Insulin and DM PDF

Insulin and Oral Diabetes Drugs Advanced Pharmacology Key Points/Objectives Undiagnosed Type II diabetes is common, as the average patient will have diabetes for 4-7 years prior to diagnosis Be able to categorize and explain the mechanism of action of the various oral hypo...

Insulin and Oral Diabetes Drugs Advanced Pharmacology Key Points/Objectives Undiagnosed Type II diabetes is common, as the average patient will have diabetes for 4-7 years prior to diagnosis Be able to categorize and explain the mechanism of action of the various oral hypoglycemic drugs discussed Sulfonylurea drugs interfere with the preischemic conditioning effect seen with the volatile anesthetics and may worsen outcome in the event of an ischemic event Metformin, a biguanide, has shown benefit in reducing progression to overt diabetes in middle-aged, obese patients. You may, therefore, see it being used by a patient who denies a history of diabetes Key Points/Objectives Have a general idea of the onset and duration of the insulins we discuss. Not exact times, but short-intermediate-long acting, etc Intensive insulin therapy will reduce the long-term complications of diabetes, but at the risk of an increased incidence of hypoglycemic events Multiple comorbidities exist in the patient with long-standing diabetes which may impact an anesthetic Key Points/Objectives Be able to distinguish between the typical patient population, presentation, laboratory findings, and management of diabetic ketoacidosis versus hyperglycemic hyperosmolar syndrome There are many acceptable ways to manage a patient’s perioperative insulin regimen. Just like formulating an anesthetic plan, there is no one-size-fits-all recipe Control of Insulin Release Basal secretion at a low rate Much higher release in response to glucose and other stimulants: Other sugars Certain amino acids Vagal input Glucagon-like polypeptide-1  GLUCOSE HOMEOSTASIS 200 LIVER BRAIN 100 PLASMA GLUCOSE INSULIN GLUCAGON PANCREATIC FAT/ ISLET INSULIN MUSCLE 6 Glucose Counterregulatory Mechanism Hyperglycemia producing hormones Glucagon Epinephrine Growth hormone Cortisol Glucagon has the primary role Stimulates glycogenolysis and gluconeogenesis Inhibits glycolysis Normal Physiology 4.5 4 3.5 3 2.5 Glucose Er 2 1.5 1 Production Utilization Wiri-2 0.5 0 0 2 4 6 8 10 8 Classification of Diabetes Type 1a Autoimmune destruction of β cells resulting in: Completely absent, or negligible circulating insulin Type 1b Absolute insulin deficiency, not immune mediated Type 2 Not immune mediated Relative insulin deficiency coupled with insulin resistance Type 3 Multiple other specific causes, including: MODY (Maturity Onset Diabetes of the Young) Drug induced Non-pancreatic diseases Type 4 Gestational diabetes Diagnosed in ~4% of pregnancies Further sub-categorized by the White, or other, system Type 1 Accounts for < 10% of diabetes in U.S. Incidence increasing by 3-5%/ year Destruction of pancreatic β cells resulting from T cell mediated autoimmune process. Etiology unclear, but may be triggered by environmental factors in a genetically susceptible patient. Viral illness (particularly an enterovirus) Drugs or chemicals Dietary proteins Hyperglycemia does not present until 80-90% of β cell function is lost Type 1 Symptoms Fatigue Weight loss Polyuria Polydipsia Blurry vision Intravascular volume depletion Beta cell destruction is typically complete within 3 years in children. Progression is slower in adults. Type 2 Accounts for ~90% of diabetes in U.S. Typically seen in middle to older age patients who are overweight Estimated that the average patient has diabetes for 4-7 years prior to diagnosis. So you will frequently see undiagnosed, untreated diabetics presenting for surgery. Type 2 Relative β cell insufficiency + insulin resistance Early See increased pancreatic insulin secretion to compensate for the increased peripheral insulin resistance Later As pancreatic β cell function decreases over time, it’s unable to compensate for insulin resistance, and hyperglycemia results Time course May progress over years to decades