The medicinal chemist attempts to design and synthesize a pharmaceutical agent that has a desired biological effect on the human body or some other living system. Such a compound could also be called a ‘drug’, but this is a word that many scientists dislike because society views the term with suspicion. With media headlines such as ‘Drugs Menace’ or ‘Drug Addiction Sweeps City Streets’, this is hardly surprising. However, it suggests that a distinction can be drawn between drugs that are used in medicine and drugs that are abused. Is this really true? Can we draw a neat line between ‘good drugs’ like penicillin and ‘bad drugs’ like heroin? If so, how do we define what is meant by a good or a bad drug in the first place? Where would we place a so-called social drug like cannabis in this divide? What about nicotine or alcohol? The answers we get depend on who we ask. As far as the law is concerned, the dividing line is defi ned in black and white. As far as the party-going teenager is concerned, the law is an ass. As far as we are concerned, the questions are irrelevant. Trying to divide drugs into two categories—safe or unsafe, good or bad—is futile and could even be dangerous.

First, let us consider the so-called ‘good’ drugs used in medicines. How ‘good’ are they? If a drug is to be truly ‘good’ it would have to do what it is meant to do, have no toxic or unwanted side effects, and be easy to take. How many drugs fit these criteria? The short answer is ‘none’. There is no pharmaceutical compound on the market today that can completely satisfy all these conditions. Admittedly, some come quite close to the ideal. Penicillin, for example, has been one of the safest and most effective antibacterial agents ever discovered. Yet, it too has drawbacks. It cannot kill all known bacteria and, as the years have gone by, more and more bacterial strains have become resistant. Moreover, some individuals can experience severe allergic reactions to the compound. Penicillin is a relatively safe drug, but there are some drugs that are distinctly dangerous. Morphine is one such example. It is an excellent analgesic, yet there are serious side effects, such as tolerance, respiratory depression, and addiction. It can even kill if taken in excess.

Barbiturates are also known to be dangerous. At Pearl Harbor, American casualties were given barbiturates as general anaesthetics before surgery. However, because of a poor understanding about how barbiturates are stored in the body, many patients received sudden and fatal overdoses. In fact, it is thought that more casualties died at the hands of the anaesthetists at Pearl Harbor than died of their wounds. To conclude, the ‘good’ drugs are not as perfect as one might think. What about the ‘bad’ drugs then? Is there anything good that can be said about them? Surely there is nothing we can say in defence of the highly addictive drug known as heroin? Well, let us look at the facts about heroin. It is one of the best painkillers we know. In fact, it was named heroin at the end of the nineteenth century because it was thought to be the ‘heroic’ drug that would banish pain for good. Heroin went on the market in 1898, but five years later the true nature of its addictive properties became evident and the drug was speedily withdrawn from general distribution. However, heroin is still used in medicine today—under strict control, of course. The drug is called diamorphine and it is the drug of choice for treating patients dying of cancer. Not only does diamorphine reduce pain to acceptable levels, it also produces a euphoric effect that helps to counter the depression faced by patients close to death. Can we really condemn a drug which does that as being all ‘bad’? By now it should be evident that the division between good drugs and bad drugs is a woolly one and is not really relevant to our discussion of medicinal chemistry.

All drugs have their good and bad points. Some have more good points than bad and vice versa, but, like people, they all have their own individual characteristics. So how are we to defi ne a drug in general?

