The clotting issue: etiologic factors in thromboembolism. I. Chemistry, pharmacology, and toxicity of angiographic contrast agents

Abstract

Rationale and objectives: In a decade of clinical use of nonionic contrast agents, only one scientific criticism of any significance has been leveled at them. That is, they may increase the risk of thromboembolism in diagnostic and interventional clinical angiography. The author examines the hypothesis that contrast molecules exert their intrinsic toxicity through hydrophobic and Coulomb interactions with biological molecules. Because nonionic molecules are hydrophilic and have no charge and therefore no Coulomb component, they should be less toxic.

Methods: The basic chemical and pharmacologic properties of iodinated contrast agents are outlined and their effects on hematology are discussed. The author also reviews studies on the development of ionic and nonionic agent formulations and the evolution of theories on their toxicity. The relative toxicity of ionic versus nonionic agents also is considered.

Results: Three factors are found to correlate well with contrast toxicity: partition coefficient, protein-binding capacity, and pi-electron density in the benzene ring system. Any increase in pi-electron density increases hydrophobicity, while any reduction in pi-electron density decreases hydrophobicity. The more hydrophobic molecules have a lower osmolality. Nonionic agents are observed to exhibit lower toxicity than low-osmolality ionic agents. Because of their greater hydrophilicity, based on better masking of the hydrophobic core by hydrophilic side chains, and their lack of charge, nonionic contrast agents have a reduced potential for interactions, rendering them more inert and less toxic. The uniformity of results in the different systems previously studied and the constant hierarchy of relative effects are striking.

Conclusions: Fundamental understanding of the molecular basis of contrast toxicity indicates that it is not possible to synthesize a contrast molecule that will have strong anticoagulant effects and yet retain a low toxicity. Having marked anticoagulant effects is an indicator of toxicity: a more anticoagulant agent is more toxic. It is similarly not possible to manipulate incipients in the formulations to achieve strong anticoagulant properties without also modifying toxicity. There also is a trade-off between reducing chemotoxicity and reducing osmolality, since, if we successfully shield the hydrophobic core of the molecule, we limit the degree to which the osmolality of the solution will be reduced below that predicted on simple chemical considerations. These then are the essential points to bear in mind in any discussion of the clotting issue. For reasons of their structure and the nature of additives in their formulations, second-generation nonionic agents have little effect on biological systems. Therefore, they have only a limited impact on the coagulation cascade exactly in line with their low toxicity. Consequently, nonionic contrast agents have established themselves, with both radiologists and patients, as the agents of choice and are now accepted as better tolerated and safer than ionics--in terms of both a reduced incidence of idiosyncratic/anaphylactoid reactions and high-dose tolerance--in interventional radiology and pediatrics.