Type 2 Three important defects in Type 2 Diabetes Increased rate of hepatic glucose release due to: Decrease in insulin’s normal inhibitory effects on liver Abnormalities in regulation of glucagon secretion Impaired basal and stimulated insulin secretion Insulin resistance Resulting in inefficient use of glucose by peripheral tissues Skeletal muscle Adipose tissue Liver Type 2 Inherited component Insulin resistance Contributing factors Obesity Sedentary lifestyle Increasing prevalence related to obesity with 85% of affected children being overweight Obese patients show a compensatory hyperinsulinemia to maintain normoglycemia in the face of insulin resistance May desensitize target tissues  IMPAIRED INSULIN SECRETION IN TYPE 2 DIABETES 16 Insulin Resistance Defined as “less than a normal response to a given plasma insulin concentration” Causes Abnormal insulin molecule Circulating insulin antagonists Counterregulatory hormones Free fatty acids Insulin receptor antibodies Postprandial hyperglycemia is primarily due to underuse of glucose by peripheral tissues, particularly muscle. EE.EE itavsue PROGRESSION NORMAL GLUCOSE TOLERANCE IMPAIRED GLUCOSE TOLERANCE Increased body weight Decreased insulin secretion Reduction in peripheral insulin action DIABETES + Increased hepatic glucose production 18 Metabolic Syndrome Insulin resistance Hypertension Dyslipidemia Procoagulant state Obesity Premature atherosclerosis Subsequent cardiovascular disease Affects at least 25% of the U.S. population. Hemoglobin A1C Valuable assessment of long-term glycemic control. Glucose freely crosses RBC membranes and glycosolates hemoglobin. Percentage of hemoglobin molecules participating in this is proportional to the plasma glucose concentration over the previous 60-90 days. Normal range = 4 - 6% Increased risk of micro- and macrovascular disease starts at ~6.5% Treatment of Type 2 Diet and weight loss Improves hepatic and peripheral tissue insulin sensitivity Enhances postreceptor insulin action May increase insulin secretion Exercise Oral hypoglycemics Iwish thataᵗhg Oral Hypoglycemics Secretagogues Amylin analogue (Pramlintide) Increase insulin availability Suppresses glucagon release Sulfonylureas Delayed gastric emptying Meglitinides CNS-mediated decrease in appetite D-phenylalanine derivatives Incretin-based therapy Biguanides Potentiates insulin release to Suppress excessive hepatic glucose glucose stimulation release Suppresses glucagon release Metformin Delayed gastric emptying CNS-mediated decrease in appetite Thiazolidinediones Improve insulin sensitivity SGL2 Inhibitors Glitazones Sodium-glucose transporter 2 accounts for 90% of glucose reabsorption in the kidney α-glucosidase inhibitors Inhibition impairs glucose Delay gastrointestinal glucose reabsorption, resulting in glycosuria absorption 22 Secretagogues Sulfonylureas Mechanism of action Increase insulin release from pancreas Enhance insulin stimulated utilization of glucose in peripheral tissues May decrease serum glucagon levels Often the initial treatment for Type 2 diabetes Due to progressive dysfunction of β cells, they are not effective indefinitely. Side effects: Hypoglycemia most common Cardiovascular? Sulfonylureas First generation Tolbutamide Short T1/2 = less hypoglycemia Chlorpropamide T1/2 = 32 hours. Higher incidence of hypoglycemia, particularly in elderly population Tolazamide Very slow absorption. No effect for several hours Second generation Glyburide and Glimepiride Once daily dosing before breakfast Glipizide T1/2 very short ~2-4 hours Once before breakfast or multiple doses before meals Minimal chance of hypoglycemia due to short half life Tachyphylaxis to Sulfonylureas Etiology Progressive loss of β cell mass Reduced physical activity Decreased lean body mass Increased fat deposition Secretagogues3ahhhh Mabout hypoglycemia Meglitiinides Repaglinide Regulate potassium efflux through the ATP-dependent potassium channels Very rapid onset Cleared in liver Used alone, or in combination with metformin D-phenylalanine derivatives Nateglinide Acts through closure of ATP-dependent K+ channels