X-RAY

Contrast Media
In Diagnostic Imaging

November 1999

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Pioneers in non-ionics
AMIPAQUE

1974

Nycomed launches the first non-ionic

X-ray contrast medium - AMIPAQUE

1982

Launch of OMNIPAQUE- our first

ready-to-use non-ionic X-ray contrast
medium

1991

Launch of IMAGOPAQUE - non-ionic

X-ray contrast medium

1993

Launch of VISIPAQUE - the worlds

first isotonic non-ionic X-ray contrast
medium for intravascular use

1993

Launch of the worlds first non-ionic

contrast agent for MRI, OMNISCAN

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OMNIPAQUE - a well documented product

Experience across all indications

and patient groups

Experience from over 200,000,000

examinations (2002) world-wide

Available world-wide

Available in a wide range of

presentations

TRUST IN EXPERIENCE

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OMNIPAQUE - a proven product

Over 4,000 published papers

More than 35 doctoral theses on

OMNIPAQUE

The gold standard against which

other X-ray contrast media are
evaluated

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The concept of an ideal contrast medium is the

driving force behind contrast media development

The diagnostic effect

without adverse reactions

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COO

CATION

Main classes of
X-ray contrast media
e.g.
Diatrizoates,
HypaqueTM

Ionic monomer

COO CATION

Non-ionic monomer

I
R

Ionic dimeric monoacid

e.g.
OMNIPAQUE , IMAGOPAQUE ,
iopromide

e.g.
ioxaglate

R
e.g.
VISIPAQUE

Non-ionic dimer

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Transformation of ionic to non-ionic medium

COO-

CATION+

(OH)n

(OH)n

I
Ionic medium

I
(OH)n
I

Non-ionic medium

Eliminating carboxyl decreases neurotoxicity

Eliminating ions decreases osmotoxicity

Adding hydroxyl groups decreases chemotoxicity

Almn T, Excerpta Medica ICS 816; 1989:25-45

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History of X-ray contrast media

-1

1895

Wilhelm Conrad Rntgen discovers X-rays

1896

1911

Experiments with metallic oxides or

bismuth-subnitrate as contrast media in
animals and amputated limbs
BaSO4 for gastrointestinal examinations

1918

Air for gastrointestinal examinations

1920s

Iodinated oils for myelography and bronchography.

NaI for urography and angiography

1920s

Selectan, diodone (and many other compounds)

for urography and angiography

(end)

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History of X-ray contrast media

-2

1934

Registration of Nycomeds first X-ray contrast medium

(CM) in Norway (Urotrast = licensee product)

1944

The first triiodinated contrast medium - acetrizoate

1950s

Diatrizoate (amidotrizoate) metrizoate,

iothalamate etc.

1960s

Balanced Na- and meglumine salts

1962

ISOPAQUE (metrizoate), Nycomeds first

original X-ray CM

1970s

Several low-osmolar, non-ionic monomers and

ionic dimers (iohexol, iopamidol, iopromide,
ioxaglate etc.)

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History of X-ray contrast media

-3

1974

AMIPAQUE (metrizamide), the worlds first non-ionic lowosmolar X-ray CM, after an idea conceived by Torsten
Almn

1982

OMNIPAQUE(iohexol), a non-ionic
monomeric X-ray CM

1990s

Non-ionic dimers (iodixanol, iotrolan)

1991

IMAGOPAQUE (iopentol), a non-ionic

monomeric X-ray CM

1993

VISIPAQUE (iodixanol), a non-ionic isotonic

X-ray CM, registered

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purpose

Enhancing too many structures in the body>

increasing/creating contrast image through changes in:

Consentrations in tissue
Attenuation value
Signal quality.

Visualizing of functions:
-Elimination ( kidney ,liver)
-transport processes(bloodstream,CSF,intestinal,liver)
-perfusion( all tissue)
-permeability/barriers
-metabolisme(MRS)

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Classification: > Negative: gases ,air

> Positive: Ba SO4, Iodinated
iodinated : Oily, water Soluble.( ionic non ionic)

Ionic :

Monomer:

Oral Cholegraphic
Uro/angiographic agent

- Dimer:

i.v cholegraphic
Angiographic

Non Ionic:

Monomer:
DAILY USE

Dimeric

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BaSo4

Insoluble sulfate for diagnosis GI tract

Unabsorbtable

Available as powder/ suspension

Concentration 1g/cc 2.5g/cc

Must be changed if perforation is suspected.

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Water soluble , almost always use Iodine

element:

High contrast density

Low toxicity

Non ionic superior than ionic;

better neural tolerance

incidens of general reanctions( nausea,vomiting,allergy like,
idiosyncratic reaction is far lower.
Low osmolality
No vascular pain, endothelial damage,distrurbance BBB

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Molecular structure
OH

CONHCH2CHCH2

OH

CH2CHCH2 N
CO
OH

Iodine content:

46.6%

OH

CH3

OH

CONHCH2CHCH2
OH

Molecular weight:

821 dalton

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Quantitative composition
OMNIPAQUE
mgI/ml

140

180

200

240

300

350

Ingredients
mg/ml

Iohexol

302

388

431

518

647

755

Trometamol

1.21

1.21

1.21

1.21

1.21

1.21

NaCaEDTA

0.10

0.10

0.10

0.10

0.10

0.10

5M HCl acid
to pH 6.8-7.6

q.s.

q.s.

q.s.

q.s.

q.s.

q.s.

