Antidiabetics Flashcards
What is the incretin effect?
Oral glucose results in a higher insulin level compared to IV glucose due to incretins released by the gut that enhances insulin secretion.
What is the molecular pathway that leads to insulin release?
- increase blood glucose
- glucose enters pancreas via GLUT-2
- increased glycolysis and TCA cycle leading to increased ATP
- ATP closes potassium channel decreasing amt of K+ leaving cell and causing depolarization
- cell depolarization causes calcium channels to open and release pf insulin via exocytosis occurs
What are the 3 injected, rapid-acting insulin analogs?
- Insulin Lispro
- Insulin Aspart
- Insulin Glulisine
[modified B-chain]
*These are given to mimic the prandial release of insulin [given 15 minutes before meal] and given with longer acting insulins to assure proper glucose control
“There is no LAG”
Short acting insulins?
This is regular insulin that is a soluble crystalline zinc formation and is given 30 minutes before a meal. It is usually give via SC but may be given via IV in emergencies.
Intermediate-acting insulins?
Neutral protamine Hagedorn (NPH) - aka isophane insulin which is a suspension of crystalline zinc insulin combined with protamine
Given SC along with rapid- or short-acting insulin for mealtime control – helps maintain BASAL CONTROL.
Insulin Glargine?
Long-acting insulin, A chain mutation [Asn to Gly] - administered as an acidic depot solution that precipitates as glargine in the SC tissue (pH = 7.4). There is then slow dissolution of free glargine hexamers from precipitated glargine (stabilized aggregates)
Insulin Detemir?
Long-acting insulin, B chain mutation [addition of 2 Arg AA]
What are the major difference b/t insulin analogs and normal human insulin preparations?
Insulin analogs mimic physiologic insulin profiles more closely than human insulin preparations. Rapid-acting analogs have improved postprandial glycemic control and less risk of hypoglycemia. There is a better improvement of HbA1C levels and reduced hypoglycemia as compared to regular insulin or human insulin preparations.
When are IV infusions of insulin given?
- pts with ketoacidosis
- during perioperative pd
- during labor and delivery
- intensive care situations
[regular human insulin is used in IV therapy]
Basal-bolus insulin regimes?
One daily shot of glargine or detemir to provide basal coverage then doses of Lispro, Aspart, or Glulisine to provide coverage for each meal.
Long acting insulin is given t bedtime or morning and if pt skips meal, they omit the premeal bolus. An increase in premeal bolus is needed if pt eats a large meal than normal.
Insulin pump therapy?
Use of insulin pump is the best way to mimic normal insulin secretion. It is a battery-operated pump and computer program that delivers predetermined amts of insulin.
Glulisine, Lispro or insulin aspart is used in insulin pump.
AE of insulin?
- Hypoglycemia (manage with orange juice or sugar-containing beverage),
- Allergic reaction - immediate type I HSN often due to noninsulin protein contaminants
- Lipodystrophy at injection site
- Drug interactions
What drugs cause hypoglycemia?
- Ethanol - inhibits gluconeogenesis
- B-blockers - blocks effect of catecholamines on gluconeogenesis and glycolysis as well as masking sympathetically mediated symptoms of hypoglycemia
- Salicylates - enhance pancreatic B-cell sensitivity to glucose potentiating insulin secretion
What drugs cause hyperglycemia?
Counter action of insulin – Epinephrine, Glucocorticoids, Atypical antipsychotics, HIV protease inhibitors
Inhibit insulin secretion directly - Phenytoin, clonidine, Calcium channel blockers
inhibit insulin secretion indirectly by depleting potassium - diuretics
How do you manage diabetes in hospitalized pts?
Insulin administration - oral antidiabetics should be discontinued during acute illness and replaed iwth insulin
Sulfonylurea?
Insulin secretagogues - non-insulin antidiabetic agent that reduces fasting plasma glucose and HbA1c by stimulating insulin release from B cells by binding to SUR1 subunit and blocking ATP-sensitive K+ channels in B cell membranes.
1st gen - Chlorpropamide
2nd gen - Glyburide, Glipizide, Glimepiride
AE - hypoglycemia, weight gain
1st generation sulfonylurea?
Chlorpropamide
- long half life
- hypoglycemia is common, esp in elderly pts
- hyperemic flush when alcohol is ingested due to inhibition of aldehyde dehydrogenase
- SIADH elicited
2nd generation sulfonylureas?
