Diabetes Oral Medications Flashcards
four main stays in the medication treatment of type 2 diabetes mellitus:
- Oral Medication
- Oral Medication PLUS Insulin Therapy
- Insulin Therapy
- Injectable Glucose Lowering Agents
What is first line medication for diabetes
Metformin - a biguanide
Metformin MOA
Metformin works to decrease hyperglycemia by suppressing the hepatic glucose production in the liver but the actual cellular mechanism is poorly understood.
Metformin also increases insulin sensitivity in the body, and stimulates peripheral glucose uptake in the skeletal muscle. Specifically, it inhibits glycogenolysis in the liver which helps to prevent hyperglycemia. The effect of these mechanisms is a lower blood glucose.
Metformin side effects
The most common adverse effect of metformin is GI related-diarrhea, gas and bloating. Improves if taken with meals
The other side effect associated with metformin is lactic acidosis.
Metformin should be used cautiously in individuals with renal or liver dysfunction or failure.
Advantages of metformin
he first advantage is that metformin does NOT cause hypoglycemia. The second advantage is that metformin is NOT associated with weight gain. Because of its relative effectiveness, ease of therapy (oral medication) and minimal side effects, metformin is one of the most common medications prescribed in type 2 diabetes.
Examples of sulfonylureas
Medications in this class include glyburide, glipizide, and glimepiride.
You may sometimes hear this class of medications referred to as insulin secretagogues.
Sulfonylurea MOA
Sulfonylureas decrease hyperglycemia in type 2 diabetes mellitus because they directly increase insulin production from the pancreas.
The sulfonylureas work by closing the ATP sensitive K+ channel (bottom left channel in the image above). This causes the potassium in the cell to rise leading to depolarization of the cell, calcium influx and insulin secretion from the beta cell. The net effect is an INCREASE in insulin secretion from the beta-cell.
Mechanism of insulin secretion
When glucose enters the beta cell, the ATP K+ channel is closed leading to depolarization of the cell. The calcium channels then opens leading to calcium influx and release of insulin from the cell.
sulfonylurea side effects
Because sulfonylureas increase insulin production, one of the significant side effects is hypoglycemia.
Additionally, because of the increase in insulin production, which is an anabolic hormone, sulfonylureas are also associated with weight gain, which can be an undesirable side effect for many individuals with type 2 diabetes already struggling with being overweight and/or obese.
Thiazalidenidiones examples
Agents in this class of drugs include the “glitazones” including rosiglitazone and pioglitazone.
These medications are also referred to as insulin sensitizers.
Thiazolidinediones MOA
The glitazones are ligands of the peroxisome proliferator-activated receptor gamma (PPAR-γ) part of the steroid and thyroid superfamily of nuclear receptors.
thiazolidinediones work by 3 main actions: first, by decreasing insulin resistance by increasing glucose uptake in the tissues and by decreasing hepatic glucose output into the blood. Two, they have been found to preserve beta cell function of the pancreas. Finally, they prevent free fatty acid (FFA) release from adipose tissue.
What are peroxisome proliferator-activated receptor gamma (PPAR-γ)
PPAR-γ receptors are found in muscle, liver and fat and PPAR-y regulates the expression of genes involved in lipid and glucose metabolism, insulin signal transduction and adipocyte differentiation.
Thiazolidenidiones side effects
They are associated with weight gain and anemia.
Additionally, they can cause edema and heart failure and are therefore contraindicated in a patient already in congestive heart failure or in liver failure.
What is Dipeptidyl peptidase IV (DPP-4)
DPP-4 is an enzymes that breaks down GLP-1 and GIP (referred to an incretins) in the gut. Remember GLP-1 (called glucagon-like peptide-1) and GIP (called gastric inhibitory peptide) are released in the gut in response to food intake and their job is to stimulate insulin release in the pancreas
Examples of DPP-4 inhibitors
Common DPP-4 inhibitors include sitagliptin, alogliptin, and saxogliptin.
DPP-4 inhibitors MOA
DPP-4 inhibitors prevent the rapid inactivation of GLP-1 and GIP in the gut in response to food. Because of the action of incretins, the DPP-4 inhibitors allow incretins to increase insulin secretion.
Additionally, DPP-4 inhibitors also decrease gastric emptying and post-meal glucagon release
DPP-4 inhibitors side effects
DPP-4 inhibitors are well tolerated.
