Introduction to Pharmaceutics 30:721:301 PDF Fall 2024

Introduction to Pharmaceutics 30:721:301 B.B. Michniak-Kohn, Ph.D., Director, Center for Dermal Research CDR Professor of Pharmaceutics, Ernest Mario School of Pharmacy centerfordermalresearch.org & michniaklab.org Fall 2024 Radio...

Introduction to Pharmaceutics 30:721:301 B.B. Michniak-Kohn, Ph.D., Director, Center for Dermal Research CDR Professor of Pharmaceutics, Ernest Mario School of Pharmacy centerfordermalresearch.org & michniaklab.org Fall 2024 Radiopharmaceuticals & Radioactive Decay  Objectives of Lecture You should be able to understand radioactive decay & concept of half life You should know the equation for half life Know examples of radiopharmaceuticals & their uses in pharmacy practice Understand basic calculations for units and decay B. Michniak 3  Why are we studying this topic? Clinical relevance In both therapeutics as well as diagnostics Many hospital settings now use and often custom- make radionuclide preparations Pharmacists specialize in this area Imaging of patients and instrumentation designs are improving and expanding Future will include more opportunities in this niche area Something you may now know: All smoke detectors contain americium-241 in small amounts… B. Michniak 4  What is nuclear pharmacy? Nuclear pharmacy/medicine: is a pharmaceutical/medical specialty that uses radioactive materials to both diagnose the body and treat disease; documents organ function and structure; uses relatively small amounts of radioactive materials (radiopharmaceuticals) to diagnose and treat which are substances that are localized in specific organs, bones, or tissues. 5  Some history…. First radiopharmacy lab set up in Chicago in 1950s NIH set up a radiopharmacy in 1958 First monographs for USP radiopharmaceuticals prepared by Dr. Christian from Purdue University in 1950s Centralized nuclear hospital pharmacies set up in 1969 First MS degree in Radiopharmacy established at USC in 1968 Section on Nuclear Pharmacy established at APhA in 1975 B. Michniak 6 I. Radioactive decay and radiopharmaceuticals Materials: Ansel and Stoklosa 12th edition, Pharmaceutical Calculations,pp.311-319 Allen, Pharmaceutical Dosage Forms, 8th Ed, pp.570  Radiation Radiation: Energy in the form of particles or electromagnetic waves Ionizing Radiation: Radiation with sufficient energy to remove an electron from an atom or molecule.  Radioactivity The process by $- which unstable atoms spontaneously transform to new atoms* and in the process emit radiation. * The “new atom” may be the same atom in a lower energy state.  Natural Radioactivity in Your Body Nuclide Activity. Uranium 30 pCi (1.1 Bq) Thorium 3 pCi (0.11 Bq) Potassium 40 120 nCi (4.4 kBq) Radium 30 pCi (1.1 Bq) Carbon 14 0.4 µCi (15 kBq) Tritium 0.6 nCi (23 Bq) Polonium 1 nCi (37 Bq)  Alpha Decay Helium Nucleus – Very massive and doubly ionized Only a hazard via ingestion or inhalation of alpha emitter Not usually an external radiation hazard Stopped by paper and dead layer of skin Uranium, Thorium, Radon and radon daughters  Beta Decay Energetic electron – singly ionized External hazard to skin and eyes Internal hazard via ingestion or inhalation of beta emitter A 1 MeV beta can travel up to 12 feet in air and 1 cm in plastic Phosphorus, Tritium, Carbon, Sulfur  Gamma Decay X-rays and gamma rays are photons – no charge External radiation hazard to deep organs and tissues Internal hazard via ingestion or inhalation of gamma emitter Lead (high electron density) is good for shielding X and gamma rays Iodine 125 gamma rays (30 keV) can be easily stopped with 1/8 inch of lead  alpha particle He++ beta particle e- gamma ray photon x-ray e- paper plastic lead e- Neutron shielding material depends on the energy of the neutrons  Geiger Muller Counter Geiger counters are used to detect ionizing radiation, usually beta particles and gamma rays, but certain models can detect alpha particles. An inert gas-filled tube (usually helium, neon or argon with halogens added) briefly conducts electricity when a particle or photon of radiation makes the gas conductive. The tube amplifies this conduction by a cascade effect and outputs a current pulse, which is then often displayed by a needle or lamp and/or audible clicks. B. Michniak 15  Typical background is 0.03 mR/hr or 100 cpm GM pancake probe NaI probe Battery check Range selector  Background Radiation 360 millirem per year Sources of Average Radiation Dose to the U.S. Population Cosmic, 27 8% Internal, 39 Terrestrial, 28 Nuclear Medicine, 14 10% 8% 4% Medical x-rays, 39 11% Consumer Products, 10 3% Radon, 200 Other, 3 55% 0.8% In the United States, radiation absorbed dose, effective dose, and exposure are measured and stated in units called rad, rem, or roentgen (R).  