L5- Diabetes MellitusIMAM.ppt

What is diabetes?  Diabetes mellitus (DM) is a chronic condition that is characterised by raised blood glucose levels (Hyperglycemia). 1 Regulation of Plasma Glucose Level 2 How Insuline Decrease Plasma Glucose Level? 3 Classification of DM 1. Type 1 DM • It is due to insulin deficiency an...

What is diabetes?  Diabetes mellitus (DM) is a chronic condition that is characterised by raised blood glucose levels (Hyperglycemia). 1 Regulation of Plasma Glucose Level 2 How Insuline Decrease Plasma Glucose Level? 3 Classification of DM 1. Type 1 DM • It is due to insulin deficiency and is formerly known as. • Type I • Insulin Dependent DM (IDDM) • Juvenile onset DM 2. Type 2 DM • It is a combined insulin resistance and relative deficiency in insulin secretion and is frequently known as. • Type II • Noninsulin Dependent DM (NIDDM) • Adult onset DM 4 3. Gestational Diabetes Mellitus (GDM):  Gestational Diabetes Mellitus (GDM) developing during some cases of pregnancy but usually disappears after pregnancy. 4. Other types:  Secondary DM 5 Etiology 1. Etiology of Type 1 Diabetes 6 7 2. Etiology of Type 2 Diabetes 8 a 9 10 11 12 Characteristics Type 1 Type 2 5-10% 90% Usually < 30 yr + some adults Usually > 40 + some obese children Usually none Insulin is low, normal or high Pathogenesis Autoimmune process Defect in insulin secretion, tissue resistance to insulin, increased HGO Family history Generally not strong Strong Uncommon Common History of ketoacidosis Often present Rare except in stress Clinical presentation moderate to severe symptoms: 3Ps, fatigue, wt loss and ketoacidosis Mild symptoms: Polyuria and fatigue. Diagnosed on routine physical examination Insulin, Diet Exercise Diet ,Exercise Oral antidiabetics,Insulin 13 % of diabetic pop Age of onset Pancreatic function Obesity Treatment Risk Factors • Type 2 DM – Family History – – – Obesity Habitual physical inactivity Previously identified impaired glucose tolerance (IGT) or impaired fasting glucose (IFG) – Hypertension – Hyperlipidemia 14 15 Treatment Desired outcome - Relieve symptoms Reduce mortality Improve quality of life Reduce the risk of microvascular and macrovascular disease complications - Macrovascular complications: Coronary heart disease, stroke and peripheral vascular disease - Microvascular Complications: Retinopathy, nephropathy and neuropathy 16 Treatment How to achieve the goals ? - Near normal glycemic control reduce the risk of developing microvascular disease complications - Control of the traditional CV risk factors such as smoking, management of dyslipidemia, intensive BP control and antiplatelet therapy. 17 Treatment General approaches - Medications Dietary and exercise modification Regular complication monitoring Self monitoring of blood glucose Control of BP and lipid level 18 Treatment Glycemic goals 19 Treatment Complication monitoring - Annual eye examination Annual microalbuminuria Feet examination BP monitoring Lipid profile 20 Treatment Nonpharmacological therapy Diet - For type 1 the goal is to regulate insulin administration with a balanced diet - In most cases, high carbohydrate, low fat, and low cholesterol diet is appropriate - Type 2 DM patients need caloric restriction 21 Treatment Nonpharmacological therapy Activity - Exercise improves insulin resistance and achieving glycemic control. - Exercise should start slowly for patients with limited activity. - Patients with CV diseases should be evaluated before starting any exercise 22 23 Treatment Pharmacological therapy - Insulin (Type 1 and Type 2 DM) Sulfonylurea (Type 2 DM) Biguanides (Type 2 DM) Meglitinides (Type 2 DM) Thiazolidinediones Glitazones (Type 2 DM)  -Glucosidase inhibitors (Type 2 DM) 24 Pharmacological Treatment of Type 2 DM Strategy for Controlling Hyperglycemia Absorption