You are on page 1of 16

Faculty of Pharmacy & Drug Manufacturing

Pharos University

DIAGNOSTIC AGENTS
Used either to demonstrate Abnormalities in
structure or Impairment of functions of body organs.
The most widely used methods for non-invasive
imaging are:
(without exploratory surgery)

1. Scintigraphy (Nuclear medicine scanning)


2. Radiography
(X-ray and Computed Topography (CT)
3. Ultrasonography (US)
4. Magnetic Resonance imaging (MRI)
Diagnostic agents are important adjuncts to the 1st
three of these procedures.

Dr. Doaa Issa 1


Faculty of Pharmacy & Drug Manufacturing
Pharos University

Terminology
Radiographic Procedure Tissue (Organ) Visualized
1 Angiography Blood vessels
2 Cholecystography Gall bladder
3 Cholangiography Gall bladder and Bile ducts
4 Hepatography Liver
5 Urography Urinary tract
6 Bronchography Lungs
7 Lymphography Lymph nodes and vessels
8 Esophago graphy Esophagus
9 Histero salpin gography Uterus and fallopian tubes
Spinal cord & subarachiniod
10 Myelography
spaces

Characteristics of an Ideal Diagnostic


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

Dr. Doaa Issa 2


Faculty of Pharmacy & Drug Manufacturing
Pharos University

Classification of Diagnostic Agents


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
Agents used as X-
X-ray 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

Dr. Doaa Issa 3


Faculty of Pharmacy & Drug Manufacturing
Pharos University

I. Drugs Used As X-Ray Contrast Media


1. Agents Used To Outline the Gall Bladder
and Bile Ducts
A. Cholecystographic Agents
 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
1. lopanoic Acid (Telepaque) H2N

Superior opacification with low toxicity


I I
It should be taken 14 hrs
COOH
before X-ray examination
After a fat free meal H3C
2-(3-Amino-2,4,6-triiodobenzyl)butyric acid
C2H5
H
COOH
CHO
Perkin's Cond.
+ ( H5C2-CH2-CO)2 -O
NaOC2H5/ Xylene
-H2O NO2
NO2
α-Ethyl-m-nitrocinnamic acid
m-Nitrobenzaldehyde
Rreduction
Raney Ni

C2H5

COOH

ICl/ Acetic acid


Iopanoic acid

NH2

Dr. Doaa Issa 4


Faculty of Pharmacy & Drug Manufacturing
Pharos University

2. Locetamic Acid (Cholebrine)


I
H2N

I I
CH3 Normal cholecystogram
H3C N the contrast medium is seen
COOH
evenly filling the gallbladder
O

3-[Acetyl(3-amino-2,4,6-triiodophenyl)amino]-
2-methyl-propionic acid.

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)

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

Dr. Doaa Issa 5


Faculty of Pharmacy & Drug Manufacturing
Pharos University

B. Cholagiographic Agents
o They are moderately strong dibasic tri-iodobenzoic
acid 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.

lodipamide Meglumine (Cholografin Meg)


COOH COOH
I I I I
O O OH OH
HO
N N NH-CH3
(CH2 )4
H H I
I OH OH
2

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

Dr. Doaa Issa 6


Faculty of Pharmacy & Drug Manufacturing
Pharos University

 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.

2. Agents Used To Outline the GIT


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.

A barium enema clearly displays a colonic herniation


herniation

Dr. Doaa Issa 7


Faculty of Pharmacy & Drug Manufacturing
Pharos University

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

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)

i. Iothalamic Acid COOH


I I
Water soluble salts: O
H
lothalamic sodium injection (BP, USP) H3C N
N CH3
lothalamic meglumine injection (BP, USP) H
I O

5-Acetamido-2,4,6-triiodo-N-methyl-isophthalamic acid
These are used in:
Intravascular angiography
Aortography
Selective renal arteriography
Urography

Aortography Cerebral Angiography

Dr. Doaa Issa 8


Faculty of Pharmacy & Drug Manufacturing
Pharos University

COOH
ii. Diatrizoic Acid Gastrografin I I
O O

H3C N N CH3
H H
I
3,5-Diacetamido-2,4,6-triiodobenzoicacid

- It is used for angiocardiography, aortography and


urography
- 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)

Synthesis of Diatrizoic acid

COOH COOH COOH


COOH
Nitration SnCl2 I I
1) ICl / Acetic acid
2) Acetylation
O 2N NO 2 H N NH2 H 3 C-CO-HN NH-CO-CH3
2
I

