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Dimercaprol

British anti-Lewisite, often referred to by its acronym BAL, is a compound developed by the British biochemists at Oxford University during World War II. It was developed secretly as an antidote for the arsenic-based chemical warfare agent Lewisite, effectively rendering it obsolete. Today, it is used medically in treatment of arsenic, mercury and lead, and other heavy metal poisoning. In addition, it is used for the treatment of Wilson's disease, a genetic disorder in which the body tends to retain copper. more...

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Biochemical function

Heavy metals act by chemically reacting with adjacent sulfhydryl residues on metabolic enzymes, creating a chelate complex that inhibits the affected enzyme's activity. British anti-Lewisite competes with the sulfhydryl groups for binding the metal ion, which is then excreted in the urine.

BAL is itself toxic, with a narrow therapeutic index and a tendency to concentrate arsenic in some organs. Other drawbacks include the need to administer it by painful intramuscular injection.

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Compounding for the effects of weapons of mass destruction
From International Journal of Pharmaceutical Compounding, 1/1/03 by Sammarco, Domenic A

Abstract

As incidents of terrorism become more common, pharmacists and medical professionals must plan for a possible domestic terrorist attack involving biologic, chemical, or nuclear weapons. For the United States to be truly prepared, federal, state, and local agencies must have the knowledge, intelligence, training, and supplies to counter this realistic threat of the twenty-first century. Terrorists often use chemical, biologic, or limited nuclear warfare in which weapons are easier to produce, smaller in size, and have a profound psychologic and physical impact.

Preparing for War-Related Incidents

To prepare for incidents involving weapons of mass destruction, healthcare providers must equip themselves with information, contingency plans, and coping procedures. The purpose of this article is to provide pharmacists with a summary of such plans and procedures as well as a list of extemporaneously compounded pharmaceuticals for use as primary or secondary chemotherapeutic agents against weapons of mass destruction. Those pharmaceutical products include (but are not limited to) antidotes, antibiotics, antitoxins, and other agents used to care for victims.

All disasters begin as a local event, and even small communities must be prepared to handle a mass-casualty incident. Most federal and state assistance will probably arrive after the local system of aid has been overwhelmed. Pharmacists must become involved in community disaster planning (see the example plan). Because in such circumstances healthcare providers must manage many patients who require urgent care, pharmacists will be pressed into action to deliver the pharmaceuticals needed to save lives, relieve pain, and limit the score or spread of the causative agent.

Suggestions for Pharmacy Participation in a Community Disaster Plan

A pharmacist can create a disaster-preparedness plan in his or her own practice setting. The following suggestions should be considered for inclusion in such a plan:

1. Include local hospitals in the planning phase.

2. Contact wholesalers and establish a site for receiving medications and supplies during a crisis.

3. Compile a list of contact information for pharmacies, wholesalers, manufacturers, hospitals, schools of pharmacy, and communications companies located in the community.

4. Create an extemporaneous compounding formulation procedure and a protocol for supplying chemotherapeutic agents.

The National Pharmaceutical Stockpile (NPS) includes eight prepositioned pharmaceutical packages ("Push Packages"), each of which contains medical supplies sufficient to prevent and treat anthrax, plague, and tularemia in nearly 1 million people. Although those prepositioned packages are important, they may create a false sense of security. Limited selection, bulk packaging, and transportation issues could affect the benefits of the NPS. Developing a formulary that includes primary, secondary, and manufacturing protocols may provide another alternative to depending on the intervention of the Centers for Disease Control and Prevention during disasters that may be caused by agents not addressed in the NPS Push Package.

Disasters may start a chain reaction of events that may have many effects. The anthrax-letter incident, which killed a handful of innocent Americans in 2001, created an onslaught of ciprofloxin (Cipro) sales as Americans prepared to protect themselves from inhalation anthrax. The possibility of attacks on American nuclear facilities has created a similar but somewhat lesser response regarding the use of potassium iodide as a therapeutic agent. Pharmaceutical providers must have as many contingency plans as possible to provide chemotherapeutic agents against the effects of such disasters.

