D.

1 Pharmaceutical products and drug action

Drug development

What you should know

At the end of this Subtopic D1 - Pharmaceutical products and drug action, you should be
able to:

➢ What you should know

➢ At the end of this Subtopic D1 - Pharmaceutical products and drug action, you should be
able to:
➢
➢ Identify the main steps in the development of synthetic drugs.
➢ Discuss different drug administration methods.
➢ Identify the considerations of different drug administration methods, including dosage,
tolerance, addiction and side-effects.
➢ Recall that the structure of the drug and the site of activity affect the drug-receptor
interaction.
➢ Define bioavailability.
➢ Discuss factors affecting bioavailability, including drug administration methods and
polarity/functional groups.
➢ Discuss the experimental foundations for therapeutic index and therapeutic window
through both animal and human studies.
➢ Calculate the therapeutic index for both animal and human studies, using LD50, TD50
and ED50 values.

● Discuss the term ‘side effects’ in relation to the two drugs aspirin and morphine.

Side effects are the unwanted effects of a drug. They may be mild or severe and possibly even
life- threatening and can vary from person to person.

a. aspirin is taken as an analgesic (pain killer) then common side effects include bleeding of
the stomach and also thinning of the blood. However this second ‘side effect’ of aspirin
can alter the reason why aspirin is taken and become the main effect when aspirin is
prescribed for people at risk of heart problems or a stroke to lower the risk of blood
clotting.
b. morphine (strong pain killer) side effect is constipation so sometimes morphine is
prescribed for someone suffering from diarrhoea. Other unwanted side effects of
morphine can include headaches, nausea and dizziness as well as the possibility of
addiction.
The administration of the drug could be altered to minimise these effects, or sometimes another
medicine must also be prescribed to manage the side effects. For example, intravenous injection
allows the medicine to be delivered to the active site much more quickly than other forms of
administration; but for medicines with unpleasant side-effects, intravenous injection could result
in a severe onset of the side-effects. Another method with a slower delivery to the active site,
such as oral ingestion, might be preferred to manage the side-effects of the drug.

● Explain why morphine is usually administered as a salt (morphine sulfate or

morphine hydrochloride) rather than in its pure form.

Morphine acts directly on the central nervous system. Morphine itself is only sparingly soluble in
water. Because they are far more polar, ionic salts of morphine are considerable more soluble in
water so enable the morphine to be carried around the body more effectively.

● Discuss why the ‘thalidomide story’ was more of a scandal than simply a tragedy.

Thalidomide was introduced as a sedative in the 1950s. It was found to be an effective

anti-emetic and was given to pregnant women to prevent morning sickness. At that time no real
research had been done on the possibility of drugs crossing the placental barrier to the foetus.
The drug was produced by a German company called Grünenthal and by the Distillers Company
in the UK. Although their own research showed some problems they did not initially withdraw
the drug even when there were reports that babies were being born with severely deformed
limbs. This was because they were making large profits from its sales. The drug was eventually
withdrawn in the early 1960s after more than 10,000 babies had been born with the deformities.
In 1968 a successful court case led to the Distillers Company paying out a large sum of money in
compensation. Since the thalidomide affair there has been a much stricter policy of regulating
and licensing new drugs.

● Identify the main steps in the development of synthetic drugs. How drugs are
obtained
Natural home remedies are not enough and synthetic drugs must be developed to cure an illness
or alleviate the discomfort of symptoms.
For example, mint leaves can alleviate a stomach upset, cloves can help with a toothache and
vinegar can treat sunburn.
Some medicines are extracted from natural sources, like plants or animals. For example, quinine
was extracted from the bark of the cinchona tree as a muscle relaxant by the indigenous Quechua
population in South America and later used very effectively as a treatment for malaria in Europe
beginning in the 1600s, saving countless lives throughout history. Malaria is an infectious
disease carried by mosquitoes and causes flu-like symptoms, but can lead to respiratory distress,
renal (kidney) failure and even death. Currently, over 200 million cases of malaria occur every
year, and it is estimated to be the cause of 600,000 deaths in 2010 (World Health Organization).
Quinine is not typically prescribed any more as there are other medicines that are more effective,
including a variety of anti-malarial drugs that prevent a person from contracting malaria in the
first place.