Dr. Doaa Issa 9


Faculty of Pharmacy & Drug Manufacturing
Pharos University

Iothalamic Acid Diatrizoic Acid


COOH COOH
I I I I
O O O
H
N
H3C N CH3 H3C N N CH3
H H H
I O I

lopanoic Acid Locetamic Acid


I
I
H2N
H2N

I I
CH3 I I
CH3
H3C N H3C N
COOH COOH
O O

4. Agents Used to Outline Various Cavities


I- Myelographic Agents
They are both water and oil soluble contrast agents, used to
opacify the spinal cord and subarachinoid spaces.
Water soluble agent:
OH
H
i. lohexol (Omnipaque
) O N OH

I I
OH
H
 It provides improved image N OH
HO N
details with low risk of OH I O
toxicity. COCH3

5-[N-(2,3-Dihydroxypropylacetamido)]-
N,N'-bis(2,3-dihydroxypropyl)-2,4,6-triiodo-
benzene-1,3-dicarboxamide

Dr. Doaa Issa 10


Faculty of Pharmacy & Drug Manufacturing
Pharos University

Oily agents are::

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.

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.

Propyliodone (Dinosil)

Propyl 2-(3,5-diiodo-4-oxo-1,4-
dihydropyridin-1-yl)acetate

Dr. Doaa Issa 11


Faculty of Pharmacy & Drug Manufacturing
Pharos University

II. Agents used to test for organ functions

1. Agents Used to Test for Renal Functions

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.

i. Aminohippurate Injection (USP)


COOH
H
N
N-(4-Aminobenzoyl)glycine sodium saltH2 N
O
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)
Synthesis of Aminohippuric acid
CO -Cl CONHCH2COOH CONHCH2COOH

H2 NCH2COOH Reduction

Pyridine Zn/HCl

NO 2 NO 2 NH2

Dr. Doaa Issa 12


Faculty of Pharmacy & Drug Manufacturing
Pharos University

ii. lodohippurate Sodium CONHCH2COONa

I132
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
activities in the two kidneys are unequal

iii. Inulin
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. Mannitol (BP and USP) OH OH

HO
It is obtained commercially by OH

OH OH
the catalytic reduction of glucose.
It is used to as diagnostic agent for kidney function and also
as osmotic diuretic.

Dr. Doaa Issa 13


Faculty of Pharmacy & Drug Manufacturing
Pharos University

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.

2. Agents Used to Test for Liver Functions


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.
Br
i. Sulfobromophthalein Sodium Br
O

Disodium salt of phenol tetrabromophthalein- O SO3 Na

3,3’-disulfonate Br
Br OH
It is the best agent used to test for
liver function. SO3 Na
HO
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.

Dr. Doaa Issa 14


Faculty of Pharmacy & Drug Manufacturing
Pharos University

Synthesis of Sulfobromophthalein Sodium


Br
O O
Br
Fusion
O + O
Br
Br O O Br O
Br
O SO3 Na Br
O OH
Br Br
1. Sulphonation
Br OH Drug O
2. Na salt formation
Br
Br OH
SO3 Na
HO

Assay of Sulfobromophthalein OH

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.

3. 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.
Hypoacidity Pernicious Anemia
Cancer
Hyperacidity Gastric ulcer
Deudenal ulcer
Betazole Hydrochloride (Histalog)
3-(2-Aminoethyl)-1H-pyrazole
NH2 NH2
Isosteric with histamine
N
The drug is administered either N
2 HCl
I.M or S.C. for chemical testing N
N
H
of low gastric secretion as it H

increases HCl secretion. Betazole Histamine

Dr. Doaa Issa 15


Faculty of Pharmacy & Drug Manufacturing
Pharos University

ORGAN
IMAGING
2,4,6-TRIIODO
PH.ALKANOIC

CHOLECYSTO CHOLANGIO ANGIO/URO MYELO BRONCHO


GRAPHY GRAPHY GRAPHY GRAPHY GRAPHY

DIMER 3,5-SUBS
BENZOIC

LOCETAMIC IOTHALAMIC PROPYL


IODIPAMIDE IOHEXOL IODONE
ACID ACID

IOPANOIC DIATRIZOIC
LIPOIDOL
ACID ACID

ORGAN
FUNCTIONING
RENAL LIVER STOMACH

AMINOHIPPURATE SULFO.Br.PHTHALEINE BETAZOLE

IODOHIPPURATE OSMOTIC-
TUBULAR
DIAGNOSTIC
CAPACITY
INULIN

MANNITOL GLOMERULAR
MALFUNCT FILTERATION
ION

Dr. Doaa Issa 16