PA2107 Lectures 2&3 Diabetes Mellitus
PA2107 Lectures 2&3 Diabetes Mellitus PA2107
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This 6 page Class Notes was uploaded by Joan Loo on Thursday August 13, 2015. The Class Notes belongs to PA2107 at National University of Singapore taught by in Summer 2015. Since its upload, it has received 109 views. For similar materials see Pharmacology 2 in Pharmaceutics at National University of Singapore.
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Date Created: 08/13/15
hy perglycemic factor that storage and anabolic Universal inhibitor of mobilises glucogen stores hormone secretory cells PA2107 Lectures 2amp3 Insulin and AntiDiabetic Drugs These notes are largely extracted from Basic and Clinical Pharmacology 11th Edition AChain T 1 15 1o 11 12 13 1 Gllucagon j hallrn j Somatostatin Val Ala Leu Tyr Le 10 m 8 19 20 11 Modulates appetitde gastric 12 13 14 15 16 17 1 emptying glucagon and insulin secretion httpwwwcinchemorgcontent451104F1largejpg Focus on insulin Insulin consists of two chains A and B linked together by disulfide bonds Preproinsulin is synthesized in the endoplasmic reticulum consisting of A B and C chains and a signal peptide It then enters the Golgi apparatus where the signal peptide is excised Finally proinsulin is processed within the Golgi apparatus of the beta cells and packaged into granules where it is hydrolysed into insulin Insulin is secreted at a low basal rate When there are appropriate stimuli insulin is released in large amounts The strongest stimulus is high blood glucose concentrations Other stimuli include other sugars eg sucrose certain amino acids hormones such as glucagonlike polypeptide1 GLPl glucagon and vagal activity The parasympathetic system rest amp relax can also stimulate insulin release Inhibitory signals include somatostatin leptin and chronically elevated glucose and fatty acid levels The sympathetic system fight or flight can also inhibit insulin secretion High blood 39 glucose levels ATP binds to K channels close ATPdependent K preventing efflux channels of K from the cell Increased intracellular ATP Depolarisation of cell Vottagedependent calcium channels open causing influx of calcium How insulin is released Exocytosis of Release of insulin vesicles containing insulin Normal W is 140 mmol Normal Ca2 is 01 pmol due to small conc of Ca2 it can serve as a second messenger as just a small change will be able to effect big physiological action Insulin is degraded in the liver 60 and kidneys 40 However in insulintreated diabetics receiving subcutaneous insulin injections this ratio is reversed as much as 60 of exogenous insulin is cleared by the kidney The halflife of circulating insulin is 35 min After insulin is released from the body it targets tissues with insulin receptors ie the liver muscles and adipose tissues The full insulin receptor consists of two asubunits entirely extracellular and two Bsubunits with tyrosine kinases transmembranal The binding of an insulin molecule to the OL subunit causes conformational changes in the Bsubunits The Bsubunits are brought closer together and they crossphosphorylate the tyrosine residues on each other The activated tyrosine kinases phosphorylate the docking proteins inuin receptor substrates 1 amp 2 IRS1 amp IRS2 IRS1 and 2 then bind to and activate other kinases most significantly phosphatidylinositol3kinase which produces further phosphorylations Alternatively the may bind to mitogenactivated protein kinase MAPK This network of protein phosphorylation ultimately leads to the translocation of Glut4 receptors from the cytosol to the cell membrane where they increase glucose uptake promote glycogen synthesis protein synthesis and liposynthesis through various mechanisms Liver Muscle Adipose tissue Glut2 Glut4 Glut4 Inhibits glycogenesis Inhibits conversion of fatty acids and aa into keto acids Inhibits conversion of aa to glucose Promotes glucose storage as glycogen induces glucokinase and glycogen synthase inhibits phosphorylase Increasestriglyceride synthesis Increases protein synthesis by increasing aa transport and ribosomal protein synthesis Increases glycogen synthesis by increasing