The Pharmaceutical Journal
Vol 274 No 7331 p23-24
1/8 January 2005

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American Society of Health-system Pharmacists

Pharmacists must learn about chemical agents and their antidotes

Chemical agents take effect in seconds or minutes and so preparedness is a vital part of the emergency response, according to Edward P. Krenzelok, director of the Pittsburgh Poison Centre. Do not wait until disaster strikes to make contact with local officials, he continued.

The release of sarin gas by the Aum Shinrikyo cult in the Tokyo underground system had shown how devastating a chemical attack could be. No one learned about chemical terrorism in pharmacy school and so we now need to learn about the agents that could be used and the corresponding antidotes or treatments.

Agents that were originally developed for unconventional warfare could now be used by terrorists. These include nerve agents, pulmonary irritants, asphyxiants, vesicants and lachrymators. Of these, the first four were the most likely agents to be used by terrorists.

Nerve agents are predominantly cholinesterase inhibitors that lead to a rapid build up of acetylcholine and a consequent cholinergic crisis and a number of agents of increasing potency have been developed.

Both acetylcholinesterase (in red blood cells and tissues) and butyrocholinesterase (in serum) are inhibited. The result is widespread muscarinic effects (“every organ that can secrete or excrete will do so”) and nicotinic effects, which include fasciculation and paralysis of respiratory muscles. People can drown in their own secretions, and suction to remove fluids is vital, said Dr Krenzelok. A useful acronym to help remember the effects of nerve agents is SLUDGE: salivation, lachrymation, urination, defaecation, general weakness and emesis.

How many patients in this condition could you care for, he asked.

When dealing with any attack it is important to decontaminate victims, although this may be pointless for those who have been exposed to vapours, and to protect the “first responders”. Toxicity should be reversed using large doses of atropine. Initial doses of 2-4mg are required followed by sufficient amounts to reverse life-threatening oral and bronchial secretions.

Dr Krenzelok described how a patient who had taken malathion had required atropine at a dose of 60mg/h at one stage. He advised that large quantities of atropine sulphate injection 1mg/ml (for ease of calculation) should be available in the event of a chemical attack. Diazepam injection may also be need to treat seizures.

It may be possible to give pralidoxime to regenerate some cholinesterase if victims are reached early, because it takes several hours for the enzyme to “age” and become irreversibly bound to nerve agents. The exception is soman, which ages within minutes. Mark-1 injectors (automatic injection devices) effectively “spray” pralidoxime through muscle tissue, greatly increasing bioavailability. Intravenous administration is ideal but this is often not practical in the field. After the emergency response, supportive care will be needed.

Prophylactic pyridostigmine reversibly blocks some of the acetylcholinesterase and protects it from irreversible block by a nerve agent. This was used on soldiers during the first Gulf war; 50 per cent complained of symptoms so it is unlikely to be helpful in a civilian response, noted Dr Krenzelok.

Pulmonary irritants

Phosgene and chlorine are both pulmonary irritant gases that were used during the 1914– 18 war. Pulmonary irritants can be gases, vapours or aerosols and their effectiveness as weapons often depends on favourable environmental conditions; for example, a warm environment can increase vaporisation and therefore toxicity. Particle size is also relevant as particles of less than 10µm are respirable.

The clinical effects of pulmonary irritants are asphyxiation, local tissue damage, systemic damage and allergic reactions.

Chlorine is a yellow-green gas with an acrid, pungent smell. It is dense and settles in low-lying areas (eg, trenches). It is considered to be a significant risk because it is so readily available. When combined with moisture in the lungs it readily forms hydrochloric acid and hydrochlorous acid leading to laryngospasm and pulmonary oedema. Mild exposure to chlorine causes nasal and ocular irritation; moderate exposure causes choking, severe chest discomfort, hoarseness and stridor leading to pulmonary oedema over two to four hours. Significant exposure provokes severe dyspnoea and pulmonary oedema within 30 to 60 minutes.

Phosgene is four times heavier than air and in low concentrations smells like musty hay. It has a boiling point of 7.5C, and so exists mainly as a gas. When inhaled it is rapidly hydrolysed to form carbon dioxide and hydrochloric acid. The clinical effects of exposure range from mild cough and dyspnoea to laryngospasm, severe dyspnoea and pulmonary oedema, depending on the degree of exposure.

There are no antidotes for chlorine or phosgene and care is mainly supportive. It is important to enforce rest, manage airway secretions and treat hypoxia and hypotension. In particular, bronchospasm and pulmonary oedema should be anticipated, said Dr Krenzelok.

Vesicants

Mustard gas is a vesicant that causes significant incapacitation but rarely kills — approximately 2 per cent of those accidentally affected during the 1939–45 war died, said Daniel J. Cobaugh, of the ASHP research and education foundation. Vesicant agents developed for unconventional warfare include sulphur mustard, nitrogen mustard and Lewisite (an arsenical compound). The mustards are yellow-brown oily liquids that smell of mustard, garlic or horseradish. The gas is 5.4 times denser than air and tends to persist in the environment. They have low volatility — sulphur mustard freezes at 13.9C, although it can be mixed with Lewisite to depress the freezing point. The mustards are thought to act as alkylating agents, cause inhibition of glycolysis and inhibition of glutathione and have weak cholinergic effects. Clinically, the skin, eyes and airways are most commonly affected. Frequent effects include conjunctival pain, blepharospasm, lachrymation, erythema and blistering of the skin, burning nasal pain, a barking cough, toneless voice and other respiratory symptoms. Respiratory effects are more common at higher temperatures (they were more frequently seen in Iranian victims of mustard gas during the Iran–Iraq war than among victims of the First World War). Moist areas with thin skin, such as the axillae, genitals and perineum are particularly vulnerable to the dermal effects of mustard gas. Exposed skin develops a characteristic “string of pearls” pattern of small vesicles that eventually coalesce to form larger blisters. Lesions can be similar to third degree burns.

