To the Editor:—
It has been reported that hemorrhagic shock altered pharmacodynamics of propofol: the potency of propofol increased during hemorrhagic shock.1,2A proposed explanation for this increase of propofol potency is that hemorrhagic shock leads to an increase in circulating beta endorphins.3Recent work by Depaepe et al. , however, has revealed that endorphin antagonism with naloxone does not influence end-organ sensitivity during hemorrhagic shock in the rat.4Other potential sources of increased end-organ sensitivity to propofol is the increase of unbound propofol; this can be achieved through competitive displacement interactions with other drugs or endogenous substances or decreases in the level of proteins.
It is now widely accepted that the pharmacological effects of a drug are elicited by the unbound fraction in the blood. Only those drug molecules that are not bound to plasma protein are able to pass through blood vessels and reach their target sites within the tissue. Therefore, changes in the protein-binding characteristics of a drug may alter its pharmacological potency and pharmacokinetics.
For drugs that are restrictively cleared, regardless of route of administration, an increase in the unbound fraction leads to accelerated total body clearance, thereby reducing the total concentration of drug. The unbound concentration at steady state is unchanged because an increase in the unbound concentration gradually returns to the control value after redistribution.5Thus the ultimate effect of changes in protein binding is only transient.
In contrast, for drugs that are nonrestrictively cleared and administered intravenously, an increase in the unbound fraction could not affect total body clearance because such drugs are extracted by the eliminating organ so efficiently that protein binding dose not limit their removal. The total concentration of drug would initially fall because an increase in the unbound fraction leads to an increase in the volume of distribution. However, after redistribution the concentration returns to the control value. Thus, the total concentration at steady state is unchanged and an increase in the unbound fraction leads to an immediate and sustained increase in the unbound concentration. This is of clinical significance for highly protein-bound drugs with narrow therapeutic indices such as propofol.6
Recently, we reported that a significant (twofold) increase in the concentration of unbound propofol occurred without alteration in the total propofol concentration in blood during cardiopulmonary bypass.7This increase in the unbound fraction was caused mainly by a lower concentration of albumin. The increase of propofol potency during hemorrhagic shock might be explained in the same way. The increase of unbound propofol without alteration in the total propofol concentration in blood can occur as a result of the loss of serum albumin accompanying hemorrhage—especially followed by crystalloid resuscitation.
* Gunma University, Graduate School of Medicine, Maebashi, Japan. firstname.lastname@example.org