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D1 Pharmaceutical products
Medicines have been used to treat illness and disease for thousands of years, well before the development of chemistry as a science. Papyri record the use of herbal medicines by the Ancient Egyptians as far back as 2100 BC, and the Chinese have been using some traditional Chinese medicines for over 5000 years. Herbal and folklore medicines were crude preparations derived from plants, animals and minerals; in the 19th century much work was carried out on the isolation and extraction of pure medicinal compounds from plants, which allowed the extracts to be studied.Very few drugs used today are based on these remedies, however, as most were found to be either ine ective or toxic. The 20th century saw a vast increase in our understanding of the processes occurring in the body that are responsible for causing diseases, and this has aided the understanding of the mechanisms of how drugs work against the diseases. Drug therapy has come a long way since herbal and folklore medicines of the past; the majority of drugs are not derived from natural sources (although their structures may be based on natural products) but are synthesised in the chemistry laboratory. Nowadays, a large amount of research is carried out to develop speci c drugs to target speci c processes, in the hope that safer and more e ective drugs can be developed. To begin with, we need to de ne the terms drug and medicine. These terms are often used interchangeably, but they do have slightly di erent de nitions. A drug is any substance that, when applied to or introduced into a living organism, brings about a change in biological function through its chemical action. The change in biological function may be for the better, i.e. in the treatment of diseases, or for the worse, i.e. poisons, which cause toxicity. Drugs can be: • relatively crude preparations, obtained by extracting plant or animal materials • pure compounds isolated from natural sources • semi-synthetic compounds, produced by chemical modi cation of pure natural compounds • synthetic compounds. The last of these is the most recent and common; most drugs are wholly synthetic. A medicine is something that treats, prevents or alleviates the symptoms of disease. Medicines thus have a therapeutic action. Medicines are usually compound preparations, which means they contain a number of ingredients: the active drug itself plus non-active substances that improve the preparation in some way, e.g. improve the taste, consistency or administration of the drug. Drugs produce an e ect on the body by interacting with a particular target molecule. This target molecule is usually a protein, such as an enzyme or receptor, but may also be another molecule such as DNA or
CHEMISTRY FOR THE IB DIPLOMA © CAMBRIDGE UNIVERSITY PRESS 2011
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Describe the physiological e ects of medicines and drugs on the body Explain the stages involved in the development of a new drug Describe the various routes that can be used to administer drugs Describe the terms ‘therapeutic window’, ‘tolerance’ and ‘side e ects’ and relate how dose of the drug can a ect its physiological e ect
Note on naming drugs The international non-proprietary name (INN) has been used in the naming of the drugs in this chapter. In the USA, some drugs have a di erent name or are spelt slightly di erently; these so-called United States adopted names (USAN) are written in brackets following the INN. For example, the INN is paracetamol, whereas the USAN is acetaminophen; it has thus been written: paracetamol (acetaminophen). Where the proprietary name (trade name) has been included for the drug, it is followed by the symbol ®. For example: diazepam (valium®). Some illicit drugs, such as methamphetamine, have ‘street’ names – these have been included in brackets after the drug name.
Enzymes are biochemical catalysts that catalyse nearly all the chemical reactions that occur in the body. Receptors are proteins found on the surface of cells or inside cells that bring about a response in that cell when molecules bind to them.
D MEDICINES AND DRUGS
In general, a drug or medicine has one or more of the following e ects on the body: • alters the physiological state, including consciousness, activity level or coordination • alters incoming sensory sensations • alters mood or emotions Enzymes are biochemical catalysts that catalyse nearly all the chemical reactions that occur in the body. Receptors are proteins found on the surface of cells or inside cells that bring about a response in that cell when molecules bind to them.
lipids in the cell membrane. When the drug binds to its target molecule, it can either stop it from functioning or stimulate it; in either case, the binding of the drug to its target produces some kind of biological e ect, which can either cause a bene cial (therapeutic) e ect on the body or a harmful (toxic) e ect.
The placebo effect
A placebo is something that looks exactly like a real medicine but does not contain any active drug in it; it is made from an inert substance such as starch (if it is formulated as a tablet). Placebos are used in clinical trials of new drugs (see next page). It is found that some people who take the placebo feel better, even though it contains only inactive ingredients. This is known as the placebo e ect. It is not fully understood why the placebo e ect occurs: it may be purely psychological, i.e. the person taking the placebo believes that they are taking the active drug and therefore anticipates that it will have some bene cial e ect on them; this makes them feel better after taking it. However, other researchers believe that actual physical changes occur in the body after taking a placebo, such as the release of endorphins (naturally occurring opioids that can reduce pain and stress). Another reason why placebos may seem to cause improvements in health is because some symptoms may get better or worse naturally during the course of an illness. Therefore, any improvements may be attributed to placebos incorrectly when they are in fact a natural healing of the condition.
There are many stages involved in the drug development process, and it can take as many as 12 years and cost hundreds of millions of dollars to bring a new drug onto the market. Research and development of new drugs is carried out mainly by pharmaceutical companies. The decision on which disease or condition to research is based on a number of factors, with probably the biggest factor being economic considerations – i.e. is the market big enough to give a pro t? Diseases of Westernised countries show a bigger return than those in developing countries, and thus conditions such as obesity and depression are more popular targets than, for example, tropical diseases. Other considerations include medical reasons (Is there a medical need for the new drug?) and scienti c reasons (Is there much known about the disease?). In any case, the ultimate goal of the research is to either nd a drug that is better than existing drugs available for the same disease, i.e. more e ective and with fewer side e ects, or to nd a drug to treat a new disease, e.g. HIV/AIDS in the 1980s. The rst stage in the drug development process is the identi cation of lead (rhymes with ‘seed’) compounds. This is through biological testing of compounds obtained by, for example: • isolation from natural sources • chemical synthesis • searching through existing ‘banks’ of compounds already synthesised. Lead compounds have a desirable biological activity that is therapeutically relevant. They generally do not have a high amount of biological activity and are not ideal drug candidates to take forward
2 D MEDICINES AND DRUGS CHEMISTRY FOR THE IB DIPLOMA © CAMBRIDGE UNIVERSITY PRESS 2011
to the clinic – for example they may have undesirable side e ects. They act as a starting point, however, for chemical modi cation: a number of analogues are synthesised and tested to nd more active and less toxic compounds, which can then be further developed. This is known as lead optimisation. Once a compound has been chosen for further development, the next stage is to test that compound for toxicity in animals. Toxicity testing involves a range of di erent studies that look for di erent types of toxicities when the drug is given over di erent time periods. A number of drugs fail at this stage of the development process, and therefore alternative drug structures need to be identi ed and then developed.
If the drug is shown to be relatively safe in animals, it is then given to humans in clinical trials. This is the next stage of the drug development process, and its aim is to nd out if the drug is e ective in humans and whether or not it is safe to use (drugs may be non-toxic in animals yet toxic in humans – there may be variation in the way that di erent species are a ected by drugs). There are three phases of clinical trials. The rst phase (known as Phase I) is carried out on a small number of healthy volunteers (usually less than 100), and its purpose is to nd the dose range of the drug that gives a therapeutic e ect and also to identify any side e ects. If the drug passes Phase I, it then enters Phase II clinical trials, where it is tested on a small number of volunteer patients who have the disease or condition on which the drug acts. Phase II establishes whether or not the drug is e ective in these patients and also identi es any side e ects. If deemed safe and e ective, the drug then enters Phase III. In Phase III clinical trials, the drug is tested on a much larger group of volunteer patients. This phase con rms the e ectiveness of the drug in the larger group and compares its activity with other existing drug treatments or placebo. For example, half of the patients are given the new drug and half given the placebo (they will not know which they have been given, and usually neither will the investigators in the study). The drug is assessed to see if it causes more of an improvement of the condition and fewer side e ects in the patients to whom it has been given compared with those people given the placebo. Phase III clinical trials assess whether the drug is truly e ective or whether any bene cial e ects seen are due to the placebo e ect. Phase III trials may also identify side e ects not found in previous trials, as the number of patients exposed to the drug is larger. If the drug passes Phase III clinical trials, then a marketing authorisation may be obtained by the pharmaceutical company from the relevant regulatory authority, which allows the drug to enter the market and be used on patients in the wider community.
Toxicity used to be assessed by determining what is known as the LD50 of that particular drug. LD50 is the dose of the drug required to kill 50% of the animals tested (‘LD’ thus stands for lethal dose). However, measuring the LD50 can result in the deaths of a large number of animals, and so many countries have phased out this test in favour of other tests in which few or no animal deaths result. Another drawback with LD50 is that it does not give any information on long-term toxicity of the drug or toxicities that are non-lethal, for example infertility or brain damage.
The case of thalidomide
Testing procedures for new drugs are far more comprehensive nowadays than they were 50 years ago; toxicity testing is carried out on at least two species of animals, and a number of di erent toxicities are looked for, including teratogenicity studies (toxicity to the foetus) in pregnant animals. In the 1950s, however, it was not a requirement for new drugs to
Not all adverse side e ects will be identi ed by these clinical trials, because only a relatively small number of patients are included in the trials for a relatively short period of time. Therefore the patients in the studies may not be fully representative of the patients who will take the drug when it is marketed, and rare side e ects, or those that occur only after longterm use, may not be identi ed. Therefore, in many countries, post-marketing surveillance of approved drugs is in operation, which evaluates the drug’s longterm safety in the wider patient population. In some cases, a drug that has been on the market for a number of years may be withdrawn because of serious side e ects reported after widespread use.
CHEMISTRY FOR THE IB DIPLOMA © CAMBRIDGE UNIVERSITY PRESS 2011
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usually it is an undesirable e ect.e. In animal studies. then the TD50 is 100 times larger than the ED50. Therefore. morphine is a strong analgesic used to treat pain. If a drug has a high (or wide) therapeutic index. i. For example. so therefore it would require a 100-fold increase in the therapeutic dose to cause a toxic e ect in 50% of the population. nausea and vomiting – these are side e ects of morphine. one that alleviates symptoms or treats a particular disease. This tragedy could have been avoided if the drug had been evaluated for teratogenicity before it was marketed. it was also e ective at relieving sickness and so was widely given to pregnant women in their rst three months of pregnancy to alleviate morning sickness. The result was devastating. For example. factors such as age. i.be tested on pregnant animals because it was not known that drugs could pass from the mother to the foetus and cause abnormalities. this means that there is a large di erence between the dose of the drug that causes a therapeutic e ect compared with the dose that causes a toxic e ect. 75 mg of aspirin is given once daily as an anti-clotting agent in heart attack victims. e.e. it relates the dose of a drug required to produce a desired therapeutic e ect to that required to produce a toxic e ect. especially if it is caused by taking the drug in relatively large doses. if the TI is 100. i. Side e ect: an unintended secondary e ect of the drug on the body. whereas 300–900 mg up to four times daily may be given when used as an analgesic for pain relief. and these e ects may be a therapeutic e ect or a side e ect. but in some patients it can cause constipation. paracetamol (acetaminophen) can cause irreversible damage to the liver when taken in overdose – this is a toxic e ect. then it may be called a toxic e ect. The therapeutic index (TI) of a drug is the ratio of the toxic dose to the therapeutic dose. a high therapeutic index is therefore a desirable property of a drug. we said that it is any substance that brings about a change in biological function through its chemical action. Those drugs with therapeutic indexes less than 2 are said to have a narrow therapeutic index – this type of drug must be used with caution. When we described the term ‘drug’ above. The sedative thalidomide was introduced in the late 1950s and was used throughout the world. Also. For example. This range of doses of a drug that gives safe e ective therapy is known as the therapeutic window. Individual patients vary considerably in their response to drugs. and a number dying in infancy.g. it is important to know the range of doses over which a drug may be given safely. as it was thought to be safe with very few side e ects.: TI = TD50 ED50 Therapeutic window: the range of doses of a drug (or range of concentrations of drug in the blood plasma) that gives safe. with thousands of children being born with missing or malformed limbs. and therefore these drugs will be more likely to cause toxic e ects. and so in the early 1960s toxicity studies were widened to include this test for all drugs that were to be used in pregnant women. As well as being a sedative. ED50: the dose required to produce a therapeutic e ect in 50% of those tested (‘ED’ stands for e ective dose). Relationship between drug dose and physiological effect Therapeutic e ect: a desirable and bene cial e ect. as there is very little di erence between the therapeutic and toxic dose. sex and weight can all a ect how e ective (or how toxic) the drug is. e ective therapy. If the side e ect is harmful to the body. some conditions may require higher doses of drug than others. the TI is usually the ratio of the TD50 to the ED50.e. 4 D MEDICINES AND DRUGS CHEMISTRY FOR THE IB DIPLOMA © CAMBRIDGE UNIVERSITY PRESS 2011 . Therefore drugs cause physiological e ects on the body. TD50: the dose required to produce a toxic e ect in 50% of the animals tested (‘TD’ stands for toxic dose).
