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Study Guide: Diabetes and
Pharmacological Management
- Distinguish the difference in the pathophysiology of Type 1 and Type 2 diabetes. Type One Pancreatic atrophy and loss of beta cells; hyperglycemia when 80- 90% cells lost. Macrophages, T-cytotoxic cells, antibodies Alterations in insulin (usually don’t produce any), amylin (controls hunger sensations), and glucagon. Genetic susceptibility Environmental factors – exposure to certain drugs, foods and viruses Usually leads to absolute insulin deficiency Type Two Ranges from insulin resistance w/ relative insulin deficiency to insulin secretory defect w/ insulin resistance Can lead to a later beta cell loss Caused by genetic-environmental interactions Risks: age, obesity, hypertension, physical activity and family history Metabolic syndrome Might not have crisis symptoms for weeks – body is still making some insulin so some glucose is being brought into the cells and used for energy production. Don’t develop acidosis
- Understand the role of hormones in glucose regulation. Hight blood glucose – Beta cells of pancreas release insulin tells body cells to take up more glucose (store as fat), tells liver to take up glucose and store as glycogen. Low blood glucose – Alpha cells of pancreas release glucagon tells liver to
break down glycogen and release glucose to blood. Also a decreased secretion of amylin – controls hunger sensations and suppresses glucagon release
- Identify the symptoms of hypoglycemia. Shaking Sweating Anxious Dizziness Hunger Fast heart beat Weakness, fatigue Headache Irritable
- Differentiate the pathophysiology of DKA and HHS. o Diabetic Ketoacidosis – occurs with Type 1 Characterized by hyperglycemia, acidosis and ketonuria Insulin normally stimulates lipogenesis and inhibits lipolysis- prevents catabolism. With insulin deficiency, lipolysis is enhanced and there is an increase in nonesterified fatty acids delivered to the liver. Consequence is increased glyconeogenesis which contributes to hyperglycemia and production of ketone bodies by mitochondria of the liver at a rate that exceeds peripheral use. Accumulation of ketone bodies drop pH=metabolic acidosis. Symptoms: Kussmaul respirations, postural dizziness, CNS depression, ketonuria, anorexia, nausea, ab pain, thirst and polyuria. Treatment: managed with combination of fluids, insulin and electrolyte replacement. o Hyperglycemic hyperosmolar syndrome – uncommon but significant in type 2 Occurs more in elderly who have other comorbidities – infections or cardiovascular or renal disease. Differs from DKA in degree of insulin deficiency (more profound in DKA) and the degree of fluid deficiency (more in HHS)
Were the first oral antidiabetics available Work by promoting insulin release – can only be used with type 2 diabetes Major side effect: hypoglycemia – more common in people with kidney or liver dysfunction because sulfonylureas are eliminated by hepatic metabolism and renal excretion so they may accumulate to dangerous levels with impaired fxn. Controversial if it causes cardiovascular toxicity Avoid during pregnancy Two groups: first-generation agents and second-generation agents (newer) Second generation much more potent so doses much lower. Also, significant drug-drug interactions less common – mostly replaced 1 st^ gen Mechanism of action: stimulate the release of insulin from pancreatic islets. If the pancreas is incapable of insulin synthesis they will be ineffective. They promote insulin release by binding with and blocking ATP-sensitive potassium channels in the cell membrane. This causes the membrane to be depolarized and permits the influx of calcium – which causes insulin release. Glipizide and glyburide are examples Meglitinides: AKA glinides
Antidiabetic agents that have the same mechanism as sulfonylureas – stimulation of pancreatic insulin released Only two available ( repaglinide (prandin) and nateglinide (starlix)) Repaglinide – blocks ATP-sensitive potassium channels on pancreatic beta cells, facilitates calcium influx which leads to increased insulin release. For type 2 diabetes only. If patient does not respond to sulfonylureas will not respond to this agent either – same mechanism. Approved for monotherapy or combined therapy w/ metformin or a glitazone. Adverse effects: generally well tolerated, hypoglycemia only adverse effect – patients w/ liver dysfunction, metabolism may be slowed so it increases the risk of hypoglycemia. Nateglinide: Nearly identical to Meglitinide Treatment of type 2 diabetes – either combination or with metformin or a glitazone. Nateglinide has slightly faster onset (30min vs. hour) and shorter duration (2 hrs vs. 4 hrs) Because of rapid onset, may be better for controlling postprandial rise in glucose. Because of shorter duration less effective than repaglinide for controlling fasting glucose.
