Lecture 6: Oral Hypoglycemic Agents

What specific receptor do Sulfonylureas bind to on the beta cell?

The sulfonylurea receptor (SUR1).

Sulfonylureas block which ion channel to initiate depolarization?

The ATP-sensitive Potassium (K+) channel.

The depolarization caused by sulfonylureas leads to the influx of which ion?

Calcium (Ca++).

Because they stimulate insulin release, sulfonylureas require the patient to have what specific physiological function?

Functional islet cells.

Name three second-generation sulfonylureas.

Glyburide (Glynase), Glipizide (Glucotrol), and Glimepiride (Amaryl).

Why are second-generation agents preferred over first-generation agents?

They are more potent.

What is the major adverse effect associated with sulfonylureas?

Hypoglycemia.

In which patient populations should sulfonylureas be used with caution due to hypoglycemia risk?

Elderly patients and those with cardiovascular disease.

What effect do sulfonylureas typically have on body weight?

Associated with weight gain.

Sulfonylureas are chemically noted to contain what element, posing an allergy risk?

Sulfur.

How are second-generation sulfonylureas excreted?

By the kidneys and bile.

Sulfonylureas are useful for controlling which two types of hyperglycemia?

Fasting and postprandial hyperglycemia.

Name two Meglitinide drugs.

Repaglinide (Prandin) and Nateglinide (Starlix).

How does the mechanism of Meglitinides compare to Sulfonylureas?

They also close potassium channels to stimulate insulin release.

How does the onset of action of Meglitinides compare to Sulfonylureas?

They have a rapid onset of action.

When are Meglitinides typically administered?

Before meals to cover postprandial hyperglycemia.

Do Meglitinides contain sulfur in their structure?

No.

How does the risk of hypoglycemia with Meglitinides compare to Sulfonylureas?

It is less problematic with Meglitinides.

Name two common adverse effects of insulin secretagogues (Sulfonylureas/Meglitinides) besides hypoglycemia.

Allergies, anemias, or GI disturbances.

What is the generic name for Glucophage?

Metformin.

Does Metformin stimulate insulin release?

No.

What is the primary mechanism of action of Metformin in the liver?

Reduces hepatic gluconeogenesis.

How is Metformin eliminated from the body?

It is not metabolized and the parent compound is renally excreted.

Metformin is considered first-line therapy because it targets what characteristic of Type 2 Diabetes?

Insulin resistance.

What serious metabolic adverse effect is a risk with Metformin, particularly in renal impairment?

Lactic acidosis.

Why is Metformin contraindicated in renal impairment?

Drug accumulation increases the risk of lactic acidosis.

Does Metformin typically cause hypoglycemia or weight gain?

No.

Metformin interferes with the absorption of which vitamin?

Vitamin B12.

What is the most common side effect profile for Metformin?

GI disturbances.

What advice can assist with the transient GI side effects of Metformin?

Taking the drug with food.

Besides the liver, Metformin increases glycolysis in which tissues?

Peripheral tissues.

Name two Thiazolidinediones (TZDs).

Rosiglitazone (Avandia) and Pioglitazone (Actos).

What nuclear receptor do TZDs bind to?

PPAR gamma.

Through PPAR gamma, TZDs regulate genes involved in the metabolism of what?

Lipid and glucose metabolism.

TZDs increase the expression of what transport proteins?

Glucose transporters.

Do TZDs stimulate insulin release?

No (they are insulin sensitizers).

Because they do not cause hypoglycemia alone, TZDs are described as what type of agent?

Euglycemics.

Name a cardiovascular contraindication for TZD use.

Heart failure.

What adverse effect regarding fluid balance is associated with TZDs?

Fluid retention and Edema.

What adverse effect on the skeletal system is observed with TZD use?

Loss of bone mineral density.

Pioglitazone reduces the levels of drugs metabolized by which enzyme system?

P450 enzymes (e.g., Oral contraceptives, Cyclosporine).

Pioglitazone is contraindicated in patients with a risk for what specific cancer?

Bladder cancer.

Besides insulin sensitivity, Pioglitazone decreases plasma levels of what lipid component?

Triglycerides/Fatty acids.

Name two Alpha-glucosidase inhibitors.

Acarbose (Precose) and Meglitol (Glyset).

What is the mechanism of action of Alpha-glucosidase inhibitors?

They delay the digestion and absorption of starches and disaccharides.

Structurally, these drugs are analogs of what?

Oligosaccharides.

What is the primary clinical benefit of delaying starch absorption?

Decreases postprandial glucose elevations.

What is the main adverse effect limiting the use of Alpha-glucosidase inhibitors?

GI disturbances (gas, bloating, diarrhea).

Do Alpha-glucosidase inhibitors cause hypoglycemia when used alone?

No.

Name three GLP-1 receptor agonists.

Exenatide, Liraglutide, Dulaglutide, Semaglutide, Lixisenatide, or Tirzepatide.

Unlike endogenous GLP-1, synthetic analogs are resistant to what?

Degradation (metabolically stable).

GLP-1 agonists stimulate insulin release in response to what?

Intestinal glucose (anticipation of absorption).

Besides insulin release, GLP-1 agonists decrease the secretion of what hormone?

Glucagon.

What effect do GLP-1 agonists have on the stomach?

They slow gastric emptying.

Tirzepatide acts as an agonist at which two receptors?

GLP-1 and GIP receptors.

What are the most common adverse effects of GLP-1 agonists?

Nausea, vomiting, and diarrhea.

Which GLP-1 agonists are noted for inducing thyroid tumors in rodents?

Exenatide and Liraglutide.

Patients should report persistent abdominal pain immediately due to the risk of what condition?

Pancreatitis.

Which oral GLP-1 agent is mentioned in the text?

Rybelsus (Semaglutide).

Saxenda, Zepbound, and Wegovy are approved for what indication?

Weight loss.

Name three DPP-4 inhibitors.

Sitagliptin, Saxagliptin, Linagliptin, or Alogliptin.

What is the mechanism of action of DPP-4 inhibitors?

They inhibit the metabolism of endogenous incretins (increasing their levels).

Unlike GLP-1 agonists, what is the effect of DPP-4 inhibitors on body weight?

They are body weight neutral.

Which specific adverse effect involving joints is associated with DPP-4 inhibitors?

Severe arthralgia.

Which two DPP-4 inhibitors may increase the risk of Heart Failure (HF)?

Saxagliptin and Alogliptin.

Sitagliptin inhibits DPP-4 only in the presence of what condition?

Hyperglycemia.

Like GLP-1 agonists, DPP-4 inhibitors carry a risk for what abdominal condition?

Pancreatitis (Alogliptin mentioned specifically).

Name three SGLT2 inhibitors.

Canagliflozin, Dapagliflozin, Empagliflozin, Ertugliflozin, or Sotagliflozin.

What is the mechanism of action of SGLT2 inhibitors?

They inhibit renal glucose reabsorption (causing glucosuria).

SGLT2 inhibitors are responsible for blocking reabsorption in which part of the kidney?

Proximal tubule.

Because of their mechanism, SGLT2 inhibitors increase the risk of what type of infections?

Genital and urinary tract infections.

SGLT2 inhibitors are contraindicated in patients with reduced function of which organ?

Kidneys.

What serious metabolic condition can occur with SGLT2 inhibitors?

Ketoacidosis.

Glucagon acts through adenyl cyclase to increase what intracellular messenger?

cAMP.

Besides hypoglycemia, Glucagon is used to reverse the overdose of what drug class?

Beta-blockers.