Substance that has been identified from a plant or animal has been proven to have effective
medicinal properties
made on a large scale in order to meet the needs of our population. Scientists may use animals or
bacteria to produce some substances, as with synthetic insulin to treat diabetes. In 1921,
Canadian scientists Frederick Banting and Charles Best first successfully used insulin extracted
from the pancreas of cattle to treat children suffering from diabetes. Today, insulin is synthesized
using bacteria or yeast to meet the public demand. Banting and Best had first tested their
methods using dogs, as shown in the video below.

Pharmaceutical companies are always developing new synthetic drugs to work more effectively
with fewer side effects than naturally sourced medicines. Synthetic drugs are made in a
laboratory, using chemical reactions to produce and isolate the active medicinal agent. For
example, aspirin is a common pain reliever that was first extracted from the bark of willow trees,
but is now made commercially by reacting acetic anhydride with salicylic acid. The product,
acetylsalicylic acid, is then isolated from the other product acetic acid and purified from any
other contaminants.

The development of new synthetic drugs

The pathway to making a drug available can take many years and cost a lot of money. Scientists
– biologists, chemists and physicists – work together collaboratively (Aims 9 and 10) to research,
develop and test new drugs to be more effective with lower risks and side effects. The basic drug
discovery process is outlined in the video below.
The maximum yield of the product is the goal, to minimise costs and maximise profits for the
drug company. You may have performed an experiment in class where you measure the
percentage yield of your product. One of the challenges faced in drug synthesis is to extract a
large yield of a high purity sample.
Case study
Health or profit? Pharmaceutical companies have the potential to treat illness, but they are also
operating as a business and have the potential to earn huge profits. What moral or ethical
responsibilities do drug companies have to the human population that may not be able to afford
the medicine they are producing? A classic example is medicines used to treat HIV/AIDS that
are sold at a high cost and are unaffordable to many in Africa, where HIV/AIDS is prevalent.

Part of the drug development process is to conduct a 'double blind test' where a placebo is
offered to one group of patients, while the other group receives the drug. A placebo is a pill,
lotion or injection that does not contain the active ingredient that the drug has, and is used to see
if the drug does have a measurable effect compared to not using the drug. Many times, people
taking the placebo report to have improvements in their health, even though they are not taking
the actual drug. This "placebo effect" has been noted in numerous studies. Below is a video
discussing the placebo effect.

Q
1. Medicines can be...
A. Formed by chemical reactions in laboratories.
B. All responses are correct.
C. Extracted from plants.
D. Synthesised by microorganisms.
Drug administration
● Discuss the three different ways in which drugs can be administered by injection.
State three other ways in which drugs can be administered.
1. Drugs can be injected
a. under the skin (subcutaneous) for topical effects such as for local anaesthetics.
b. into the muscle (intramuscular)
c. directly into a vein (intravenous). Injecting directly into a vein produces the quickest
reaction that affects the whole body.
Other ways
a. mouth (orally)
b. by inhalation
c. Absorption in the rectum or vagina (e.g. suppositories).
d. topically on the surface of the skin.
e. Applied into the ear or eye (e.g. drops of prepared solutions).
Factors to consider when determining mode of administration:
1. Metabolism The speed and ability of the body to absorb and use the medicine, known as
metabolism, plays a large role in determining the method of administration. Injection of
the drug directly into the bloodstream has a much faster metabolism than oral ingestion,
for example. Some drugs are best employed with a quick absorption of the entire dose,
such as with an insulin injection when treating diabetes, while others are more effective
when absorbed slowly over time, such as the hormones used in birth control skin patches.
2. Dosage of a drug partially determines the method of administration. The dosage refers to
the amount of the drug that the person would be required to take, which may be measured
in units of grams or millilitres, for example.
The dosage of the drug also includes the frequency of administration required to maintain the
level needed to have a medicinal effect in the body, based on the concentration in the
bloodstream. Some medicines may only require a single dose, while others may need to be taken
multiple times per day. Medicines with very low doses could be better administered by oral
ingestion of a prepared syrup that is diluted with a solvent (such as water or ethanol) and other
ingredients, like flavouring, rather than by injection with a very small volume of a concentrated
preparation. Ingesting a larger volume of a diluted syrup would help to ensure that the entire dose
has been administered.
3. Tolerance of the drug. When some drugs are taken for an extended period of time, the
effective action of the drug on the body can decrease with each exposure. This can be due
to decreased absorption of the drug with prolonged usage, which can occur if the nasal or
digestive tract becomes irritated, making injection possibly a better option. This
sometimes also requires a dose to be increased over time in order to have the same
desired effect on the body.
Many medicines also have the potential for addiction. Addiction can occur when the body
quickly adapts to the presence of the medication and experiences negative effects in its absence.
This can lead to physical or emotional discomfort and 'cravings' for the drug. How and why drug
addiction occurs is still unclear. Some medicines, especially those used for pain, can quickly
become habit-forming, especially when taken by a method that has a quick absorption, such as
with injection or inhalation. A slower, time-released method, such as with oral ingestion or a skin
patch, can help to keep the levels of medicine in the body lower and more consistent, and avoid
dependency.
Drug activity
After the drug is administered, it is absorbed by the body and travels through the bloodstream,
but then what happens? How does swallowing a pill relieve a headache? The drug must interact
with specific sites in the body where it has an effect: the "target site".
Some drugs have an effect on specific types of cells, such as with chemotherapy drugs and
cancer cells. The target cells are identified by three-dimensional receptors into which the drug
fits like a key in a lock. If the drug passes by cells that do not contain the receptor, it will not
bind to the cell and have a medicinal effect.