- Glyburide (Glubenclamide) - causes hypoglycemia in 20-30% of pts
- Glipizide - shortest half-life of more potent agents
- Glimepiride - causes hypoglycemia in only 2-4% of pts
- more potent than 1st generation
- lacks AE of 1st generation
Meglitinides [Repaglinide and Nateglinide]?
Stimulates insulin release by binding to SUR1 and inhibiting ATP-sensitive K+ channel. It is not as effective as sulfonylurea in reducing fasting blood glucose and HbA1C levels.
- rapid onset, short duration
- postpradial glucose regulator
- must be taken before each meal
- does NOT contain sulfur
AE - weight gain, hypoglycemia (more for Repaglinide compared to Nateglinide)
Metformin?
This is the only currently available biguanide that does NOT cause insulin secretion or hypoglycemia, even at large doses. It is just as effective as sulfonylureas in reduces fasting blood glucose and HbA1C levels.
Metformin reduces glucose levels by inhibiting gluconeogenesis by reducing gene expression of gluconeogenic enzymes via AMPK (AMP-activated protein kinase). It also increases insulin-mediated glucose utilization in muscle and liver.
Other effects - reduces plasma triglyceride level and decreases body weight
First line agent - type 2 diabetes mellitus
AE - GI (anorexia, nausea, vomiting, abdominal discomfort, diarrhea), long term use may interfere with B12 absorption, risk of fatal LACTIC ACIDOSIS, contraindicated in pts with renal disease, hepatic disease, hypoxia, alcoholism
**different from sulfonylureas which increase weight
Thiazolidinediones (TZDs)?
Pioglitazone and Rosiglitazone
These medications decrease insulin resistance [insulin sensitizers decreasing insulin resistance] by acting as an agonist at the intracellular PPAR-gamma (peroxisome proliferator-activated receptor-gamma) receptors in muscle, fat and liver. By activating the receptors these medications promote glucose uptake and utilization in adipose tissue. They are less effective compared to sulfonylureas and metformin at decreases fasting plasma glucose levels and HbA1C.
- Glitazone has a slow onset and an offset over weeks to months
- Pioglitazones effects on lipids are more favorable than those of rosiglitazone [improvement in HDL, TG, LDL particle size and concentration]
AE - FLUID RETENTION, weight gain, edema, exacerbates CSF, contraindicated in pts with class III and IV heart failure
1st TZD years ago was Troglitazone but it caused liver toxicity leading to death therefore was withdrawn from the market. Since then if you are on a glitazone liver functioning must be monitored.
a-glucosidase inhibitors?
Acarbose
Any consumed carbs need to be broken down in to monosaccharides to be absorbed. One of the enzymes that creates monosaccharides is a-glucosidase. Acarbose competitively inhibit intestinal a-glucosidase to reduce postprandial digestion of starch and disaccharides as well as postprandial hyperglycemia and hyperinsulinemia. This medication evokes a modest/small drop in HbA1C and fasting plasma glucose.
AE - flatulence, diarrhea, abdominal pain (contraindicated in pts with IBS), associated with reversible hepatic enzyme elevation so liver functioning tests need to be monitored
Exenatide?
Injectable analog of glucagon-like-polypeptide 1 (GLP-1) [Incretin] derived from the salivary gland of gila monster. incretins released by the gut enhance insulin secretion so oral glucose stimulates massive insulin increase compared to IV glucose. B-cells have receptors for the incretins that further stimulate the release of insulin.
Exenatide - full agonist at human GLP-1 receptor and is resistant to the enzyme (dipeptidyl peptidase IV) that breaks down natural incretins.
MOA..
• Enhances glucose-dependent insulin secretion.
• Suppresses postprandial glucagon release.
• Slows gastric emptying.
• Decreases appetite.
• May stimulate β-cell proliferation.
• Approved to improve glycemic control in adults
with type 2 diabetes
AE - nausea, vomiting, diarrhea, acute pancreatitis, should not be used in pts with gastroparesis
Sitaglipitin?
Inhibitor of DPP-IV - enzyme that breaks down endogenous incretins and increases circulating GLP-1 and insulin levels. Administered orally and given to improve glycemic control in adults with type 2 diabetes mellitus.
AE - pancreatitis, HSN reaction
