Contrast Media

Contrast Media

• &

Contrast Reactions

Objectives

• Define contrast media
• Outline Ideal properties of RCM
• Describe the historical development of RCM
• Classify contrast media
• Describe adverse effects of CM

Outline drugs use in management of ADR of CM

Definitions: Contrast media

CM are Diagnostic agents used in radiology to;

Enhance or create visual contrast in an image between the organ, vessel or tract in which they are present and the surrounding tissues in the body

Importance of Contrast media

• Enable to visualise certain anatomical structures or physiological functions within the human body when the imaging techniques on their own cannot provide this information.

Importance of Contrast media

• Instilling contrast changes, absorption characteristics of the area
• Alters subject contrast and density differences
• Enhancing density differences within an area will improve visibility

Four basic densities on Radiograph

• Air
• Soft tissues
• Fatty tissues
• Calcified structures

Soft tissues have same absorptive capacity and cannot be distinguished

Why use contrast agents

Different tissues within the body attenuate the beam of x-rays to different degrees.

The degree of attenuation of an x-ray beam can be varied, especially as the number of electrons encountered during the beams path can vary.

• Fundamentally the number of electrons in the path of the beam is dependent upon:
• The thickness of the object being studied.
• The density of the object being studied.

The number of electrons per atom of the element (Z).

Requirements of a contrast agent (2)

• The agent should have rapid elimination.
• The agent should not be carcinogenic.
• The agent should have a viscosity appropriate to the patient when introduced.
• The agent should cause minimal distress to the patient when introduced.

The agent should be cost-effective.

Ideal Properties of CM

• Provides maximum opacity to X-rays;
• is biologically inert;
• has high water solubility;
• is chemically stable;
• selectively excreted;
• has a low viscosity;
• exerts minimal osmotic effects;
• is safe (minimal or no toxicity);
• is not expensive
• Easy to administer

Non-floculating (allow the organ to be properly demonstrated)

Ideal Properties:

• Osmolarity
• Homeostasis: body’s ability to maintain a stable internal condition.
• Osmolarity:
• A measure of the total number of particles in solution per kg of H2O.
• the key to understanding IV contrast differences

The characteristic of contrast media MOST responsible for adverse reactions.

High osmolar agents ( hypertonic) contain more solutes than there are in the cells.

• Solutions of this type are given to patients who have edema because of fluid retention.
• High osmolar contrast agents draw fluid out of the cells and cause dehydration.

Hypaque 60, Cysto Conray,

High Osmolar CM

Low Osmolar CM

• Low osmolar agents (hypotonic) contain fewer solutes (more water) than the cell.
• These solutions are infused slowly into a dehydrated patient to rehydrate.
• Low osmolar contrast agents also draw fluid out of the cells but to a lesser degree.

Omnipaque, Isoview, Optiray.

Effects of Osmolality

• Increase can cause fluid overload
• Patients with renal failure
• Patients with cardiac problems – altered pumping ability
• shortness of breath
• crackles in lungs
• decrease in O2 saturations
• anxiety and tachynpnea
• wet cough

sweating

Effects of Osmolality

• Calcium binding in cells & tissues
• Increase osmolarity increases calcium binding
• Therefore, can cause heart irregularities
• arrhythmias
• Bradycardia
• Rigidity of red blood cells

RBCs need space to move through blood vessels

Ideal Properties:

• ii) Viscosity
• Friction:
• Size of molecule
• Concentration of molecule

Heating reduces viscosity allows for rapid injection

iii) Electron density & RCM

• CM are opaque to X rays
• Do not allow x-rays to pass through them
• Have a high electron density
• Repelling x rays (moving electrons)
• Most heavy metals
• Are electron dense but
• Too toxic to be used clinically
• Iodine is electron dense & safe

Hence most CM contain iodine

Methods of administration of CM

• Orally.
• Rectally.
• Intra-venously – (injection / infusion).
• Mechanically – Filling of a body cavity or potential space., Intra-vaginally
• Intra-thecally