One definition could be to classify drugs as ‘compounds which interact with a biological system to produce a biological response’. Th is definition covers all the drugs we have discussed so far, but it goes further. There are chemicals that we take every day and which have a biological effect on us. What are these everyday drugs? One is contained in all the cups of tea, coffee, and cocoa that we consume. All of these beverages contain the stimulant caffeine. Whenever you take a cup of coffee, you are a drug user. We could go further. Whenever you crave a cup of coffee, you are a drug addict. Even children are not immune. They get their caffeine ‘shot’ from Coke or Pepsi. Whether you like it or not, caffeine is a drug. When you take it, you experience a change of mood or feeling. So too, if you are a worshipper of the ‘nicotine stick’. The biological effect is different. In this case you crave sedation or a calming influence, and it is the nicotine in the cigarette smoke which induces that effect. There can be little doubt that alcohol is a drug and, as such, causes society more problems than all other drugs put together. One only has to study road accident statistics to appreciate that fact. If alcohol was discovered today, it would probably be restricted in exactly the same way as cocaine. Considered in a purely scientific way, alcohol is a most unsatisfactory drug. As many will testify, it is notoriously difficult to judge the correct dose required to gain the beneficial effect of ‘happiness’ without drifting into the higher dose levels that produce unwanted side effects, such as staggering down the street. Alcohol is also unpredictable in its biological effects. Either happiness or depression may result, depending on the user’s state of mind. On a more serious note, addiction and tolerance in certain individuals have ruined the lives of addicts and relatives alike. Our definition of a drug can also be used to include other compounds which may not be obvious as drugs, for example poisons and toxins. They too interact with a biological system and produce a biological response—a bit extreme, perhaps, but a response all the same. The idea of poisons acting as drugs may not appear so strange if we consider penicillin. We have no problem in thinking of penicillin as a drug, but if we were to look closely at how penicillin works, then it is really a poison. It interacts with bacteria (the biological system) and kills them (the biological response). Fortunately for us, penicillin has no such effect on human cells. Even those drugs which do not act as poisons have the potential to become poisons—usually if they are taken in excess. We have already seen this with morphine. At low doses it is a painkiller; at high doses, it is a poison which kills by the suppression of breathing. Therefore, it is important that we treat all medicines as potential poisons and treat them with respect. There is a term used in medicinal chemistry known as the therapeutic index , which indicates how safe a particular drug is. The therapeutic index is a measure of the drug’s beneficial effects at a low dose versus its harmful effects at a high dose. To be more precise, the therapeutic index compares the dose level required to produce toxic effects in 50% of patients with the dose level required to produce the maximum therapeutic effects in 50% of patients. A high therapeutic index means that there is a large safety margin between beneficial and toxic doses. The values for cannabis and alcohol are 1000 and 10, respectively, which might imply that cannabis is safer and more predictable than alcohol. Indeed, a cannabis preparation (nabiximols) has now been approved to relieve the symptoms of multiple sclerosis. However, this does not suddenly make cannabis safe. For example, the favourable therapeutic index of cannabis does not indicate its potential toxicity if it is taken over a long period of time (chronic use). For example, the various side effects of cannabis include panic attacks, paranoid delusions, and hallucinations. Clearly, the safety of drugs is a complex matter and it is not helped by media sensationalism. If useful drugs can be poisons at high doses or over long periods of use, does the opposite hold true? Can a poison be a medicine at low doses? In certain cases, this is found to be so. Arsenic is well known as a poison, but arsenic-derived compounds are used as antiprotozoal and anticancer agents. Curare is a deadly poison which was used by the native people of South America to tip their arrows such that a minor arrow wound would be fatal, yet compounds based on the tubocurarine structure (the active principle of curare) are used in surgical operations to relax muscles. Under proper control and in the correct dosage, a lethal poison may well have an important medical role. Alternatively, lethal poisons can be the starting point for the development of useful drugs. For example, ACE inhibitors are important cardiovascular drugs that were developed, in part, from the structure of a snake venom. As our definition covers any chemical that interacts with any biological system, we could include all pesticides and herbicides as drugs.

They interact with bacteria, fungi, and insects, kill them, and thus protect plants. Even food can act like a drug. Junk foods and fizzy drinks have been blamed for causing hyperactivity in children. It is believed that junk foods have high concentrations of certain amino acids which can be converted in the body to neurotransmitters. These are chemicals that pass messages between nerves. If an excess of these chemical messengers should accumulate, then too many messages are transmitted in the brain, leading to the disruptive behaviour observed in susceptible individuals. Allergies due to food additives and preservatives are also well recorded.

Some foods even contain toxic chemicals. Broccoli, cabbage, and cauliflower all contain high levels of a chemical that can cause reproductive abnormalities in rats. Peanuts and maize sometimes contain fungal toxins, and it is thought that fungal toxins in food were responsible for the biblical plagues. Basil contains over 50 compounds that are potentially carcinogenic, and other herbs contain some of the most potent carcinogens known. Carcinogenic compounds have also been identified in radishes, brown mustard, apricots, cherries, and plums. Such unpalatable facts might put you off your dinner, but take comfort—these chemicals are present in such small quantities that the risk is insignificant. Therein lies a great truth, which was recognized as long ago as the 15^th century when it was stated that ‘Everything is a poison, nothing is a poison. It is the dose that makes the poison’. Almost anything taken in excess will be toxic. You can make yourself seriously ill by taking 100 aspirin tablets or a bottle of whisky or 9 kg of spinach. The choice is yours! To conclude, drugs can be viewed as actual or potential poisons. An important principle is that of selective toxicity . Many drugs are effective because they are toxic to ‘problem cells’, but not normal cells. For example, antibacterial, antifungal, and antiprotozoal drugs are useful in medicine when they show a selective toxicity to microbial cells, rather than mammalian cells. Clinically effective anticancer agents show a selective toxicity for cancer cells over normal cells. Similarly, effective antiviral agents are toxic to viruses rather than normal cells.

KEY POINTS

• Drugs are compounds that interact with a biological system to produce a biological response.
• No drug is totally safe. Drugs vary in the side effects they might have.
• The dose level of a compound determines whether it will act as a medicine or as a poison.
• The therapeutic index is a measure of a drug’s beneficial effect at a low dose versus its harmful effects at higher dose. A high therapeutic index indicates a large safety margin between beneficial and toxic doses.
• The principle of selective toxicity means that useful drugs show toxicity against foreign or abnormal cells but not against normal host cells.