Contrast agents used in radiology

Introductory Slides on contrast agents used in X-ray, MRI, and Sonography.

1. Terminologies Osmosis: Osmosis is a term reserved to describe the movement (diffusion) of water through a membrane from the side where there is a higher concentration of water molecules to the side where there is a lower concentration of water molecules. Dialysis: refers to the diffusion of solute( ions and molecule) particles through a membrane along their concentration gradient.

2. Tonicity Tonicity: A semi-quantitative descriptor of the concentration of one solution compared to another based on non permenat solutes present . Isotonic solution. An Isotonic solution with plasma will not cause the net movement of water into or out of RBC. H ypotonic solution :cause red blood cells to swell as water moves into the cell.They may burst (haemolyse) if the influx of water is too great. Hypertonic solution: A hypertonic solution will cause a net outflow of water from a red blood cell and the cell membrane will wrinkle (crenate) as the cell volume decreases. concentration of non-permeant solutes in the solution

3. Contrast Agents Used in Radiology

4. Osmolality: is a property of intravascular contrast media that refers to number of particles in solution , per Unit liquid, as compared to blood. Measured in milliosmoles per kilogram (mOsm/ kg) of water. Blood Plasma = 290 mOsmo/kg. Viscosity : Physical property that may be described as thickness or friction of fluid as it flows. Influence the injectibility of intravascular agents. Viscosities are a function of solution concentration, molecular shape, and weak interactions among the contrast agents and water molecules, including contrast media self association . Ionocity: Ionic Agents contains molecule that will diassociate into ions when dissolved in aqueous solution . NonIonic Agents contains molecule that that do not diassociate into ions.

5. Historical Development Source: A Guide to Radiologic Procedures, Chapman and Nakienly 5 th Edition

6. TIME

7. Ionic Contrast Media : are salts of iodinated benzoic acid derivatives and consists of positive charge cation and negative charge anion, and are completely disassociated (ionized) in solution Contrast Agent Ratio = Number of iodine atoms/ Number of particle

8. Two commonly used substances are Iothalamate and diatrizoate . Each of these contains methlyglucamine (meglumine salts) or sodium salts or both. Methlyglucamine are less toxic but more viscous than sodium . All Positive contrast media are made up of cation (+) and anion (-) charge. Cation is either the sodium or meglumine compound. Na + , Meg + Anion is basically the same in all media (COO-) with the exception of one side chain and this determines the remainder of the contrast media.

9. All Iodine based contrast agents are based on benzene ring to which three iodine atoms are attached. Monomer = one Tri-Iodinate Benzene ring Dimer = Two Tri-Iodinated Benzene ring For every three iodine atoms in a contrast solution there are two particles for osmolality, one anion and one cation.

10. Ionic Monomer : ratio of three iodine atoms per molecule to two particles in solution, i.e. a ratio of 3:2 or 1.5 Ionic Dimer : ratio of six iodine atoms per molecule to two particles in solution, i.e. a ratio of 6:2 or 3 Viscosity (mPa.s) of Iodixanol 320 iodine-based contrast media at a concentration around 300 mgl ml-1 and at 37 C Source:Contrast Media Safety Issue and ESUR Guideline.

11. Later cation (Na/ Meg +) were replaced by glucose that does not disassociate into solution. Result: Three Iodine atoms for contrast and only one particle for osmolality. The Osmolality (weight if ion) is a significant factor for side effect : HOCM when adminsitered IV, they prompt a sudden shift in body fluid from the interstitial space and cell into systemic circulation. Incidence of side-effects, particularly above 800 mosm kg-1 .