Annual Dose from Background Radiation Total exposure Man-made sources Medical X-Rays Radon 55.0% 11 Other 1% Internal 11% Man-Made 18% Consumer Nuclear Products 3% Cosmic 8% Terrestrial 6% Medicine 4% Total US average dose equivalent = 360 mrem/year  Biological Effects Many groups exposed to ionizing radiation at high levels resulted in adverse effects. Somatic effects – Prompt - skin burns and cataracts – Delayed - cancer Genetic effects Teratogenetic effects  500+ rad X-Ray Burns 5,000+ rad P-32 - 6.5 rad/hr/uCi S-35 - 2.5 rad/hr/uCi  Cancer Radiation can damage cells through two methods; – Production of free radicals and – Direct damage to the DNA. Risk factor for radiation dose: – 4% increase in risk of dying of cancer for every 100 rem of dose. – Normal cancer risk is 20%. Radiological Hazards  Radiation Protection Basics Ø Time:minimize the time that you are in contact with radioactive material to reduce exposure Ø Distance:keep your distance. If you double the distance the exposure rate drops by factor of 4 Ø Shielding: Ø Lead, water, or concrete for gamma & X-ray Ø Thick plastic (lucite) for beta rays  External Radiation Inverse Square Law ØRadiation levels decrease as the inverse square of the distance (i.e. move back by a factor of two, radiation levels drop to one fourth) ØApplies to point sources (distance greater than 5 times the maximum source dimension) I 1 R 12 = I 2 R 22 where I = Intensity (exposure rate) at position 1 and 2 and R = distance from source for position 1 and 2 R2 I2 (mrem/hr) Source I1 (mrem/hr) R1 Position 2 Position 1  Radioisotopes “Isotopes”: these have identical chemistry but are atoms that have same nuclear charge and hence same atomic # but different mass Same # of protons but varying # of neutrons Radioisotopes are unstable & undergo radioactive transformations Also known as “radionuclides” A drug made with a radionuclide is a “radiopharmaceutical” Naturally occurring or artificially produced Radium was first one used in medicine Many now used and examples follow…. B. Michniak 25  Radiopharmaceuticals A radiopharmaceutical is a radioactive pharmaceutical agent used for diagnostic or therapeutic procedures These are regulated by the FDA as well as the Nuclear Regulatory Commission (NRC) May also be regulated by the State Board of Pharmacy B. Michniak 26  Examples of Radiopharmaceuticals Chromic Phosphate P 32 suspension Sodium Iodide I 123 solution Technetium Tc 99m Medronate Injection Urea C 14 capsules Water O 15 injection Xenon Xe 133 injection Methionine C 11 injection Thallous chloride TI 201 injection B. Michniak 27 Examples of radioisotope half lives 14C 5,700 years 198 Au 2.70 days 81mKr 13.1 secs (krypton) 75 Se 120 days (selenium) 57 Co 270 days (cobalt) B. Michniak 28  Rate of radioactive decay It is always a constant fraction of total # of undecomposed atoms present Rate of disintegration is: - dN / dt= l N where N is # of undecomposed atoms at time t, and l is the decay constant or the fraction disintegrating per unit of time B. Michniak 29  Rate of radioactive decay Constant units are reciprocal time (secs, mins, hrs). Equation may be integrated to give exponential decay law: N = N0 e-lt N0 is # atoms originally present when t=0 B. Michniak 30  Half life When t1/2 occurs when N = 1/2 N0 Then 1/2 N0 = N0-lt1/2 Solving the above equation: ln 1/2 = - lt1/2 (& ln a = 2.302 log a) [Ln is the same as loge] Hence t1/2 = 0.693 / l NEED TO KNOW THIS EQUATION FOR EXAM B. Michniak 31  Units of radioactivity Quantity of activity is expressed in absolute units (total # of atoms disintegrating per unit time) Basic scientific unit is the Curie-quantity of isotope in which 3.7 x 1010 (37 billion) atoms disintegrate per second. System International (S.I.) unit is the Becquerel (1 disintegration/sec) The USP has adopted the Becquerel as its main unit hence this is the BASIC UNIT for PHARMACISTS B. Michniak 32  Conversions : examples any conversion factors needed will be provided in exams 1 Ci = 3.7 x 1010 Bq 1 mCi = 37 MBq 1 Bq = 2.7 x 10 -11 Ci 1 MBq = 27µ Ci B. Michniak 33  Conversion Calculations Sodium Chromate Cr 51 injection is administered in a dose of 3.7 MBq for the determination of blood volume. Express this dose in terms of microcuries. B. Michniak 34  Answer Sodium Chromate Cr 51 injection is administered in a dose of 3.7 MBq for the determination of blood volume. Express this dose in terms of microcuries. 