Intra-arterially

Routing of Contrast Media

• Direct
• Barium studies
• Myelography
• Angiography
• Arthrography
• Indirect
• Intravenous Pyelogram (IVP)

Oral Cholecystogram (OCG)

Routes of administration

Classification of Contrast Media

• Classification based on physical properties
• (i) Negative CM
• Gaseous substances : N20, CO2, Inert gases
• low atomic number and specific weight
• Absorb X-rays to a lesser extent than the surrounding body structures
• (ii) Positive CM
• All substances which, because of their higher
• specific weight and atomic number

Absorb Xrays to a greater extent than body tissues

Classification of Contrast Media

• (iii) Double contrast agents
• Incorporates the use of both positive & negative contrast media.
• eg during a double contrast Barium enema examination.

Co2 + BaSo4 = Double Contrast

Classification of Contrast Media

• (a) Positive Contrast Media
• (i) Iodinated CM
• (a) Water Insoluble CM
• (b) Triiodobenzoic Derives
• Monomeric ICM
• Monomeric NICM
• Dimeric ICM
• Dimeric NICM
• (c) Oily CM
• (ii) Barium Sulphate
• (iii) CM for Ultra sound
• (iv) CM for MRI

Gadolinium Based

(a) Positive Contrast Agents

• Radiopaque = iodinated/barium
• Appear light (decreased density)
• High atomic number

Barium: BaSO4 Suspension

(b) Negative Contrast Agents

• Radiolucent
• Appear dark (increased density)
• Low atomic number
• Gas…air…crystals…carbon dioxide
• Double contrast studies:
• Stomach
• Large intestine
• Arthrography: knee, shoulder, wrist, hip

Adverse reaction: Air emboli

History of Contrast Media

1895 Wilhelm Conrad Röntgen discovers X-rays

Early Contrast Media: 1905-20

Colloidal Silver

• Thorium dioxide: isotonic (little pain)
• Lithium iodide
• Iodinated oil
• All are Highly toxic
• E.g. silver precipitate & cause cell necrosis

No vascular application possible

Historical Development

• 1896 First oral radiopaque compound to visualise GIT – Bismuth TOXIC
• 1910 BaSO4 for GIT examinations (Safer)
• 1904 Colloidal silver used in retrograde urography
• 1920’s – Sodium Iodide used to treat syphilis.
• 1923 First use of iodine salts to visualise urinary tract

1925 Iodinated organic compound synthesised

Historical Development

• 1927 First product for excretory urography
• 1950 Acetrizoate (triiodobenzoic acid derivative)

1954 Less toxic Diatrizoate introduced

Early contrast Media: 1920s

I.V Iodides used to treat syphilis in a patient Observed that Urinary tract was visible on X ray after treatment with Sodium Iodide which was excreted via the kidneys Scientists wondered whether these cpds could be used as contrast agents?

Early contrast Media: 1928

• Pylognost patented as Sodium Iodide/Urea
• Opacified the kidney
• NaI dissociates to Na+ & I – ions (2 particles)
• Disadvantages:
• Iodide ions are quite toxic
• 2 particles in solution double the osmolarity
• Large amounts of NaI required for visualisation

This meant osmolarity & toxicity was high

Aromatic cpds:

• Iodinated pyridine
• Iodinated pyridine was used to treat syphilis
• First use of iodine bound to aromatic ring to reduce toxicity of iodide ions
• Advantages
• Forms a stable C – I bond (no free iodine)

Iodine bound to the ring is less toxic than the free Iodide ions

Development of Iodinated Pyridines

• The success of iodinated pyridine led to….
• Synthesis of more compounds better than iodinated pyridine & less toxic
• Iodomethamate
• Addition of COOH group (position 2 & 6)
• 2 one Iodine group ( position 3 & 5)
• O group at position 4

Methyl group at position 1

Improvements

Nitrogen atom was masked with methyl group- toxicity reduced More iodine atoms give more iodine @ molecule & hence increases electron density & visibility COOH improves solubility

