Diagnostic Agents

Faculty of Pharmacy & Drug Manufacturing

Pharos University

Dr.Dr.Dr.Dr. Doaa IssaDoaa IssaDoaa IssaDoaa Issa

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Used either to demonstrate AbnormalitiesAbnormalitiesAbnormalitiesAbnormalities in structure or Impairment of functionsImpairment of functionsImpairment of functionsImpairment of functions of body organs.

The most widely used methods for non-invasive imaging are:

(without exploratory surgery)

1. ScintigraphyScintigraphyScintigraphyScintigraphy (Nuclear medicine scanning)

2. RadiographyRadiographyRadiographyRadiography

(X-ray and Computed Topography (CT)

3. UltrasonographyUltrasonographyUltrasonographyUltrasonography (US)

4. Magnetic Resonance imagingMagnetic Resonance imagingMagnetic Resonance imagingMagnetic Resonance imaging (MRI)

Diagnostic agents are important adjuncts to the 1st three of these procedures.

DIAGNOSTIC AGENTSDIAGNOSTIC AGENTSDIAGNOSTIC AGENTSDIAGNOSTIC AGENTS


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TerminologyTerminologyTerminologyTerminology

Uterus and fallopian tubesHistero salpin gography9

Spinal cord & subarachiniod

spacesMyelography10

EsophagusEsophago graphy8

Lymph nodes and vesselsLymphography7

LungsBronchography6

Urinary tractUrography5

LiverHepatography4

Gall bladder and Bile ductsCholangiography3

Gall bladderCholecystography2

Blood vesselsAngiography1

Tissue (Organ) VisualizedRadiographic Procedure

Characteristics of an Ideal Diagnostic Characteristics of an Ideal Diagnostic Characteristics of an Ideal Diagnostic Characteristics of an Ideal Diagnostic

Agent:Agent:Agent:Agent:

1. It should have maximum opacity to X-ray

2. Chemically stable

3. Highly water soluble (for Urographic and Angiographic agents which are used as sodium or

meglumine salts for I.V. administration)

4. Minimum osmotic effect

5. Low toxicity

6. Low viscosity

7. Selective tissue uptake


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I. Agents used as X-ray contrast media

II. Agents used to test for organ functions

III. Agents used to determine blood volume

IV. Agents used for miscellaneous diagnostic tests

Classification of Diagnostic AgentsClassification of Diagnostic AgentsClassification of Diagnostic AgentsClassification of Diagnostic Agents

Classification of Classification of Classification of Classification of Agents used as XAgents used as XAgents used as XAgents used as X----ray contrast mediaray contrast mediaray contrast mediaray contrast media

1. Agents Used To Outline the Gall Bladder and Bile Ducts

2. Agents Used To Outline the GIT

3. Agents Used For Angiography and I.V. Urography

4. Agents Used to Outline Various Cavities

I- Myelographic Agents

II- Bronchographic Agents


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� All cholecystographic agents are analogs

of 2,4,6-triiodophenylalkanoic acids.

� They have enough hydro- and lipophilicity

to allow intestinal absorption and hepatic excretion.

The Oral Contrast Agents

� Once in circulation, they bind to serum albumin

� In the liver, converted into water soluble glucuronide conjugate

� Excreted in the bile and stored in the gall bladder

I. Drugs Used As X-Ray Contrast Media1.Agents Used To Outline the Gall Bladder

and Bile Ducts

A. A. A. A. CholecystographicCholecystographicCholecystographicCholecystographic AgentsAgentsAgentsAgents

1. 1. 1. 1. lopanoiclopanoiclopanoiclopanoic AcidAcidAcidAcid (Telepaque)

Superior opacification with low toxicity

It should be taken 14 hrs

before X-ray examination

After a fat free meal

I

H2N

I

I

H3C

COOH

2-(3-Amino-2,4,6-triiodobenzyl)butyric acid

CHO

NO2

+ H5C2-CH2-CO)2 -O(

Perkin's Cond.

