Water-soluble Iodinated Contrast Agents T.

PEYROUX February 2005

BASIC STRUCTURE OF TRI-IODINATED CONTRAST AGENTS

R3

R1

R2

Atomic number of iodine: 53

HISTORY OF IODINATED CONTRAST AGENTS (1)

Mono-iodinated monomers Di-iodinated monomers Highosmolality tri-iodinated monomers

COOM

COO-

M+

Na+ MEGLUMINE

R1

R2

R1

R2

IODINATED ORGANIC SALT

IN SOLUTION: 3 IODINE ATOMS YIELD 2 PARTICLES

ratio: number of iodine atoms = 3 number of particles 2

HISTORY OF IODINATED CONTRAST AGENTS (2)

Reduction of osmolality: 2 possible routes
DIMERIC ROUTE
M+ R3 COO-

NONIONIC ROUTE
O C-NH-R 3

R1
6 IODINE ATOMS - 2 PARTICLES

R2

R1

R2

3 IODINE ATOMS - 1 PARTICLE

6 3 increase in the ratio: number of iodine atoms 2 or 1 number of particles =

HISTORY OF IODINATED CONTRAST AGENTS (3)

NONIONIC MONOMER
O C-NH-R 3 R3

NONIONIC DIMER
R4

R1

R2

R1

R2
6 IODINE ATOMS - 1 PARTICLE

3 IODINE ATOMS - 1 PARTICLE

ratio: number of iodine atoms number of particles

6 1

CLASSIFICATION OF IODINATED CONTRAST AGENTS

UROGRAPHIC/ANGIOGRAPHIC WATER-SOLUBLE CAs
HIGH OSMOLALITY IONIC LOW OSMOLALITY IONIC NONIONIC OXILAN IOMERON HEXABRIX IOPAMIRON IVEPAQUE OMNIPAQUE ULTRAVIST VISIPAQUE XENETIX

OTHER WATERSOLUBLE CAs

IODISED OIL

UROGRAFIN RADIOSELECTAN TELEBRIX

TELEBRIX HYSTERO TELEBRIX GASTRO GASTROGRAFIN GASTROVIEW LIPIODOL

CLASSIFICATION

Osmolality Osmolality
(mOsm/kg) (mOsm/kg)

High High (>1500) (>1500)

Low Low (600-1000) (600-1000)

Iso Iso (280) (280)

Ionicity Ionicity
# Benzene # Benzene Chemical Chemical Name Name

Ionic Ionic
Monomer Monomer Diatrizoate Diatrizoate

Ionic Ionic
Dimer Dimer Ioxaglate Ioxaglate

Nonionic Nonionic
Monomer Monomer Iohexol Iohexol Iopamidol Iopamidol Iobitridol Iobitridol Ioxilan Ioxilan 10-20 10-20

Nonionic Nonionic
Dimer Dimer Iodixanol Iodixanol

Viscosity Viscosity (mPa.s) (mPa.s)

14 14

15 15

26 26

PHYSICAL AND CHEMICAL CHARACTERISTICS OF CONTRAST AGENTS

Iodine concentration Osmolality Viscosity Hydrophilicity Ionic or nonionic agent

IODINE CONCENTRATION (1)

This determines the opacity of the contrast agent, and therefore its efficacy It is expressed as g/100 ml or mgI/ml depending on the product category From 120 mgI/ml to 400 mgI/ml

IODINE CONCENTRATION (2)

The choice of the iodine concentration depends on: - the procedure (existence or not of natural contrast) - the patient (bodyweight) - the apparatus

OSMOLALITY

This depends on the number of particles in solution It partly determines the diffusion of the contrast agent outside the vessel and into the parenchyma (and consequently its vascular residence time) It is expressed as mOsm/kg H2O Contrast media: from 290 mOsm/kg H2O to 2100 mOsm/kg H2O

Thomson Learning Australia

Water will travel across a membrane from a less concentrated solution To a more concentrated solution until the solutions have equal concentrations of solute Osmolality depends on the concentration of the particles, not on their size

OSMOLALITY

100 mOsm/kg

200 mOsm/kg

300 mOsm/kg

400 mOsm/kg

500 mOsm/kg

HYPOTONIC

ISOTONIC

HYPERTONIC

INTERACTION WITH RED BLOOD CELLS Nonionic monomers + blood echinocytes

Nonionic dimer (iodixanol) + blood stomatocytes Ioxaglate no effects on RBC shape and less disturbances on viscometric characteristics of blood

