Guidelines for poison control
II. Technical guidance - 7. Antidotes and their availability
Antidotes may play an important role in the treatment of poisoning. While good supportive care and elimination techniques may, in many cases, restore a poisoned patient to good health and stabilize his or her body functions, the appropriate use of antidotes and other agents may greatly enhance elimination and counteract the toxic actions of the poison. In certain circumstances they may significantly reduce the medical resources otherwise needed to treat a patient, shorten the period of therapy, and, in some cases, save a patient from death. Thus, antidotes may sometimes reduce the overall burden on the health service of managing cases of poisoning. In areas remote from good hospital services, and particularly in developing countries that lack adequate facilities for supportive care, antidotes may be even more essential in the treatment of poisoning.
Physicians frequently express concern about the difficulty of obtaining certain antidotes in an emergency. The IPCS and the EC, in consultation with the World Federation, are undertaking a project designed to evaluate the efficacy of antidotes and to encourage their availability. In a preparatory phase of this project an antidote was defined as a therapeutic substance used to counteract the toxic action(s) of a specified xenobiotic. A preliminary list of antidotes, and of other agents used to prevent the absorption of poisons, to enhance their elimination, and to counteract their effects on body functions, was established; preliminary classification of these agents was based on urgency of treatment and efficacy in practice. Agents that correspond to the WHO concept of an essential drug were designated as such, and some have already been incorporated into the WHO List of Essential Drugs1. Antidotes and substances for veterinary use were also listed. Methods and principles for the evaluation of antidotes and other agents used in the treatment of poisoning were drafted and are being used as a framework for preparing monographs on specific antidotes, which are being published in a special series.2
1 The use of essential drugs. Model List of Essential Drugs (ninth list). Seventh report of the WHO Expert Committee. Geneva, World Health Organization, 1997 (WHO Technical Report Series, No. 867).
2 IPCS/EC Evaluation of antidotes. Cambridge, Cambridge University Press.
Early in the course of this preparatory work, it became apparent that the availability of antidotes differed from one country to another. A survey of selected poison information centres was undertaken in order to identify the specific difficulties experienced in obtaining antidotes. Results showed that poison centres in industrialized countries generally have few problems in obtaining most antidotes, although administrative difficulties and the lack of suitable preparations and of importers and manufacturers hinder access to certain antidotes. Centres in developing countries, however, reported many problems in obtaining even the common antidotes that are readily available elsewhere. Problems generally arose in the following three interrelated areas:
*scientific, technical, and economic considerations
*regulatory and administrative requirements
*considerations of time and geography
The efficacy of a substance used as an antidote must be scientifically validated, initially through animal experiments, preferably using species that exhibit a pattern of toxicity similar to that in humans. The clinical efficacy of an antidote in humans may be mare difficult to ascertain and document than that of other pharmaceutical agents, since there is little opportunity for clinical trials. The potential toxicity of an antidote is important in deciding its use, and the possibility of adverse reactions should always be considered. An antidote known to be non-toxic may be used in cases of poisoning even if its efficacy is uncertain; a toxic antidote, however, should be used only if its therapeutic effect is known and the diagnosis certain. Adverse effects and chronic toxicity may be less important than in the case of an ordinary pharmaceutical agent, since an antidote is likely to be used only once. It is important that increased toxicity does not result from mobilization of the toxic substance from tissue stores or from changes in tissue distribution, as in the case of the transient rise in blood levels of lead, and precipitation of acute encephalopathy, after inappropriate use of antidotes in children.
The importance of full validation of the efficacy of substances to be used as antidotes must be emphasized.
Improved knowledge of the mechanisms of toxicity of different poisons and of the kinetics of toxic substances may also facilitate the development and use of specific antidotes. Once an effective antidote has been identified, there remains the problem of its manufacture as a pharmaceutical substance suitable for use in humans. The formulation of a preparation for oral use will, in many cases, make it easier to administer the antidote, for example in ambulatory patients.
