Oral antidiabetics by Dr. Mushtaq Ahmed, Associate Professor, Pharmacology, PIMS Punjab

Oral antidiabetics by Dr. Mushtaq Ahmed, Associate Professor, Pharmacology, PIMS Punjab

• 1.
  DR. MUSHTAQ AHMED AssociateProfessor, Pharmacology Punjab Institute of Medical Sciences, Jalandhar, INDIA
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  Diabetes Mellitus Diabetes mellitus(DM) is a metabolic disorder resulting from a defect in insulin secretion or insulin action, or both  Classification of DM  Type 1 • Immune Mediated • Idiopathic  Type 2 (Maturity onset)  Other specific types  Gestational Diabetes mellitus
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  Prevalence of DM India is the “Diabetes Capital” of the World  In 2010 - >200 million people worldwide had DM and 300 million will subsequently have the disease by 2025  India had 32 million diabetic subjects in the year 2000 and this number would increase to 80 million by the year 2030  There is increased incidence of DM in urban population than rural
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  Classification  Type 1 Immune Mediated  Idiopathic  Type 2 (Maturity onset)  Other specific types  Gestational Diabetes mellitus
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  Development and Progressionof Type 2 Diabetes* Progression of Disease Impaired Glucose Tolerance Insulin level Insulin resistance Hepatic glucose production Diabetes Diagnosis Postprandial glucose Fasting glucose β-cell function Frank Diabetes 4–7 years 0 50 100 Relative%
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  Insulin resistance Genetic susceptibility, obesity, Westernlifestyle Type 2 diabetes IR b-cell dysfunctionb Pathophysiologic Defects in Type 2 Diabetes
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  b - cellDysfunction Chronic hyperglycaemia Oversecretion of insulin to compensate for insulin resistance High circulating free fatty acids Glucotoxicity Pancreas Lipotoxicity b- cell dysfunction
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  Insulin resistance –reduced response to circulating insulin Insulin resistance  Glucose output  Glucose uptake  Glucose uptake Hyperglycaemia Liver Muscle Adipose tissue IR Insulin Resistance
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  Causes of InsulinResistance  Defect (structural) in insulin molecule  Elevated levels of insulin antagonists (counter-regulatory hormones)  Target tissue defects (Major cause)
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  Sites of actionof Antidiabetics
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  What is therole of an ideal oral hypoglycaemic agent?  Conserve islet cell function - delay the subsequent use of insulin.  Improve patient compliance- single daily dosing.  Reduce the incidence of hypoglycaemic events
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  Management of Diabetes    
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  Role of Exercisein Type 2 DM • Exercise - probably the best treatment for type 2 diabetes • Lowers blood sugar • Decrease insulin resistance • Raise metabolism • Improve blood flow through capillaries • Improve stroke volume & blood lipids • Control & prevent moderate hypertension • Decrease body mass
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  Pancreas – thesite of action  Stimulate insulin secretion • Sulfonylurea • Meglitinide Pancrease
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  Classification of OralAntidiabetics  Oral Hypoglycaemic Agents 1. Sulphonylureas First Generation: Tolbutamide, Chlorpropamide Second Generation: Glibenclamide (glyburide), Glipizide, Gliclazide, Glimepiride 2. Meglitinide Analogues: Repaglinide, Nateglinide
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  Oral Hypoglycaemic Agents Sulphonylureas First Generation Tolbutamide • O.O.A. is within one hour & lasts for 6-12 Hrs • It is weaker, short acting, less likely to cause hypoglycemia Chlorpropamide • O.O.A. is within one hour & lasts for 24-60 Hrs • It is more potent, long lasting, risk of prolonged hypoglycemia • Potentiates ADH action
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  Sulphonylureas (contd)  SecondGeneration Glibenclamide (glyburide) • O.O.A. is within 1-4 hours & lasts for 10-24 Hrs • It is more potent than tolbutamide, risk of severe hypo. Glipizide • O.O.A. is within 1-3 hours & lasts for 10-24 Hrs • Less potent than glibenclamide but more potent than tolbutamide • Risk of prolonged hypoglycemia Gliclazide • O.O.A. & D.O.A, same as glipizide • More potent than tolbutamide • Has an antioxdent and antiplatelet action • Less weight gain Glimepiride: • Same as glipizide