glucose transport inducing glycogen synthase and inhibiting phosphorylase Uptake of glucose is slow and is the ratelimiting step in carbohydrate metabolism Main function of insulin here is to increase import of glucose via Glut4 Increases triglyceride storage Lipoprotein lipase is induced and activated by insulin to hydrolyse triglycerides from lipoproteins Glucose transport into cell provides glycerol phosphate to permit esterification of fatty acids supplied by lipoprotein transport Intracellular lipase is inhibited by insulin If blood insulin levels are too low there would be higher free fatty acids in the blood Free fatty acids are converted to ketones in the liver High levels of free fatty acids and ketones can bring about ketoacidosis and must be treated with insulin Other effects of insulin include decreasing protein catabolism and inhibiting the oxidation of aa in the liver Also insulin helps the transport of potassium calcium neuclosides and inorganic phosphate into the cell The transport of potassium into the cell is clinically important as insulin can be used in the treatment of hyperkalemia Focus on Diabetes Mellitus DM is a chronic metabolic disorder characterized by high blood glucose concentrations This may be caused by insulin deficiency andor insulin resistance Hyperglycemia can be diagnosed based on fasting plasma glucose of gt70 mmolL normal lt60 mmolL or plasma glucose gt111 mmolL two hours after starting a meal normal lt78 mmolL Type 1 Insulindependent DM orjuvenileonset diabetes This is a result of an autoimmune disease that destroys pancreatic betacells Body has no ability to produce insulin so patient must start treatment with insulin Type 2 Noninsulindependent diabetes This is a result of insensitivity of insulin receptors on peripheral tissues as well as insensitivity of betacells to BGC 2 Type 3 Others Type 4 Gestational DM in pregnant women where the placenta releases hormones that increase BGC Symptoms of DM include constant hunger and thirst weight loss and passing more urine DM may be treated by insulin therapy esp for Type 1 Insulin therapy may be delayed in the case of the other types of DM by the use of oral antidiabetic agents Insulin therapy Insulin preparations Products Mutation of insulin Onset and duration Rapidacting insulin Lispro B chain 28 Lys 29 Pro O 0102 h Aspart B chain 28 Asp DOA 35 h O 0307 h Shortacting Insulin Generic DOA 58 h Intermewateawng Lente Mixture of insulin types 0 1 2 h insulin DOA 1824 h A chain 21 Gly Longacting insulin Insulin glargine 2 Arg attached to Cterminus DOA gt 30h of B chain Small volumes of insulin can be administered subcutaneously with the help of needles eg NovoPen while larger amounts can be introduced intramuscularly For fast effects in emergencies regular insulin is introduced intravenously Longacting insulin is not used in these circumstances as it is hard to control and the BGC may be lowered too much Rapidacting insulin is not used because it is often expensive Insulin cannot be taken orally because insulin is digested in the GIT For Type 1 DM insulin is the only treatment available other drugs are not suitable because of their adverse effects or their dependence on residual betacell function Insulin can also be used to treat Type 2 DM Type 4 DM gestational hyperglycemic diabetes emergencies and hyperkalemia The side effects of insulin include hypoglycemia overdose allergic reactions and insulin resistance when insulin receptors are no longer sensitive to insulin in which a higher dose of insulin must be given Oftentimes rebound hyperglycemia somogyi effect may happen This must be differentiated from situations in which an insufficient dose of insulin has been prescribed resulting in hyperglycemia Rebound hyperglycemia somogyi effect Insufficient dose of insulin After taking insulin dose night time insulin levels After insufficient dose of insulin night time are high resulting in low BGC The body then insulin levels are not high enough causing high responds to low BGC by hormonal adjustments BGC resulting in higher BGC Insulin dosing frequency will be increased to Insulin dose will be titrated up to achieve good prevent such an effect control of