12. Contrast Agent Ratio Contrast Agent Ratio = Number of iodine atoms/ Number of particle The higher osmolality agents have more particles per iodine atom and therefore have lower ratios. Ionic Monomer = 3/2=1.5 ( Three iodine atoms per molecules to two particles in the solution ) { Diatrizoate – Urografin, Metrizoate – Isopaque, Iothalamate – Conray } Ionic Dimer = 6/2= 3 ( Three Iodine atom to two particle in solution ) ( Ioxaglate- Hexabrix) Non Ionic Monomer = 3/1 = 3 ( Three Iodine atom to one particle in solution) { Iopamidol – lekpamidol, Iohexol -Omnipaque, Ioversol – Optiray, Iopromide – Ultravist} Non Ionic Dimer = 6/1= 6 ( Six Iodine atom to one in solution) { Iotrolan – Isovist, Iodixanol – Visipaque)

13. Osmolality (mOsmol/kg) of iodine-based contrast media at a concentration around 300 mgl/ml

14. Approx Osmolality Of Iodinated Contrast (300mgI/ml) Non ionic Dimer = 290 Non Ionic Monomer = 400 – 670 Ionic Dimer = 490 Ionic Monomer = 1500 Safest in NonIonic Monomer = Iomeprol Safest in NonIonic Dimer = Iodixanol

15. Viscosity (mPa.s) of iodine-based contrast media at a concentration around 300 mglml-1 and at 37 C

16. Highest Viscosity: NonIonic Dimer: Iodixanol : 11 mPa.s Lowest Viscosity: NonIonic monomer: Iomeprol: 4.1 mPa.s Ionic monomer: 2.5 – 4.5 mPa.s Ionic Dimer: Ioxaglate: 7 mPa.s Non Ionic Monomer: 4.2 – 7.5 mPa.s Non Ionic Dimer: 11 m Pa.s

17. Company Product Name and concentration available Chemical Name Osmolality at 300 mgI/ml Viscocity BAYER Ultravist (240/300/370 IOPROMIDE 407 4.9 GE Omnipaque 240/300/350 IOHEXOL 672 6.3 GE Visipaque 270 IODIXANOL 290 6.3 BRACCO Isovue 250/300/370 IOPAMIDOL 616 4.7 BRACCO Iomeron (250/300/350/ 400 ) IOMEPROL 500 4.5 MallincKrodt Optiray 240/300/320/350 IOVERSOL 651 5.5

18. The chemical difference between Ionic and NonIonic contrast differs in the number of particles in the substance and not the number of iodine compounds. Later cation (Na/ Meg +) were replaced by glucose that does not disassociate into solution. Result: Three Iodine atoms for contrast and only one particle for osmolality. The Osmolality (weight if ion) is a significant factor for side effect : HOCM when adminsitered IV, they prompt a sudden shift in body fluid from the interstitial space and cell into systemic circulation. I ncidence of side-effects , particularly above 800 mosm kg-1 .

19. Total Iodine Delivered: 100 ml X 370mgI/ml =37000mgI = 37gm Dose : Upper Limit : 200 ml, 320mgI/ml = 64 gm of iodine . Pediatric dose: 2ml/kg, Adult = 1.5ml/kg

20. Percent concentration (Grams per 100ml) Percent concentration = is a statement about how many grams of solute have been dissolved in each 100 ml of solution – ‘percent’ means literally ‘in the hundred’. Eg: 5% (5 gram in 100 ml) glucose solution has 5 g of glucose dissolved in enough water to make 100 ml of solution .

21. Barium Sulphate Barium must be small : 0.1 – 3 mm Non-ionic suspension medium is used: for otherwise barium particles would clump: resulting solution has pH of 5.3: makes it stable in gastric acid.

