D Medicines and drugs - pedagogics.capedagogics.ca/cambridge/source_data/options/Options_D.pdf · Drugs produce an e˜ ect on the body by interacting with a particular target molecule

D MEDICINES AND DRUGS 1CHEMISTRY FOR THE IB DIPLOMA © CAMBRIDGE UNIVERSITY PRESS 2011

D Medicines and drugs

D1 Pharmaceutical products

IntroductionMedicines 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

Learning objectives

• 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 drugsThe 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.

2 CHEMISTRY FOR THE IB DIPLOMA © CAMBRIDGE UNIVERSITY PRESS 2011D MEDICINES AND DRUGS

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 effectA 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.

Drug developmentThere 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

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.


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.

Clinical trialsIf 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.

The case of thalidomideTesting 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 long-term use, may not be identi� ed. Therefore, in many countries, post-marketing surveillance of approved drugs is in operation, which evaluates the drug’s long-term 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.

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.


be tested on pregnant animals because it was not known that drugs could pass from the mother to the foetus and cause abnormalities. The sedative thalidomide was introduced in the late 1950s and was used throughout the world, as it was thought to be safe with very few side e� ects. As well as being a sedative, 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, with thousands of children being born with missing or malformed limbs, and a number dying in infancy. This tragedy could have been avoided if the drug had been evaluated for teratogenicity before it was marketed, 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.

Relationship between drug dose and physiological effectWhen we described the term ‘drug’ above, we said that it is any substance that brings about a change in biological function through its chemical action. Therefore drugs cause physiological e� ects on the body, and these e� ects may be a therapeutic e� ect or a side e� ect.

If the side e� ect is harmful to the body, then it may be called a toxic e� ect, especially if it is caused by taking the drug in relatively large doses. For example, paracetamol (acetaminophen) can cause irreversible damage to the liver when taken in overdose – this is a toxic e� ect.

The therapeutic index (TI) of a drug is the ratio of the toxic dose to the therapeutic dose, i.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.

In animal studies, the TI is usually the ratio of the TD50 to the ED50, i.e.:

TI = TD50

ED50

If a drug has a high (or wide) therapeutic index, 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. For example, if the TI is 100, then the TD50 is 100 times larger than the ED50, so therefore it would require a 100-fold increase in the therapeutic dose to cause a toxic e� ect in 50% of the population; a high therapeutic index is therefore a desirable property of a drug. 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, as there is very little di� erence between the therapeutic and toxic dose, and therefore these drugs will be more likely to cause toxic e� ects.

Individual patients vary considerably in their response to drugs; factors such as age, sex and weight can all a� ect how e� ective (or how toxic) the drug is. Also, some conditions may require higher doses of drug than others, e.g. 75 mg of aspirin is given once daily as an anti-clotting agent in heart attack victims, whereas 300–900 mg up to four times daily may be given when used as an analgesic for pain relief. Therefore, it is important to know the range of doses over which a drug may be given safely. This range of doses of a drug that gives safe e� ective therapy is known as the therapeutic window.

Therapeutic e� ect: a desirable and bene� cial e� ect, i.e. one that alleviates symptoms or treats a particular disease.

Side e� ect: an unintended secondary e� ect of the drug on the body; usually it is an undesirable e� ect. For example, morphine is a strong analgesic used to treat pain, but in some patients it can cause constipation, nausea and vomiting – these are side e� ects of morphine.

TD50: the dose required to produce a toxic e� ect in 50% of the animals tested (‘TD’ stands for toxic dose).ED50: the dose required to produce a therapeutic e� ect in 50% of those tested (‘ED’ stands for e� ective dose).

Therapeutic window: the range of doses of a drug (or range of concentrations of drug in the blood plasma) that gives safe, e� ective therapy.


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, the drug would be ine� ective; above this, the drug would show toxic e� ects. At the start of therapy with a drug, blood levels of drug are below the therapeutic level (unless it is injected directly into the bloodstream), but as the dose is repeated, blood levels increase and enter the therapeutic window. 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. This is especially important for drugs with a narrow therapeutic index, as described above.

When certain drugs are given repeatedly to a patient, the intensity of the therapeutic response to a given dose may change with time, and tolerance to the drug may develop.

Tolerance may develop for two possible reasons:1 repeated use of the drug stimulates increased metabolism of that drug,

i.e. 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, for example by desensitising the target receptors with which the drug binds so that it is not able to produce its e� ect.

Routes of administration of drugsThere are various routes by which a drug can be administered to a patient. Which route is chosen is dependent on a number of factors, such as: the chemical and physical properties of the drug, the speed at which the drug needs to act and the condition of the patient, e.g. conscious or unconscious. The � ve major routes of administration are: oral, rectal, pulmonary, topical and by injection.

OralThe majority of drugs are given orally, i.e. taken by mouth, in the form of tablets, capsules, syrups and suspensions. They pass into the stomach and intestines, and are then absorbed into the bloodstream, where they can travel to their site of action. For example, opioids such as morphine will cross into the brain and cause pain relief. The advantage of the oral route is that it is convenient for the patient and is easy to self-administer; disadvantages are that the onset of drug action is relatively slow because the drug must � rst be absorbed from the gut. Also some drugs, e.g. insulin, are destroyed by enzymes in the gut and so cannot be given by this route.

RectalDrugs are incorporated into suppositories for administration into the rectum. They are useful if the patient is not able to take oral medication: for example, if they are unconscious or if they are vomiting. Drugs given by suppository can have either a local e� ect (e.g. to treat haemorrhoids) or can enter the bloodstream and have an e� ect on other parts of the body (e.g. morphine suppositories to treat cancer pain).

PulmonaryDrugs are administered to the lungs in the form of gases/volatile liquids (e.g. general anaesthetics) or aerosol/dry powder inhalers (e.g. to treat

Tolerance is when the body becomes less responsive to the e� ects of the drug, and so larger and larger doses are needed to produce the same e� ect. This means that the patient may be at more risk of toxic side e� ects.


asthma). The lungs have a very large surface area, and therefore absorption of the drug into the blood is very rapid and thus the drug has a fast onset of action. This route is also useful if treatment of a lung disease such as asthma is required, as the drug is delivered directly to its site of action.

TopicalThis refers to applying the drug to the skin in the form of creams, ointments and lotions, for example. Topical administration is used primarily for local e� ects such as treating acne, dermatitis or skin infections, but transdermal patches (e.g. containing nicotine) may also be used and allow penetration of the drug through the skin for access to the blood circulation.

By injectionThere are three main types of injection: intravenous, intramuscular and subcutaneous. Intravenous injections are the most common; they are used when a rapid therapeutic response is required, because the drug is injected directly into the bloodstream. Intramuscular injections are injected into skeletal muscle, usually in the arm, thigh or buttock. Aqueous solutions of drug are rapidly absorbed into the bloodstream, but if the drug is dissolved or suspended in oil, 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. Subcutaneous injections are injected directly under the skin; absorption of drug into the blood is slow, giving a sustained e� ect. Insulin is given by subcutaneous injection.

Examiner’s tip‘By injection’ is referred to on the IB syllabus as the parenteral route, although strictly speaking, ‘parenteral’ means any route other than via the gut, so includes injection, the pulmonary route and the topical route.

D2 AntacidsNormally the pH in the stomach is between 1 and 2, owing to the production of hydrochloric acid by the millions of gastric glands that line the stomach. 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.g. bacteria) that may enter the digestive system with food, so the low pH plays a role in the body’s natural immunity to disease-causing microorganisms; (2) the digestive enzymes in the stomach (e.g. pepsin, which breaks down proteins) require a low pH for optimum catalytic activity.

A layer of mucus lines the stomach, and protects the stomach wall from damage by the acid. However, irritation to the stomach lining can occur by the production of excess acid – for example, caused by drinking too much alcohol, eating large (especially fatty) meals, smoking or stress. Certain drugs can irritate the stomach lining directly, whereas drugs such as aspirin can lower the production of mucus in the stomach, making the stomach lining more susceptible to acid. This can result in the following:

Test yourself1 What is the ultimate purpose of clinical trials?2 Aspirin can cause erosion of the stomach lining,

resulting in ulceration. 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

• Discuss the use of antacids to treat excess acidity in the stomach


• indigestion: irritation of the stomach lining caused by excess acid, producing pain or discomfort in the upper abdomen and/or nausea

• heartburn (acid re� ux): acid from the stomach rising up into the oesophagus, causing a burning sensation

• peptic ulcer: erosion of part of the gut lining, caused by acid penetrating the mucous layer. This can be a serious condition if left untreated, as internal bleeding can occur. Aspirin and other related anti-in� ammatory drugs can cause ulcers in some patients.Antacids are used to treat these conditions. They are weakly basic

compounds that neutralise the acid, thus relieving the pain, discomfort or burning sensation and allowing repair of the mucous layer. In the case of peptic ulcer, neutralisation of the acid prevents further erosion of the gut lining, thus allowing the ulcer to heal.

