Pharmacological Reviews, Vol 14, 447-472, Copyright © 1962 by the American Society for Pharmacology and Experimental Therapeutics

THE PHARMACOLOGY OF TRIS(HYDROXYMETHYL) AMINOMETHANE (THAM)

¹ Department of Anesthesiology, College of Physicians and Surgeons, Columbia University, New York, N. Y.

THAM is a titrating agent in vivo as well as in vitro, and its ionized fraction acts in the kidney as a non-reabsorbable cation. Since, at normal blood pH, THAM is 70% ionized, the larger part of the compound remains in the extracellular fluid and is rapidly excreted in the presence of a functional kidney. By reducing the pCO₂ in the extracellular space, THAM could reduce intracellular pH as well. However, such a reduction of intracellular pCO₂ is limited by TIJAM's depressant effect on ventilation, an effect which rapidly restores to normal and then elevates plasma pCO₂ in the presence of an alkaline pH. The fraction of THAM which penetrates into the cells is, at intracellular pH, 90% ionized and may "overtitrate" the intracellular spaces. As ionized THAM accumulates in the cell, K+ moves out in order to restore the normal Donnan ratio. In addition to this action on by migration, THAM does not act as a simple buffer inside the cell but most likely interacts with enzyme systems. These interactions remain to be determined and distinguished from the pH effect of THAM. Compounds similar to THAM which would penetrate at a relatively slow rate into cells and modify intracellular pH would be very useful (90) in experimental work in order to alter the activity of specific enzymes. However, their ready availability is unlikely, primarily because of the instability of most organic compounds in vivo. Meanwhile, THAM is a very useful tool for the physiologists and pharmacologists who wish to study the effects of acid-base balance alterations. When used judiciously it has also been helpful in clinical medicine. During acidosis, severe metabolic disturbances overwhelm homeostatic mechanisms and many forms of therapy become ineffective. The administration of THAM, by restoring pH of body fluids to normal, potentially can provide optimum conditions for the restoration of homeostasis and for standard therapeutic procedures.

Note:

This work was supported in part by grants from the National Institutes of Health, The United States Army Medical Research and Development Command, the National Aeronautics and Space Administration, and Abbott Laboratories. The author gratefully acknowledges the cooperation of Dr. R. K. Richards, Dr. K. J. Frederick, and Dr. S. J. Anderson and Miss Ann Dalziel from the Abbott Research Laboratory as well as the cooperation of Dr. R. J. Hickey an Dr. J. A. Riddick from the Commerical Solvents Corporation Research Laboratory. The assistance of Mariagnes Verosky and Iris Schwartz in the editing and reviewing of the manuscript is also gratefully acknowledged.