Nursing 3703 Pharmacology By Linda Self Antidiabetic Drugs Nursing 3703 Pharmacology By Linda Self

Diabetes Mellitus Chronic systemic disease characterized by metabolic and vascular abnormalities Disorder of carbohydrate metabolism Results from inadequate production or underutilization of insulin

Diabetes Mellitus Characterized by glucosuria and hyperglycemia Two forms—Type 1 and Type 2 Type 1—patient secretes no insulin. Cause is felt to be autoimmune. Type 2- patient secretes insufficient amounts of insulin and insulin receptors are resistant to existent circulating insulin Type 1 hereditary. Triggered by viral infection that inflames the beta cells of the pancreas. Exact mechanism is not known.

Diabetes Mellitus Symptoms: hyperglycemia, glucosuria, polyuria, polydipsia, polyphagia, and possibly itching. Fasting blood glucose is higher than 126 Manifested by: weight loss, weakness, increased frequency of infections, poly’s

Diabetes Mellitus Without intervention, significant complications will ensue. Include: retinopathies, glaucoma, neuropathies, cardiovascular disease.PVD. Increased incidence of toxemia of pregnancy.

Pathophysiology Insulin secreted by beta cells Insulin binds with and activates 80% of cells Liver, muscle, and fat cells are primary tissues for insulin action With insulin receptor binding, cell membranes permeable to glucose into the cells

Pathophysiology cont. Increased cell permeability also allows for amino acids, fatty acids and electrolytes to enter cells Changes cause anabolism and inhibit catabolism Anabolism includes use and storage of glucose, amino acids, and fatty acids.

Pathophysiology cont. Carbohydrate metabolism Insulin increases glucose transport into liver, skeletal muscle, adipose tissue, the heart, and even uterus. Must be present for muscle and fat tissues to use glucose for energy Insulin regulates glucose metabolism to produce energy for cellular functions If excess glucose is present after need is met, it is converted to glycogen and stored or converted to fat and stored. The excess glucose transported to liver cells is converted to fat only after glycogen stores are saturated. Liver is especially important in restoring blood sugar levels by breaking down glycogen or by forming new glucose.

Pathophysiology cont. Fat Metabolism Insulin promotes glucose into fat cells where it is broken down One of breakdown products is A-glycerophosphate, combines with fatty acids which ultimately forms triglycerides This is the mechanism by which insulin promotes fat storage Actually, insulin transport of glucose into fat cells results first in alpha-glycerophosphate which combines with fatty acids and produces alpha-glycerophosphate, This then is converted to triglycerides.

Fat Metabolism When insulin is lacking, fat is released into the bloodstream as free fatty acids. Blood concentrations of triglycerides, cholesterol and phospholipids are also increased Thus the high lipid concentration probably contributes to the accelerated atherogenesis seen in diabetics. Some of the free fatty acids may be converted to ketones, resulting in ketosis.

Protein Metabolism Insulin increases the total amount of body protein by increasing transport of amino acids into cells and synthesizing protein within the cells Insulin potentiates the effects of growth hormone Lack of insulin causes protein breakdown into amino acids These amino acids are not replaced by synthesis of new proteins; thus, protein wasting occurs resulting in weakness, weight loss and abnormal functioning of many body organs

Endogenous Insulin Glucose is the major stimulus of insulin secretion Oral glucose is more effective than intravenous glucose because glucose in digestive tract increases the release of gastrin, secretin, chlecystokinin, and gastric inhibitory peptide Also stimulates vagal activity

Endogenous Insulin Other hormones that raise blood glucose levels include: Cortisol Glucagon Growth hormone Epinephrine Estrogen Progesterone

Endogenous Insulin Factors that inhibit insulin secretion include: Hypoxia Hypothermia Stimulation of alpha adrenergic 2 receptors

Classification of Two Types of Diabetes Type 1 diabetes results from an autoimmune disorder that destroys pancreatic beta cells Usually has sudden onset Associated with high incidence of complications Requires exogenous insulin 10% of those with diabetes are type I

Diabetic Ketoacidosis (DKA) Life-threatening complication occurs with insulin deficiency Glucose cannot be used by body cells for energy so fat is mobilized for this purpose Mobilized fat is then extracted by liver and broken down into glycerol and fatty acids Fatty acids further broken down into ketones