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  Sulphonylureas  M.O.A • StimulatesInsulin release from β- cells • Inhibits SUR-1 receptors present on ATP sensitive K+ channels → depolarization followed by Ca+ entry → insulin release • Glucagon levels are suppressed  Pharmacokinetics • well absorbed • PPB is high • Metabolized in liver or kidney and excreted in urine  Adverse effects • Hypoglycemia • Weight gain • Cross placental barrier – fetal hypoglycemia (avoid in gestational DM)  Contra indications • Ketocanazole, chloramphenicol and anticoagulants- inhibit their metabolism • Sulfonamides, salicylates etc- protein binding displacement • Propranolol masks the symptoms of sulfonylureas
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  Meglitinide Analogues Repaglinide • ItsO.O.A is within one hour & lasts for 4-5 hrs • Dose 0.25-4mg before each meal Nateglinide • Its O.O.A & D.O.A, same as repaglinide • Dose 60-120mg before each meal • Hypoglycemic risk is low  M.A.O • Stimulate insulin release, same as sulfonylurea • Administered before meal to control PP blood glucose
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  Advantages of Nateglinide/Repaglinide Flexibility in mealtime dosing - „Ramzan Drug‟  No significant increase in bodyweight  Can be utillised in mild to moderate renal failure  Nateglinide: approved in hepatic failure Dosage: Repaglinide: 0.5mg/1mg/2mg/4mg per dose per meal Nateglinide: 60mg/120mg per dose per meal Lower incidence of hypoglycemia
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  Useful Situations – Elderlypatients in whom hypoglycaemia is a concern – Patients with kidney failure or mild hepatic impairment – patients taking low-dose sulphonylureas who encounter problems with hypoglycaemia – Patients with irregular meal patterns Int J Clin Pract. 2003 Jul-Aug;57(6):535-41.
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  Summary of insulinrelease and MOA of Antidiabetics ATP Dependent K+ Channel
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  Insulin actions atthe target cells
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  Sites of actionof Antihyperglycemic Agents Liver Muscle Adipose tissue • Bigunides - Metformin • Thiazolidonediones – Rosiglitazone etc. U P T A K E UTILIZATION Of GLUCOSE
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  Antihyperglycemic Agents  Biguanides Metformin  The primary drug of choice for diabetes by ADA guidelines. • Does not stimulate insulin release • Not dependent on functional β- cells for its action • Does not lower blood glucose in normal subjects • Causes anorexia, no weight gain • As monotherapy, rarely causes hypoglycemia Dose: 500mg twice a day after meals
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  Biguanides Contd Advantages:  Perpetuatesweight loss  Can be combined with insulin to reduce insulin requirements  Decreases risk of macro & microvascular disease Disadvantages:  Nausea, Vomiting and diarhorrea (5%), Vitamin B12 Deficiency (0.5%)
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  Adverse effect:  Nausea,metallic taste, anorexia, flatulence & diarrhoea  Non diabetic use of Metformin: Hirsutism with PCOD to enhance fertility in women  Phenformin • Its use has been discontinued because of lacticacidosis Biguanides Contd
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  Biguanides Contd  M.O.A •Increased uptake and utilization of glucose by muscles → reduce insulin resistance • Inhibition of hepatic and renal gluconeogenesis → reduce hepatic glucose output • Slowing of glucose absorption from GIT • Promotion of insulin binding to its receptor  PK • No PPB, Plasma t1/2 2-3 hours • Excreted unchanged by kidneys
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  Thiazolidinediones (Glitazones)  Newclass of drugs – acts as agonist to nuclear receptor PPAR-Ƴ in adipose tissue, sk. Muscle and liver. Pioglitazone • D.O.A. more than 24hrs • 10-45 mg OD Rosiglitazone (withdrawn from the market in Oct. 2010 b/o risk of Heart failure and MI) • D.O.A. same as pioglitazone • Dose 4-8mg OD
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  Glitazones Contd  MOA •Stimulates (nuclear receptor) i.e. Peroxisome Proliferator Activated Receptor-gamma (PPAR-Ƴ) → promotes transcription of insulin responsive genes which control glucose & lipid metabolism → ↑ insulin sensitivity & ↓ insulin resistance • Promotes uptake and utilization of glucose by increasing the GLUT-4 transpotors • Decrease glucose output by inhibiting gluconeogenesis  AE • Weight gain. hepatotoxicity is rare, yet LFT are advisable  CI • Hepatic failure, pregnancy, lactating mother, children and heart failure
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  GIT As aSite of Target Alpha glucosidase enzyme facilitates digestion of complex starches, oligosaccharides and disaccharides into monosaccharides so that these are absorbed from the small intestine. The digestion is also facilitated by pancreatic alpha amylase.
