Radiocontrast Agents, Radiopharmaceuticals, & Hazardous Drugs Lecture Notes PDF

Radiocontrast Agents, Radiopharmaceuticals, and Hazardous Drugs 1  Learning Objectives At the end of this lecture and the associated tutorial you should know and understand the nature, design, properties and use of: Contrast agents used in X-ray and magnet...

Radiocontrast Agents, Radiopharmaceuticals, and Hazardous Drugs 1  Learning Objectives At the end of this lecture and the associated tutorial you should know and understand the nature, design, properties and use of: Contrast agents used in X-ray and magnetic resonance imaging Radiopharmaceuticals (radioactive agents) used in diagnostic imaging and radiotherapy Hazardous drugs 2  Outline 1. X-Ray Imaging 2. Magnetic Resonance Imaging (MRI) 3. Isotopes and Radioactivity 4. Medical Uses of Radioisotopes 5. Hazardous Drugs 3 Energy increases Image from: https://image.shutterstock.com/z/stock-vector-the-electromagnetic-spectrum- vector-diagram-different-types-of-electromagnetic-radiation-by-their-154169990.jpg 4 1. X-Ray Imaging 5  Normal X-ray imaging is good for studying bones and joints, fractured bones, and bone cancer, but not good for imaging soft tissues Images from: https://www.cedars-sinai.edu/Patients/Programs-and-Services/Spine-Center/Conditions-and-Treatments/Diagnostic-Studies/Images/ 479337_NORMAL_cerv_X-ray.jpg http://motocrossactionmag.com/Uploads/Media/News/collar-bone-xray%20medium.jpg 6 http://www.pethealthnetwork.com/sites/default/files/articles/max-bone-cancer-fb.jpg Normal X-ray imaging is limited for detecting breast cancer until it is well established The breast image at left was produced by traditional mammography. The yellow arrow points to a just visible detected mass. The image at right is of the same breast but was produced by 3-D mammography, or tomosynthesis. The yellow arrow points to the same mass, which is more clearly outlined and visible Image from: http://barnesjewishblog.org/wp-content/uploads/2014/10/Tomosynthesis.jpg Commentary from: http://barnesjewishblog.org/3-d-mammograms-improve-breast-cancer-screening/ 7 X-ray contrast agents enhance images X-ray image of colon after administration of BaSO4 suspension enema 8 Image from: http://jhurads4anatomy.com/storage/ss1/docs/20090819025014647/XRAYbariumenema6536395LABELS.jpg X-ray contrast media X-ray image of small intestine after oral administration of BaSO4 suspension. Image shows signs of Crohn’s disease Image from: http://193.224.48.74/tiki-download_file.php?fileId=782&display 9 Some ionic iodinated X-ray contrast agents that improve clarity of image Diatrizoate Iodipamide Iothalamic acid (Iothalamate) 10 Some non-ionic iodinated X-ray contrast agents Iodixanol Iohexol 11 X-ray angiograms using an iodinated contrast agent Images from: https://www.researchgate.net/profile/Prem_Anandan/publication/276328344/figure/fig3/AS:294501861085191@1447226123167/ Fig-3-Coronary-angiogram-showing-proximal-LAD-lesion-with-thrombus.png http://www.garyboyarsky.com/STENT%20AFTER%202001.jpg 12 2. Magnetic Resonance Imaging (MRI) 13  Magnetic Resonance Some atomic nuclei (e.g. 1H, 13C) are magnetised. Their magnetic dipoles are normally randomly oriented. In a strong, externally applied magnetic field the dipoles align parallel to the direction of the magnetic field. If a radio waves are passed through the nuclei the nuclei absorb energy and begin to resonate and spin like tops around the lines of the magnetic field. The radiofrequency at which the nuclei resonate depends upon the intensity of the electric field immediately around them. When the incoming radio waves are turned off, the nuclei relax, their dipoles return to their original, random orientations, and the previously absorbed energy is released as radio waves which can be detected electronically. 