Diabetes Mellitus Pharmacology Presented by: Wanda Lovitz, APRN

Diabetes Pharmacology: Objectives Discuss the nursing implications of oral anti-diabetes agents and and injectable anti-diabetes agents including Byetta and insulins. Describe teaching guidelines for clients receiving oral anti-diabetes agents, insulins, or glucose-elevating drugs.   Discuss the mechanisms of action, therapeutic uses, adverse effects, and interactions of the various type of agents for type 1 diabetes mellitus. Discuss the mechanisms of action, therapeutic uses, adverse effects, and interactions of the various types of insulins.

Drugs to Know glyburide (Micronase)…sulfonylurea glipizide (Glucotrol)…sulfonylurea metformin (Glucophage)… biguanide pioglitazone (Actos)… glitazone (TZD) sitagliptin (Januvia)…incretin enhancer/DPP-4 inhibitor exanatide (Byetta)…incretin mimetic/enhancer/GLP-1 agonist (INJECTABLE FOR TYPE II) Insulins: Novolog, Regular, NPH, Lantus & Levemir Glucagon…glucose elevating drug used as tx for HYPOGLYCEMIA

High blood sugar can cause many problems Type 2 Diabetes can lead to: Heart Disease Eye Damage Nerve damage/neuropathy Foot Problems Kidney Disease Depression Managing type 2 diabetes properly can help stop or slow down these problems

Agents used to treat Diabetes Oral Agents Sulfonylureas Biguanides Thiazolidinediones (TZDs) DPP-4 inhibitors Combinations Injectable …but NOT insulin Incretin mimetic exenatide/Byetta Insulins Novolog (rapid) Regular (short) NPH (intermediate) Lantus/Levemir (long) Agents to RAISE blood sugar 1. Glucagon 2. Dextrose 50%

Normal blood sugar ranges

American Diabetes Association (ADA) Blood Sugar Goals (FOR THE DIABETIC): 70-130 mg/dL before meals Less than 180 mg/dL two hours after starting a meal (2H PP = 2 hours post prandial) Less than 7% hemoglobin (A1C) level

What is a Hemoglobin A1C? A serum blood test which measures the average glucose level over the preceding 2-3 months Is a better indicator of glycemic control over time than the FBS Note that a HbA1C of 6% corresponds to an AVERAGE blood sugar of 135

A better estimate of glycemic control over time: the Ha1C Excess glucose attaches to RBC. The life of a RBC is about 3 months

Target sites of the oral agents Pancreas Liver Intestine Adipose tissue Muscle Kidneys

Limitations of oral agents for TYPE II diabetics only! Usually started after diet and exercise fail to adequately control blood sugars Can typically reduce HbA1c by 0.5 – 2.0% Mechanism of action addresses THE SYMPTOMS of diabetes rather than the underlying pathophysiology Many UNDESIRABLE SIDE EFFECTS which often affects adherence (hypoglycemia, n/v, peripheral edema, weight gain) BETA CELL FUNCTION TENDS TO WORSEN OVER TIME Clinicians often fail to intensify therapy/start insulin to obtain good control

Oral agents: nursing implications Wanda as a “Baby Nurse” Oral agents: nursing implications Nursing implications – monitoring of glucose levels and glycosylated hemoglobin (HA1C) assessing for sulfa hypersensitivity (sulfonylureas) administering most agents with meals understanding the onset of action, peak, and duration associated with oral agents assessing patient teaching needs assessing for hypoglycemia

Patient Voices: Larry with Type II http://www.nytimes.com/interactive/2009/08/04/health/TE_DIABETES.html Copy and paste the address above into your browser to hear several different patients talk about living with diabetes.