The scientific study of antidotes thus has implications for drug regulation authorities and governments, for the commercial sector, and for poison information centres.
* Drug regulation authorities and governments. Comprehensive scientific studies will enable regulatory authorities to facilitate the registration of useful, effective antidotes. Governments are responsible for ensuring the availability of antidotes and should recognize the importance of this group of therapeutic agents and the need to support their scientific study.
* The commercial sector. The manufacture and supply of antidotes are usually the responsibility of the commercial sector, which may also need to support appropriate studies. Industries involved in the manufacture and supply of potentially toxic agents must consider their possible effects on users and on others who may be exposed; they should ensure that appropriate antidotes are available on the local market.
* Poison information centres. Poison information centres, and especially the treatment units, have an essential role in monitoring the use of antidotes. Ideally, data on antidote use should be collected in an internationally standardized manner to allow results to be compared and recommendations made. International exchange of information should be encouraged to allow critical assessment of the efficacy and side-effects of antidotal agents. Health care professionals should be aware that the data required at the time certain antidotes were registered may have been quite limited and may therefore need updating in the light of more recent findings.
Even an effective and readily available antidote will be useless if the attending physician is unable to establish a correct diagnosis or is uninformed about the availability or indications for use of the antidote. Information programmes should be arranged by toxicological and poison information centres in order to familiarize clinical personnel with the proper use of antidotes, particularly for individuals in high-risk groups, such as those exposed to hazardous chemicals in the course of their work.
Registration of a pharmaceutical for use as an antidote would seem a satisfactory means of dealing with problems of distribution and availability. However, some pharmaceutical manufacturers are disinclined to register antidotes because of the small volume of production required to meet market demand. It is therefore suggested that a means should be found of encouraging industries that market potentially toxic drugs or chemicals to provide information on antidotal treatment, and to facilitate the provision and registration of appropriate antidotes. Pharmaceutical companies that produce antidotes should be encouraged to register them in their countries of use. It would also be helpful to ease the administrative procedures required to permit the use of an antidote - for example by making it an "orphan drug"1 or a "common drug" for which the registration procedure is less complicated.
Chemicals as antidotes
Some chemical substances with antidotal properties, for example calcium chloride, sodium nitrite, and methylene blue, are marketed as chemicals but are not available in appropriate formulations for use as drugs. It is therefore important to ensure that the quality and purity of these chemicals will permit their administration as antidotes. Pharmacopoeia commissions should consider issuing monographs on such chemicals.
Formulation of antidotes
Certain pharmaceutical agents may be registered for uses other than as antidotes and are thus not available in appropriate formulations, or in adequate quantities, to meet the needs of poisoned patients. Additional authorization for use of these agents as specific antidotes should not present a major problem, but the necessary procedures need to be facilitated.
National distribution of antidotes
Demographic, geographical, and economic factors sometimes hinder the availability of antidotes. In addition, the high cost that results from infrequent demand and short shelf-life may prevent their widespread distribution. A central "bank" of antidotes could be an economic and effective means of ensuring distribution, and this should be organized by health authorities in such a way that any poison victim may be assured of receiving an antidote within the appropriate period of time.
1Orphan drugs: drugs for diseases or conditions that occur so infrequently that there is no reasonable expectation of the costs of developing and marketing being recovered through revenues from sales. The United States Government provides incentives for the production of such drugs, including tax credits, seven-year exclusive rights, facility in the Food and Drug Administration registration process, and a financial grant to cover part of the clinical research.
When considering the cost of antidotes, governments should take into account the social and medical consequences of failure to treat poisoned patients in an appropriate manner and the continued economic burden on local or national resources that may ensue.
In general, pharmaceutical companies will manufacture and supply antidotes only if they are encouraged by adequate economic returns for their investment and by simple registration procedures. To this end, governments should consider recent WHO recommendations1 concerning products for export and facilitate the registration of antidotes already evaluated and registered elsewhere.