There is no antidote to sulphur mustard and the management of exposed cases depends largely on rapid decontamination and supportive care. Skin lesions are treated as burns and analgesics are needed for the intense pain. Eye lesions are treated with mydriatics and lubricants. Respiratory function is supported with humidified air, cough suppressants and occasionally, artificial ventilation. Causes of death include respiratory infection and bone marrow suppression.

Asphyxiants

In 1982, seven people died in the US after ingesting Tylenol (paracetamol) tablets that had deliberately been contaminated with cyanide — an event that illustrated the relative ease with which cyanide could be used. Cyanide products include hydrogen cyanide, cyanogen chloride and cyanogen bromide. Its asphyxiant effects are due primarily to its ability to interfere with cellular cytochrome oxidase, causing paralysis of cellular respiration. Cyanide causes respiratory, neurological and cardiovascular toxicities and can also cause haemorrhagic gastritis. “Cherry-red” skin is more often a post-mortem finding than a useful clinical finding, noted Dr Cobaugh. The treatment of victims of cyanide poisoning involves intensive supportive care and the administration of sodium nitrite and sodium thiosulphate. Nitrites generate methaemoglobin, which combines with cyanide to form the non-toxic substance cyanomethaemoglobin. Methaemoglobin does not have a higher affinity for cyanide than does cytochrome oxidase, but there is a much larger potential source of methaemoglobin than there is of cytochrome oxidase. The efficacy of methaemoglobin is therefore primarily the result of mass action. Sodium thiosulphate converts cyanide to the less-toxic thiocyanate, which is excreted in the urine. An alternative antidote would be hydroxocobalamin, which binds strongly to cyanide to form cyanocobalamin (vitamin B12) and, compared with nitrite therapy, it has the advantage of not interfering with tissue oxygenation. The disadvantage of hydroxocobalamin as a cyanide antidote is the large dose (4g) required for it to be effective. Unfortunately, hydroxocobalamin is not licensed by the US Food and Drug Administration and is not held in the strategic national stockpile, said Dr Cobaugh.

Asked how hospitals should prepare for the first 12 hours after a chemical attack, before the stockpile is distributed, Dr Krenzelok said that large quantities of atropine powder should be kept in order to prepare large quantities of high-concentration injection extemporaneously. The purpose of the small, local emergency supply is to treat front-line care staff to ensure that the hospital stays operational. “Think about your staff and their families — if they cannot be sure that they will be treated they will not turn out to work,” he said. He also advised that, in the event of a chemical or biological attack, antidotes and antibiotics would acquire a high “street value” and security in the pharmacy would need to be strengthened.

Bar coding systems are an important aspect of patient safety

The implementation of bar code systems for medicines in hospitals is an important part of a successful medication safety and error reduction programme, said Brad C. Ludwig, assistant director, Pharmacy Operations, University of Wisconsin Hospitals and Clinics (UWHC), Madison. In a hospital that administers over 10,000 doses each day, the “5 Rs” assume significant importance — right drug, right dose, right route, right time and right patient. He identified the advantages of point-of-care bar code scanning as improving patient care by reducing administration errors, improving documentation quality, improving nursing and patient satisfaction in the process and capturing costs more accurately. In an ideal world, the bar code should be attached to the lowest unit of use by the pharmaceutical industry but the system must be sufficiently flexible to enable the pharmacy to generate its own bar code labels to attach to extemporaneously prepared medicines.

Three types of bar code are available but the one-dimensional linear bar code was chosen as the standard since most commercial bar code readers could read it with a high degree of accuracy. However, it holds a limited amount of data and since the amount of data increases, so the size of the label increases.

The two-dimensional linear bar code can store up to 100 times more data, can be printed with a standard printer and is no more expensive but it has to be read with a more expensive 2D scanner, but the bar code can easily be damaged or stained. Data matrix bar codes can be up to 30 times smaller and can be read even if 60 per cent is damaged. They are extremely accurate but can only be read by expensive, specially programmed scanners. Mr Ludwig went on to describe the patient ID bracelet and the employee ID badge. Durability, low cost and the capacity to accommodate 1D or data matrix bar codes are essential factors to consider when negotiating contracts for badges and bracelets. More importantly, it is essential to establish secure procedures to deal with the issue to starters and recovery from leavers of badges and to deal with lost or stolen badges. The results of the UWHC project showed that there was an overall 87 per cent reduction in drug administration errors (from 9.1 to 1.2 per cent). In particular, drug dose errors had been eliminated and “wrong drug” errors had been reduced by 51 per cent. These two categories of error are most likely to cause harm, he noted.

As with any new technology, new sources of error, including staff taking short cuts, were identified. On some occasions nurses did not scan bar codes but used the over-ride function to save time. Other violations included not scanning patients at the bedside but using duplicate wristbands and giving doses without scanning and completing the process later.

He ended by emphasising the importance of maintaining up-to-date bar code databases — a task that had been underestimated at UWHC.