Radiopharmaceuticals and Radio Opaque Contrast Media: Practice, Prospects and Potentials.

 

Dibyajyoti Saha1*, Milan Hait2, Mayukh Jana3, Suprodip Mandal3 and Utpal Jana4

1School of Pharmacy, Chouksey Engineering College, Lal Khadan, Masturi Road, Bilaspur-  495004, C.G.

2Dept. of Chemistry, Dr.C.V. Raman University, Kargi Road, Kota, Bilaspur, C.G.

3Dept. of Pharmacy, Bharat Technology, Uluberia-711316, W.B.

4Dept. of Pharmacy, Annamalai University, Annamalai Nagar.

*Corresponding Author E-mail: saha.dibyajyoti@gmail.com

 

ABSTRACT:

The compounds or substance which emit radiation and which are used in medicine area called radiopharmaceuticals. Radio opaque substances are those compounds (both inorganic and organic) that have the property of casting a shadow on x-ray films. Radiopharmaceuticals preparations are the preparations containing one or more radionuclides. Radionuclides are radioactive and transform spontaneously into other nuclides. The unstable nuclei undergo spontaneous nuclear changes in order to achieve stability by emitting radiation are called radioisotopes or radionuclides. The radioactive substances disintegrates or decays with the emission of certain particles or certain quantities of energy which is always characteristics of the isotope.The present article gives various ideas about radiations, radioactivity, radioisotopes, radio opaque and contrast media, radioactive pollution as well as quality control and also pharmaceutical applications of radioisotopes.

 

KEYWORDS: Radiopharmaceuticals, Radio opaque, Contrast media, Radioisotopes.

 


INTRODUCTION:

Many heavy elements like uranium, thorium, radium and their compounds emit radiations spontaneously. These radiations can penetrate through solid material, can ionize gases, produce a glow on zinc sulphate paint or affect the photographic plates. The substance which emits such radiation is called as radioactivity. For therapeutic and diagniostic purposes they are referred as ‘Radiopharmaceuticals’. The radioactive isotopes continue to decay for a particular period of time. Half life is defined as the time in which the amount of radio nuclides decays to half of its initial value1.The X-rays  contrast media are the chemical compounds which have the ability to absorb x-rays and block the passages of X-rays. Thus, they are opaque to X-rays examination. All   radio opaque are not radiopharmaceutical unless they contain a radio isotope in their structure or formula2.

 

RADIOACTIVITY AND ITS UNITS:

Henry Beequerel (1896) first noted that elements like uranium, thorium etc. affected photographic plates, when placed nearby these elements.

This phenomenon was considered as a new form of activity and called radioactivity .The element like uranium, radium, cobalt phosphorous , iodine etc. are called radioactive elements. The activity of any radioactive material decreases with time. This is called as radioactive decays. Radiation dosimetry in simple terms means measurement of dose of radiation or radioactivity an object is exposed to or absorbs3.

 

v  Properties of Radioactivity or Radioactive decay particles3,4:

I. ALPHA Particles:

1. They affect photographic plates.

2. They produce fluorescence.

3. They have maximum ionizing power.

4. They have maximum penetrating power.

5.  They have equivalent to nuclei of helium atoms.

6. They are heavy and positively charged.

7. They are affected by strong magnetic field.

8. They possess discrete energies.

9.  Their penetration power is few cms in air and a fraction of millimeter in body tissues.

10. Their velocities are 3*107m/s.

11. They have max kinetic energy.

12. When emitted atomic mass decreases by 4 and atomic no by 2.

13. They are not used in the pharmaceutical preparations.

 

II. BETA Particles:

1. They affect photographic plates.

2. They produce fluorescence.

3. They have moderate ionising power.

4. They have moderate penetrating power.

5. They may be negatively and positively charged.

6. It has the same mass as an electron.

7. Their penetration power is few meters in air and about few cms  in body tissues.

8. Their velocities are 1.2 to 2.7*108 m/s.

9. They have max kinetic energy.

10. When emitted atomic no increases by 1.

11. Ionization power is less than alpha particles.

12. They have high penetration power.

13. They are affected by strong magnetic field.

14. They are used as pharmaceuticals preparations.

15. Its max energy is 1.5 Mev and the mean energy is 0.6 Mev.

 

