X-ray contrast medium

exogenous substance used to alter the contrast in X-ray imaging by affecting the attenuation of X-rays. Introduction of gases (air, CO2) into hollow viscera, cavities, vessels or surrounding structures will reduce the attenuation of X-rays; such substances are called negative contrast media. Examples are use of air in double contrast examinations of the gastrointestinal tract, air encephalography (an obsolete technique), and carbon dioxide digital subtraction angiography. The vast majority of X-ray contrast media are positive or radiopaque, i.e., they increase the attenuation of X-rays. The increased attenuation is accomplished by two different atoms; barium, which is used in the form of insoluble barium sulphate for examinations of the gastrointestinal tract, and iodine, which is the main component of all other X-ray contrast media.

Iodinated contrast media
may be divided into water-soluble, water-insoluble, and oily contrast media (Fig. 1). Water-insoluble contrast media include aqueous suspension of propyliodone (Dionosil), used in bronchography. Oily contrast media include Lipiodol, a stable compound of 40% iodine in poppy seed oil, introduced in the 1920s, and later replaced by Lipiodol Ultra Fluid and Ethiodol, ethyl esters of iodinated fatty acids of poppy seed oil containing 48% and 37% iodine, respectively. These oils are still to some extent used for lymphography, and by some also for hysterosalpingography. Iodophenylundecylic acid (iophendylate) was introduced in 1944 as a contrast medium for oil myelography (brand names: Pantopaque, Myodil).

The water-soluble contrast media represent by far the largest group of iodinated contrast media. The first water-soluble iodinated contrast media emerged in the late 1920s with the development of two monoiodinated pyridine derivatives, "Selectan-Neutral" and "Uroselectan" (Fig. 2). These were actually "byproducts" of research on iodinated pyridones used in the treatment of syphilis. Soon followed di-iodinated pyridones with higher solubility, iodomethamate (e.g. "Uroselectan B") and iodopyracet (e.g. "Diodone") (Fig. 3). These second generation pyridine-based compounds became the standard intravascular contrast media until their replacement in the early 1950s by the tri-iodinated benzene ring compounds. All water-soluble iodinated contrast media developed thereafter are derivatives of tri-iodinated benzoic acid (Fig. 4). The derivatives are named monomeric when they contain only one benzene ring, and dimeric when they contain two benzene rings.

Monomeric ionic contrast media constitute two main groups, oral cholegraphic contrast media and uro/angiographic media (Table 1). The uro/angiographic media are all salts of derivatives of tri-iodinated benzoic acid, and differ only in the side-chains at position 3 and 5 (R1 and R2 in Fig. 4). An example is given in Fig. 5. The cations of the salts are mainly either sodium or meglumine, or a mixture of both. Sodium salts are generally more toxic to vascular endothelium and to blood-brain barrier and neural tissue than meglumine. A mixture of sodium and meglumine has lower cardiotoxicity than either salts alone. Some manufacturers have partially replaced sodium with calcium and magnesium to reduce toxicity.

Table 1 . X-ray contrast medium; Monomeric ionic contrast media for uro/angiography