The most commonly used antacids are metal hydroxides, carbonates and hydrogencarbonates (bicarbonates), e.g.:

• magnesium hydroxide

• aluminium hydroxide

• calcium carbonate

• sodium hydrogencarbonate.Some antacid preparations contain mixtures of two di� erent antacids,

such as magnesium salts and aluminium salts (usually magnesium and aluminium hydroxides). The rationale for using these two di� erent antacids is that magnesium salts are faster acting and so work quickly to neutralise the acid, but aluminium salts have a slower and more prolonged e� ect, so the time interval between doses is increased. Also, magnesium salts in repeated doses can cause a laxative e� ect, but this is o� set by aluminium salts, which can produce constipation.

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, e.g.:

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, antifoaming agents may sometimes be included in the preparation, for example activated dimeticone (dimethicone), which relieves � atulence.

Alginates may also be found in some antacid preparations. These form a ‘raft’ that � oats on top of the stomach contents, thus reducing re� ux into the oesophagus, which causes heartburn.

Test yourself4 How many moles of HCl would be neutralised by 0.2 moles of: a sodium hydrogencarbonate b aluminium hydroxide?


D3 Analgesics

Analgesics are drugs that reduce pain.

There are two main types of analgesics: mild analgesics and strong analgesics. They exert their pain relief action in di� erent ways.

Mild analgesics, such as aspirin and ibuprofen, prevent the production of prostaglandins in the body by inhibiting an enzyme known as cyclooxygenase (COX), which is a key enzyme in the synthesis of prostaglandins.

When injury to a tissue occurs; for example, prostaglandins are synthesised in the damaged tissue cells and bind to receptors; this stimulates sensory nerve � bres at the site of the injury to send signals to the brain, which are then interpreted as pain. They also cause dilation (widening) of the blood vessels in the damaged tissue, leading to an in� ammatory response (swelling, redness, 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.e. fever).

Strong analgesics, such as morphine, temporarily bind to opioid receptors in the brain and spinal cord. This blocks the transmission of pain signals in the brain and increases the pain perception threshold: i.e. even though pain in the a� ected tissue is still occurring, the patient is not as aware of it. Also, opioids increase the tolerance to pain, which means that even if pain is felt by the patient, they are more able to tolerate it. Morphine and compounds that have morphine-like e� ects are known as opioids (opium-like).

Mild analgesics

AspirinAs far back as the 5th century BC, it was known that chewing willow bark could give pain relief. Willow bark contains a compound called salicin, which is a sugar derivative of salicylic acid, and which gets converted to salicylic acid in the body. Salicylic acid (Figure D1) is a good analgesic but causes severe irritation of the stomach lining, resulting in vomiting and gastric bleeding. In the 1890s, a derivative of salicylic acid, called acetylsalicylic acid (Figure D1), began to be used medically and over 100 years on, 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.

Learning objectives

• Describe the di� erent ways that analgesics cause pain reduction in the body

• Explain how derivatives of salicylic acid are used as mild analgesics, and compare the advantages and disadvantages of aspirin and paracetamol (acetaminophen)

• Compare the structures of the opioid analgesics – morphine, codeine and diamorphine – and discuss their advantages and disadvantages

Prostaglandins cause a number of physiological e� ects in the body, including the induction of pain, in� ammation and fever.

In general, mild analgesics intercept the pain stimulus at the source of the pain (except paracetamol), usually by inhibiting the production of pain mediators called prostaglandins, whereas strong analgesics temporarily bind to opioid receptors in the brain, preventing the transmission of pain signals.

The analgesic action of paracetamol is still unclear, even though it has been in clinical use for over 50 years. Some researchers believe that paracetamol may stop the production of prostaglandins (other than by COX inhibition) in the brain.

C

OH

OHalcohol / phenol

carboxylic acid

salicylic acid

O

COH

COH3C

carboxylic acid

acetylsalicylic acid

O

ester

O

Figure D1 Structures of salicylic acid and acetylsalicylic acid (aspirin).


Aspirin is used all over the world as an analgesic and anti-in� ammatory agent. It belongs to a group of drugs known as non-steroidal anti-in� ammatory drugs (NSAIDs), of which ibuprofen is also a member. It is useful in treating painful conditions such as headache, fever, and conditions in which both pain and in� ammation are present, such as arthritis.

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, via its anti-blood-clotting e� ect. A number of studies have also indicated that low-dose aspirin may prevent certain cancers, in particular colorectal cancer. However, further research is needed in this area.

As we have already seen, aspirin exerts its e� ects through the inhibition of an enzyme called COX, which plays a key role in prostaglandin synthesis. As well as mediating pain, fever and in� ammation, prostaglandins also have a number of other roles in the body, one of which is maintaining the mucous layer in the stomach. Therefore, one of the side e� ects of aspirin is gastric irritation, both directly by the drug itself but mainly indirectly through its inhibition of prostaglandin synthesis and therefore depletion of the protective mucous layer. This can lead to peptic ulcer and possibly stomach bleeding in some patients.

Another disadvantage of using aspirin is that some people may be sensitive to it (known as hypersensitivity), especially those people who su� er from asthma, in whom aspirin can trigger an asthma attack. 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, a potentially fatal condition that a� ects all organs of the body, especially the brain and liver.

Paracetamol (acetaminophen)Paracetamol (Figure D2) is a mild analgesic that also reduces fever. It can be used safely in babies and children and has very few side e� ects. However, it can cause liver damage (and less frequently kidney damage) when taken in overdose. It does not reduce in� ammation and does not have an anti-clotting e� ect, so is used to treat fewer medical conditions than aspirin.

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; paracetamol is not anti-in� ammatory and does not prevent blood clotting

• paracetamol can be used safely in children, 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; side e� ects with paracetamol are rare, except in overdose, where it causes liver damage, which may lead to death.

Strong analgesicsWhereas mild analgesics such as aspirin and paracetamol are used for relatively mild pain, such as headache or toothache, the opioid analgesics are strong analgesics used for moderate to severe pain, such as in terminally ill patients. Sometimes mild analgesics may be combined with strong analgesics in some preparations: for example, paracetamol and codeine are often used together.

HOalcohol / phenol

amideC

NH

H3C O

Figure D2 The structure of paracetamol.


OpioidsOpioids have been used for thousands of years; they were originally derived from the juice of unripe seed pods of the poppy Papaver somniferum. This juice is known as opium (the Greek word for ‘juice’), which contains a mixture of approximately 25 di� erent nitrogen-bearing compounds (known as alkaloids), the most important of which is morphine. Morphine was � rst isolated in 1803 and is chie� y responsible for the biological e� ects of opium; it accounts for approximately 10% of the opium mixture. Codeine, a milder analgesic than morphine, is also found naturally in opium, although in smaller proportions.

Opioids cause a number of e� ects on the body through binding to opioid receptors. These include analgesia, sedation, a feeling of wellbeing, suppression of the cough re� ex and constipation. They are used medically for pain relief and treatment of cough and diarrhoea.

The chemical structures of codeine and morphine are shown in Figure D3. As can be seen, they are very similar in structure, 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. Interestingly, when codeine enters the body, some of it is acted on by enzymes, which remove the methyl group to give a hydroxyl group; thus codeine is converted to morphine. It is this conversion to morphine that accounts for the therapeutic properties of codeine.

N-CH3

H3CO

O

HOalcohol

ether

amine

codeine

benzene ring

N-CH3

HO

O

HOalcohol

alcohol / phenol

amine

morphine

benzene ring

N-CH3

O

amine

diamorphine

benzene ring

O

O

O

O

H3C

H3C

ester

ester

Diamorphine (heroin) (Figure D3) is a semi-synthetic morphine derivative. The di� erence in the structures is that diamorphine contains two ester (CH3COO–) groups, whereas morphine contains two –OH groups.

Diamorphine is synthesised by an esteri� cation reaction between the two hydroxyl groups in morphine and ethanoic acid, to form two ethanoate ester groups. Diamorphine is more lipid-soluble (owing to the replacement of the –OH groups, which can take part in hydrogen bonding, by the ester groups, 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, lipid-soluble molecules across and hinders large, polar

Figure D3 Structures of codeine, morphine and diamorphine. Note that the tertiary amine and benzene ring are essential for analgesic activity.

A tertiary amine has N joined to three C atoms (three alkyl groups).


molecules). Once diamorphine has entered the brain, it is hydrolysed by enzymes to the monoester (only one ester group present) and to morphine, which bind to opioid receptors and produce an analgesic e� ect.

Effects of opioid analgesicsStrong opioids such as morphine and diamorphine are used medically for the relief of severe pain; they are especially e� ective in visceral pain (i.e. pain in the internal organs, such as liver and lungs). They are commonly used to relieve the pain associated with cancer in terminally ill patients. Morphine may also be used for the short-term control of diarrhoea, due to its constipating e� ect, and to control distressing cough in lung cancer patients, due to its cough-suppressant e� ect. Milder opioids such as codeine are used to relieve moderate pain. Codeine is also used as a cough suppressant for dry coughs and as an anti-diarrhoeal drug.