Figure 4. The cell membrane contains receptors that drugs interact with to make changes in
the body at a cellular level.

Other drugs work to increase or decrease the action of enzymes in the body. For example,
penicillin, a common antibiotic, works to inhibit the enzyme needed for bacteria to form their
cell wall. As a result, the bacteria cells burst without the structure of their rigid cell wall.

When a drug is taken, the entire dose does not always make it to the target site.
Bioavailability is the fraction of the administered dosage that reaches the target site. There are
several reasons why a portion of the drug does not make it to where it is needed in the body.
Some of these reasons include the administration of the drug, polarity and functional groups.

Definition
Bioavailability is the fraction of the administered dosage that reaches the target site.
When a medication is administered intravenously – that is, by injection into a blood vessel – the
bioavailability is 100%. For several reasons, however, many drugs are not administered using
this method, so all other methods of administration have bioavailability less than 100%. When a
medicine is ingested orally, the acidity of the stomach or small intestine may destroy some of
the drug, the drug may not be completely absorbed or it might even be absorbed by the bacteria
in the small intestine.

Figure 6. Different types of injections. Only intravenous has 100% bioavailability.

The physical properties of the drug, such as the polarity, may also affect the bioavailability.
Since the drug must eventually reach the blood, which is polar as it has a water solvent, the drug
must have some polarity, since "like dissolves like". For the drug to enter the cell, it must also
have some nonpolarity to pass through the cell membrane. Therefore, drugs must have both
polar and nonpolar properties.

Important
Drugs must have both polar and nonpolar functional groups to be absorbed by the body and at
the cellular level.
The types of functional groups on the drug will determine its overall polarity. Polar functional
groups include hydroxyl, carboxyl or amino groups. Nonpolar functional groups include alkyl
side chains and phenyl rings. The structure of acetylsalicylic acid, a common pain reliever
known as aspirin, is shown below. You can identify both polar (carboxyl) and nonpolar (phenyl)
functional groups, making this medicine suitable for oral ingestion and absorption into the body.

Figure 7. Molecular structure of acetylsalicylic acid (aspirin).

 If the drug is administered orally (usually with a sip of water), then a polar drug will generally
dissolve within the polar environment of the contents of the stomach. If the drug is not very
polar, it might bind to food particles instead, preventing it from being absorbed. This is why
drugs are sometimes required to be taken either with food or on an empty stomach to ensure
better absorption (and thus greater bioavailability).

Case study
Grapefruit and its juice has been known to affect the absorption of certain medicines such as
some cholesterol-lowering drugs in the small intestine. The fruit interferes with enzymes in the
lining of the small intestine that destroy the medicine. This leads to greater absorption of the
drug, and thus greater bioavailability, but at dangerous or toxic levels. Patients on these
medications would be advised not to consume grapefruit or its juice while taking these drugs, as
the effect of the fruit can last for more than 24 hours.

Figure 8. A medicine bottle containing a warning about the dangers of grapefruit and some
medicines.

