Anti diabetic drugs

Anti diabetic drugs

• 1.
  Diabetes Mellitus
• 2.
  Definition:- Heterogeneous group ofcommon metabolic disorder characterized by an elevation of blood glucose caused by a relative or absolute deficiency of Insulin  Diabetes= more urine+ mellitus= sugar 3rd leading cause of death & 2nd leading cause of blindness and renal failure Classical symptoms:- Polyuria, polydipsia,Polyphagia Cause:- 1. Insulin deficiency (↓circulating level of insulin) 2. Insulin resistance(↓ response of target tissue to insulin)
• 3.
  Types:- Type-1 diabetes(IDDM/juvenile onset Type-2 diabetes (NIDDM/maturity onset Type-3 diabetes (other types) Type-4 diabetes (Gestational ) Cause due to absolute lack of insulin so, regular Injection of Insulin are needed Juvenile-onset DM- commonly develops below 20 years of age & persist through out the life Approximately 10% of diabetics suffer from type-1
• 4.
  Cause:- Auto immunedisease of pancreatic β-cells Resulting Degeneration of β-cells •Genetic factor •Environmental factor •Immunological factor Subtype:- Type-1A (Autoimmune disease due to destruction of β-cells) Type-1B (Idiopathic, viral disease(Echovirus),Thyroid Disease) Diabetic ketoacidosis:- Initial symptom complex that leads to a diagnosis of type-1 DM Symptoms :- Nausea/vomiting Thirst/Polyuria Abdominal pain Tachycardia Dehydration/Hypotension
• 5.
  Occurs in peoplewho are over 40 year & over weight Due to ↓ sensitivity of receptors , there is ↓ response to insulin Commonly form of Diabetes Genetic defects Obesity lifestyle Adipokines, leptin deficiency Compensatory β-cell hyperplasia – Normoglycemia β-cell failure (Early)– Impaired Glucose tolerance β-cell failure (Late)– Diabetes
• 6.
  Lack of Insulin ↓Anabolism ↑Catabolism↑secretion of Glucagon, Cortisol, Catecholamine GH Hyperglycaemia Glycosuria Osmotic diuresis Fatigue Polyuria Polydipsia Salt & water depletion Tachycardia Hypotension Glycogenolysis Glyconeogenesis Lipolysis Loss of Weight Acidosis DEATH
• 7.
  Insulin  Insulin wasdiscovered by Banting & Best. Insulin analogs – genetic engineering by changing AA sequence or by adding a molecule Structure:- Polypeptide consisting of an A and B chain of 21 and 30 amino acid Molecular weight 5800 KD Two chains are linked by a pair of S-S bonds An intrachain S-S bond connects 6th and 11th amino acid within A chain Forms a dimer with 2 Zn ions
• 8.
   A triangulargland, which has both exocrine and endocrine functions  Acinar cells produce an enzyme-rich juice used for digestion (exocrine product)  Pancreatic islets (islets of Langerhans) produce hormones involved in regulating blood glucose level. Pancreas
• 9.
  Islets of Langerhans 1million islets 1-2% of the pancreatic mass Beta (β) cells produce insulin Alpha (α) cells produce glucagon Delta (δ) cells produce somatostatin F cells produce pancreatic polypeptide
• 10.
  Structure Pro-insulin 21AA 30AA Insulin
• 11.
  Synthesis of insulin Insulin gene encodes a large precursor of insulin (preproinsulin)  During translation, the signal peptide is cleaved (proinsulin)  During packaging in granules by Golgi, proinsulin is cleaved into insulin and C peptide
• 12.
  PK Degraded within theliver and kidneys  80% metabolized in the liver  Half-life of about 5 minutes  Degraded by hepatic glutathione insulin dehydrogenase  Enzyme disrupts S-S bonds
• 13.
  Regulation of Insulin secretion Itis mainly regulated by feed back control Three types of regulation  Chemical regulation  Hormonal regulation  Neural regulation
• 14.
  Chemical regulation
• 15.
  Stimulator of insulinsecretion  Gastro Inhibitory Peptide (GIP)  Vasoactive Intestinal Peptide (VIP)  Cholecystokinin (CCK)  Secretin, Gastrin, Glucagon  Epinephrine (β-receptor) Inhibitor of insulin secretion  Somatostatin  Epinephrine (α-receptor) Hormonal regulation
• 16.
  Hormonal regulation
• 17.
  Neural regulation Islet issupplied by both parasympathetic and sympathetic nerves. It contain both α and β adrenergic receptor. Primary central site of regulation insulin secretion is hypothalamus. Ventrolateral nuclei, ventromedial nuclei.
• 18.
  Mechanism of action AkT Shc Grb2SOS Ras Raf
• 19.
  Liver Muscle Adipose ↓glucose production ↑ Glucose transport ↑ glucose transport ↑ glycolysis ↑ glycolysis ↑ lipogenesis& lipoprotein lipase activity ↑ TG synthesis ↑ glycogen deposition ↓ intracellular lipolysis ↑ Protein synthesis ↑ protein synthesis
• 20.
  Insulin preparation Rapid acting insulinanalogue Regular insulin Insulin lispro Insulin Aspart Insulin Glulisine Intermediate Acting insulin analogue •NPH •Lente Longer acting insulin Analogue Insulin glargine Insulin detemir Newer Insulins Albulin Inhaled Insulin Enteral Insulin Orally absorbed insulin Transdermal Insulin Nanoinsulin
• 21.
  Rapid -Acting Analogues Rapidonset and shorter duration of action. Administered immediately before meals because peak of onset corresponds more closely with the post prandial glucose peak This avoids post prandial hypoglycaemia that occurs due to long duration of action of soluble insulin . The shorter duration of action of these analogues leads to lower incidence of hypoglycaemia.
