Drug Criteria & Outcomes
Medications Used in Radiological Emergencies
By Lydell Collier, PharmD Candidate, Harrison School of Pharmacy, Auburn (AL) University
Richard Cramer, PharmD, Drug Information Coordinator, Huntsville (AL) Hospital
Since Sept. 11, 2001, terror has become a common word in the American vocabulary. A recent addition are the words "dirty bomb." A dirty bomb is a conventional explosive mechanism that contains radioactive material in a radiological dispersal device. Dirty bombs are more likely to spread radionuclides in a localized area, and the identity of the radionuclides is unpredictable. The elements that compose a dirty bomb could be products stolen or obtained from nuclear power plants, defense facilities, nuclear pharmacies, medical facilities, and industrial facilities using radionuclides. Most experts in emergency planning believe that a dirty bomb is more likely to be a weapon of choice if the United States is attacked by terrorists.
The FDA has approved potassium iodide tablets, insoluble Prussian Blue, Ca-DTPA, and Zn-DTPA to protect the body or enhance the elimination of radioactive or nonradioactive material from the human body. All of these drugs are part of the national pharmaceutical stockpile of drugs. This article will examine these four drugs as well as other medications that could be used in the case of a radiological emergency.
Potassium Iodide (KI)
Iodine, which can be made radioactive and used in a dirty bomb, is important in the body’s synthesis of thyroid hormones, and its deficiency in the normal diet is a cause of hypothyroidism. The body is not able to tell the difference between the radioactive and nonradioactive forms of this element. Thus, when presented with a radioactive form of iodine, the body may convert it to iodide and use it to synthesize thyroid hormones, which will be radioactive. The radioactive hormones will be distributed, metabolized, and excreted in the same manner as the nonradioactive hormones, but will deliver a radiation dose to tissues while it remains in the body.
Thyroid uptake of iodide is an active transport process. Once the gland is saturated, any excess iodine will be rapidly excreted. Therefore, by providing the body with sufficient nonradioactive iodide immediately before or at the time of ingestion of any radioactive iodine, the thyroid’s absorption of the radioiodine will be prevented or minimized, thus protecting the body from the radioactive form of iodide.
KI tablets are relatively inexpensive and available in strengths of 65 and 130 mg. Recommendations for dosing of KI tablets can be found in Table. KI should be taken as soon the patient has been exposed to the radioactive iodine and still may have some protective effect even if it is taken three to four hours after exposure. Because the radioactive iodine will be present in the initial blast and decays quickly, a single dose of KI usually is all that is required. The only FDA-approved forms of KI for radiation emergencies include: IOSAT, ThyroShield, and Thyrosafe. Contraindications for emergency use of KI include iodine allergy, dermatitis herpetiformis, and hypocomplementemic vasculitis. Gastrointestinal symptoms, skin rash, confusion, numbness, and eosinophilia represent the majority of adverse effects reported from KI use.
Prussian Blue (Radiogardase-Cs)
The FDA approved insoluble Prussian Blue, also known as ferric ferrocyanide, as an agent to delay the absorption of cesium-137 (Cs-137) and thallium (Tl) from the gastrointestinal tract. Cs-137 is produced during fission reactions and is a likely component of a dirty bomb. Thallium causes gastrointestinal, neurological, and ocular toxicity in both its stable and radioactive forms. Thallium is absorbed through the skin, and nonradioactive salts have been used as depilatory drugs or as insecticides and rodenticides.
Soluble salts of cesium and thallium are absorbed from the gastrointestinal tract and enter the enterohepatic circulation, prolonging their presence in the body. They are distributed consistently throughout body tissues. Cs-137 has a half-life of 30 years and will produce a continual radiation dose to all body tissues.
Insoluble Prussian Blue is not absorbed when it is taken orally, and about 99% is excreted in the feces. If it is administered immediately after the ingestion of cesium or thallium, Prussian Blue combines with the radiated metal ion to form an insoluble compound that is excreted in the feces, reducing the absorption of these compounds into the body. Continued administration greatly reduces reabsorption of cesium or thallium from the enterohepatic pathway.
