β-Adrenergic Blockade Affects Initial Drug Distribution Due to Decreased Cardiac Output and Altered Blood Flow Distribution

Abstract

␤-Adrenergic receptor blockers decrease intravenous anesthetic dose requirements. The present study determined the effect of propranolol on indocyanine green and antipyrine disposition from the moment of rapid intravenous injection. Antipyrine is a physiological marker that distributes to a volume as large as total body water in a blood flow-dependent manner and is a pharmacokinetic surrogate for many lipophilic drugs, including intravenous anesthetics. Antipyrine and indocyanine green disposition were determined twice in five healthy adult males in this Institutional Review Board-approved study, once during propranolol infusion. After rapid indocyanine green and antipyrine injection, arterial blood samples were collected frequently for 2 min and less frequently thereafter. Plasma indocyanine green and antipyrine concentrations were measured by high-performance liquid chromatography. Indocyanine green and antipyrine disposition were characterized, using SAAM II, by a recirculatory pharmacokinetic model that describes drug disposition from the moment of injection. Parameters were compared using the paired t test. The disposition of indocyanine green demonstrated that propranolol decreased cardiac output at the expense of the fast peripheral (nonsplanchnic) intravascular circuit. The area under the antipyrine concentration versus time relationship was doubled for at least the first 3 min after injection due to both decreased cardiac output and maintenance of nondistributive blood flow at the expense of a two-thirds reduction of blood flow (intercompartmental clearance) to the rapidly equilibrating (fast, splanchnic) tissue volume. The increase in antipyrine area under the curve due to propranolol-induced alteration of initial antipyrine disposition could explain decreased intravenous anesthetic dose requirements in the presence of ␤-adrenergic receptor blockade.␤-Adrenergic receptor blockade has been reported to decrease intravenous anesthetic dose requirements. Chronically administered propranolol decreased the sufentanil dose required to produce unconsciousness (Stanley et al., 1982). The acute administration of esmolol decreased potent volatile anesthetic requirements to prevent movement in response to skin incision by interacting with small doses of alfentanil (Johansen et al., 1998). In addition, although ␤-blockade produced by a bolus and infusion of esmolol did not affect the hypnotic concentration of propofol, it decreased the propofol dose requirement significantly, as reflected in the increased bias and inaccuracy of a target-controlled infusion (Orme et al., 2002). Although the mechanism by which ␤-blockers decrease intravenous anesthetic dose requirements is unclear, the latter observation suggests that the interaction is pharmacokinetic (Orme et al., 2002). Pharmacokinetic interactions with ␤-blockers are not unexpected because they decrease cardiac output and hepatic blood flow, so they would be expected to decrease the elimination clearance of high clearance drugs (Conrad et al., 1983). How...

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