Antidiabetic Medications

Normal Glucose

Type 2 Diabetes
High blood glucose Impaired GI motility

1. Defective beta cell function

Diminished phase 1 insulin release Delayed phase 2 insulin release

2. Overproduction of glucagon

1. Tissues less sensitive to insulin 2. Liver produces excess glucose

Image Obtained From: Diabetes 101: Overview of Drug Therapy by Jennifer Danielson, RPh, CDE

Type 2 Video from diabetes.com

ORAL ANTI DIABETICS

Biguanides
Metformin Glucophage (Glucophage XR) 500, 850, 1000 mg 500, 750 mg XR tablets tablets

Pharmacokinetics Given orally, Not bind to plasma proteins, Not metabolized, Excreted unchanged in urine, t 1/2 2 hr Indication Type II Diabetes Mellitus, MOA Decrease hepatic glucose production, decrease intestinal absorption of glucose and increase insulin sensitivity therefore increasing peripheral glucose uptake

Biguanides (cont)
SIDE EFFECT N/V/D Upset stomach/dyspepsia take with food Metallic taste Minimal Weight Loss Alcohol may increase likelihood of lactic acidosis Does not cause hypoglycemia

Biguanides (cont)
Special Population Considerations: Geriatric: limited data suggests starting doses should be 33% lower for geriatric patients than that of an adult dose. Titration should also to a lower limit. Cautions/Severe Adverse Reactions Black Box Lactic Acidosis: D/C immediately and notify practitioner if: myalgia, malaise, hyperventilation, unusual somnolence. Alcohol potentiates this reaction. Advise patients not to consume excessive amounts of alcohol.

Biguanides (cont)
CONTRAINDICATIONS Renal disease or renal dysfunction (Scr > 1.5 mg/dL in males, >1.4 mg/dL in females) Abnormal Scr (serum creatinin) from any cause including: shock, acute MI, or septicemia Metabolic acidosis (including diabetic ketoacidosis (DKA) Heart failure requiring pharmacologic therapy; active liver failure

Sulfonylureas
Glimepiride Glipizide Glyburide (Glibeclamide) (Amaryl) (Glucotrol, Glucotrol XL) (DiaBeta) 1, 2, 4 mg (2.5), 5, 10 mg (XL) 1.25, 2.5, 5 mg tablets tablets tablets

Pharmacokinetics Well absorp from GIT, metab.by hepar,, excr urine glucose lowering effect: 30 minutes with peak at 1.5-3 hours lasting 24 hours, duration 10-24h MOA Stimulating insulin release from beta-cells of pancreatic islets Indications Adjuncts to diet and exercise to lower blood glucose in patients w/ type II diabetes mellitus

Sulfonylureas (Oral Hypoglycemic drugs)

First generation

Second generation

Short acting

Intermediate acting

Long acting

Short acting

Long acting

Tolbutamide

Acetohexamide Tolazamide

Chlorpropamide

Glipizide

Glyburide (Glibenclamide Glimepiride

Sulfonylureas (cont)
Side Effects

Hypoglycemia GI upset/abdominal pain Dizziness Weight gain Heartburn/epigastric fullness Possible disulfiram-like reaction with alcohol (mainly w/ glyburide)

Sulfonylureas (cont)
Special Population Considerations: Pediatric: safety and efficacy not established for px under age 16 Hepatic/Renal Dysfunction: conservative dosing and titration recommended. Caution/Severe Adverse Reactions Syndrome of Inappropriate Anti-diuretic Hormone (SIADH) CONTRAINDICATIONS Diabetes complicated by ketoacidosis Type I DM Diabetes w/ pregnancy. Pregnancy Cat: C (except glyburide: B)

Meglitinides
e.g. Repaglinide, Nateglinide
PHARMACOKINETICS Taken orally, Rapidly absorbed ( Peak approx. 1hr ) Metabolized by liver, t1/2 = 1 hr, Duration of action 4-5 hr
MECHANISM of ACTION as do Sulfonylureas, to cause insulin release from -cells. CLINICAL USE Approved as monotherapy and in combination with metformin in type 2 DM SIDE EFFECTS: Hypoglycemia Wt gain ( less than SUs ) Caution in px with renal & hepatic impairement.