Prussian Blue is given in 500 mg capsules that can be swallowed whole; patients who cannot swallow pills can break the capsules and mix the contents in food or liquid. Breaking open the capsules will cause the patients’ mouths and teeth to be blue during the time of treatment, and patients should be warned that their feces also will have a blue color. Adverse effects reported with the use of Prussian Blue include mild constipation, gastric distress, and hypokalemia.
The dose of Prussian Blue depends on the person’s age and the amount of contamination in the body. The appropriate daily dose of Prussian Blue should be based on the suspected level of internal contamination (e.g., low: 3 g daily; intermediate: 3-10 g daily; high: 10-20 g daily). The drug is usually given three times a day for a minimum of 30 days. Recommendations for thallium are similar to those for Cs-137, but an initial loading dose of 3 g should be administered.
The FDA has approved two chelating agents, pentetate calcium trisodium (Ca-DTPA) and pentetate zinc trisodium (Zn-DTPA), for treatment of internal contamination with plutonium, americium, or curium to increase the rate of elimination of these agents from the body. All forms of these elements are radioactive and could be present in a dirty bomb, especially plutonium and americium. Both calcium and zinc in the DTPA is exchanged with the transuranium element, and the transuranium-DTPA complex is stable and excreted in the urine. Neither drug is effective for uranium or neptunium exposure.
Both chelating agents can be delivered through continuous intravenous (IV), but they cannot be used simultaneously. Each administration IV dose of Ca- or Zn-DTPA should be 1 g for adults or 14 mg/kg for children, and doses should not be fractionated. An inhaled version can be prepared for those whose lungs have been contaminated by radioactive material. The route of administration may be either slow intravenous push of the drug over a period of three to four minutes, intravenous infusion (1 g in 100-250 mL D5W, Ringers Lactate, or normal saline), or inhalation in a nebulizer (1:1 dilution with water or saline). Ca-DTPA is more effective than Zn-DTPA, but it is more likely to result in the chelation of other essential metals, such as zinc, magnesium, and manganese, and cause depletion of these minerals.
Therefore, Ca-DTPA should be administered for the first 24 hours as soon as possible after the ingestion or inhalation of the radioactive elements, followed by Zn-DTPA. The chelating effects of these compounds are similar after the first 24 hours. Therapy may continue for a few days up to several months or longer, depending on the type and extent of exposure and results of excretion testing. These drugs should not be taken by patients who have kidney disease or bone marrow complications.
Ca-DTPA should be used cautiously in patients with hemochromatosis, as deaths have been reported in patients receiving up to four times the recommended dose. Adverse effects include headaches, lightheadedness, chest pain, metallic taste in the mouth, nausea, diarrhea, injection site reactions, and itching. Cough and wheezing have been reported in patients receiving the inhalation route.
Monitoring for both drugs include baseline blood and urine samples, CDC with differential, BUN, serum electrolytes and chemistries, and blood and urine radioassays. Serum zinc and CBC should be monitored more closely in patients receiving more than one dose of Ca-DTPA. A quantitative baseline estimate of total internalized transuranium elements and measures of radioactivity elimination should be obtained. Radioactivity in blood, urine, and feces should be measured weekly during therapy. In pregnancy, multiple doses of Ca-DTPA appear to be teratogenic due to depletion of zinc body stores; therefore, treatment of pregnant women should begin and continue with Zn-DTPA.
Both medications are available in 1 g vials for distribution by the Radiation Emergency Assistance Center/Training Site.
Colony-Stimulating Factors (Cytokines)
Granulocyte colony-stimulating factors (G-CSF) are produced by recombinant DNA technology with the purpose of stimulating the growth of white blood cells. Three recombinant colony-stimulating factors (filgrastim, pegfilgrastim, and sargramostim) are currently licensed for use in patients with neutropenia. Pegfilgrastim is a long-acting formulation of filgrastim. Filgrastim and sargramostim have been used in radiation accident victims.
Just like a cancer patient who has received chemotherapy or radiation therapy, a person who has received a high dose of radiation may experience bone marrow destruction. Since G-CSF has been used successfully for cancer patients to stimulate growth of white blood cells, making them less vulnerable to infections, it is expected to help patients who have bone marrow damage from very high doses of radiation in much the same way. G-CSF can speed up the process of white blood cell creation, reducing the time that the patient is vulnerable to infection.
