Abstract
The institution of CPB has profound effects on the plasma concentration, distribution and elimination of drugs. The major factors responsible for this are haemodilution, altered plasma protein binding, altered regional blood flow, hypothermia, isolation of the lungs from the circulation and sequestration of drugs into components of the extracorporeal circuit. These changes, which are influenced by physicochemical and pharmacokinetic characteristics, result in an alteration in free drug and effector-site concentration.
The institution of CPB has profound effects on the plasma concentration, distribution and elimination of drugs. The major factors responsible for this are haemodilution, altered plasma protein binding, altered regional blood flow, hypothermia, isolation of the lungs from the circulation and sequestration of drugs into components of the extracorporeal circuit. These changes, which are influenced by physicochemical and pharmacokinetic characteristics, result in an alteration in free drug and effector-site concentration.
Factors during CPB Affecting Drug Pharmacokinetics
Haemodilution
The CPB circuit is primed with 1,500–2,000 ml of crystalloid solution, corresponding to a potential 30% increase in circulating blood volume, with associated haemodilution occurring when CPB is instituted. The immediate effect of this haemodilution is a decrease in circulating free drug concentration, a reduction in the concentration of plasma proteins and a reduction in the haematocrit.
The eventual plasma concentration of a drug is dependent on its plasma protein binding (PPB), its original volume of distribution and the extent of equilibration between tissue and plasma at the time of institution of CPB. An important consideration is the distinction between the total plasma concentration and the ‘free’ or unbound fraction. The free concentration of the drug is that which moves to the effector site and can be eliminated. The impact of haemodilution on the unbound fraction of drugs tends to be greater for drugs that have high PPB. This may result in a greater transfer of drug from the blood–prime mixture to the tissues, and thus a lower eventual circulating drug concentration. The volume of distribution (Vd) is another factor determining the circulating concentration of drugs during CPB. Drugs with a large inherent Vd tend to be less affected by haemodilution, as there is a large tissue reservoir from which the drug can diffuse back into the circulation to plasma.
Heparin administration can result in the displacement of plasma-protein-bound drugs (e.g. propofol). The mechanism appears to be heparin-induced lipase release, leading to the hydrolysis of plasma triglycerides to form non-esterified fatty acids, which bind competitively to plasma proteins. The administration of protamine reverses this effect.
The acute effects of haemodilution only (disregarding the effects of altered distributional changes from changed PPB and so increased free fractions) can be established from the formula:
where ΔCss is change in drug concentration, Css is the drug concentration prior to haemodilution, Vpp the volume of pump prime and V1 is the Vd of the central compartment or the α phase.
The effects of haemodilution mean that the apparent Vd and effective (free) concentration of a drug are greater if administered during, rather than before, CPB.
Hypotension and Altered Blood Flow
CPB is associated with hypotension and altered regional blood flow, particularly at the onset of CPB, during aortic cross-clamping and declamping, and during cardioplegia administration. This is due to reduced blood viscosity and SVR. Associated alterations in hepatic and renal blood flow may affect the metabolism and elimination of drugs.
Hypothermia
The solubility of gases in blood is inversely proportional to temperature. Changes in inhaled or sweep gas volatile anaesthetic concentration will therefore take longer to alter the effect-site partial pressure.
Hypothermia may affect the hepatic metabolism and elimination of drugs by direct (enzymatic) inhibition and altered intrahepatic blood flow. Moreover, hypothermia may interfere with the binding affinity of some drug receptors and increase the relative potency of volatile anaesthetic agents (Box 25.1).
Box 25.1 The impact of hypothermia on drug pharmacokinetics
↓ Absorption of drugs administered other than by the IV route
↓ Drug distribution from central to peripheral compartments (↓Vd)
Altered CNS drug penetration
↓ Rate of reuptake of drug from peripheral tissues to the central compartment and subsequent reductions in hepatic clearance, leading to prolonged elimination half-time
↓ Biotransformation rate with decreased clearance and increased elimination half-time
Altered renal drug excretion as a result of ↓ renal perfusion, ↓ GFR and ↓ tubular secretion
Acid–Base Status
CPB using pH-stat blood-gas management increases drug delivery by increasing the cerebral blood flow, and alters the degree of ionization and protein binding of some drugs, leading to altered free (active) drug concentrations.
Lung Isolation
Exclusion of the lungs during CPB interrupts the normal PA blood flow, although bronchial blood flow remains intact. The lungs act as a reservoir for basic drugs such as lidocaine, propranolol and fentanyl that are administered prior to CPB and so, with re-establishment of the pulmonary circulation, upon separation from CPB, the sequestered drug may return to the circulation. This may raise the systemic concentration above earlier levels or re-establish plasma concentrations sufficient to exert a pharmacological effect.
Sequestration in the CPB Circuit
In vitro experiments have demonstrated that a significant amount of fentanyl, alfentanil, volatile anaesthetic agents, propofol, barbiturates and GTN can be sequestered in bypass equipment. While theoretically there is a possibility for reducing the plasma concentration due to circuit uptake, there was no evidence that this has any clinical relevance.
Factors during CPB Affecting Drug Pharmacodynamics
Changes in drug effects secondary to CPB are poorly described.
Temperature: Hypothermia reduces anaesthetic requirements and decreases opioid and nicotinic receptor affinity.
Acid–base status: Acidosis is associated with alterations in plasma electrolyte concentrations, which may increase susceptibility to arrhythmias and enhance digoxin toxicity.
Related posts:
Full access? Get Clinical Tree