Hyperglycemia vs Hypoglycemia High blood sugar FBG levels of greater than 126 on 2 or more occasions=DM Insulin Resistance when FBG is greater than 100 but less than 126 BG normally rises after food consumption Should return to near normal in 2H = 2hPP Hypoglycemia Low blood sugar Most people are symptomatic with when levels are below 60 Diabetics may have ‘hypoglycemic’ reactions when BS drops after they receive anti-diabetic meds Especially if oral intake is insufficient

SULFONYLUREAS MOA: (1) act in pancreas to  insulin production INSULIN SECRETOGOGUES Think of sulfonylureas as “oral insulin” Sulfonylureas increase insulin output from the pancreas Any agent that increases insulin output from the pancreas has the potential to cause hypoglycemia

Sulfonylureas First-generation agents – chlorpropamide (Diabinese), older, less potent drugs Second-generation agents – *glyburide (Micronase) glipizide (Glucotrol) glimepiride (Amaryl); newer, more potent drugs

SULFONYLUREAS Adverse effects - nausea, vomiting, epigastric discomfort, heartburn, skin rash, HYPOGLYCEMIA, photosensitivity, hematologic problems (e.g., hemolytic anemia), thrombocytopenia), WEIGHT GAIN Contraindication: allergy to sulfa

Sulfonylurea: glyburide/Micronase glyburide/Micronase is the most frequently prescribed 2nd generation sulfonylurea Micronase has a slower onset and longer duration of action than another frequently rx sulfonylurea -*glipizide (Glucotrol) These agents are beneficial in controlling glucose levels throughout the day and night glyburide/Micronase is sometimes used with glipizide/Glucotrol to better control glucose levels at meals = SYNERGISTIC EFFECT Onset 1 – 1.5 hours; peak 4 hours; duration 20-24 hours

BIGUANIDE: metformin *THE most popular oral anti-diabetic agent in the U.S. metformin (Glucophage) often used as monotherapy with type 2 diabetes may also be used with a sulfonylurea MOA: (1) DECREASES HEPATIC GLUCOSE PRODUCTION and production of triglycerides and cholesterol from the liver (2) enhances glucose transport into cells IMPROVES INSULIN SENSITIVITY by increasing peripheral glucose uptake and use (3) decreases glucose uptake in the intestine SOME WEIGHT LOSS EXPECTED 

MOA: metformin/Glucophage 1. intestinal absorption of glucose 2.  hepatic glucose production 3. insulin sensitivity by  glucose uptake in tissue Advantage over sulfonylureas: Since it has little to no effect on pancreatic output, NOT AS MUCH CONCERN WITH HYPOGLYCEMIA!

BIGUANIDE: (metformin/Glucophage) Onset several DAYS peak 2-4 weeks Adverse effects: abdominal bloating nausea, vomiting, DIARRHEA diarrhea can be uncontrollable; fecal incontinence issues for some “Metformin moment” risk for LACTIC ACIDOSIS in pts with  creatinine can be life threatening! Nursing implications – recognize that it will not immediately lower BG monitor serum glucose level give 30 minutes before a meal Hold before any test which requires IV contrast dye d/t risk of lactic acidosis!!

THIAZOLIDINEDIONES /GLITAZONES or TZDS MOA: 1. Decreases INSULIN RESISTANCE does this by: increasing sensitivity of insulin receptors increaseing glucose uptake and use in skeletal muscle 2. Decreases fatty acid output in adipose tissue 3. Decreases glucose output in the liver

Insulin Resistance

TZD: pioglitazone/Actos Available agents pioglitzaone/Actos rosiglitazone (Avandia) Adverse effects EDEMA weight gain mild anemia MAY CAUSE LIVER DAMAGE Onset unknown; peak unknown, duration 12-24 hours

TZDs pioglitazone/Actos rosiglitazone/Avandia ADVANTAGE of glitazones: DOES NOT CAUSE HYPOGLYCEMIA since they do not have an affect on pancreatic production of insulin May PRESERVE SOME BETA CELL FUNCTION MAY HAVE PROTECTIVE VASCULAR effects (lowering chlolesterol) DISADVANTAGE: may be toxic to the LIVER Must have LFTs (ALT and AST) monitored

Newest Class: Incretin MIMETICS: exenatide INJECTION (Byetta) Incretins are INTESTINAL HORMONES released in response to ingestion of food Incretins increase the insulin response and depress the gluconeogenesis in the liver ↑insulin and ↓ glucose = lower BG Incretins naturally decrease appetite NOTE: The incretin response is DIMINISHED in type II diabetics! Incretin mimetics, mimic the response of endogenous incretin So….. Mimicking/enhancing the incretin response would result in lower glucose levels

exenatide/Byetta

exenatide/Byetta “Incretin Enhancer” Given as a SQ INJECTION within 1H of morning and evening meal (BID) Major SE is NAUSEA AND HYPOGLYCEMIA Not a substitute for insulin!! Serious SE: pancreatitis Should NOT be used in Type I DM!! Is NOT to be used to treat DKA Average weight loss is 5-10 pounds