Opioid analgesics have a number of side e� ects associated with their use: in the short term they can cause nausea and vomiting, constipation, respiratory depression (slowed or shallow breathing), drowsiness and euphoria; in the long term they cause dependence and tolerance, chronic constipation and decrease in sex drive.

There are two types of dependence: psychological dependence, 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; and physical dependence, in which the body cannot function without the drug and deprivation results in withdrawal symptoms.

Illicit drug users su� er both physical and psychological dependence, whereas patients taking opioids for medical reasons generally su� er only physical dependence. Tolerance occurs in both types of user, thus requiring higher doses to be taken to cause the same e� ect (therapeutic or euphoric).

Abuse of opioidsOpioids have been taken for non-medical reasons for centuries. As well as dulling pain, they cause a pleasant, dreamy and relaxed state known as euphoria, with heroin also causing a feeling of warmth and thrill when injected intravenously. Because heroin is lipophilic, it enters the brain quickly and so causes a ‘euphoric rush’. However, dependence and tolerance develop quickly, and the drug user soon starts to need larger and larger doses to retain this ‘rush’. If the user is denied the drug, withdrawal symptoms occur, including anxiety, cold sweats, vomiting and jerking of the legs. Treatment of opioid dependence is di� cult; 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.

Opioid dependence is a worldwide problem and is associated with a signi� cant amount of crime. 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. Users who inject heroin intravenously are also at increased risk of infection from hepatitis or HIV, spread by sharing needles.


D4 DepressantsDepressants are drugs that depress (i.e. slow) the nerve impulses in the brain and spinal cord (known as the central nervous system (CNS)), causing a reduction in brain activity, reduced heart rate and reduced rate of breathing. Because they act on the CNS, they are also referred to as CNS depressants.

Test yourself5 Name the two functional groups attached to the

phenyl ring in aspirin below:6 Structurally, how does diamorphine di� er from

morphine?

COH

COH3C

O

O

Learning objectives

• 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, 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

F3C

CH2 NH2

CH2 CH3Cl–O

+

The e� ects of CNS depressants are dose-dependent, i.e. their e� ects change as the dose of the drug increases. At low to moderate doses, they produce a calming e� ect and relieve anxiety without causing sleep; at higher doses, they induce sleep; at very high doses, they can cause unconsciousness, coma and ultimately death.

Two common examples of CNS depressants are benzodiazepines (used to treat anxiety and/or insomnia) and alcohol.

Figure D4 Structure of fl uoxetine hydrochloride, an antidepressant.

Note: CNS depressants are not to be confused with the medical condition ‘depression’, which is characterised by a feeling of extreme sadness and despair, sometimes so severe that it can lead to suicide. Depression is treated with antidepressants such as � uoxetine hydrochloride (Prozac®) (Figure D4), which acts by increasing the levels of serotonin in the brain, a chemical involved in wellbeing. Some CNS depressants may be used alongside antidepressants, however, to relieve associated symptoms of depression, such as anxiety (see benzodiazepines later on page 16).


Physiological and social effects of ethanolAlcohol is the name commonly given to ethanol (C2H5OH). Ethanol has some medical e� ects: for example it is used as an antiseptic, swabbed onto skin before injections – it kills bacteria and some viruses and fungi present on the skin surface, thus preventing infection of the puncture site from occurring. It may also be used to prevent infection of minor cuts and abrasions. Ethanol is also sometimes used to harden the skin to prevent bedsores in bed-ridden patients.

When taken internally as an alcoholic beverage, ethanol acts as a CNS depressant and can have a number of physiological e� ects on the body. These e� ects change as the amount of alcohol consumed increases, and in extremely large amounts it can result in coma and death. The short-term and long-term physiological and social e� ects of drinking alcohol are listed below.

Short-term effects

• loss of concentration

• mood changes, such as a feeling of euphoria

• often an increase in con� dence, which can result in silly, aggressive (leading to violence) or dangerous, risk-taking behaviour (such as dangerous driving)

• loss of self-restraint, which can result in o� ensive behaviour

• loss of coordination, slurred speech, di� culty in carrying out even simple tasks

• drowsiness and induction of sleep

• extremely high intake may result in coma and death.

Long-term effects

• dependence occurs with long-term regular intake of large amounts of alcohol (referred to as ‘alcoholism’); withdrawal e� ects occur when alcohol intake is stopped suddenly and include severe tremor, anxiety, agitation and racing heart – this is known as ‘delirium tremens’

• cirrhosis of the liver

• heart disease

• increased risk of several types of cancer, including liver cancer, 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, it can cause deformities and brain and heart defects in the developing foetus; a study has also shown that drinking alcohol during pregnancy can increase the risk of leukaemia in the child, but more studies are being carried out to further investigate this � nding.

Alcohol abuse can have detrimental e� ects on the drinker’s family and on society as a whole: it can result in driving accidents, accidents at work, domestic violence, non-domestic violent attacks and breakdown of the family unit. Many governments have sought to minimise alcohol abuse by passing laws or initiating educational campaigns; however, social and commercial pressures continue to have a strong in� uence.


Detection methods for ethanolDrink-driving is a major cause of road tra� c accidents. Alcohol can have a number of e� ects that impair the ability of that person to drive safely: reduced coordination, increase in con� dence leading to risky manoeuvres, inability to concentrate, impaired judgement and a reduction in reaction time. All these can contribute to causing accidents while driving, so laws are in place to limit the amount of alcohol that can be drunk before driving a motor vehicle. In the UK and many other countries, this limit is 80 mg of alcohol per 100 cm3 of blood plasma. Alcohol levels can be detected in a number of ways: by testing the breath, blood or urine.

Breath testingThis 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. In the lungs, an equilibrium is established between alcohol dissolved in blood plasma and alcohol in the breath. Therefore, the amount of alcohol in the breath can be used to determine the amount of alcohol in the blood plasma.

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, which contains dichromate(VI) crystals. These crystals are orange, 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; the ethanol is � rst oxidised to ethanal and then to ethanoic acid in the process. The degree of colour change is directly related to the level of alcohol in the breath, and this colour change is measured using a photocell.

The half equations are as follows:Conversion of ethanol to ethanoic acid:

C2H5OH + H2O → CH3COOH + 4H+ + 4e− Oxidation

Conversion of dichromate(VI) to chromium(III) ions:

Cr2O72− + 14H+ + 6e− → 2Cr3+ + 7H2O Reduction

The overall equation is:

2Cr2O72− + 3C2H5OH + 16H+ → 4Cr3+ + 3CH3COOH + 11H2O

orange green

The oxidation of ethanol may also be shown as:

C2H5OH + 2[O] → CH3COOH + H2O

where [O] represents oxygen from the oxidising agent.

These chemically based breathalysers are now largely replaced with a newer, more accurate, type of hand-held analyser, which uses a fuel cell sensor to detect alcohol in the breath. In this type of analyser, the breath enters a fuel cell with two platinum electrodes and any alcohol in the breath gets chemically oxidised, resulting in the generation of an electric current; the more alcohol present, the higher the current.

As well as hand-held analysers that are used at the roadside, there are also desktop analysers that are located in police stations and that may


be used to provide evidence if the case goes to court. An example is an intoximeter, and this uses infrared spectroscopy to detect ethanol in the sample of breath provided. Infrared spectroscopy is based on the vibration of bonds within molecules; molecules will absorb infrared radiation that corresponds in energy to these vibrations (see Option A on the CD-ROM). Depending on the type of bonds and functional groups present in the molecule, a particular absorption spectrum will be produced that is characteristic for that molecule. The intoximeter measures the amount of infrared energy absorbed at a particular frequency as it passes from the source (the infrared lamp), through the sample of breath, to the detector. The amount of energy absorbed when a breath sample is present is compared with the amount absorbed when no sample is present, to indicate the concentration of ethanol in the sample. Ethanol will produce major absorption bands at 3340 and 2950 cm−1, corresponding to the O–H and C–H vibrations, respectively. However, as O–H vibrations are also present in water vapour in the atmosphere and breath, the C–H vibration at 2950 cm−1 is used to test for ethanol. The newer models of intoximeter now contain a combination of infrared analyser and fuel cell analyser, for increased accuracy and speci� city.

Blood and urine analysisSamples of blood or urine may be taken from the suspect and sent for analysis by gas–liquid chromatography (see Option A). This technique involves injecting a small sample of the blood or urine into the machine and vaporising it. 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). 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. Compounds that are less volatile and/or that dissolve more readily in the liquid stationary phase travel more slowly through the column. The time taken for a particular compound to travel through the column to the detector is known as its retention time. Di� erent compounds have di� erent retention times, and thus ethanol can be identi� ed in the sample due to its retention time. The compounds in the sample are detected and recorded as a series of peaks, with each peak representing a compound in the sample. The area under the peak is used to determine the concentration of the compound when compared with a known standard, 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).