Oral The majority of drugs are given orally. rectal. This means that the patient may be at more risk of toxic side e ects. The advantage of the oral route is that it is convenient for the patient and is easy to self-administer. When certain drugs are given repeatedly to a patient. This is especially important for drugs with a narrow therapeutic index. For example. to treat haemorrhoids) or can enter the bloodstream and have an e ect on other parts of the body (e.g. the drug would be ine ective. the drug would show toxic e ects. morphine suppositories to treat cancer pain). and so larger and larger doses are needed to produce the same e ect. capsules. if they are unconscious or if they are vomiting. Pulmonary Drugs are administered to the lungs in the form of gases/volatile liquids (e. Routes of administration of drugs There are various routes by which a drug can be administered to a patient. Also some drugs. in the form of tablets. topical and by injection. for example by desensitising the target receptors with which the drug binds so that it is not able to produce its e ect. conscious or unconscious.g.g. Rectal Drugs are incorporated into suppositories for administration into the rectum. taken by mouth. the body is able to prepare the drug more quickly for excretion so that lower levels remain in the body to cause an e ect 2 the body may adapt so that it o sets the e ect of the drug. i. It is important that the dose strength and frequency of dosing is such that the blood concentration of the drug is kept within the therapeutic window. disadvantages are that the onset of drug action is relatively slow because the drug must rst be absorbed from the gut. and tolerance to the drug may develop. i.g. e. They are useful if the patient is not able to take oral medication: for example.e. syrups and suspensions. are destroyed by enzymes in the gut and so cannot be given by this route. the speed at which the drug needs to act and the condition of the patient. pulmonary. general anaesthetics) or aerosol/dry powder inhalers (e. blood levels increase and enter the therapeutic window. the intensity of the therapeutic response to a given dose may change with time.g. and are then absorbed into the bloodstream. but as the dose is repeated. insulin. to treat CHEMISTRY FOR THE IB DIPLOMA © CAMBRIDGE UNIVERSITY PRESS 2011 D MEDICINES AND DRUGS 5 .The therapeutic window may also be used to describe the range of concentrations of drug in the blood plasma that gives safe e ective therapy – below this range of concentrations. above this. blood levels of drug are below the therapeutic level (unless it is injected directly into the bloodstream).g. Tolerance may develop for two possible reasons: 1 repeated use of the drug stimulates increased metabolism of that drug. At the start of therapy with a drug. opioids such as morphine will cross into the brain and cause pain relief. such as: the chemical and physical properties of the drug. e. Tolerance is when the body becomes less responsive to the e ects of the drug. as described above. Which route is chosen is dependent on a number of factors. Drugs given by suppository can have either a local e ect (e. where they can travel to their site of action.e. The ve major routes of administration are: oral. They pass into the stomach and intestines.
containing nicotine) may also be used and allow penetration of the drug through the skin for access to the blood circulation. Intravenous injections are the most common. By injection Examiner’s tip ‘By injection’ is referred to on the IB syllabus as the parenteral route. Certain drugs can irritate the stomach lining directly. Is this a therapeutic e ect or a side e ect of aspirin? 3 Is a drug with a narrow therapeutic window more or less likely to cause toxic side e ects than a drug with a wide therapeutic window? Learning objectives D2 Antacids Normally the pH in the stomach is between 1 and 2. caused by drinking too much alcohol. making the stomach lining more susceptible to acid. ointments and lotions. they are used when a rapid therapeutic response is required. whereas drugs such as aspirin can lower the production of mucus in the stomach. eating large (especially fatty) meals. smoking or stress. owing to the production of hydrochloric acid by the millions of gastric glands that line the stomach. This route is also useful if treatment of a lung disease such as asthma is required. but if the drug is dissolved or suspended in oil.g. Subcutaneous injections are injected directly under the skin.g. thigh or buttock. as the drug is delivered directly to its site of action. There are three main types of injection: intravenous. bacteria) that may enter the digestive system with food. resulting in ulceration. intramuscular and subcutaneous. Test yourself 1 What is the ultimate purpose of clinical trials? 2 Aspirin can cause erosion of the stomach lining. so the low pH plays a role in the body’s natural immunity to disease-causing microorganisms. irritation to the stomach lining can occur by the production of excess acid – for example. Intramuscular injections are injected into skeletal muscle. pepsin. absorption of drug into the blood is slow. which breaks down proteins) require a low pH for optimum catalytic activity. The stomach is maintained at such a low pH for two main reasons: (1) the acidic environment is not tolerated by the majority of microorganisms (e. because the drug is injected directly into the bloodstream. for example. The lungs have a very large surface area. Aqueous solutions of drug are rapidly absorbed into the bloodstream. dermatitis or skin infections. ‘parenteral’ means any route other than via the gut. (2) the digestive enzymes in the stomach (e. A layer of mucus lines the stomach. usually in the arm. but transdermal patches (e. then the drug will be released slowly from the muscle into the blood to give a sustained release of the drug over a long period.g. so includes injection. This can result in the following: CHEMISTRY FOR THE IB DIPLOMA © CAMBRIDGE UNIVERSITY PRESS 2011 • Discuss the use of antacids to treat excess acidity in the stomach 6 D MEDICINES AND DRUGS . Topical administration is used primarily for local e ects such as treating acne. and therefore absorption of the drug into the blood is very rapid and thus the drug has a fast onset of action. although strictly speaking. Topical This refers to applying the drug to the skin in the form of creams. and protects the stomach wall from damage by the acid. giving a sustained e ect. the pulmonary route and the topical route. Insulin is given by subcutaneous injection. However.asthma).
The most commonly used antacids are metal hydroxides. carbonates and hydrogencarbonates (bicarbonates). caused by acid penetrating the mucous layer.: • magnesium hydroxide • aluminium hydroxide • calcium carbonate • sodium hydrogencarbonate. causing a burning sensation • peptic ulcer: erosion of part of the gut lining. discomfort or burning sensation and allowing repair of the mucous layer. Antacids are used to treat these conditions. which can produce constipation.g. e. The rationale for using these two di erent antacids is that magnesium salts are faster acting and so work quickly to neutralise the acid. magnesium salts in repeated doses can cause a laxative e ect. These form a ‘raft’ that oats on top of the stomach contents.g.2 moles of: a sodium hydrogencarbonate b aluminium hydroxide? CHEMISTRY FOR THE IB DIPLOMA © CAMBRIDGE UNIVERSITY PRESS 2011 D MEDICINES AND DRUGS 7 . Also. The neutralising reactions for hydroxide salts are: Al(OH)3(s) + 3HCl(aq) → AlCl3(aq) + 3H2O(l) Mg(OH)2(s) + 2HCl(aq) → MgCl2(aq) + 2H2O(l) Metal carbonates and hydrogencarbonates react with the acid to give the salt plus water plus carbon dioxide. In the case of peptic ulcer.indigestion: irritation of the stomach lining caused by excess acid. thus reducing re ux into the oesophagus. such as magnesium salts and aluminium salts (usually magnesium and aluminium hydroxides). as internal bleeding can occur. producing pain or discomfort in the upper abdomen and/or nausea • heartburn (acid re ux): acid from the stomach rising up into the oesophagus. e. Aspirin and other related antiin ammatory drugs can cause ulcers in some patients. so the time interval between doses is increased. • Test yourself 4 How many moles of HCl would be neutralised by 0. thus allowing the ulcer to heal. antifoaming agents may sometimes be included in the preparation. for example activated dimeticone (dimethicone). which relieves atulence. thus relieving the pain. but aluminium salts have a slower and more prolonged e ect. Alginates may also be found in some antacid preparations. neutralisation of the acid prevents further erosion of the gut lining. Some antacid preparations contain mixtures of two di erent antacids. They are weakly basic compounds that neutralise the acid. which causes heartburn. but this is o set by aluminium salts. This can be a serious condition if left untreated.: CaCO3(s) + 2HCl(aq) → CaCl2(aq) + H2O(l) + CO2(g) NaHCO3(s) + HCl(aq) → NaCl(aq) + H2O(l) + CO2(g) Because carbon dioxide can cause bloatedness and atulence.
8 D MEDICINES AND DRUGS CHEMISTRY FOR THE IB DIPLOMA © CAMBRIDGE UNIVERSITY PRESS 2011 . which is a key enzyme in the synthesis of prostaglandins. which means that even if pain is felt by the patient. such as morphine. redness. the patient is not as aware of it. Some researchers believe that paracetamol may stop the production of prostaglandins (other than by COX inhibition) in the brain. leading to an in ammatory response (swelling. preventing the transmission of pain signals. for example. • • • Describe the di erent ways that analgesics cause pain reduction in the body Explain how derivatives of salicylic acid are used as mild analgesics. When injury to a tissue occurs. O C carboxylic acid O C carboxylic acid OH OH O C H3C OH alcohol / phenol salicylic acid ester O acetylsalicylic acid Figure D1 Structures of salicylic acid and acetylsalicylic acid (aspirin). resulting in vomiting and gastric bleeding. Mild analgesics. Willow bark contains a compound called salicin. temporarily bind to opioid receptors in the brain and spinal cord. it is still in widespread use. Acetylsalicylic acid is the chemical name for aspirin – it is an ester of salicylic acid and is far less irritating to the stomach than salicylic acid. opioids increase the tolerance to pain. even though pain in the a ected tissue is still occurring. In general. and compare the advantages and disadvantages of aspirin and paracetamol (acetaminophen) Compare the structures of the opioid analgesics – morphine. which is a sugar derivative of salicylic acid. mild analgesics intercept the pain stimulus at the source of the pain (except paracetamol). began to be used medically and over 100 years on. Mild analgesics Aspirin As far back as the 5th century BC. prostaglandins are synthesised in the damaged tissue cells and bind to receptors. Strong analgesics. including the induction of pain. and which gets converted to salicylic acid in the body. prevent the production of prostaglandins in the body by inhibiting an enzyme known as cyclooxygenase (COX). usually by inhibiting the production of pain mediators called prostaglandins. a derivative of salicylic acid.Learning objectives D3 Analgesics Analgesics are drugs that reduce pain.e. This blocks the transmission of pain signals in the brain and increases the pain perception threshold: i. which are then interpreted as pain. whereas strong analgesics temporarily bind to opioid receptors in the brain. The analgesic action of paracetamol is still unclear. even though it has been in clinical use for over 50 years. Morphine and compounds that have morphine-like e ects are known as opioids (opium-like). such as aspirin and ibuprofen. in ammation and fever. it was known that chewing willow bark could give pain relief. called acetylsalicylic acid (Figure D1). this stimulates sensory nerve bres at the site of the injury to send signals to the brain. fever). Salicylic acid (Figure D1) is a good analgesic but causes severe irritation of the stomach lining. They also cause dilation (widening) of the blood vessels in the damaged tissue. codeine and diamorphine – and discuss their advantages and disadvantages Prostaglandins cause a number of physiological e ects in the body. In the 1890s. There are two main types of analgesics: mild analgesics and strong analgesics.e. They exert their pain relief action in di erent ways. heat and pain at the site of injury) and can also stimulate the hypothalamus in the brain to cause an increase in body temperature (i. Also. they are more able to tolerate it.
