Quiz 8

MoA: Stimulate insulin release from pancreatic beta-islet cells by binding to and blocking an ATP-ase sensitive K+ channel. Causing depolarization and an increase in intracellular Ca2+ which leads to the release of the hormone. Could also decrease the hepatic clearance of insulin.
Hepaticially metabolized.
Adverse effects: (Very low) Hypoglycemia, many drug interactions, possible disulfiram-like reaction with ethanol.
Individual dosing, used in combination with insulin
5-10% resistent
Contraindicated in Type 1 DM, pregnancy, lactation, hepatic and renal failure

Sulfonylureas, First Generation Agents

First Generation Sulfonylurea
Serum half life of 7 hours
Active Metabolites

First Generation Sulfonylurea
Serum half life 4.5-6.5 hours
NO Active Metabolites

First Generation Sulfonylurea
Serum half life 36 hours
Active Metabolites

First Generation Sulfonylurea
Serum half life 6-8 hours
Active Metabolites

Second Generation Sulfonylurea
Serum half life 2-4 hours
NO Active Metabolites

Second Generation Sulfonylurea
Nonmicronized Serum half life 10 hours
Micronized Serum half life 4 hours
Weakly active metabolites

Third Generation Sulfonylurea
Serum half life 9 hours
Active Metabolites
MoA: Appears to cause translocation of GLUT-4 glucose transporter to the cell surface from the cytoplasm, insulin like activity. May bind to a different protein than the usual sulfonylurea receptor on the beta-islet cell.

Second Generation Sulfonylurea agents

Thiazolidinedione oral agents

MoA: Increase the activity of the nuclear receptor PPAR-gama that regulate genes responsible for the control of glucose and insulin metabolism in adipose, liver and skeletal muscle tissues (Increase tissue sensitivity)
Indicated for Type 2 DM, often in combination
Work only in the presence of insulin
Watch for hepatic failure
taken without regards to food
Contraindicated in patients at risk for heart failure
Edema, weight gain of 6 lbs, increase plasma volume, and fatigue common side effects

Thiazolidinedione
Tightly controlled dispensing
Metabolized by CYP2C8 lesser extend by 2C9

Thiazolidinedione
Metaboliced by CYP3A4
Decreases the efficacy of OC, additional birth control needed, monitor ALT for hepatotoxicity

Indications: Type 2 diabetes with diet and exercise, can be used in combination with a thiazolidinedione
NON-sulfonylurea analog of glyburide
MoA: Stimulate insulin release for pancreatic Beta-islet cells by binding to and blocking an ATP-ase sensitive K+ channel. This causes depolarization and an increase in intracellular Ca+2 which leads to the release of the hormone. May also decrease the hepatic clearnace of insulin.
Metabolized by CYP3A4
Takes 15-30 minutes preprandially, skip (add) a meal then skip (add) a dose

Indication: Type 2 DM with diet and exercise or in combination with a sulfonylurea
MoA: Decrease heaptic gluconeogenesis and intesintal glucose absorption, increase peripheral tissue and insulin sensitivity, does NOT cause insulin release in the the pancreas
Half-life is 1.3-4.5 hours, can cause decrease in B12 and folate absorption
Contraindicated in hepatic and renal failure or a history of lactic acidosis, stop taking if MI occurs of septicemica
NO PROTEIN BINDSING, NO METABOLISM with rapid renal excretion

Indications: Type 2 DM
Unreleated to sulfonylureas, D-phenylglycine analog
MoA: Stimulates insulin release in the pancreas by interacting with a ATP-sensitive K+ channel on intact pancreatic beta-cells, leads to beta cell depolarization that opens a Ca2+ channel causing insulin secretion.
Highly slective with low affinity for heart ad skeltal muscle K+ channels, 98% albumin binding, CYP2C9 (70%) and 3A4 (30%) metabolism

Alpha-glucosidase inhibitors
Type 2 diabetes adjunct to sulfonylureas, insulin or agents
MoA: decrease carbohydrate absorption by competitively inhibiting the intestinal enzyme alpha-glucosidase, amino group prevents protonation of glycosidic bond in the saccharides by an essential carboxylic acid group in the enzyme active site
Take drug with first bite of meals 3 times a day
Adverse: Diarrhea, flatulence, GI issues that resolve after 2 weeks

Alpha-glucosidase inhibitor
Minimal systemic absorption
Increase in serum transaminase at dose higher than 100 mg

Alpha-glucosidase inhbitor
Rapid and complete systemic absorption

Combination products for type 2 diabetes?