1 MBq = 0.027 mCi (conversion factor) 1 (MBq)/ 3.7 (MBq) = 0.027 (mCi)/ XX (mCi) hence XX = 0.1 mCi XX = 100 microCuries B. Michniak 35  Half life calculations The half life of 198Au is 2.70 days. Calculate its disintegration constant. T1/2 = 0.693/l (remember equation for exam) l = 0.693 / 2.70 = 0.2567 day-1 B. Michniak 36  Continued… The original quantity of a radioisotope is given as 500 microCuries (18.5 MBq)/ ml. If the quantity remaining after 16 days is 125 µCi (4.625 MBq) /ml, calculate a) the disintegration constant and b) the half life of the isotope. B. Michniak 37  Answer N = N0 e-lt and ln N / N0 = - lt l = 2.303/ 16 log 500/125 l =disintegration constant = 0.087 day-1 t1/2 = 0.693 /l = 8.0 days B. Michniak 38 B. Michniak 39 B. Michniak 40  Radioisotope Contrast Media These are chemical compounds containing elements of high atomic number which will stop passage of X rays Many contain barium or iodine Barium sulfate is agent of choice for imaging GI tract Its usefulness is that it is insoluble in acidic gastric juices Major side effect is constipation Usual oral dose of barium sulfate is 200-300 g. B. Michniak 41 Radiopharmaceuticals in USP The USP 27-NF 22 lists 70 official radioactive pharmaceuticals The commonly used examples will follow and include: Technetium-99m Strontium-89 Chloride (Metastron) Yttrium-90 Thallous-201 Chloride Gallium-67 citrate Indium-111 Chloride Sodium Iodide-123 Sodium Iodide-131 Samarium-153 B. Michniak 42  Sodium Iodide-123 (123I) Oral capsule and better than 131I in that it delivers lower radiation and better image quality Used to diagnose and evaluate thyroid function Emits only gamma rays Drugs can interfere with thyroid uptake of radionuclide: corticosteroids, benzodiazepines, vitamins, expectorants, antitussives and topicals which contain iodine All should be withheld prior to 123I use B. Michniak 43  Iodine 131 131Iodine: is produced in a reactor; is used in diagnostic procedures involving the thyroid and also for the treatment of thyroid disorders; can be administered in capsule or liquid solution form; requires special precautions to be implemented during administration. 44  Technetium-99m (99mTc) Possesses a relatively short half life of 6 hours Offers an abundance of gamma photons for imaging without the hazard of beta particles Can be used as a binding agent for several pharmaceuticals used for imaging Kits are available to prepare 99mTc compounds that assist in hepatobiliary imaging (mebrofenin) and ischemic heart disease (sestamibi-”Cardiolite”, tetrofosmin). Potential use to label monoclonal antibodies Inexpensive and easy to obtain B. Michniak 45  Technetium 99m 99mTclabeled radiopharmaceuticals are easily produced by simply adding 99mTcO4 to many choices of “cold kits”. 46  Technetium 99m In short, 99mTcO4 is added to a vial containing a chemical compound that binds to the radionuclide. The result is a radiopharmaceutical which will be taken up in the designated organ for imaging (or analysis) with a gamma camera. 47  Strontium-89 Chloride (89Sr) (Metastron) Sterile, non-pyrogenic aqueous solution for IV use & contains no preservatives Decays by beta emission, with half life of 51 days Beta emission is very harmful to skeletal tissue Used exclusively for bone scans (bone tumors, and metastatic lesions in bone) Acts like calcium analogues i.e. clears rapidly from blood stream & selectively localizes in bone mineral. Toxic- cannot give to patients with platelet counts below 60,000 & WBC counts below 2400. B. Michniak 48  Yttruim-90 (90Y) Trivalent radioactive metal, pure beta emitting radionuclide Half life 2.68 days Application is in radioimmunotherapy (RIT) of solid large tumors & lymphomas TheraSphere (patented 1998) are insoluble glass microspheres that are used for hepatocellular carcinoma The microspheres bond yttrium & target liver When injected these stay localized in the liver and minimize side effects of the radionuclide The 90Y decays to form stable zirconium-90. B. Michniak 49  Thallous-201 Chloride (201Tl) Sterile, non-pyrogenic solution for IV Half life of 73.1 hours The potassium analog undergoes rapid transport to the myocardium- useful for visualization of myocardial infarction or ischemic heart disease Often used with exercise stress testing and can