Pharmacotherapy of Diabetes Mellitus PDF

Pharmacotherapy of Diabetes Mellitus Dr Manal Buabeid 1  Learning Outcomes  Describe the types and causes of diabetes mellitus (DM).  Identify the treatment of diabetes mellitus (classes of antidiabetic drug).  Characterize the antid...

Pharmacotherapy of Diabetes Mellitus Dr Manal Buabeid 1  Learning Outcomes  Describe the types and causes of diabetes mellitus (DM).  Identify the treatment of diabetes mellitus (classes of antidiabetic drug).  Characterize the antidiabetic drugs that are different types of Insulin.  Describe the characteristics of the oral antidiabetic Secretagogue drugs.  Explain the actions of parenteral antidiabetic drugs e.g. Incretin mimetics.  Identify other oral antidiabetic drugs by their effect on glucose transport. 2  Diabetes Mellitus (DM) DM is a clinical syndrome characterized by disturbance in carbohydrate, fat, protein metabolism due to either insulin deficiency or insulin resistance. resistance Types of DM: Type 1-IDDM: It is an autoimmune disease characterized by a loss of pancreatic Beta cells. Type 2 –NIDM: a disease characterized by ß- cells that desensitized to a glucose challenge & peripheral tissues that are resistant to insulin. (produce insulin but do not release or utilize it normally). Gestational DM: Appears during pregnancy and disappears after labor. 3 Manifestations of DM Polyuria, Polydipsia, Polyphagia, and Loss of weight. Complications of DM: Chronic hyperglycemia leads to Neuropathy, Retinopathy, Nephropathy, Angiopathy, Recurrent infections, Diabetic ketoacidosis. Drugs that impair glucose tolerance include oral contraceptives (combination), thiazide diuretics & corticosteroids. 4 Diagnosis of DM Urine analysis (Glucosuria & Ketonuria). Blood glucose (BG) [Fasting & 2-hr after oral 75 g glucose]. Glycated hemoglobin (HbA1C (for detecting average blood glucose for last 3 months). Normal Prediabetes DM Fasting BG < 110 mg/dl 110 - 125 mg/dl ≥ 126 mg/dl Non- fasting / < 200 mg/dl ≥ 200 mg/dl Random glucose 2-hr after oral 75 g 140 - 199 mg/dl ≥ 200 mg/dl glucose HbA1C < 6% 6 – 6.4% ≥ 6.5% 5 Diabetes Mellitus (DM) Type 1 Type 2 Age of onset Usually < 30yrs Usually > 30yrs Acuteness of onset Usually sudden Usually gradual Presenting features Polyuria, polydepsia, Often asymptomatic polyphagia, acidosis Obesity Often thin Common (trunkal) Insulin requirement Always Often unnecessary Insulin sensitivity Sensitive Resistance Control by oral agents Never Frequent Control by diet alone Never Frequent Ketoacidosis Frequent Seldom, unless under stress Specific Human Leukocyte Yes No Antigen (HLA) 6 Tyrosine Kinase receptor I Cell Activation of Membrane enzyme Intracellular reuptake of glucose, K+, Mg+2, R Po4 & amino acid membrane Activation of - ↑ Glycogenesis Cellular enzyme “by ↑ Glycogen synthesis” Tyrosine - ↑ Protein synthesis-anabolic ↓AA “by no conversion of AA to Glucose” Kinase ↓ Gluconeogenesis. - ↑ Lipogenesis - ↓FFA Inactivation of - ⇩ Glycogenesis Cellular enzyme - ⇩ Protein synthesis ↑catabolic- ↑ Gluconeogenesis “by conversion of AA to Glucose” - ↑ Lipolysis - ↑ FFA 7 As a result of Tyrosine Kinase inhibition 1- ⇧ glucose in blood (hyperglycemia) Glucose is NOT reuptaken by cells & No conversion to Glycogen. 