Insulin & Anti-diabetic Agents PDF

Insulin & Anti-diabetic Agents  Pancreatic Glands Exocrine glands: – Pancreatic acini – Produce pancreatic digestive enzymes Endocrine glands: – Form clusters called pancreatic islets (islets of Langerhans) – Secrete hormones  Cells of Pancreatic Islets...

Insulin & Anti-diabetic Agents  Pancreatic Glands Exocrine glands: – Pancreatic acini – Produce pancreatic digestive enzymes Endocrine glands: – Form clusters called pancreatic islets (islets of Langerhans) – Secrete hormones  Cells of Pancreatic Islets Alpha cells: – Secrete glucagon Beta cells: – Secrete insulin Delta cells: – Secrete somatostatin PP (F) cells: – Secrete pancreatic polypeptide  Effects of Glucagon 1. Stimulates production of glucose in liver (gluconeogenesis) 2. Stimulates breakdown of glycogen into glucose in skeletal muscles and liver cells (glycogenolysis) 3. Stimulates breakdown of triglycerides in adipose tissue and fatty acid release (lipolysis)  Effects of Insulin 1. Accelerates glucose uptake and utilization by cells 2. Stimulates glycogen formation (glycogenesis) 3. Stimulates triglyceride formation in adipose tissue (lipogenesis) 4. Stimulates amino acid absorption and protein synthesis  Insulin vs. Glucagon Actions Glucagon Insulin ­ blood glucose ¯ blood glucose  Mechanism of Insulin Action Insulin binds specific insulin receptors on the cell membranes Main Target Organs of Insulin  Blood Glucose Levels Normal blood glucose levels: – Fasting: 70 - 110 mg/dl – 2 hours after meals (PP2): < 180 mg/dl Abnormal blood glucose levels: – Hypoglycemia: < 70 mg/dl – Hyperglycemia: > 110 mg/dl (fasting) § Impaired glucose tolerance: 110 - 180 mg/dl § Diabetes mellitus: > 180 mg/dl Diabetes Mellitus  Types of Diabetes Mellitus Primary DM: – Type 1: Insulin Dependant DM (IDDM) – Type 2: Non-Insulin Dependant DM (NIDDM) Secondary DM: – Pancreatic disease: e.g., pancreatitis, tumor – Endocrine disease: e.g., Cushing’s syndrome – Drug induced: e.g., thiazide diuretics – Infection: e.g., congenital rubella Gestational DM: – During pregnancy  Primary DM Type 1 Type 2 b cell destruction ® b cell dysfunction ® Abnormality insulin deficiency insulin resistance Incidence Less common More common Age of onset < 30 years > 40 years Autoimmune + Etiology precipitating factor* Multifactorial Autoantibodies 60-85% < 10% * Precipitating factor: usually unknown but it can be a viral infection as mumps, rubella, measles or coxackie  Primary DM Type 1 Type 2 Genetics Lesser impact Greater impact Identical twins 30-40% affected 70-90% affected Body weight Low Overweight/obese Diabetic More common Less common ketoacidosis HHS (HONK) Less common More common Oral hypoglycemics Treatment Insulin ± insulin  Obesity & Type 2 DM Obesity is associated with an increased risk of type 2 DM ­ body weight by ~10 kg ® ­ risk of DM by 3-fold Obesity ® earlier age of onset of DM Obesity, Inactivity & Unhealthy Diet In adults… & children too!  The Deadly Quartet Obesity Diabetes Hypertension Dyslipidaemia  Clinical Feature of DM Polydipsia Polyuria Nocturia Glycosuria Complications  Complications of DM Acute Chronic DKA HONK CAD Others Angiopathy Microangiopathy Macroangiopathy PAD etc … CVA Infection Skin Retinopathy Nephropathy Neuropathy  Treatment of DM Diet control Antidiabetic agents Treatment of complications Insulin & Anti-diabetic Agents  Treatment of DM Diet control Antidiabetic agents Treatment of complications  Diet Control minimize sugar have an amt physical or that your meds reduce body improve insulin can control weight activity  Antidiabetic Agents Insulin ↳ I more common with type Oral hypoglycemic agents Type 2 DM (NIDDM) Insulin  Canadian medical doctor & scientist Frederick Banting received Nobel Prize for co-discovery & first human trial of insulin in treating diabetes mellitus  Indications of Insulin Therapy Type I diabetes > - insulin deficient - body does not produce Type II diabetes: -when this doesn't work , switch to insulin – Inadequate control by oral hypoglycemics – Stressful conditions: e.g., infection – During pregnancy switch insulin then to after ! delivery of baby she ge nt s can continue a mic , Gestational diabetes oral hypoglycemics oglyc e yp Oral h  