from Diet Biosynthesis in Liver -Glucosidase Biguanides Inhibitors Cellular Uptake Serum Sugar Biguanides; thiazolidinediones Pancreas Insulin Sulfonylureas Meglitinide 25 1. Sulfonylureas Pharmacological effect • Stimulate the pancreatic secretion of insulin 26 Sulfonylureas (Cont’d) Classification • First generation • e.g. tolbutamide, chlorpropamide, and acetohexamide • Lower potency, more potential for drug interactions and side effects • Second generation • e.g. glimepiride, glipizide, and glyburide • higher potency, less potential for drug interactions and side effects • All sulfonylurea drugs are equally effective in reducing the blood glucose when given in equipotent doses. 27 Major Pharmacokinetic Properties of Sulfonyl Ureas Eqv. Dose (mg) Duration (h) Active metabolites 10001500 12-24 Yes (p-OH derivative) Chlorpropamide 250-375 24-60 Yes (2’-OH and 3’OH groups) Tolazamide 250-375 12-24 No (4-COOH derivative) 10 10-24 No (cleavage of pyrazine ring) 5 16-24 Some (trans + cis 4’-OH groups) 1-2 24 Yes (-OH on CH3 of R’ 28 group) First Generation Tolbutamide Second generation Glipizide Glyburide (glibenclamide) Third generation Glimepiride Sulfonylureas (Cont’d) Efficacy – HbA1c: 1.5 – 1.7% reduction. – FPG: 50 – 70 mg/dL reduction. – PPG: 92 mg/dL reduction. Adverse effects – Hypoglycemia – Hyponatremia (with tolbutamide and chlorpropamide) – Weight gain 29 Sulfonylureas (Cont’d) Drug interactions 30 2. Short-acting Secretogogues – Repaglinide – Nateglinide Pharmacological effect – Stimulation of the pancreatic secretion of insulin – The insulin release is glucose dependent and is decreased at low blood glucose – With lower potential for hypoglycemia (incidence 0.3%) – Should be given before meal or with the first bite of each meal. If you skip a meal don’t take the dose! 31 Secretogogues (Cont’d) Adverse effect – Incidence of hypoglycemia is very low about 0.3 % Drug Interactions – Inducers or inhibitors of CYP3A4 affect the action of repaglinide – Nateglinide is an inhibitor of CYP2C9 32 3. Biguanides Metformin (Glucophage) Pharmacological effect – Reduces hepatic glucose production – Increases peripheral glucose utilization Adverse effects – Nausea, vomiting, diarrhea, and anorexia – Phenformin: another biguanide, was taken off the market because it causes lactic acidosis in almost 50% of patients – As a precaution metformin should not be used in patients with renal insufficiency, CHF, conditions that lead to hypoxia 33 4. Glitazones (PPAR Agonists) PPAR Agonists: Peroxisome proliferator-activated receptor  gonists - Rosiglitazone - Pioglitazone Pharmacological effect – Reduces insulin resistance in the periphery (Sensitize muscle and fat to the action of insulin) and possibly in the liver – The onset of action is slow taking 2-3 months to see the full effect – Edema and weight gain are the most common side effects. (no hepatotoxicity) 34 -Glucosidase Inhibitors - Acarbose - Miglitol Pharmacological effect • Prevent the breakdown of sucrose and complex carbohydrates – The net effect is to reduce postprandial blood glucose rise – The effect is limited to the luminal side of the intestine with limited systemic absorption. Majority eliminated in the feces. – Postprandial glucose conc is reduced. – FPG relatively unchanged. – Average reduction in HbA1c: 0.3-1.0% 35 II. Oral hypoglycemic and other drugs, used in DM type 2 1. Biguanides: Metformin •usually first line drug for type 2 DM •reduces intestinal glucose absorption •stimulates anaerobic glycolysis •stimulates glucose uptake •enhances insulin receptor binding Metformin •excreted exclusively by the kidney •does not increase weight and preferable in the obese •GI side effects •rarely lactic acidosis 2. Sulfonylureas I generation: •Chlorpropamide and Tolbutamide (Out) II generation: •Glibenclamide (Maninil: tab. 5 mg) •Gliclazide (Diaprel MR) •Glipizide •Gliquidone Mechanism of action •promote enhanced insulin release from the pancreas •leads to a reduction in hepatic glucose production Unwanted effects •Hypoglycemia, weight gain •facial flushing following alcohol ingestion Sulfonylureas – important drug interactions: •displacement from protein binding sites – salicylates and sulphonamides •interference with hepatic metabolism – inducers: rifampicin, phenytoin – inhibitors: cimetidine •reduction of renal elimination – allopurinol, salicylates 3. Meglitinides: stimulate the release of insulin from pancreas by closing ATP-dependent potassium channels. - Nateglinide - Repaglinide 4. Glucosidase inhibitors - Acarbose (Gluco Bay): p.o. •Inhibits intestinal alpha-glucosidase •Decreases intestinal absorption of the mono- and polysaccharides. •Produces flatulence and diarrhoea. diarrhoea 5. Thiazolidinediones (TZDs) They increase tissue insulin sensitivity but have serious ADRs and the EMA recommended in Sept (2010) that they be suspended from the EU market: market - Rosiglitazone (Avandia) has high cardiovascular risks. risks - Pioglitazone causes bladder tumors. tumors - Troglitazone causes hepatitis. hepatitis 6. Glucagon-like peptide-1 (GLP-1) agonists (in type 2 DM): increase pancreatic secretion of insulin: Exenatide Bydureon (s.c./7 days): $323/4 doses, resp. $4200 per year Liraglutid Liraglutid is a GLP-1 agonist, which reduces, BM, HbA1C, and systolic blood pressure, and improves beta cell function of the pancreas (s.c. once a day) 7. Inhibitors of Dipeptidil peptidase-4 (DPP-4): prevent degradation of incretin GLP-1 Sitagliptin (p.o.) Vildagliptin (p.o.) 8. Inhibitors of reabsorption of glucose (SGLT2 inhibitors): p.o. •Canagliflozin blocks in renal proximal tubule sodium / glucose co-transporter protein 2 (SGLT2), which re-absorbed 90% of the filtrated glucose. The result is increased glucosuria and plasma glucose levels are lowered. ADRs: Hypoglycaemia, vulvovaginal candidiasis urinary tract infections, polyuria, frequent urination. Pharmacotherapy :Type 2 DM General considerations: - Consider therapeutic life style changes (TLC) for all patients with Type 2 DM - Initiation of therapy may depend on the level of HbA1C - HbA1C < 7% may benefit from TLC - HbA1C 8-9% may require one oral agent - HbA1C > 9-10% my require more than one oral agent 49 Pharmacotherapy :Type 2 DM Obese Patients >120% LBW: Metformin or glitazone Add SU or short-acting insulin secretagogue Add Insulin or glitazone 50 Pharmacotherapy :Type 2 DM Non-obese Patients <120% LBW: SU or short-acting insulin secretagogue Add Metformin or glitazone Add Insulin 51 Pharmacotherapy :Type 2 DM Elderly Patients with newly diagnosed DM : SU or short-acting insulin secretagogue or a-glucosidase inhibitor or insulin Add or substitute insulin 52 Pharmacotherapy :Type 2 DM Early insulin resistance : Metformin or glitazone Add glitazone or metformin Add SU or short-acting insulin secretagogue or insulin 53 Clinical Trials: Diabetes Mellitus 1- Diabetes Prevention Program • Population: Over-weight patients with impaired glucose tolerance. • Intervention: Low-fat diet and 150 min of exercise per week. • Results: Decrease the risk of progression to Type 2 DM by 58% 54 Pharmacotherapy :Type 1 DM The choice of therapy is simple All patients need Insulin 55 Insulin Pharmacological effect: Anabolic Anticatabolic - - Glucose uptake Glycogen synthesis Lipogenesis Protein synthesis - Triglyceride uptake Inhibits gluconeogenesis Inhibits glycogenolysis Inhibits lipolysis Inhibits proteolysis Inhibits fatty acid oxidation 56 Insulin (Cont’d) Strength - The number of units/ml e.g. U-100 , U-20, U-10 Source - Pork: Differs by one a.a. - Beef-Pork - Human (recombinant DNA technology) 57 Insulin (Cont’d) Onset and