paracetamol is not anti-in ammatory and does not prevent blood clotting • paracetamol can be used safely in children. Aspirin is also taken in low doses to help prevent recurrent heart attack or stroke in patients who have previously su ered a heart attack or stroke. the opioid analgesics are strong analgesics used for moderate to severe pain. It belongs to a group of drugs known as nonsteroidal anti-in ammatory drugs (NSAIDs). Another drawback of aspirin is that it is not recommended to be taken by children under 16 years because it has been associated with Reye’s syndrome. except in overdose. especially those people who su er from asthma. a potentially fatal condition that a ects all organs of the body. so is used to treat fewer medical conditions than aspirin. This can lead to peptic ulcer and possibly stomach bleeding in some patients. Paracetamol (acetaminophen) Paracetamol (Figure D2) is a mild analgesic that also reduces fever. in whom aspirin can trigger an asthma attack. Another disadvantage of using aspirin is that some people may be sensitive to it (known as hypersensitivity). such as arthritis. and conditions in which both pain and in ammation are present. It is useful in treating painful conditions such as headache. side e ects with paracetamol are rare. CHEMISTRY FOR THE IB DIPLOMA © CAMBRIDGE UNIVERSITY PRESS 2011 D MEDICINES AND DRUGS 9 . paracetamol and codeine are often used together. However. such as headache or toothache. further research is needed in this area. aspirin exerts its e ects through the inhibition of an enzyme called COX. H3C C NH O amide HO alcohol / phenol Figure D2 The structure of paracetamol. it can cause liver damage (and less frequently kidney damage) when taken in overdose.Aspirin is used all over the world as an analgesic and antiin ammatory agent. As we have already seen. one of the side e ects of aspirin is gastric irritation. especially the brain and liver. Sometimes mild analgesics may be combined with strong analgesics in some preparations: for example. However. one of which is maintaining the mucous layer in the stomach. such as in terminally ill patients. fever. whereas aspirin should be avoided in children under 16 years due to risk of Reye’s syndrome • aspirin can cause side e ects such as gastric irritation and hypersensitivity reactions in some patients. It can be used safely in babies and children and has very few side e ects. both directly by the drug itself but mainly indirectly through its inhibition of prostaglandin synthesis and therefore depletion of the protective mucous layer. of which ibuprofen is also a member. prostaglandins also have a number of other roles in the body. Therefore. which plays a key role in prostaglandin synthesis. via its anti-blood-clotting e ect. fever and in ammation. A number of studies have also indicated that low-dose aspirin may prevent certain cancers. It does not reduce in ammation and does not have an anticlotting e ect. As well as mediating pain. in particular colorectal cancer. Strong analgesics Whereas mild analgesics such as aspirin and paracetamol are used for relatively mild pain. where it causes liver damage. The advantages and disadvantages of aspirin and paracetamol are: aspirin has an anti-in ammatory and anti-blood-clotting e ect so can • be used to treat in ammation and prevent heart attack and stroke. which may lead to death.
by the ester groups. Codeine. thus codeine is converted to morphine. although in smaller proportions. when codeine enters the body. the only di erence being a methoxyl (–OCH3) group on the benzene ring in codeine instead of a hydroxyl (–OH) group (an –OH group attached directly to a benzene ring gives rise to a phenol) in morphine. lipid-soluble molecules across and hinders large. which remove the methyl group to give a hydroxyl group. which can take part in hydrogen bonding. some of it is acted on by enzymes. Note that the tertiary amine and benzene ring are essential for analgesic activity. is also found naturally in opium. These include analgesia. to form two ethanoate ester groups. Diamorphine is more lipid-soluble (owing to the replacement of the –OH groups. The di erence in the structures is that diamorphine contains two ester (CH3COO–) groups. This juice is known as opium (the Greek word for ‘juice’). morphine and diamorphine. whereas morphine contains two –OH groups. sedation. They are used medically for pain relief and treatment of cough and diarrhoea. Diamorphine is synthesised by an esteri cation reaction between the two hydroxyl groups in morphine and ethanoic acid. they are very similar in structure. a milder analgesic than morphine. The chemical structures of codeine and morphine are shown in Figure D3.Opioids Opioids have been used for thousands of years. it accounts for approximately 10% of the opium mixture. which contains a mixture of approximately 25 di erent nitrogen-bearing compounds (known as alkaloids). It is this conversion to morphine that accounts for the therapeutic properties of codeine. Morphine was rst isolated in 1803 and is chie y responsible for the biological e ects of opium. a feeling of wellbeing. they were originally derived from the juice of unripe seed pods of the poppy Papaver somniferum. As can be seen. ether alcohol / phenol O benzene ring H3CO benzene ring HO H3C ester O benzene ring O N-CH3 amine O N-CH3 amine O N-CH3 amine HO alcohol codeine HO alcohol morphine H3C ester O O diamorphine Figure D3 Structures of codeine. Diamorphine (heroin) (Figure D3) is a semi-synthetic morphine derivative. A tertiary amine has N joined to three C atoms (three alkyl groups). suppression of the cough re ex and constipation. the most important of which is morphine. which cannot) than morphine and therefore is able to cross the blood–brain barrier more easily and enter the brain (the blood–brain barrier is essentially a lipid barrier that prevents the entry of potentially toxic substances from the capillaries into the brain – it allows small. polar CHEMISTRY FOR THE IB DIPLOMA © CAMBRIDGE UNIVERSITY PRESS 2011 10 D MEDICINES AND DRUGS . Interestingly. Opioids cause a number of e ects on the body through binding to opioid receptors.
dreamy and relaxed state known as euphoria. respiratory depression (slowed or shallow breathing). pain in the internal organs. and the drug user soon starts to need larger and larger doses to retain this ‘rush’. Users who inject heroin intravenously are also at increased risk of infection from hepatitis or HIV. and to control distressing cough in lung cancer patients. it enters the brain quickly and so causes a ‘euphoric rush’. Milder opioids such as codeine are used to relieve moderate pain. Effects of opioid analgesics Strong opioids such as morphine and diamorphine are used medically for the relief of severe pain. dependence and tolerance develop quickly. it is hydrolysed by enzymes to the monoester (only one ester group present) and to morphine. due to its constipating e ect.molecules). If the user is denied the drug. withdrawal symptoms occur. Opioid analgesics have a number of side e ects associated with their use: in the short term they can cause nausea and vomiting. There are two types of dependence: psychological dependence. Once diamorphine has entered the brain. such as liver and lungs). As well as dulling pain. Users may nd that they can no longer a ord to pay for the increasing doses needed and so resort to criminal activity in order to pay for their drugs. cold sweats. thus requiring higher doses to be taken to cause the same e ect (therapeutic or euphoric).e. Opioid dependence is a worldwide problem and is associated with a signi cant amount of crime. which bind to opioid receptors and produce an analgesic e ect. in the long term they cause dependence and tolerance. They are commonly used to relieve the pain associated with cancer in terminally ill patients. in which the body cannot function without the drug and deprivation results in withdrawal symptoms. Treatment of opioid dependence is di cult. including anxiety. in which the drug taker craves the drug if deprived of it for a short time and must get further supplies in order to satisfy their need to take the drug. constipation. they cause a pleasant. chronic constipation and decrease in sex drive. Because heroin is lipophilic. Codeine is also used as a cough suppressant for dry coughs and as an anti-diarrhoeal drug. vomiting and jerking of the legs. Abuse of opioids Opioids have been taken for non-medical reasons for centuries. and physical dependence. whereas patients taking opioids for medical reasons generally su er only physical dependence. Tolerance occurs in both types of user. Illicit drug users su er both physical and psychological dependence. they are especially e ective in visceral pain (i. Morphine may also be used for the short-term control of diarrhoea. CHEMISTRY FOR THE IB DIPLOMA © CAMBRIDGE UNIVERSITY PRESS 2011 D MEDICINES AND DRUGS 11 . However. it may involve a gradual reduction of the dose of the drug and administration of a substitute called methadone. which also binds to opioid receptors but has a prolonged action and reduces the craving and prevents withdrawal symptoms. with heroin also causing a feeling of warmth and thrill when injected intravenously. spread by sharing needles. due to its cough-suppressant e ect. drowsiness and euphoria.
how does diamorphine di er from morphine? Learning objectives D4 Depressants Depressants are drugs that depress (i. which is characterised by a feeling of extreme sadness and despair.e. causing a reduction in brain activity. however. slow) the nerve impulses in the brain and spinal cord (known as the central nervous system (CNS)).Test yourself 5 Name the two functional groups attached to the phenyl ring in aspirin below: O C OH O C H3C O 6 Structurally. reduced heart rate and reduced rate of breathing. The e ects of CNS depressants are dose-dependent. Depression is treated with antidepressants such as uoxetine hydrochloride (Prozac®) (Figure D4). the blood and the urine Describe some e ects of taking ethanol with other drugs Identify and describe the structures of some benzodiazepines and uoxetine Note: CNS depressants are not to be confused with the medical condition ‘depression’. Two common examples of CNS depressants are benzodiazepines (used to treat anxiety and/or insomnia) and alcohol. to relieve associated symptoms of depression. their e ects change as the dose of the drug increases. they induce sleep. such as anxiety (see benzodiazepines later on page 16). a chemical involved in wellbeing. • • • • • Outline the general e ects of CNS depressants Discuss the social and physiological e ects of drinking alcohol Describe the methods used to detect alcohol in the breath. coma and ultimately death. F3C CH2 CH3 NH2 Cl– + O CH2 Figure D4 Structure of ﬂuoxetine hydrochloride. sometimes so severe that it can lead to suicide. they produce a calming e ect and relieve anxiety without causing sleep. Because they act on the CNS. i. which acts by increasing the levels of serotonin in the brain. they are also referred to as CNS depressants. they can cause unconsciousness. an antidepressant.e. at higher doses. At low to moderate doses. 12 D MEDICINES AND DRUGS CHEMISTRY FOR THE IB DIPLOMA © CAMBRIDGE UNIVERSITY PRESS 2011 . Some CNS depressants may be used alongside antidepressants. at very high doses.
accidents at work. social and commercial pressures continue to have a strong in uence. Short-term effects • • • • • • • • loss of concentration mood changes. such as a feeling of euphoria often an increase in con dence. withdrawal e ects occur when alcohol intake is stopped suddenly and include severe tremor. domestic violence. slurred speech. aggressive (leading to violence) or dangerous. CHEMISTRY FOR THE IB DIPLOMA © CAMBRIDGE UNIVERSITY PRESS 2011 D MEDICINES AND DRUGS 13 . thus preventing infection of the puncture site from occurring. Ethanol has some medical e ects: for example it is used as an antiseptic. • • • • Alcohol abuse can have detrimental e ects on the drinker’s family and on society as a whole: it can result in driving accidents. agitation and racing heart – this is known as ‘delirium tremens’ cirrhosis of the liver heart disease increased risk of several types of cancer. and in extremely large amounts it can result in coma and death. When taken internally as an alcoholic beverage. which can result in o ensive behaviour loss of coordination. It may also be used to prevent infection of minor cuts and abrasions. Many governments have sought to minimise alcohol abuse by passing laws or initiating educational campaigns. breast cancer and bowel cancer (even small amounts of alcohol taken daily can increase the risk of the latter two types of cancer) if taken in large amounts during pregnancy. risk-taking behaviour (such as dangerous driving) loss of self-restraint. The short-term and long-term physiological and social e ects of drinking alcohol are listed below. a study has also shown that drinking alcohol during pregnancy can increase the risk of leukaemia in the child. however. but more studies are being carried out to further investigate this nding. which can result in silly. non-domestic violent attacks and breakdown of the family unit. These e ects change as the amount of alcohol consumed increases. Long-term effects dependence occurs with long-term regular intake of large amounts of alcohol (referred to as ‘alcoholism’). including liver cancer. it can cause deformities and brain and heart defects in the developing foetus. swabbed onto skin before injections – it kills bacteria and some viruses and fungi present on the skin surface.Physiological and social effects of ethanol Alcohol is the name commonly given to ethanol (C2H5OH). anxiety. Ethanol is also sometimes used to harden the skin to prevent bedsores in bed-ridden patients. di culty in carrying out even simple tasks drowsiness and induction of sleep extremely high intake may result in coma and death. ethanol acts as a CNS depressant and can have a number of physiological e ects on the body.