Using Extemporaneous Compounded and/or Manufactured Treatments Against Agents of Mass Destruction

Chemical Agents

The extreme toxicity, availability, and rapid onset of action of many chemical agents have made those substances desirable to terrorists. Agents of chemical warfare are usually classified into several groups:

* Blood agents (hydrogen cyanide, cyanogens chloride)

* Nerve agents (tabun, sarin, soman)

* Lung agents (phosgene, diphosgene)

* Blister agents (mustard, lewisite)

Blood Agents or Cyanide

Certain types of cyanide are referred to as "blood agents." Nitrate is the common ingredient used to displace cyanide from the oxygen that is carried in hemoglobin after contact with a blood agent has occurred. Other pharmaceuticals that serve as adjunctive therapy for cyanide poisoning are injectable sodium bicarbonate, which can correct metabolic acidosis, and benzodiazepines (eg, diazepam or lorazepam), which are used as anticonvulsants. Formulations that counteract the effects of blood agents:

* Sodium nitrate 3% injection

* Sodium thiosulfate 25% injection

* Sodium bicarbonate 8.4 injection

* Diazepam 5-mg/mL injection

* Lorazepam 2-mg sublingual tablets

Nerve Agents

Nerve agents are also classified as organophosphates. Nerve agents inhibit the enzyme acetylcholinesterase. Chemotherapeutic intervention consists of the use of four antidotal agents: atropine sulfate, which blocks muscarinic receptor sites; pralidoxime chloride (2-PAM), which regenerates cholinesterase activity; and diazepam or lorazepam, both of which are used as anticonvulsants. Topical ophthalmic homatropine or atropine can be used to relieve dim vision, pain, and possible nausea. Formulations that counteract the effects of nerve agents:

* Pralidoxime chloride (1-g injection)

* Atropine sulfate injection (1 mg/mL)

* Diazepam 5-mg/mL injection

Lung Agents

The third class of chemical agents is often referred to as "lung agents," "pulmonary agents," or "choking agents." Used in World War I, chlorine and phosgene were deadly and unpredictable gases. Because of their many industrial applications, those pulmonary toxins are readily available to terrorists in large quantities. Because no specific antidotes exist for those lung and eye irritants, supportive care may be provided by the use of bronchodilators such as nebulized albuterol sulfate or sodium bicarbonate 3.75% solution. Methylprednisolone acetate injection also has been used as supportive therapy to counteract the effects of those agents. Formulations that counteract the effects of lung agents:

* Albuterol sulfate 0. 5 % inhalation solution

* Sodium bicarbonate 3.75% inhalation solution

* Methylprednisolone acetate 40-mg/mL injection

Blister Agents

The final group of chemical agents is the vesicants, which are often referred to as "blister agents." Those potent alkylating agents include nitrogen mustard, phosgene oxime, and Lewisite, all of which produce scarring blisters, vesiculation, eye damage, and airway damage. Treatment may include the application of topical silver sulfadiazine or topical mafenide acetate. Only one blister agent, Lewisite, has an antidotal compound (dimercaprol), which acts as a chelating agent for arsenicals and other heavy metals. Dimercaprol skin and eye ointment that is applied to victims after decontamination may reduce the severity of lesions. Dimercaptosuccinic acid has been used successfully in animals for the treatment of Lewisite exposure and lead ingestion. Available in 100-- mg capsules, dimercaptosuccinic acid can be administered orally to treat multiple exposures to blister agents.

Formulations that counteract the effects of blister agents:

* Silver sulfadiazine cream

* Mafenide acetate cream

* Dimercaprol injection

* Dimercaptosuccinic acid 100-mg capsules

Biologic Agents of War

Chemical nerve agents cause immediate death or severe injury at the site of attack, but biologic agents, which have a characteristic incubation cycle, cause delayed signs and symptoms. Frontline clinicians and primary care practitioners must identify and manage exposed patients, and pharmacists must become knowledgeable about the primary, secondary, and therapeutic classes of pharmaceutical treatment. Pharmacists must review the qualitative and quantitative variables of biologic agents. An extensive list of oral and parenteral pharmaceuticals may be required in extraordinarily large amounts to treat an outbreak of illness caused by a biologic weapon. The duration of illness, the virulence of an outbreak of disease, and the number of patients affected are important variables that affect the pharmaceutical component of direct patient care. Uncommonly used vaccines and antitoxins should be prepositioned with the assistance of federal government storage and distribution programs. Pharmacists should be collecting detailed information about the diagnosis of diseases, patient management techniques, vaccines, and potential chemotherapeutic agents so that they can educate the public and health practitioners. The list of medical resources included in this article will also be of use.