NaOC2H5/Xylene

-H2O

m-Nitrobenzaldehyde

NO2

COOHH

C2H5

α-Ethyl-m-nitrocinnamic acid

Rreduction

Raney Ni

NH2

COOH

C2H5

Iopanoic acidICl/ Acetic acid


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2. 2. 2. 2. LocetamicLocetamicLocetamicLocetamic AcidAcidAcidAcid (Cholebrine)

I

H2N

I

I

H3C N

O

COOH

CH3

After a fatty meal,

the gallbladder has contracted.

the fundus and the neck of the gallbladder and cystic duct

is filled with contrast medium

and the common bile duct (arrows)

3-[Acetyl(3-amino-2,4,6-triiodophenyl)amino]-

2-methyl-propionic acid.

Normal cholecystogram

the contrast medium is seen

evenly filling the gallbladder

N.B:

Agents that lack substituents at the 5-position

of the benzene ring generally bind strongly to serum albumin

and are cleared through the liver

whereas agents containing a substituent in the 5-position

lack such binding and are generally excreted by the kidneys


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o They are moderately strong dibasic tri-iodobenzoicacid dimers linked by a polymethylene chain of variable length.

o They are water soluble and completely

ionized at the physiological pH.

o They are usually administered as meglumine salts

to reduce adverse reactions.

B. B. B. B. CholagiographicCholagiographicCholagiographicCholagiographic AgentsAgentsAgentsAgents

lodipamidelodipamidelodipamidelodipamide MeglumineMeglumineMeglumineMeglumine (Cholografin Meg)

HH

HO

OH

OH

NH-CH3

OH

OH

2

N

I

COOH

I

I

(CH2)4

I

I

COOH

I

N

O O

3,3’-(Adipoyldiimino)-bis-(2,4,6-triiodobenzoic acid) meglumine salt

(Meglumine is N-methylglucamine)

image showing the biliary tree and the main pancreatic duct


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� It is administered I.V. as either the sodium or the

meglumine salts when the oral drugs give

unsatisfactory results.

� The drug will appear in the bile after 15 min. and

the biliary ducts will appear within 25 min. Maximum

filling and opacification will take place within 2-2.5

hours.

� The drug is highly bound to plasma proteins so it may

produce hepato-toxicity and jaundice like symptoms.

Barium Sulfate (BaSO4) (Barium Meal)

� It is administered orally in the form of suspension

� It is used for:

� Detecting abnormalities of the

esophagus and the stomach.

� Examination of the colon

(given rectally as enema)

� The particle size of BaSO4

should be very fine otherwise any

lumps will give false diagnosis of

Non existing abnormalities.

2. Agents Used To Outline the GIT

A barium enema clearly displays a colonic colonic colonic colonic herniatioherniatioherniatioherniationnnn


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The use of radiographic agents for

visualization of urinary tract and blood vessels

is based on:

The rapid renal excretion of water soluble iodinated benzoic

acid salts

(NO protein binding due to substitution at position 5)

3. Agents Used For Angiography and I.V. Urography

i. i. i. i. IothalamicIothalamicIothalamicIothalamic AcidAcidAcidAcid

Water soluble salts:

lothalamic sodium injection (BP, USP)

lothalamic meglumine injection (BP, USP)

H

H

COOH

I

I

NN

O

CH3H3C

I

O

These are used in:

Intravascular angiography

Aortography

Selective renal arteriography

Urography

5-Acetamido-2,4,6-triiodo-N-methyl-isophthalamic acid

Cerebral AngiographyAortography


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ii. ii. ii. ii. DiatrizoicDiatrizoicDiatrizoicDiatrizoic Acid Acid Acid Acid Gastrografin

3,5-Diacetamido-2,4,6-triiodobenzoicacid

- It is used for angiocardiography, aortography andurography

- Gastrografin is a mixture of diatrizoate meglumine

(66%) and diatrizoate sodium (10%) solution, may be

used as an alternative to barium sulfate for

radiographic examination of the GIT ( in allergic patient -

Barium might leak into the abdominal cavity) (oral or rectal

administration)

H

COOH

I

I

NNH3C

I

CH3

O O

H

COOH COOH

O2N NO

2

COOH

NH2 NH

2

Nitration

COOH

II

I

NH-CO-CH3

ICl / Acetic acid

H3C-CO-HN

SnCl2 1)

2)Acetylation

Synthesis of Synthesis of Synthesis of Synthesis of DiatrizoicDiatrizoicDiatrizoicDiatrizoic acidacidacidacid