12

-Glucosidase Inhibitors
e.g. Acarbose Pharmacokinetics
Given orally Not absorbed from intestine except small amount t1/2 3 - 7 hr Excreted with stool

Mechanism of Action
13
Inhibits intestinal alpha-glucosidases and delays carbohydrate absorption, reducing postprandial increase in blood glucose

-Glucosidase Inhibitors
(Contd.) Side Effects
Flatulence, Loose stool or diarrhea, Abdominal pain Alone does not cause hypoglycemia

Indications
Patients with Type II inadequately controlled by diet with or without other agents( SU, Metformin) Can be combined with insulin may be helpful in obese Type II patients 14 (similar to metformin)

Thiazolidinediones (TZD)
Pioglitazone Rosiglitazone (Actos) (Avandia) 15, 30, 45 mg 2, 4, 8 mg tablets tablets

Indications As adjunct to diet and exercise for type II diabetes MOA Increase insulin sensitivity by affecting PPAR- (peroxisome proliferators-activated receptor) at adipose tissue, skeletal muscle and in the liver. Glucose uptake , gluconeogenesis

TZD (cont)
Side Effects Weight gain Edema Hypoglycemia esp. when used with other antidiabetic medications and insulin (not w/ metformin) May cause or exacerbate heart failure with risk of fluid retention URI, sinusitis, pharyngitis Myalgia Headache

TZD (cont)
Cautions/Severe Adverse Reactions Black Box: Heart Failure (for all thiazolidinediones, mainly due to rosiglitazone) Hepatic failure Anemia Bone loss Ovulation in premenopausal women Pregancy Cat: C

TZD (cont)
Special Populations Considerations: Congestive Heart Failure: should be initiated at lowest approved dose with longer intervals between dose increases for class II. Use is not recommended in patients with Class III or IV CHF CONTRAINDICATIONS Class III-IV heart failure Active liver disease (ALT > 2.5 upper limit of normal)

Insulin
Indications Type I diabetes mellitus, type II diabetes mellitus (+pregnant), hyperkalemia, DKA/diabetic coma MOA Stimulating peripheral glucose uptake and inhibiting hepatic glucose production Side Effects Hypoglycemia (BG < 70 mg/dL) esp with higher doses Anxiety, blurred vision, palpitations, shakiness, slurred speech, sweating Weight gain

Insulin (cont)
Administration: Subcutaneous injection Rotate site Check blood sugars regularly Storage: Refrigerate until use Once vial is punctured, it is good for 28 days and can be left at room temperature (except for glargine which is 90 days)

Insulin Action

Rapid/immediate

Blood concentration

Intermediate

Fast Slow

10

12

14

16

18

20

22

24

Time (hr)

Insulin (cont)
Cautions/Severe Adverse Reactions Severe hypoglycemia (seizure/coma) (BG < 40 mg/dL) Edema Lipoatrophy or lipohypertropy at injection site CONTRAINDICATIONS Severe hypoglycemia Allergy or sensitivity to any ingredient of the product

Adjunctive Therapy in Diabetes Mellitus Type II

Hypoglycemia

Complication of treatment! Make sure patients inform the people around them of these symptoms and what to do! Symptoms: Anxiety, blurred vision, palpitations, shakiness, slurred speech, sweating Treatment: glucose/simple sugars: 3-4 glucose tablets, can of soda (NOT diet!) Treatment: glucagon injection

Dose: 1 mg IM, IV, SQ; may repeat in 20 minutes if needed

Adjunctive Therapy (cont)

Energy balance, diet, exercise Low-carb, low-fat, calorie-restricted diet is recommended Exercise increase uptake glucose Cardiovascular disease/Hypertension Systolic blood pressure goal < 130 mm Hg Angiotensin Converting Enzyme II Inhibitor (ACE-I) is first line

Adjunctive Therapies (cont)

Dislipidemia Patients with type II diabetes have an LDL goal < 100 mg/dL Weight loss First line therapy: statins (i.e. atorvastatin, simvastatin, rosuvastatin etc.) Fiber, omega-3 fatty acids (fish oils) can be used as adjunct therapy Antiplatelet agents Consider starting daily low dose aspirin (81 mg) to prevent ischemic events

Adjunctive Therapies (cont)

Smoking cessation Regular Screening for Cardiovascular Diseases and Coronary Artery Disease Depression/Stress/Anxiety/Other psychosocial conditions need to be screen for regularly Diabetic neuropathies especially in extremities need to be screened for on a regular basis

Fastidious foot care Regular foot exams (annually)

Eye exams Monitor kidney function

Sites of Action by Therapeutic Options

PANCREAS LIVER

Therapy: Biguanides Thiazolidinediones

INCREASED GLUCOSE PRODUCTION

DECREASED INSULIN SECRETION

Therapy: Sulfonylureas Meglitinides Insulin

HYPERGLYCEMIA

INTESTINE

DECREASED PERIPHERAL GLUCOSE UPTAKE ADIPOSE TISSUE

Therapy: INCREASE Alpha-glucosidase GLUCOSE ABSORPTION inhibitors

MUSCLE

Therapy: Thiazolidinediones (Biguanides)

Adapted from Sonnenberg and Kotchen Curr Opin Nephrol Hypertens 1998;7(5):551-555.

Stepwise management of type 2 diabetes

Insulin oral agents

Oral combination

Oral monotherapy

Diet & exercise

STEPWISE MANAGEMENT OF DIABETES MELITUS

Diagnosis Health education Diet, exercise, weight control

Oral agent monotherapy SU, metformin, meglitinide, thiazolidinedione, acarbose

Oral agent combination therapy (2 different classes) Insulin + oral agent Insulin