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Although there are a wide range of recognised poisons and toxic substances, it is important to remember that some of the most well-known poisonous substances are in fact drugs that are used worldwide to treat various symptoms and cure diseases. Due to the complex nature of the human body, it is practically guaranteed that a useful drug will produce unwanted effects, but some drugs can produce dangerous effects that can lead to the withdrawal of a potentially useful drug. Toxicity refers to these sometimes deadly effects; all drugs have adverse effects at normal doses, but it is only the dangerous ones which are referred to as toxic.

Drugs may have toxic effects on various organs, with some potential drugs being abandoned due to toxic effects, and overdoses of some existing drugs leading to death. Doctors are often placed in difficult positions while trying to decide whether the benefits of a drug outweigh its risks, and must be forever vigilant in looking for unknown effects.

A History of Drug Toxicity

One of the first major incidences of drug toxicity in the 20th Century was in the USA in 1937 and involved a drug known as sulphanilamide, an antibacterial agent used to treat streptococcal infections. The drug had been used safely for quite some time in its tablet and powder forms, but it emerged that there was a call for the drug to be available in liquid form. This lead to the production of an 'elixir of sulphanilamide', which the pharmacists in the USA found would dissolve in diethylene glycol. With the promise of increased profits, the elixir was immediately mass-produced without testing, and sent all over the country. In one month, over a hundred patients were dead, but it was not the drug that had killed them. The solvent, diethylene glycol, is rather similar to common antifreeze (ethylene glycol) and is a deadly poison, but this fact had somehow been ignored.

Thalidomide

Although this sort of incidence is now avoided by careful testing of new formulae, other drugs can have toxic effects that are much more difficult to detect. One of the most famous examples of a drug that has been prescribed to the public and then hastily withdrawn is thalidomide. Introduced in the 1957 in West Germany to treat morning sickness in pregnant women, thalidomide had not been tested thoroughly enough to discover its teratogenic effects (see below). It was only when the pregnant women who had been treated with the drug started giving birth to deformed children with shortened limbs and no external ears that thalidomide was withdrawn.

By then, the drug was being used throughout Europe, and had damaged 15,000 foetuses, 12,000 of which were deformed, and half of which died during the first year of life. Although the use of thalidomide in pregnant women is now banned, a new use for the drug has been found in patients with multiple myeloma and leprosy, and also has applications in Behcet's syndrome, AIDS and tuberculosis. This is partly due to the fact that the drug has been refined so that it only includes the (+) isomer, which has beneficial effects, and not the (-) isomer, which caused the many deformities associated with the drug.

Many More Examples

Although pharmacologists now had the experience provided by the thalidomide tragedy, it still proved difficult to detect the harmful side-effects of many drugs. In the four decades that followed, many discoveries were made, all of them after the drug was released:

• The contraceptive pill, which in the 1960s contained 75mg of oestrogen, was found to increase the rate of thrombosis to a much higher rate than that found in pregnant women. The risk has since been reduced by using only a third of the quantity of oestrogen.
• Clioquinol, an anti-infective agent, was found to cause SMON¹, a condition affecting the spinal cord and optic nerve, leading to disturbances of vision and movement as well as mental disorders.
• In 1967, it was discovered that phenytoin, an antiepileptic drug, can cause decalcification of bones leading to rickets in children and osteomalacia in adults. This is due to the drug increasing the production of a hormone that decalcifies bone.
• During the 1970s, the beta-blocker² practolol was found to cause an immune reaction known as oculomucocutaneous syndrome, causing inflammation of the eyes, mucous membrane and skin.
• In 1982, benoxaprofen, an NSAID³ used to treat arthritis, was released onto the market after tests on rhesus monkeys showed that it was safe. Sixty deaths and 3,500 serious illnesses occurred in the UK alone before the drug was found to damage the liver, and also cause inflammation when patients were exposed to sunlight.
• In 1984, it was discovered that fenclofenac, another NSAID used to treat arthritis and inflammation, also caused severe liver damage. It had been released to the public after passing tests on ten different species of animal.
• Ten years later, it was found that the NSAID phenylbutazone caused liver and bone marrow damage as well as inflammation on exposure to sunlight. The effects on bone marrow were only discovered in lab cultures of human cells after many cases of aplastic anaemia, a disease where the bone marrow fails to produce sufficient blood cells.
• During the late 1990s, both pemoline, a treatment for ADHD⁴, and troglitazone, a drug used to regulate type-2 diabetes, were both shown to damage the liver.