DPP-4 INHIBITOR/incretin enhancer: sitagliptin/Januvia A once a day oral agent Is a DPP-4 inhibitor – Blocks DPP-4 DPP-4 breaks down the hormone incretin Low levels of incretin result in a DECREASE in the response from the pancreas and less insulin is secreted Low levels of incretin also result in an increase in glucose output from the liver Leading to . . . . . Hyperglycemia

MOA: sitagliptin/Junuvia So…DPP-4 inhibitors slow the degradation of incretins thus prolonging the action of the incretins increasing/enhancing incretin levels The result in an  in output of insulin from the pancreas and a in glucose output from the liver End result is lower glucose levels

DPP-4 inhibitors: MOA

Summary Slide: Effects of oral agents on diabetes

Combination Drugs: Many out there glyburide/metformin (Glucovance) 1.25/250; 2.5/500; 5/500 rosiglitzone/metformin (Avandamet)

Summary Slide/ Side Effects of Antidiabetic Agents

Anti-diabetic Agents: the Insulins

INSULINS Various types of insulins: Effects similar to the endogenous insulin produced from the pancreas Primary treatment for type 1 diabetes may also be used in the management of type 2 diabetes and gestational diabetes Various types of insulins: rapid acting short acting intermediate acting long acting mixed Pork, beef in the past Now human source insulins Human more effective, causes fewer SE and has a lower incidence of resistance

Which type of diabetic patients receive insulin? TYPE I DM and TYPE II DM

Insulin as the “key” Insulin allows the glucose to get inside the cell Without insulin, the glucose stays in the bloodstream causing hyperglycemia

RAPID ACTING INSULINS Nursing implication Types of rapid acting insulins: lispro (Humalog) aspart *(Novolog) Onset 0-15 minutes!!! Peak 1H Duration 3H Used with sliding scale regimens (SSC) “CORRECTION INSULIN” “BOLUS INSULIN” Nursing implication risk for hypoglycemia by making sure that the meal is available before administering Subcutaneous use: Humalog and Novolog Intravenous use (Novolog only)

SHORT ACTING INSULINS Regular Onset 30-60 minutes (sub-cu) Intravenous or subcutaneous use Onset 30-60 minutes (sub-cu) Peak 2-3H Duration 4-6H Also used with SLIDING SCALE/CORRECTION REGIMENS

INTERMEDIATE ACTING INSULINS Neutral Protamine Hagedorn (NPH) forms Types include: *Humulin N and Novolin N Onset 1-2.5 hours Peak 6-14 hours Duration 18-24 hours CLOUDY insulin NPH is given BID NPH is normally given 30 min before 1st meal of the day (2/3 dose) and (1/3 dose) before the evening meal or at bedtime. BID dosing

LONG ACTING “BASAL” INSULINS Two types: *glargine/Lantus detemir/Levemir Onset 2-4 hours; Duration 24 hours Closest insulin to the body’s own basal insulin Constant duration with NO DEFINED PEAKS A basal or slow acting insulin Important note: Lantus and Levemir MUST NOT BE MIXED with any other insulin

MIXED/Combination Insulins Developed to more closely stimulate varying levels of normal endogenous insulin production Varying types – Humulin 70/30, 50/50, Novolin 70/30 Contain varying amounts of intermediate and short acting insulin

INSULIN REGIMENS BASAL/BOLUS INSULIN Basal insulin: example: Lantus or Levemir provides “basal” coverage usually once a day dose Bolus insulin: example: Regular or Novolog given before meals to “cover” elevated BS FSBS or CHO count done to determine dose CORRECTION INSULIN/Sliding scale regimens (SSI/SSC)- regular insulin dosages are adjusted based on finger stick blood sugar(FSBS) TYPICALLY AC AND HS May or may not be used with a basal insulin

Comparison of action of NPH and Lantus Note that the Regular insulin peaks in about 3H and is just about gone within 10H. Note that the Lantus has no peaks and is present for about 24H. Also, the action of Lantus most resembles the body’s own (endogenous) insulin.