The ionic monomeric contrast media for intravascular use are so-called high-osmolar contrast media (HOCM), having an osmolality seven to eight times that of plasma in ordinary clinical use. This hyperosmolality is (partly) responsible for several subjective and objective adverse effects such as pain, endothelial damage, thrombosis and thrombophlebitis, disturbance of the blood-brain barrier, bradycardia in cardioangiography and increased pressure in the pulmonary circulation. The introduction of low-osmolar contrast media (LOCM) has substantially reduced these side effects. Osmolality is dependent upon the number of molecules per volume unit solution. The ionic monomeric agents are salts that dissociate into two molecules, one anion containing the radiopaque property due to three iodine atoms, and one cation without radiopaque properties. These agents are also called 3:2 or ratio 1.5 agents (three iodine atoms per two molecules). There are three strategies to obtain contrast media with lower osmolality without loss of X-ray absorption: the production of 1) non-ionic monomers, 2) ionic dimers or 3) non-ionic dimers. Non-ionic contrast media do not dissociate and their water-solubility is generally achieved by several hydrophilic hydroxyl groups. Tri-iodinated non-ionic monomers have approximately half the osmolality of that of ionic monomers (they are 3:1 or ratio 3 agents). The first low-osmolar contrast medium to be produced, was metrizamide (Amipaque), after an idea of Almén (1969). This was a non-ionic monomer, where the carboxyl group in position 1 had been replaced by a D-glucose group providing many hydroxyl groups (Fig. 6). Unfortunately, metrizamide could only be produced as a freeze-dried powder, and had to be dissolved at the time of use. Since then, several other more convenient ready-to-use solutions of non-ionic monomeric contrast media have appeared (Table 2). These contrast media have hydrophilic hydroxyl groups attached to all three side chains, a feature that has also contributed to reducing their toxicity. In addition to osmolality, toxicity is also dependent upon chemical structure, an intrinsic toxicity sometimes named chemotoxicity. Although the mechanism of contrast medium toxicity is not completely understood, it is believed that "chemotoxicity" is related to the protein-binding capacity of the medium, which is caused by non-specific weak interactions between the contrast medium and surrounding biological molecules (e.g. enzymes). The interaction is mediated through electrical forces, which are present only for ionic agents, and through interaction between hydrophobic portions of the molecule, which for contrast media is mainly the benzene ring. The many hydrophilic side groups of the second generation non-ionic monomers protect the inner hydrophobic benzene ring from interaction, thereby reducing "chemotoxicity". The relative hydrophobicity/hydrophilicity of the molecule is called its partition coefficient, a low partition coefficient being advantageous because a high hydrophilicity contributes to low protein binding. An example of these contrast media is given in Fig. 7.

Table 2 . X-ray contrast medium; Monomeric nonionic contrast media for uro/angiography

Metrizamide and iohexol may be used for myelography as well.

Dimeric contrast media with two tri-iodinated benzene rings constitute three main groups; ionic intravenous cholegraphic contrast media, monoacidic ionic contrast media, and non-ionic contrast media. The two latter groups both belong to the so-called low-osmolar contrast media. There is only one monoacidic ionic dimer; sodium meglumine ioxaglate (Hexabrix). The dimeric anion has one carboxyl group, the other has been replaced by a non-ionizing side group (Fig. 8). This gives six iodine atoms per two particles; the contrast medium is a 6:2 (=3:1) or ratio 3 agent (similar to the non-ionic monomers). Owing partly to its ionic character, partly to its fewer hydroxyl groups, ioxaglate is more toxic than the non-ionic monomers with similar osmolality (but less toxic than the ionic monomers owing to lower osmolality).

The non-ionic dimers constitute the last step in the evolution of water-soluble contrast media (Table 3). They yield six iodine atoms per molecule (ratio 6 agents). One of them (iotrolan) is nearly iso-osmolar to plasma (0.32 osm/kg H2O), while another (iodixanol) is actually hypo-osmolar to plasma. Iso-osmolarity to plasma (0.29 osm/kg H2O) is achieved at any iodine concentration by addition of an appropriate amount of saline. These agents have a very low toxicity owing partly to their iso-osmolarity, partly their non-ionic character, and partly to the fact that they possess a very large number of hydroxyl groups (low partition coefficient). The molecular structure of iodixanol is shown in Fig. 9. See also iotrolan.

Table 3 . X-ray contrast medium; Dimeric nonionic contrast media

The various water-soluble contrast media for urography and angiography (ionic and non-ionic monomers, non-ionic dimers) are all extracellular contrast media, and are excreted unmetabolized by glomerular filtration. Approximately 85-90% of the injected dose is found in urine within the first 6 hours; 95-100% within the first 24 hours. Generally less than 2% may be found in faeces.

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