Diabetes Mellitus Pharmacology III Past Paper PDF Fall 2024-2025

FALL 2024-2025 PCT414 Pharmacology III Diabetes Mellitus Assoc. Prof. Mennatallah Ismail Intended learning outcomes 1- Discuss the causes and main symptoms of diabetes mellitus 2- Review the physiological importance of insulin 3- Identify different types of diabetes m...

FALL 2024-2025 PCT414 Pharmacology III Diabetes Mellitus Assoc. Prof. Mennatallah Ismail Intended learning outcomes 1- Discuss the causes and main symptoms of diabetes mellitus 2- Review the physiological importance of insulin 3- Identify different types of diabetes mellitus 4- Differentiate between the different insulin preparations 5- Outline the main classes of the oral antidiabetic agents and their main side effects Diabetes Mellitus It is a group of metabolic diseases characterized by hyperglycemia attributed to a either relative or absolute insulin deficiency or insulin resistance. Symptoms include polydipsia, polyphagia and polyuria. Glycosuria occurs as the glucose level exceeds renal sugar threshold (RST= 180 mg/dl). Dehydration, loss of body weight, weakness, fatigue and visual disturbances are also present. Physiologic effects of insulin Insulin is sometimes referred to as the “storage hormone” because it allows glucose to enter the cells and promotes formation of glycogen (in muscles and liver), triglycerides, and protein while inhibiting their breakdown. In case of diabetes mellitus, glucose is not utilized by the body (due to absence of insulin or decrease sensitivity of peripheral tissues to insulin), leading to hyperglycemia. Classification of Diabetes 1. Type 1 diabetes (Insulin-dependent diabetes mellitus, IDDM, juvenile onset). 2. Type 2 diabetes (Non–insulin-dependent diabetes mellitus, NIDDM, adult onset). 3. Gestational diabetes (GDM). 4. Diabetes due to other causes such as: a. Medications (Thiazides, corticosteroids, oral contraceptives). b. Infection as some viruses have been associated with direct β-cell destruction 1  Type 1 diabetes Type 2 diabetes Gestational diabetes Pathophysiology It is an autoimmune Insulin resistance in A temporary condition disease in which peripheral tissue, which occurs during pregnancy, autoantibodies attack β- is first compensated by which usually disappears cells, eliminating the hyperinsulinemia. after delivery. production of insulin However, over time β- This increases the risk of cells become exhausted developing type 2 and their mass declines, diabetes later in life leading to insulin deficiency Prevalence 5-10% of cases 90-95% of cases 2-4% of all pregnancies Onset Sudden, usually during Gradual, commonly over childhood age 35 Body weight Normal Obese Ketoacidosis Common Rare Treatment Insulin  Non-pharmacological Diet, exercise and insulin intervention  Oral antidiabetic agents  Insulin (uncontrolled, stress, pregnancy) Complications of uncontrolled DM Uncontrolled Diabetes leads to multiple complications that can result in disability, reduced quality of life, and death. 1- Acute complications: Diabetic ketoacidosis (DKA) 2- Chronic complications  Microvascular complications: o Retinopathy, which may lead to blindness before age of 65 o Nephropathy, a common cause of end stage renal disease (ESRD) o Neuropathy, a common cause of amputation.  Macrovascular complications: (ischemic heart disease, stroke and peripheral vascular disease (PVD)), and diminished quality of life. Combination of neuropathy, PVD and infection may manifest as foot ulceration or gangrene (diabetic foot).  Nonvascular complications: Gastroparesis (managed by erythromycin), sexual dysfunction and skin changes. 2  Management of Type 1 DM Insulin preparations are classified according to their duration of action as follows: Duration Type Insulin Onset Comment (Hours) Lispro Not like the other types, I- Rapid acting 15-20 min their duration of action (Prandial/Bolus Aspart (given 15 min 3-4 remains constant insulin) before meals) irrespective of dose Glulisine 30-60 min Regular insulin can be (given 30 II- Short-acting Regular (Crystalline zinc) 5-8 given IV in emergency min before Safe in pregnancy. meals). NPH (Neutral protamine -Doesn't need to be given III- Intermediate Hagedorn, insulin 2 hours 16-18 with meals. acting isophane) -Given once or twice daily - Doesn't need to be given with meals. Glargine 4-6 hours 15-24 IV- Long acting -Supplied at pH = 4. basal insulin -Usually given once daily. is meant to cover - Doesn't need to be given the body’s basal Detemir 2-4 hours 20-24 with meals. metabolic insulin -Supplied at pH = 4. requirement -May be given once daily. (regulating hepatic It is longest acting insulin glucose production) and unlike insulin glargine, Degludec 2-4 hours 24-42 it can be mixed with other insulins too. 3 Insulin regimens  Premixed insulin Commercial insulin products containing more than one type of insulin. Examples of short acting with intermediate: Mixtard® containing 70% NPH+ 30% Regular insulin.  