The Effect of Glucagon and Insulin on the Prothrombin Response to Coumarin Anticoagulants ∗

Abstract

Discussion and Summary

The response to drugs such as the coumarin anticoagulants may be altered by factors which either affect the physiologic disposition of the drug, or the site at which the drug acts. Clues as to the nature of the drug action may be obtained by studying the factors which influence sensitivity to the drugs without altering the fate of the drug.

The effect of Vitamin K in blocking the action of coumarin anticoagulants is well documented, and is not correlated with changes in the physiologic disposition of coumarins as reflected in plasma levels of the drug. In contrast, the effect of barbiturates is mediated through altered disposition of the coumarins (1,4). The tranquilizers chlorpromazine and reserpine exaggerate prothrombin response while not influencing plasma levels of the coumarin drug. This effect may be correlated with the action of these agents on NAD synthesis (5).

The mechanism by which starvation causes an exaggerated response to coumarins is not known. Elements of protein origin are probably involved (2). The finding of a similar effect by glucagon suggests that the metabolic fate of tyrosine and/or tryptophan may be important to prothrombin synthesis. The fact that saline diluted plasma demonstrates the glucagon effect at least as well as undiluted plasma indicates an exaggerated prothrombin deficiency rather than a superimposed heparin-like effect.

The observation that insulin has no detectable effect on sensitivity to acenocoumarin, but can block the sensitizing effect of glucagon may have clinical significance in helping to explain the “unpredictable” manner in which sensitivity to anticoagulants may be altered by an agent under one set of conditions, and not under another.

It remains to be determined whether the effect of starvation on sensitivity to coumarin anticoagulants is mediated through a stimulation of endogenous glucagon production during starvation.