All of these examples illustrate the difficulties in detecting harmful effects without giving the drug in question to humans. Although the governments of most countries require drugs to be tested on animals before use on humans, these tests can be deceiving. Harmful effects seen in humans are often not seen in rodents, and it is also conceivable that drugs which are perfectly harmless to humans could have adverse effects on other species. There are also laws limiting the numbers of animals that can be used, and so rare toxic effects that only affect animals with certain conditions are unlikely to be seen until the drug is released for use by humans. The advent of good clinical practice in the wake of the thalidomide tragedy has helped to reduce the effects of these problems, but they are still a hazard that needs careful monitoring.

Different Types of Drug Toxicity

Just as drugs come in many varieties and have varying beneficial and adverse effects, so there are different ways in which they can cause potentially toxic effects. Often it is not the drug itself that causes the trouble, but a breakdown product or 'metabolite' which remains active and has unwanted actions. There are even more complex situations than this, such as the case of thalidomide, where the drug taken is broken down by the body into two components. One of these acts to reduce morning sickness, while the other causes malformation of the foetus.

In some cases, drugs are in fact chosen for their toxic nature when being used to treat malignant tumours and metastases. In these cases, the cytotoxic and mutagenic properties of these drugs are selected to kill mainly the cancer cells, but can also have negative effects on normal cells.

Cytotoxicity

This is the simplest form of drug toxicity, where the drug or an active metabolite causes serious damage to the cells. Often, the cells of a specific organ are affected, causing a potentially fatal loss of function of the liver or kidney⁵, damage to the eyes or ears⁶, or abnormal clotting of the bloodstream. Other organs can also be affected; for example, aspirin is known to cause stomach ulcers in some patients, especially after an overdose.

Another well known cytotoxic drug is paracetamol, also known as acetaminophen, which can fatally damage the liver when taken in high doses. This happens because paracetamol is broken down by the body into various metabolites, one of which is NAPQI. NAPQI is harmful to the liver, but is normally inactivated by glutathione. However, the body only has limited reserves of glutathione, and an overdose of paracetamol will produce enough NAPQI to deplete these reserves, allowing the NAPQI to freely destroy the liver cells. Paracetamol overdose is treated using methionine or N-acetylcysteine, both of which raise the levels of glutathione and thus inactivate the harmful NAPQI. It is now possible to quickly determine the level of paracetamol in the blood using an enzyme immunoassay, allowing those with a toxic level to be treated quickly.

Carcinogenicity

Some drugs can cause damage or mutations to DNA, leading to changes in cell metabolism and the promotion of tumours. Carcinogenic drugs may also activate oncogenes - versions of genes which promote disregulation of cell processes, leading to transformation of normal cells to cancerous cells. An example of a drug with carcinogenic properties in stilboestrol, an oestrogen analogue which increases the probability of developing endometrial cancer or breast cancer.

Mutagenicity

Some drugs can cause permanent changes to the DNA of germ cells⁷, leading to mutations which are inherited by a patient's children. An example is nitrogen mustard, a compound similar to mustard gas, which is used to destroy cancer cells in chemotherapy. The drug destroys cancer cells by linking their DNA strands together with a nitrogen atom, but can also link the DNA of germ cells, leading to deletions of DNA bases, thereby causing mutations. For this reason, known mutagens are usually only used to deliberately kill cancer cells.

Teratogenicity

As in the case of thalidomide, some drugs can cause defects in the development of the foetus, leading to gross abnormalities of the baby - the word teratogen comes from the Greek teratos, meaning 'monster'. The type of abnormality seen depends on the stage at which the drug is taken, as different organs develop at different times during pregnancy. For instance, thalidomide taken after 21 days of pregnancy will often lead to lack of external ears and paralysis of the cranial nerves⁸, whereas thalidomide taken after 27 days will lead to limb malformation. This latter deformity is known as phocomelia, meaning 'seal-like limbs'.