• Disadvantage

BUT , N is still part of the ring, Pyridine is Toxic

Further Improvements

• Relationship between molecular structure & toxicity
• Presence of side chain separating I atoms lowers toxicity
• Nitrogen as part of the ring added to toxicity
• Substitution at all H positions lowers toxicity

This led to development of iodinated benzenes

Iodinated Benzoic Acids

UROKON:

• Sodium salt of Tri Iodo benzoic acid

With NH- CO- CH3 (acetamino) side chain

Basic structure of organic CM

ANION six-carbon bonded hexagon called benzene ring

• negatively charged
• CATION= positively charged attaches to acid group
• 3 iodine atoms = triiodinated
• 1 acid group Negatively charged
• Dissociate on injection
• chemical structures that increase solubility and excretion
• Positively charged sodium or methylglucamine
• I
• R1
• R2

IONIC CONTRAST MEDIA

Diatrizoate (1954)

• very successful CM
• Cheap & easy to make
• Still in use in developing countries
• Less toxic than previous CM
• Disadvantages
• Tri Iodo Benzoic acid not very water soluble

Salts of Tri Iodo Benzoic acid are water soluble & are readily made

Diatrizoate

• 3-5 di acetamido 2,4,6 triodo benzoic acid
• Two acetamido ( NH-CO-CH3) groups at 3 & 5
• Three iodo groups at 2,4,6 ( Tri iodo)
• Used as both Na & Meg salts

Salts can be varied to give the desired solubility & viscosity Side chains: modified to be more hydrophilic of lipophylic depending on type of radiography

Diatrizoate

• The Na+ dissociates to give 2 particles in solutn (Na+ & diatrizoate)
• Both are charged particles & contribute equally to the osmolarity

Hence osmolarity is doubled

Basic features of a good CM

• So far achieved with diatrizoate
• High iodine concentration
• Iodine in a stable bond which can be autoclaved & stored
• Water soluble
• Low viscosity
• Reduced chemotoxicity ( chemical induced)

Osmolarity near to body fluids

Diatrizoate toxicity

• Toxicity originate from iodine:Iodine itself is toxic
• Separation of iodine atoms reduces toxicity
• Masking of the iodine with side chains reduces toxicity
• Ionic effects
• If the osmolarity is reduced, these effects are also reduced
• Chemotoxic effects:
• Due to protein binding

Increased by non polar groups

Review ionic effects – Toxicity

• All CM discussed so far are salts
• Therefore all are IONIC
• Dissociate into 2 particles: doubles osmolarity
• One particle carries no iodine & is redundant
• Salts are very soluble in water
• Benzene ring is non polar & water insoluble
• Salts are needed to make CM water soluble

If CM is not a salt, another answer must be found to solve the solubility problem

Review ionic effects – Toxicity

• Main Disadvantage of ionic contrast media:
• Are Hypertonic at concentrations Used to get a good visualisation
• Hyperosmolar inject (often 1.4OsM) leads to:
• Loss of intracellular water
• RBC crenation
• Vascular damage
• Increased blood volume
• Vasodilation
• Considerable pain,heat sensation & swelling

Need to dev, a CM with osmolarity close B/fluids (0.3)

Triiodobenzoic Acid Derivatives

• Compounds derived from benzene

Benzene: toxic, water insoluble liquid

Triiodobenzoic Acid Derivatives

• Carbons on benzene ring numbered 1 to 6
• Acid group at position 1  benzoic acid

Acid group permits formation of salts or amides and influences water-solubility

Triiodobenzoic Acid Derivatives

• Substitution at positions 3 & 5  2,4,6-triiodobenzoic acid derivatives
• Groups at positions 3 & 5  reduce toxicity and lipophilia

Group at position 5 determines route of elimination

Triiodobenzoic Acid Derivatives

• Summary
• -COOH = salt or amide binding, water solubility
• -I = contrast-giving component
• -R1, -R2 = reduction of toxicity & lipophilia

-R2 = elimination pathway

(i) Monomeric ICM

• Oral Cholegraphic agents
• Iopodate
• Iobenzamic acid
• Iopronic acid
• Iopanoic acid
• Iocetamic
• Uro/angiographic agents
• Diatrizoic acid
• Iothalamic acid
• Iodamic acid
• Ioxithalamic

