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Correspondence  |   May 2005
Pharmacodynamics of Propofol during Hemorrhagic Shock
Author Affiliations & Notes
  • Daisuke Takizawa, M.D.
    *
  • * Gunma University, Graduate School of Medicine, Maebashi, Japan.
Article Information
Correspondence
Correspondence   |   May 2005
Pharmacodynamics of Propofol during Hemorrhagic Shock
Anesthesiology 5 2005, Vol.102, 1068-1069. doi:
Anesthesiology 5 2005, Vol.102, 1068-1069. doi:
To the Editor:—
It has been reported that hemorrhagic shock altered pharmacodynamics of propofol: the potency of propofol increased during hemorrhagic shock.1,2 A proposed explanation for this increase of propofol potency is that hemorrhagic shock leads to an increase in circulating beta endorphins.3 Recent 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.4 Other 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.5 Thus 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.7 This 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.
References
Johnson KB, Eagan TD, Kern SE, McJames SW, Cluff ML, Pace NL: Influence of hemorrhagic shock followed by crystalloid resuscitation of propofol: A pharmacokinetic and pharmacodynamic analysis. Anesthesiology 2004; 101:647–59Johnson, KB Eagan, TD Kern, SE McJames, SW Cluff, ML Pace, NL
Johnson KB, Eagan TD, Kern SE, White JL, McJames SW, Syroid N, Whiddon D, Church T: The influence of hemorrhagic shock on propofol: A pharmacokinetic and pharmacodynamic analysis. Anesthesiology 2003; 99:409–20Johnson, KB Eagan, TD Kern, SE White, JL McJames, SW Syroid, N Whiddon, D Church, T
Molina P: Opiate modulation of hemodynamic hormonal, and cytokine response to hemorrhage. Shock 2001; 15:471–8Molina, P
De Paepe P, Van Sassenbroeck D, Belpaire F, Buylaert W: Influence of naloxon on the increased sensitivity to propofol during hypovolemia in the rat. Crit Care Med 2001; 29:997–9De Paepe, P Van Sassenbroeck, D Belpaire, F Buylaert, W
Benet LZ, Hoener BA: Changes in plasma protein binding have little clinical relevance. Clin Pharmacol Ther 2002; 71:115–21Benet, LZ Hoener, BA
Wilkinson GR, Shand DG: Commentary: A physiological approach to hepatic drug clearance. Clin Pharmacol Ther 1975; 18:377–90Wilkinson, GR Shand, DG
Hiraoka H, Yamamoto K, Okano N, Morita T, Goto F, Horiuchi R: Changes in drug plasma concentrations of an extensively bound and highly extracted drug, propofol, in response to altered plasma binding. Clin Pharmacol Ther 2004; 75:324–30Hiraoka, H Yamamoto, K Okano, N Morita, T Goto, F Horiuchi, R