Chapter 9 & 10 Antioxidants and Autoxidation & Diagnostic Agents

Chapter 9:
Antioxidants and Autoxidation

Introduction
• Cells are made up of molecules which consists of
one or more atoms of one or more elements joined
together by chemical bond.
• When weak bond splits, it leaves unpaired
electrons, which is called free radical.
• Examples:
– Superoxide anion radicals(O2•–),
– Nitric Oxide Radicals(•NO),
– Singlet Oxygen(o–) and
– Hydrogen Peroxide (H2O2)
Tadesse B. (PhD) MedChem I 2
Introduction…
• These free radicals are formed as a normal
products of aerobic metabolism in a cell.
• But when produced at higher level under
different pathophysiological condition,
– These highly unstable and reactive free radicals capable
of damaging macromolecules of the cells due to
oxidative stress
• Oxidative stress is an imbalance of free radicals and
antioxidants in the body.
– To protect against harmful effects of these free
radicals, the cells have protective molecules called
antioxidant.
Oxidation and Reduction
Oxidation Reduction
• Addition of oxygen • Addition of hydrogen
• Removal of hydrogen • Removal of oxygen
• Loss of electron • Gain of electron

Autoxidation
• Autoxidation:
– Spontaneous oxidation of compounds by direct
combination with oxygen (as in air) at ordinary
temperatures.
• The rancidity of fats & oils is caused by autoxidation
– It is a condition in which aerial oxidation of unsaturated
fat present in food gives it an unpleasant flavour and
odor.
– Rancidity makes food undesirable for consumption.
– When unsaturated fats are exposed to air, it converts
into hydroperoxide
• Antioxidant is used to prevent oxidation and rancidity
Antioxidant
• An antioxidant is an agent that is added to
pharmaceutical preparation to prevent oxidation
and subsequent spoilage of drugs.
• It is a molecule capable of inhibiting the
oxidation of other molecules.
• Oxidation reactions can form free radicals and
these start chain reactions that damage cells
• Antioxidants terminate these chain reactions by
removing free radical intermediates & inhibit
other oxidation reactions
Ideal Requirements of Antioxidants
• It should:
– Prevent oxidation of product
– Effective in low concentration
– Stable
– Non-toxic and non-irritant
– Not cause allergic reaction
– Not affect color, odor and taste of preparation
– Be compatible with ingredients, container and closure
– Physiologically inert
– Be cheap and easily available

Mechanism of Antioxidant
• Antioxidants can decrease the oxidative damage;
– Directly via reacting with free radicals
– Indirectly by inhibiting the activity or expression of
free radical generating enzymes or enhancing the
activity or expression of intracellular antioxidant
enzymes

Classification of Antioxidant
Organic Antioxidant Inorganic Antioxidant
• They have antimicrobial • They act as reducing agents
property • They prevent oxidation and
• They can prevent spoilage get oxidized themselves
of products a) Sulfur dioxide
a) Tocopherols (Vitamin E) b) Nitrogen
b) Phenols c) Hypophosphoric acid
c) Parabens d) Sodium meta bisulfate
d) Gallic acid e) Sodium thiosulfate

Inorganic Antioxidant

Sulfur dioxide
• Molecular formula: SO2 Uses
• Molecular weight: 64.066 g/mol  It is used as antioxidant
• Prepared by burning of sulfur in  It is used as stabilizer in
air. soft drink
Physical property
 It has been used in
 It is colorless, non inflammable refrigerator
gas
 Has pungent odor  Used in fermentation
 Its aqueous solution is acid to  Used in treatments of
litmus. tonsillitis with glycerin
 miscible with water
 Stored in strong metallic cylinder
 Incompatible with oxidizing
agent

Nitrogen
• Molecular formula: N2 Uses
• Molecular weight:  It is used as antioxidant for
14.0067 g/mol. preservation of liquid
Physical property dosage form
 It is colorless  It is used to replace air
 non inflammable gas containers for parenteral
and solutions for topical
 Inert gas application
 miscible with water  It has been used to retard
 Stored in black painted oxidation in qualitative test
airtight cylinder for carbon monoxide

Hypophosphoric acid
• Molecular formula: H₃PO₂
• Molecular weight: 66 a.m.u
Physical property
 It is colorless or slightly yellow liquid
 Odorless
 Syrupy, become solid at 17.6 °C and melts at 26.5 °C
 Miscible with water, alcohol and ether
 Monobasic reducing agents
Pharmaceutical uses
 It was used as brain and nerve tonic
 It is used as antioxidant in pharmaceutical
preparations