Rapid onset and brief duration Increases insulin secretion following a glucose load, but Greatly diminished effect with normoglycemia, therefore Very low incidence of hypoglycemic episodes Biguanides Metformin Earlier drug, phenformin withdrawn due to higher incidence of lactic acidosis, particularly with renal compromise Mechanisms Increase glucose transport across cell membranes, enhancing glucose utilization by muscle and fat Decrease plasma triglycerides and LDL cholesterol Reduce postprandial free fatty acids and their oxidation Used alone or in combination with a sulfonylurea Low incidence of hypoglycemia Thiazolidinediones Pioglitazone and Rosiglitazone Decrease insulin resistance by binding peroxisome proliferator-activated ThroughadrifferentMechanism receptors γ (PPAR-γ) PPAR-γ receptors located in muscle liver and fat, and are important regulators of: Insulin action Expression and release of mediators of: Insulin resistance Lipid homeostasis Adipocyte differentiation Thiazolidinediones Other benefits: Influence genetic expression for encoding proteins for: Glucose and lipid metabolism Endothelial function Atherogenesis Therefore, may influence diabetic dyslipidemia as well as hyperglycemia Seem to be effective in preventing development of diabetes in patients with prediabetes. Side effects: Fluid retention presenting as peripheral edema Alpha Glucosidase Inhibitors Competitive inhibitors of α-glucosidases in proximal intestine, which are necessary for breakdown of complex starches prior to absorption. Acarbose Miglitol Slow digestion of carbohydrates reducing post-prandial blood sugar Used alone, or in combination with sulfonylureas. Have shown some usefulness in preventing overt diabetes in prediabetic patients. 8ft Side effects: Flatulence Diarrhea Abdominal pain Amylin Analogs Pramlintide Injected immediately before meals to modulate postprandial glucose levels via: Suppression of glucagon release Delayed gastric emptying CNS mediated appetite suppression Approved in both Type 1 and Type 2 DM Can not be mixed with insulin in same syringe Incretin-Based Therapies Glucagon-like polypeptide-1 (GLP-1) receptor agonists With an oral glucose load the incretins (GLP-1 and GIP)are released and amplify the glucose-mediated insulin secretion Dipeptidyl peptidase 4 (DPP-4) inhibitors DPP-4 results in the breakdown of GLP-1 and GIP, so inhibiting it prolongs the action of GLP-1 and GIP Actions of these drugs are dependent on glucose level with increased effect at higher glucose levels and decreased effect at normoglycemia Results in less risk of hypoglycemia than the sulfonylureas Incretin-Based Therapies Analogs of GLP-1 (glucagon-like polypeptide 1) Adjunct treatment for Type 2 DM Potentiates glucose-mediated insulin secretion Suppresses postprandial glucagon release Delayed gastric emptying Central anoretic effect Associated with occasional necrotizing, hemorrhagic pancreatitis Exenatide – before breakfast and dinner Linaglutide – once daily Albiglutide – once a week Dulaglutide – once a week  Sitagliptin Saxagliptin Linagliptin Alogliptin Inhibit dipeptidyl peptidase-4 which normally degrades GLP-1 Therefore, increases levels of GLP-1 and GIP resulting in decreased postprandial glucose levels via: Increased glucose-mediated insulin release Decreased glucagon release Side effects: URI, nasopharyngitis, headaches Sodium-Glucose Co-Transporter 2 Inhibitors (SGLT2) SGLT2 involved in 90% of glucose reabsorption in the kidney Normally the kidneys will start to spill glucose at ~ 180 mg/dL In the presence of an SGLT2 inhibitor, glycosuria is “allowed at a much lower threshold ~ 70-90 mg/dL Inhibition of the SGLT2 transporter results in glycosuria and a reduction in blood glucose levels Effects Decreased HbA1C Potential weight loss Decreased bone density with increased fractures Questionable increase in breast and bladder CA with dapaglifozin Canaglifozin Dapaglifozin Empaglifozin Bile Acid Sequestrant Colesevelam Originally intended as a cholesterol lowering drug Useful as a hypoglycemic agent Mechanism unclear May interfere with enterohepatic