the breath enters a fuel cell with two platinum electrodes and any alcohol in the breath gets chemically oxidised. there are also desktop analysers that are located in police stations and that may 14 D MEDICINES AND DRUGS CHEMISTRY FOR THE IB DIPLOMA © CAMBRIDGE UNIVERSITY PRESS 2011 . Therefore. so laws are in place to limit the amount of alcohol that can be drunk before driving a motor vehicle.Detection methods for ethanol Drink-driving is a major cause of road tra c accidents. resulting in the generation of an electric current. In the lungs. inability to concentrate. Alcohol can have a number of e ects that impair the ability of that person to drive safely: reduced coordination. Breath testing This is a common test carried out at the roadside and involves the motorist breathing into a device that detects the amount of alcohol in the breath. The half equations are as follows: Conversion of ethanol to ethanoic acid: C2H5OH + H2O → CH3COOH + 4H+ + 4e− Conversion of dichromate(VI) to chromium(III) ions: Cr2O72− + 14H+ + 6e− → 2Cr3+ + 7H2O The overall equation is: 2Cr2O72− + 3C2H5OH + 16H+ → 4Cr3+ + 3CH3COOH + 11H2O orange green Oxidation Reduction The oxidation of ethanol may also be shown as: C2H5OH + 2[O] → CH3COOH + H2O where [O] represents oxygen from the oxidising agent. In the UK and many other countries. These crystals are orange. an equilibrium is established between alcohol dissolved in blood plasma and alcohol in the breath. The degree of colour change is directly related to the level of alcohol in the breath. which contains dichromate(VI) crystals. Alcohol levels can be detected in a number of ways: by testing the breath. and any ethanol present in the motorist’s breath will cause a change in colour of the crystals to green as they are reduced to chromium(III) ions. type of hand-held analyser. the amount of alcohol in the breath can be used to determine the amount of alcohol in the blood plasma. this limit is 80 mg of alcohol per 100 cm3 of blood plasma. the higher the current. As well as hand-held analysers that are used at the roadside. All these can contribute to causing accidents while driving. These chemically based breathalysers are now largely replaced with a newer. blood or urine. and this colour change is measured using a photocell. which uses a fuel cell sensor to detect alcohol in the breath. increase in con dence leading to risky manoeuvres. impaired judgement and a reduction in reaction time. the ethanol is rst oxidised to ethanal and then to ethanoic acid in the process. There are three main ways that alcohol can be measured in the breath: the rst is by a chemical test in the form of a breathalyser. In this type of analyser. more accurate. the more alcohol present.
so care must be taken when alcoholic drinks are taken by people on certain medication (the increase in e ect may be harmful to the body. to indicate the concentration of ethanol in the sample. However.be used to provide evidence if the case goes to court. as O–H vibrations are also present in water vapour in the atmosphere and breath. have an e ect on the body that is greater than the sum of their individual e ects. this can possibly result in unconsciousness and even death CHEMISTRY FOR THE IB DIPLOMA © CAMBRIDGE UNIVERSITY PRESS 2011 Synergism is when two or more drugs. to the detector. respectively. Di erent compounds have di erent retention times. Depending on the type of bonds and functional groups present in the molecule. the C–H vibration at 2950 cm−1 is used to test for ethanol. Infrared spectroscopy is based on the vibration of bonds within molecules. and thus ethanol can be identi ed in the sample due to its retention time. and in some cases fatal). Ethanol will produce major absorption bands at 3340 and 2950 cm−1. and this uses infrared spectroscopy to detect ethanol in the sample of breath provided. The amount of energy absorbed when a breath sample is present is compared with the amount absorbed when no sample is present. This sample vapour is carried through a column by an inert gas such as helium (the gas is known as the mobile phase). the column is packed with solid particles that are coated with a non-volatile liquid (known as the stationary phase). given at the same time. certain drugs can increase the e ects of other drugs when given at the same time. and thus the concentration of ethanol in the sample can be determined by looking at the area under the peak that has the particular retention time characteristic for ethanol (when run under the same conditions). The time taken for a particular compound to travel through the column to the detector is known as its retention time. Compounds that are less volatile and/or that dissolve more readily in the liquid stationary phase travel more slowly through the column. through the sample of breath. The intoximeter measures the amount of infrared energy absorbed at a particular frequency as it passes from the source (the infrared lamp). This technique involves injecting a small sample of the blood or urine into the machine and vaporising it. with each peak representing a compound in the sample. The newer models of intoximeter now contain a combination of infrared analyser and fuel cell analyser. Synergistic effects of ethanol Ethanol is an example of a drug that can increase the e ects of other drugs. molecules will absorb infrared radiation that corresponds in energy to these vibrations (see Option A on the CDROM). a particular absorption spectrum will be produced that is characteristic for that molecule. Blood and urine analysis Samples of blood or urine may be taken from the suspect and sent for analysis by gas–liquid chromatography (see Option A). The compounds in the sample are detected and recorded as a series of peaks. D MEDICINES AND DRUGS 15 . The area under the peak is used to determine the concentration of the compound when compared with a known standard. The compounds in the sample travel through the column at a rate dependent on their boiling points and their relative solubilities in the liquid stationary phase. Two examples of the synergistic e ects of alcohol with other drugs are: 1 an increased sedative e ect when alcohol is taken with other CNS depressants such as benzodiazepines and barbiturates. In other words. An example is an intoximeter. for increased accuracy and speci city. corresponding to the O–H and C–H vibrations.
What is the name given to this type of e ect? 9 Copy the structure below and draw a circle around the amide functional group. diazepam and nitrazepam are very similar in structure – they both contain two benzene rings. however. 16 D MEDICINES AND DRUGS CHEMISTRY FOR THE IB DIPLOMA © CAMBRIDGE UNIVERSITY PRESS 2011 . Two examples of benzodiazepines are diazepam (Valium®) and nitrazepam (Mogadon®) (Figure D5). They are mainly used to relieve anxiety and induce sleep but are also used as anticonvulsants in epilepsy and as a premedication before operations. by reference to the IBO Chemistry Data booklet. it is mentioned as being a CNS depressant in the syllabus.2 an increased risk of haemorrhage (bleeding) in the stomach when alcohol is taken with aspirin. CNS depressants other than alcohol Benzodiazepines are another type of commonly used CNS depressant. it has a nitro. Therefore.substituent in the same position. Benzodiazepines cause dependence and withdrawal symptoms. As can been seen from Figure D5. H3C N O Cl chloro C N imine benzene ring diazepam O N amide H3C benzene ring N O O2N C N O2N nitro C N imine benzene ring nitrazepam Figure D5 Structures of diazepam and nitrazepam. They act by binding to speci c receptors in the brain called benzodiazepine receptors.substituent whereas in nitrazepam. and some studies indicate that in many countries they are still being overprescribed. The only di erence between diazepam and nitrazepam is that in diazepam the fused benzene ring has a chloro. it can result in increased drowsiness in that patient. one of which is fused to a diazepine ring (the seven-membered rings shown in Figure D5). they have been overprescribed by doctors in the past. whereas nitrazepam is used as a sleeping tablet for insomnia. Examiner’s tip Fluoxetine hydrochloride (Figure D4) has only a low potential to act as a CNS depressant. The diazepine ring contains an amide group and a C=N (known as an imine). H 3C benzene ring amide Test yourself 7 Why is the O–H vibration at 3340 cm−1 not used in the infrared detection of ethanol in the breath? 8 If alcohol is drunk by a patient taking benzodiazepines. it is advised that they should be used only in severe or distressing cases of anxiety and insomnia. To reduce incidences of dependence. diazepam is useful in treating anxiety. you should be able to identify it and describe its structure.
As well as these e ects. both of which have been linked to brain damage after long-term use of these drugs. Derivatives of amphetamine include methamphetamine (‘speed’. ca eine and nicotine. reduced appetite. stimulants also cause an increase in respiration and heart rate. as well as directly binding to receptors at the end of the nerve junctions. This system is responsible for subconscious control over most of the internal organs in the body and prepares the body for stressful situations. Each one will now be looked at in turn. HO HO H C OH epinephrine secondary amine CH3 primary amine H CH2 N H CH2 CH CH3 N H amphetamine H C H H C H N H H phenylethylamine Figure D6 Structures of epinephrine and amphetamine. Epinephrine and norepinephrine have many e ects. including the phenylethylamine structure. ‘crystal meth’) and ecstasy (‘E’). they increase brain activity and mental alertness. Amphetamines are similar in structure to epinephrine and norepinephrine. an List the general physiological e ects of CNS stimulants Compare the structures and e ects of amphetamines and epinephrine (adrenaline) Describe the short. unlike depressants.D5 Stimulants Stimulants also act on the CNS but. increasing blood ow to the muscles. They are used to treat narcolepsy (a condition in which the person falls asleep suddenly at inappropriate times during the day) and have also been used to aid weight loss and to enhance performance. including: increasing blood pressure and heart rate. There are di erent types of stimulants. CHEMISTRY FOR THE IB DIPLOMA © CAMBRIDGE UNIVERSITY PRESS 2011 D MEDICINES AND DRUGS 17 . Amphetamines are known as sympathomimetic drugs. known as the ‘ ght or ight’ response. They reduce drowsiness. dilation of the pupils in the eyes. They are believed to exert their actions by increasing the release of norepinephrine at nerve junctions. as they are derivatives of phenylethylamine (the structures of amphetamine and epinephrine are shown in Figure D6).and longterm e ects of nicotine Describe the e ects of ca eine and compare its structure with that of nicotine Sympathomimetics mimic the e ects of stimulating the sympathetic nervous system. lethargy and fatigue and also improve attention and focus. increasing the breakdown of glycogen to glucose in the liver to raise blood glucose levels. They can also suppress the appetite and so have been used in the management of obesity to facilitate weight loss. for example by students before exams or by athletes. Learning objectives • • • • Amphetamines Amphetamines are closely related to epinephrine (adrenaline) and norepinephrine (noradrenaline). and increasing mental alertness. three common examples are amphetamines. dilating the vessels in the lungs to increase oxygen supply to the heart and muscles. Their actions result in e ects including increased heart rate. which are major hormones and neurotransmitters (chemicals that allow communication between nerve cells) of the sympathetic nervous system.