The Ideal Insulin Regimen Simulates the body’s own normal insulin output Combines “Basal” insulin with “mealtime” insulin Is called a “basal-bolus” regimen Bolus also known as “correction” insulin- it corrects high BS before a meal- “sliding scale insulin” Uses rapid- and short-acting (bolus) insulin before meals PLUS Uses a background insulin once a day Commonly prescribed as 4 injections a day: Lantus or Levemir at bedtime Novolog or Regular before each meal

Adverse Effects of Insulin Insulin Reaction AKA: HYPOGLYCEMIA – occurs when there is more insulin in the blood than is needed for the amount of circulating glucose Causes: Med error Patient exercised and insulin peaked Patient doesn’t eat after taking insulin SX usually seen when BG 60 or less R/t hypoglycemia, hyperglycemia, or hyper-insulinemia Localized allergic reactions at the injection site Generalized urticaria and swollen lymph glands

Insulin delivery methods Wireless pumps Insulin pens

GLUCOSE – ELEVATING DRUGS GLUCAGON & 50% DEXTROSE MOA: STIMULATES hepatic production of glucose from glycogen stores. Used to treat hypoglycemia. RAISES THE BLOOD SUGAR Administered IM, IV, or SC Indication: To treat hypoglycemic reactions Adverse effects – nausea and vomiting, tachycardia, and anaphyaxis **50% Dextrose (D50W) IVP is also given to raise low blood sugar for severe hypoglycemia**

Summary Slide: Hypoglycemia vs Hyperglycemia

Case study: Bill Bill is a 68 year old male hospitalized at UKMC for treatment of a left leg wound INFECTION. Because he has had a flare of his asthma, Bill was also placed on po PREDNISONE. PMH of type 2 DM and is currently taking metformin (Glucophage) and glyburide (Micronase). He is ordered FSBS with SSI. His BS at 7:00 am is 352 and the nurse gives him 12 units of Regular insulin per the SSI protocol. He c/o nausea and only drinks 30cc of juice for breakfast. At 10:30 he is c/o being “shaky”, is diaphoretic and his HR is 110. A FSBS shows his glucose is now 44. Discussion Questions Bill’s BG is very high. What are the factors that may be contributingto this spike? His wound infection and the prednisone would both cause elevated BG levels. What has happened to Bill? Hypoglycemic reaction What are the contributing factors? Did not eat breakfast, so not enough CHO and the SSI given caused his BG to drop too much What action/actions should the nurse take? Use the Rule of 15 and give Bill food/drink that contains 15 GM of CHO to quickly raise his BS. Can then follow with a comples CHO such as peanut butter and crackers to help stabilize his BG.

Case Study: Bryan Bryan is a 9 year old boy who has had type 1 since the age of 6. He has an insulin pump and does that delivers a basal dose of Lantus insulin. He also gives himself correction Novolog insulin as needed before meals (AC). Bryann has been in good control and his last Ha1c was 6.5%. Bryan is being treated with antibiotics for a sinus infection.Today he is brought to the ED after collapsing on the soccer field. He is responsive but confused, has a RR of 32 with deep rapid respirations and you note a “fruity” smell to his breath. A FSBS is 448. Discussion Questions: What is going on? Acute complication of type I DM...DKA Why? High BS causing formation of ketones as fat is being used for energy What further information would you want to collect? Any s/s of infection? Infection can cause elevated BG as well What do you anticipate the MD will order? Either IV insulin (regular or humalog) to quickly bring down his blood sugar. IV fluids to treat the dehydation that occurs with DKA If blood gases were drawn, what would you anticipate his PH to be? Metabolic acidosis

Case Study: Mary Assessment data: FSBS was 623 Mucous membranes dry Only responsive to painful stimuli There is a Stage III decubitus ulcer on her sacrum that is draining purulent material Discussions Questions: What is going on with Mary? Acute complication of type II DM...HHNKS Why factors might have contributed to this condition? Dehydration What treatment will likely be ordered? IV insulin to quickly lower the BG and IVF to treat the dehydration How could this be prevented? By improved care in ensuring Mary ate and drank adequately. Mary, an 82 year old resident of a nursing home, is brought to the ED for evaluation because this morning the staff could not awaken her for breakfast. Mary has a h/o left sided weakness d/t a CVA and mild dementia. The nurse tech accompanying her to the ED tells you she has been having a hard time getting Mary to eat and drink for the last couple of weeks.

TIME IS UP!