- Describe the mechanism of action of biguanides. Metformin is an example for patients with type 2 diabetes – usually started right after diagnosis mechanism of action: lowers blood glucose and improves glucose tolerance in three ways. o Inhibits glucose production in the liver o Reduces (slightly) glucose absorption in the gut o Sensitizes insulin receptors in target tissues (fat and skeletal muscle) This all increases glucose uptake in response to whatever insulin is available. Does not stimulate insulin release like sulfonylureas, this means it does not actively drive glucose down=little risk for hypoglycemia. Side effects: decreased appetite, nausea, and diarrhea. Sometimes deficiencies in vit. B12 and folic acid. Lactic acidosis, rare but fatal. Gestational diabetes and Polycystic ovary syndrome
Acarbose and miglitol Act in intestine to delay absorption of carbohydrates For type 2 diabetes Mechanism of action: delays absorption of dietary carbs and reduces the rise in blood glucose after a meal. Also lowers A1c For carbs to be absorbed – oligosaccharides and complex carbs must be broken into monosaccharides by alpha-glucosidase Acarbose inhibits this enzyme and slows digestion of carbs which reduces the postprandial rise in blood glucose. Does not depend on the presence of glucose Adverse effects: flatulence, cramps, abdominal distention, borborygmus (rumbling bowels) and diarrhea. Result from bacterial fermentation of unabsorbed carbs in coon. Can also decrease absorption of iron – poses risk for anemia. Long term, high-dose can lead to liver dysfunction.
- What is the mechanism of action of thiazolidinediones (TZD)? AKA glitazones Reduce glucose levels by decreasing insulin resistance Only for type 2 diabetes – mainly as add on to metformin Pioglitazone (actos) – reduces insulin resistance and may also decrease glucose production o mechanism of action: activation of a specific receptor type in cell nucleus (peroxisome proliferator-activated receptor gamma). By activating this pioglitazone turns on insulin-responsive genes that help regulate carb and lipid metabolism. Promotes increased glucose uptake by skeletal muscle and adipose cells and partly decreases glucose production by liver. o Insulin must be present for drug to work o Adverse effects: generally well tolerated. Most common rxns are upper resp. tract infection, headache, sinusitis and myalgia. o Greatest concern is heart failure secondary to renal retention of fluid. o Poses risk for hypoglycemia, especially when combined with insulin…
- What is the mechanism of action of DPP4 inhibitors? Promote glycemic control by enhancing the actions of incretin hormones AKA gliptins – considered to be 3 rd line drug for diabetes Sitagliptin (Januvia) – enhances the actions of incretin hormones that: Stimulate glucose dependent release of insulin Suppress postprandial release of glucagon (hormone that decreases glucose production in liver) o Inhibits dipeptidyl peptidase 4 (DPP-4) – this enzyme inactivates
the incretin hormones o Type 2 diabetes – needs insulin to work
o Casual plasma glucose test Blood drawn at any time Glucose level >200 suggests diabetes To make definitive diagnosis patient must also display classic signs o Oral glucose tolerance test (OGTT)
Used when diaetes is suspected but could not be definitively diagnosed by measuring fasting or casual levels Performed by giving oral glucose load and measuring plasma glucose 2 hours later Normal: 2-hour glucose <140 mg/dL Diabetes suggested if > In 2010 recommended alt test based on measuring blood levels of hemoglobin A1c o A1c reflects avg. blood glucose over previous 2-3 months o A1c of 6.5% or higher considered diagnostic o Not appropriate for everyone – some people have conditions that skew results Example: pregnancy, chronic kidney or liver disease, severe bleeding or blood transfusion (recent), certain blood disorders 15.Describe the risk factors for and pathophysiology of microvascular and macrovascular complications of diabetes. Microvascular Damage to small blood vessels and capillaries Basement membrane of capillaries thicken=blood flow in narrow vessels falls Destruction of small vessels leads to kidney damage, blindness, and neuropathies Directly related to degree and duration of hyperglycemia. o Retinopathy: causes visual loss – accelerated by hyperglycemia, hypertension and smoking o Nephropathy: damage to kidneys o Sensory and motor neuropathy: nerve degeneration (sensory and motor) o Autonomic neuropathy: gastroparesis (delayed stomach emptying) o Amputations secondary to infection o Erectile dysfunction Macrovascular Cardiovascular disease leading cause of death – heart disease, hypertension and stroke Pathology due to atherosclerosis which develops earlier in diabetics than nondiabetics and progresses faster.