bowel and stomach cancers. Thus tobacco has a number of detrimental e ects on the body and accounts for millions of deaths per year worldwide. and prolonged and high doses can result in the individual experiencing delusions and hallucinations. The long-term e ects of nicotine and tobacco smoke are not the same. Because it is a lipophilic molecule (its structure is shown in Figure D7). Nicotine is the most active ingredient of tobacco and is highly addictive. Long-term e ects of smoking tobacco other than those described above for nicotine.increase in mental alertness. feelings of well-being (euphoria) and increased energy. Tolerance and dependence develop quickly after repeated use. and 90% of lung cancer deaths are due to smoking. and an increased risk of several cancers. which are described below. Nicotine exerts its actions by binding to receptors and causing the release of a number of neurotransmitters and hormones. 18 D MEDICINES AND DRUGS CHEMISTRY FOR THE IB DIPLOMA © CAMBRIDGE UNIVERSITY PRESS 2011 . it crosses the blood–brain barrier easily (it can take less than 10 seconds for inhaled nicotine to reach the brain from the lungs). throat. nicotine patches). These released neurotransmitters and hormones do not just cause stimulation of the CNS but have a number of other e ects around the body. smoke-free legislation and reducing tobacco advertising. A number of the diseases associated with smoking are not due to nicotine. the addictive properties. include lung diseases. but to the highly complex mixture of chemicals that are found in tobacco smoke (as many as 260 di erent chemicals have so far been identi ed). Lung cancer is the leading cause of cancer-related deaths in the UK and USA. However. increased appetite and a craving for tobacco. withdrawal symptoms include irritability. liver. Effects of nicotine N tertiary amine CH3 N Figure D7 The structure of nicotine. withdrawal symptoms and social and peer pressures associated with smoking make it a di cult habit to quit. Nicotine is highly addictive. widespread availability of nicotine replacement therapy (e.g. Long-term effects of nicotine high blood pressure increased risk of heart disease and coronary thrombosis (heart attack) increased risk of stroke increased risk of peptic ulcer and slower healing of peptic ulcer (possibly due to an increase in gastric acid secretion). These include increased education and support. It is a volatile alkaloid and is easily inhaled with tobacco smoke into the lungs. such as bronchitis and emphysema. including lung. Short-term effects of nicotine • • • • • • • • • increased alertness and concentration relief of tension reduced appetite increased blood pressure and heart rate decreased urine output. Many countries have introduced measures to try to minimise the impact of tobacco smoking on society. including epinephrine and norepinephrine. wakefulness.
ca eine can cause dependence. a cup of ground co ee contains between 80 and 120 mg of ca eine. whereas a cup of tea can contain as much as 90 mg of ca eine (although the average is 40 mg per cup). increasing urinary output. There are many di erent types of antibacterial drugs. It has some similarities to the structure of nicotine. he left out a plate of bacterial culture exposed to the atmosphere for a few days and when he came back to look at it. They were discovered by chance in 1928 by a Scottish physician and microbiologist called Alexander Fleming. Ca eine is believed to exert its actions in the body by binding to and blocking speci c receptors that normally bind to a molecule called adenosine. a naturally occurring basic compound containing nitrogen). As well as CNS e ects. irritability and an inability to concentrate and focus. it increases alertness and concentration and reduces feelings of fatigue. in that it also contains a tertiary amine and heterocyclic rings containing nitrogen (like nicotine. ca eine can act as a weak diuretic. These drugs are able to be toxic to the bacteria while being relatively safe to the patients that take them. who was working on some bacterial cultures at the time. By mistake. with withdrawal symptoms including headaches. some energy drinks and some medicines. O HN O N CH3 N N CH3 D6 Antibacterials Antibacterial drugs are one of the most frequently prescribed medicines. Ca eine is also found in cola. it is an alkaloid. The structure of ca eine is shown in Figure D8. They achieve this by acting on sites in the bacterial cell that are either di erent from those in our cells or that do not exist in our cells at all. irritability and sleeplessness. He noticed that the plate was dotted with bacterial colonies CHEMISTRY FOR THE IB DIPLOMA © CAMBRIDGE UNIVERSITY PRESS 2011 Learning objectives • • • Describe how penicillin was discovered and developed Explain the mechanism of action of penicillins and describe the e ects of modifying the sidechain Discuss the importance of patient compliance and the implications of penicillin overprescribing D MEDICINES AND DRUGS 19 . it can also act as a respiratory stimulant and is used clinically to reduce incidence of apnoea (cessation of breathing) in premature infants. In high doses. such as painkillers. Describe the di erence between the structures of theobromine and ca eine. however. but the most commonly prescribed are the penicillins. H3C amide O CH3 N O N CH3 N aimine N tertiary amide Figure D8 The structure of caffeine. Ca eine acts as a stimulant of the CNS: in small doses. In some people. ca eine can cause anxiety. Test yourself 10 Theobromine (shown below) is found in chocolate and is structurally related to ca eine. he saw that it had been contaminated with a mould (which he later identi ed as Penicillium notatum).Caffeine Ca eine occurs naturally in co ee and tea.
The penicillin rst isolated and puri ed by Florey and Chain is called benzylpenicillin (or penicillin G. allowing the bacteria to withstand high osmotic pressures. In early 1941. C CH3 Although a number of structures for penicillin had been proposed R CH N by scientists. this penicillin has a number of disadvantages. however. (a) The general structure of penicillins. see Figure D9). by making derivatives of penicillin G that have modi ed side-chains (R in the general penicillin structure in Figure D9) that can resist stomach acid and be given by the oral route. resulting in a weakened cell wall and causing the bacterial cell to burst due to the high osmotic pressure caused by water from the surroundings entering the bacterial cell. if the ring is broken in any way. b Action=of H2C penicillin on bacterial cell walls R Bacterial cells di er from our own cells in that they contain a cell wall. the penicillin is no longer active. He called this substance penicillin but was not able to isolate and purify the active substance and concluded that it was too unstable to be used clinically. working in Oxford. However. 20 D MEDICINES AND DRUGS CHEMISTRY FOR THE IB DIPLOMA © CAMBRIDGE UNIVERSITY PRESS 2011 .except around the area contaminated by the mould and concluded that the mould was producing a substance that was somehow inhibiting the growth of these bacterial cultures. which contains a polymer made up of sugar chains cross-linked with peptides (short stretches of amino acids). this polymer has a mesh-like structure and gives strength to the cell wall. and in 1940 they were able to produce enough penicillin to be tested in mice. and by 1943 penicillin was being produced on a large scale for use by the armed forces. such as by acid or bacterial enzymes (see below). followed up on Fleming’s ndings. This β-lactam ring is essential for the antibacterial activity of penicillin. the rst tests of penicillin in humans were carried out. (b) the side-chain for benzylpenicillin (penicillin G). it was not until 1945 that X-ray crystallography studies by 3 O Dorothy Hodgkin at Oxford University con rmed β-lactam be a bicyclic it to ring COOH carboxylic acid structure (Figure D9) containing a β-lactam ring (a cyclic amide that is part of a four-membered ring). It was not until a decade later that scientists Howard Florey and Ernst Chain. Scientists have overcome this problem. Penicillin acts by irreversibly inhibiting an enzyme involved in the cross-linking of this polymer. one of which is that it is easily broken down by stomach acid and must be given by injection. Florey. a amide b O C R H N N R= S CH3 CH3 COOH carboxylic acid H2C O β-lactam ring Figure D9 All penicillins have the same basic bicyclic structure. but different penicillins have different side-chains. Chain and Fleming shared the Nobel amide Prize in Physiology or Medicine in 1945 ‘for the discovery of penicillin H O N S and its curative e ect in various infectious diseases’. inatime to save many lives during the latter part of World War II.
TB is treated with a combination of antibacterial agents over a long period. scientists have now developed penicillins that are less sensitive to the e ects of this enzyme. and some bacteria are resistant to more than one type. thus it is important to carry out research into the discovery and development of new antibacterial agents. however. otherwise failure to kill all the bacteria in the infection can lead to development of resistance in those bacteria that survive. therefore. both for human use and for animals. improving the way that antibiotics are prescribed. which causes tuberculosis (TB) in humans. Some strains of bacteria have developed ways to counteract the e ects of certain penicillins by producing an enzyme known as penicillinase. Penicillin G is an example of a penicillin that is inactivated by penicillinase. and if the patient does not follow their treatment regime properly. for example. Test yourself 11 The antibacterial agent on the right is phenoxymethyl penicillin. can become resistant to the antibacterial agents used to treat it if. It is important. Mycobacterium tuberculosis. Thus. that antibacterials are taken according to the instructions of the doctor (called patient compliance) and that the whole course of treatment is taken. Bacterial resistance has developed not just for penicillins. taken or used in livestock is essential if the development and spread of resistant bacteria is to be controlled. Overprescribing of antibacterials for minor infections has increased the exposure of bacteria to the antibacterial agents and has thus increased the number of resistant bacteria. Antibacterials are also used extensively in animal feeds to lower the occurrence of infections in the livestock. Such widespread bacterial resistance is also due to the extensive use of antibacterials. by modifying the side-chain in the penicillin structure. this can increase the chances of resistance developing in those bacteria. as well as the overuse and misuse of antibacterials. but for most other types of antibacterials too. These antibacterials given to healthy animals can become resistant. which has developed because of the innate ability of bacteria to mutate DNA in order to survive in hostile environments. Copy the structure and draw a circle around the part of the molecule that is essential for its antibacterial activity. making them extremely di cult to kill. Bacterial resistance is a widespread problem. the patient does not take the treatment correctly. O H2C C O O H N N S CH3 CH3 COOH CHEMISTRY FOR THE IB DIPLOMA © CAMBRIDGE UNIVERSITY PRESS 2011 D MEDICINES AND DRUGS 21 . which opens the β-lactam ring of the penicillin. thus rendering it inactive. and these resistant bacteria can be passed on to humans via meat and dairy products.Bacterial resistance The widespread use of penicillins has resulted in the development of bacteria that have become resistant to their antibacterial e ects – this is known as bacterial resistance and arises because of mutations in the DNA of bacteria to aid their survival.
this is particularly true of viruses such as HIV • viruses use the host cell’s own processes and materials to produce new viruses. mumps and polio. Viruses di er greatly in shape and size from one type of virus to the next but. such as the common cold. excrete or grow. Vaccines stimulate the body’s natural defences (the immune system) to produce antibodies against the virus. • • • Outline the main di erences between viruses and bacteria Describe the various modes of action of antivirals Discuss why it is di cult to solve the global AIDS problem. which get assembled into functional new viruses and leave the cell to go on to infect other cells. Antiviral drugs work in a number of ways. such as acquired immunode ciency syndrome (AIDS). they are able to reproduce outside host cells by cell division. also have a lipid envelope that surrounds the capsid (Figure D10). so if infection does occur. Viruses are not considered to be living cells – they do not feed.Vaccines have been used successfully against a number of viruses. despite these di culties. To gain entry into host cells. this must rst be converted into DNA before it is inserted). such as the human immunode ciency virus (HIV). viruses must rst attach to the surface of the host cell. ranging from mild infections. The genetic material of the virus is released into the cytoplasm and is then incorporated into the host cell’s DNA (if the virus contains RNA. and its role is to protect the genetic information in the core. However. It can be di cult to nd e ective methods of preventing and treating viral infections for a number of reasons: • once inside the host cell. and they consist only of what is necessary to invade the host cell and then take over that cell to produce copies of themselves.Learning objectives D7 Antivirals Viruses Viruses are parasites – they invade host cells and use the materials and processes within those cells in order to produce new viruses. the immune system is prepared and can stop the infection before it takes hold. Viruses cause a number of illnesses and diseases. viruses can multiply very quickly and can have already spread throughout the body by the time that symptoms have appeared • viruses can mutate their DNA or RNA. they have a core consisting of their genetic information (carried in the form of either DNA or RNA). including measles. Bacteria. This capsid consists of identical protein sub-units. which can make them resistant to drugs and can prevent vaccinations from being e ective. known as a capsid. also. resulting in a slight change in viral structure. Some viruses. on the other hand. in general. called capsomeres. are living cells and are far more complex in structure and function than viruses. they cannot replicate outside of host cells. The cell then starts producing viral proteins and viral DNA or RNA. several vaccines and antiviral drugs have been developed and used successfully to prevent and treat viral infections. which is surrounded by a protein coat. CHEMISTRY FOR THE IB DIPLOMA © CAMBRIDGE UNIVERSITY PRESS 2011 22 D MEDICINES AND DRUGS . including the e ects and treatment of HIV Treatment and prevention of viral diseases Figure D10 The HIV virus. to potentially fatal diseases. so it can be di cult to design drugs that target only the virus and do not a ect the host cell.