Aspelin P et al. Blood Cells 1977; 3: 397-407 Aspelin P et al. Acta Radiol 1987; 370 Suppl. 79-83 Hardeman MR et al. Invest Radiol 1991; 26: 810-819 Lerche D, Hennicke G Clin Hemorheol 1992; 12: 341-355 Strickland NH et al. Clin Radiol 1992; 45: 240-242 Bucherer C et al. Invest Radiol 1994; 29: 1026-1030

VISCOSITY
This depends on the compound, the iodine concentration and the temperature

6 5 4
Viscosity (mPa.s) Viscosity (mPa.s)

42 38 35 32 27 25 20 15 10

3 2 1 0 10 15 20 25
Temperature (C)

30

35

40

10

20

30

40

50

60

70

80

90

Iodine oncentration (mgl/ml)

Viscosity of Hexabrix 200 depending on the temperature

Viscosity of Xenetix at 20C depending on the iodine content

HYDROPHILICITY

This depends on the structure of the molecule (presence of OH radicals) Partly determines the diffusion of the contrast agent into tissues Partly determines its safety profile
OH

OH CH2 OH CH CH2 H N CO OH CH2 CH CH2 CH2 OH CO N CH3 CH2 CH OH N CO CH3

Xenetix molecule (iobitridol)

NEW CONTRAST MEDIA : MORE HYDROPHILIC

From above
Benzene ring + iodine atoms = lipophilic

Lateral view

HIGH OSMOLAR IONIC

Hydrophilic "shield"

NONIONIC MONOMER

IONIC OR NONIONIC CONTRAST AGENT ?

Ionic agents may contain sodium, which plays a role in myocardial contractility. Studies on human blood have shown that platelet activation is more inhibited by ionic products than by nonionic products.

OSMOLALITY AND VISCOSITY (high-osmolality contrast media)

OSMOLALITY
(mOsm/kg H2O)

VISCOSITY
at 37 (mPa.s)

RADIOSELECTAN 76% TELEBRIX 12 Na TELEBRIX 30M TELEBRIX 35

2100 610 1500 2100

8.5 1.1 5.2 7.5

OSMOLALITY AND VISCOSITY (low-osmolality dimers)

OSMOLALITY
(mOsm/kg H2O)

VISCOSITY
at 37 (mPa.sec)

VISIPAQUE 320 HEXABRIX 320

290 600

11.4 7.5

OSMOLALITIES AND VISCOSITIES (low-osmolality monomers)

OSMOLALITY
(mOsm/kg H2O)

VISCOSITY
at 37 (mPa.sec)

IOMERON 300 IOPAMIRON 300 IVEPAQUE 300 OMNIPAQUE 300 OPTIRAY 300 ULTRAVIST 300 XENETIX 300 OXILAN 300

521 616 640 690 630 607 695 580

4.5 4.7 6.5 6.1 5 4.6 6 5.1

PHARMACOKINETICS OF IODINATED CONTRAST AGENTS (1)

a two-compartment model
BLOOD CELLS

CELLS INTERSTITIUM

PLASMA

Distribution phase: Cp >> Ci Steady state: Cp Ci

URINE

PHARMACOKINETICS OF IODINATED CONTRAST AGENTS (2)

INJECTION OF UROGRAPHIC/ANGIOGRAPHIC CONTRAST AGENT

PHASE Vascular Interstitial Urinary

INTERVAL Very brief Brief Long

PROCEDURE CT angiography/angiography CT IVU

PHARMACOKINETICS OF IODINATED CONTRAST AGENTS (3)

plasma, tissue and urinary kinetics

% of injected dose

100 90 80 70 60 50 40 30 20 10 0

Plasma concentration Interstitial concentration Urinary concentration

20

40

60 80 100 120 minutes

From the TELEBRIX expert report

ADMINISTRATION ROUTES

Intravenous injection Intra-arterial injection Injection in cavity Subarachnoid injection

INTRAVENOUS INJECTION

Intravenous Urography
small volumes injected (abt 1 ml/kg) manual bolus injection agent with high iodine concentration

CT
often large volumes injected rapid automatic injection Either high iodine conc. or high injection speed

INTRA-ARTERIAL INJECTION

Specific features of the arterial route

Specific features of the arterial route Rapid, direct injection The procedure is often long and involves equipment

High risk of thrombosis Pain Renal risk

SUBARACHNOIDAL INJECTION

USE A NONIONIC AGENT ! IONIC AGENTS ARE STRICTLY CONTRA-INDICATED

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MAIN ADVERSE REACTIONS RELATED TO ADMINISTRATION OF IODINATED AGENTS

