OHA Series - Sulphonylureas

Sulphonylureas are probably the second most common oral hypoglycemic drugs in use today. They play an important role in ensuring that patients with type II diabetes delay being dependant on insulin therapy. They belong to a class of oral hypoglycemic medications called insulin secretagogues.

How did we stumble upon these drugs?

Sulfonylureas were an accidental boon for patients with diabetes mellitus. In 1937, Ruiz and colleagues were the first to note the hypoglycemic effect of synthetic sulphur compounds. In 1942, this effect was confirmed by a group of French scientists who were exploring the antibiotic effects of sulpha drugs. Finally, in 1946, Lobatieres and his colleagues were able to confirm that all sulpha drugs had the ability to stimulate insulin release from beta cells.

A whole decade later, in 1956, the first generation of sulhpnylureas were approved commercially. This generation included drugs like tolbutamide, chlorpropamide, acetohexamide and tolzamide.

In 1984, the second generation of sulphonylureas, glyburide and glipizide, were approved for use.

Finally in 1995, glimipride, the third generation of sulphonylureas was introduced for commercial use.

Mechanism of action - How do they work?

Normally, in most cells, there is an ATPase channel that is in charge of RE-polarising the cell after depolarisation has occurred. These channels actively pump potassium back into the cell and allow the cell to relax. This inflow of potassium is matched with an outflow of sodium and calcium to maintain the membrane potential and overall equilibrium.

The function of sulphonylureas is to block this potassium ATPase on pancreatic beta cells. This results in depolarisation of the cells. There is an influx of calcium ions to equalise the electrical gradient. This calcium influx results in the exocytosis of insulin from presynthesied vacuoles within the cell.

Basically what this means is, because the potassium ATPase is blocked, calcium comes in and kicks insulin out.

Since these drugs increase the secretion of insulin from our pancreatic cells, they are called insulin secretagogues.

The problem with this is that an increase in insulin levels leads to weight gain. Remember that.

The Cardiac Con of Sulphonylureas - How do they affect the heart?

We just saw the mechanism of action of sulphonylureas. But these drugs come with an unfortunate issue - they do not specifically block the potassium ATPase on the beta islet cells of the pancreas alone. They also affect cardiac and vascular smooth muscle cells.

In the vascular smooth muscle cells, sulphonylureas hinder relaxation and can predispose to hypertension.

In the cardiac muscles as well, sulphonylureas hinder relaxation. Normally the hearts of patients who have angina, undergo a phenomenon called ischemic preconditioning which allows what heart to cope with ischemia better. Similar to a sweat more in training and bleed less in battle kind of phenomenon. Sulphonylureas inhibit this ischemic preconditioning and increase the risk of cardiovascular morbidity and mortality.

Indication - When should we prescribe these drugs?

Most newly diagnosed type II diabetic patients can be started on second or third generation sulphonylureas.

Adverse Effects

1. Hypoglycemia - drug should always be prescribed along with food to avoid this

2. Weight gain - due to increased insulin release

3. Syncope, dizziness

4. Nervousness, anxiety, depression

5. Sweating

6. Increased LDH

7. Diarrhea, flatulence

Contraindications - When should you avoid these drugs?

1. Type I Diabetes mellitus

2. Diabetic ketoacidosis

3. Ischemic heart disease (relative contraindication)

Author:
Narendran Sairam

Sources and citations

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