III.GAMMA Particles:

1. They affect photographic plates.

2. They produce fluorescence.

3. They have maximum ionizing power.

4. They have maximum penetrating power.

5. They have and neutral charged.

6. They have electromagnetic waves.

7. Their velocities are 3*108m/s.

8. They have max kinetic energy.

9. No change in atomic mass or atomic no.

10. It travels with the speed of light.

11. Photons type behavior are present.

12. Not affected by electronic or magnetic field.

13. A very thick lead sheet is required to protect from these radiation.

 

 

v  Half life of Radioactive compounds:

Radioactive isotopes continue to decay for a particular period of time. Half life is defined in which the amount of radio nuclides decays to half of its initial value.

For e.g. Polonium-212: Half life 3-10 seconds.

Iodine-131; Half life 8 days.

Uranium-238: Half life 4.5-10 year.

Zinc-65: Half life 150 days.

Sodium-22: Half life 2-6 years.

 

v  Units:

·         Curie(c).

·         Millicurie(mc)

·         Microcurie(μc)

·         Roentgen(R)

·         Relative Biological Effectiveness(RBE)

·         Radiation Absorbed Dose(RAD)

·         Roentgen Equivalent Man(REM)

·         Exposure Rate Constant.

Pharmaceuticals dosage forms may be described in terms of RAD units5.

PREPARATION OF RADIO ISOTOPES IN LABORATORY:

The preparation of radio isotopes in a laboratory should include following special rooms6:

·         Dispensary

·         Counting Room

·         Hot Laboratory

·         Store

·         Annexe.

 

 

The various types of equipments are required to prepare radio isotopes. They are in the following6:

·         Beakers

·         Pipettes

·         Surgical Rubber Gloves

·         Trays

·         Long Forceps

·         Tissue Papers

·         Carriers ( for containers)

·         Waste Bin

·         Aseptic Screen.

 

 

MEASUREMENTS OF RADIOACTIVITY:

The measurement of radioactivity of a substances consist in the determination of the rate of emission of α, γ rays by it. These radiations are also known as ionizing radiation because they are capable of causing ionization, either directly or indirectly. The following instruments are used for measurement of radioactivity7, 8:

·         The Geiger-Muller Counter

·         Scintillation Counter

·         Ionization chamber

·         Proportional chamber

·         Auto radiography

·         Semiconductor detector

·         Photographic plate method

·         Bubble Chamber

·         Wilsons Cloud Chamber

·         Nuclear Emulsion

·         Film Badges

·         Electroscope

·         Cerenkov Detectors

·         Thermo­­-Luminescence Dosimeters

·         Track Etch Detectors.

 

 

BIOLOGICAL EFFECTS OF RADIATION:

Ionization and excitation of molecules in the body cause abnormal chemical reaction. The effect of abnormal chemical reactions depends on number of factors such as3, 9:

1.       The energy of the radiation.

2.       Dose rate of the radiation.

3.       The particular tissue and surface area exposed.

4.       The ability of the radiation to penetrate tissue.

5.       Time of the exposure.

 

The various biological effects are in the following:

1.       Skin Damages: Erythema, Brittleness, Dryness, Burns.

2.       Somatic Effects: Anemia, Leukemia, Cancer, Cataract.

3.       Genetic Effects: Chromosomes damage and increase the chance of gene manipulation.

4.       Direct radiation effects.

5.       Indirect radiation effects.

6.       Effect on Rate of cell divisions.

7.       Effect on human body:

·         Short term effects.

·         Long term effects.

 

STORAGE, HANDLING AND PRECAUIONS OF RADIOACTIVE MATERIALS:

A care should be taken to protect people and personnel from harmful radiation during handling and storage of radioactive materials emits. The following precautions are taken while working with radio detectors, radio assays, traces experiments, manufacturing or handling of radioactive materials1, 8:

1.  These materials should be handled with forceps or suitable instruments and direct contact should be avoided.

2.  Any substances which is taken internally (food, drinks, smokes etc.) should not be carried in laboratory where radioactive materials are used.

3.   Sufficient protective clothing or shielding must be used while handling the materials.

4.  Radioactive materials should be kept is suitable labeled containers, shield by lead bricks and preferably in remote corner.