O HN H2N N N N H2 C CH2 O CH2 OH Figure D11 The structure of aciclovir. and also because the virus uses many of the host cell’s processes and materials to replicate. because the virus is able to mutate rapidly. the viral enzyme reverse transcriptase converts the viral RNA into DNA so that it can be integrated into the T cell’s DNA. However. so it is di cult to target the virus without a ecting the host cell too. to gain entry into the cell. AIDS AIDS was rst recognised in 1981 and was found to be caused by the HIV virus a few years later. and they play a vital role in the body’s natural defence against infection. not DNA. There are now believed to be over 33 million people infected with HIV worldwide. HIV infection is so lethal if left untreated because the HIV virus invades cells that form part of the immune system. it stops viral DNA replication and thus stops the virus from multiplying. some of the T cell membrane forms the envelope around the HIV virus. HIV is a retrovirus – its genetic information is carried in the form of RNA. which is used in AIDS treatment. because their immune systems are not strong enough to ght against them. The HIV virus is able to infect these T cells because they contain speci c receptor proteins on their surface to which the virus attaches. Some stop the viruses from infecting host cells by preventing them from binding to the host cell surface and gaining access into the cell.• • • Some alter the cell’s genetic material by becoming incorporated into the growing DNA strand and halting its synthesis. The viral genes contained in the DNA are used to produce viral proteins and viral RNA within the cell. there CHEMISTRY FOR THE IB DIPLOMA © CAMBRIDGE UNIVERSITY PRESS 2011 D MEDICINES AND DRUGS 23 . An example of a drug that acts in this way is aciclovir (acyclovir) (Figure D11). When the newly formed viruses leave the T cell. which is essential to the assembly of functional new HIV viruses. Some drugs used to treat AIDS work in this way. and these get assembled into new HIV viruses. and this results in a decrease in the number of T cells in the body and thus a weakened immune system. Developing a method of eradicating HIV is di cult. The T cell thus stops carrying out its role as an immune cell and instead becomes a factory for HIV viruses. People with AIDS are thus susceptible to potentially fatal infections and also some types of cancer. these cells are white blood cells known as T cells. it inhibits the HIV enzyme protease. Once inside the cell. Some inhibit the activity of enzymes within the host cell that are necessary for the formation of new viruses. which is used to treat cold sores. Death of the T cell can occur due to the viruses exiting the cell. and approximately 2 million deaths occur each year from AIDS. An example is indinavir.
leading to cis and trans isomerism. We will now look at some examples of how the structure of a molecule (or the spatial arrangement of atoms within a molecule) can in uence its ability to produce a therapeutic e ect and. they do not kill the virus. for example. and the rst antiretroviral drug that came onto the market to treat AIDS. more and more patients in poorer countries are now receiving treatment. • • • Describe the importance of geometrical isomerism and chirality in drug action Explain the signi cance of the β-lactam ring to the antibacterial e ect of penicillin Explain why diamorphine is a stronger and faster-acting analgesic than morphine Geometric isomerism Geometric isomerism is a form of stereoisomerism. Cis and trans isomers can have very di erent e ects on the body – one isomer may be able to bind to a speci c target and produce a therapeutic e ect. This compound has a square planar geometry and can exist in both cis and trans forms (Figure D12). azidothymidine (AZT). In the case of geometric isomers. these result when there is restricted rotation somewhere in the molecule. they have saved the lives of millions of people since their introduction. Test yourself 12 In what form do bacteria carry their genetic information and how does this di er for viruses such as HIV? Learning objectives HL D8 Drug action The action of a drug on a particular physiological process in the body (or in a microorganism) is related to the chemical structure of that drug. Geometric isomerism exists in both inorganic and organic molecules. However. Drugs are also available that stop the virus from binding to the T cell’s receptor proteins and thus gaining entry into the host cell. Other viral enzymes that are inhibited by drugs are the viral enzyme that integrates the DNA into the host cell’s DNA (called integrase) and the enzyme that assembles the viral proteins to produce new viruses (called protease). cause a toxic e ect. However. so AIDS su erers in poorer countries (where the majority of AIDS cases are found) would not generally have had access to these life-saving drugs. However. in some cases. both in animal studies and human trials. Much research is also underway to nd an e ective vaccine that can be used against HIV. all these drugs only delay the progression of AIDS. 24 D MEDICINES AND DRUGS . One of these enzymes is reverse transcriptase. this results in termination of DNA synthesis. are some di erences that can be targeted: the HIV virus uses certain viral enzymes in the replication process that are di erent to those found in the host cell. however. to try to stop the spread of the virus. where isomers have a di erent spatial arrangement of atoms. nevertheless. together with a global commitment to make these treatments universally available. and so the virus cannot replicate. The ability of the virus to mutate and change its structure has made it di cult to nd a suitable vaccine that can prime the host’s natural immunity against such variations in structure. to ensure that prevention measures (such as education and condoms) and antiretroviral treatments are available to all. promising results are being reported by researchers. whereas the other isomer may not be able to bind and be totally inactive. the prices of the most commonly used antiretroviral treatments have decreased signi cantly over the last few years and. where a reduction in infection rates has been shown. More work still needs to be done. and an example of an inorganic molecule displaying geometric isomerism is diaminedichloroplatinum(II). AZT inhibits reverse transcriptase and gets incorporated into the DNA strand that is being synthesised by the enzyme.One problem with antiretroviral therapy was that it was expensive. The cis isomer (known as cisplatin) is used in the treatment of cancers such as CHEMISTRY FOR THE IB DIPLOMA © CAMBRIDGE UNIVERSITY PRESS 2011 H3N Pt H3N Cl Cl Cl Pt H 3N NH3 Cl cisplatin transplatin Figure D12 Structures of cisplatin and transplatin. acts by targeting this enzyme. because its structure determines how well the drug is able to bind to a particular receptor or inhibit a particular enzyme.
and two mirror images (known as enantiomers) exist. Once inside the cell. O H N S-thalidomide (teratogenic) O O O N H H N O R-thalidomide O O N H O Figure D15 Enantiomers of thalidomide. These enantiomers can behave very di erently in the body as a result of their di erent shapes when in a three-dimensional environment. (b) the enantiomer is only able to form two bonds with groups at the active site and is inactive. and therefore the groups are in the wrong orientation to bind to DNA. whereas the other enantiomer may not be able to bind as strongly because the groups are in the wrong orientation to form bonds (Figure D14). such as in an enzyme or receptor. Figure D14 Representation of a chiral drug binding to a theoretical enzyme active site. Transplatin (see Figure D12) is ine ective as an anticancer agent. the molecule is said to be chiral. For example. CHEMISTRY FOR THE IB DIPLOMA © CAMBRIDGE UNIVERSITY PRESS 2011 D MEDICINES AND DRUGS 25 . mirror Cisplatin is able to bind to two adjacent guanine residues in the DNA strand and produce its anticancer e ect because the two chloride ions in the molecule are cis. lung cancer and bladder cancer. by binding elsewhere. whereas the other enantiomer may produce a toxic e ect. See Option F on the CD-ROM for an explanation of S-enantiomer. Chirality (optical isomerism) When a molecule has a carbon atom bonded to four di erent groups. preventing the cells from dividing and resulting in cell death. one enantiomer may produce a therapeutic e ect by binding to its target. the two water ligands are released and the platinum forms bonds with nitrogen atoms in two adjacent guanine bases within the DNA. 2+ enzyme active site a A b a B c C D enzyme active site a A b b B H3N Pt H3N OH2 OH2 H3N Pt H3N G G one strand of the DNA double helix no bond c formation D C A B C D D A C B G = guanine Figure D13 The active form of cisplatin and its binding to DNA. one enantiomer may be able to bind e ectively to the enzyme or receptor protein because its functional groups are in the correct orientation to form bonds with the protein. which stops the cell from copying its DNA (known as DNA replication).testicular cancer. In the bloodstream. Cisplatin carries out its HL anticancer action by binding to DNA in cancer cells. there is a slow displacement of the chloride ions by water.This results in the DNA strand becoming distorted. because its chloride ions are trans. In some cases. ultimately leading to cell death. (a) The enantiomer is able to form three bonds with groups at the active site and is active. generating a positively charged activated platinum complex (Figure D13). cisplatin is neutral and will cross the cell membrane into the cell.This activated complex binds strongly to DNA. Thalidomide is an example of a chiral drug that was given as the mixture of enantiomers (known as the racemic mixture) to pregnant women for morning sickness. It was later discovered that one of the enantiomers (the S-enantiomer) was responsible for producing a teratogenic e ect and caused limb deformities in the foetus (Figure D15). Cisplatin is a platinum complex containing two adjacent chloride ions.
The ring contains two carbons and a nitrogen that are sp3 hybridised and that would therefore have bond angles of 109. thus preventing cell wall synthesis. A covalent bond is formed between the enzyme and the carbonyl carbon. testing must be carried out on each enantiomer separately and also on the racemic mixture. and they di er in the side-chain (R). to produce their analgesic e ect. modifying this side-chain can produce penicillins that are more stable to stomach acid and more resistant to penicillinase enzymes.5°. making the carbonyl carbon more δ+. Drugs that act on the CNS. Ring strain O C R O cysteine H N N S CH3 CH3 COOH valine O C R H N N Enz S CH3 CH3 O COOH Figure D16 General structure of penicillin. plus one carbon that is sp2 hybridised and that would normally have a bond angle of 120°. the bond angles are approximately 90°. and this strained β-lactam ring is essential for the antibacterial e ect of penicillins. The β-lactam ring in penicillins is highly strained. such as the opioid analgesics.Giving the single enantiomer would not have helped in the case of thalidomide. The polarity of a drug molecule can in uence how well the drug crosses barriers within the body. To do this. This basic structure is derived from two amino acids called valine (Val) and cysteine (Cys). Polarity For a drug to carry out its therapeutic e ect. Pharmaceutical companies now tend to either synthesise or separate out the active single enantiomer of a drug and develop this instead of the racemic mixture. producing the racemic mixture. making it relatively easy to break open so that the strain can be relieved. As we have already seen. They consist of a four-membered ring (called a β-lactam) fused to a vemembered (thiazolidine) ring. and the β-lactam ring is opened in the process. All penicillins have the basic structure outlined in Figure D16. need to be able to cross into the brain in order to bind to opioid receptors. if a new drug is going to be marketed as the racemic mixture. Penicillins produce their antibacterial e ect by irreversibly inhibiting a bacterial enzyme (called transpeptidase) that forms cross-links in the sugar-peptide layer of the bacterial cell wall. this therefore puts strain on the bonds in the ring. they must rst pass through 26 D MEDICINES AND DRUGS CHEMISTRY FOR THE IB DIPLOMA © CAMBRIDGE UNIVERSITY PRESS 2011 . forming an irreversible covalent bond and resulting in opening of the β-lactam ring. HL Nowadays. and attack of the β-lactam carbonyl carbon by the transpeptidase enzyme. because these atoms are in the form of a four-membered ring. This allows it to be attacked readily by a lone pair of electrons in the transpeptidase enzyme (Figure D16). this irreversible bonding to the enzyme blocks its active site and prevents it from carrying out cross-linking. The amide in the ring is also highly reactive because the lone pair of electrons on the nitrogen cannot overlap with the π bond of the C=O (due to the restrictions of the four-membered ring). such as cell membranes and the blood–brain barrier and can thus a ect the distribution of the drug in the body. as the enantiomers interconvert when in the body. However. it rst needs to reach its site of action in the body (few drugs are delivered straight to their target site – the majority must travel through the body from where they were administered). to give a dipeptide-like structure. Ring strain plays an important role in the antibacterial activity of penicillins. there are many di erent penicillins. The inhibition involves the amide of the β-lactam ring being attacked by the enzyme (the dipeptide-like structure of penicillin is believed to resemble the natural peptide on which the enzyme acts to form cross-links).