circulation May interfere with glucose absorption  DRUG EFFECT ON HYPO- CLASS INSULIN GLYCEMIA COMMENTS MECHANISM Sulfonylureas Stimulate insulin Yes Weight gain can occur. Glyburide secretion Glipizide Glimepiride Secretagogues Stimulate insulin Yes Short action. Less nighttime hypoglycemia. Repaglinide secretion (rarely) Postprandial effect. Nateglinide Iii Biguanides Decreased hepatic No Weight loss may occur. Daily dosing. Metformin glucose production Decreases micro- and macrovascular disease. Thiazoladinediones Decreased insulin No Useful in insulin resistant patients. Pioglitazone resistance Rosiglitazone α-Glucosidase Decreased glucose No May produce significant GI distress. inhibitors absorption Acarbose Miglotol Amylin analog Decreased postprandial Yes N/V, diarrhea. Pramlintide glucose Incretin therapy Exenatide Decreased postprandial Yes N/V, diarrhea. Sitagliptin glucose SGLT2 Inhibitors Glycosuria Bone loss Canaglifozin ?Breast/bladder cancer? 37 General Treatment Guidelines Initial Therapy Usually with a sulfonylurea or biguanide “Treat to failure” Combination Therapy Most common is a sulfonylurea + biguanide May add a glitazone or α-glucosidase inhibitor as “triple therapy” Addition of Insulin If combination oral therapy ineffective Usually start with a bed-time dose of intermediate acting insulin Goals in DM2 Therapy Tight control Slows progression of microvascular and possibly macrovascular disease Management of abnormalities in insulin resistance/ Metabolic Syndrome Hb A1c < 7% LDL < 100 mg/dl HDL > 40 mg/dl in men, >50 mg/dl in women Triglycerides < 200 mg/dl BP < 130/80 mmHg Glycemic goals Fasting and preprandial glucose 90-130 mg/dl Peak postprandial glucose < 180 mg/dl donthorite TYPE 2 DIABETES TREATMENT ALGORHYTHM 40 Insulin PREPROINSULIN PROINSULIN INSULIN + C PEPTIDE 42 Control of Insulin Release Basal secretion at a low rate Much higher release in response to glucose and other stimulants: Other sugars Certain amino acids Vagal input Glucagon-like polypeptide-1 44 Biphasic Insulin Secretion Normal individuals have two phases of insulin secretion in response to a meal Phase I - rapid rise and fall Phase II - slower, more gradual increase Type 1 (IDDM) diabetes No insulin secretion Type 2 (NIDDM) Phase I - absent Phase II - blunted Distribution and Degradation Endogenousinsulin Insulin circulates as the free monomer Degradation in the liver operates at near maximal capacity ~60% Degradation in the kidney ~35-40% t1/2 of insulin ~ 3-5 minutes STIMULATION and ACTION of INSULIN 47 INSULIN RECEPTOR Found on most tissues Recognition site 2 α subunits external to cell 2β subunits span the cell membrane β subunits contain a tyrosine kinase Phosphorylate docking proteins Cascade of phosphorylations Second messenger Multiple effects Translocation of GLUT Increased glycogen formation Protein synthesis Lipogenesis Activation of transcription factors 48  Regulation of Glucose Transport Glucose transport is a crucial component of the physiological effects of insulin Glucose transported into cells by facilitated diffusion by means of (GLUT) Insulin stimulates reversible translocation of glucose transporters to the plasma membrane don't GLUT-1 and GLUT-4 - muscle and fat cells GLUT-2 pancreas, liver Watterson RECRUITMENT OF GLUCOSE TRANSPORTERS (GLUT) 50 Insulin Conventional insulin therapy Twice daily injections Intensive insulin therapy Three or more daily injections or continuous infusion Basal Insulins Intermediate NPH, lente, lispro protamine, aspart protamine Long-acting Ultralente, glargine, detemir, degludec Prandial Insulins Short-acting Regular Rapid-acting Lispro, aspart, glulisine ONSET and DURATION of VARIOUS INSULINS 52 APPROACHING PHYSIOLOGIC INSULIN RELEASE 53  COMMON INSULINS dittorite 54  CONVENTIONAL THERAPY war mitter breakfast lunch supper Attepper Bedtime 55 INTENSIVE THERAPY 3/DAY 56 INTENSIVE THERAPY 4/DAY 57 INTENSIVE THERAPY 4/DAY 58 INTENSIVE THERAPY WITH CONTINUOUS 59 CONVENTI0NAL vs. INTENSIVE THERAPY buta inlongtermissues 60 Hypoglycemia Signs and Symptoms Sweating, hunger, paresthesias, palpitations, tremor, anxiety