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  α-Glycosidase Inhibitors Acarbose, Miglitol,Voglibose  Work on the brush border of the intestine cause carbohydrate malabsorption • Reduce post meal hyperglycemia • Regular use tend to lower HbA1c, triglycerides and body weight • Do not directly affect insulin secretion • No hypoglycemia • Dose: 50-100mg TDS
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  α-Glycosidase Inhibitors contd. M.O.A • Reduce PP digestion and absorption of carbohydrates by inhibiting α – glucosidase enzyme  PK • Absorption of acarbose is minimal, but miglitol is absorbed well • A Part of acarbose is excreted unchanged while a part is metabolized by intestinal bacterial flora
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  α-Glycosidase Inhibitors Contd. Advantages: • Selective for postprandial hyperglycaemia • No hypoglycaemic symptoms  Disadvantages: • Abdominal distension and flatus • Only effective in mild hyperglycaemia  Dose:  Acarbose - 25 mg to 50mg TID  Miglitol - 25mg to 100mg TID  Voglibose - 0.2 to 0.3 mg TID
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  What are Incretins? I s a group of hormones (GLP & GIP) – released after meals and augment glucose-dependent insulin secretion  GLP-1 (glucagon-like peptide 1) (*More Imp) • is a prominent insulinotrophic incretin. • half life- 1-2 min. • metabolized quickly by DPPIV enzyme.  GIP: Glucose-dependent insulinotrophic polypeptide Small effect in Type 2 diabetes.
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  Incretin concept  Insulinsecretion dynamics is dependent on the method of administration of glucose  Intravenous glucose gives a marked first and second phase response  Oral glucose gives less marked first and second phase insulin response, but a prolonged and higher insulin concentration
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  Insulinconcentration 0 10 2030 40 50 60 70 80 90 Minutes Glucose given orally Glucose given intravenously Insulin secretion profiles
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  Insulinconcentration 0 10 2030 40 50 60 70 80 90 Minutes Glucose given orally Glucose given intravenously to achieve the same profile Incretin effect Iso - glycemic profiles
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  20001960 ‘Enteroinsular axis’ named Incretin defined Discovered as proglucagon geneproduct Receptor cloned 1930 19801970 1990 Normalisation of BG in type 2 diabetes Insulinotropic action of incretins confirmed Incretin and enteroinsular axis further defined History of GLP-1
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  GLP-1 localisation  Cleavedfrom proglucagon in intestinal L-cells (and neurons in hindbrain/hypothalamus)  Secreted in response to meal ingestion  Cleared via the kidneys
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  Incretin-Mimetics  Incretin–mimetics • GlucagonLike Peptide – 1 (GLP-1) → released after meals from the upper & lower bowel → augment glucose dependent insulin secretion, during the phase of nutrition absorption from GIT • t ½ GLP-1 – 1 to 2 min • Metabolized quickly by DPP-IV enzyme Exenatide [incretin (GLP-1) agonist] • Obtained from salivary gland venom of Gila monster • Resistant to DPP-IV degradation • Potent agonist of GLP-1 receptor, Orally inactive • Given SC (5-10μg) twice daily, 30-60 min before meals • It reduces only post meal glucose rise  MOA • Stimulates insulin secretion from β- cells • Decreases glucagon release  AE • Diarrhea, nausea, anorexia