The increased analgesic e ect (potency) of diamorphine compared with morphine is believed to be due to more diamorphine penetrating the blood–brain barrier compared with morphine as a result of it being more non-polar. O H3C ester O HO alcohol HO alcohol O N-CH3 O + N-CH3 O N-CH3 H3C ester O O diamorphine H3C ester O O 6-acetylmorphine HO alcohol morphine Figure D17 Conversion of diamorphine into 6-acetylmorphine and morphine. Diamorphine (heroin) is a semi-synthetic derivative of morphine that is identical to morphine except that it contains two ethanoate ester groups instead of the two hydroxyl groups in morphine. which then bind to the opioid receptors and produce an analgesic e ect. These two ester groups make the diamorphine molecule less polar than morphine. which allows it to cross the blood–brain barrier more easily. but in the brain its ester groups are hydrolysed by enzymes. Test yourself 13 Cisplatin binds primarily to guanine bases in DNA. and is thus able to produce a more rapid onset of action (this fast penetration into the brain also produces the ‘euphoric rush’ often described by intravenous heroin users). Diamorphine is able to cross the blood–brain barrier faster than morphine. as mentioned previously. what is the name given to the type of bond formed between the guanine nitrogen and platinum? O N NH N NH2 14 Copy the structure below and draw a circle around the sp2 hybridised carbon in the β-lactam ring: O C C H2 NH N S CH3 CH3 O COOH N deoxyribose 15 Which functional groups in diamorphine make it more lipophilic than morphine and therefore more able to cross the blood–brain barrier? CHEMISTRY FOR THE IB DIPLOMA © CAMBRIDGE UNIVERSITY PRESS 2011 D MEDICINES AND DRUGS 27 . Therefore. The polarity of a drug will a ect its ability to cross this blood–brain barrier – as the barrier consists of lipid membrane.the blood–brain barrier. there is more drug (following hydrolysis) to interact with the opioid receptors. Diamorphine itself does not bind very well to opioid receptors. when we looked at HL opioid analgesics. producing an increased analgesic e ect. non-polar molecules cross more readily than polar molecules. producing 6-acetylmorphine and morphine (Figure D17). The part of the guanine molecule that binds to the platinum complex is shown below. the metabolites responsible for its analgesic effect.
In combinatorial chemistry. which stick out from the surface of the bead. followed by synthesis and biological evaluation of a range of compounds that are structurally related (called a compound library). this target could be a receptor.Learning objectives HL D9 Drug design Earlier in this chapter. producing what is called a combinatorial library. Combinatorial chemistry (or combinatorial synthesis) is usually an automated (or semiautomated) method that can produce a large number of related compounds in a short period of time. where compounds are designed based on what is known about the target molecule (or existing drugs that act on the target). Combinatorial chemistry Combinatorial chemistry has developed owing to the advances that have arisen in the biological testing of compounds. we talked about how the drug development process begins with the search for a lead compound for a particular target. • • • • • Describe how compound libraries are created and used in drug design Discuss the techniques of combinatorial chemistry and parallel synthesis in drug design Describe the use of computers in aiding the drug design and discovery process Discuss how the polarity of a molecule can be modi ed to increase its aqueous solubility and how polarity can a ect absorption and distribution of the drug Describe the use of chiral auxiliaries in the synthesis of single enantiomer drugs Reminder: the ‘lead’ in ‘lead compound’ rhymes with ‘seed’. Instead of synthesising every compound individually. As we discussed. time-consuming and expensive. a lead compound has a desirable biological activity on the target and is generally used as a starting point for the synthesis of more active and less toxic compounds. techniques needed to be developed that could synthesise large numbers of compounds quickly. in order for pharmaceutical companies to produce enough compounds to be used in high-throughput screening. Traditionally. these functional groups covalently bond with the starting material. these compounds in the library are synthesised individually and evaluated to see whether any show activity. The chemical reactions can be carried out using solid-phase techniques or can be prepared in solution. which make better drug candidates to take forward for further development. this technique synthesises a large number of compounds simultaneously. The discovery of lead compounds can involve rational drug design. pharmaceutical companies now tend to use techniques that can produce and evaluate compounds on a much larger scale in order to speed up the discovery of new lead compounds. A method called highthroughput screening can test a large number of compounds against one or more biological targets (for example enzymes) very rapidly. Solid phase This is the most common method used in combinatorial chemistry and involves bonding the starting material for the reaction onto a solid support. This method has been used widely to produce large numbers of peptides (amino acids joined together). and we will use the synthesis of a tripeptide to illustrate this method. These new techniques are called combinatorial chemistry and highthroughput screening. Although this method of lead identi cation is often used in many research departments in universities. a range of di erent starting materials are covalently bonded to separate resin beads. a process that is labour-intensive. Thus. an enzyme or another biomolecule such as DNA. The starting materials (amino acids 28 D MEDICINES AND DRUGS CHEMISTRY FOR THE IB DIPLOMA © CAMBRIDGE UNIVERSITY PRESS 2011 . This support is usually a resin-based bead that contains functional groups at the end of side-chains. A method called mix and split can then be used to produce very large combinatorial libraries (thousands of compounds may be made simultaneously this way).
resin bead A B C Bonding of starting material to bead A B C Combine. Combinatorial libraries consisting of thousands of compounds can be made in this way. in which case. the mix and split process would be repeated the appropriate number of times until the required combinatorial library was produced. the number of portions corresponding to the initial number of starting materials. the beads are then HL combined. and this generates nine di erent dipeptides in three di erent reaction mixtures. in the latter case. Each of the mixtures of beads is then put into a separate reaction vessel and a di erent reactant (amino acid) is added to each mixture. Any mixtures showing favourable activity would then be investigated further to identify the compounds responsible CHEMISTRY FOR THE IB DIPLOMA © CAMBRIDGE UNIVERSITY PRESS 2011 D MEDICINES AND DRUGS 29 . to generate 27 tripeptides in three reaction vessels (Figure D18). if three di erent amino acids were used. each would be bonded onto its own set of beads and then all three sets of beads would be combined. mix and split into three equal portions ABC D ABC E ABC F Addition of reagent and first synthetic reaction This method can be used to synthesise peptides and nonpeptides. The reaction is allowed to proceed. The mixture of beads would then be divided into three equal portions. mixed and then divided (split) into equally sized portions. mix and split into three portions plus addition of next reagent and second synthetic reaction ABCAB DDDE E I I I I I CABC E F F F I I I I 27 products synthesised ABCAB DDDE E GGGGG CABC E F F F GGGG ABCAB DDDE E HHHHH CABC E F F F HHHH Figure D18 Synthesis of a combinatorial library using the mix and split method. the reactants could be any monomeric unit or precursor molecule.in this case) are rst bonded to separate resin beads. mixed and split into three equal portions (each portion contains all nine dipeptides). The beads from all three reaction mixtures are then combined. ABC DDD G ABC E E E H I ABC F F F Combine. these mixtures are usually separated from their solid support and then tested for biological activity as a mixture. Each portion is then put into a separate reaction vessel and is reacted with a further reactant (amino acid). For example. Test yourself 16 How many di erent compounds would be produced if these 27 tripeptides were subjected to the mix and split process a further two times? Mixtures of compounds are produced using this method. with each portion containing a mixture of all three amino acids (Figure D18).
Once a lead compound has been discovered. speeding up the drug discovery process and making it more e cient. not mixtures. such as alcohol. it is also used to produce smaller and more focused libraries. Thus computers can help in reducing the number of compounds that need to be synthesised and tested. Computers in drug design Computers play an important role in the drug design process. It can allow pharmaceutical companies to screen its compound libraries virtually to see which of the structures could be potentially active and therefore lead compounds. receptors or enzymes) studied. but some drugs. the active site of an enzyme and seeing how well it is able to interact with binding regions in the enzyme. Using molecular modelling software.g. the IB syllabus refers to it as a separate method. This can involve ‘docking’ the molecule into. Once the pharmacophore has been derived. Structure modiﬁcation to change polarity Most drugs are administered via the oral route and therefore must rst be absorbed from the gastrointestinal tract before reaching the blood circulation and distributing to the various body tissues. individually so that further tests can be carried out on them. 30 D MEDICINES AND DRUGS CHEMISTRY FOR THE IB DIPLOMA © CAMBRIDGE UNIVERSITY PRESS 2011 . a number of di erent starting materials are reacted with a number of di erent reagents simultaneously. so that more active compounds can be produced. which vary only slightly from the lead compound. This method can be used to screen chemical structures in compound databases to see which structures bind well with the target enzyme (and which should therefore be active) and which do not.HL for the activity. The reactions take place in separate reaction vessels: for example. The mix and split method thus provides an e cient way of producing a large number of compounds to be tested for biological activity and thus speeds up the drug discovery process. to derive the pharmacophore: this describes the type and position of functional groups in the molecule that interact with the target site. three-dimensional models of drug molecules can be produced using computers and their interactions with biological targets (e. wells on a plastic plate. The syllabus uses the term ‘combinatorial chemistry’ to describe the mix and split method. It is often used for lead optimisation and structure–activity relationship determination. This di ers from the mix and split method of combinatorial chemistry described above as it produces separate compounds.The majority of drug absorption occurs in the intestines because they have a very large surface area. for example. Computers can also be used to analyse structure–activity relationships. the method is used to synthesise a large number of analogues individually. Another technique used to produce combinatorial libraries is that of parallel synthesis. These analogues are then tested for biological activity and the information can be used to determine how di erences in the structure a ect activity. the reactions are run in parallel. giving the drug molecule its biological activity. The information can also be used to search compound libraries to see which compounds possess the required pharmacophore. i. Several hundred di erent compounds can be synthesised in parallel using this method.e. any active compounds would then be resynthesised Examiner’s tip Although parallel synthesis is a method used in combinatorial chemistry. can also be absorbed through the stomach. the information can be used to design compounds that possess the necessary characteristics for binding to the target. In parallel synthesis.
For a drug to enter the blood circulation after oral administration. Once in the bloodstream. An example of an acidic drug is aspirin. These drugs can be made into salts by reacting the amine group with a strong acid. this can a ect the amount of drug that gets absorbed. amphetamines and some antidepressants. One way to increase the aqueous solubility of an acidic or basic drug is to make the ionic salt of the drug. where the acid is converted into the anion (COO−). to produce the basic cation. The most common type of salt for basic drugs is the hydrochloride salt. CHEMISTRY FOR THE IB DIPLOMA © CAMBRIDGE UNIVERSITY PRESS 2011 D MEDICINES AND DRUGS 31 . If the rate at which the drug dissolves is slower than the rate at which it gets absorbed. Thus the drug must have the correct balance of aqueous and lipid solubility to be e ectively absorbed and distributed. Many drugs contain an amine group. O carboxylic acid HL O salt C OH + NaOH O C H3C aspirin C O–Na+ + H2O O C O H3C aspirin sodium O Figure D19 Conversion of aspirin into aspirin sodium. such as hydrochloric acid. and the formation of the sodium salt of aspirin is shown in Figure D19. and the formation of uoxetine hydrochloride is shown as an example in Figure D20. such as the opioid analgesics. it must rst dissolve in the aqueous environment of the intestines before it can be absorbed across the lipid membranes of the intestinal wall. this contains a carboxylic acid group that can be reacted with a strong alkali to form the salt. The most common salts of acidic drugs are the sodium salts. the drug needs to travel through the aqueous blood plasma and distribute through the body to reach its site of action (a process that can involve crossing lipid and aqueous environments). F3C H2 C CH3 N H amine fluoxetine O + HCl C H2 F3C H2 C + CH3 N Cl– H2 salt fluoxetine hydrochloride O C H2 Figure D20 Conversion of ﬂuoxetine into ﬂuoxetine HCl. The sodium salt of aspirin is more water-soluble than aspirin and so is absorbed more rapidly into the bloodstream.