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H

H

COOH

I

I

NN

O

CH3H3C

I

O H

COOH

I

I

NNH3C

I

CH3

O O

H

I

H2N

I

I

H3C N

O

COOH

CH3I

H2N

I

I

H3C N

O

COOH

CH3

IothalamicIothalamicIothalamicIothalamic AcidAcidAcidAcid DiatrizoicDiatrizoicDiatrizoicDiatrizoic AcidAcidAcidAcid

LocetamicLocetamicLocetamicLocetamic AcidAcidAcidAcidlopanoiclopanoiclopanoiclopanoic AcidAcidAcidAcid

They are both water and oil soluble contrast agents, used to

opacify the spinal cord and subarachinoid spaces.

Water solubleWater solubleWater solubleWater soluble agent:

i. lohexol (Omnipaque) H

HN

IOH

I

NHO

OH O

OH

COCH3

I

NO

OH

OH

4. Agents Used to Outline Various Cavities

I- Myelographic Agents

5-[N-(2,3-Dihydroxypropylacetamido)]-

N,N'-bis(2,3-dihydroxypropyl)-2,4,6-triiodo-

benzene-1,3-dicarboxamide

� It provides improved image

details with low risk of toxicity.


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ii. Lipoidol (Ethiodized Oil) (Ethiodol)

(Iodized Oil Injection)

It is an Iodine addition product of vegetable oils:

ethyl ester of

fatty acids of poppy seed oil. It contains 35-42%

of organically combined Iodine.

Oily agents Oily agents Oily agents Oily agents are::::

II- Bronchographic Agents

After intra-tracheal administration, the preparation

coats the bronchial tree and the alveolar spaces

and are excreted from lungs by coughing or

absorption.

Irritation is the major drawback; sometimes

general anesthesia is required for administration

and therefore their use is now limited.

PropyliodonePropyliodonePropyliodonePropyliodone ((((DinosilDinosilDinosilDinosil)

Propyl 2-(3,5-diiodo-4-oxo-1,4-

dihydropyridin-1-yl)acetate


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The rate of excretion of some drugs in the urine has been

proposed to be a Measure Of The Functional Capacity of

the kidneys.

After administration of the drug, urine samples are

collected and analyzed for the drug content. For example,

Glomerular Filtration Rate can be measured by the renal

plasma clearance of mannitol and creatinine.

II.II.II.II. Agents used to test for organ functionsAgents used to test for organ functionsAgents used to test for organ functionsAgents used to test for organ functions

1. Agents Used to Test for Renal Functions1. Agents Used to Test for Renal Functions1. Agents Used to Test for Renal Functions1. Agents Used to Test for Renal Functions

i. i. i. i. AminohippurateAminohippurateAminohippurateAminohippurate Injection Injection Injection Injection (USP)

N-(4-Aminobenzoyl)glycine sodium salt

It is used as sodium salt in the form of

injection with pH range of 7.0 -7.2 for the

Determination Of

Tubular Functional Capacity (TFC)

H

H2N

O

N

COOH

Pyridine Zn/HCl

ReductionH2NCH2COOH

CONHCH2COOH

NH2NO2

CONHCH2COOHCO-Cl

NO2

Synthesis of Synthesis of Synthesis of Synthesis of AminohippuricAminohippuricAminohippuricAminohippuric acidacidacidacid


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ii. ii. ii. ii. lodohippuratelodohippuratelodohippuratelodohippurate SodiumSodiumSodiumSodium

N-(2-lodobenzoyl)glycine sodium salt

Performance of kidneys can be

determined by injecting a radioactive

compound which can be quickly and exclusively excreted

by kidneys

Renal malfunction can be indicated when the measured measured

activitiesactivities in the two kidneys are unequal

132I

CONHCH2COONa

iii. iii. iii. iii. InulinInulinInulinInulin

It is present in the form of 10% inulin and 0.8% NaCI injection

It is used to evaluate the glomerular filtration

rate (GFR) because it is filtered by the glomeruli,

excreted unchanged and not reabsorbed by

the tubules.

iv. iv. iv. iv. MannitolMannitolMannitolMannitol (BP and USP)(BP and USP)(BP and USP)(BP and USP)

It is obtained commercially by

the catalytic reduction of glucose.

