Open Collections

The risks of the use of tolbutamide and related oral hypoglycemic drugs in the management of non-insulin-dependent diabetes mellitus

University of British Columbia

The study of the University Group Diabetes Program and a number of other clinical studies have consistently demonstrated that the long-term treatment with tolbutamide and possibly other oral hypoglycemic sulfonylureas can increase cardiovascular mortality, especially the mortality due to myocardial infarction, in the patients with non - insulin - dependent diabetes mellitus (NIDDM). There are three hypotheses to explain this adverse effect. Hypothesis 1 is that tolbutamide causes myocardial infarction by increasing the cardiac metabolism of oxygen as the result of a positive inotropic effect. It is proposed that the pathological changes which occur in diabetic hearts make them particularly susceptible to this effect. Tolbutamide has positive inotropic effects both in vivo and in vitro. Hypothesis 2 is that tolbutamide causes or worsens hyperinsulinemia which may directly or indirectly be associated with the coronary heart disease in patients with NIDDM . Tolbutamide induces the secretion of insulin from the pancreatic beta cells. Since patients with NIDDM often have high circulating insulin levels , the treatment with tolbutamide can worsen the hyperinsulinemia in NIDDM patients. When taken together, epidemiological, prospective and clinically cross - sectional studies demonstrate that insulin resistance and compensatory hyperinsulinemia correlated with increased risk of coronary heart disease . Therefore, the long-term administration of tolbutamide could increase the incidence and severity of coronary heart disease . Hypothesis 3 is that tolbutamide has an arrhythmogenic effect. One possible mechanism is that tolbutamide, through its action in blocking ATP-regulated potassium (KATP) channels, may cause arrhythmias by blocking cardiac ATP-regulated potassium channels during myocardial ischemia. During ischemia, the KATP channels are opened by the decrease of the intracellular ATP level; the opening of the KATP channel results in a shorting of the action potential which decreases the contraction of heart muscle, thus protecting the damaged portion. Tolbutamide, by blocking the KATP channels during the myocardial ischemia, prevents the decrease of the contraction of the heart muscle, resulting in increased energy consumption in the ischemic heart, and increasing the risk of potentially fatal dysrhythmias. Other presently unknown mechanisms for arrhythmias are also possible. There is sufficient evidence and plausible mechanisms whereby tolbutamide may lead to adverse cardiovascular outcome. Therefore, until better evidence is available, the safest therapy for asymptomic non-insulin-dependent diabetics is diet restriction plus physical exercise.

Thesis/Dissertation

application/pdf

2009-03-10

For non-commercial purposes only, such as research, private study and education. Additional conditions apply, see Terms of Use https://open.library.ubc.ca/terms_of_use.

http://hdl.handle.net/2429/5821

Pharmacology

University of British Columbia

UBCV

DSpace