Confusion, weakness, drowsiness, blurred vision, loss of consciousness Treatment Responsive patient Give glucose – as candy, syrup, IV Unresponsive Glucagon injection Oral? INSULIN EFFECTS ON: Gluconeogenesis Glycogenolysis Glycogenesis Lipolysis Lipogenesis 62 COMPLICATIONS OF POOR GLYCEMIC CONTROL 63 DIABETES CONTROL AND COMPLICATIONS TRIAL (DCCT) Reported in 1993: 1441 Type 1 diabetics at 29 centers over 7 years. Comparison of intensive vs. conventional insulin therapy. CONVENTIONAL INTENSIVE HbA1c 8.9% 7.2% Blood Glucose 225 mg/dl 155 mg/dl Retinopathy 60% Nephropathy 60% Neuropathy 60% Cholesterol 34% 64 Microvascular Complications Nephropathy ESRD in 30-40% of Type 1 and 5-10% of Type 2 Process accelerated by: Hypertension Hyperglycemia Hypercholesterolemia Microalbuminuria One third of dialysis patients in U.S. have diabetes. Peripheral neuropathy 50% of patients with diabetes for > 25 years Diabetic Retinopathy Risk reduced with strict glycemic and BP control Macrovascular Complications Cardiovascular disease is the #1 cause of death in diabetics. area Diabetic dyslipidemia is the major contributor. Elevated triglycerides Low HDL Abnormally small, dense, more atherogenic LDL Prevention: Statin therapy Tight glucose control Treatment of hypertension Aspirin prophylaxis Diabetic Autonomic Neuropathy (DAN) Clinical DAN develops over years depending on degree of metabolic control. Early = parasympathetic Resting tachycardia Loss of HR variability during deep breathing Later = sympathetic BP manifestations, including severe postural hypotension May also effect: GI tract resulting in gastroparesis Hypoglycemia awareness Diabetic Gastroparesis Symptoms Nausea / vomiting Early satiety Bloating Epigastric pain Treatment Strict control of blood glucose Multiple small meals Reduced fat content Prokinetics, such as metoclopramide Hypoglycemic Unawareness Normally Low blood glucose stimulates catecholamine release which produces hypoglycemic symptoms Diaphoresis Tremulousness Diabetic Autonomic Neuropathy Counterregulatory hormone responses impaired Warning signs absent Diabetic Ketoacidosis Etiology Infection or acute illness (30-40%) CVA MI Acute pancreatitis Insulin ommission (15-20%) New onset diabetes (15-20%) Mortality Overall (5-10%) Over age 65 (15-28%) With coma (~40%) Diabetic Ketoacidosis Increased glucose levels exceed the capacity of the kidney for tubular reabsorption resulting in: Osmotic diuresis Marked hypovolemia Excess glucose counterregulatory hormones (glucagon) activates lipolysis releasing free fatty acids Gluconeogenesis and ketogenesis in liver tightly coupled resulting in: Excess production of ketones in liver with substrate available from lipolysis. Increased ketoacid creates metabolic acidosis Diabetic Ketoacidosis Potassium deficit of 3-5 mEq/kg Impaired myocardial contractility Diaphragmatic and skeletal muscle dysfunction Conduction abnormalities Treatment Volume resuscitation (NS) Insulin Potassium and phosphate replacement Sodium bicarbonate for pH < 7.1 Magnesium as needed Hyperglycemic Hyperosmolar Syndrome Metabolic disturbances Severe hyperglycemia Hyperosmolarity Dehydration Typically evolves over days to weeks with increased blood sugar and a persistent glycosuric diuresis. Glucose load exceeds the renal tubules capacity for reabsorption resulting in a severe solute diuresis and total body water depletion. Hyperglycemic Hyperosmolar Syndrome Presentation Polyuria/ polydypsia Hypovolemia/ hypotension Tachycardia Organ hypoperfusion Treatment Fluid resuscitation (initially 0.45%NS, later NS) Insulin (bolus + infusion) Electrolyte correction if needed Mortality (10-15%) DIABETIC KETOACIDOSIS vs HYPERGLYCEMIC HYPEROSMOLAR SYNDROME DKA HHS > 300 Glucose (mg/dL) > 600 < 7.3 pH > 7.3 < 18 HCO3- (mEq/L) >15 < 320 SOsm (mOsm/L) > 350 ++ to +++ Ketones 75 Surgery and Diabetes Stress response of surgery Increased Catecholamines Cortisol Growth hormone Insulin resistance of surgery Reduction of peripheral tissue sensitivity to insulin Acute hyperglycemia Increased risk of myocardial ischemia Worse outcome with CNS ischemia