Source of Insulin Bovine - COW Porcine pork > - Human recombinant: grown in mimic bacteria insulin – Least antigenic very good ! > - – Standardized to 100 U/ml Administration: – Injection: SC, IV, IM most everyday route ↳ the common – Alternative methods: e.g., pump ,  Pharmacokinetics of Insulin Insulin Onset Peak Duration Fast (Rapid) 5-15 min 3/4-1 h 2-4 h Short 1/2-1 h 2-3 h 5-8 h Intermediate 1-2 h 4-12 h 10-20 h less Long 1-2 h minimal 18-24 h day than a more risk of hypoglycemia 1-2 h minimal >24 h t Ultra-long than day 2 intermediate long  Insulin Preparations Fast-acting: Lispro – Aspart Short-acting: Regular (crystalline) insulin Intermediate-acting: NPH (Neutral Protamine Hagedorn) Long-acting: Detemir – Glargine Ultra-long: Degludec Mixed types: (combinations) get the benefit of each Rapid onset + prolonged duration e.g., NPH/regular 70/30  Insulin Regimens Conventional therapy: more common , more relaxed compared to intensive – One or two injections per day – Daily self monitoring of glucose * intensivetherapy a higher risk – Lower risk of hypoglycemia Intensive therapy: reserved to conditions when the control of diabetes is challenging – Multiple daily injections – Daily self monitoring of glucose and dose adjustment > - risks less – Reduction in retinopathy, nephropathy, and neuropathy – Higher risk of hypoglycemia (3-fold more than conventional) ↳ but fighter control , need tighter monitoring  Daily Insulin Schedule Injection Major End of Type Time Effect Effect > - short acting on ly BF ® Before cover breakfast Fast/Short Before 1 NPH/Long lunch lunch breakfast long acting covers Lunch ® > Before - (BF) lunchtime dinner dinner short acting only Dinner ® > Before bed - cover dinner time Fast/Short 2 NPH/Long Before bed snack snack acting covers dinner long > Before BF - entire rest the Overnight of night (next day)  Daily Insulin Schedule short acting long acting ­ Injection 1 ­ Injection 2 Daily route of injection: SC - usually unless subcut have other route  Absorption of SC Insulin trate of absorption obese Highly variable: -some people individuals - some people skinny – Interindividual > differe between - e.. g massaging site > - of injection – Intraindividual > some - rate of conditions affect will absorb absorption faster Xe Factors affecting absorption:.. injecting same g Spot will develop fibrosis which – Site of injection: -best site decrease absorption § Abdomen > arm > buttock > thigh – Blood flow to site of injection – Depth of injection – Exercise increases absorption – Massage of the area increases absorption  Alternatives to Insulin Injection other than SC injection > controlled and programmed to Insulin pumps – commonly used - the time and administer helpful sense insulin , type very to teens with Insulin pens (insulin containing cartridges) – commonly used Transdermal: jet injection, patches there was > in 2006 - 2007 but it - inhaled insulin veryexpensive > - new promising formula that seems was Inhaled insulin – Afrezza (WHO approved in 2014) good market and so took off very Oral formulas (designed to resist insulin digestion in the GIT) – under investigation avoid injections available > - yet - not Commonly Used Insulin Delivery Devices Inhaled insulin  Complications of Insulin Therapy Systemic: - When you take is i > - advise pt to take with brain meal death > cause severe – Hypoglycemia ® most dangerous - can cow insulin most allergenic – Insulin allergy ® rare with human insulin > - insulin > - followed by pork recombinant the least > - human – Insulin resistance when body does > - respond not to insulin anymore Local: avoid by : – Lipoatrophy ® change site of injection – Hypertrophy Oral Hypoglycemics  Oral Hypoglycemic Agents substance that stimulates secretion of another substance Sulfonylureas - Insulin secretagogues Meglitinides > - both stimulates secretion of insulin Biguanides Thiazolidinediones (TZDs, glitazones) Alpha-glucosidase inhibitors Others … Sulfonylureas  Mechanism of Action Nat in to induce Ap send + isletsbringstop ↑ , K of pancreatic out for repolarization & Ap need to send it Stimulate insulin secretion by β-cell: , out - on the cell membrane – Inhibit K channels on β-cell ® causing depolarization ® ­ calcium entry ® ­ insulin release > - inhibit It channels > - inhibit sending kt out so it stays inside cell cell > stays with lots of positively - charged ions inside > - maintain depolarisation 4) keep cell active ↳ keep making + releasing insulin  Mechanism of Action Stimulate insulin secretion by β-cell: – Inhibit K channels on β-cell ® causing depolarization ® ­ calcium entry ® ­ insulin release ­ receptor sensitivity ® potentiate insulin action at insulin sensitive different tissues 4 makes accepting to more to receptormore , effect produce insulin to -needs pancreas that can make insulin Require functional β-cells to work: – Only useful for type 2 NOT type 1 DM in type make insulin ↳ because pancreas cannot  Pharmacokinetics -taken orally so goes to GI absorbed intestine then go through Bind to plasma proteins > - blood to and in blood > thing after it does its Metabolized in the liver - stimulate B-cells theneed , we don't anymore them Excreted through kidneys metabolised by kidneys > - will via be and excreted liver Exaggerated effects in elderly and renal or liver disease * be cautious if pt Cross the placenta ® teratogenic effect liver/kidney it has disease as can 4) CANNOT USE DURING PREGNANCY accumulate because rate of metabolism ↓ * no ACE inhibitors and sulfonylureas during pregnancy  Drug Interaction Drugs ­ hypoglycemic effects: increase sulfonylureas effect – NSAIDs, warfarin, MAO inhibitors, alcohol, some antibacterials 4 antidepressants but not (e.g., sulfonamides) used because much effect of adverse - inhibit liver enzymes inhibit = of metabolism of drugs rate – Microsomal enzyme inhibitors (e.g., cimetidine) Drugs ¯ hypoglycemic effects: – Microsomal enzyme inducers (e.g., rifampicin) – Phenytoin (inhibits insulin release) b blockers mask symptoms of hypoglycemia  Preparations First generation: Go – E.g., tolbutamide, chlorpropamide Second generation: – E.g., glipizide, glibenclamide, gliclazide Third generation: 2 ways to classify : sulfonylureas – Glimepiride to 1) chronological according the times they were developed ↳ first second , third gen , 2) according to onset of duration of action ↓  Duration of Action Sulfonylurea Duration Dose Agent (hours) Frequency Tolbutamide 6-10 BID-TID Glipizide Glibenclamide 12-16 OD-BID Gliclazide Glimepiride 12-24 OD Chlorpropamide 24-72 ↳ willbuildupaa an  Adverse Effects -ultra-long Hypoglycemia (specially chlorpropamide) GI disturbances Hepatic toxicity Allergic skin reactions Other Oral Hypoglycemics * COMPLETELY DIFFERENT MECHANISM THAN SULFONYLUREAS => inhibit Biguanides making glucose by the liver Mechanism of action: does Finhibit to not pancreas come close – ¯ gluconeogenesis Stimulate in liver - – ­ glucose uptake by skeletal muscles - about Indications: best for type I diabetes and overweight as doesn't > - care it induces beta a little anorexia-which is adverse effect cells or channels – First choice for obese patients with type 2 potassium For taken alone – Can be combined with sulfonylurea or [insulin] biguanide can be used ↳ if type I diabetes Advantage: for -it doesn't 4 combined with insuli insulin levels = no hypoglycemia – Do not cause hypoglycemia as they do not alter insulin levels > - minimise making glucose and shift glucose to inside of cell to reduce blood sugar level  Biguanides Side Effects: overweight people ↑ lowkey good for – Anorexia: dose dependent, can be severe – Nausea, diarrhea, metallic taste – Lactic acidosis: contraindicated in renal failure Metformin (dimethylbiguanide): – Only drug approved in this class – 2 tablet forms: § Glucophage™ § Glucophage XR™ (extended-release tablets)  Meglitinides -disadvantage - willhave tokeep takingenymia short duration of action is not strong Short acting insulin secretagogues , enough to cause it – Action is similar to sulfonylureas – Short acting (t1/2: 1 hour) Indications: – Type 2 DM: § Can be combined with metformin Adverse effects: – Hypoglycemia (rare) E.g., repaglinide, nateglinide L - * xy2-linide = meglitinides  Thiazolidinediones (TZDs) Mechanism of action: – Activate a transcription regulator, PPARγ (peroxisome proliferator-activated receptor gamma) ® § improve glucose uptake in skeletal muscles § ¯ hepatic