duration of effect Changing the properties of insulin preparation can alter the onset and duration of action - Lispro: (Monomeric) absorbed to the circulation very rapidly - Aspart: (Mono- and dimeric) absorbed to the circulation very rapidly - Regular: (Hexameric) absorbed rapidly but slower than lispro and aspart 58 Insulin (Cont’d) Onset and duration of effect - Lent insulin: Amorphous precipitate of insulin and zinc and insoluble crystals of insulin and zinc. Releases insulin slowly to the circulation - NPH: R-insulin + Protamine zinc insulin. Releases insulin slowly to the systemic circulation - Insulin glargine: Prepared by modification of the insulin structure. Precipitate after S.C. injection to form microcrystals that slowly release insulin to the systemic circulation (N.B. cannot be mixed with other insulins) 59 Insulin (Cont’d) Onset and duration of effect - Rapid-acting insulin - e.g. Insulin lispro and insulin aspart - Short-acting insulin - e.g. Regular insulin - Intermediate-acting insulin - e.g. NPH and Lente insulin - Long-acting insulin - e.g. Insulin Glargine - Mixture of insulin can provide glycemic control over extended period of time - e.g. Humalin 70/30 (NPH + regular) 60 Insulin (Cont’d) Adverse effects - Hypoglycemia - Treatment: - Patients should be aware of symptoms of hypoglycemia Oral administration of 10-15 gm glucose IV dextrose in patients with lost consciousness 1 gm glucagon IM if IV access is not available - Skin rash at injection site - Treatment: Use more purified insulin preparation - Lipodystrophies (increase in fat mass) at injection site - Treatment: rotate the site of injection 61 Insulin (Cont’d) Drugs interfering with glucose tolerance • The most significant interactions are with drugs that alter the blood glucose level: - Diazoxide Thiazide diuretics Corticosteroids Oral contraceptives Streptazocine Phenytoin • All these drugs increase the blood glucoseconcentration. • Monitoring of BG is required 62 Insulin (Cont’d) Methods of Insulin Administration • Insulin syringes and needles • Pen-sized injectors • Insulin Pumps 63 Pharmacotherapy :Type 1 DM The goal is: To balance the caloric intake with the glucose lowering processes (insulin and exercise), and allowing the patient to live as normal a life as possible 64 Insulin Concentration Pharmacotherapy :Type 1 DM Breakfast Lunch Supper Time of day Normal insulin secretion during he day - Constant background level (basal) - Spikes of insulin secretion after eating 65 Pharmacotherapy :Type 1 DM - -The insulin regimen has to mimic the physiological secretion of insulin - With the availability of the SMBG and HbA1C tests adequacy of the insulin regimen can be assessed - More intense insulin regimen require more intense monitoring 66 Pharmacotherapy :Type 1 DM Example: 1- Morning dose (before breakfast): Regular + NPH or Lente 2- Before evening meal: Regular + NPH or Lente Require strict adherence to the timing of meal and injections 67 Pharmacotherapy :Type 1 DM Modification - NPH evening dose can be moved to bedtime - Three injections of regular or rapid acting insulin before each meal + long acting insulin at bedtime (4 injections) - The choice of the regimen will depend on the patient 68 Pharmacotherapy :Type 1 DM How much insulin ? - A good starting dose is 0.6 U/kg/day - The total dose should be divided to: - 45% for basal insulin - 55% for prandial insulin The prandial dose is divided to - 25% pre-breakfast - 15% pre-lunch - 15% pre-supper 69 Pharmacotherapy :Type 1 DM Example: For a 50 kg patient - The total dose = 0.6X50 = 30 U/day - 13.5 U for basal insulin (45% of dose) - Administered in one or two doses - 16.5 U for prandial insulin (55% of dose) The 16.5 U are divided to: - 7.5 U pre-breakfast (25%) - 4.5 U pre-lunch (15%) - 4.5 U pre-supper (15%) 70 Pharmacotherapy :Type 1 DM Monitoring - Most Type 1 patients require 0.5-1.0 U/kg/d - The initial regimen should be modified based on: - Symptoms - SMBG - HbA1C 71 Pharmacotherapy :Type 1 DM Monitoring 72 Pharmacotherapy :Type 1 DM Insulin Pump Therapy - This involves continuous SC administration of short-acting insulin using a small pump - The pump can be programmed to deliver basal insulin and spikes of insulin at the time of the meals - Requires intense SMBG - Requires highly motivated patients because failure to deliver insulin will have serious 73 consequences Pharmacotherapy :Type 1 DM Insulin Pump 74 Diabetes Mellitus Complications 1. Hypoglycemia - Cause: Missing meals or excessive exercise or too much insulin - Symptoms: Tachycardia, palpitation, sweating, nausea, and vomiting. Progress to mental confusion, bizarre behavior and coma - Treatment: Candy or sugar IV glucose Glucagon 1 gm IM - Identification: MedicAler bracelet 75 Diabetes Mellitus Complications 2. Diabetes retinopathy - Microaneurysm Hemorrhage Exudates Retinal edema other 76 Diabetes Mellitus Complications 3. Diabetes nephropathy - 30-40 % of all type 1 DM patients develop nephropathy in 20 years - 15-20 % of type 2 DM patients develop nephropathy - Manifested as: - Microalbuminuria - Progressive diabetic nephropathy leading to endstage renal disease 77 Diabetes Mellitus Complications Diabetes nephropathy (Cont’d) - All diabetic patients should be screened annually for microalbuminurea to detect patients at high risk of developing progressive diabetic nephropathy - Tight glycemic control and management of the blood pressure can significantly decrease the risk of developing diabetic nephropathy. - ACE-inhibitors are recommended to decrease the progression of nephropathy 78 Diabetes Mellitus Complications 4. Diabetes neuropathy Autonomic neuropathy: - Manifested by orthostatic hypotension, diabetic diarrhea, erectile dysfunction, and difficulty in urination. 79 Diabetes Mellitus Complications 5. Peripheral vascular disease and foot ulcer Incidence of gangrene of the feet in DM is 20 fold higher than control group due to: - Ischemia - Peripheral neuropathy - Secondary infection 80 Special Patient Population 1. Adolescent Type 2 DM - Type 2 DM is increasing in adolescent - Lifestyle modification is essential in these patients - If lifestyle modification alone is not effective, metformin the only labeled oral agent for use in children (10-16 years) 81 Special Patient Population 2. Gestational DM - Dietary control - If blood glucose is not controlled by dietary control, insulin therapy is initiated - One dose of NPH or NPH + regular insulin (2:1) given before breakfast. Adjust regimen according to SMBG. - Sulfonylureas: Effective, but require further studies to demonstrate safety. 82 Special Situations 3. Diabetic ketoacidosis - It is a true emergency - Usually results from omitting insulin in type 1 DM or increase insulin requirements in other illness (e.g. infection, trauma) in type 1 DM and type 2 DM - Signs and symptoms: - Fatigue, nausea, vomiting, evidence of dehydration, rapid deep breathing, fruity breath odor, hypotension and tachycardia 83 Special Situations Diabetic ketoacidosis (Cont’d) - Diagnosis - Hyperglycemia, acidosis, low serum bicarbonate, and positive serum ketones - Abnormalities: - Dehydration, acidosis, sodium and potassium deficit - Patient education is important 84 Special Situations Diabetic ketoacidosis (Cont’d) Management: - Fluid administration: Rapid fluid administration to restore the vascular volume, - IV infusion of insulin to restore the metabolic abnormalities. Titrate the dose according to the blood glucose level. - Potassium and phosphate can be added to the fluid if needed. Follow up: - Metabolic improvement is manifested by an increase in serum bicarbonate or pH. 85