Sodium Meta Bisulfate
• Molecular formula: Pharmaceutical uses
Na2S2O5  It is used in injection as
• Molecular weight: antioxidant to prevent
190.107 g/mol oxidation of phenol.
Physical property  It is used as antioxidant
 It is colorless or yellowish to preservation of food
crystal materials.
 Has odour of SO2  It has been used topically
 Has acid saline taste in treatment of
dermatological
 Freely soluble with water problems.
and slightly soluble alcohol
Sodium Thiosulfate
• Molecular formula: Uses
Na₂S₂O₃·5H₂O.
• Antioxidant
• Molecular weight:
158.11 g/mol • Antidote for cyanide
Physical property poisoning
 It is colorless, transparent – It converts cyanide to
crystal thiocyanate
 Soluble with water, insoluble • Treatment for iodine
in alcohol toxicity
 Stored in tightly closed light • In skin disorder
resistant container
 Incompatible with oxidizing
• Laboratory agent
agent

Organic Antioxidant

Vitamin E (Tocopherols)
• Have a chromane ring (Tocol) system, with an isoprenoid side
chain
– Four tocopherols identified
• Are methyl substituted tocol derivatives
– , ,  &  tocopherol
» -tocopherol is 5,7,8-trimethyl tocol
» -tocopherol is 5,8-dimethyl tocol
» -tocopherol is 7,8-dimethyl tocol
» -tocopherol is 8-methyl tocol

Vitamin E (Tocopherols) cont.
• Stored in adipose tissue
• The most powerful natural antioxidant
• Protect RBC from hemolysis
• Acts as an antimutagen & slows progression
of Alzheimer’s disease

Structure-Activity Relationship of Vitamin E
• In terms of biological activity
– >>>
• In terms of antioxidant activity
–  >  > > 
• Esters of tocopherols (acetate, propionate, butyrate)
– More active than the parent vitamin
• Ethers of tocopherols are inactive
• Activity decreases on
– Oxidation of tocopherols to respective quinons
– Replacement of methyl groups with ethyl
– Reduction in size of the alkyl side chain or introduction of
double bonds in the side chain
• Introduction of a 3,4-double bond
– Reduces activity by 2/3
19
Tadesse B. (PhD) MedChem I
Chapter 10: Diagnostic Agents

Contents
• Introduction
• Classification
• Radiopharmaceuticals
• Radiological Contrast Media

Introduction
What is diagnosis?
• Diagnosis is the process of identifying of an illness or
disorder in a patient through physical examination,
medical tests, or other procedures
What is diagnostic agents?
• Diagnostic agents are compounds used in diagnosis to
detect impaired function of the body organ and to
recognize abnormalities in tissue structure
• Diagnostic agents are chemical or substances used to detect
abnormalities in tissue and organs or to test on organ
function.
• Do not have medicinal & pharmacological effects
– X-ray film used for radiography
– Radio opaque
– Some of used in organ visualization
Introduction…
• Radioactivity is the radioactive decay (radiation)
of some elements like radium, polonium etc.
– Alpha, Beta, gamma and X-rays are types of
radiation
• Radiation technology or radiography
– It is an important tool for diagnosis as well as in
therapy (mainly for cancer therapy and radio
immunoassay)

Introduction…
1) Angiography-Blood vessels
2) Arthrography-Joints
3) Bronchography-Lungs (diagnosis of alveolar disease)
4) Cholangiography-Gall bladder and bile duct
5) Hepatography- Radiography of the Liver
6) Lymphography-Lymph nodes & vessels
7) Myelography-Brain & spinal cord
8) Pyelography-Kidney and ureter
9) Splenohepatography-Liver & spleen
10) Urography-Urinary tract

Classification of diagnostic agents
• 1) Radiopharmaceuticals
• 2) Radio opaque/contrast for radiography
• 3)Compounds for testing functional capacity

1) Radiopharmaceuticals (Radio isotopes)
• Radioactive compounds
• Used for diagnosis & therapeutics treatment of human
diseases
• Given by various routes (mouth, injection, eye, bladder) in
small amounts
• Dosage can variate depend on type of test
• Given under direct supervision of a specialist doctor
• Unit: Curie, becquerels
– One becquerel is defined as the activity of a quantity of
radioactive material in which one nucleus decays per second
– The curie (symbol Ci) is a non-SI unit of radioactivity
originally defined in 1910 (1 Ci = 3.7×1010 decays per second)

Radiopharmaceuticals…
Ideal Properties:
• Easy availability
• Short effective half life
• Particle emission is adequate
• High target to non-target activity ratio
• No pharmacological effect
• Sterile & pyrogen free