Synergistic effects of ethanolEthanol is an example of a drug that can increase the e� ects of other drugs, 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, and in some cases fatal). 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; this can possibly result in unconsciousness and even death

Synergism is when two or more drugs, given at the same time, have an e� ect on the body that is greater than the sum of their individual e� ects. In other words, certain drugs can increase the e� ects of other drugs when given at the same time.


2 an increased risk of haemorrhage (bleeding) in the stomach when alcohol is taken with aspirin.

CNS depressants other than alcoholBenzodiazepines are another type of commonly used CNS depressant. They are mainly used to relieve anxiety and induce sleep but are also used as anticonvulsants in epilepsy and as a premedication before operations. They act by binding to speci� c receptors in the brain called benzodiazepine receptors. Two examples of benzodiazepines are diazepam (Valium®) and nitrazepam (Mogadon®) (Figure D5); diazepam is useful in treating anxiety, whereas nitrazepam is used as a sleeping tablet for insomnia. Benzodiazepines cause dependence and withdrawal symptoms; they have been overprescribed by doctors in the past, and some studies indicate that in many countries they are still being overprescribed. To reduce incidences of dependence, it is advised that they should be used only in severe or distressing cases of anxiety and insomnia.

As can been seen from Figure D5, diazepam and nitrazepam are very similar in structure – they both contain two benzene rings, one of which is fused to a diazepine ring (the seven-membered rings shown in Figure D5). The diazepine ring contains an amide group and a C=N (known as an imine). The only di� erence between diazepam and nitrazepam is that in diazepam the fused benzene ring has a chloro- substituent whereas in nitrazepam, it has a nitro- substituent in the same position.

Clchloro

C

ON

Nimine

amide

benzene ring

benzene ring

diazepam

H3C

O2Nnitro

C

ON

Nimine

amide

benzene ring

benzene ring

nitrazepam

H3C

Figure D5 Structures of diazepam and nitrazepam.

Examiner’s tipFluoxetine hydrochloride (Figure D4) has only a low potential to act as a CNS depressant; however, it is mentioned as being a CNS depressant in the syllabus. Therefore, you should be able to identify it and describe its structure, by reference to the IBO Chemistry Data booklet.

Test yourself7 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 can result in increased drowsiness in that patient. 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.

O2N C

ON

N

H3C


D5 StimulantsStimulants also act on the CNS but, unlike depressants, they increase brain activity and mental alertness. They reduce drowsiness, lethargy and fatigue and also improve attention and focus. They can also suppress the appetite and so have been used in the management of obesity to facilitate weight loss. As well as these e� ects, stimulants also cause an increase in respiration and heart rate.

There are di� erent types of stimulants; three common examples are amphetamines, ca� eine and nicotine. Each one will now be looked at in turn.

AmphetaminesAmphetamines are closely related to epinephrine (adrenaline) and norepinephrine (noradrenaline), which are major hormones and neurotransmitters (chemicals that allow communication between nerve cells) of the sympathetic nervous system. This system is responsible for subconscious control over most of the internal organs in the body and prepares the body for stressful situations, known as the ‘� ght or � ight’ response.

Epinephrine and norepinephrine have many e� ects, including: increasing blood pressure and heart rate; increasing blood � ow to the muscles; increasing the breakdown of glycogen to glucose in the liver to raise blood glucose levels; dilating the vessels in the lungs to increase oxygen supply to the heart and muscles; and increasing mental alertness.

Amphetamines are known as sympathomimetic drugs. 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, for example by students before exams or by athletes.

Amphetamines are similar in structure to epinephrine and norepinephrine, as they are derivatives of phenylethylamine (the structures of amphetamine and epinephrine are shown in Figure D6). They are believed to exert their actions by increasing the release of norepinephrine at nerve junctions, as well as directly binding to receptors at the end of the nerve junctions. Their actions result in e� ects including increased heart rate, dilation of the pupils in the eyes, reduced appetite, an

Sympathomimetics mimic the e� ects of stimulating the sympathetic nervous system.

HO

HO

CH2

CH3

HC

H

OH

epinephrine

secondaryamine

N

primaryamine

CH

CH3

H

HCH2

amphetamine

N

H

HN

phenylethylamine

C

H

H

C

H

H

Figure D6 Structures of epinephrine and amphetamine, including the phenylethylamine structure.

Derivatives of amphetamine include methamphetamine (‘speed’, ‘crystal meth’) and ecstasy (‘E’), both of which have been linked to brain damage after long-term use of these drugs.

Learning objectives

• List the general physiological e� ects of CNS stimulants

• Compare the structures and e� ects of amphetamines and epinephrine (adrenaline)

• Describe the short- and long-term e� ects of nicotine

• Describe the e� ects of ca� eine and compare its structure with that of nicotine


increase in mental alertness, wakefulness, feelings of well-being (euphoria) and increased energy. Tolerance and dependence develop quickly after repeated use, and prolonged and high doses can result in the individual experiencing delusions and hallucinations.

Effects of nicotineNicotine is the most active ingredient of tobacco and is highly addictive. It is a volatile alkaloid and is easily inhaled with tobacco smoke into the lungs. Because it is a lipophilic molecule (its structure is shown in Figure D7), it crosses the blood–brain barrier easily (it can take less than 10 seconds for inhaled nicotine to reach the brain from the lungs). Nicotine exerts its actions by binding to receptors and causing the release of a number of neurotransmitters and hormones, including epinephrine and norepinephrine. These released neurotransmitters and hormones do not just cause stimulation of the CNS but have a number of other e� ects around the body, which are described below.

Short-term effects of nicotine

• increased alertness and concentration

• relief of tension

• reduced appetite

• increased blood pressure and heart rate

• decreased urine output.

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).Nicotine is highly addictive; withdrawal symptoms include irritability,

increased appetite and a craving for tobacco. The long-term e� ects of nicotine and tobacco smoke are not the same.

A number of the diseases associated with smoking are not due to nicotine, 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). Long-term e� ects of smoking tobacco other than those described above for nicotine, include lung diseases, such as bronchitis and emphysema, and an increased risk of several cancers, including lung, throat, liver, bowel and stomach cancers. Lung cancer is the leading cause of cancer-related deaths in the UK and USA, and 90% of lung cancer deaths are due to smoking. Thus tobacco has a number of detrimental e� ects on the body and accounts for millions of deaths per year worldwide.

Many countries have introduced measures to try to minimise the impact of tobacco smoking on society. These include increased education and support, widespread availability of nicotine replacement therapy (e.g. nicotine patches), smoke-free legislation and reducing tobacco advertising. However, the addictive properties, withdrawal symptoms and social and peer pressures associated with smoking make it a di� cult habit to quit.

CH3

N

N tertiaryamine

Figure D7 The structure of nicotine.


CaffeineCa� eine occurs naturally in co� ee and tea; 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). Ca� eine is also found in cola, some energy drinks and some medicines, such as painkillers.

The structure of ca� eine is shown in Figure D8. It has some similarities to the structure of nicotine, in that it also contains a tertiary amine and heterocyclic rings containing nitrogen (like nicotine, it is an alkaloid, a naturally occurring basic compound containing nitrogen).

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. Ca� eine acts as a stimulant of the CNS: in small doses, it increases alertness and concentration and reduces feelings of fatigue. In high doses, however, ca� eine can cause anxiety, irritability and sleeplessness. As well as CNS e� ects, ca� eine can act as a weak diuretic, increasing urinary output; it can also act as a respiratory stimulant and is used clinically to reduce incidence of apnoea (cessation of breathing) in premature infants. In some people, ca� eine can cause dependence, with withdrawal symptoms including headaches, irritability and an inability to concentrate and focus.

Figure D8 The structure of caffeine.

Test yourself 10 Theobromine (shown below) is found in chocolate and is

structurally related to ca� eine. Describe the di� erence between the structures of theobromine and ca� eine.

O

CH3

NN

NHN

O

CH3

D6 AntibacterialsAntibacterial drugs are one of the most frequently prescribed medicines. These drugs are able to be toxic to the bacteria while being relatively safe to the patients that take them. 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.

