Drugs forDiabetesMellitus

Internal Medicine2010

Islets of Langerhansa cells – glucagon

b cells – insulind cells – Somatostatin

PP cells – pancreatic polypeptide

Drugs used in Diabetes Mellitus

Insulin per orem

Rapid Short-Acting

Intermediate Acting

Slow, long acting

Insulin Secretagogue

Biguanides

Insulin Synthesizer

Glucosidase inhibitor

Insulin• duplicate normal physiologic secretion of

insulin• type 2 DM

• use during times of illness or stress to maintain glycemic control

• patients who are unable to maintain adequate control

• exact time course of each insulin will depend on each particular preparation and site of injection

Effects of Insulin• Liver

• Increases storage of glucose as glycogen in liver• Decrease protein catabolism

• Muscle• Stimulates glycogen synthesis and protein

synthesis• Adipose Tissue

• Facilitates triglyceride storage by: 1. activating plasma lipoprotein lipase2. Increasing glucose transport into cells via GLUT 4

transporters3. Reducing intracellular lipolysis

Normal Plasma Glucose and Insulin Profile

Human Insulin• 1982: "recombinant DNA" into lab-cultivated

bacteria or yeast• very short half life • insulin preparations are formulated to release

insulin slowly into circulation• recombinant human insulin has replaced animal-

derived insulin, such as pork and beef insulin• insulin analogs

• structure differs slightly from human insulin to change onset and peak of action

Insulin and Insulin Analogs

Insulin Onset of action(minutes)

Time to peak concentration(minutes)

Maximum duration of action (hours)

Regular insulin 30-60 90-120 5-12

Insulin lispro(Humalog)

10-15 30-60 3-4

Insulin aspart 10-15 40-50 3-5

Insulin glulisine 10-15 55 3-5

NPH insulin 60-120 240-480 10-20

Insulin glargine 60-120 None 24

Insulin detemir 60-120 None 20

Short and Rapid-Acting Insulin• act as mealtime insulin• administer before meals to mimic

physiologic increases of insulin which occurs after meals

ASPART, GLULISINE, LISPRO• more rapid onset of action and shorter

duration of action than regular insulin• premeal control before the next meal may

be difficult due to short duration of action if used alone

Crystalline zinc (Regular) Insulin• as a mealtime insulin, its use may be limited

because onset is not so rapid to meet the quick, unpredictable increase in postprandial blood glucose

• considered basal insulin• can be given IV or SQ• given 30 to 45 minutes ac

Intermediate and Long-Acting Insulins• given SQ only• intend to mimic normal physiologic basal

insulin secretion• usually given 1-2 times/day

LENTE• Intermediate-Acting Insuline

ULTRALENTE, DETEMIR, GLARGINE• Basal/ Long-Acting Insulins

Combinations• short- and long-acting combinations are

available commercially or may be combined in a single syringe by the patient

• 30% R/ 70% NPH• 50/50• 20/80

Different Insulin Regimen• 2 daily injections• Multiple Daily Insulin Injection• Continuous Subcutaneous Insulin Infusion

Adverse Reactions• Hypersensitivity reactions• Hypoglycemia• Lipoatrophy or lipohyperthrophy

Oral Antidiabetic Agents• sensitizers

• Biguanides: Metformin• TZDs (PPAR): Pioglitazone, Rivoglitazone,

Rosiglitazone• Dual PPAR agonist: Muraglitazar

Oral Antidiabetic Agents• secretagogues

• K+ ATP• sulfonylureas

• 1st gen: Gliclazide• 2nd gen: Glibenclamide, Glipizide• 3rd gen: Glimepiride

• meglitinides: nateglinide, repaglinide• GLP-1 analogs: exenatide• DPP-4 inhibitors: saxagliptin, sitaglipitin

Oral Antidiabetic Agents• α –glucosidase inhibitors

• acarbose, voglibose, miglitol• amylin

• pramlintide• SLGT2 inhibitors

• dapaglifozine• others

• benfluorex, tolrestat

SulfonylureasMechanism of Action• Stimulate insulin release from pancreatic β cells• Decrease hepatic clearance of insulin• Primarily act by binding to the SUR subunit of the

ATP-sensitive potassium (KATP) channel and inducing channel closure

SulfonylureasAbsorption, Fate, and Excretion• absorbed from git• decreased absorption with food and hyperglycemia• 90 to 99% protein bound in plasma• metabolize in liver• metabolites excreted in kidney• 2nd gen half life

• short (3 to 5h)• long duration of action (12 to 24h)

Sulfonylureas1st GENERATION• Chlorpropamide/ Tolazamide/ Tolbutamide: once

daily dosing, administer with breakfast

2nd GENERATION• Glibenclamide/ Gliclazide/ Glimepiride: once daily,

administer with breakfast• Glipizide: 15-30 min before breakfast

Sulfonylureas• Adverse Reactions: hypoglycemia, allergic

reactions. GI upset• use with caution in patients with hepatic or renal

failure• should not be used in DKA, major surgery, severe

infections. stress or trauma, sulfa allergy• disulfiram reaction may occur with chlorpropamide

and alcohol

Generic Name

Daily Dose

Duration of Action

Clearance

Glimepiride

1 – 8 mg 24H H, R

Glipizide 2.5 – 40 mg

12-18H H

Glipizide (ER)

5 – 10 mg 24H H

Glyburide 1.25 – 20 mg

12-24H H, R

Glyburide (Micronized)

0.75 – 12 mg

12-24H H, R

Repaglinide

0.5 – 16 mg

2-6H H

MeglitinidesREPAGLINIDE• initial dose: 0.5 mg PO prior to meals; max:

16mg/day• MOA: derivative of benzoic acid; stimulate insulin

release by closing ATP-dependent K channels in pancreatic β cells

• absorbed rapidly from GIT; peak blood levels within 1 hour

• Metabolize• 90% in liver• 10% in kidney

MeglitinidesNATEGLINIDE• 120mg PO 1-30min prior to main meals• MOA: from D-phenylalanine; stimulate insulin

release by closing ATP-dependent K channels in pancreatic β cells

• Reduce postprandial hypoglycemia• Metabolize:

• 84% IN LIVER• 16% IN KIDNEY

BiguanidesMETFORMIN• absorbed mainly in small intestine• stable but does not bind with protein• excreted unchanged in urine• half life – 2 hours

MOA:• decrease hepatic glucose production -

gluconeogenesis• increase insulin action in muscle and fat

BiguanidesMETFORMIN

CONTRAINDICATIONS: renal impairment, hepatic disease, past history of lactic acidosis, cardiac failure, chronic hypoxic lung disease

• Withheld for 48 hours after giving contrast media – to insure N kidney

ADVERSE REACTIONS: lactic acidosis, diarrhea, GI discomfort, nausea, metallic taste, anorexia

• uptitrate slowly

Thiazolidinediones (TZDs)• selective agonist for nuclear peroxisome

proliferator-activated receptor-gamma (PPAR)• requires insulin• insulin resistance in peripheral tissue

Thiazolidinediones (TZDs)ROSIGLITAZONE AND PIOGLITAZONE• OD dose• Absorbed within 2 hours• Max effect observed in 6 to 12 weeks• Metabolized in Liver

• Cytochrome P450 enzymes• Monitor liver enzymes regularly

• May be given to patients with renal insufficiency• AE: anemia, weight gain, edema• C/I: Heart Failure

Glucosidase Inhibitor• GI absorption of starch, dextrin, disaccharide by

inhibiting the action of intestinal brush border ( glucosidase)

• slow carbohydrate absorption

Thank you!!!