Basal/bolus Insulin regimen Basal/bolus Insulin therapy employs a long- acting insulin preparation either once or twice daily (basal therapy) and pre-meal injections with a rapid- acting insulin (bolus therapy). Indications of insulin therapy 1. Type 1 DM 2. Type 2 DM if not controlled on oral hypoglycemic agents. 3. In gestational diabetes. 4. In complications like diabetic ketoacidosis (IV regular insulin is preferred). 5. Acute non-diabetic hyperkalemia (insulin is given with glucose which helps intracellular passage of K+) Routes of Administration 1- S.C. 2- Regular Insulin can be given IV 3- Inhalational 4- Insulin pump, Continuous subcutaneous insulin infusion (CSII): Insulin pump, Continuous subcutaneous insulin infusion (CSII) Complications of insulin therapy 1. Most common complication is hypoglycemia that can be treated by glucose (oral or IV) or glucagon. It occurs more in children than adults. 2. Other adverse reactions include weight gain, local injection site reactions, and lipodystrophy. It can result in impaired and erratic insulin absorption, leading to poor glycemic control. Lipodystrophy can be minimized by rotation of injection sites. 3. Allergic reactions usually to porcine insulin, so human insulin should be used. 4  Management of Type 2 DM Antidiabetic agents The noninsulin antidiabetic drugs include  Insulin secretagogues  Insulin sensitizing agents  Incretin based therapy  Drugs affecting glucose absorption or excretion  An amylin analog called pramlintide 1- Insulin secretagogues Sulfonylureas Glinides (Meglitinides) The first generation agents Nateglinide Tolbutamide, cholorpropamide Repaglinide The second generation agents (fewer side In contrast to sulfonylureas, they have a effects, used nowadays) rapid onset and short duration of action Glipizide These are intended to be taken before meals Glyburide (Glibenclamide) to control postprandial glycaemia. Gliclazide Glimepiride Mechanism of action Their main mechanism of action includes stimulation of insulin release from the pancreatic β-cells. They block ATP-sensitive K+ channels, preventing K+ efflux, resulting in depolarization, Ca2+ influx, and insulin exocytosis. Major side effects are hypoglycemia and weight gain 2- Insulin sensitizing agents The insulin-sensitizing agents include metformin, thiazolidinedione compounds such as pioglitazone 5  Biguanides Metformin is the only biguanide approved by FDA. Metformin exerts its antihyperglycemic effects primarily in the liver, but it also has actions in skeletal muscle and adipose tissue. Metformin is a first-line drug for the treatment of type 2 diabetes. Metformin can be used alone or in combination with other antidiabetic agents or insulin. Mechanism of action  The most important effect of metformin is the reduction of hepatic glucose output due to inhibition of gluconeogenesis in the liver. Metformin activates AMPK 5′adenosine monophosphate (AMP)-activated protein kinase. It reduces expression of genes for gluconeogenesis enzymes such as glucose-6- phosphatase.  Metformin also slows intestinal absorption of sugars and improves peripheral glucose uptake and utilization in skeletal muscle and adipose tissue. Unlike the insulin secretagogues, metformin does not stimulate insulin secretion or cause hypoglycemia or weight gain. Other uses  Polycystic ovary syndrome  It typically has a favorable effect on plasma lipid levels (LDL and triglyceride) and may enable loss of weight. It is particularly appropriate for obese patients with insulin resistance and for patients with hyperlipidemia. Side effects  Gastrointestinal disturbances nausea, diarrhea  It also has a metallic taste  Lactic acidosis (increase level of lactic acid leading to nausea, vomiting, increase respiratory rate and heart rate). Long-term use may interfere with vitamin B12 absorption. Contraindicated in renal impairment and stop using the drug if GFR