BGC Oral antidiabetic agents These include sulfonylureas biguanides thiazolidinediones and aglucosidase inhibitors SULFONYLUREAS glibenclamide tolbutamide and chlorpropamide The KATP channels in the betacells are made up of sulfonylurea receptors SURs and Kir subunits Both of these must be present to obtain functional channel activity Sulfonylureas work by binding to the SURs inhibiting the efflux of K through the channels This results in depolarization opening the voltagesensitive calcium channel causing calcium influx thus triggering the release of insulin Sulfonylureas thus have similar actions to ATP p 1 Sulfonylureas act as secretagogues and work by increasing insulin release from pancreatic betacells and reducing serum glucagon concentration They are used primarily in Type II DM Their side effects include 1 Extra information Hypoglycemia overdose esp in elderly because kidney function is impaired in the elderly and kidney function is required for removal of sulfonylureas 2 Gastrointestinal upset Allergic skin rash and bone marrow damage 9quot 4 Increase in cardiovascular death KATP is a cardioprotective protein Because KATP is also expressed in heart muscles sulfonylureas also affect the heart CI in ischemic heart disease 5 Weight gain due to increased appetite Tolbutamide Well absorbed Metabolised in liver Short DOA tlz 45 h Safest sulfonylurea for elderly 0520g in divided doses First generation Chlorpropamide Metabolised in liver to products that have some biologic activity CI in patients w hepatic or renal insufficiency elderly Long DOA t12 32 h Dosages gt 500 mg daily increase risk ofjaundice SE hyperemic flush after alcohol ingestion and diutional hyponatremia 100500 mg as single or divided doses Tolazamide Comparable to chlorpropamide in potency More slowly absorbed 9 slow onset of action Metabolised in liver to products that have some biologic activity Shorter DOA t12 7 h 100 mg to 1 g in single or divided doses Glibenclamide aka glyburide Metabolised in liver to products w very low hypoglycemic activity tlz 1024 h Few side effects other than hypoglycemia CI in hepatic impairment and renal insufficiency Starting dose 25 mgd maintenance about 5 10 mgd OM Second generation Glipizide Short t12 24 h Good for reducing postprandial hyperglycemia Take 30 min before breakfast absorption is delayed when taken w food Metabolised in liver to inactive products 10 excreted unchanged CI in patients w hepatic or renal impairment Lower risk of hypoglycemia due to short DOA Starting dose 5 mgd up to 15 mgd given as a single dose When higher doses are needed should be divided and given before meals BIGUANIDES metformin Metformin acts as an insulinsparing agent They are first line therapy for Type 2 DM as they do not cause weight gain or hypoglycemia obvious benefit over sulfonylureas Can also be used to prevent Type 2 DM treating prediabetes Actions 1 Reduce hepatic glucose production through activation of the enzyme AMPactivated protein kinase AMPK 2 Impairs renal guconeogenesis 3 Slows absorption of glucose from GIT Not mentioned in textbook but 4 Increase glucose to lactate conversion by in Dr Bian s notes Increases enterocytes 9 some risk of high lactic acid levels insulin sensitivity by increasing 5 Direct stimulation of glycolysis in tissues insulin receptor density 6 Increased glucose removal from blood 7 Reduction of plasma gucagon levels Does not depend on functioning pancreatic beta cells Little risk of hypoglycemia when on metformin therapy PK Not protein bound Drug may affect hepatic metabolism of lactic acid resulting in accumulation of lactic acid 9 dose related lactic acidosis Metabolised and excreted by kidneys as active compound 9 CI in patients with renal insufficiency tlz of 153 h Adverse Anorexia NampV abdominal discomfort and diarrhea in up to 20 of patients dose effects related and tend to occur at onset of therapy but usually transient In 35 of patients persistent diarrhea causes discontinuation of metformin therapy Reduced absorption of 312 Possible lactic acidosis but usually only comes about together with hypoxia or renal or hepatic insufficiency CI Renal disease alcoholism hepatic disease or conditions