5.  Areas where radioactive materials are used or stored should be monitored constantly (tested regularly for radioactivity).

6.     The final disposed of radioactive material should be done with great care to animals and environment.

 

QUALITY CONTROL OF RADIOPHARMACEUTICALS:

The numbers of chemicals are use in preparations of radiopharmaceuticals. A series of tests are carried out on these materials to ensure their quality so that dosage forms prepared should be of the safety and desired efficiency. The various important aspects are1, 4:

1.       Identification of radio nuclides.

2.       Radioactive content.

3.       Radio nuclidic purity.

4.       Radio chemical purity.

5.       Specific activity.

 

The various factors are in the following:

1.       Sterility.

2.       Pyrogenicity.

3.       Isotonicity.

4.       PH.

5.       Storage.

 

PHARMACEUTICALS APPLICATIONS OF RADIOISOTOPES:

The various pharmaceutical applications of radioisotopes are in the following2, 4,5,10:

I.        PATHWAYS :

1.       Therapeutic applications of isotopes:-

Ø  External sources as used in therapy:

a)       Teletherapy.

b)       Surface sources.

c)       Extracorporeal irradiation.

 

 

Ø  Internal Sources as used in therapy:

a)       Infusion.

b)       Interstitial implant.

c)       Selectively absorbed or concentrated,

d)       Locally injected radiopharmaceuticals.

e)       Intravenously or orally administered radiopharmaceuticals.

 

 

2.       Diagnostic application of radioisotopes:-

Ø  In vitro quantitative analysis:

a)       Radiometric analysis.

b)       Competitive radio assay or saturation analysis.

c)       Receptor assays.

d)       Activation analysis.

e)       Functional radio assay.

 

 

Ø  In vivo quantitative studies:

a)       Thyroid studies.

b)       Red blood cell volume and plasma volume.

c)       Red blood cell survival time.

d)       Shilling test.

 

 

Ø  Scanning techniques:

a)       Cardiovascular studies.

b)       Bone imaging.

c)       Renal studies.

d)       Lung imaging.

e)       Thyroid and Para thyroid imaging.

f)        Brain imaging.

g)       Liver, spleen and bone marrow imaging.

h)       Tumor localization.

 

 

3.       Radiation Sterilization:

It can be brought about either by electromagnetic radiations or by particulate radiations.

 

Table1.   Some inorganic commonly used Radiopharmaceuticals are in the following:

Products

Applications

Ammonium Bromide (Br-82), Injection

Extra cellular water measurement

Calcium chloride (Ca45/Ca47), Solution

Study of calcium metabolism disorders, bone cancer and other bone lesions

Chlormerodrin (Hg-197/Hg-203), Injection

Scintillation scans of kidneys, brain etc.

(Radio)-Cromated Serum Albumin (Cr-51), Injection

Plasma volume determinations, placental localization procedures

Chromic chloride (Cr-51), Injection

Study of protein loss from GIT and absorption

Colloidal Gold (Au-198), Injection

Scintillation scan of liver, study of reticuloendothelial systems (RES); treatment of disorder secondary to neoplastic (cancer) situations, especially in pleural and peritoneal cavities, etc.

Cyanocobalmin (Co-57, Co-58, Co-60), Capsules and Solutions

Co-57/58: Diagnosis of pernicious anemia

Co-60: Treatment of advanced stages of cancer involving cervix, vagina, uterus, bladder, mouth, tongue and lips etc.

Ferric Chloride/Citrate (Fe-59), Ferrous Citrate (Fe-59) solution and Injections

Study of iron metabolism and RBC formation

Indium Chloride in Chelate Form (In-113m), Injection

Brain and renal scans; and plasma volume measurement

Iodinated (I-125) Serum Albumin, Injection;

Iodinated (I-133) Serum Albumin, Injection

Determination of plasma volume, total blood volume,

Circulation time and cardiac output; localization of neoplasm of the brain

Potassium Chloride (K-42) Injection

Study of potassium ion (K+) exchange

Rubidium Chloride (Rb-86) Injection

Myocardial blood flow determination

Selenomethionine (Se-75)

Pancreas and parathyroid gland scans

Sodium Chloride (Na-24) Injection

Study of Na+ exchange

Sodium Fluoride (F-18)