The most common side effects of DPP-4 inhibitors include mild GI distress, upper respiratory symptoms and headaches.
Examples of Alpha-glucosidase inhibitors
Medications belonging to this class of drugs include acarbose and miglitol.
MOA of alpha-glucosidase inhibitors
Alpha-glucosidase inhibitors help to prevent post-prandial hyperglycemia by slowing the complex carbohydrate absorption in GI tract due to the inactivity of the alpha-glucosidase enzyme by competitive inhibition.
The overall effect is to delay the absorption of starches and disaccharides.
What does alpha-glucosidase do
Alpha-glucosidase is an enzyme that is located in the intestinal brush border of the gut that is responsible for breaking down carbohydrates into simple sugars, such as glucose.
Side effects of alpha-glucosidase inhibitors
Common side effects GI upset, bloating, abdominal cramping, diarrhea, and flatulence likely as a result of the delayed gastric emptying. This drug is not metabolized and is cleared by the kidney so it should not be used in renal failure.
This class of medication is desirable for some individuals because weight gain is NOT associated with its use.
Sodium-Glucose Cotransporter 2 (SGLT2) Inhibitor examples
include the “gliflozins” : canagliflozin, dapagliflozin and empagliflozin.
MOA of SGLT2 inhibitors
SGLT2 inhibitors prevent the renal reabsorption of glucose in the proximal tubule. Because glucose is not resorbed, plasma glucoses decreases, but the urinary glucose level increases.
SGLT2 inhibitors side effects
Side effects include polyuria, polydipsia, dehydration, and increase risk of urinary tract infections. Another side effect likely as a result of this increase in glucose excretion is vaginal candidiasis.
SGLT-2 inhibitors should be used cautiously in an individual with kidney insufficiency or failure.
What are incretins
incretins are glucagon-like peptide 1, called GLP-1, and gastric inhibitory peptide, called GIP, which are released in the gut in response to food.
The action of incretins is to cause the release of insulin from the pancreas
Incretin mimetics example and route of admin
Injectable
Agents in the class of medications include exenatide and liraglutide. As noted earlier, liraglutide was recently FDA approved for use in children
Incretin mimetics MOA
When incretins are injected, they work to increase the glucose dependent insulin secretion from the beta cells. They also delay gastric emptying which increases satiety of individuals and they also decrease post-meal glucagon production.
While incretins are rapidly inactivated by DPP-4, incretin mimetics are largely resistant to this degradation by DPP-4
Incretin mimetics side effects
The most severe side effect is the potential of pancreatitis which is thought to be due to the proliferative effects of incretins on the pancreas. Because they promote satiety, weight loss is often associated with this medication. Incretins can also cause GI side effects. In particular, they can cause nausea, vomiting and constipation
Incretins can cause hypoglycemia when combined with other oral anti-diabetic drugs, especially sulfonylureas, and the doses of those other glucose lowering medications may need to be decreased when exenatide is added to prevent hypoglycemia.
What is amylin
Amylin is an enzyme that is secreted by the beta cells in the pancreas in addition to insulin. Causes satiety
Example of amylin analogue and route of admin
pramlintide
Injectable
Amylin analogue MOA
When secreted by the beta cells of the pancreas, amylin has several actions in the body. Like the incretins, it delays gastric emptying and increases satiety. Amylin also decreases post-meal glucagon production which decreases post-prandial hyperglycemia following a meal.
The amylin analogues, when injected, have a similar effect and studies have demonstrated that patients can use lower doses of exogenous insulin when also taking an amylin analogue.
Amylin analogues side effects
Because Amylin affects gastric emptying, it has been associated with GI side effects including nausea and weight loss.
Amylin is also associated with a risk of hypoglycemia.
Theme of coordinated therapy
Management of type 2 diabetes mellitus is not a one size fits all regimen. Many factors come into play regarding the choice of medications including efficacy, ease of administration, side effects and cost.
Lifestyle changes is first-line as this chart indicates. Metformin then is typically first-line therapeutic option given its high efficacy, low cost and low/neutral risk of hypoglycemia. Additionally, this chart also demonstrates that some patients may be on 3 or 4 different medications to treat hyperglycemia caused by type 2 diabetes mellitus. Insulin therapy is also an option that is effective, and many patients in their disease progression of type 2 diabetes will ultimately require insulin as well.