There are many di� erent types of antibacterial drugs, but the most commonly prescribed are the penicillins. They were discovered by chance in 1928 by a Scottish physician and microbiologist called Alexander Fleming, who was working on some bacterial cultures at the time. By mistake, 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, he saw that it had been contaminated with a mould (which he later identi� ed as Penicillium notatum). He noticed that the plate was dotted with bacterial colonies

Learning objectives

• Describe how penicillin was discovered and developed

• Explain the mechanism of action of penicillins and describe the e� ects of modifying the side-chain

• Discuss the importance of patient compliance and the implications of penicillin overprescribing

CH3

H3C

N

Oamide

amide

N

O N

Ntertiaryaimine

CH3


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. 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. It was not until a decade later that scientists Howard Florey and Ernst Chain, working in Oxford, followed up on Fleming’s � ndings, and in 1940 they were able to produce enough penicillin to be tested in mice. In early 1941, the � rst tests of penicillin in humans were carried out, and by 1943 penicillin was being produced on a large scale for use by the armed forces, in time to save many lives during the latter part of World War II. Florey, Chain and Fleming shared the Nobel Prize in Physiology or Medicine in 1945 ‘for the discovery of penicillin and its curative e� ect in various infectious diseases’.

Although a number of structures for penicillin had been proposed by scientists, it was not until 1945 that X-ray crystallography studies by Dorothy Hodgkin at Oxford University con� rmed it to be a bicyclic structure (Figure D9) containing a β-lactam ring (a cyclic amide that is part of a four-membered ring). This β-lactam ring is essential for the antibacterial activity of penicillin; if the ring is broken in any way, such as by acid or bacterial enzymes (see below), the penicillin is no longer active.

O

O

H2CR =

CH3

CH3N

HN

COOH

SC

R

carboxylic acid

amide

a

b

β-lactam ring

O

O

H2CR =

CH3

CH3N

HN

COOH

SC

R

carboxylic acid

amide

a

b

β-lactam ring

Figure D9 All penicillins have the same basic bicyclic structure, but different penicillins have different side-chains. (a) The general structure of penicillins; (b) the side-chain for benzylpenicillin (penicillin G).

Action of penicillin on bacterial cell wallsBacterial cells di� er from our own cells in that they contain a cell wall, 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, allowing the bacteria to withstand high osmotic pressures. Penicillin acts by irreversibly inhibiting an enzyme involved in the cross-linking of this polymer, 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.

The penicillin � rst isolated and puri� ed by Florey and Chain is called benzylpenicillin (or penicillin G; see Figure D9). However, this penicillin has a number of disadvantages, one of which is that it is easily broken down by stomach acid and must be given by injection. Scientists have overcome this problem, however, 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.


Bacterial resistanceThe 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. Some strains of bacteria have developed ways to counteract the e� ects of certain penicillins by producing an enzyme known as penicillinase, which opens the β-lactam ring of the penicillin, thus rendering it inactive. Penicillin G is an example of a penicillin that is inactivated by penicillinase; scientists have now developed penicillins that are less sensitive to the e� ects of this enzyme, however, by modifying the side-chain in the penicillin structure.

Bacterial resistance has developed not just for penicillins, but for most other types of antibacterials too, and some bacteria are resistant to more than one type, making them extremely di� cult to kill; thus it is important to carry out research into the discovery and development of new antibacterial agents. Mycobacterium tuberculosis, which causes tuberculosis (TB) in humans, can become resistant to the antibacterial agents used to treat it if, for example, the patient does not take the treatment correctly. TB is treated with a combination of antibacterial agents over a long period, and if the patient does not follow their treatment regime properly, this can increase the chances of resistance developing in those bacteria. It is important, therefore, that antibacterials are taken according to the instructions of the doctor (called patient compliance) and that the whole course of treatment is taken; otherwise failure to kill all the bacteria in the infection can lead to development of resistance in those bacteria that survive.

Such widespread bacterial resistance is also due to the extensive use of antibacterials, both for human use and for animals. 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. These antibacterials given to healthy animals can become resistant, and these resistant bacteria can be passed on to humans via meat and dairy products.

Bacterial resistance is a widespread problem, which has developed because of the innate ability of bacteria to mutate DNA in order to survive in hostile environments, as well as the overuse and misuse of antibacterials. Thus, improving the way that antibiotics are prescribed, taken or used in livestock is essential if the development and spread of resistant bacteria is to be controlled.

Test yourself 11 The antibacterial agent on the right is

phenoxymethyl penicillin. Copy the structure and draw a circle around the part of the molecule that is essential for its antibacterial activity.

O

OCH3

CH3

H2C

N

HN

COOH

SC

O


D7 Antivirals

VirusesViruses are parasites – they invade host cells and use the materials and processes within those cells in order to produce new viruses; they cannot replicate outside of host cells.

Viruses di� er greatly in shape and size from one type of virus to the next but, in general, they have a core consisting of their genetic information (carried in the form of either DNA or RNA), which is surrounded by a protein coat, known as a capsid. This capsid consists of identical protein sub-units, called capsomeres, and its role is to protect the genetic information in the core. Some viruses, such as the human immunode� ciency virus (HIV), also have a lipid envelope that surrounds the capsid (Figure D10).

Viruses are not considered to be living cells – they do not feed, excrete or grow, and they consist only of what is necessary to invade the host cell and then take over that cell to produce copies of themselves. Bacteria, on the other hand, are living cells and are far more complex in structure and function than viruses; also, they are able to reproduce outside host cells by cell division.

To gain entry into host cells, viruses must � rst attach to the surface of the host cell. 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, this must � rst be converted into DNA before it is inserted). The cell then starts producing viral proteins and viral DNA or RNA, which get assembled into functional new viruses and leave the cell to go on to infect other cells.

Treatment and prevention of viral diseasesViruses cause a number of illnesses and diseases, ranging from mild infections, such as the common cold, to potentially fatal diseases, such as acquired immunode� ciency syndrome (AIDS). 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, 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, resulting in a slight change in viral structure, which can make them resistant to drugs and can prevent vaccinations from being e� ective; this is particularly true of viruses such as HIV

• viruses use the host cell’s own processes and materials to produce new viruses, so it can be di� cult to design drugs that target only the virus and do not a� ect the host cell.

However, despite these di� culties, several vaccines and antiviral drugs have been developed and used successfully to prevent and treat viral infections.

Vaccines stimulate the body’s natural defences (the immune system) to produce antibodies against the virus, so if infection does occur, the immune system is prepared and can stop the infection before it takes hold. Vaccines have been used successfully against a number of viruses, including measles, mumps and polio. Antiviral drugs work in a number of ways.

Learning objectives

• 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, including the e� ects and treatment of HIV

Figure D10 The HIV virus.


• Some alter the cell’s genetic material by becoming incorporated into the growing DNA strand and halting its synthesis. An example of a drug that acts in this way is aciclovir (acyclovir) (Figure D11), which is used to treat cold sores; it stops viral DNA replication and thus stops the virus from multiplying.

• Some inhibit the activity of enzymes within the host cell that are necessary for the formation of new viruses. An example is indinavir, which is used in AIDS treatment; it inhibits the HIV enzyme protease, which is essential to the assembly of functional new HIV viruses.

• 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 drugs used to treat AIDS work in this way.

H2C

H2NCH2 OH

CH2

NN

O

NHN

O

Figure D11 The structure of aciclovir.

AIDSAIDS was � rst recognised in 1981 and was found to be caused by the HIV virus a few years later. There are now believed to be over 33 million people infected with HIV worldwide, and approximately 2 million deaths occur each year from AIDS.

HIV is a retrovirus – its genetic information is carried in the form of RNA, not DNA. HIV infection is so lethal if left untreated because the HIV virus invades cells that form part of the immune system; these cells are white blood cells known as T cells, and they play a vital role in the body’s natural defence against infection. 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, to gain entry into the cell. Once inside the cell, the viral enzyme reverse transcriptase converts the viral RNA into DNA so that it can be integrated into the T cell’s DNA. The viral genes contained in the DNA are used to produce viral proteins and viral RNA within the cell, and these get assembled into new HIV viruses. The T cell thus stops carrying out its role as an immune cell and instead becomes a factory for HIV viruses. When the newly formed viruses leave the T cell, some of the T cell membrane forms the envelope around the HIV virus. Death of the T cell can occur due to the viruses exiting the cell, and this results in a decrease in the number of T cells in the body and thus a weakened immune system. People with AIDS are thus susceptible to potentially fatal infections and also some types of cancer, because their immune systems are not strong enough to � ght against them.

Developing a method of eradicating HIV is di� cult, because the virus is able to mutate rapidly, and also because the virus uses many of the host cell’s processes and materials to replicate, so it is di� cult to target the virus without a� ecting the host cell too. However, there


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. One of these enzymes is reverse transcriptase, and the � rst antiretroviral drug that came onto the market to treat AIDS, azidothymidine (AZT), acts by targeting this enzyme. AZT inhibits reverse transcriptase and gets incorporated into the DNA strand that is being synthesised by the enzyme; this results in termination of DNA synthesis, and so the virus cannot replicate. 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). 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. However, all these drugs only delay the progression of AIDS, they do not kill the virus; nevertheless, they have saved the lives of millions of people since their introduction.

Much research is also underway to � nd an e� ective vaccine that can be used against HIV, to try to stop the spread of the virus. 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. However, promising results are being reported by researchers, both in animal studies and human trials, where a reduction in infection rates has been shown.