2- Glucose in urine = Glycosuria when blood sugar exceeds 180 mg/ 100 ml (the renal threshold) ⇨ Polyuria (production of large volumes of dilute urine associated with cellular K+ depletion & polydipsia - intensive thirst-); + Polyphagia (Eat a lot). So, NO energy the body will “try” to get it from Protein 3- ⇧ catabolic activity (protein)⇨ Gluconeogenesis (source of energy) ⇨ muscle wasting ⇨ loss of body mass (reduce body weight). Also, the body will “try” to get energy from Fat 4- ⇧ in lipolysis ⇨ (↑ FFA) ketone bodies ⇨ ketonuria & Acidosis (ketoacidosis coma) in advanced stages 8  Treatment of DM  Diet control & exercise  Diet + Insulin – Type 1  Diet + Oral hypoglycemic drugs – Type 2.  Patient education. 9  Type 1 DM  Insulin is essential & a true replacement therapy in patients with Type 1 DM. Also it is NOT essential (BUT NOT contraindicated) in patients with Type 2 DM - with cases of pregnancy, before surgery, severe infection & ketoacidotic coma.  Insulin is given SC or IV in emergency therapy. BUT NOT ORALLY WHY? Source of insulin: 1- Beef, pork ⇨ antigenic & can induce allergy & resistance from body. 2- Human insulin by genetic engineering (Expensive compared with no 1). Not antigenic. 10  Types of Insulin Rapid acting insulins, duration lasts 2-5 hr e.g. Aspart peak 10 - 20 min Lispro peak 15 - 30 min Glulisine peak 20 – 30 min given by SC before meal. 11  Types of Insulin Short acting insulins, insulins duration lasts 3-8 hr e.g. Regular Insulin peak 30 – 60 min (Neutral, Soluble), & given by SC & The ONLY form given by IVI in emergencies such as Diabetic ketoacidosis) 12 Types of Insulin Intermediate acting insulins, insulins last up to 12 hr e.g. NPH=Neutral NPH Protamine Hagedorn (Isophane Insulin) peak 1 – 2 hr Given by SC 13 Types of Insulin Long acting insulins, last up to 24 hr e.g. Detemir peak 60 – 90 min. Glargine No peak. 14 15 “Effect of insulin on glucose uptake and metabolism. 1.Insulin binds to its receptor, 2.which in turn starts many protein activation cascades. 3.These include: translocation of Glut-4 transporter to the plasma membrane & influx of glucose, 4.glycogen synthesis, 5.glycolysis and 6.fatty acid synthesis. 16 Actions of Insulin Skeletal Adipose Liver muscle tissue Increases glycogen Increases glycogen synthesis Increases triglyceride storage synthesis Increases protein Reduces protein catabolism Reduces protein catabolism synthesis It uses GLUT 2 to move It uses GLUT 4 to move It uses GLUT 4 to move most sugar into cell membranes sugar into cell membranes sugar into cell membranes. Increased synthesis, using: Pyruvate kinase Increased synthesis/ activity in Phosphofructokinase adipose tissue under influence of Glucokinase insulin through Lipoprotein Lipase. Lipase 17 S/Es of Insulin: Hypoglycemia ⇨ hypoglycemia coma, treated by giving IVI of glucose & glucagon (SC / IM), IM Immunological reaction, Skin reaction (lipo-atrophy at injection site) & Hypokalemia. Hypokalemia WHAT IS THE TREATMENT? (MW) 18  Type 2 DM Oral Anti-diabetic drugs Mechanisms to reduce blood sugar:  Secretagogues Sulfonylureas, Meglitinide.  Reduce the bio-synthesis of glucose in liver – Biguanides (Metformin).  Increase the sensitivity of target cells to insulin – Thiazolidinediones.  Retard the absorption of sugars from the GI tract – Acarbose, Miglitol. 