H O O COCH3 32 D MEDICINES AND DRUGS CHEMISTRY FOR THE IB DIPLOMA © CAMBRIDGE UNIVERSITY PRESS 2011 . thus forcing the reaction to follow a certain path which favours the production of one of the possible enantiomers (Figure D21). An example in which chiral auxiliaries have been used successfully is in the production of the anticancer drug paclitaxel (Taxol®) (Figure D22) – a natural product. obtained from Paci c yew tree bark.HL Chiral auxiliaries in asymmetric synthesis Many drugs in development contain chiral centres and thus can exist as two enantiomers (non-superimposable mirror images). The physical presence of the chiral auxiliary allows the reagent in the next stage of the reaction to approach from one side of the molecule only. but it is usual for pharmaceutical companies to develop just one enantiomer of a drug. Once the reaction is complete. the chiral auxiliary can then be recycled for use in other experiments. the chiral auxiliary is removed to leave the desired enantiomer. for reasons already explained. As synthetic reactions normally produce a mixture of both enantiomers (a racemic mixture). Semisynthesis of this drug allows it to be made on a large scale and lessens the environmental impact. the synthesis of the racemic mixture may be carried out. One method to achieve asymmetric synthesis involves the use of a chiral auxiliary. H3COC–O O CH3 OH CONH O O OH HO O C O Figure D22 The structure of paclitaxel (Taxol®). for example. this is known as asymmetric synthesis. followed by separation using chiral chromatography (normal chromatography does not separate enantiomers). O without a chiral O auxiliary propanoic acid (non-chiral) normal synthesis O OH + OH NH2 OH NH2 addition of a both enantiomers produced chiral auxiliary removal of O O auxiliary O OH NH2 chiral intermediate NH2 single enantiomer produced Figure D21 The use of a chiral auxiliary in asymmetric synthesis. There are various ways of achieving this. or a synthetic reaction may be used that selectively produces one of the enantiomers of the product. This chiral auxiliary is a pure enantiomer and combines with the non-chiral reactant to form a chiral intermediate. as extracting the drug from its natural source results in killing of the trees. a method must be used to obtain the required single enantiomer of the drug.
anxiety. whereas psilocybin and mescaline are mild hallucinogens. • Psilocybin: a mild hallucinogen with e ects that are milder than those of LSD and include causing distortion in sight.g. in that they are all amines. heightened mood. LSD and psilocybin contain an indole ring. crawling geometric patterns across objects.Test yourself 17 Penicillin G (right) can be made more water-soluble by converting it into a salt. belief in ability to y. draw the structure of a possible salt that can be made from penicillin G. dilated pupils. which subsides once use has stopped. Stimulation of these receptors results in altered nerve transmission. disorientation in time and space. speeding up and slowing down of time and movements. they a ect thought processes and cause distortions in the perception of reality. however its structure can be represented as an indole ring where the 5-membered ring is not closed. feeling of invulnerability. Physical e ects include increase in blood pressure. psilocybin and tetrahydrocannabinol (THC) Compare the structures of LSD. nausea and vomiting. sound and objects. O C C H2 NH S N CH3 CH3 O COOH D10 Mind-altering drugs Humans have used mind-altering drugs derived from plants and fungi for thousands of years. mescaline and LSD These three drugs are all hallucinogens. which is a benzene ring fused to a ve-membered ring containing nitrogen (Figure D23). double vision. mescaline does not contain the indole ring: it is a phenylethylamine-based compound. ashbacks when the drug is not being used. increased sensation of insight. mescaline found in the peyote cactus and cannabis found in the hemp plant Cannabis sativa. By looking at its structure. LSD is a potent hallucinogen. which is found in the ergot fungus. sound and time. mescaline. Some LSD users experience feelings of despair and fear of insanity or death. All three drugs are similar in chemical structure. psilocybin and mescaline is given below. A summary of the various e ects of LSD. Examples include psilocybin. • LSD: a potent hallucinogen causing psychological e ects of distortion of colour. and mood alterations. intense feelings of wonder. dilated pupils. causing sensory distortion. Another common mind-altering drug is lysergic acid diethylamide (LSD). e. spiritual experience. this does not occur naturally but is synthesised from lysergic acid. LSD is not addictive but rapid tolerance can develop. changes in body temperature and increase in blood glucose. found in many species of ‘magic’ mushrooms. Learning objectives • • • Psilocybin. These drugs are believed to exert their hallucinogenic e ects by binding to serotonin receptors in the brain (serotonin is an indolecontaining neurotransmitter that transmits nerve impulses between nerve cells). mescaline and psilocybin Discuss the arguments for and against the legalisation of cannabis D MEDICINES AND DRUGS 33 . CHEMISTRY FOR THE IB DIPLOMA © CAMBRIDGE UNIVERSITY PRESS 2011 Outline the e ects of lysergic acid diethylamide (LSD).
Anxiety. ashbacks. attening of three-dimensional objects. 34 D MEDICINES AND DRUGS CHEMISTRY FOR THE IB DIPLOMA © CAMBRIDGE UNIVERSITY PRESS 2011 . appearance of visual patterns. and the phenylethylamine-based compound mescaline. which are found in the parts of the brain responsible for pleasure. Cannabis is a mild sedative. producing a feeling of relaxation and wellbeing. Cannabis Cannabis (marijuana) is obtained from the owering parts. leaves and seeds of Cannabis sativa. nausea and vomiting. • Mescaline: a mild hallucinogen producing changes in visual perception. cannabis obtained from the resin is called hashish. causing changes in perception of sight and sound. memory. intensi cation of colours. stems. and sensory and time perception. concentration. short-term CH3 OH alcohol benzene ring phenol ether tetrahydrocannabinol (THC) H3C H3C CH2 O CH2 CH2 CH2 CH3 Figure D24 The structure of tetrahydrocannabinol (THC). The main compound in cannabis that is responsible for its activity is tetrahydrocannabinol (THC) (Figure D24). it carries out its e ect by binding to cannabinoid receptors.HL CH2CH3 diethylamide H3CH2C LSD OH P O– N C O CH3 N tertiary amine N H indole ring NH indole ring indole-based H CH2 CH2 N+ CH3 quaternary amine CH3 phosphate O indole ring psilocybin H3CO ethers H3CO OCH3 mescaline N H CH2 CH2 NH2 primary amine H3CO CH2 CH2 H2N Phenylethylamine-based H3CO OCH3 can be represented as similar in structure to non-ring closed indole Figure D23 Structures of the indole-based compounds LSD and psilocybin. as well as slowing down of time. it is also a mild hallucinogen. anxiety.
legally obtainable. owing to cancer-causing agents present in the smoke. • Cannabis can cause serious disease. such as for symptom relief in multiple sclerosis.      CHEMISTRY FOR THE IB DIPLOMA © CAMBRIDGE UNIVERSITY PRESS 2011 D MEDICINES AND DRUGS 35 . Alzheimer’s disease and Parkinson’s disease. Arguments against legalisation • The possibility that cannabis use may lead to using harder drugs such as heroin and cocaine. and some of the arguments for and against legalisation are listed below: Arguments for legalisation • There is strong evidence that cannabis can produce medical bene t in certain cases. Section 20). such as alcohol and tobacco. although tolerated in small amounts in some countries. mood changes and wakefulness. c What possible e ects could occur if alcohol and diazepam were taken together? What is the name given to this type of e ect? d Name a structural di erence between diazepam and nitrazepam (structures are included in the IBO Chemistry Data booklet. and weight gain and increase in appetite for anorexic patients with HIV/ AIDS. Cannabis possession is illegal in most countries. There is much debate as to whether or not cannabis should be legalised. The long-term use of cannabis can lead to withdrawal symptoms. Exam-style questions 1 Ethanol and diazepam are both depressants. heart disease and mental illness. ii State the oxidation and reduction half equations for the oxidation of ethanol and reduction of dichromate(VI). b Name two physiological e ects of using diazepam at moderate doses. One type of breathalyser uses dichromate(VI).memory loss. drugs. including irritability. an increase in the risk of developing mental health problems such as schizophrenia has also been shown after regular use of cannabis. There is also some evidence that cannabis can be e ective in glaucoma. with 4% of the world’s adult population using it at least once per year. a Breathalysers are used to detect ethanol levels in motorists. • Many believe that cannabis is less harmful to the individual than other. • Making cannabis illegal takes away the individual’s personal freedom to choose. Smoking cannabis may also increase the risk of developing lung cancer. decreased concentration and ability to learn. Legalisation of cannabis Cannabis is the most commonly used illicit drug. such as cancer. i Describe the colour change that occurs when alcohol is present in the breath. and can also cause dependence. epilepsy. increased heart HL rate and increased risk of heart attack are other e ects associated with cannabis. relief from nausea and vomiting in patients receiving cancer chemotherapy.
locally? 4 a Name the acid found in the gastric juice in the stomach.  3 Drugs and medicines can have a number of physiological e ects on the body. b Describe how mild analgesics. carry out their analgesic e ect. i Name the enzyme produced by penicillin-resistant bacteria. such as asthma.  ii What e ect does this enzyme have on the activity of the penicillin? Brie y explain why. i There are three main ways of giving a drug by injection. e Drugs can be administered to a patient via a number of di erent routes.  ii State the type of reaction used to convert morphine to diamorphine. such as aspirin and ibuprofen. Write the equation for the reaction between calcium carbonate and this acid. c Discuss why AIDS is such a lethal disease and why it is so di cult to eradicate on a global scale.    36 D MEDICINES AND DRUGS CHEMISTRY FOR THE IB DIPLOMA © CAMBRIDGE UNIVERSITY PRESS 2011 . Describe how they carry out their analgesic e ect.2 Analgesics are used to reduce pain.  iii Which part of the penicillin structure can be modi ed to make the penicillin less sensitive to the actions of this enzyme?  6 a How do viruses and bacteria di er in the way that they replicate? b Name two di erent ways in which antiviral drugs work. d Describe the three main stages in the drug development process. Which of these gives the fastest response. b Calcium carbonate is an antacid used to neutralise excess acid in the stomach. 5 a Brie y outline the mechanism by which penicillins carry out their antibacterial activity. a Morphine and diamorphine are both strong analgesics. a Explain the meaning of the following terms: i therapeutic e ect ii side e ect iii tolerance b What does the term ‘therapeutic window’ mean? c Describe the placebo e ect. c Discuss why alginates are added to some antacid preparations.   c The structures of morphine and diamorphine can be found in Section 20 of the IBO Chemistry Data booklet. and why? ii Which route would be chosen to treat a lung condition.  iii Describe two possible social problems that can occur through heroin addiction.             b Some bacteria have developed resistance to penicillins by producing an enzyme that deactivates the penicillin. i Describe how the structure of diamorphine di ers from morphine. with respect to the functional groups present.
9 a Discuss why cisplatin is an e ective anticancer compound. c Describe two long-term e ects of nicotine consumption.7 Structures can be found in Section 20 of the IBO Chemistry Data booklet. b Draw the β-lactam ring and explain why it is essential for the antibacterial e ect of the penicillins. and write a suitable equation. b Describe two ways that computers can be used in the virtual screening of compounds. HL      8 a Discuss the techniques of combinatorial chemistry (mix and split) and parallel synthesis and explain why they are a more e cient way of discovering new drugs. i It can be described as a sympathomimetic – what does this term mean? ii How does the amine in amphetamine di er to that in epinephrine? b Ca eine and nicotine are also stimulants. c Discuss how aspirin (the structure is included in Section 20 of the IBO Chemistry Data booklet) can be made more water-soluble.         CHEMISTRY FOR THE IB DIPLOMA © CAMBRIDGE UNIVERSITY PRESS 2011 D MEDICINES AND DRUGS 37 . 10 a Describe the similarities in structure between LSD and psilocybin and name two psychological e ects of taking LSD. similar in structure to epinephrine. b Discuss the main arguments for and against cannabis legalisation. d Describe the use of chiral auxiliaries in asymmetric synthesis. Compare their structures in terms of functional groups. Draw the structure of the inactive isomer as part of your answer. a Amphetamine is a CNS stimulant. d Name one long-term e ect of smoking tobacco that is not due to the e ects of nicotine. whereas its geometrical isomer is not.