Ioglicic

(ii) Monomeric NICM

• Myelographic agents
• Metrizamide
• Uro/angiographic agents
• Iopamidol
• Iohexol
• Iopromide
• Iopentol
• Iomeprol

Ioxilan

New Advances

• CM did not dissociate in solution usual osmolarity would be halved
• This would require covalent/ molecular cpds
• Molecular cpds do not dissolve in water?
• The molecular cpd must have ENOUGH POLAR groups to ensure water solubility

Led to development of non ionic CM

Development of Non ionic CM

• Began modification of original classic formula
• Metrizamide ( sugar, OH groups)
• Iohexol ( many Polar groups)
• Iopromide (many polar groups)
• Very well tolerated
• Even better than expected osmolarity
• Aggregation of particles lowers osmolarity

Bad effects due to hyperosmolarity reduced

Toxic effects: NICM

• Iodine related toxic effects
• Separation of I atoms reduces toxicity
• Ionic effects: are reduced with low osmolarity
• Chemotoxicity:
• Protein binding reduces excretion via kidney
• Caused

Lipophylic gps on CM increase protein binding

Toxic effects: NICM

Some degree of lipophylicity is deliberately retained on a CM for radiography of the liver or bile ducts CM stays in the body for longer periods of time in the system longer

(iii) Dimeric ICM

• Cholegraphic agents
• Iodopamic
• Ioglycamic
• Iodoxamic
• Iotroxic
• Angiographic & myelographic agents
• Iocarmic acid

Ioxaglic

Ionic Dimers also Exist

• Ioxaglic acid : a mono acid dimmer
• HEXABRIX: Sodium & Meglumine salts in 1:2 ratio
• Osmolarity same as non ionic CMs
• Aggregates can be formed which lower osmolarity further
• Reactions similar to NICM

Hexabrix very successful CM bse of low osmalar solutions (LOCM)

(iv) Dimeric NICM

• Myelographic
• Iotrolan
• Uro/angiographic
• Iodecol

Iodixanol

Further development of NICM

Non Ionic Dimers

• To increase number of Iodine in one molecule
• Hence increase electron density
• Iotralan
• 2 benzene rings
• Very large molecule
• Ioxilan

Ioversal

Further development of NICM

• Optiray (ioversal)
• NICM with increased hydrophilicity
• More hydrophylic less likely to diffuse lipid bilayers of neural cells
• Less neuronotoxicity

Not fully evaluated

Disadvantages of NICM

• Expensive compared to ICM
• Some situations may prove better with ICM e.g. Hexabrix

Less interactions with fibrinolytics

Commonly used preparations

• Ionic contrast media : – monomers :
• Diatrizoate based

Urograffin (60,76)

Angiograffin(65)

• Unique ( JB chemicals )
• Trazograph ( 76,60,plus)
• May and Baker
• iothalamate based :

conray (280,420)

Commonly used preparations

• Non ionic monomers : most commonly used media
• Nycomed
• Omnipaque : iohexol
• Optiray : ioversol
• Ultravist : iopromide
• Lek-Pamidol : iopamidol

Iopamiro : iopamidol

Commonly used preparations

• Non ionic dimers :
• Isovist : iotrolan

Visipaque : iodixanol

Barium Sulphate CM

• An opaque white mixture
• Water soluble ionic salt ( Ba 2+ & SO4 2-)
• Doesn't dissolve
• Toxic- used only in Gastrointestinal Tract

Should not enter into cells, only in body cavities

Barium Complications Adverse reactions

• Barium NOT water soluble
• Not absorbed
• Perforation trauma i.e. BE
• Extravasation into abdominal cavity
• Can cause peritonitis

Surgery to remove

Diverticulitis and colitis cause inflammation and degradation of colon. Colon can rupture.