Radiopharmaceuticals…
Examples of Radiopharmaceuticals (For Diagnostic purpose)
1. Biliary tract blockage: Tc99m disofenin
2. Blood volume studies: Sodium chromate Cr51
3. Blood vessel disease: Sodium pertechnetate Tc99m
4. Bone diseases: Sodium Fluoride F18
5. Bone marrow disease: Cr51, Tc99m sulfur colloid
6. Brain disease & tumors: Indium Iu111
7. Cancer tumor: Gallium citrate Ga67, Sodium Fluoride F18
8. Heart disease: Ammonia N13, Rubidium Rb82, Thallus
chloride Tl201
9. Kidney disease: Iodohippurate sodium I125, Tc99m
10. Liver disease: Ammonia N13, Tc99m, Albumin colloid
11. Lung disease: Krypton Kr81m, Xe133
Tc: Technetium; Tl: Thallium
2) Radiological Contrast Media
(Radio Opaque Agents)
• Having property of opacifying X-ray radiations
• Any substance which, when administered to a
patient, improves the visualization of an
organ or tissue is called a contrast media.
• Either inorganic as well as organic

Radiological Contrast Media…
A) Positive Contrast Media:
• Having ability to absorb X-rays (e.g. Radioopaques)
Subdivided in to:
i. Heavy Metals & their salts (Inorganic)
ii. Iodized oils
iii. Iodinated organic compounds (Organic)
a) water soluble contrast media
b) water insoluble contrast media
B) Negative contrast media:
• Transparent to X-rays
• Renders the structure of a tissue more
translucent
– E.g. Air, Oxygen, Nitrogen etc.
• Usually not used for diagnostic purpose
• Iodine compounds are usually more useful

Characteristics:
• Adequate radioopacity which require iodine content
50% or more
• High water solubility (40% and above)
• Low viscosity, no osmotic effect
• Ability to administered & excretion
• Chemical stability
• Minimum toxicity & patient acceptance
• Readily available & low cost
Positive Contrast Media…
A) Heavy metals and salts:
• High atomic number and radioopaque. It includes:
i) Barium Sulphate (BaSO4)
• Low systematic toxicity
• Low water solubility
• Lack of osmotic activity
• Used for examination of GIT
• Used as suspension or thick cream
• Orally or through rectal route
• Sodium citrate is added to stabilize preparation
• Sorbitol added to enhance function

Positive Contrast Media…
ii) Metallic salt
• Tantalum oxide for Bronchography & esophagography)
• Calcium tungstate & Barium titanate for stomach, small
intestine, esophagus)
iii) Ferrites(Fe2O3):
• About 80% opacity than that of BaSO4
• Contain Zn, Cu, Mn, Ni and Mg
• Used for Bronchi, stomach & small intestine studies

• Positive Contrast Media…
B) Iodized oils:
• Preparation: Iodination of vegetable oils with
hydroiodic acid give iodized oils
• Iodinated fatty acid derivatives
• Yellow to amber colored oils
• Decompose on exposure to light and air
• Upon administration liberate inorganic iodine in body
which appear in urine
• Used in Hepatography, Lymphography &
Hepatospleenography

c) Organic Iodine Compound:
• Most widely used
• Tetraiodo phenolphthalein was first agent
• Amount of iodine is important for opacity
Sub-classification:
a) Water soluble contrast media
b) Water insoluble contrast media

c) Organic Iodine Compound…
Classification (Based on chemical features)
a. Triiodobenzoate-metrizoate h. Dimeric triiodoisophthalamates-
b. Triiodoisophthalamates-Iothalamic Iosefamic acid
acid i. Other dimers & polymers-Iozomic
c. Triiodophenyl alkanoates-Ipodates acid
d. Triiodophenoxy alkanoates- j. Diiodophenyl alkanoates-
Iopronic acid Iodoalphionic acid
e. Triiodobenzamide-Metrizamide k. Diiodopyridones-Propylidone
f. Triiodo anilides-Iocetamic acid l. Iodophthaleins-Iodophthalein
g. Dimeric triiodobenzoates- m. Miscellaneous-Iodohippurate
Iodipamide sodium

Organic Iodine Compound…
a) Water soluble contrast media:
• E.g. Diatrizoate sodium
– Diatrizoate meglumine
– Sodium iothalamate
– Metrizoic acid
– Iodipamide
– Ipodate sodium
– Iodohippurate sodium
• Mainly used for Urography & Angiography
• Administered by retrograde method (i.e.by mechanical means)
• Mild toxicity

a) Water soluble contrast media:
1. Diatrizoate sodium:
• Sodium salt of substituted
triiodobenzoic acid
• Iodine content : about 62%
• Used for Angiography &
Urography
• Also available as meglumine salt
– Meglumine is a sugar alcohol
derived from glucose that contains
an amino group modification.