One problem with antiretroviral therapy was that it was expensive, 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, the prices of the most commonly used antiretroviral treatments have decreased signi� cantly over the last few years and, together with a global commitment to make these treatments universally available, more and more patients in poorer countries are now receiving treatment. More work still needs to be done, however, to ensure that prevention measures (such as education and condoms) and antiretroviral treatments are available to all.

Test yourself 12 In what form do bacteria carry their genetic information and

how does this di� er for viruses such as HIV?

D8 Drug actionThe 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, because its structure determines how well the drug is able to bind to a particular receptor or inhibit a particular enzyme, for example. 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, in some cases, cause a toxic e� ect.

Geometric isomerismGeometric isomerism is a form of stereoisomerism, where isomers have a di� erent spatial arrangement of atoms. In the case of geometric isomers, these result when there is restricted rotation somewhere in the molecule, leading to cis and trans isomerism. 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, whereas the other isomer may not be able to bind and be totally inactive.

Geometric isomerism exists in both inorganic and organic molecules, and an example of an inorganic molecule displaying geometric isomerism is diaminedichloroplatinum(II). This compound has a square planar geometry and can exist in both cis and trans forms (Figure D12). The cis isomer (known as cisplatin) is used in the treatment of cancers such as

Learning objectives

• 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

HL

Pt

H3N

H3N

Cl

Cl

cisplatin

Pt

H3N

Cl

Cl

NH3

transplatin

Figure D12 Structures of cisplatin and transplatin.


testicular cancer, lung cancer and bladder cancer. Cisplatin carries out its anticancer action by binding to DNA in cancer cells, preventing the cells from dividing and resulting in cell death.

Cisplatin is a platinum complex containing two adjacent chloride ions. In the bloodstream, cisplatin is neutral and will cross the cell membrane into the cell. Once inside the cell, there is a slow displacement of the chloride ions by water, generating a positively charged activated platinum complex (Figure D13). This activated complex binds strongly to DNA; the two water ligands are released and the platinum forms bonds with nitrogen atoms in two adjacent guanine bases within the DNA. This results in the DNA strand becoming distorted, which stops the cell from copying its DNA (known as DNA replication), ultimately leading to cell death.

Pt

H3N

H3N

OH2

OH2

Pt

one strand of theDNA double helix

G = guanine

H3N

H3N

G

G2+

enzyme active site

A

BC

c

a

bD

a

enzyme active site

no bondformation

b

A

BD

c

a

bC

A

BC

D

mirror

A

BC

D

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. Transplatin (see Figure D12) is ine� ective as an anticancer agent, because its chloride ions are trans, and therefore the groups are in the wrong orientation to bind to DNA.

Chirality (optical isomerism)When a molecule has a carbon atom bonded to four di� erent groups, the molecule is said to be chiral, and two mirror images (known as enantiomers) exist. These enantiomers can behave very di� erently in the body as a result of their di� erent shapes when in a three-dimensional environment, such as in an enzyme or receptor. For example, 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, 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). In some cases, one enantiomer may produce a therapeutic e� ect by binding to its target, whereas the other enantiomer may produce a toxic e� ect, by binding elsewhere.

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).

Figure D13 The active form of cisplatin and its binding to DNA.

Figure D14 Representation of a chiral drug binding to a theoretical enzyme active site. (a) The enantiomer is able to form three bonds with groups at the active site and is active; (b) the enantiomer is only able to form two bonds with groups at the active site and is inactive.

S-thalidomide(teratogenic)

O

N

NH

H

OO

O

R-thalidomide

O

N

NH

H

OO

O

Figure D15 Enantiomers of thalidomide.

See Option F on the CD-ROM for an explanation of S-enantiomer.

HL


Nowadays, if a new drug is going to be marketed as the racemic mixture, testing must be carried out on each enantiomer separately and also on the racemic mixture. 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.

Ring strainRing strain plays an important role in the antibacterial activity of penicillins. All penicillins have the basic structure outlined in Figure D16. They consist of a four-membered ring (called a β-lactam) fused to a � ve-membered (thiazolidine) ring. This basic structure is derived from two amino acids called valine (Val) and cysteine (Cys), to give a dipeptide-like structure. As we have already seen, there are many di� erent penicillins, and they di� er in the side-chain (R); modifying this side-chain can produce penicillins that are more stable to stomach acid and more resistant to penicillinase enzymes.

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, thus preventing cell wall synthesis. 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). A covalent bond is formed between the enzyme and the carbonyl carbon, and the β-lactam ring is opened in the process; this irreversible bonding to the enzyme blocks its active site and prevents it from carrying out cross-linking.

The β-lactam ring in penicillins is highly strained, and this strained β-lactam ring is essential for the antibacterial e� ect of penicillins. The ring contains two carbons and a nitrogen that are sp3 hybridised and that would therefore have bond angles of 109.5°, plus one carbon that is sp2 hybridised and that would normally have a bond angle of 120°. However, because these atoms are in the form of a four-membered ring, the bond angles are approximately 90°; this therefore puts strain on the bonds in the ring, making it relatively easy to break open so that the strain can be relieved. 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), making the carbonyl carbon more δ+. This allows it to be attacked readily by a lone pair of electrons in the transpeptidase enzyme (Figure D16), forming an irreversible covalent bond and resulting in opening of the β-lactam ring.

PolarityFor a drug to carry out its therapeutic e� ect, 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). The polarity of a drug molecule can in� uence how well the drug crosses barriers within the body, such as cell membranes and the blood–brain barrier and can thus a� ect the distribution of the drug in the body. Drugs that act on the CNS, such as the opioid analgesics, need to be able to cross into the brain in order to bind to opioid receptors, to produce their analgesic e� ect. To do this, they must � rst pass through

Giving the single enantiomer would not have helped in the case of thalidomide, as the enantiomers interconvert when in the body, producing the racemic mixture.

O

O

CH3

CH3N

HN

COOH

SC

R

valinecysteine

O

O

CH3

CH3N

HN

COOHEnz

SC

R

Figure D16 General structure of penicillin, and attack of the β-lactam carbonyl carbon by the transpeptidase enzyme.

HL


Test yourself

HLthe blood–brain barrier, as mentioned previously, when we looked at opioid analgesics. The polarity of a drug will a� ect its ability to cross this blood–brain barrier – as the barrier consists of lipid membrane, non-polar molecules cross more readily than polar molecules.

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. These two ester groups make the diamorphine molecule less polar than morphine, which allows it to cross the blood–brain barrier more easily. Diamorphine itself does not bind very well to opioid receptors, but in the brain its ester groups are hydrolysed by enzymes, producing 6-acetylmorphine and morphine (Figure D17), which then bind to the opioid receptors and produce an analgesic e� ect. Diamorphine is able to cross the blood–brain barrier faster than morphine, 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). 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. Therefore, there is more drug (following hydrolysis) to interact with the opioid receptors, producing an increased analgesic e� ect.

N-CH3

HO

O

alcoholHO

alcohol

6-acetylmorphine

+N-CH3

O

diamorphineO

O

O

O

H3C

H3C

ester

esterO

OH3C

ester

N-CH3

O

HOalcohol

morphine

Figure D17 Conversion of diamorphine into 6-acetylmorphine and morphine, the metabolites responsible for its analgesic effect.

13 Cisplatin binds primarily to guanine bases in DNA. The part of the guanine molecule that binds to the platinum complex is shown below; what is the name given to the type of bond formed between the guanine nitrogen and platinum?

14 Copy the structure below and draw a circle around the sp2 hybridised carbon in the β-lactam ring:

15 Which functional groups in diamorphine make it more lipophilic than morphine and therefore more able to cross the blood–brain barrier?

O

NN

N

deoxyribose

NH

NH2

O

CH3

CH3N

COOH

SNHC

H2

O

C


D9 Drug designEarlier in this chapter, we talked about how the drug development process begins with the search for a lead compound for a particular target; this target could be a receptor, an enzyme or another biomolecule such as DNA. As we discussed, 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, which make better drug candidates to take forward for further development. The discovery of lead compounds can involve rational drug design, where compounds are designed based on what is known about the target molecule (or existing drugs that act on the target), followed by synthesis and biological evaluation of a range of compounds that are structurally related (called a compound library). Traditionally, these compounds in the library are synthesised individually and evaluated to see whether any show activity, a process that is labour-intensive, time-consuming and expensive. Although this method of lead identi� cation is often used in many research departments in universities, 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. These new techniques are called combinatorial chemistry and high-throughput screening.

Combinatorial chemistryCombinatorial chemistry has developed owing to the advances that have arisen in the biological testing of compounds. A method called high-throughput screening can test a large number of compounds against one or more biological targets (for example enzymes) very rapidly. Thus, in order for pharmaceutical companies to produce enough compounds to be used in high-throughput screening, techniques needed to be developed that could synthesise large numbers of compounds quickly. Combinatorial chemistry (or combinatorial synthesis) is usually an automated (or semi-automated) method that can produce a large number of related compounds in a short period of time. Instead of synthesising every compound individually, this technique synthesises a large number of compounds simultaneously, producing what is called a combinatorial library.