Water for
injection

1 ml

1 ml

1 ml

1 ml

1 ml

1 ml

Physico-chemical
Data on file 1980, Nycomed Amersham

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Osmolality of contrast media formulations

ionic monomers

2000

mOsm/kg H2O

1600

1200

non-ionic monomers

800

400

blood
0

100

non-ionic dimers
150

200

250

300

350

400

mg I/ml
Eivindvik K et al, Acta Radiol Suppl. 1995; 399:32-38

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Viscosity
Hypaque

ioxaglate

OMNIPAQUE

iopamidol

ioversol

10.6

iopromide

10.6

Viscosity at 37C (mPas)

9.8
8.6
7.7
7.0
6.1

5.4

5.4

4.1

282 - 320
ionics
Physico-chemical

8.9

300 - 320
non-ionics

370
ionic

350 - 370
non-ionics

Concentration (mg I/ml)

1. Dyvik K et al, Acta Radiol suppl. 95; 399: 43-49
2. Rees CR et al, Cardiovasc Radiol 1988; 166: 53-56

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Pharmacokinetics in humans

Distribution half-life
= 21.8 min (independent of dose)

Elimination half-life
= 121.2 min (independent of dose)

No metabolites detected

About 99% of the contrast medium was excreted

during the first 24 hours after injection

Aakhus T et al, Acta Radiol 1980; Suppl 362: 131-134

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A universal contrast medium

Periperal & visceral

arteriography

Phlebography

CT enhancement

Cardioangiography

Urography

Cerebral
angiography

Digital subtraction
angiography

Paediatric radiology

Myelography

Body cavities

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The Effects oc CM

Primary

The only one effect is desired that is Attenuation of radiation.

Secondary

All other effects :

Chemotoxicity:
protein binding,effect cell membrane, enzym blocking,
vasoactive substance release

Osmotoxicity: pain, vasodilatation.

Ion toxicity :
high/low consentration ions interfering cellular function

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Classification of adverse events:

Mild:

Intermediate:

Does not require medical treatment,does not interferre th examination

Necessary medical treatment, examination delayed/affected

Serious:

Necessary medical treatment & hospitalization,or will have permanen

sequelae.

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Other classificatios

Systemic effects

Renal effects

Cardiovascular & hematologic effects

Cardiac effects

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Cardioangiography

Conclusion
Hill et al.
This study confirms in a large randomized trial of
cardiac angiography that the incidence of adverse
reactions of all types is significantly lower with
OMNIPAQUE than with diatrizoate.

Hill J et al, Am J Cardiol 1993; 72: 770-775

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Cardioangiography / PTCA

Conclusion
Vacek et al.
When contrast media like OMNIPAQUE or
ioxaglate are to be used, the non-ionic contrast
medium OMNIPAQUE is significantly safer than
the ionic dimer ioxaglate.

Vacek JL et al, Am J Cardiol 1990; 66: 1277-1278

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Nephrotoxicity in renal insufficiency

Distribution of serum creatinine level changes at 48 hours
decreased

no change

increase <25%

All patients

increase >25%

iothalamate
OMNIPAQUE

*
0

Diabetics

10

20

30

40

50

Patients
(n=101)

iothalamate
OMNIPAQUE
*
* p<0.05 between groups

Harris KG et al, Radiology 1991; 179: 849-852

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Surveillance

Conclusion
Katayama et al.
The use of non-ionic contrast media significantly
reduces the prevalence of severe adverse reactions
(at all levels of risk) and represents the most
effective means of achieving greater safety in
contrast media examinations.

Katayama et al, Radiology 1990; 175: 621-628

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Surveillance

Conclusion
Palmer
It is safer to be at high risk and receive a non-ionic
medium
than
to be at low risk and receive a conventional ionic
medium.

Palmer, Australas Radiol 1988; 32: 426-428

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Surveillance

Conclusion
Wolf et al.
The choice of contrast agent emerges as the most
potent risk factor.

Wolf et al, Invest Radiol 1991; 26: 404-410

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Non-ionic is economic
It is simplistic to believe that it is just a matter of
comparing the cost of a non-ionic agent to a comparable
amount of ionic contrast.
Conclusion from The Ontario Association of Radiologists in 1994.
Report: The Use of Iondinated Contrast Media in Diagnostic Imaging.

... our data suggest that the use of a low-osmolality

contrast agent in all patients could substantially reduce
the number of moderate and severe reactions, at minimal
incremental cost.
Finding from a clinical trial (Steinberg EP et al, N Engl J Med 1992; 326: 425-430) comparing the costeffectiveness of diatrizoate with OMNIPAQUE in 505 patients undergoing cardioangiography.

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IV-54 1978 Indonesia stamp features a drawing of a patient

having a cerebral angiogram. The right side of the stamp
features a drawing of a pressure injector used to inject contrast
media into patients' blood vessels. Stamps of this type are used
to educate the public.

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IV-55 1966 Belgium stamp features a portrait of the German

chemist August Kekule,
and the benzene ring structure he discovered in 1865.

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IV-56 1981 Algeria stamp was issued to announce an International

Congress on Echinococcosis. The lung, liver, and brain are highlighted.
This interesting stamp design also features barium in the small intestine.