INSULIN & ITS PREPARATIONS
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The document discusses pancreatic hormones and insulin. It describes the four main cell types in the islets of Langerhans and the hormones they secrete, including insulin secreted by beta cells. Insulin was discovered in 1921 and contains two polypeptide chains connected by disulfide bonds. Insulin regulates glucose levels by facilitating glucose transport and storage and inhibiting gluconeogenesis. Various insulin preparations are discussed, from conventional insulin to highly purified pork insulin to human insulin produced through recombinant DNA technology to analogues like insulin lispro and glargine which have altered pharmacokinetic properties.
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INSULIN & ITS PREPARATIONS
- 1. “PANCREATIC HORMONES” INSULIN By Mr.S.KAMESHWARAN.,M.Pharm.,(Ph.D). Associate Professor, Excel College of Pharmacy Komarapalayam,Namakkal- Tamilnadu
- 2. PANCREATIC HORMONES The part of the pancreas with endocrine function is made up of approximately a million cell clusters called islets of Langerhans. Four main cell types exist in the islets. They classified by their secretion: α alpha cells secrete glucagon (increase glucose in blood), β beta cells secrete insulin (decrease glucose in blood), Δ delta cells secrete somatostatin (regulates/stops α and β cells) and PP cells, or γ (gamma) cells, secrete pancreatic polypeptide.
- 4. INSULIN Discovered in 1921 by Banting & Best Insulin contain 2 polypeptide chain Insulin has 51 amino acids A chain has 21 AA, B chain has 30AA Both chains are connected by DISULFIDE BONDS Molecular weight is about 6000 Daltons Pork insulin is much similar to human insulin than beef insulin
- 5. Beeta CELLS OF PANCREAS Synthesis SINGLE CHAIN PEPTIDE PREPROINSULIN (110AA) REMOVAL OF 24AA To form PRO INSULIN Under goes PROTEOLYSIS IN GOLGI APPARATOUS SPLIT OFF OFCONNCETING (C) PEPTIDE (35AA) INSULIN, C PEPTIDE STORED IN GRANULES WITH IN CELL C PEPTIDE IS SECRETED IN BLOOD ALONG WITH INSULIN
- 6. INSULIN WITH C PEPTIDE INSULIN
- 7. REGULATION OF INSULIN SECRETION: Normal condition – 1U insulin is secreted/ hour from our pancreas Much larger quantity is secreted after every meal Secretion controlled by chemical, hormonal & neural mechanisms
- 8. FUNCTIONS OF INSULIN: “INSULIN FAVOURS THE STORAGE OF FUEL” Facilitates glucose transport across cell membrane in to fat and skeletal muscle Glucose transporter glycoprotein (GLUT 4) present intracellularly This involved in the transport of glucose across the cell membrane Conversion of GLUCOSE - GLUCOSE 6 PHOSPHATE is enhanced by the production of enzyme GLUKOKINASE Insulin facilitates GLYCOGEN SYNTHESIS from GLUCOSE in liver, muscle, fat by the enzyme GLYCOGEN SYNTHASE Insulin decrease GLYCOGENOLYSIS in liver
- 9. Insulin INHIBITS GLUCONEOGENESIS from protein, FFA, Glycerol in liver Insulin inhibits LIPOLYSIS in adipose tissue & FAVOURS TRIGLYCERIDE SYNTHESIS Increase TRANSCRIPTION of vascular endothelial lipoprotein lipase – increase the clearance of VLDL & CHYLOMICRONS facilitate amino acid entry, protein synthesis & inhibit the protein breakdown in muscle & other cells
- 10. MECHANISM OF ACTION Liver and fat contains more number of insulin receptors than others INSULIN BINDS TO THE SPECIFIC RECEPTOR PRESENT ON THE CELL MEMBRANE ESPECIALLY BINDS TO THE ALPHA SUBUNITS OF THE INSULIN RECEPTOR AGGREGATION AND INTERNALIZATION OF THE RECEPTOR ACTIVATION OF TYROSIN KINASE ACTIVITY OF BEETA SUBUNITS OF INSULIN RECEPTOR THEY PHOSPHORYLATE ON EACH OTHER PRODUCE INSULIN RECEPTOR SUBSTRATE PROTEIN (IRS 1 & IRS2 ------------------------------------------------------------------------------------------------------------------- SECOND MESSENGER MAP KINASE PATHWAY PHOSPHORYLATION ATP PIP3 TRANSCRIPTION FACILITATE GLUCOSE TRANSPORT ACROSS CELL STIMULATE/ INHIBIT MRNA MEMBRANE ENZYME RESPONSIBLE FOR INSULIN ACTION PROTEIN SYNTHESIS EG: GLUCOKINASE SPECIFIC CELL PROLIFERATION
- 11. 28/05/16
- 12. 28/05/16
- 13. PHARMACOKINETICS: Distributed only extracellularly It is a Peptide, It is digested in G.I.T, if given orally External /natural insulin metabolized in liver, minor in kidney & muscle During metabolism Reduction in disulfide bonds A & B chains separated & broke down in to amino acids
- 14. INSULIN PREPARATIONS CONVENTIONAL INSULIN PREPARATIONS HIGHLY PURIFIED INSULIN HUMAN INSULIN INSULIN ANALOUGES
- 15. CONVENTIONAL INSULIN PREPARATIONS They are initially prepared from beef & pork pancreas But it contain 1% of other proteins like pro insulin, polypeptides & pancreatic proteins etc. These contaminations may lead to severe adverse activities In developing countries they have been totally replaced by highly purified pork insulin/ recombinant human insulin/ insulin analogues But it India, still we are using conventional preparations because of its low cost Eg: REGULAR INSULIN LENTE INSULIN ISOPHANE INSULIN PROTAMINE ZINC SUSPENSION