19  Type 2 DM  Secretagogues A) Sulphonylurea: Chlorpropamide (LA), Tolbutamide (SA) {First generation} Glyburide (LA), Glimepiride, Glibenclamide & Glipizide (SA) {Second generation} – more potent & less S/Es. B) Meglitinide {Third generation} e.g. Repaglinide, Nateglinide They block ATP-dependent K+ channel on the membrane of pancreatic ß- cells resulting in ↑ K+ intracellular → depolarization → open of Ca+2 channel → Ca+2 influx, to release more insulin. They are not function when the pancreas is not producing insulin. (30%) 20 21 Oral hypoglycemic agents S/E of Secretagogues: Weight gain, hypoglycemia (LA). D/I: Alcohol may potentiate hypoglycemia effect, Also, Sulphonamides can enhance the hypoglycemic effect of Sulphonylureas. They are to be avoided in elderly (except Tolbutamide) & in those with hepatic (ALL) & renal insufficiency (Tolbutamide Not in RF). Also, in pregnancy & lactation 22  Biguanides e.g. Metformin (Glucophage), Actions of Metformin Adipose/ Gut & Liver Kidney Pancreas peripheral tissue Activates AMP- Activates AMP- Activates AMP- Slows glucose stimulated protein stimulated protein stimulated protein uptake in the gut kinase kinase kinase Inhibits Inhibits Increases glucose Reduces plasma gluconeogenesis gluconeogenesis uptake glucagon levels 23 Metformin (Glucophage)  It is excreted unchanged by the kidney.  They can produce lactic acidosis making ketoacidosis coma worse & rarely cause hypoglycemia (BUT euglycemia).  The more frequent S/Es are NVD  Hence, they have very limited use particularly in obese patients (suppress appetite) & can be used alone or with sulphonylureas).  They are NOT given patient with Hepatic & Renal insufficiency & HF, also pregnancy.  In long-term use →Vitamin B12 malabsorption & folate deficiency. 24  Post insulin receptor actions: “insulin sensitizers” e.g. Rosiglitazone, glitazone Pioglitazone  Given ORALLY & used specially in Type 2 DM especially in patient with insulin resistance.  They are considered as “euglycemics”  They stimulate the Tyrosine Kinase like insulin. S/Es: Elevated hepatic enzymes C/Is: Hepatic impairment & HF. 25  Alpha (a)- glucosidase inhibitors: e.g. Miglitol, Acarbose, Used in the treatment of obesity & type 2 DM as monotherapy or with sulphonylureas. a- glucosidase inhibitors in the intestinal tract reduces breakdown of more polysaccharides to monosaccharides. So, this limits glucose absorption following carbohydrate ingestion. It is not absorbed systemically. S/Es: abdominal pain, diarrhea, flatulence. C/Is: pregnancy & breastfeeding. 26  Incretin-Based Therapies  Glucagon like Peptide: GLP-1 analogue: analogue GLP-1 receptor agonists Exenatide and Liraglutide  They are is similar in structure to GLP-1 but was modified to resist breakdown by the enzyme DPP-4.  GLP is an incretin released from the small intestine which increase the glucose dependent insulin secretion.  Xenatide suppress glucagon release and reduce appetite.  It is administered by SC injection. injection 27  Sitagliptin Sitaglipti Oral Exenatide Injection Food DPP-4 intake Inhibitors GLP-1 analogue DPP-4 Inactivate GLP-1 ↑Insuli n Incretins (GLP1) ↓Glucose Pancreas levels ↓Glucag on Dipeptidyl peptidase 4 (DPP-4) inhibitors: inhibitors Sitagliptin, Saxagliptin, & Vildagliptin 28  Gliptins, or DPP-4 inhibitors Sitagliptin, Vildagliptin, Saxagliptin & Linagliptin an oral anti-diabetic drug. It inhibit the dipeptidyl peptidase-4 (DPP-4), DPP-4 an enzyme which inactivates the incretins GLP-1 (glucagon-like peptide-1) and GIP ( Gastric inhibitory peptide), that are released in response to a meal. It potentiates the secretion of insulin and suppress the release of glucagon by the pancreas. 