DKA Accumulation of ketones results in acidemia Attempts to buffer acidic H+occurs by ionic exchange, intracellular potassium exits cells. H+ ions enter cells. Result is excretion of potassium in urine. Kidneys attempt to buffer by excreting ketones Pulmonary attempt to buffer by Kussmaul breathing

Clinical S/S of DKA Kussmaul breathing Nausea and vomiting Thirst Polydipsia, polyphagia and polyuria Hypotension Tachycardia shock

Type 2 Diabetes Mellitus Characterized by hyperglycemia and insulin resistance Results from increased production of glucose by liver and decreased uptake of glucose in liver, muscle and fat cells Insulin resistance—higher than usual concentrations of insulin are required

Type 2 Diabetes Mellitus Occurs at any age Gradual onset Less severe symptoms initially Easier to control More MIs and strokes 90% of those with diabetes are Type 2 multifactorial

Hyperosmolar hyperglycemia nonketotic coma (HHNC) Occurs in Type 2 Diabetes Because patient has some endogenous insulin, no ketosis develops Blood sugars can be >800-1000 Can result in hypovolemic shock, renal problems, stroke, coma and even death

Metabolic Syndrome or Syndrome X Comprised of a set of risk factors which include: Central abdominal adiposity (men waist size greater than 40 inches, women greater than 35 inches Fasting triglycerides greater > or equal to 150 mg/dl HDL cholesterol (less than 40 in men, less than 50 mg/dl in women

Metabolic Syndrome cont. 4. Blood pressure greater than or equal to 130/85 5. Fasting glucose greater than or equal to 110mg/dL Also possess prothrombotic and proinflammatory tendencies In US, 20% of adults (47 million) have metabolic syndrome with prevalence approaching 50% in elderly. Seen more often in those who are overweight. Root cause is poor eating habits and sedentary lifestyle.

Metabolic Syndrome cont. All factors are interrelated Obesity and lack of exercise tend to lead to insulin resistance Insulin resistance has a negative effect on lipid production. Increase VLDL, LDL, TG and decreasing the HDL. Insulin resistance leads to increased insulin and glucose levels in blood. Increased glucose and insulin in blood affect kidneys by holding onto sodium which then increases BP and can lead to hypertension. Also chronically elevated glucose levels damage blood vessels and organs.

Hypoglycemic Drugs Insulin lower glucose levels by increasing glucose uptake by cells Indicated for Type 1 DM, often in Type 2 DM, in those with chronic pancreatitis, in those on TPN, to treat hyperkalemia (infusion with dextrose and insulin) Available insulins are pork and human

Age-Related considerations Type 1 DM in children Consistent diet, blood glucose monitoring, insulin injections and exercise Blood sugar control essential to maintain normal growth and development Infections and illnesses can cause wide fluctuations

Type 1 DM in children cont. Children highly susceptible to dehydration Rotation of sites is very important Avoiding hypoglycemia is a major goal in infants and young children d/t damaging effects on growth and development

Type 1 DM in children s/s of hypoglycemia include: hunger, sweating, tachcardia, irritability and lethargy.

Age related considerations in older adults Close monitoring of blood glucose levels Visual impairment may affect their ability to self administer medication May have renal insufficiency so caution w/certain antidiabetic meds a concern Caution with metformin if renal impairment Glitazones can predispose to fluid retention and heart failure

Insulin Human insulin is chemically identical to endogenous insulin but it is not derived from the human pancreas Cannot be given orally Insulins differ in onset and duration of action. Ultra-short, short, intermediate and long acting.

Rapid acting insulin Insulin lispro (Humalog) or insulin aspart (Novolog) are very shorting acting insulins More effective in decreasing post-prandial hyperglycemia Less likely to cause hypoglycemia before the next meal Onset is 15’, peaks in 1-3 hours, duration is 3-5 hours

Insulin cont. Short acting Insulins Regular Iletin II, Humulin R, Novolin R May be given sub Q or IV May be given as a continuous IV drip The only insulin that may be given IV Onset is ½-1 hour, peak is 2-3 hours and duration is 5-7 hours

Intermediate-acting Insulins Isophane insulin suspension (NPH, NPH Iletin II, Humulin N, Novolin N) Onset is 1-1.5 hours, peaks in 8-12 hours and duration is 18-24