Bone scanning and study of bone metabolism

Sodium Iodide (I-125), Solution Sodium Iodide (I-131), Capsules and Solutions

Thyroid scanning and study of thyroid uptake

Sodium Iodohippurate (I-131), Injection

Renal scanning and study of renal function

Sodium Phosphate (P-32) solution

Treatment of polycythemia vera (over production of RBC)

Sodium Rose Bengal (I-131) Injection

Liver scan, liver function test

Sodium Sulphate (S-35) Solution

Extracellular fluid volume determination

Sodium Pertechnetate (Tc-99m), Injection

Brain scanning, thyroid function tests

Technetium Sulphate (Tc-99m) Collodial Solution

Liver and spleen scans

Yb-169-DTPA (Diethylenetriaminopentacetate)

Brain scanning and determination of glomerlar filtration of glomerular filtration rate in kidneys.

 

 


RADIOACTIVE POLLUTION11:

Radioactive substances and nuclear radiations (i.e. α, β and γ- particles) produced during nuclear reactions affect our environment adversely and thus radioactive pollution is created.

Ø  Sources:

1.       Low level radioactive liquid wastes, radioactive gaseons wastes, dusts are released during during nuclear explosions.

2.       The radioactive substances produce energy which is so strong that the living cells are damaged or destroyed.

3.       People working with radioactive elements develop tumors.

4.       Radioactive elements affect our soil and through this human beings and animals are also affected.

5.       Nuclear explosions which are operated in sea make sea water polluted. This affects the aquatic life.

6.       The γ-radiation may be pass freely in human body, where they loss energy. Lastly, produces disease like leakaemania and cancer.

7.       U-235 is used as a nuclear fuel which may damage the health of human beings and animals.

 

Ø  Control:

Most of the nuclear wastes are being stored in strong leak proof containers. These will be disposed off whenever a safe method of their disposal is found out.

 

RADIO OPAQUE CONTRAST MEDIA:

Radio opaque contrast media are chemical compounds of elements of high atomic number. They hinder the passage of X- rays and used as diagnostic aid in radiology emits X-rays which can pass soft tissues of the body but are observed at hard tissues (bone). The ray produces a black spot on photographic plate by forming complex with silver bromide. Wherever these rays does not form a bright spot of the similar shape, as that of X-ray observing object is formed. Certain inorganic agents like iodine or barium salts can act as radio contrast media, by absorbing at soft tissues and these tissues becomes capable of absorbing X-rays. The barium sulphate salt is given to identify of ulcer in G.I.T. whenever ulcer is formed, broken mucosa retains barium sulphate and this spot (ulcer) is identified with the help of X-ray film. X-rays are electromagnetic radiations of short wavelength and have high penetrating power. The electrons of high atomic number element can interact with X-rays8, 9.

 

The relative difference between the light and dark areas on a radiographic image reflects is called radiographic contrast. Any agent or compound administrated to a patient to improve the visualization of an organ or tissue is called a contrast agent. They can be classified as negative or positive. An ideal contrast agent should have the following properties:

 

1.       Ready availability and low cost.

2.       Excellent X-ray absorption characteristics at the X-ray      energies used in diagnostic radiology.

3.       Minimum toxicity and ready patient acceptance.

4.       Chemical stability.

5.       High water solubility with low viscosity and no     significant osmotic effects.

6.       The ability to be administered for selective tissue uptake and excretion.

 

Barium sulphate is ideal contrast agent for oral and rectal studies of the GI tract. Contrast media are used in very large quantities and are usually administered over a short time. The majority of contrast agents used to opacity blood vessels and increase contrast in solid organs such as the liver are water soluble organic iodides12.

The various types of common contrast agents are in the following11:

1.       High-osmolality (1,400-2,938 mosm/kg) (“ionic”) agents;

Conray 60 (60% meglumine iothalamate), Hypaque 50 (50% sodium diatrizoate), Reno-M-60 (60%meglumine diatrizoate) etc.

2.       Low-osmolality (“nonionie”) agents (290 to 862mosm/kg);

Amipaque (metrizamide), Isoune (iopamidol) – Bracco Diagnostics, Xenetrix (iobitridol) etc.