The chemical reactions can be carried out using solid-phase techniques or can be prepared in solution.

Solid phaseThis is the most common method used in combinatorial chemistry and involves bonding the starting material for the reaction onto a solid support. This support is usually a resin-based bead that contains functional groups at the end of side-chains, which stick out from the surface of the bead; these functional groups covalently bond with the starting material. In combinatorial chemistry, a range of di� erent starting materials are covalently bonded to separate resin beads. 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).

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. The starting materials (amino acids

Learning objectives

• 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’.

HL


in this case) are � rst bonded to separate resin beads; the beads are then combined, mixed and then divided (split) into equally sized portions, the number of portions corresponding to the initial number of starting materials. For example, 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. The mixture of beads would then be divided into three equal portions, with each portion containing a mixture of all three amino acids (Figure D18). 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. The reaction is allowed to proceed, and this generates nine di� erent dipeptides in three di� erent reaction mixtures. The beads from all three reaction mixtures are then combined, mixed and split into three equal portions (each portion contains all nine dipeptides). Each portion is then put into a separate reaction vessel and is reacted with a further reactant (amino acid), to generate 27 tripeptides in three reaction vessels (Figure D18).

resin bead

B

BA C

E

HG I

CA

B CA

B

E

C

D

H

A

E

H

B

E

H

B

D

H

A

F

H

B

F

H

C

F

H

C

E

H

A

F

G

B

F

G

C

F

G

C

E

G

A

A

F

I

B

F

I

C

F

I

C

E

I

D

H

C

D

I

A

E

I

B

E

I

B

D

I

A

D

I

C

D

G

A

E

G

B

E

G

B

D

G

A

D

G

C

E

A

E

F

B CA

B

F

C

F

A

F

D

B CA

B

D

C

D

A

D

Bonding of starting material to bead

Combine, mix and split into three equal portions

Addition of reagent and firstsynthetic reaction

Combine, mix and split into threeportions plus addition of next reagentand second synthetic reaction

27 products synthesised

Figure D18 Synthesis of a combinatorial library using the mix and split method.

HL This method can be used to synthesise peptides and non-peptides; in the latter case, the reactants could be any monomeric unit or precursor molecule. 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.

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; these mixtures are usually separated from their solid support and then tested for biological activity as a mixture. Any mixtures showing favourable activity would then be investigated further to identify the compounds responsible


for the activity; any active compounds would then be resynthesised individually so that further tests can be carried out on them. 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.

Another technique used to produce combinatorial libraries is that of parallel synthesis. This di� ers from the mix and split method of combinatorial chemistry described above as it produces separate compounds, not mixtures; it is also used to produce smaller and more focused libraries. In parallel synthesis, a number of di� erent starting materials are reacted with a number of di� erent reagents simultaneously, i.e. the reactions are run in parallel. The reactions take place in separate reaction vessels: for example, wells on a plastic plate. Several hundred di� erent compounds can be synthesised in parallel using this method. It is often used for lead optimisation and structure–activity relationship determination. Once a lead compound has been discovered, the method is used to synthesise a large number of analogues individually, which vary only slightly from the lead compound. 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, so that more active compounds can be produced.

Computers in drug designComputers play an important role in the drug design process. Using molecular modelling software, three-dimensional models of drug molecules can be produced using computers and their interactions with biological targets (e.g. receptors or enzymes) studied. This can involve ‘docking’ the molecule into, for example, the active site of an enzyme and seeing how well it is able to interact with binding regions in the enzyme. 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. 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.

Computers can also be used to analyse structure–activity relationships, to derive the pharmacophore: this describes the type and position of functional groups in the molecule that interact with the target site, giving the drug molecule its biological activity. Once the pharmacophore has been derived, the information can be used to design compounds that possess the necessary characteristics for binding to the target. The information can also be used to search compound libraries to see which compounds possess the required pharmacophore.

Thus computers can help in reducing the number of compounds that need to be synthesised and tested, speeding up the drug discovery process and making it more e� cient.

Structure modifi cation to change polarityMost 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. The majority of drug absorption occurs in the intestines because they have a very large surface area, but some drugs, such as alcohol, can also be absorbed through the stomach.

Examiner’s tipAlthough parallel synthesis is a method used in combinatorial chemistry, the IB syllabus refers to it as a separate method. The syllabus uses the term ‘combinatorial chemistry’ to describe the mix and split method.

HL


For a drug to enter the blood circulation after oral administration, it must � rst dissolve in the aqueous environment of the intestines before it can be absorbed across the lipid membranes of the intestinal wall. If the rate at which the drug dissolves is slower than the rate at which it gets absorbed, this can a� ect the amount of drug that gets absorbed. Once in the bloodstream, 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). Thus the drug must have the correct balance of aqueous and lipid solubility to be e� ectively absorbed and distributed.

One way to increase the aqueous solubility of an acidic or basic drug is to make the ionic salt of the drug. An example of an acidic drug is aspirin; this contains a carboxylic acid group that can be reacted with a strong alkali to form the salt, where the acid is converted into the anion (COO−). The most common salts of acidic drugs are the sodium salts, and the formation of the sodium salt of aspirin is shown in Figure D19. The sodium salt of aspirin is more water-soluble than aspirin and so is absorbed more rapidly into the bloodstream.

COH

carboxylic acid

+ NaOH + H2O

aspirin aspirin sodium

O

CO–Na+

COH3C

saltO

O

COH3C

O

Figure D19 Conversion of aspirin into aspirin sodium.

Many drugs contain an amine group, such as the opioid analgesics, amphetamines and some antidepressants. These drugs can be made into salts by reacting the amine group with a strong acid, such as hydrochloric acid, to produce the basic cation. The most common type of salt for basic drugs is the hydrochloride salt, and the formation of � uoxetine hydrochloride is shown as an example in Figure D20.

HL

F3C

CH3C

H2

H2C

O

+HCl

aminefluoxetineNH

F3C

CH3Cl–C

H2

H2C

Osaltfluoxetine

hydrochloride

+N

H2

Figure D20 Conversion of fl uoxetine into fl uoxetine HCl.


Chiral auxiliaries in asymmetric synthesisMany drugs in development contain chiral centres and thus can exist as two enantiomers (non-superimposable mirror images), but it is usual for pharmaceutical companies to develop just one enantiomer of a drug, for reasons already explained. As synthetic reactions normally produce a mixture of both enantiomers (a racemic mixture), a method must be used to obtain the required single enantiomer of the drug. There are various ways of achieving this; for example, the synthesis of the racemic mixture may be carried out, followed by separation using chiral chromatography (normal chromatography does not separate enantiomers), or a synthetic reaction may be used that selectively produces one of the enantiomers of the product; this is known as asymmetric synthesis.

One method to achieve asymmetric synthesis involves the use of a chiral auxiliary. This chiral auxiliary is a pure enantiomer and combines with the non-chiral reactant to form a chiral intermediate. 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, thus forcing the reaction to follow a certain path which favours the production of one of the possible enantiomers (Figure D21). Once the reaction is complete, the chiral auxiliary is removed to leave the desired enantiomer; the chiral auxiliary can then be recycled for use in other experiments.

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. Semi-synthesis of this drug allows it to be made on a large scale and lessens the environmental impact, as extracting the drug from its natural source results in killing of the trees.

propanoic acid(non-chiral)

chiral intermediatesingle enantiomer

produced

addition of achiral auxiliary

both enantiomers produced

normal synthesiswithout a chiral

auxiliary

removal ofauxiliary

OH

NH2

O

O

OH +

O

NH2

OH

O

NH2

NH2

OH

O

O

Figure D21 The use of a chiral auxiliary in asymmetric synthesis.

HL

H3COC–O

CH3

OH

OH

HO

O

O

O

O

CONH

O

C

H

OO

COCH3

Figure D22 The structure of paclitaxel (Taxol®).


Test yourself

O

CH3

CH3N

COOH

SNHC

H2

O

C

D10 Mind-altering drugsHumans have used mind-altering drugs derived from plants and fungi for thousands of years. Examples include psilocybin, found in many species of ‘magic’ mushrooms, mescaline found in the peyote cactus and cannabis found in the hemp plant Cannabis sativa. Another common mind-altering drug is lysergic acid diethylamide (LSD); this does not occur naturally but is synthesised from lysergic acid, which is found in the ergot fungus.

Psilocybin, mescaline and LSDThese three drugs are all hallucinogens; they a� ect thought processes and cause distortions in the perception of reality. LSD is a potent hallucinogen, whereas psilocybin and mescaline are mild hallucinogens. All three drugs are similar in chemical structure, in that they are all amines; LSD and psilocybin contain an indole ring, which is a benzene ring fused to a � ve-membered ring containing nitrogen (Figure D23); mescaline does not contain the indole ring: it is a phenylethylamine-based compound, however its structure can be represented as an indole ring where the 5-membered ring is not closed.