29   SGLT-2 Inhibitors e.g. Dapagliflozin, Canagliflozin and Empagliflozin  Kidney continuously filters glucose through Glomerulus which is reabsorbed back from PT by Na+ - glucose co- transporter-2 (SGL-2). SGL-2  Sodium-glucose co-transporter-2 (SGLT-2) inhibitors are considered a new class of oral hypoglycemics. hypoglycemics  Effective even in case of low reserve of the pancreatic beta cell. “An insulin independent mechanism of action”  Advantages of SGLT-2 inhibitors, weight loss and no hypoglycemia 30 31 Adverse effects related to SGLT-2 inhibitors  An increase in the risk of fungal infection of the urinary tract (Vulvovaginal Candidiasis),  Increase in frequency of urination and increase in the potassium concentration in the blood (hyperkalemia).  Acute kidney injury in patients who are treated with Canagliflozin and Dapagliflozin. agliflozin  The drug should be avoided in patients with predisposing factors for acute kidney injury, and appropriate dose adjustments need to be made in renal impairment patients.  An increased risk of venous thromboembolism and hemoconcentration consequent to the volume depletion. 32 Endocrine pancreas Glucagon  It has positive inotropic action and chronotropic action on the heart.  It acts by stimulation of glucagon receptors and not through beta 1 receptors.  This is the basis for using glucagon in beta blocker overdose. 33 34 Comparing the effects of insulin on the skeletal muscle and adipose tissue, which statement is correct. a.In the presence of insulin, skeletal muscle decreases triglyceride synthesis while adipose tissue also increases triglyceride synthesis. b.In the presence of insulin, skeletal muscle increases glycogen synthesis while adipose tissue increases triglyceride synthesis. c.In the presence of insulin, skeletal muscle decreases glycogen synthesis while adipose tissue decreases triglyceride synthesis. d.In the presence of insulin, skeletal muscle decreases glycogen synthesis while adipose tissue increases triglyceride synthesis. e.In the presence of insulin, skeletal muscle increases triglyceride synthesis while adipose tissue increases glycogen synthesis. 35 Which intracellular enzyme is NOT upregulated in the presence of insuli a.Phosphofructokinase b.Glucokinase c.Pyruvate kinase d.Lipoprotein lipase e.Glycogen phosphorylase 36  To which membrane protein do sulfonylurea drugs bind and modify? a.Membrane bound calcium channels. b.Membrane bound sodium channels. c.Intracellular receptors. d.Intranuclear receptors. e.Membrane bound potassium channels. Which patient should receive sulfonylurea drugs?.17 year old male with type 1 diabetes..21 year old male with cystic fibrosis-related diabetes..75 year old female with type 2 diabetes and early stage Alzheimer's dis.29 year old female with autoimmune pancreatitis..45 year old female with history of diabetes mellitus type 2. 37  is a main reason metformin is a popular medication to treat diabetes ty ients can not become hypoglycemic tformin releases an exact amount of insulin y and effective advertising campaign by Bristol-Myers Squibb tformin decreases insulin sensitivity ients can not become hyperglycemic Which of the following is NOT a mechanism of action for metformin? a.Decreases glucose uptake in the gut b.Decreases the reabsorption rate of glucose in urine, reducing blood glucose levels. c.Activates AMP in the liver d.Activates AMP in adipose tissue e.Activates AMP in the kidney 38 Which of the following is the major drawback to using acarbose in most patients? a.Constipation b.Frequent episodes of hypoglycemia c.Weight gain d.It is difficult to remember to take the pill before a meal e.GI upset Which of the following is NOT an effect of PPAR-gamma activation? a.Increased glucose uptake in adipocytes b.Affects fat distribution in the body c.Activates the satiety receptors in the brain d.Inhibits hepatic