Drug Allergy

Allergies are a well-known problem, with the offending substances ranging from peanuts to pollen. Drug allergies work in the same way, with the body developing antibodies to a drug, causing the immune system to overreact, leading to the usual range of symptoms including itching, wheezing and rashes. However, when the drug causes an anaphylactic shock, where the patient's immune system responds strongly enough to cause difficulties in breathing, low blood pressure, inflammation and even heart failure, the drug is noted as toxic to that individual, and cannot be given to them again. Penicillin is a good example of a drug that can cause allergic reactions and anaphylaxis, with a breakdown product of the drug causing an immune reaction.

Measuring Toxicity

A simple yet crude measure of the toxicity of a drug is the LD₅₀, which is the dose of a drug which kills 50% of treated animals within a specified short period of time. This quantity varies widely from 10 grams per kilogram of body weight for alcohol, to just 0.00001 milligrams per kg for the botulinus toxin produced by the botulinium bacterium. Various other animal tests are used, and drugs are also added to colonies of bacteria and cultures of human cells to determine their carcinogenic and mutagenic effects.

Avoiding Unwanted Toxicity

Unwanted toxic effects can be avoided by banning dangerous drugs, or by strictly controlling their uses. Drugs must go through both rigorous animal testing and small-scale trials on humans to detect unexpected effects, with some dangerous drugs only being dropped after humans have reacted to them⁹. It is now common practice for pharmaceutical companies to advise doctors not to prescribe their drugs to pregnant women, and up to half the drugs listed in the British National Formulary¹⁰ come with such warnings. Women of child-bearing age are often advised to use contraception while taking potentially teratogenic drugs.

Meanwhile, drugs that are potentially fatal after an overdose are sold in restricted amounts in blister packs, making it difficult to take enough pills for the drug to have toxic effects. Child-proof containers have also been developed, and clear labelling is used to warn patients of risks. Doctors are now very careful when prescribing drugs which may interact with one another to cause increased effects, and they are also careful to keep up-to-date with the latest toxicity reports in journals. Previously unknown adverse effects of drugs are reported to the authorities using a standard procedure.

Treating Unwanted Toxicity

Treatment of toxicity refers to the treatment of overdoses, where the drug is likely to cause harmful effects if its effects are not quickly countered. The first line of defence is to remove the drug from the patient before it is fully absorbed, and techniques include:

• Irrigation to remove drugs applied to the eyes or skin.
• Gastric lavage, where the stomach is washed out and drained using tubes.
• Activated charcoal, which is swallowed and soaks up the drug from the gut.
• Ipecac syrup, which causes vomiting in order to empty the stomach.
• Cathartics, laxatives which purge the drug from the gut.

A second line of defence involves the removal of the drug from the bloodstream by various methods, including:

• Changing urine pH to increase excretion of the drug into the urine.
• Forced diuresis, where drugs are given to increase urine production.
• Haemodialysis, where the blood is passed through a machine to remove the drug.
• Exchange transfusion to replace the patient's drug-filled blood with fresh blood.

A vitally important line of defence is the administration of an antidote, which either removes the harmful substance from the blood or counters its effects. Pralidoxine is used as an antidote to nerve gas, and ethanol is given to counter methanol¹¹, while hydroxycobalamin is used to treat cyanide poisoning, although it must be administered quickly. An example of an antidote with an opposing effect is atropine, which in large doses causes muscle paralysis, is used to oppose the effects of an overdose with anti-cholinesterases, drugs which increase the firing of nerves attached to muscles.

Medical professionals can find information about the effects of various poisons and overdoses from the National Poisons Helpline and its accompanying Toxbase website. The helpline is manned by practicing clinical toxicologists and is a great source of information about obscure overdoses, including the necessary treatment and management of the patient.

And Finally...

Having read the above, it is very easy to worry about the possibility of any drug having potentially harmful effects. It is of course true that many drugs can be dangerous at high doses, but it is for this reason that doctors only prescribe small quantities of drugs which should not be exceeded. Drugs which can have carcinogenic effects usually only cause cancer in a minority of patients, and are used because their benefits vastly outweigh the risks. Meanwhile, potentially teratogenic drugs are not prescribed to pregnant women, and mutgenic drugs are usually only used in chemotherapy, where the mutagenic effect is required to kill off cancer cells. All in all, doctors are provided with a vast quantity of information about harmful effects in the British National Formulary and have been trained to make careful decisions about which drugs to prescribe to patients.