• Synthesis of Diatrizoate sodium

2. Sodium Iothalamate:
• Structural isomer of diatrizoic acid
• One actamide (CH3CONH-) group replaced by methyl carbamoyl
(-CONHCH3) group
• Available as meglumine salt
• Used in Angiography
• Chemical Name: sodium 3-acetamido-2,4,6-triiodo-5-
(methylcarbamoyl)benzoate

• Synthesis of sodium Iothalamate

• 3) Ipodate sodium
• Ipodate sodium (sodium iopodate) is an iodine-containing radiopaque
contrast media used for X-rays.
• The drug is given orally & the resulting contrast allows for easy resolution
of the bile duct and gall bladder
• 4) Iodipamide:
• Adipiodone (or iodipamide) is a pharmaceutical drug used as a radiocontrast

agent in X-ray imaging
• 5) Iodohippurate sodium:
• ortho-Iodohippuric acid (ortho-iodohippurate, OIH) is an analog of p-
aminohippuric acid for the determination of effective renal plasma flow
44
Tadesse B. (PhD) MedChem I
• Organic Iodine Compound…
b) Water insoluble contrast media
• E.g. Iopanoic acid
– Propyliodone
– Iophendylate
– Iocetamic acid
– Iodoxamide
• Very slightly water soluble
• Mainly used for Cholecystography, Bronchography
and Myelography
• Patient should not drink or eat before 6 hrs.

• b) Water insoluble contrast media…

3) Diagnostic Chemicals
a) For kidney function:
• p-aminohippuric acid, Inulin, Phenolsulphophthalein
• para-aminohippuric acid (PAH), a derivative
of hippuric acid, is a diagnostic agent useful in medical
tests involving the kidney used in the measurement
of renal plasma flow
• Using inulin to measure kidney function is the
"gold standard" for comparison with other
means of estimating glomerular filtration rate
• Phenolsulphophthalein test to estimate the overall

blood flow through the kidney in 1911 & it was the first
test of kidney function and was used for almost a
century but is now obsolete.
Diagnostic Chemicals…
b) For liver function:
• Rose Bengal, Sulphobromophthalein sodium

c) For Gastric Function:
• Histamine phosphate, Pentagastrin, Xylose
• Pentagastrin is a synthetic polypeptide that has
effects like gastrin when given parenterally.
• It stimulates the secretion of gastric acid,
pepsin, and intrinsic factor, and has been used
as a diagnostic aid as the pentagastrin-
stimulated calcitonin test.
• Histamine phosphate is indicated as a diagnostic aid

for the evaluation of gastric acid secretory
function
• A xylose test is most often used to help diagnose

malabsorption disorders, conditions that affect your
ability to digest and absorb nutrients from food
d) For cardiac function:
• Evans blue dye
• Evans blue dye (EBD) is a commonly used marker for measuring

plasma volume and also for the study of microvascular leakage in
animal models

e) Miscellaneous:
i) Fluorescein sodium
• Fluorescein is a diagnostic contrast agent
particularly used in various ophthalmic
procedures, such as checking for any
corneal or vessel abnormalities
ii) Congo red
• In histology and microscopy, Congo red is used for staining in amyloidosis,

and for the cell walls of plants and fungi, and for the outer membrane of
Gram-negative bacteria.
• Apple-green birefringence of Congo red stained preparations under polarized
light is indicative of the presence of amyloid fibrils

Diagnostic Drugs
a) Phentolamine & Tyramine:
pheochromocytoma
b) Dexamethazone: Endocrine gland
dysfunction
c) Mannitol: Renal function
d) L-arginine: growth hormone secretion


Chapter 9 & 10 Antioxidants and Autoxidation & Diagnostic Agents

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Chapter 9:

Antioxidants and Autoxidation

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• Adipiodone (or iodipamide) is a pharmaceutical drug used as a radiocontrast

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• Phenolsulphophthalein test to estimate the overall

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• Histamine phosphate is indicated as a diagnostic aid

• A xylose test is most often used to help diagnose

• Evans blue dye (EBD) is a commonly used marker for measuring

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ii) Congo red

• In histology and microscopy, Congo red is used for staining in amyloidosis,

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