Reactions related to osmolality

Heat sensation or pain Haemodynamic effects

Renal risk Risk of thrombosis Allergic risk Extravasation of the contrast agent

EFFECTS OF OSMOLALITY

FLUID OVERLOAD
INFLUX OF WATER INTERSTITIAL DIFFUSION

EFFECTS OF OSMOLALITY
BEFORE INJECTION AFTER INJECTION VEIN ARTERY

H2O H2O

Tissues

Vessel VOLUME EXPANSION STEADY STATE

CAPACITANCE SYSTEME HEAT

RESISTANCE SYSTEM PAIN

EFFECTS OF OSMOLALITY Osmolality-related risks in patients with:

Heart failure Coronary insufficiency Renal failure Dehydration Sensitivity to changes in water balance: neonates, patients in shock, postoperative patients, etc. Myeloma

INTERACTION WITH THYROID FUNCTION (1)

Trace quantities of free iodide can interfere with thyroid metabolism Maximum levels of iodide in CM solutions: about 20 g/ml. In practice: 4-5 times less. 100 ml of CM 4-15 times daily needs in iodine

armourthyroid.com

INTERACTION WITH THYROID FUNCTION (2) In practice Palpable nodules (> 1 cm) and multinodular goitres: special caution mandatory. Palpation. Dysthyroidisms: -no contra-indication in well-controlled known hyperthyroidisms (Basedow's disease..) -risk of worsening or triggering off hyperthyroidism in patients with pre-existing thyroid disease (elderly patients..) TW De Bruin: 7 cases of hyperthyroidism requiring hospitalization in 24,600 CT exams. Pre-existing goitre in all 7 patients. (Lancet 1994; 343: 1160-1161)

INTERACTION WITH THYROID FUNCTION (3) In practice

Thyroid scintigraphy: exogenous iodine can interfere with the fixation of the radioactive tracer and make difficult the interpretation of subsequent scintigraphy for about 2 weeks. Scintigraphy should be made before radiological/cardiological procedures involving CM. If not the case: wait for at least 3 weeks before any examination of the thyroid

INTERACTION WITH THYROID FUNCTION (4) In the foetus

Mature towards the 20th week of gestation Ftal thyroid independent of the mother's hormonal activity Iodides freely cross placental barrier and taken up by ftal gland Risk of hypothyroidism and goitre if iodine overload in the final 3 months of pregnancy

Interaction with Metformin (Glucophage) (1)

Interaction with Metformin (2)

Biguanides: a) for treatment of overweight diabetic pts inadequately treated by diet b) As adjunct therapy when sulfonylurea alone fails c) Sometimes in combination with insulin

Approx. 90% of metformin is excreted via the kidneys in 24 hrs Pts with renal insufficiency: slow accumulation of biguanides in the tissues

Risk of lactic acidosis

Interaction with Metformin (3)

Lactic acidosis: accumulation of lactic acid in the blood > 5 mmol with an accompanying blood pH < 7.25. Lactic acidosis with metformin: 0.03 cases/1000 pts/year Approx. 50% of cases resulting in death Glucophage: contra-indicated in pts with renal insufficiency Pts with diabetic nephropathy and renal insufficiency: the highest risk of developing contrast nephropathy

Interaction with metformine (4) ESUR Guidelines

* SCr measured in every diabetic pt treated with biguanides prior to intravascular contrast medium. Low osmolar CM should always be used Elective studies:
SCr normal: the procedure should be performed and intake of metformin stopped from the time of the study. Restarted only if renal function/SCr remains within the normal range SCr abnormal: metformin withdrawn and procedure delayed for 48 h. Metformin only restarted 48 h after procedure, if renal function/SCr is unchanged

Emergency: SCr normal: as in elective studies

SCr abnormal: weighing risk/benefit ratio. If yes: withdrawal of metformin + hydration + monitoring of renal function, serum lactic acid and blood pH
Thomsen HS et al. Eur Radiol 1999; 9: 738-740

CONTRAST AGENT EXTRAVASATION (1)

Caution required during automatic injection Risk of necrosis in subcutaneous tissues The severity partly depends on the quantity of contrast agent injected and on patient age

CONTRAST AGENT EXTRAVASATION (2)

Management:
Monitor status of skin, muscle, vessels and nerves Raise the affected limb Local treatment (hyaluronidase) Systemic anti-inflammatory agents

CONCLUSION

CONTRAST AGENTS ARE SAFE if certain precautions are taken, particularly in patients at risk DO NOT CONFUSE: - osmolality-related risks - and allergic risks