The therapeutic index

When a drug is developed, the dosage must be determined. There is an effective window where
the dosage of the drug is most active. If the dose is below this window, the concentration of the
drug in the body will be too low and thus not have a measurable effect, but if the dosage is too
high, it could be dangerous and cause serious side effects or even death. The dosage of the drug
must be within this therapeutic window.
Many factors, such as age, gender and body mass, determine the effectiveness of a drug's action
on the body, so only trial and error during clinical trials can determine the effective dosage of a
drug. Since drugs are often produced in standard dosages, these factors must be averaged over
the general population, so clinical trials focus on the drug having an effect on 50% of the
population of the drug trial.

During the animal testing phase, scientists administer different quantities of the drug to
determine the dose required to have the desired medical effect. The minimum dose required to
have an effect on 50% of the population is known as the effective dose, known as ED50
(Effective Dose for 50% of the population). Scientists must also determine the lethal dose, which
is the dose of the drug that is enough to kill half of the population, known as LD50 (Lethal Dose
for 50% of the population).

Drug trials in animals and humans come with moral, as well as legal, requirements that vary
from one country to another. The IB Animal Experimentation Policy states that "experiments that
administer drugs or medicines, or those that manipulate the environment or diet [of any animal]
beyond that which can be regarded as humane, are unacceptable in IB schools".
In human drug trials, the lethal dose is not something scientists seek to determine, but rather the
toxic dose is measured as the upper limit of the therapeutic window. The lethal dose could be
extrapolated for the weight of a human, using the dose and weight of the animal used. This is the
dose where a serious toxic effect is observed for 50% of the population, the TD50. The method
for measuring toxicity may vary depending on the type of drug, but could include blindness,
birth defects or another serious medical condition, such as causing cancer. The toxic dose would
be lower than the lethal dose.

Definition
ED50 - the minimal effective dose for 50% of the population (animal and human trials).

LD50 - the lethal dose for 50% of the population (animal trials).

TD50 - the toxic dose for 50% of the population (human trials).

Important
The ED50 and LD50 (for animals) and TD50 (for humans) make the therapeutic window.
Knowing the minimum and maximum doses enables scientists and doctors to determine how
much to prescribe to a patient (between the blue and orange lines on the graph below).
 Figure 2. The relationship between the effective, toxic and lethal doses.

The therapeutic window of a drug is often represented by a ratio, known as the therapeutic index
(TI). The TI is calculated using the LD50 and ED50, as shown in the formula below:

Examiner Tip
Please note that these formulas are NOT included in your data booklet. Therefore, you must
remember both formulas for therapeutic index for the exam and be able to use them.
Here is an example of a calculation involving TI. If a drug was found to have a medicinal effect
on 50% of laboratory rats at a dose of 2mg and to be lethal to 50% of laboratory rats at a dose of
10mg, the therapeutic index would be:
Be Aware
Note that the therapeutic index has no units of measurement. Both the LD50 and ED50 for
animal studies (and likewise the TD50 and ED50 for human studies) must be in the same unit of
measurement. When divided, these units cancel and thus TI has no units.
The magnitude of the therapeutic index is an indication of the "safety" for the dosage of the drug.
For drugs with a smaller TI value (close to 1), the dosage of the drug must be carefully
administered because the minimum effective dose and the toxic or lethal doses are very similar.
This is especially true for drugs or administration methods with a high bioavailability, since a
large portion of the dosage is reaching the active site. Doctors would have to prescribe the drug
very carefully and patients would have to also be mindful not to exceed the dosage of the drug.
For drugs with a high TI value, the drug would be viewed as being more safe and also doctors
would have more flexibility in prescribing a range of different doses, as required by the patient.
This is also the case for drugs or administrations with a low bioavailability, since a small portion
of the dosage reaches the active site. Many of the drugs available without a prescription would
have a high TI value and also sometimes give the consumer options for the dose (i.e. take 1-2
tablets every 4 hours as needed).

QThe therapeutic window gives information on the amount of a drug that can be safely
administered to give the desired effect without causing adverse harm. It is effectively the
safety range of the drug and is related to the therapeutic index.
Therapeutic index = LD50 / ED50
Explain what is meant by Effective Dose 50 and Lethal Dose 50 and discuss the problems
associated with determining the LD50

The ED50 is the dosage of the drug required to bring about a noticeable effect in fifty percent of
the population. The LD50 is the dosage required to bring about the death of 50% of the animal
population to whom the drug has been administered.
Determining the LD50 causes the ethical problem that animals must be killed in the interests of
scientific research. There is also the problem that different animals react to drugs in different
ways so there is no easy way to extrapolate the finding to human beings.