predisposing to tissue anoxia eg chronic cardiopulmonary dysfunction Dose Can be initiated as a oncedaily dose for fasting hyperglycemia or before meals for postprandial hyperglycemia Start w 500 mg ON w addition of 500 mg if dose is insufficient An additional 500 mg tab can be added to breakfast or lunch Otherwise 850 mg can be taken BD or TID max recommended dosage of 225 g if needed Dosages should always be divided because ingestion of more than 1000 mg at any one time provokes significant GI AE THIAZOLIDINEDIONES Tzds rosiglitazone Tzds are insulin sensitizers and decrease insulin resistance Tzds are ligands of peroxisome proliferatoractivated receptorgamma PPARy part of the steroid and thyroid superfamily of nuclear receptors These PPAR receptors are found in muscle fat and liver PPARy forms a heterodimer with another transcription factor the retinoid X receptor RXR Tzds bind to PPARy RXR complex so that the complex binds DNA and promotes transcription of several genes involved in lipid and glucose metabolism such as lipoprotein lipase fatty acid transporter adipocyte fatty acidbinding protein Glut4 and others Possible benefit in the prevention of Type 2 DM But adverse effects limit their use Actions Reduces hepatic glucose output Increases glucose uptake into muscle tissue Decrease triglyceride levels in the blood Increase lipogenesis and enhance uptake of fatty acids and glucose 9WD 5 PK Rapidly absorbed highly protein bound Metabolised in the liver to minimally active metabolites AE Fluid retention presenting as mild anemia and peripheral edema especially when used with insulin or insulin secretagogues Doserelated weight gain average 13 kg possibly fluid related Increased risk of heart failure Possible increased risk of bone fractures in women CI Pregnancy significant liver disease heart failure Dose Pioglitazone 15 45 mg OM Rosiglitazone 28 mg OM ALPHAGLUCOSIDASE INHIBITORS acarbose miglitol Alphaglucosidase inhibitors are insulinsparing drugs These drugs must be taken 30 min before the meal They are competitive inhibitors of the a glucosidases and reduce postprandial BGC rise by 30 50 so less insulin needed also They delay the digestion and absorption of starch and disaccharides Both miglitol and acarbose target the a glucosidases sucrose maltase glucoamylase and dextranase Acarbose has a small effect on a amylase Miglitol differs structurally from acarbose and is six times more potent in inhibiting sucrose Miglitol also works on isomaltase and Bglucosidases Their adverse effects include elevated liver enzymes due to small portion of alphaglucosidase inhibitors being absorbed requiring metabolism in the liver flatulence and diarrhea Other drugs not covered in lectures Meglitinides are insulin secretagogues of which repaglinide is an example They modulate betacell insulin release by regulating potassium efflux through the KATP channels earlier discussed Meglitinides have two binding sites in common with the sulfonylureas and one other unique binding site Repaglinide has a very fast onset of action peaking 1 h after ingestion DOA 58 h Indicated for postprandial rise in BGC Dose 0254 mgd max 16 mgd to be taken just before meals Hepatically cleared by CYP3A4 possible drug interactions Caution in renal andor hepatic impairment Nateglinide a Dphenylalanine derivative acts as an insulin secretagogue It stimulates very rapid and transient release of insulin from beta cells through closure of KATP channels It also partially restores initial insulin release in response to an intravenous glucose tolerance test possible advantage because Type 2 DM is associated w loss of this initial insulin response The restoration of more normal insulin secretion may suppress glucagon release early in the meal and result in less endogenous or hepatic glucose production May help therefore for isolated postprandial hyperglycemia Dose titration is not required taken just before meals Absorbed within 20 min after PO peaks in lt1h t12 15 h overall DOA lt4h metabolized by CYP2C9 and CYP3A4 possible drug interactions Very low risk of hypoglycemia safest among all and safe in those w reduced renal function
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