If antidotes cannot be supplied by the pharmaceutical industry, other means of ensuring their availability should be considered. These could include the establishment of government manufacturing facilities, a manufacturing pharmacy laboratory, or a system that allows the importation of antidotes registered elsewhere.
Other ways of using resources efficiently, such as rationalizing the purchase and distribution of antidotes, should also be considered by health authorities and should take into account the time within which antidotes need to be available for use in treatment. Local transport conditions should also be considered.
Registration and administrative requirements
Antidotes are pharmaceutical products, and almost all countries have an official body concerned with the registration and approval of pharmaceutical substances. Many antidotes are drugs that have undergone a full range of tests before registration and are authorized for distribution and use in many countries. Such tests usually cover the physicochemical properties, stability of the formulation, and toxicity as determined by animal experiments, pharmacological studies, and clinical trials. However, certain pharmaceutical agents that have been evaluated for other uses may require additional authorization for antidotal use. This type of registration should present no major problem and could follow the procedure for a new antidote referred to in the next paragraph. There may, however, be a need to develop special formulations to allow sufficient quantities to be available for administration as an antidote.
1 WHO Expert Committee on Specifications for Pharmaceutical Preparations. Thirty-fourth report. Geneva, World Health Organization, 1996 (WHO Technical Report Series, No. 863): Section 6.2, The WHO Certification Scheme on the Quality of Pharmaceutical Products Moving in International Commerce.
For a new pharmaceutical substance to be used only as an antidote, the registration procedure could be modified so that it is less comprehensive than that for a normal drug. Authorities often accept different criteria for the registration of certain pharmaceutical substances, for example anticancer drugs, because of the special conditions that apply to their use. A new antidote could be considered in a similar light, thereby facilitating its registration and encouraging manufacturers to make it more widely available.
As already mentioned, a number of chemical substances that are not strictly pharmaceutical products, such as calcium chloride, sodium nitrite, and methylene blue, may be used as antidotes. If they are to be made available for administration to poisoned patients, their quality and purity become important considerations.
Some antidotes that have been registered and approved in individual countries, after extensive testing, are faced with trade or administrative barriers when their importation into other countries is considered; examples include activated charcoal, syrup of ipecacuanha, and oximes. Countries should select from the list of essential antidotes those agents that are most appropriate to their needs; in some cases, these drugs are already listed in the WHO List of Essential Drugs.1
In some countries, existing regulations may inhibit the use of certain substances - for example, antidotes still undergoing clinical trial and not yet registered - in the treatment of poisoning, even when these substances would be of value in clinically oriented poison control centres. Special legal provision should be made for practising physicians in clinical toxicology and poison control centres to use these agents - particularly in "life-saving" circumstances - on the basis of their own judgement. In addition, it should be possible to stock these substances under controlled conditions at poison control centres and to exchange them between such centres. These measures would encourage the interchange of experience and improve the database for subsequent registration. It is important, though, that a mechanism be established to ensure the purity and sterility of unregistered antidotal agents.
1 The use of essential drugs. Model List of Essential Drugs (ninth list). Seventh report of the WHO Expert Committee. Geneva; World Health Organization, 1997 (WHO Technical Report Series, No. 867).
Considerations of time and geography
The availability of an antidote is highly dependent on its distribution within a country as well as its source, particularly if it has to be imported from another country. The best way of ensuring the importation of antidotes into a country might be to entrust it entirely to a central organization or institution. The establishment of a central agency responsible for the importation and distribution of antidotes is therefore recommended; alternatively, the task could be entrusted to clinically oriented poison control centres.
Many countries already have such centralized systems for the importation of pharmaceutical agents. It is essential for the institutions concerned to consult and cooperate with national poison control and clinical toxicology centres, or associations of such centres, so that the importation of antidotes reflects local needs. Where certain antidotes are not available, either from local manufacturers or as imports, the central institution may cooperate with poison centres in recommending their local manufacture by hospital pharmacies or through pharmaceutical associations. Furthermore, in the event of an emergency or chemical disaster, an exchange arrangement between poison centres in different countries might make it possible to obtain a supply of some antidotes that are commercially available elsewhere.