Figure 3. Directions on medicines often give options for dosing, but only for medicines
with a high TI value.

D.2 Aspirin and penicillin

What you should know

At the end of this Subtopic D2 - Aspirin and penicillin, you should be able to:

● Aspirin is prepared from a reaction between salicylic acid and acetic anhydride.
● Aspirin works by interfering with the production of prostaglandins, which are responsible
for the sensation of pain in the body.
● Aspirin can be used as a pain reliever, fever reducer and anticoagulant to prevent heart
attack and stroke.
● Aspirin can be modified to sodium salicylate to increase solubility and thus
bioavailability.
● Aspirin has a synergistic effect when taken with alcohol.
● Penicillins are produced by fungi/moulds.
● The key feature of penicillin is a beta-lactam ring.
● Penicillins work to interfere with the cell wall production in bacteria, thus stopping
bacterial infections.
● Different side chains to the penicillin molecule result in different forms of penicillins that
can be used to treat different types of bacterial infections and provide different routes of
administration.
● Bacteria can produce penicillinase, which destroys the beta-lactam ring, and makes the
bacteria antibiotic-resistant.
● Over-prescribing penicillin can result in some bacteria becoming resistant to penicillin.
Essential idea: Natural products with useful medicinal properties can be chemically altered to
produce more potent or safer medicines.

Aspirin and penicillin are both naturally-occurring medicines that have made a large impact on
how diseases are treated. Prior to their discovery, infections or traumas would have taken weeks
or months, rather than days, for the body to fight. Some infections would have also left the
patient with permanent effects, such as blindness or loss of hearing, from a fever or an ear
infection. We take for granted the ability to purchase medicines for a quick fix for our ailments,
but these naturally-occurring medicines have been used for centuries and are now produced
large-scale for our ever-growing population.

History of aspirin
"Take two aspirin and call me in the morning" is a classic piece of advice from doctor to patient.
Aspirin has been the cure-all for more than a century – everything from muscle aches to fevers,
swelling and even pain during childbirth. For many years, doctors were unaware of how aspirin
worked to effectively relieve a variety of ailments, but today we have a better understanding of
how the drug reaches the target site.

Aspirin had its early beginnings in 400 BC, when the Greeks would give women in childbirth tea
made from the leaves of the willow tree. The leaves and bark were found to have medicinal
properties and were found to be used in many parts of the world as a pain reliever, fever reducer
and anti-inflammatory. It wasn't until the 1820s in Europe that the active ingredient was isolated
from the bark of the willow tree and called "salicin". Salicin is transformed to salicylic acid,
which was found to be more effective, but irritated the stomach. In Germany in 1897, Felix
Hoffmann at Bayer Pharmaceuticals produced acetylsalicylic acid, which was found to be as
effective as salicylic acid and caused less stomach irritation. Bayer patented the drug and called
it aspirin and began to produce it for consumers two years later.

Figure 2. The structures of salicin, salicylic acid and acetylsalicylic acid. Note the
similarities in structure and the differences in functional groups.
 History of penicillin
Penicillins are produced by moulds which are a type of fungi. Fungi can be unicellular
organisms, such as yeast and mould, or multicellular, such as mushrooms. Moulds have been
used since ancient times to treat illnesses, although the action remained unknown for centuries.
Poultices of warm soil, wet bread or mushrooms were used in many cultures for centuries to treat
wounds. It wasn't until the 1800s in Europe that scientists were able to isolate the active
compound that was responsible for the treatment of disease.

Figure 3. Structure of penicillin, where 'R' is a variable side chain that provides differences in
action and bioavailability. The beta-lactam ring is a key feature of all penicillins.
D.2 Aspirin and penicillin

The synthesis of aspirin

Aspirin is an example of how a naturally-occurring compound has myriad benefits. From the
first extraction from willow bark, scientists have improved upon the process of synthesising pure
forms of aspirin. Today, aspirin is prepared from salicylic acid and acetic anhydride to produce
aspirin (acetylsalicylic acid) and acetic acid (also known as ethanoic acid), as shown in Figure 1.
Note that this is an esterification​reaction with the product, aspirin, containing an ester functional
group.