gluconeogenesis e.Increases glucose uptake in myocyte 39  Which of the following is NOT a side effect of the TZD class of medication? a.Bone fracture b.Frequent hypoglycemia c.Heart failure d.Fluid retention e.The drug requires frequent liver enzyme checks h statement most accurately describes the mechanism of action of incre s on the small bowel to reduce blood sugar. s of the pancreas to reduce blood sugar. s on the pancreas to increase blood lipase levels. s on the pancreas to increase blood sugar. s on the kidney to reduce blood sugar. 40 What is the difference between DPP-4 inhibitors and GLP- 1 analogues? a.GLP-1 analogues decreases HbA1c by a greater amount than DPP-4 inhibitors b.GLP-1 analogues increase risk of pneumonitis DPP-4 inhibitors increase risk of GI upset c.GLP-1 analogues are pills DPP-4 inhibitors are injections d.GLP-1 analogues act on DPP-4 to increase levels of incretins DPP-4 inhibitors acts as an analogue of incretin e.DPP-4 inhibitors act on DPP-4 to increase levels of incretins GLP-1 analogues acts as an analogue of incretin 41 42 43 44 45 46 Anti-diabetic drugs Glucagon like Peptide : GLP-1 analog: Xenatide : 47 48 49 50  Oral Mechanism Advantages Disadvantage Cos Class s t Biguanide Activates AMP- Extensive Gastrointestinal Low s kinase (?other) experience Lactic acidosis  Hepatic No hypoglycemia (rare) glucose Weight neutral B-12 deficiency production ?  CVD Contraindications Sulfonylu Closes K Extensive Hypoglycemia Low ATP  Weight reas experience channels  Microvascular Low durability  Insulin risk ? Blunts secretion ischemic preconditioning Meglitinid Closes K  Postprandial Hypoglycemia Mod ATP  Weight es glucose. channels Dosing flexibility ? Blunts  Insulin ischemic secretion preconditioning Dosing frequency Diabetes Care 2015;38:140-149; 1. Properties of anti-hyperglycemic agents  Weight Diabetologia 2015;58:429-442 51 TZDs PPAR- activator No hypoglycemia Low  Oral Mechanism Advantages Disadvantag Cost Class es - Inhibits - No hypoglycemia Mod Glucosida glucosidase Nonsystemic Gastrointestina. se Slows  Postprandial l inhibitors carbohydrate glucose Dosing digestion / ?  CVD events frequency absorption Modest  A1c DPP-4 Inhibits DPP-4 No hypoglycemia Angioedema / High inhibitors Increases incretin Well tolerated urticaria (GLP-1, GIP) levels ? Pancreatitis ?  Heart failure Bile acid Bind bile acids No hypoglycemia High sequestra ?  Hepatic  LDL-C Gastrointestina nts glucose production l Modest  A1c Dosing frequency Dopamine Activates DA No hypoglyemia Modest  A1c High -2 receptor ?  CVD events Dizziness, agonists Alters fatigue Diabetes Care 2015;38:140-149; 52 hypothalamic 1. Properties of anti-hyperglycemicDiabetologia agents Nausea 2015;58:429-442 Injecta Mechanism Advantages Disadvantages Cost ble Class Amylin Activates  Weight Gastrointestinal High mimetic amylin receptor  Postprandial Modest  A1c s  glucagon glucose Injectable  gastric Hypo if insulin emptying dose not reduced  satiety Dosing frequency Training requirements GLP-1 Activates GLP-  Weight Gastrointestinal High recepto 1 R No hypoglycemia ? Pancreatitis r  Insulin,   Postprandial  Heart rate agonist glucagon glucose Medullary ca s  gastric  Some CV risk (rodents) emptying factors Injectable  satiety Training requirements Insulin Activates Universally Hypoglycemia Variabl insulin receptor effective Weight gain e Myriad Unlimited efficacy ? Mitogenicity Diabetes Care 2015;38:140-149;  Microvascular 1. Properties of anti-hyperglycemic agents Diabetologia 2015;58:429-442 Injectable 53