- 16. REGULAR INSULIN: Also known as – soluble insulin It is a buffered solution of unmodified insulin, stabilized by small amount of zinc The insulin molecules are self aggregated to form hexamers around zinc ions After s.c injections, Insulin monomers are released gradually by dilution Absorption occurs slowly Peak action produced after 2-4 hours, lasts up to 6-8 hours High dose produce long action
- 18. LENTE INSULIN: It is also known as Insulin zinc suspension 2 types of suspensions are there 1st type – contain LARGER PARTICLES (CRYSTALLINE) – produce LONG ACTION 2nd type – contain SMALLER PARTICLE (AMORPHOUS) – produce SHORTER ACTION 7:3 ratio of above preparation is called as LENTE INSULIN This has intermediate duration of action
- 19. ISOPHANE INSULIN: Also called as NEUTRAL PROTAMINE HAGEDORN (NPH) NPH was created in 1936 Small quantity of positively charged polypeptide - protamin is added to the insulin Which forms the complex with insulin molecules On s.c. injection this complex dissociate slowly and give intermediate duration of action Longer duration of action than regular and lente insulin
- 20. PROTAMIN ZINC INSULIN (PZI) : Contain excess amount of protamin Insulin is released more slowly from the complex on s.c. injection Produce prolonged duration of action
- 21. HIGHLY PURIFIED INSULIN: Purification techniques were introduced in 1970s Applied to produce highly purified & non antigenic insulin Pork insulin is used for this purpose Gel filtration: Gel filtration reduces the pro insulin content to 50-200 ppm But other pancreatic peptide insulin derivative remains In this stage it is called as – SINGLE PEAK INSULIN Ion exchange chromatography: above single peak insulin is further purified by this ion exchange chromatography of this method removes most contaminants & reduce the pro insulin to < 10ppm this stage the insulin called as – HIGHLY PURIFIED INSULIN/ MONO COMPONENT INSULIN They are more stable
- 22. HUMAN INSULIN: In 1980s by recombinant DNA technology the human insulin were prepared They have same amino acid sequence as natural human insulin It is produced by recombinant DNA technology in E.Coli Use of human insulin has rapidly overtaken the purified animal insulins It is more water soluble Hydrophobic than porcine/ pork insulin Injected through s.c. route
- 23. INSULIN ANALOUGE: Using recombinant DNA technology analogues of insulin have been produced This analogues has Modified pharmacokinetics action on s.c. injection Similar pharmacodynamic effects Greater stability & consistency Eg: INSULIN LISPRO INSULIN ASPART INSULIN GLARGINE INSULIN DETEMIR
- 24. INSULIN LISPRO It is produced by reversing proline & lysine at the B28 & B29 carboxy terminus It forms weak hexamers, dissociate rapidly on s.c. injection Peak, short duration of action Have to be injected immediately before or even after the meal Better control of meal time glycemia It can be used 2-3 times daily meal time insulin lispro injection Hypoglycemia is less common
- 25. INSULIN LISPRO
- 26. INSULIN ASPART: PROLIN is present at B28 carboxy terminus of human insulin This prolin at B28 is replaced by aspartic acid Which reduce the tendency of self aggregation Duration, action profile is similar to insulin lispro Mimics physiological insulin release pattern after meal
- 27. INSULIN ASPART
- 28. INSULIN GLARGINE: Long acting, bio synthetic insulin, Has 2 additional arginine residues at the carboxy terminus of B chain Glycine replaces asparagines at A21 Insulin dissociates slowly & it maintained up to 24 hours Once daily injection can be provided It does not control meal time glycemia
- 29. INSULIN GLARGINE
- 30. INSULIN DETEMIR it is a long-acting human insulin analogue for maintaining the basal level of insulin Insulin detemir differs from human insulin in that the amino acid threonine in position B30 has been omitted, and a C14 fatty acid chain has been attached to the amino acid B29. produced by a process that includes expression of recombinant DNA in Saccharomyces cerevisiae followed by chemical modification insulin detemir reduces HbA1c to target levels of 7.0% for 70% of patients, similar to human basal insulin, NPH, but without the same risk of hypoglycemia and with somewhat less weight gain.
- 32. USES: Diabetes mellitus Diabetic ketoacidosis life-threatening complication in patients with diabetes mellitus. - Due to shortage of insulin – cell does not receive energy – liver starts breakdowns –fat – to keton as energy source - buildup of excess ketones – makes blood acidic. Nonketotic hyperglycemic coma complication of diabetes mellitus (predominantly type 2) high blood sugars cause severe dehydration, coma and death)
- 33. “THANK U”