antibody formation
• Urticaria
• Pancreatitis
• Risk of endocrine cancer (FDA black box warning)
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71. DIPEPTIDYL PEPTIDASE-4 (DPP-4)
INHIBITORS
• Sitagliptin
• Saxagliptin
• Linagliptin
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72. Mechanism of action
Incretin hormones
Dipeptidyl peptidase – 1
degradation
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Sitagliptin
Sexagliptin
Linagliptin
• Increase circulating levels of native GLP-1
• Glucose-dependent insulinotropic polypeptide (GIP),
• Increasing glucose-mediated insulin secretion
• Decreasing glucagon levels.
Inhibition of enzyme

73. Sitagliptin
• Orally well absorbed
• Bioavailability 85%
• Reach PPC with in 1-4 h
• Half life is 12 h
• Oral dose is 100 mg
• Metabolized via CYP3A4
• Excreted via urine by tubular secretion
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74. ADR
• Nasopharyngitis
• Upper respiratory infections
• Headaches
• Hypoglycemia
• Post marketing report
• Acute pancreatitis
• Hypersensitivity reactions
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75. Sexagliptin
• Orally well absorbed
• Dose is 2.5 to 5 mg daily
• Less protein binding
• Reach peak plasma conc within 2 h
• Undergo metabilosm by CYP3A4/5 to form active
molecule
• Peak plasma conc of metabolite is 4 h
• Both are excreted via urine
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76. ADR
• Increased rate of infections
• Upper respiratory tract and urinary tract
• Headaches, peripheral edema
• hypoglycemia
• Hypersensitivity reactions
• urticaria, facial edema
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77. ANY QUESTIONS
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