Figure 1. The reaction for the synthesis of aspirin from salicylic acid.
In the reaction the acetic anhydride molecule is cleaved, with one part of the molecule replacing the
hydrogen atom of the –OH group on the salicylic acid and the other part of the molecule accepting
the hydrogen atom to form acetic acid. This reaction, as with other esterification reactions, requires
an acid catalyst and heat to drive the reaction forward. The aspirin product is white crystals that can
be collected by filtration (gravimetric or vacuum filtration) when the mixture cools in an ice bath
following the reaction.

Commercially, aspirin production is a little different to the small-scale process in a classroom laboratory.
The drug company Bayer held the patent on the synthesis of aspirin from 1899 until the 1930s, when
the drug patent ran out and it could be made by other companies, making it a generic drug. Drug
companies must take great care to ensure that they are producing a high yield of a very pure sample.
If the reaction yield is low, due to the reaction not going to completion, loss of product in the
collection method or impure reagents, then the company will lose money, so this is economically
unfavourable. Likewise, if the yield is low, the purity of the product will also be low, and it could be
dangerous for the company to distribute a product that contains impurities or does not contain the
dose it claims to have on the product label.

Exam tip
Like for all esterification reactions, heat and a strong acid (H2SO4) are required to catalyse the
reaction and ensure a greater product yield.
To improve the purity of the product, the aspirin crystals are subjected to a recrystallisation
process. Recrystallisation of aspirin (and many other organic solids) generally involves taking the
dried white crystals that were obtained and dissolving them in warm 95% ethanol in a flask.
When the crystals have all been dissolved, an equal volume of water is added and the contents
cooled on ice until the aspirin crystals recrystallise (and return to white). The sample is then
filtered again, and recrystallisation can be repeated many times to ensure improved purity of the
sample. This process works by removing impurities by dissolving them in ethanol, which has
polar and nonpolar properties. The impurities will dissolve and be rinsed away with the
ethanol/water mixture, leaving behind the pure aspirin crystals, which have a melting point of
136°C, meaning it will become a solid when cooled to room temperature.

Figure 2. The process of recrystallisation.

Definition
Recrystallisation is the process of purifying a solid organic product using the following steps:

1. Add a small amount of a solvent (generally ethanol is used) and place in a hot water bath
to dissolve crystals.
2. Add cold water and/or use an ice bath to lower temperature to crystallisation point of
organic product.
3. Collect solid organic product using filtration (vacuum or gravimetric). Any impurities
will remain dissolved and flow through.
In order to test the purity of a sample, several methods can be used. A simple melting point
determination is something you might do in your classroom laboratory. Aspirin has a melting
point of 136°C and a pure sample will melt very close to this temperature; the sample will also
melt over a narrow range of temperatures, known as the melting point range. An impure sample
will have a melting point lower than the theoretical temperature, as impurities disrupt the
crystalline structure, weakening the attractive forces between particles. The lower the purity, the
greater temperature difference from the theoretical melting point, and the broader the melting
point range.

Case study
If you are comparing a commercially prepared sample of aspirin to a sample made in your school
laboratory, you may notice a big difference, especially in the mass of the tablet with the dose of
aspirin. Other additives are included by drug companies to the tablet to add bulk, minimise the
potential stomach upset (such as in 'buffered aspirin') and to help with ingestion, by adding a
lubricant to aid in swallowing. Some additives may include corn starch, vegetable oil, sugars or
artificial colours.
Commercially, purity can also be tested using infrared spectroscopy. Infrared spectroscopy (IR)
identifies specific types of bonds in a molecule. For aspirin, the types of bonds expected in a
pure sample are strong absorption around 1700 cm-1 for the C=O bond in carboxylic acids, and
broad absorption around 2800 cm-1 for the O-H bond in carboxylic acids. Using IR is helpful to
determine if the sample tested contains the type of bonds (and thus specific functional groups)
expected in aspirin, or it might identify the bonds present in the impurities.
Figure 3. The infrared spectrum of aspirin. Note the strong absorptions at 1700 cm-1 and 2800
cm-1

Exam tip
Your data booklet contains the structure of aspirin in Table 37 and the IR data in Table 26 for all
of the bonds you would expect to find in aspirin and in other organic compounds. You do not
need to memorise the IR profile of aspirin, but you are expected to use your data booklet to
identify the wave numbers for the specific bonds.