22. Barium Swallow: E-Z HD 250 %, 100 ml Barium Meal: E-Z HD 250% w/v Barium Follow through: E-Z Paque 60- 100 % w/v 300ml Barium Enema: Polibar 115% w/v 500ml A Guide to Radiological Procedures: Chapman and Nakienly: 5 th Edition

23. Gadolinium Based Contrast Agents Non Specific Extracellular gadolinum chelates: do not bound to protein and excreted solo by kidney.: Organ Specific Agents/ Protein Bind Agents: Gadofosvoset-Angiography, Gadoxetate- liver Imaging

24. Chemical Structure of ligand to which the Gadolinum is Bound: Liner or Cyclic which may be Ionic or NonIonic: Ionic ( which have charge in solution) The stability of gadolinium contrast agents depends on their kinetic, thermodynamic and conditional stability: Osmolality varies between: 600 – 2000 mosmol/kg Contrast agents with cyclic ligands, in which gadolinium is caged in a preorganised cavity, are more stable than those with linear ligands.

25. Company Generic Name Trade Name Chemical Structure/ Charge Concentration (mmol/L) Protein Binding Thermodynamic Statbility constatnt Kinetic Stability(Half life at pH of 1) Elimination Pathway Path GE Gadodiamide Omniscan Linear/ NonIonic 0.5 none 16.9 <5 sec Kidney ECF Mallinckrodt Gadoversetamide Optimark Linear/ NonIonic 0.5 none 16.6 <5 sec Kidney ECF BAYER Gd_DTPA Gadopentate Dimeglumine Magnevist Linear/ Ionic 0.5 none 22.1 <5 sec Kidney ECF BRACCO Gd_BOPTA Gadobenate dimeglumine Multihance Linear/Ionic 0.5 <5% 22.6 <5sec Kidney >96%, Bile <4% ECF HB BAYER Gadoxetate Eovist/ promovist Linear/Ionic 0.25 <15% 23.5 <5 sec Kidney 50%, Bile 50% HB ECF

26. Company Generic Name Trade Name Chemical Structure/ Charge Concentration (mmol/L) Protein Binding Thermodynamic Statbility constatnt Kinetic Stability(Half life at pH of 1) Elimination Pathway Path Bayer Gadofosveset Trisodium Albavar, Vasovist Linear/ Ionic 0.25 >85% Kidney > 91% ECF BRACCO GADOTERIDOL Prohance Macrocyclic/ NonIonic 0.5 none 23.8 3.9 hours Kidney ECF BAYER Gadobutrol Gadovist Macrocyclic/ NonIonic 1 none 21.8 43 hours Kidney ECF Guerbet/ GE Gadoterate meglumine Dotarem/ Clariscan Macrocyclic/Ionic 0.5 none 25.8 1month 338(hr) Kidney ECF Amag Ferumoxytol Feraheme 30mg/ml RES

27. How to calculate Contrast Volume V = D X W / C Volume (mL) D = Dose / Wt (mmol/kg) W = weight(Kg) C = concentration (mmol/L) Volume (mL) = 11 D = 0.1 W = 55 C = 0.5 Standard Adult: 0.2ml/kg Gadovist Volume: 11/ 5.5 A human being would not survive 0.1 mmol kg -1 free gadolinium injected into the circulation .

28. Ultrasound Contrast Agent (UCA) UCA are blood-pool agents , which produce their effect by increased back-scattering of sound compared to that from blood, other fluids, and most tissues . microbubble contrast agents change grey and dark areas to a brighter tone when the contrast medium enters in fluid or blood. UCA may be useful for imaging solid organs , e.g. liver, kidney , breast, prostate and uterus. They can also be used to enhance cavities, e.g. bladder, ureters, Fallopian tubes and abscesses .

29. Classification: 5 different categories Non encapsulated gas microbubbles. Encapsulated gas microbubbles. Stabilized gas microbubbles. Microparticles suspension Gastrointestional

30. Based on pharmacokinectic property and efficacy Non-transpulmonary UCAs: which do not pass the capillary bed of lung : Show on B-mode only in R ventricle and have short duration effect Transpulmonary blood pool UCAs with shorter half (< 5min) life which produces low signal using harmonic imaging. Transpulmonary blood pool UCAs with longer half life (>5min) which produces high signal using harmonic imaging using low acoustic power. Transpulmonary UCAs with specific liver and spleen

31. THANKYOU