3.       Miscellaneous infrequently used biliary contrast agents;

Teletrast, Telepaque (iopanoic acid); Cholebrine, Cholimil (iocetamic acid) etc.

4.       Oily and fat soluble contrast agents (water-Insoluble agents);

Dionosil (propyliodone), Lipiodol (iodinated poppy seed oil) etc.

5.       Gadolinium-based magnetic resonance imaging (MRI) agents;

Dotarem (gadoterate meglumine); Eouist (godoxeic acid); Gadouist (gadobutrol) etc.

 

The radiology procedures are in the following11:

1.       Plain film radiology:- Routine chest, abdomen, skeletal studies.

2.       Contrast Studies:-

·         Barium studies : Esophagram, Ugi examination, SBFT, BE and other specialized GI tract examinations.

·         Water insoluble contrast studies : Lymphangiography, bronehography, myelography.

·         Gallbladder studies : Abdominal ultrasound, oral cholecystography, intravenous cholagiography.

3.       Studies using water soluble contrast agents :-

Exeretory urography (IVP), Venography, Arteriography, Contrast-enhance CT and MRI, arthrography, myelography, hysterosalpingography.

4.       Cross section imaging studies.

5.       Ultrasound examinations.

6.       CT studies.

7.       MRI studies.

 

CONCLUSION:

Lastly, radiopharmaceuticals are more or less like pharmaceutical preparations (solutions, injections etc.) with all the usual controls for such preparations5. In radio opaque contrast media, barium sulphate and some bismuth compunds are useful for diagnostic purpose.

 

The field of radiopharmaceuticals is a rather new one for this country. The educational institutes should initiate various activities in the field so that more and more of the pharmacy students may take interest in this field. Competent persons who are solely devoted to this field should be engage for the teaching purposes10.

 

REFERENCES :

1.        Kasture A.V., Wadodkar S.G.; Pharmaceutical Inorganic Chemistry; Nirali Prakashan, Pune; 7th edition; 2006; pp 184-192.

2.        Chaudhary N.C., Gurbani N.K.; Pharmaceutical Chemistry- I; Vallabh Prakashan, Delhi; 2nd edition; 2004; pp 168-189.

3.        Siddique A.A., Wani S.M.; Inorganic Pharmaceutical Chemistry;Birla Publications Pvt. Ltd., Delhi; 3rd edition; 2009; pp 142-151.

4.        Tipnis H.P., Dhake A.S.; Inorganic Pharmaceutical Chemistry (Theory); Career Publications, nasik; 2nd edition ; 2008; pp 189-212.

5.        Chatwal G.R., Pharmaceutical Chemistry Inorganic; Himalaya Publishing House, Mumbai; 2nd Revised edition; 2004; pp 382-410.

6.        Nand P, Khar R.K.; A Textbook of Hospital and Clinical Pharmacy Theory and Practical; Birla Publications Pvt. Ltd., Delhi; 7th edition; 2010; pp 163-177.

7.        Agrawala S.K., Lal K.; Advanced Inorganic Chamistry; Pragati Prakashan, Meerut; 9th edition; 2009 pp 957-408.

8.        Bhandari A., Singh G.K.; Pharmaceutical Chemistry- I; CBS Publishers and Distributors, Delhi; 1st edition; 2004; pp 112-121.

9.        Ali M.; Textbook of Pharmaceutical chemistry- I(Inorganic); CBS Publishers and Distributors, delhi; 1st edition; 2003; pp 213-227.

10.     Rao G.D.; Inorganic Pharmaceutical Chemistry; Birla Publications Pvt. Ltd., Delhi; 4th edition; 2009; pp 136-141.

11.     Malik W.U., Tuli G.D.,Madan R.D.; Selected topics in Inorganic Chemistry; S. Chand and Company Ltd., Delhi; 1st edition; 1997; pp 635-657.

12.     Block J.H., Bwale J.M. Jr. (2004); textbook of Organic Medicinal and Pharmaceutical Chemistry by Wilson and Gisvold’s, Lippincott Williams and Wilkis Publication, 11th edition.

 

 

 

Received on 16.02.2011          Accepted on 25.03.2011        

© Asian Pharma Press All Right Reserved

Asian J. Res. Pharm. Sci. 1(1): Jan.-Mar. 2011; Page 04-08