Since many antidotes are expensive, infrequently used, and have a limited shelf-life, central stocking of antidotes makes sound economic sense; it makes inspection easier and ensures a supply of products that have not lost their effectiveness. However, any such centralized system must be able to guarantee that a poisoned patient will receive an antidote within the time required for treatment. Certain agents used in the treatment of poisoning, for example, syrup of ipecacuanha and activated charcoal, are used frequently; others are required for use immediately, e.g. those used in the treatment of cyanide poisoning. Antidotes have been classified as those needed:
*immediately (within 30 minutes)
*within 2 hours
*within 6 hours.
Antidotes needed immediately must be stocked at all hospitals, as well as in health centres or doctors' surgeries if the nearest hospital is some distance away. It may also be necessary to have certain antidotes available at places of work for use under medical supervision (e.g. in factories using cyanide). Antidotes needed within 2 hours can be stocked at certain main hospitals; patients can be taken to these hospitals for treatment or the antidotes can be transported - within the time limit - to the health facilities at which treatment is provided. Antidotes needed within 6 hours may be stocked at central regional depots, provided that there are adequate facilities for transporting them within the time limit. For all categories of antidotes, there is the further option of keeping a small amount, sufficient to start treatment, in stock locally, further supplies being obtained from a central source as required.
Where certain types of poisoning are frequent, or in areas where certain chemicals are heavily used, the appropriate antidotes may be kept in ambulances, operated by physicians, that are sent out to treat cases of poisoning. Poisoning by natural toxins may be seasonal and may be specific to certain regions (e.g. snake-bites in rural areas during planting and harvesting seasons). Antivenoms may be sent to rural areas during these seasons to be readily available in case of need. The rapid transport of antidotes may be needed in certain cirumstances, and appropriate advance arrangements should be made, e.g. for the use of official cars, aircraft, or trains. In certain situations, arrangements for the rapid transport of patients to hospitals with appropriate facilities and antidotes may be necessary. Comprehensive instructions on interim treatment measures should be given to first-aid workers or other medical or paramedical professionals.
In deciding where antidotes should be stocked, a number of factors should be taken into consideration, notably the following:
*the size of the country and the area to be covered by a depot
*the density of the population
*the incidence of poisonings that require special therapeutic measures and/or antidotes
*the social and economic activities of the region that may be associated with a high risk of poisoning
*the distances of hospitals and health centres from the depot
*communications (road, air services, etc.) between the depot and the hospitals or health centres
*the cost of antidotes and of the wastage caused by expiry of effectiveness compared with the cost of transport in case of emergency.
The most logical location for a regional central depot is a poison information centre or central hospital pharmacy. The economic management of the supply of antidotes could be improved by a central, preferably computerized, record system, regularly updated. The need to hold contingency stocks of antidotes for response to chemical disasters should be considered, especially in areas where large amounts of potentially hazardous chemicals are being manufactured, used, transported or stored. There, regional cooperation between centres, permitting the exchange of information on the availability of antidotes, is highly desirable.
The conditions under which antidotes are stored are important determinants of their maximum shelf-life and an essential consideration when storage depots are chosen.
Greater efforts should be made to find antidotes with longer shelf-lives and improved stability under harsh conditions, particularly of temperature and humidity, for use in areas where proper storage cannot be achieved.
Special problems of developing countries
In addition to the general problems of availability discussed above, it is recognized that developing countries may have special problems as regards antidotes. Many of these countries do not have poison information centres and lack the facilities available in developed countries for supportive treatment of poisoning. Consequently, they may have a greater need for certain antidotes, for example naloxone. It is important that these countries should establish centres to provide the relevant information, to recommend, whenever appropriate, the use of antidotes, and to coordinate the distribution of antidotes.