The possibility that biologic weapons will be used against the United States is no longer unthinkable. Saddam Hussein's aggression during the Persian Gulf War and the anthrax-containing letter that was sent to several individuals in the United States via US mail have provided our nation with a wakeup call. The importance of education, emergency planning, and predisaster training are paramount in developing medical countermeasures.

Bacteria usually cause disease in human beings and animals by one of two mechanisms: invading host tissues or producing poisons (toxins). Many pathogenic bacteria use both mechanisms. Diseases caused by bacteria often respond to therapy with antibiotics. In Table 1, the relationships of disease, vaccine, chemotherapy, and chemoprophylaxis are shown. The drugs that may be manufactured in larger quantities as a contingent to disaster planning are specified within Table 1.

Biologic weapons are more effective if they are used against unsuspecting, unprotected, and nonimmune civilian populations than they are if used against a fast-moving military organization. The actions of a terrorist group (like the attack in New York City on September 11, 2001) may not follow those of a typical military operation. If used against civilian populations, biologic weapons may enable terrorists to cause a large number of casualties and create international panic.

Biologic terrorism could range from the use of sophisticated biologic weapons (dried anthrax spores or botulinum toxins) to that of unsophisticated agents (Salmonella or other common bacteria). The question is not whether biologic agents will be used but which medical countermeasures should be in place when they are used.

Nuclear Agents of War

The traditional concept of nuclear warfare has been minimized to the somewhat reduced terrorist class of "dirty bombs," which are conventional explosives used to spread hazardous radioactive material. Three types of harmful radiation are emitted by radioactive materials: alpha-radiation, beta-radiation, and gamma-radiation.

The inhalation or ingestion of alpha-radiation or beta-radiation particles poses the greatest hazard. gamma-Rays, which are the most harmful type of radiation overall, can penetrate most sheltering material in a wide area.

Exposure to a harmful radiologic agent may require treatment with either a chelator or a radionuclide blocker. In Table 2, a list of specific radionuclide chelating agents for the treatment of patients exposed to radiologic agents is provided, and in Table 3 a list of general radionuclide chelating agents is provided. Additional information about this specialized class of drugs can be obtained on a 24-hour basis from the Radiation Emergency Assistance Center/Training Site (REACT/TS), Post Office Box 117, MS39, Oak Ridge, Tennessee 37831-0117 (telephone number: 865-576-3131 or 865-576-1005).

A variation of radionucleotide chelation that entraps and removes the radioactive agent is referred to as a "radionuclide-- blocking agent." Those agents saturate tissues with a nonradioactive element that reduces the uptake of radioactive iodine. The most commonly known radionuclide blocking agents are potassium iodide tablets and Lugol's solution, both of which reduce the uptake of radioactive iodine by thyroid tissue.

After a radioactive incident, pharmacists will be asked to produce more pharmaceutical options with fewer assets in a very short period of time. The roadmap of product procurement and manufacturing options must be accurate and current. Extemporaneous compounded formulations and procedures must be created, reviewed, and tested before an emergency occurs. Preestablished reference publications, bulk materials, source information, and pharmaceutical items (antidotes, antibiotics, antitoxins, other supportive-care agents) will facilitate hands-on training in the treatment of the biological, chemical, and nuclear casualties of war.

Pharmacists' involvement in disaster planning is the first step in preparing for a terrorist attack. The keystone of countermeasures for weapons of mass destruction is the development of a medical formulary that coordinates primary and secondary treatments for the effects of specific agents of war. Treatment options and understanding the dosing variables of antitoxins, vaccines, antibiotics, and prophylactic treatments for adolescent and pediatric patients should not be overlooked. The use of chemotherapeutics (and their respective teratogenic effects) in pregnant patients should be noted in each treatment protocol.

A nuclear, biologic, or chemical attack will create drug shortages. In developing courses of action to compensate for those shortages, pharmacists should include a preplanned rationing procedure and a supportive networking pharmacy agreement. The self-reliant adaptability and multitasking skills of compounding pharmacists can provide alternative drug treatment options, save lives, and change the consequences of a catastrophic attack.