Exam 2: Lecture X, Oral Hypoglycemic Agents Flashcards
Oral Hypoglycemic agents used…
in patients with type 2 diabetes if cannot be managed by diet
pt who develop diabetes after 40 respond well
combo w/insulin maybe required
** should not be given to type 1**
Type 2 diabetes has insulin secreted only during….
phase 2
Sulfonylureas
developed as a result of finding that sulfonamide derivative produced decreased blood glucose levels
had their effect by stimulating insulin release from pancreatic beta cells, functional islet cells are important
Sulfonylurea MOA
stimulate insulin secretin from beta-cells
possibly sensitize beta-cells to glucose
increase activity/number of peripheral insulin receptors
possible reduce glucagon secretion
Sulfonylureas therapeutic uses
Type 2, 50-80% pt initially respond well
with chronic admin, reduced glucose levels maintained
cannot prevent longterm complications of diabetes
Sulfonylurea + suboptimal insulin = therapy Type 2
Sulfonylureas pharmacokinetics
- Absorbed from the small intestine
- Food/hyperglycemia may reduce absorption
- Significant binding with PP - 90-99% (may interact with other drugs)
- Excreted in the urine (*elderly patients/renal/hepatic insufficiency)
- Cross placenta
- Stimulate fetal beta-cells to release insulin
Sulfonylureas precautions
- Not recommended for children, pregnant, lactating women.
- Contraindicated in patients with allergy to sulfa agents
- Not to be used during severe infections, injury, surgery (use insulin)
- Therapy is associated with the cardiovascular mortality
Tolbutamide (Orinase)
- least potent
- onset: 30 min
- duration: 6-12 h
- metabolites - inactive
- excreted renally
- has diuretic activity
Tolazamide (Tolinase)
- onset: 6h
- duration: 10-14 h (24h)
- metabolites are weaker than parent compound
- excreted renally
- has diuretic activity
Clorpropamide (Diabinese)
- rapidly absorbed
- duration: 60 h
- excreted renally (parent compound/metabolites)
- can potentiate ADH secretion
- transient leucopenia
- disulfiram-like* reaction with alcohol **
- *disulfiram –>↓ aldehyde dehydrogenase –> ↑acetyl aldehyde**
Glipizide (Glucotrol)
shortest half-life 2 hours
- duration 24 hours
- completely metabolized in liver
- few adverse effects**
Glimepiride (Amaryl)
- half-life 5 hours
- duration 24 hours
- completely metabolized in liver
- small dose effectively lowers sugar level**
Glyburide (Micronase, DiaBeta)
- duration: 24 h
- most potent
- metabolites in liver - little activity
- has diuretic activity
- higher incidences of hypoglycemia**
Sulfonylureas Adverse Effects
3-5% of patients
- Hypoglycemia
- elderly
- hepatic/renal insufficiency
- glyburide, chlorpropamide - higher incidence - Cutaneous reactions
- rashes
- photosensitivity - GI reactions
- Hematological reactions
- leukopenia
- thrombocytopenia
- hemolytic anemia - Inappropriate secretion of ADH / disulfiram-like reaction chlorpropamide)
Meglitinides —– Repaglinide (Prandin TM )
Nateglinide (Starlix TM)
- Relatively novel drugs. D-phenylalanine derivative
- Inhibit ATP-sensitive K+ channels in pancreatic beta-cells
- Stimulates the release of insulin within few minutes
- Metabolized in liver/Excreted in the bile
- Patients with Type-2DM
- Act synergistically with metformin and thiazolidinediones,
- Act together with sulfonylureas
- Act together with NPH insulin
Meglitinides MOA
Inhibit ATP-sensitive K+ channels in pancreatic beta-cells
Stimulates the release of insulin within few minutes
Metoformin (Glucophage)
Biguanide
Patients with T2DM
Requires presence of insulin
Duration of Action = 6-12hr
Biguanides MOA
- Increased tissue sensitivity to insulin
- Increased activity insulin receptor tyrosine kinase activity
- Increased activity of post-receptor signaling pathway
- Increased function of insulin/glucose sensitive transporters
- Increased movement of transporters into the cell membrane
- Increased movement of glucose into the skeletal muscles
- Increased glycogen synthesis/storage
** increase a bunch of shit, leading to decrease blood glucose)**
Biguanides Contraindications
- Myocardial infarction!!