14 Magnetic Resonance of a Hydrogen Nucleus Images from: https://chem.libretexts.org/@api/deki/files/5119/image004.png?revision=1 https://musculoskeletalkey.com/wp-content/uploads/2016/05/C1-FF1-2.gif 15  Nuclear Magnetic Resonance Image from: https://www.utu.fi/en/units/sci/units/chemistry/research/mcca/PublishingImages/Applied%20NMR%201w%20480.jpg 16 1H NMR Spectroscopy: Example 17 Image from: https://i.pinimg.com/originals/93/5c/9f/935c9f3755c96ac12637ae942f2406ea.png  18 Image from: http://www.compoundchem.com/wp-content/uploads/2015/02/Analytical-Chemistry-1-H-NMR-Chemical-Shifts.png Image from: http://www.compoundchem.com/wp-content/uploads/2015/04/Analytical-Chemistry-13-C-NMR-Chemical-Shifts.png 19 Magnetic Resonance Imaging (MRI) Image from: http://mgh-images.s3.amazonaws.com/9780077824976/11940-6-1ICS1.png 20  Some gadolinium contrast agents that enhance MRI images Gadoteric acid Gadodiamide 21 MRI Scanner Image from: https://mm.aiircdn.com/38/540949.jpg22 MRI scan of normal brain Image from: http://www.lone-parenting.org/wp-content/uploads/2010/03/mri.jpg 23  MRI scan of brain with a large tumour Image from: https://thumbs.dreamstime.com/z/ mri-brain-brain-tumor-right-parietal-lobe-48601963.jpg 24 MRI scans of normal and cancerous prostate glands 25 Image from: https://www.alta-klinik.com/images/stories/Prostate_MRI.jpg 3. Isotopes and Radioactivity 26 Image from: https://news.nationalgeographic.com/content/dam/news/photos/000/708/70884.ngsversion.1422284569563.adapt.1900.1.jpg 27  Atomic Structure Image from: https://www.google.com.au/imgres?imgurl=https%3A%2F%2Flh6.googleusercontent.com%2Fproxy%2FhzOOq_fZb5VrujDSm1Y95ccBCSg4pgkqk 8ezYYmxyY7ouNwCPsVv6zgxJtqAuplJ45mPf4UlXc1bYSJPbuuRkxMvpuQaJSXX4dj1ab8TUpFMdrj8kBEh2BBuPwnZSvoFkajfJiSh0fM%3Ds0- d&imgrefurl=https%3A%2F%2Fagilehope.blogspot.com%2F2015%2F06%2Fscales-and-emergent-properties.html&docid=Wu- z7T4wpOVy1M&tbnid=FNrx3h5wtoZM8M%3A&vet=10ahUKEwjh_Pi0yoXYAhWIiLwKHaC-AawQMwg-KAAwAA..i&w=600&h= 264&bih=963&biw=1920&q=atom%20nucleus%20proton%20quark%20-particles&ved=0ahUKEwjh_Pi0yoXYAhWIiLwKHaC-AawQMwg- KAAwAA&iact=mrc&uact=8#h=264&imgdii=FNrx3h5wtoZM8M:&vet=10ahUKEwjh_Pi0yoXYAhWIiLwKHaC-AawQMwg- 28 KAAwAA..i&w=600  Atomic Particles Image from: https://archive.cnx.org/resources/8e7c52f3905af0ddc7a7f0ba1d0877fdc0d4692f/CNX_Chem_21_02_Nuclearrxs.jpg 29 Image from: http://s2.studylib.net/store/data/017629944_1-a3e25eb7b2ee221e0ecbec431addad7e.png 30  Isotopes Isotopes are variations of chemical elements that have the same number of protons but different numbers of neutrons in their nuclei. We identify the different isotopes of an element based on their atomic masses (the sum of their protons and neutrons). Radioactive isotopes are unstable isotopes that ‘decay’ to more stable isotopes of the same or different elements. Such isotopes used in science, industry and medicine are mostly produced as products of nuclear reactions that take place in nuclear reactors and cyclotrons. Image from: http://2.bp.blogspot.com/-4UojXSoPQkA/VYJrHRO8BmI/AAAAAAAABcU/Su6Vg1J8qm8/s1600/ISOTOP.jpg 31 Image from: http://www.pacific-tec.sg/wp-content/uploads/2015/04/radiation-photo-3.jpg 32  Radionuclide decay Isotope A → Isotope B + {ionising radiation + energy} (parent) (daughter) Note: Sometimes Isotope B (the “daughter”) is in an excited, metastable state and releases its surplus energy as a gamma photon and settles into a less energetic, more stable state. Examples: 238 → 234 + 2He4 (alpha decay) 92U 90Th 6C 14 → 7N14 + (β-) (beta decay) a neutron has decayed to a proton and an electron, thus: 0n → 1p + 1e 1 1 0 33 Types of Radioactive Decay Image from: http://philschatz.com/chemistry-book/resources/CNX_Chem_21_03_RadioDecay.jpg 34  Collision of positron and electron A positron emitted from a radionuclide will collide with an electron in the same or a nearby atom. The two particles annihilate each other and the energy they contained (E=2mc2) is converted into two gamma photons (E=2hν) which travel in opposite directions. Image from: https://i0.wp.com/neupsykey.com/wp-content/uploads/2017/05/00495.jpg?w=960 35 Penetration by radiation Image from: https://explorecuriocity.org/Portals/2/ActionProjects/radn2/r&se2.jpg 36 Decay of Cobalt-60 37 Decay of 99Mo to 99Tc and 99Ru 38 Decay of Iodine-131 T1/2 = 8 days https://www.miraikan.jst.go.jp/sp/case311e/_/rsrc/1305617697498/home/docs/1105171618/20110517_02_01.JPG 39 Radioactive Decay Image from: http://oceanexplorer.noaa.gov/edu/learning/player/lesson15/images/curve.jpg 40  Radioactive decay curve t1/2 t1/2 t1/2 t1/2 Image from: https://apparentdip.files.wordpress.com/2014/05/screen-shot-2014-05-03-at-12-49-46-pm.png 41  Units of Radioactivity Old system: 1 Curie (Ci) = 3.7 x 1010 atoms decay or transform per second 1 millicurie (mCi) = 10-3 Ci 1 microcurie (μCi) = 10-6 Ci 1 nanocurie (nCi) = 10-9 Ci Newer (SI) system: 1 Becquerel (Bq) = 1 atom decays or transforms per second 1 Kilobecquerel (kBq) = 103 Bq 1 Megabecquerel (MBq) = 106 Bq 1 Gigabecquerel (GBq) = 109 Bq 37 GBq = 1 Ci 42  Equations for Radioactive Decay Number of undecomposed radioactive atoms in sample at time zero = N0 Number of undecomposed radioactive atoms in sample at time “t” = Nt: Nt = N0.e-λt Rate of decline in N at time “t”: dN/dt = - λ.Nt Half-life (t1/2) = time period for N to decline by 50% from its value at the beginning of the time period λ = the “decay constant” or “decomposition constant” λ = Loge(2) / t1/2 = 0.693 / t1/2 λ is expressed as time-1 (X s-1, hr-1, d-1, yr-1) 43  Radioactivity Equations based on Activity Activity of sample at time zero (t0) = A0 Activity (At) of sample at time t: At = A0.e-λt Rate of decline in Activity at time “t”: dA/dt = - λ.At Decay constant (λ) and half life (t1/2): t1/2 = Ln(2)/λ = 0.693/λ λ = Ln(2)/t1/2 = 0.693/t1/2 44 4. Medical uses of Radioisotopes 45  Diagnostic uses of some isotopes 46 Image from: http://www.ijcasereportsandimages.com/archive/2014/009-2014-ijcri/RA-10012-09-2014-maloth/table1.gif  Therapeutic uses of some isotopes Image from: http://www.ijcasereportsandimages.com/archive/2014/009-2014-ijcri/RA-10012-09-2014-maloth/table2.gif 47  Gamma-Ray Imaging and Diagnosis Approximately 90% of radiopharmacy is diagnostic and approximately 10% is therapeutic. In diagnostic procedures a dilute solution of a salt (or covalent compound) of a gamma-emitting or positron-emitting isotope is administered (usually by IV infusion) to the patient and the patient is scanned for the emitted gamma-rays. The detected gamma radiation is measured and the scan data are processed by computer to produce a 2D or 3D image of the tissues and organs where the isotope has penetrated and accumulated. 48  Gamma-Ray Imaging and Diagnosis The most common isotopes used for imaging are: 18F (t1/2 = 110 mins) (positron emitter; yields 2 gamma photons) administered as fluorodeoxyglucose 99Tc (t1/2 = 6 hrs) (gamma emitter) as Na+ 99mTcO4- (sodium pertechnetate) 123I (t1/2 = 13 hrs) (gamma emitter) (administered as NaI) 131I (t1/2 = 8 days) (gamma and beta emitter) (admin. as NaI) low dose: γ used for diagnosis high dose: β for tissue ablation 49 Positron Emission Tomography (PET) Scan Image from: https://www.hmrlondon.com/img/PET.jpg 50  PET Scan showing widely dispersed bone cancer Image from: http://jnm.snmjournals.org/content/46/1/52/F1.large.jpg 51 PET Scan of Lung Cancer Image from: http://snmmi.files.cms-plus.com/images/DiscoverMI/Lung.jpg 52 Radiation (e.g. beta particles) impacting a cell’s DNA or other vital structures may damage it sufficiently to kill the cell and/or it may cause a mutation that can lead to cancer later. Image from: https://c1.staticflickr.com/4/3620/3672832923_692c0ffd9a_b.jpg53 The SI unit for the amount of radiation absorbed by the body is the Gray (Gy). 1 Gy = 1 joule of energy absorbed in 1 kg of tissue The biological effect of the radiation differs from organ to organ, and is measured in Sieverts (Sv). 54 Image from: http://media.moddb.com/images/articles/1/226/225601/1024x768_news.jpg  Therapeutic uses of Radioisotopes In radiochemical therapy (e.g. using salts or organic compounds of 131I, 111In, 89Sr, or 90Y) the dose administered (usually by IV infusion) is designed to target and bind to (or accumulate in) diseased/cancerous tissues and cause sufficient cellular damage to kill all or most of the diseased cells (or destroy their ability to divide) while minimising damage and mutations in healthy cells there and elsewhere in the body. 55 5. Handling Hazardous Drugs 56  Hazardous Drugs - Definition The US National Institute for Occupational Safety and Health (NIOSH) define “hazardous drugs” as drugs that exhibit one or more of the following six characteristics in humans or animals: 1. Carcinogenicity [i.e. the ability to cause cancer] 2. Teratogenicity or other developmental toxicity [i.e. the ability to cause foetal malformation or defects in foetal development] 3. Reproductive toxicity [i.e. the ability to impair fertility or lactation] 4. Organ toxicity at low doses [i.e. causing adverse health effects at low doses in experimental animal models or treated patients] 5. Genotoxicity [i.e. the ability to cause a change or mutation (transmissible change) in genetic material (DNA) in spermatocytes or oocytes] 6. Structure and toxicity profiles of new drugs that mimic existing drugs determined hazardous by the above criteria 57  Hazardous Drugs - Examples Some examples of hazardous drugs are: Antineoplastic (anticancer) (cytotoxic) drugs: bleomycin, cisplatin, cyclophosphamide, doxorubicin, methotrexate Non-antineoplastic drugs: abacavir, azathioprine, oestradiol, thalidomide Drugs posing reproductive risks: clonazepam, fluconazole, oxytocin, testosterone, isotretinoin 58 Many non-radioactive drugs administered parenterally (and some administered orally or topically) are classified as “hazardous drugs” and require special handling and disposal: dedicated preparation facilities and equipment protective garb for healthcare personnel handling techniques administration procedures secure disposal methods methods for cleaning up spillages to prevent or minimise unwanted exposure of healthcare personnel, patients, and anyone else potentially affected. Images from: https://www.cleanroomsupplies.com/usp-800-compliance-assistance/ 59 Workstation for Hazardous Drugs 60 Image from: http://handlewithcarehazmeds.blogspot.com/2014/11/how-to-protect-yourself-from-accidental.html Cytotoxic drug safety cabinets are similar to those for aseptic compounding, but they draw air in past the operator and they purify and recycle most of the air Image from: https://www.creativeadvertisingblog.com/cytotoxic-laminar-flow-cabinet/ 61 Spills of hazardous drugs require special clean-up procedures and protective garb Images from: https://www.berner-safety.de/berner_spillkit_xp_to_remove_cytotoxic_accidents_en_455.html 62  Please read the following online guidelines on hazardous drugs Safe handling and waste management of hazardous drugs https://www.eviq.org.au/clinical-resources/administration-of-antineoplastic- drugs/188-safe-handling-and-waste-management-of-hazardou##minimising- exposure-to-hazardous-drugs Clinical procedure - hazardous drug spill management https://www.eviq.org.au/clinical-resources/administration-of-antineoplastic- drugs/919-hazardous-drug-spill-management 63  Summary (1) Contrast Agents: X-ray contrast agents are used to enhance the sensitivity and clarity of diagnostic x-ray imaging include: barium sulfate suspension administered orally or by enema a small range of iodinated and non-iodinated compounds injected into the bloodstream. MRI contrast agents are used to enhance the sensitivity and clarity of magnetic resonance imaging include a few organometallic gadolinium complexes injected into the bloodstream. 64  Summary (2) Radiopharmaceuticals: Radiopharmaceuticals are solutions of inorganic salts or organic compounds containing certain radioactive isotopes injected into patients where the isotopes accumulate in diseased tissues (typically cancerous tumours) and emit radiation that can be detected using suitable equipment placed close to the body and used diagnostically to detect and locate those tissues, or, at sufficient doses, the radiation emitted kills the cells in the diseased/cancerous tissues concerned. Radioactivity declines exponentially over time, and the rate of decay varies from isotope to isotope. 65  Summary (3) Radioisotopes used in medicine generally have relatively short half-lives. Radioisotopes commonly used in diagnosis include: 18F (fluorine-18) 99Tc (technicium-99) 123I (iodine-123) 131I (iodine-131) Radioisotopes commonly used in radiotherapy include: 131I (iodine-131) 111In (indium-111) 89Sr (strontium-89) 90Y (yttrium-90) 66  Summary (4) Hazardous Drugs: Many anti-cancer and other high-risk drugs administered parentally, orally or topically are classified as “hazardous drugs” and require special, safe preparation, handling and disposal procedures to minimise risks to healthcare personnel, patients, and others. 67