Health authorities are sometimes unable or reluctant to facilitate the import of antidotes, since the procedures involved may be cumbersome and lengthy. Economic problems, including a shortage of convertible currency, are liable to worsen the situation. The pattern of poisoning in any given country should indicate the extent of the need to facilitate registration procedures and to acquire particular antidotes.
Good first-aid procedures and the appropriate use of antidotes may be not only lifesaving but also economically sound. Although antidotes are sometimes expensive, their use may prevent death, prolonged hospitalization, or permanent sequelae. The benefits of their use thus outweigh the costs. International agencies may be helpful in enabling some countries to acquire the antidotes they need.
Lack of adequate communication systems and transport infrastructure in certain countries may make it impossible to transport antidotes sufficiently quickly in an emergency. Measures to ensure the rapid transport of antidotes to affected areas, or, alternatively, the transport of poisoned patients to appropriate treatment facilities, are therefore of the greatest importance. It may be difficult to find adequate facilities for emergency storage depots; furthermore, local conditions and climate may make routine storage of antidotes difficult in certain areas of the country. Nevertheless, it is essential to ensure correct storage, and due account should be taken of expiry dates and the necessary conditions of temperature, light, and humidity. Proper storage conditions are also essential during the transportation of antidotes from the point of importation to local depots, and in transitional storage areas.
Antidotes for veterinary use
Poisoning in animals is a serious problem in many parts of the world, and poison information centres often receive enquiries regarding the treatment of poisoned animals. The use of antidotes in veterinary medicine poses a number of special problems as regards choice, dosage, route of administration, and availability. It is therefore recommended that each country should make separate arrangements for the examination of various aspects of veterinary use of antidotes by a working group with the necessary expertise, which should include poison specialists, veterinarians, and registration authorities.
The difficulties experienced in obtaining antidotes for the treatment of poisoned patients vary from country to country. While research in certain areas by industry, and at the international level, could improve the general availability of antidotes, each country will need to identify its own particular problems and take specific action to solve them. A combination of measures will be required, and collaboration will be necessary between the various individuals and organizations involved.
Research and development
Understanding of the metabolism, toxicodynamics, and toxicokinetics of chemicals that cause toxicity in humans can be improved to some extent through animal studies. However, human data are essential and should be obtained from properly conducted clinical studies, ideally using internationally agreed protocols. Better knowledge of the mechanism of action of toxic substances would enable more specific antidotes to be developed.
Appropriate research on antidotes is also essential and should include kinetic, toxicological, and pharmacodynamic studies in both animals and humans. Carefully controlled clinical evaluations of antidotes are often difficult to organize and execute, because of the diversity and relative rarity of poisoning incidents. Proper control of the variables involved is complicated by many factors. For all these reasons, financial support for clinical research should be increased and facilitated, and collaborative studies at both national and international level should be promoted. A concerted effort by the scientific and clinical communities, as well as the pharmaceutical industry, could encourage the development of new antidotes and approval of existing ones for use in humans. This is clearly a long- term process.
Specific studies are also necessary to develop more stable preparations with longer shelf-lives and the ability to withstand a wider range of physical conditions, particularly temperature, light, and humidity. It is important to develop simpler methods of testing the chemical stability and degradation of antidotes under unfavourable physical conditions. Research on more readily usable antidotes is needed, particularly because administration in field conditions by non-medical personnel may be necessary in the event of an emergency. Finally, research could also be directed to the possible inclusion of antidotes with commercial preparations of potentially toxic agents, as has already been done in some countries for paracetamol and methionine.