differentiate between ischemic and infarcted heart tissues. B. Michniak 50  Gallium- 67 Citrate (67Ga) Sterile pyrogen free aqueous solution Drug behaves like the ferric ion and has half life of 78 hours Can localize in viable primary & metastatic tumors & in focal sites of infection Useful in Hodgkin’s disease, lymphomas & bronchogenic carcinoma Used for diagnosis and monitoring of “fever of undetermined origin” and for Pneumocystis carinii pneumonia of AIDS Disadvantage: considerable biological variation occurs in patients B. Michniak 51  Other Radionuclides The production of other radionuclides for nuclear medicine (e.g. PET) involves the use of a cyclotron. Medical Cyclotron Industrial cyclotron 53  Imaging Equipment Following administration of the radiopharmaceutical to the patient, a gamma camera is used to image the area of interest. 55  Gamma Cameras Gamma cameras are used to show how the radiopharmaceutical distributes itself throughout the body or is taken up by specifically targeted organs. 56 Gamma Cameras (cont) 57  Gamma Cameras (cont) In most cases, gamma cameras are interfaced with a computer which controls data acquisition, processing and image display. 58  Gamma Cameras (cont) Still and dynamic images can be acquired Tomographic Dynamic Static 59  SPECT Imaging Single Photon Emission Computed Tomography (SPECT) SPECT cameras looks at a patient from many different angles and is able to demonstrate very precise detail within the patient. Information is presented as a series of planes that correspond to certain depths within the body. The planes presented may be a series of coronal, sagittal, transverse and / or oblique slices. 60 SPECT Imaging (cont) 61  Positron Emission Tomography (PET) Since 1970s PET has been used to study cerebral physiology Imaging used for mapping regional blood flow & volume, oxygen metabolism, bone remodeling, tumor receptor density, reporter gene expression, etc. Extremely sensitive technique to image body chemistry Chemical changes often occur prior to anatomic changes in the body and can be detected by PET Radionuclides which undergo positron decay usually have very short half lives (examples later) B. Michniak 62  PET (cont.) PET was once conducted only in large medical centers since many radiopharmaceuticals have short half lives and could not be obtained from commercial sources PET cyclotrons are now adjacent to pharmacies Can be used in pharmacokinetic distribution evaluations and one can check if drug reaches a specific receptor site Longer lived radionuclides are being investigated as radiolabels for monoclonal antibody based PET Uses in cancer as well as cardiovascular disorders B. Michniak 63  PET Scanners Positron Emission Tomography (PET) is used to study physiologic and biochemical processes within the body Processes studied include blood flow, oxygen, glucose and fatty acid metabolism, amino acid transport, pH and neuroreceptor densities. An on-site cyclotron is required to produce the very short half life PET radiopharmaceuticals. 65 PET Scanners (cont) 66 Mobile PET Scanner 67  Personal Monitoring For any worker who usually works in a controlled area, and may receive a significant dose from occupational exposure, individual monitoring shall be undertaken where appropriate, adequate and feasible. [GSR Part 3 Requirement 25, 3.100] 68  Personal Monitoring (cont) Doses from External Radiation Thermoluminescent (TLD) or Optically Stimulated Luminescence (OSL) dosimeter q gamma, X and beta radiation Film dosimeter q gamma, X and beta radiation 69  Personal Monitoring (cont) Doses from External Radiation (cont) Electronic dosimeter, with or without alarm Film badge, electronic dosimeter, ring badge, TLD 70  Personal Monitoring (cont) Assessing Doses from Internal Radiation Urinalysis. Whole body monitor: q gamma emitting radioisotopes. Thyroid monitoring: q iodine radioisotopes. 71  Personal Monitoring (cont) Record Keeping Employers and licensees shall maintain exposure records for each monitored worker. Records are to be maintained as required by the Regulatory Body. Information is confidential and must be kept secure. Access to records shall be provided to: q the relevant worker; q relevant employer; q Regulatory Body; q health surveillance professionals 72  Reading Information Allen 8th edition Chapter 18, pp. 591 “Preparation of the Radiopharmaceutical” Chapter 18, pp. 593 “Quality Assurance” Chapter 18, pp. 593 “Dispensing of a Radiopharmaceutical” B. Michniak 73 Thank you!!!!