Vaginal rupture: misplacement of the catheter

TYPES OF IODINATED CONTRAST AGENTS:

Oil Based:

• Made from fatty acids found in plants and animals
• Insoluble in H2O
• Relatively viscous
• Pale yellow or amber in color
• Examples: dionisol, ethiodol, pantopaque
• Intratheacal (subaracnoid space during myelogram) NEVER I.V.
• Need to remove after procedure
• Used in procedures such as:

Lymphangiography, bronchography, sialography

Ultrasound & MRI CM

Gadolinium

Gadolinium based Contrast media

• Paramagnetic agent
• Decreases T1 relaxation times

Toxic in free state

Gadolinium-Based contrast

• Excretion
• Glomerular filtration 95%
• Hepatobiliary excretion 5%
• Slower excretion in renal failure

No nephrotoxicity at approved doses (up to 0.3 mmol/kg)

Gadolinium-Based contrast

• Pregnancy
• Category C; readily crosses placenta
• Breast-feeding
• Effect not known
• .011% excreted over 33 hours, .8% absorbed from oral dose

Stop for 48 hours

Ultrasound Contrast Agents

• IMAGENT: perflexane (stable gas) lipid microspheres
• Do not give to patients with cardiac shunts
• 14% reported AE (compare to 11% with saline): headache, nausea most common
• OPTISON: human albumin microspheres with octafluoropropane
• Contraindicated if hypersensitivity to blood products
• 17% reported AE: headache, nausea, flushing, dizziness
• Pregnancy category C

Few SAEs

Enteric contrast

• Barium sulfates
• Better, cheaper than water-soluble iodinated
• Mild reactions 1/100k, severe reactions 1/500k
• Complications:
• Exacerbation of pre-existing LBO
• Extravasation leads to extensive fibrosis
• Use iodinated if barium contraindicated:
• Bowel perforation, fistula, sinus tract
• Prior to bowel surgery

Check position of percutaneous bowel catheters

Enteric contrast

• HOCM: 1500 mOsm/kg for 300 mg I/ml

• LOCM: 300-600 mOsm/kg for 300 mg I/ml
• Aspiration risk: less pulmonary edema
• Infants, children potential bowel perforation
• Small bowel: better opacification, less dilution

Reactions: rare, same risks factors as IV

Iodinated Contrast Media

Iodised Oils

• Infrequently used in radiography
• Used where water-soluble agents are contraindicated
• or where a viscous compound is required
• lymphoscintigraphy
• sialography
• Not easily absorbed & in some circumstances, carry a
• risk of oil-embolus
• Formed from poppy seed oil & examples include

Lipiodol & Myodil

Adverse effects of CM

• Mild side effects:
• GIT disturbances: altered taste
• Respiratory: cough,Nasal stuffiness
• CNS: warmth heat ,Headache, dizzness, anxiety shaking
• Skin : itching, sweat , Rash

Anaphylactic reactions: eyes , face

Adverse effects of contrast media

• Moderate Side effects

Cardiovascular S/E:

• arrhythmias, hypotension, hypertension
• Respiratory:
• dysnea,bronchospasms, wheezing
• Hypersensitivity:

laryngeal edema, pronounced cutaneous reactions

Adverse effects of CM

• Severe Adverse effects
• Anaphylactoid reactions

Non Anaphylactoid

• Chemotoxic – organ specific reactions
• Nephrotoxicity
• Cardiotoxicity
• Neurotoxicity

vasovagal

Risk factors

• Age
• Allergies
• Anxiety
• Asthma
• Cardiac diseasea
• Debility
• Dehydration
• Diabetes
• Dialysis
• Gout
• Interleukein immotherapy
• Myeloma
• Pheocytochroma
• Previous contrst reaction

Sickell cell disease

Pharmaceutical aspects of CM

• Proper storage
• Observation of expiry dates
• Examination of solution before use
• Crystallization found in solution
• Solution with high viscosity
• Risk of bacterial contamination
• Resterilization

Transfer into sterile container

Preparation:

• Used in patients who have had a contrast reaction in the past.
• Patient is unlikely to have a reaction to a non-ionic contrast agent.

Medications: Corticosteroid…Prednisone

Antihistamine…Benedryl

and 50 mg Benedryl