It is used to as diagnostic agent for kidney function and also

as osmotic diuretic.

OH

OH

OH

OH

OHHO


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Assay of Mannitol (5 or 10%) and NaCl (0.3%) Injection

* Mannitol is treated with a known excess of KIO4 in

the presence of H2SO4 where it will be oxidized into

HCHO and HCOOH.

C6H14O6+ KIO4 + H2SO4 HCHO + HCOOH + HIO3 + 8 H2O

* unconsumed KIO4 and HIO3 / Kl

equivalent amount of I2

titrated with Na2S2O3

* NaCl is determined by applying Volhard's method.

They are drugs that are administered I.V. to test

for liver function.

These drugs are excreted mainly through the liver.

The rate of clearance of these substances from the plasma

is the measure of the excretory capacity of the liver.

2. Agents Used to Test for Liver Functions2. Agents Used to Test for Liver Functions2. Agents Used to Test for Liver Functions2. Agents Used to Test for Liver Functions

O

Br

Br

Br

O

SO3Na

OH

SO3NaHO

Br

i. i. i. i. SulfobromophthaleinSulfobromophthaleinSulfobromophthaleinSulfobromophthalein SodiumSodiumSodiumSodiumDisodium salt of phenol tetrabromophthalein-

3,3’-disulfonate

It is the best agent used to test for

liver function.

It is administered IV…. 30 min after,

blood sample ….. The dye content in the alkalinized

serum is measured. Normal liver can remove most of the

amount of the injected dye within 30 min.


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+O

O

O

O

O

O

Br

Br

Br

Br

O

OBr

Br

Br

Br

OH

OH

OH

Fusion

Drug1.Sulphonation

2.Na salt formation

O

Br

Br

Br

O

SO3Na

OH

SO3NaHO

Br

Synthesis of Synthesis of Synthesis of Synthesis of SulfobromophthaleinSulfobromophthaleinSulfobromophthaleinSulfobromophthalein SodiumSodiumSodiumSodium

Assay of Assay of Assay of Assay of SulfobromophthaleinSulfobromophthaleinSulfobromophthaleinSulfobromophthalein

Oxygen flask method for either Br or S contents.

USP method: Spectrophotometrically;

The sample is dissolved in H2O, alkalinized with

Na2CO3 then the formed color is measured at 580 nm.

Hypoacidity Pernicious Anemia

Cancer

3. Agents Used to Test for Gastric Functions3. Agents Used to Test for Gastric Functions3. Agents Used to Test for Gastric Functions3. Agents Used to Test for Gastric Functions

In some cases it may be indicated to test whether

the stomach can efficiently secrete HCl or not.

Hyperacidity Gastric ulcer

Deudenal ulcer

BetazoleBetazoleBetazoleBetazole Hydrochloride Hydrochloride Hydrochloride Hydrochloride (Histalog)

Isosteric with histamine

The drug is administered either

I.M or S.C. for chemical testing

of low gastric secretion as it

increases HCl secretion.

H

2 HCl

NN

NH2

HN

N

NH2

HistamineBetazole

3-(2-Aminoethyl)-1H-pyrazole


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ORGAN

IMAGING

CHOLECYSTO

GRAPHY

CHOLANGIO

GRAPHY

ANGIO/URO

GRAPHY

MYELO

GRAPHY

LOCETAMIC

ACID

IOPANOIC

ACID

IODIPAMIDEIOTHALAMIC

ACID

DIATRIZOIC

ACID

IOHEXOL

LIPOIDOL

2,4,6-TRIIODO

PH.ALKANOIC

3,5-SUBS

BENZOIC

BRONCHO

GRAPHY

PROPYL

IODONE

DIMER

ORGAN

FUNCTIONING

RENAL LIVER STOMACH

AMINOHIPPURATE

IODOHIPPURATE

INULIN

MANNITOL

SULFO.Br.PHTHALEINE BETAZOLE

MALFUNCT

ION

GLOMERULAR

FILTERATION

TUBULAR

CAPACITY

OSMOTIC-

DIAGNOSTIC

Diagnostic Agents

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