These drugs are believed to exert their hallucinogenic e� ects by binding to serotonin receptors in the brain (serotonin is an indole-containing neurotransmitter that transmits nerve impulses between nerve cells). Stimulation of these receptors results in altered nerve transmission, causing sensory distortion, disorientation in time and space, and mood alterations. A summary of the various e� ects of LSD, psilocybin and mescaline is given below.

• LSD: a potent hallucinogen causing psychological e� ects of distortion of colour, sound and objects; double vision; crawling geometric patterns across objects; speeding up and slowing down of time and movements; heightened mood; � ashbacks when the drug is not being used; feeling of invulnerability, e.g. belief in ability to � y. Some LSD users experience feelings of despair and fear of insanity or death. Physical e� ects include increase in blood pressure, dilated pupils, changes in body temperature and increase in blood glucose. LSD is not addictive but rapid tolerance can develop, which subsides once use has stopped.

• Psilocybin: a mild hallucinogen with e� ects that are milder than those of LSD and include causing distortion in sight, sound and time; spiritual experience; increased sensation of insight; intense feelings of wonder; dilated pupils, nausea and vomiting; anxiety.

17 Penicillin G (right) can be made more water-soluble by converting it into a salt. By looking at its structure, draw the structure of a possible salt that can be made from penicillin G.

Learning objectives

• Outline the e� ects of lysergic acid diethylamide (LSD), mescaline, psilocybin and tetrahydrocannabinol (THC)

• Compare the structures of LSD, mescaline and psilocybin

• Discuss the arguments for and against the legalisation of cannabis


NHNH

indolering

indolering

indole-based

tertiaryamine

diethylamide

LSD

CH3CH2C

O

H3CO

H3CO

NH

indolering

ethers

Phenylethylamine-based

can be represented as similar in structure to non-ring closed indole

phosphate

psilocybin

mescaline

quaternaryamine

primaryamine

N

CH3

OCH3

CH2

CH2

CH2 NH2

CH2

CH3

N+

H CH3

N

CH2CH3

PO O–

OH

H3CO

H3CO

OCH3

CH2

H2N

CH2

• Mescaline: a mild hallucinogen producing changes in visual perception, � attening of three-dimensional objects, intensi� cation of colours; appearance of visual patterns; � ashbacks; nausea and vomiting; anxiety.

CannabisCannabis (marijuana) is obtained from the � owering parts, stems, leaves and seeds of Cannabis sativa; cannabis obtained from the resin is called hashish. 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, which are found in the parts of the brain responsible for pleasure, memory, concentration, and sensory and time perception.

Cannabis is a mild sedative, producing a feeling of relaxation and wellbeing; it is also a mild hallucinogen, causing changes in perception of sight and sound, as well as slowing down of time. Anxiety, short-term

Figure D23 Structures of the indole-based compounds LSD and psilocybin, and the phenylethylamine-based compound mescaline.

HL

CH2

CH3CH2

CH2

CH2H3C

H3C Oether

tetrahydrocannabinol (THC)

CH3

OH alcohol

benzenering

phenol

Figure D24 The structure of tetrahydrocannabinol (THC).


memory loss, decreased concentration and ability to learn, increased heart rate and increased risk of heart attack are other e� ects associated with cannabis. The long-term use of cannabis can lead to withdrawal symptoms, including irritability, mood changes and wakefulness; an increase in the risk of developing mental health problems such as schizophrenia has also been shown after regular use of cannabis. Smoking cannabis may also increase the risk of developing lung cancer, owing to cancer-causing agents present in the smoke.

Legalisation of cannabisCannabis is the most commonly used illicit drug, with 4% of the world’s adult population using it at least once per year. Cannabis possession is illegal in most countries, although tolerated in small amounts in some countries. There is much debate as to whether or not cannabis should be legalised, 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, such as for symptom relief in multiple sclerosis, relief from nausea and vomiting in patients receiving cancer chemotherapy, and weight gain and increase in appetite for anorexic patients with HIV/AIDS. There is also some evidence that cannabis can be e� ective in glaucoma, epilepsy, Alzheimer’s disease and Parkinson’s disease.

• Many believe that cannabis is less harmful to the individual than other, legally obtainable, drugs, such as alcohol and tobacco.

• Making cannabis illegal takes away the individual’s personal freedom to choose.

Arguments against legalisation

• The possibility that cannabis use may lead to using harder drugs such as heroin and cocaine.

• Cannabis can cause serious disease, such as cancer, heart disease and mental illness, and can also cause dependence.

HL

Exam-style questions

1 Ethanol and diazepam are both depressants.

a Breathalysers are used to detect ethanol levels in motorists. One type of breathalyser uses dichromate(VI). i Describe the colour change that occurs when alcohol is present in the breath. [1]

ii State the oxidation and reduction half equations for the oxidation of ethanol and reduction of dichromate(VI). [2]

b Name two physiological e� ects of using diazepam at moderate doses. [2]

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? [2]

d Name a structural di� erence between diazepam and nitrazepam (structures are included in the IBO Chemistry Data booklet, Section 20). [1]


2 Analgesics are used to reduce pain.

a Morphine and diamorphine are both strong analgesics. Describe how they carry out their analgesic e� ect. [1]

b Describe how mild analgesics, such as aspirin and ibuprofen, carry out their analgesic e� ect. [1]

c The structures of morphine and diamorphine can be found in Section 20 of the IBO Chemistry Data booklet. i Describe how the structure of diamorphine di� ers from morphine, with respect to the functional

groups present. [1] ii State the type of reaction used to convert morphine to diamorphine. [1] iii Describe two possible social problems that can occur through heroin addiction. [2]

3 Drugs and medicines can have a number of physiological e� ects on the body.

a Explain the meaning of the following terms: i therapeutic e� ect [1] ii side e� ect [1] iii tolerance [1]

b What does the term ‘therapeutic window’ mean? [1]

c Describe the placebo e� ect. [1]

d Describe the three main stages in the drug development process. [3]

e Drugs can be administered to a patient via a number of di� erent routes. i There are three main ways of giving a drug by injection. Which of these gives the fastest response,

and why? [2] ii Which route would be chosen to treat a lung condition, such as asthma, locally? [1]

4 a Name the acid found in the gastric juice in the stomach. [1]

b Calcium carbonate is an antacid used to neutralise excess acid in the stomach. Write the equation for the reaction between calcium carbonate and this acid. [1]

c Discuss why alginates are added to some antacid preparations. [2]

5 a Brie� y outline the mechanism by which penicillins carry out their antibacterial activity. [2]

b Some bacteria have developed resistance to penicillins by producing an enzyme that deactivates the penicillin. i Name the enzyme produced by penicillin-resistant bacteria. [1] ii What e� ect does this enzyme have on the activity of the penicillin? Brie� y explain why. [2] iii Which part of the penicillin structure can be modi� ed to make the penicillin less sensitive to the

actions of this enzyme? [1]

6 a How do viruses and bacteria di� er in the way that they replicate? [2]

b Name two di� erent ways in which antiviral drugs work. [2]

c Discuss why AIDS is such a lethal disease and why it is so di� cult to eradicate on a global scale. [4]


7 Structures can be found in Section 20 of the IBO Chemistry Data booklet.

a Amphetamine is a CNS stimulant, similar in structure to epinephrine. i It can be described as a sympathomimetic – what does this term mean? [1]

ii How does the amine in amphetamine di� er to that in epinephrine? [1]

b Ca� eine and nicotine are also stimulants. Compare their structures in terms of functional groups. [2]

c Describe two long-term e� ects of nicotine consumption. [2]

d Name one long-term e� ect of smoking tobacco that is not due to the e� ects of nicotine. [1]

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. [4]

b Describe two ways that computers can be used in the virtual screening of compounds. [2]

c Discuss how aspirin (the structure is included in Section 20 of the IBO Chemistry Data booklet) can be made more water-soluble, and write a suitable equation. [2]

d Describe the use of chiral auxiliaries in asymmetric synthesis. [3]

9 a Discuss why cisplatin is an e� ective anticancer compound, whereas its geometrical isomer is not. Draw the structure of the inactive isomer as part of your answer. [4]

b Draw the β-lactam ring and explain why it is essential for the antibacterial e� ect of the penicillins. [4]

10 a Describe the similarities in structure between LSD and psilocybin and name two psychological e� ects of taking LSD. [4]

b Discuss the main arguments for and against cannabis legalisation. [4]

HL

Documents

D Medicines and drugs - pedagogics.capedagogics.ca/cambridge/source_data/options/Options_D.pdf · Drugs produce an e˜ ect on the body by interacting with a particular target molecule