Oral Hypoglycemics Flashcards
What is the main method of treatment for DM Type 2?
- ->Oral hypoglycemics!
- Stimulates Beta cells to release insulin
Metformin:
The Gold Standard for Type 2 Diabetes (Biguanides)
-Good efficacy, low risk of hypoglycemia, no weight gain and relatively safe.
Incretins
- Endogenous (exist within the body)
- Mediate communication between the gut and the brain (potential target for weight loss drugs)
- Glucagon- like peptide (GLP-1)
- Glucose-depedent Insulinotropic Peptide (GIP)
Examples of Incretins
What are the 2 variations of Incretins?
- GLP-1 Agonists– Liraglutide
2. DPP-4 Inhibitors– Sitagliptin
Explain the basic physiology behind Insulin Release from Pancreatic Beta Cells.
-Glucose enters the cell through GLUT 4 transporters, which is metabolized in the cell to increase ATP. This increase in ATP/ ADP ratio causes the closure of KATP channels, which causes the cell to depolarize. This allows Ca2+ to enter the cell through Ca2+ channels, leading to the exocytosis of insulin from secretory granules.
How do Incretins block Insulin release from pancreatic beta cells?
Incertains augment glucose stimulated insulin release by blocking KATP channels, which makes receptors more receptive to physiological glucose levels.
-Incretins increase insulin secretion, inhibit glucagon secretion, delay gastric emptying and reduce appetite.
How are GLP-1 agonists administered?
Subcutaneous Injection
*May have a more pronounced effect on the GI tract compared to GPP-4 inhibitors (may reduce gastric emptying to interfere with drugs needing rapid absorption)
How are DPP-4 Inhibitors administered?
Oral Administration
What are the main side effects of Incretins?
-Hypoglycemia: Less common than with insulin or insulin secretagogues
- Rare, but serious risk of Pancreatic Disease
- Pancreatitis (Cancer)
Liraglutide:
GLP-1 agonist
-Side Effects:
- Gastrointestinal (N/V or constipation)
- Weight loss (approved as a weight loss drug)
- Increased risk at forming gallstones
Rare, but serious adverse effects include increased heart rate, arrhythmia and possible think with thyroid cancer.
Sitaliptin:
DDP-4 Inhibitor
Side Effects:
-Gastrointestinal: GI side effects are less common compared to Liraglutide
- Increased Risk of Infection:
- Typically upper respiratory tract or urinary tract infections.
DPP-4 inhibitors play a direct role in the immune system (lymphocytes)
Thiazolidinedione’s (TZD’s) aka “Glitazones”
- Peroxisome Proliferator Activated Receptor- gamma aka (PPAR-γ) agonist
- Regulate genes related to glucose and lipid metabolism
- Because they work on gene expression, TZD effects tend to be delayed.
Mechanism of Action of Glitazones:
- Insulin sensitizers- increase the uptake of glucose
- TZD enhances the uptake of free fatty acids into adipose tissue.
- This leaves less FA’s available to enter other tissue.
- Higher tissue adipose levels tend to reduce the sensitivity to insulin.
- Reduces hepatic production of glucose (reduces gluconeogensis)
- Reduces TG’s (increases HDL-C)
CONSISTENT SAFETY ISSUES LIMIT THEIR USE
Pioglitazone:
-Type of Thiazolidinedione
Side Effects:
- CV (heart failure)
- Edema
- Weight gain (Reduces Leptin Levels)
- Fractures (Especially in women, reduces bone density)
Alpha- Glucoside Inhibitors (AGI’s) Mechanism of Action:
- ->Glucosidases break down carbohydrates into glucose.
- AGI’s inhibit the breakdown of carbs, preventing absorption.
Acarbose:
-Alpha- glucoside inhibitor (AGI)
Side Effects:
GI: Bloating, diarrhea and pain
-Bacteria feed on undigested carbs, which release gas.
Low risk of Hypoglycemia
-If it occurs, need to administer glucose (sucrose won’t be absorbed)
Sodium- Glucose Co Transporter 2 (SGLT-2) Inhibitors Mechanism of Action:
- Inhibit renal mechanism for reabsorbing glucose.
- In non-diabetic individuals, all filtered glucose is reabsorbed. 90% of glucose reabsorption occurs at the Proximal Tubule (PT).
- Inhibiting SGLT-2 reduces glucose reabsorption leading to osmotic diuresis, and reduces blood pressure.
- Also induces weight loss.
- May reduce BP (via osmotic diuresis)
Empagliflozin:
- SGLT-2 inhibitor
- Act on the proximal tubule to inhibit the sodium- glucose co transporter.
Adverse Effects:
-Increased glucose in the nephron increases the risk of infections (UTI’s and Genital Infections)
-Dizziness and hypotension
(reduced blood volume due to the osmotic diuresis)
-Nausea
-Hyperkalemia
Rare, but serious diabetic ketoacidosis.
What drug can be combined with essentially anything in treating DM Type 2?
Metformin (Biguanide)
*Benefit of combination includes it’s effect on weight gain.
Adding 2 drugs that cause weight gain can lead to a NEUTRAL EFFECT on weight:
- Metformin + Insulin
- Metformin + Sulfonylurea
*These drugs, which increase risk of hypoglycemia, in combination actually REDUCE risk.
Adding drugs that have a neutral effect or reduce weight can ENHANCE weight gain:
-Metformin + SGLT-2 Inhibitor + DPP-4 inhibitor
Future Drugs to treat DM Type 2?
- Inhaled Insulin (Approved in the US)
- Powder Form (Inhaled through the mouth)
Issues:
- Cost: First device failed to catch on.
- Concerns over bronchospasm
- Patches (using micro needle technology)
- Stem cells (Islet cell transplants)