• 22.
  Come as ahexamer in solution Upon Sc application –delay in action due to dissociation & resorption  Peak plasma conc. Are reached 45-120 min after the application  Route:- Sc,im,iv  Preparation :- Insulin lispro & insulin aspart Regular Human Insulin
• 24.
   First recommendedDNA analogue,approved by FDA in 1996  Modification – inversion of proline at position B28 with lysine at B29 Advantage – 1.Block the formation of insulin dimer and hexamer thus allows large numbers of monomeric insulin to be available for postprandial injection 2.More flexibility and convenience 3.Better reduction in PPG and HbA1c 4.Less chances of hypoglycemia 5.Better PK and PD properties irrespective of site of injection 6. Less immunogenic 24 Insulin Lispro
• 25.
  Insulin aspart Recombinant DNAtechnology by substitution of proline at 28 posistion with aspartic acid This analogue also prevent the formation of hexamer leading to rapid absorption from subcutaneous tissue than soluble insulin More effective in GDM
• 26.
  Insulin Glulisine Substitution Two B3-aspargine lysine B29- lysine glutamine It has rapid onset and short duration of action than regular human insulin Antiapoptotic activity:- it counteracts autoimmune and lipotoxicity induced beta-cell destruction . It has advantage over regular human insulin by causing less chance of hypoglycemia by administering just before meals Tumerogenic potential:- as various studies have shown that by substitution at position B28-30 causes increased binding to IGF-1 receptor and increases mitogenic activity
• 27.
   Intermediate actinginsulin Insulin complex with protamine and Zn.dissociate slowly on S.C. administration Onset of action is delayed and duration of action is 10-20 hrs Cloudy solution Given once or twice daily Both of them associate with some problems To overcome problems two long acting insulin analogue insulin glargine and insulin detemir developed on two approach
• 28.
  1.Insulin Glargine:- First longacting basal human insulin.created by modyfying 3 aminoacid with the aim with increase DOC and no pronounced peak activity Substitution of asparagine residue with a glycine at position 21 of the A chain – stabilize the hexamer Elongating B chain at the C terminus by addition of 2 arginine residues Insulin glargine is a clear solution with a Ph of 4.0 which stabilizes the insulin hexamer.when injected into the neural pH of the subcutaneous space,aggregation occur,resulting in prolonged absorption from the injection site Due to its acidic Ph insulin glargine cannt be mixed with short acting insulin preparation that are formulated ar neutral pH At a more neutral pH of the tissue,micro precipitstion take place,which delays resorption.Resorption is also additionally delayed with a small amont of Zn. Added Glargine has the same affinity for insulin receptor as human insulin,after SC. Application glargine reaches its maximum activity after 4-5 hrs ,which then remain even without pronounced peaks Pt receiving glargine had significantly less nocturnal hypoglycemia less symptomatic hypoglycemia and less severe hypoglycemia(with blood sugar less than 2mmol/l)
• 29.
  Important benefits ofglargine includes :- •Because of longer duration of action that is 24 hrs, it can be administered once a day. •Treatment with glargine is more flexible since it can be given at any time of day but should be administered at the same time each day •Unlike traditional insulin preparations that are absorbed more rapidly fropm abdomen than the arm or leg, the site of administration does not influence the time action profile of glargine. •No higher risk of early worsening of diabetic retinopathy compared with NPH •Treat to target study compared glargine with NPH where Less hypoglycaemic episodes compared to NPH •It has been demonstrated that s.c absorption of glargine is not affected by exercise Disadvantages:- Expensive To maintain solubility, the formulation is unusually acidic so Cannot be mixed with regular insulin and hence multiple injections are required Cannot be used in children less than 6 years of age Not yet approved in pregnancy category C by FDA Glagine binds with a slightly greater affinity to IGF-1 receptors as compared to human insulin which may increase chances of malignancy Mitogenic effect
• 30.
   Soluble basalinsulin analogue at neutral pH  Threonin at B-30 is removed & acetylate with a 14-C fatty acid chain to lysine at B-29 which causes it to bind reversibly to albumin in plasma  About 98% of detemir in plasma are bound to albumin & only the free fraction can activate insulin receptor  Detemir is soluble at neutral pH & S.C. depot remains in soluble state,which makes the resorption surface larger & diminishes resorption variability  Onset of Action-1-2 hrs  DOC 24 hrs  Body weight decrease
• 31.
  1.Albulin:- Newest insulin analogues. Itis single chain analogue produced in yeast or mammalian cell Potent longer acting 2.Inhaled Insulin:- Exubera 1st inhalational drug faster onset of action even faster than IV route BA –just 10% DOA:- 5-10 hrs So high dose of insulin have to be given about 8 times Major problems:- Loss of drug with inhaler and mouth during inhalator Variation in absorption due to age related differences,respiratory tract inflammation & smoking Mild to moderate cough Shortness of breath Sore throat Dry mouth Other Newer Insulins
• 32.
  Enteral insulin:- usescarrier to enable insulin resorption through membrane Orally absorbed insulin:- (Oralin ):- Aerosol containing insulin for buccal absorption,using an applicator similar to those used for asthma medications Transdermal insulin:- The electronic adhesion is first applied to the skin vaporizing superficial dermal cells and forming micropores for insulin to pass through and then the insulin patch is applied Artificial β-cell prototype:- It is closed loop device consisting of implantable peritoneal insulin pump and glucose sensor implanted in superior venacava
• 33.
  Nanoinsulin:- Arsenic destroys insulinmolecule so diabetics living in areas with arsenic contamination of ground water suffers arsenic poisoning & unsucessful diabetic treatment. To overcome this problem insulin is coated by polymer nanoparticles called nanoinsulin