- Septicemia!!!
- History of lactic acidosis!!!
- Renal disease - can cause lactic acidosis in patients!!!
- Hepatic disease
- Lung disease
- Not to use after intravenous contrast media
- Prolonged fast/low calorie diet
Biguanides Adverse effects
Gi effects
Serum vitamin b12 levels may decline, calcium supplements reverse this
Rosiglitazone (Avandia), Pioglitazone, (Actos)
Rosiglitazone (Avandia)
Thiazolidinediones
- Contraindicated in hepatic disease
- Safety in children is not established
- Protein binding >99%
- Half-life in plasma - 160 hr
*Avandia some report that sig 43% increase risk of Heart attack patient taking
Thiazolidinediones MOA
Blocks release of new hormone - resisting (Resistance to insulin)
increase glucose transport by enhancing GLUT-4 synthesis
Alpha-glucosidase inhibitors
orally taken
inhibit enzymatic digestion of carbs in intestine
do not stimulate insulin release, or result in hypoglycemia
monothreapy in older patients
used in combo with oral anti diabetic agents and/or insulin
Contraindications = renal/hepatic disease, intestinal condition
Absorbable Alpha-glucosidase inhibitors
Miglitol, inhibit Alpha-glucosidase in other body cells
Non-Absorbable Alpha-glucosidase inhibitors
Acarbose (Precose) inhibits Alpha-glucosidase inhibitors in intestine
Amylin Analogs (hormone)
Pramlintide (Symlin TM) 2005
Pramlintide is an injectable analogue of a peptide hormone amylin
Amylin is stored with insulin in beta-cells
Amylin is co-secreted with insulin
Inhibits glucagon secretion.
Bile Acid Sequestrants
Colesevelam hydrochloride (Welchol)
Initially developed as a bile sequestrant and cholesterol-lowering agent
a) Impairs glucose absorption
b) Antihypertensive therapy in Type 2 diabetes
Contraindications:
History of pancreatitis, esophageal, gastric, or intestinal disorders
***Impairs absorption of multiple medications !!!
GLP-1 Receptor Agonist
Exenatide (Byetta), Liraglutide (Victoza)
In type 2 diabetes the release of GLP-1 is decreased.
As a result glucagon suppression is decreased
Excessive hepatic glucose output occurs – rising plasma glucose level.
Injectable GLP-1 receptor agonists help to restore GLP-1 activity.
Exenatide (Byetta)
- Increases glucose mediated insulin release
- Lowers glucagon levels**
- Slows gastric emptying
- Decreases appetite
- Duration of action up to 10 hours
- Major adverse effects are vomiting and nausea
- In rare cases serious or fatal necrotizing and hemorrhagic pancreatitis
* Liraglutide: similar to Exenatide; possible thyroid carcinoma risk
DPP-4 Inhibitors
DPP-4 degrades incretin hormones GLP-1 and GIP.
Inhibition of DPP-4 increases GLP-1 and GIP concentration.
Glucagon secretion is inhibited, and insulin secretion is increased.
Sitagliptin (Januvia TM) 2007
Saxagliptin (Onglyza TM ) 2009
Linagliptin (Trajenta TM ) 2011
Glucagon
- To treat severe hypoglycemia in diabetics
- Hypoglycemia may cause neurological damage
- Require intact hepatic glycogen stores
- Given: I.M., I.V., nasal spray
- Improvement is expected in 10 min (to minimize the risk of hypoglycemia)
- After initial improvement glucose is given to patient
- In severe beta-blocker overdose - the most effective positive inotrope
- Increases cardiac cAMP without stimulation of beta-receptors
- Typical adverse effects - nausea/vomiting
Diazoxide (Proglycem)
**Used in treatment of hypertensive emergencies **Used to treat hypoglycemia - orally
- Reduces insulin release from pancreas and insulin-secreting tumors
- Severe hypoglycemia is prevented
- Insulin synthesis is not inhibited; insulin accumulates in beta cells
- Highly bound with plasma proteins
- Half-life - 48 hours
- Typical adverse effects nausea, vomiting Na+ retention, thrombocytopenia, leukopenia