Long-acting Insulin Extended insulin zinc suspension Onset is 4-8 hours, peaks in 10-30 hours and duration is 36+ hours

Insulins cont. Insulin Mixtures NPH 70/30 (Humulin or Novolin 70/30) Durations of actions same as individual components

Insulins cont. Insulin Analogs Lispro and aspart as previously described Insulin glargine (Lantus)-once daily at bedtime. Onset is 1.1 hours, peak is none, duration is 24 hours Must not be diluted or mixed with any other insulin or solutions

Oral Hypoglycemic Drugs Five types used to treat Type 2 DM Sulfonylureas—oldest. Increase release of insulin. Also decrease production of glucose in the liver, increase the number of insulin receptors and increase peripheral use of glucose. Effective only if have functioning beta cells. Primary side effect is hypoglycemia

Sulfonylureas cont. First generation are essentially obsolete Use 2nd generation agents Are glipizide (Glucotrol), glyburide (Diabeta)and glimepiride (Amaryl) Can be used with metformin, glitazones, insulin or acarbones Caution w/renal or hepatic impairment. Not used in pregnancy.

Alpha glucosidase Inhibitors Acarbose (Precose) and miglitol (Glyset) inhibit alpha-glucosidase enzymes (maltase, amylase, sucrase) in GI tract. Delays absorption of complex CHO and simple sugars Can be combined therapy w/insulin or w/sulfonylurea Contraindicated in cirrhosis, malabsorption, severe renal impairment

Alpha-glucosidase Inhibitors Take at beginning of each meal Can cause bloating and diarrhea

Biguanides Metformin (Glucophage) increases the use of glucose by muscle and fat cells, decreases hepatic glucose production, and decreases intestinal absorption of glucose Does not cause hypoglycemia May be used alone or in combination Contraindicated in liver or renal impairment. Can result in lactic acidosis.

Biguanides cont. Must check renal function before beginning this medication Caution with parenteral radiographic contrast media containing iodine. May cause renal failure and has been associated with lactic acidosis.

Glitazones Pioglitazone (Actos) and rosiglitazone (Avandia) are also called thiazolidinediones or TZDs Are insulin sensitizers Decrease insulin resistance. Stimulate receptors on muscle, fat, and liver cells. Results in increased uptake of glucose in periphery and decreased production by the liver.

Glitazones Contraindicated in patients with liver disease or who have ALT levels > 2.5 of normal May be used as monotherapy or in combination with insulin, metformin (Glucophage) or a sulfonylurea Caution in patients with heart failure Ensure baseline LFTs are performed

Meglitinides Nateglinide and repaglinide are nonsulfonylureas that lower blood sugar by stimulating pancreatic secretion of insulin Monotherapy or in combination with metformin Should be taken before or up to 30 minutes before a meal. Dosage and frequency is flexible depending on food intake.

Herbals and Dietary Supplements that affect blood glucose levels Bee pollen, gingko biloba and glucosamine are thought to increase blood sugars or may potentially affect beta-cell function and insulin secretions (see p. 378) Basil and bay leaf may cause hypoglycemia Chromium may increase production of insulin receptors and increase insulin effectiveness

DKA IV fluids to rehydrate No use of hypotonic solutions at this time Potassium supplementation IV insulin drip with gradual lowering of blood sugars Judicious administration of sodium bicarbonate

HHNC Treatment similar to that of DKA

Diabetic management “pearls” When mixing insulins, draw up the regular insulin first Tid glucose monitoring is highly recommended Allow mild hyperglycemia for the patient undergoing surgery—treat with short acting insulins For elective surgery, schedule patient early in day to avoid prolonged fasting

“Pearls” Use U-100 syringes for U-100 vials In patients with insulin pumps, use regular insulin or insulin aspart. Generally will deliver one unit per hour w/bolus insulin before meals Tight glycemic control can reduce the complications of diabetes. Use ACE inhibitors to delay nephropathy Limit dietary intake of protein

“Pearls” Glitazones must suspect r/t hepatotoxicity Metformin cautiously with liver and renal impairment. Concern that with hepatotoxicity, because risks of lactic acidosis are increased. Rotate sites of injection of insulin to avoid development of lipodystrophy

“Pearls” Absorption of injected insulin in abdomen is not uniform with injections in arms or legs