Colony-stimulating factors are safe for most adults. Side effects include fever, diarrhea, skin rash, and weakness, with the most common side effect being mild-to-moderate bone pain. The treatment plan is to give 5 mcg/kg of patient weight of filgrastim daily for up to two weeks, either by injection or intravenous infusion or sargramostim at 250 µg/m2 per day administered subcutaneously. A third and final option is to give 6 mg pegfilgrastim subcutaneously once weekly in patients weighing more than 45 kg.
Amifostine is in a class of drugs known as radioprotectants. Radioprotectants are used to protect tissues against oxidative damage at the cellular level.
Amifostine is known as a broad-spectrum cytoprotective agent because it protects against a large array of cytotoxic therapies in multiple organ systems. The drug becomes dephosphorylated in the tissue to its active form, which is a free thiol. When in its active form, amifostine is taken up into the cells and acts as a free radical scavenger.
Amifostine was approved by the FDA for use as a protectant for normal tissues during radiotherapy of head and neck cancers. The use of this drug is limited by its side effects, which include nausea, vomiting, and hypotension. At concentrations necessary to protect against acute radiation injury, these side effects are significant, thus making its use as a prophylactic for acute radiation injury questionable. Also, there is no evidence that amifostine provides any protective value when given after exposure to ionizing radiation. Therefore, it is likely that the best use would be for first responders entering a contaminated area.
Androstenediol, one of the drugs still under development by Hollis-Eden, is being created for the treatment of ARS (acute radiation syndrome). ARS is caused when the body is exposed to high doses of radiation. When this occurs, the patient may experience severe loss of neutrophils, or thrombocytopenia. This is potentially life-threatening because of the lethal effect of high doses of whole body radiation on the bone marrow that produces these cells.
Androstenediol (5-androstenediol), is an immune-regulating hormone that stimulates myelopoiesis and increases the number of circulating platelets and certain white blood cells of the innate immune system. These changes may last for several weeks after treatment and result in enhanced resistance to infection and significantly better survival rates. It can be given prophylactically 24 hours before exposure or two to four hours after exposure. Preliminary findings in monkeys show that androstenediol significantly reduced the duration of neutropenia as well as occurrence of severe thrombocytopenia in treated animals.
In the event of a radiation emergency, there are some key points regarding contamination for the medical management of radiation casualties. The first is that all patients should be medically stabilized from their traumatic injuries before radiation injuries are considered. Additionally, exposure from a source outside the person does not make that person "radioactive." Thus, they are of no hazard to medical staff. This is different from a nuclear blast type of event where the patient needs to be isolated to prevent others from being exposed to radiation. Third, the amount of nausea, vomiting, diarrhea, and skin erythema may be an indication of the amount of radiation that a person has received.
For decontamination, the majority of surface radiation may be removed with soap, warm water, and a washcloth. All patients who have been exposed to radiation should be monitored for dehydration, electrolyte imbalances, infections, gastrointestinal destruction, and bone marrow suppression.
This article examines just a few of the antidotes available in case of a radiation emergency. Many other products are in various stages of development and in competition for government support. In today’s society, it is important that health care officials and providers are aware of the dangers a radiologic emergency would present. It is even more important that we have a basic knowledge of the antidotes mentioned in this article to provide quality health care to those who may be affected by such a tragic event.
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- Centers for Disease Control and Prevention. Radiation Emergencies, DTPA. CDC Fact Sheet, May 2005. Available at www.bt.cdc.gov/radiation/pdf/dtpa.pdf. Accessed Jan. 8, 2006.
- Centers for Disease Control and Prevention. Radiation Emergencies, Potassium Iodide. CDC Fact Sheet, May 2005. Available at www.bt.cdc.gov/radiation/pdf/ki.pdf. Accessed Jan. 8, 2006.
- Ansari A. Dirty bomb pills, shots, weeds, and spells. Health Physics News 2004;32:1-7.
- Koening K, Goans R, Hatchett R, et al. Medical treatment of radiological casualties: Current concepts. Ann Emerg Med 2005;45:643-652.