Action by industry and commerce
The pharmaceutical and chemical industries have an important part to play in the research and development activities referred to above. The pharmaceutical industry could explore ways and means of ensuring the manufacture and distribution of antidotes, including formulations for human and veterinary use which would not normally be made available if commercial criteria alone prevailed. Those industries that use or manufacture toxic chemicals could ensure the availability of, or ready accessibility to, appropriate antidotes at sites used by their workers and at nearby hospitals. This applies also to agricultural activities in which workers may be exposed to both agrochemicals and natural toxins (for example, through the bites of venomous animals) at certain times of the year, such as the planting, crop-spraying, and harvesting seasons. Industrial and commercial enterprises should ensure the proper training of their health personnel in the emergency use of antidotes. Importers and distributors of toxic chemicals should also ensure the availability of specific and effective antidotes for the substances in which they trade.
Action at national level
Poison information centres play a key role in the implementation of a national antidote programme. In general, they are in the unique position of having an overall picture of local poisoning incidents that will enable them to identify the need for specific antidotes in the country as a whole, as well as in particular areas. It is therefore a primary task of these centres to draw attention to the need for making appropriate antidotes available. They should review and evaluate the relevant literature, keep appropriate authorities informed, and facilitate any necessary activities.
Poison information centres should also stimulate the creation of a national network for the supply of antidotes, which will require their close collaboration with the responsible authorities and with hospital pharmacies.
The primary task of authorities at the national level is to ensure that the relevant legislation permits the availability of antidotes, especially those included in the WHO List of Essential Drugs),1 for purposes of evaluation. Machinery should be set up for the rapid importation, without bureaucratic hindrance, of antidotes for emergency use. Special arrangements may also be needed to permit the controlled clinical use of antidotes that are still under development.
National health authorities should encourage the manufacture and distribution of antidotes not yet available on the local market and could even provide incentives to local pharmaceutical manufacturers, hospital pharmacies, and service laboratories. The export of these antidotes could then also be encouraged. Incentives may be of a financial, fiscal, or similar nature, or provided through the development of human resources and training. National health authorities could also help with, or encourage the organization of, depots for antidotes and systems for the distribution of antidotal agents.
Action at international level
It has been suggested that the establishment of international machinery for the purchase, storage, and distribution of certain antidotes might alleviate the problems of availability in some countries, though it is recognized that this may be difficult to organize and will demand considerable economic resources and political will. If a regional cooperative group could be formed for the supply and storage of antidotes, many of the existing obstacles could be overcome. To this end, regional meetings could be held under the joint auspices of IPCS and WHO Regional Offices to determine a plan of action and to improve cooperation in this area in the various WHO regions.
1 The use of essential drugs. Model List of Essential Drugs (ninth list). Seventh report of the WHO Expert Committee. Geneva, World Health Organization, 1997 (WHO Technical Report Series, No. 867).
There is strong support for the suggestion that a list be made of the type and quantities of antidotes immediately available throughout the world. Such a list would allow authorities to locate rarely used antidotes and would also enable large quantities of antidotes to be obtained in the event of a major accident. It would be very difficult, however, to keep the list up to date.
As a result of the IPCS/EC project on antidotes, the WHO List of Essential Drugs has been updated and broadened to include a wider range of antidotes and other substances used in the treatment of poisoning, and it is hoped that this will make national health authorities less reluctant to facilitate the importation of these substances. The preparation of internationally evaluated monographs on each of these substances should also be helpful in this respect. In the same way, the exchanges of information that take place at international meetings are of great benefit to all those involved.
By making resources and experience available through their development assistance programmes, developed countries could encourage the establishment of storage depots for antidotes in developing countries. With appropriate support, poison information centres in both developed and developing countries could serve as channels for passing on experience, bearing in mind that this is a two-way process. The poison information centres of developing countries could thus gain expertise in the treatment of forms of poisoning that no longer occur commonly in the developed countries, e.g. poisoning by organophosphates.
Where suitable hospital pharmacy facilities exist in developing countries, some antidotes could be prepared locally in cooperation with local poison information centres. Education grants and training courses for pharmaceutical staff in this area would be of value and could be encouraged through international exchange programmes for the development of human resources.