Recombinant modified insulins

Recombinant modified insulin
Rapid acting product recombinant site directed mutation human insulin produced by E. coli
Lysine replaces asparagine at position 3 and glutamic acid replaces lysine at postion 29

Recombinant modified insulin
Threonine at B30 position has been deleted and a C14-fatty acid chain has been attached to the B29 amino acid lysine
Long acting 24 hour product recombinant site directed mutation human insulin produced in Saccharomyces cerevisiae followed by chemical modification with a fatty acid
98% bound to plasma albumin

Recombinant modified insulin
Forms microprecipitaes in subcutaneous tissue prolonging duration from 18-26 hours
Possible cancer risks

Recombinant modified insulin
Rapid acting, 3-5 hour duration, take 5-10 minutes before meals

Recombinant modified insulin
Rapid actinging, 3-5 hour duration, take 15 minutes before meals or immediately after eating

Recombiant/chemically modified/synthetic polypeptides

Recombiant/chemically modified/synthetic polypeptide
Incretin mimetic or glucagon-like peptide-1 receptor agonist that binds the GLP-1 receptor on the beta-islet cells causing insulin synthesis and excretion

Recombiant/chemically modified/synthetic polypeptide
Synthetic analog of human amylin a neuroendocrine hormone made by beta-islet cells that contributes to glucose control postprandial

DNA inhalation insulin product
financila failure
Rapid actiing insulin product

Incretic mimetic or glucagon-like peptide-1 receptor agonist
Peptide analog not substrates for DPP-IV

rDNA origin injection
Solution for subcutaneous use
MoA: incretin mimetic or glucagon-like peptide 1 receptor agonist as an adjunct to diet and exercise
Inject independent of meals
Risk of Thyroid C-Cell tumors

Small molecule inhbitors of DPP-IV
Monotherapy for type 2 DM or combination with metformin or thiazolidinediones
MoA: Dipeptidyl protease IV inhbitor prolongs the biological levels of the natural incretins GLP-1 and GIP thereby increasing insulin rleaseing and decreasing release of glucagon
Substrate for p-glycoprotein
take with or without food

Indications: adjunct to diet and exercise to improve glycemic control in type 2 diabetes only
MoA: dopamine receptor agonist increasing dopamine levels early in the day seems to "reset" the biological clock and improves metabolism problems that are related to diabetes
Side effects: Nausea?Vomiting, fatigue, headache, dizziness
Taken orally within 2 hours of awakening with food
also marketed as Parlodel for hyperprolactinemia, parkinsons et al (old drug but new indications)

MoA: DPP-4 inhibitor
Metabolism by CYP3A4/5 to an active metaboite
Advers effects include decrease lymphocyte count (URI, UTI), hypoglycemia, uticaria, acute pacreatitis, headaches
Inhibition of other peptides, cytokine degradation
Combination with metformin in Kombiglyze XR

DPP-IV inhibitor
Limitations of use: Should not be used in patients with type 1 diabetes or for the treatment of diabetic ketoacidosis, has not been studied in combination with insulin
Metabolism: 90% excreted unchanged with 80% via hepatobiliary rout
Drug ineractions: Substrate for P-glycoprotein, CYP3A4 inducer and mild inhibitor
Adverse effects: When used with an insulin secretagogue consider lowering the dose of the insulin secretagogue to reduce the risk of hypoglycemia
Can be taken with or without food
5 mg daily

Recombinant biotechnology product, human derived platelet growth factor
Indication: 0.1% gell topical agent used for treatment of lower extremity diabetic neuropathic ulcers assuming adequate blood supply is present (Not a substitute for good ulcer care practices, dosage calculated on ulcer size)
Contraindicated if known neoplams at site of administration
Use extreme caution in patients with known malignancy patients with 3 or more tubes have an increased risk of mortaility secondary to malignancy

Adjunct agent
Bile acid sequestrant indicated as an anjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus
Also for hyperlipidemia