glucose production § modulate lipogenesis in adipocytes § reverse insulin resistance Indications: – Type 2 DM – Alone or combined with metformin, sulfonylurea  Thiazolidinediones (TZDs) Mechanism of action: – Activate a transcription regulator, PPARγ (peroxisome these 3 proliferator-activated receptor gamma) ® 48 glucose shift factors § improve glucose uptake in skeletal muscles from blood to + - make skeletal muscles § ¯ hepatic glucose productionfat cells receptors > - in liver more sensitive ↳ § modulate lipogenesis in adipocytes to insulin § reverse insulin resistance Indications: – Type 2 DM – Alone or combined with metformin, sulfonylurea Thiazolidinediones (TZDs) Skeletal ¯ glucose ­ glucose production uptake > - modificatiit by adipocytes  Thiazolidinediones (TZDs) Adverse effects: heart failure > - Congestive ischemia > - myocardial – > - liver damage – May cause hepatic injury (monitor liver function) e.g.,: Rosiglitazone, Pioglitazone u - * xy2-glitazone = thiazolidinediones  Alpha-glucosidase Inhibitors digest sugars and helps with > absorption of glucose - tenzymes intestines in Inhibits Lα-glucosidases in intestine ® reduces absorption of carbohydrates Carbohydrates + will not bedigested minimize , from glucose absorption the source. blood Not absorbed from intestine > - glucose entering no from intestine Control post-prandial glucose levels not adequately controlled by diet and sulfonylureas accumulation of carbohydrates Side effects: will acted upon be by bacteria – GI upset and flatulence E.g., Acarbose  Recent Antidiabetic Agents Glucagon-like peptide-1 (GLP-1) agonists DPP-4 Inhibitors (gliptins) Amylin analogues Gliflozins  Glucagon-Like Peptide-1 (GLP-1) Agonists * question in exam - gastrointestinal all of the following Group of GIT hormones called “incretins*” except are insulin... secretagogues 4 GLP-1 Sulfonylureas Mechanism: 3(GLP-1 1 GIP meglinitides ↳ stimulate – ­ insulin release inhibit -glucagon tends to increase – ¯ glucagon release blood sugar level so inhibit Adjunct treatment in type 2 SC injection E.g., Exenatide * end result is reduction in blood sugar levels * Incretins: GIT hormones stimulate insulin release & inhibit glucagon release. Include GLP-1 and GIP (gastric inhibitory peptide) - increting DPP-4 Inhibitors (Gliptins) GLP-1 and GIP inhibited are by DPP-4 inhibitors reduce insulin release > - breaks down increting slows done Mechanism: functions > stimulate increase , - glucagon blood sugar : end result = ↑ level – ¯ DPP-4 enzyme ® ­ incretins ®... - Adjunct treatment in type 2 inhibited Adverse effects: – Joint pain – Heart failure – Pancreatitis query – ? pancreatic cancer Oral DPP-4 = dipeptidyl peptidase-4 E.g., sitagliptin, saxagliptin - - * xy2-gliptin = DPP-4 inhibitors  Amylin analogues made beta cells of hormone by pancreas What is Amylin? ratio of ga:l insulin with insulin 199 insulin , 1 amylin) its amylin helps but cannot work on own Mechanism: – Slows gastric emptying -slows down glucose absorption in intestine prevents – ¯ postprandial glucagon release > - glucagon formation Insulin Amylin Adjunct treatment in types 1 & 2 taking > - amylin help analogues can SC injection increase amylin speed receptors they and levels. of work act on E.g., Pramlintide (only available product)  and Gliflozins leave everything kidney > go to - ¯ SGLT-2 ® ¯ renal glucose reabsorption ® glycosuria ↳ glucose reabsorbed here helps reabsorption of glucose and > - bringing back to blood SGLT-2: sodium-glucose cotransporter 2  Gliflozins when you take keeps glucose then get rid - gliflozins it inhibits -> in renal tubules of it eventually ¯ SGLT-2 ® ¯ renal glucose reabsorption ® glycosuria , SGLT2 ↑ gliflozine SGLT-2: sodium-glucose cotransporter 2  Gliflozins Used for type 2 (alone or in combination) be Adverse effects: > - can associated with Some necrosis – Hypoglycemia -too urine glucose lost in much of toes amputation and eventually – Ketoacidosis glucose > - in urine – UTI good > - which for flourishing are 4 Can UTI bacteria Oral E.g., canagliflozin - * xyz-gliflozin = gliflozin  Actions of Antidiabetic Agents A IMPORTANT GLP-1 analogues insulin secretagogues inhibition of glucose production by liver kidney O watch vid the