THE UNIVERSITY OF NEW MEXICO HEALTH SCIENCES CENTER COLLEGE OF PHARMACY ALBUQUERQUE, NEW MEXICO Correspondence Continuing Education Courses For Nuclear Pharmacists and Nuclear Medicine Professionals VOLUME X, NUMBER 2 A Primer on Parenteral Radiopaque Contrast Agents By Peter Dawson, BSc, PhD, CPhys, MBBS, FRCP, FRCR University College London Hospitals London, United Kingdom The University of New Mexico Health Sciences Center College of Pharmacy is accredited by the American Council on Pharmaceutical Education as a provider of continuing pharmaceutical education. Program No. 039-000-02-005-H04. 3.0 Contact Hours or .30 CEUs A Primer on Parenteral Radiopaque Contrast Agents By: Peter Dawson, BSc, PhD, CPhys, MBBS, FRCP, FRCR University College London Hospitals London, United Kingdom Coordinating Editor and Director of Pharmacy Continuing Education William B. Hladik III, MS, RPh, FASHP, FAPhA College of Pharmacy University of New Mexico Health Sciences Center Managing Editor Julliana Newman, ELS Wellman Publishing, Inc. Albuquerque, New Mexico Editorial Board George H. Hinkle, MS, RPh, BCNP, FASHP, FAPhA Jeffrey P. Norenberg, MS, PharmD, BCNP, FASHP Neil A. Petry, MS, RPh, BCNP, FAPhA Laura L. Boles Ponto, PhD, RPh Timothy M. Quinton, PharmD, MS, RPh, BCNP, FAPhA Guest Reviewer Robert L. Siegle, MD Professor and Chairman Department of Radiologic Sciences Drexel University College of Medicine 245 North 15th Street, MailStop 206 Philadelphia, PA 19102-1192 While the advice and information in this publication are believed to be true and accurate at press time, the author(s), editors, or the publisher cannot accept any legal responsibility for any errors or omissions that may be made. The publisher makes no war- ranty, express or implied, with respect to the material contained herein. Copyright 2003 University of New Mexico Health Sciences Center Pharmacy Continuing Education Albuquerque, New Mexico A PRIMER ON PARENTERAL RADIOPAQUE CONTRAST AGENTS STATEMENT OF OBJECTIVES The purpose of this continuing education lesson is to increase the reader’s knowledge and understanding of the clinical applications of parenteral radiopaque contrast agents. Upon completion of this lesson, the reader should be able to: 1. Discuss in broad terms the clinical applications of contrast agents. 2. Explain the significance of iodine, its use in radiopaque contrast agents and the variations of carrier molecules used to deliver it. 3. Explain why relatively low osmolality and low chemotoxicity are desirable characteristics of contrast agents and describe how the structure of the contrast molecule influences these two characteristics. 4. Identify the risk factors for major reactions to contrast media and critically discuss pre-treatment protocols that minimize the probability of occurrence of such reactions. 5. Discuss the clinical manifestations and incidence of side effects and adverse reactions known to be associated with contrast media and identify their important causes and mediating factors. 6. Describe the manifestations and treatment of anaphylactoid reactions. 7. Discuss, in descriptive terms, contrast agent pharmacokinetics. COURSE OUTLINE VII. ANAPHYLACTOID/ IDIOSYNCRATIC I. INTRODUCTION REACTIONS A. The Term "Contrast" A. Prophylaxis of B. Historical Development Anaphylactoid Reactions B. Treatment of II. DISADVANTAGES OF Anaphylactoid Reactions CONVENTIONAL IONIC CONTRAST AGENTS VIII. A NOTE ON THE CLINICAL USE OF CONTRAST AGENTS III. LOW-OSMOLAR AGENTS A. Non-Ionic Agents IX. A BRIEF NOTE ON B. Monoacid Dimeric Agents COAGULATION AND C. Non-Ionic Dimeric PLATELETS Contrast Agents X. THE METFORMIN ISSUE IV. CONTRAST AGENT TOXICITY – THE CONCEPT XI. CONCLUSIONS OF MOLECULAR TOXICITY XII. REFERENCES V. PHARMACOKINETICS XIII. QUESTIONS VI. OSMOLALITY, MOLECULAR TOXICITY, ORGAN SPECIFIC TOXICITIES AND HIGH DOSE TOXICITY OF CONTRAST AGENTS 1 A PRIMER ON PARENTERAL an image is not the norm and usually contrast RADIOPAQUE CONTRAST AGENTS agents may be relied upon to improve the images and their information content by By: enhancement of relevant image contrast. Peter Dawson, BSc, PhD, Sometimes reference is made to "nega- CPhys, MBBS, FRCP, FRCR tive" and "positive" contrast agents. This fre- University College London Hospitals quently causes confusion. As far as x-ray London, United Kingdom contrast agents are concerned "positive" agents are those that increase the absorption of x-rays while "negative" agents decrease x- INTRODUCTION ray absorption. The iodinated agents are pos- The Term "Contrast" itive contrast agents because iodine atoms, The word "contrast" should be explained which are incorporated into their chemical at the outset so that its use in the terms "con- structures, are efficient absorbers of x-rays in trast agent" and "contrast medium" is clearly the diagnostic energy range. (So, incidental- understood. The term contrast is a photo- ly, are the barium atoms in contrast agents graphic or, more generally, a medical imag- used for studies of the gut.) Gases, such as ing term. Contrast in an image of any kind is air or CO2, on the other hand, are negative what allows detail to be discerned between agents as they do not significantly absorb x- two or more adjacent regions of the image. rays and instead allow them to pass more Black chalk on a blackboard cannot be seen readily. Thus, these gases may be very useful because there is no contrast, however, white as well, for example, in providing the con- chalk on the same blackboard produces high trast necessary to differentiate the gastroin- contrast that is readily apparent to the human testinal tract from other adjacent anatomical eye. Fortunately, there is some natural con- structures. trast in medical images of all kinds. If there were no contrast, medical images would be Historical Development of little value. Thus in a computed tomogra- Without the availability of good and rel- phy (CT) image (which has far better resolu- atively safe intravascular contrast agents, tion and display of contrast than any ordi- diagnostic radiology would not have come to nary x-ray film) darker blood vessels may be occupy the central position it currently does seen crossing a lighter liver. A tumor in the in the medical diagnostic process. The great liver will frequently, but not reliably, be bulk of "interventional radiology" proce- darker than normal liver and so will be read- dures would certainly not have emerged ily apparent because of the natural contrast without the development of the contrast associated with this imaging technology. The agent industry. The fact that most radiolo- purpose of a contrast-enhancing agent ("con- gists often take the contribution of the con- trast agent," "contrast medium") is, as the trast agent largely for granted may be seen as name suggests, to enhance such natural con- a tribute to the excellent qualities associated trast and render tissues of interest – usually with the current generation of these. those with pathology – more clearly visible. The need for intravascular contrast Now it must be said immediately that con- agents was realized very early in the history trast agents do not always succeed optimally of radiology, as witnessed by the perform- in this aim. Sometimes a tumor, to take the ance of angiograms on an amputated hand same example, may actually become less and on a cadaver kidney by Haschek and clearly visible after administration of a con- Lindenthal1 and Hicks and Addison,2 respec- trast agent. Clearly, much depends on the tively, both within a month of Roentgen’s blood supply and other structural character- report of the discovery of x-rays. The radio- istics of normal tissue and tumor. However, opaque suspensions used for these classic such worsening of the observed contrast in studies were not clinically practicable but the 2 achievements were remarkable. In subse- tional cell carcinoma,8 while local injections quent years, various agents were used to into breast and maxillary sinuses have been opacify the gastrointestinal tract, the bladder, followed by carcinoma developing at these ureters, renal pelvis and lymphatics by direct sites.9 Perivascular extravasation of contrast injection, but little progress was made with is associated with local granuloma forma- the development of agents which could be tion. safely injected into the circulation. While inorganic iodide solutions were Berberich and Hirsch3 used a strontium too toxic for general use, it was realized that bromide solution for the opacification of the elemental iodine is certainly an outstanding- peripheral veins and, in the same year, ly good choice for x-ray absorption. The K- Osborne, et al4 at the Mayo Clinic noted shell electron binding energy is approxi- opacification of the bladder in patients treat- mately 33 KeV, which is lower than, but ed with intravenous (IV) solutions of sodium close to, the mean energy used in diagnostic iodide for syphilis. They had unwittingly x-ray work, thereby maximizing the cross- performed the first IV urogram. However, section for photoelectric interactions. All the delineation of the upper urinary tract was other considerations such as chemistry aside, poor and sodium iodide solutions were rather iodine is an ideal choice of element for use in toxic for general use for urography. Enough an x-ray contrast agent at the energies typi- interest was generated, however, for Brooks5 cally used clinically. Barium, incidentally, to try sodium iodide solutions for peripheral used in studies of the gastrointestinal tract is angiography and in 1927