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  GLP-1 is secreted fromthe L-cells in the intestine This in turn… • Stimulates glucose-dependent insulin secretion • Suppresses glucagon secretion • Slows gastric emptying Long term effects demonstrated in animals… • Increases beta-cell mass and maintains beta-cell efficiency • Reduces food intake Upon ingestion of food… GLP-1 Modes of Action in Humans
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  His Ala GluGly Thr Phe Thr Ser Asp Lys Ala Ala Gln Gly Glu Leu Tyr Ser Ile Ala Trp Leu Val Lys Gly Arg Gly Val Ser Glu Phe GLP-1 7 37 NH2 Native GLP-1 has short duration of action (t½=2.6 minutes) when given intravenously DPP IV
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  Human ileum, GLP-1 producing L-cells Capillaries, DiPeptidyl Peptidase-IV (DPP-IV) Adaptedfrom: Hansen et al. Endocrinology 1999:140(11):5356-5363 Native GLP-1 is rapidly degraded by DPP-IV
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  His Ala GluGly Thr Phe Thr Ser Asp Lys Ala Ala Gln Gly Glu Leu Tyr Ser Ile Ala Trp Leu Val Lys Gly Arg Gly Val Ser Glu Phe DPP-IV (DPP4) inhibitors7 37 NH2 DPP IV
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  DPP-IV Inhibitors  DPP-IVInhibitors  Sitagliptin, Vildagliptin, Saxagliptin, Septagliptin, Allogliptin • Orally active • Selective inhibitors of DPP-IV enzyme that deactivates GLP-1  MOA • Increase insulin secretion • Decrease glucagon release • Delay gastric emptying • Suppress appetite  AE • Nasopharyngitis because substance P is also a substrate for DPP-IV, whose levels get elevated, GIT distress and diarrhea
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  Incretin hormones GLP-1and GIP are released by the intestine throughout the day, and their levels increase in response to a meal. Concentrations of the active intact hormones are increased by sitagliptin, thereby increasing and prolonging the actions of these hormones. Release of active incretins GLP-1 and GIP  Blood glucose in fasting and postprandial states Ingestion of food  Glucagon (GLP-1)  Hepatic glucose production GI tract DPP-4 enzyme Inactive GLP-1 XSitagliptin (DPP-4 inhibitor)  Insulin (GLP-1 and GIP) Glucose- dependent Glucose dependent Pancreas Inactive GIP β cells α cells  Glucose uptake by peripheral tissues 30 Mechanism of Action of Sitagliptin
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  MOA of DPPIV Inhibitors
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  Amylin - mimetics Amylin • A hormone co-secreted with insulin from β- cells • Inhibit glucagon secretion • Delay gastric emptying • Suppress appetite Pramlintide • Stimulates amylin receptor (a G-protein coupled receptor) • SC before meals • No hypoglycemia  AE • Nausea, diarrhea, headache
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  Kidney as asite of target SGLT - 2
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  SGLT-2 Inhibitors  SGLT-2Inhibitors • Newer antidiabetic drugs • Kidney continuously filters glucose through glomerulous which is reabsorbed back from PT by Na2+ glucose co-transporter -2 (SGLT-2) • Inhibition of SGLT – 2 decreases glucose re-absorption Dapaglifozin, Serglifozin, Remoglifozin  Advantages • Weight loss • No hypoglycemia  Disadvantages • Because of polyuria there will be more polydipsia • Increased risk of urinary infection in presence of glycosuria • Risk of Na2+loss