D.2 Aspirin and penicillin

How aspirin works

Uses of aspirin
1. analgesics, or pain relievers for headache, menstrual cramps, backache, arthritis or
discomfort with a cold. Aspirin is primarily used as a pain reliever
2. fever reducer
3. anticoagulant.

side-effects. It can irritate the stomach, leading to ulcers if overused. Also, it does cause the
blood to thin, which can be a problem for some people who have clotting issues. The benefits of
aspirin for various medical issues are still being discovered. Low-dose aspirin (81 mg or less) is
commonly prescribed for people with a risk of heart attack or stroke. It is also commonly
prescribed to women during pregnancy to reduce the risk of certain pregnancy complications and
is also found to improve circulation for people with diabetes.

Definition
Analgesics - medicines that provide relief from pain (analgesia). Some different analgesics
include aspirin, acetaminophen/paracetamol and opiates. Some analgesics work at the site of the
trauma while others work in the brain to alter the perception of pain.
Aspirin is both an analgesic and antipyretic.
Case study
Aspirin might be recommended to reduce fever with a variety of illnesses; however, aspirin must
not be taken if the illness is viral, as a serious complication called Reye's syndrome might occur.
Reye's syndrome is a rare complication that occurs in children and is correlated with the use of
aspirin and certain viral illnesses, such as chicken pox or influenza. Doctors are not entirely sure
why Reye's syndrome occurs, but it begins with a rash on the hands and feet and can lead to
swelling in the brain, seizures and even death if not treated.

How aspirin works for pain relief or fever

● When we experience physical trauma, the cells in our body respond with a series of steps
that ends with the production of chemical substances called prostaglandins.
● These prostaglandins result in the sensation of pain, swelling and sometimes fever.
● Aspirin works by stopping the enzyme that produces prostaglandins, which is called
cyclooxygenase (known as COX). Aspirin does not have a specific target site, but rather
acts to inhibit the production of prostaglandins throughout the body, so any and all pain,
swelling or fever will be treated.

How aspirin works as an anticoagulant

Aspirin works by slowing down the clumping of platelets, so instead of coagulating, they
anti-coagulate. People experiencing symptoms of a heart attack or stroke are sometimes
recommended to chew two aspirin tablets while on their way to hospital to reduce the severity of
the attack. Aspirin can also be taken as a prophylactic, or preventative measure, to slow or
prevent the formation of a blockage in the first place. Generally a low dose of aspirin is used for
this purpose, and is often recommended to middle-aged or elderly people with a family history of
stroke or heart disease, or even for pregnant women, as pregnancy can increase the risk of blood
clots.

Blood is slightly viscous due to the presence of dissolved fats, proteins and other components.
Since blood is travelling within a contained system of vessels pumped by the heart, any blockage
or leak could have devastating effects.

Blood flow in an unblocked vessel (top) and in a vessel that is blocked by plaque (bottom).
When a blood vessel is damaged, such as when cutting your finger, small fragments of broken
blood cells, called platelets, coagulate, or clump together, to stop the leak of blood out of the
circulatory system. This is commonly known as blood clotting. Over time, the walls of the vessel
can repair itself and the body returns to normal blood flow and pressure. For people with low
levels of platelets, such as those with the condition of haemophilia, the blood does not clot well
and this can lead to a severe loss of blood or even death.

If the blood vessels become blocked with fat and cholesterol, such as after a lifetime of an
unhealthy diet, the blockage results in parts of the body not receiving the nutrients that the blood
carries. Platelets also contribute to the blockage by perceiving the blockage as damage. If the
blockage occurs in the artery leading to the heart, the heart begins to pump harder to draw more
blood toward itself and the heart muscle becomes damaged. This is called a myocardial
infarction, or commonly a heart attack. If the blockage occurs in the artery leading to the brain,
blood and the oxygen it carries do not reach the brain, causing damage. This is called a stroke.

Case study
Since aspirin interferes with the ability of the blood to clot, continued use of higher doses of
aspirin is not recommended, as this could lead to excessive bleeding (internally or externally) if
the body experiences physical trauma. Also, people taking aspirin regularly, even low-dose
aspirin, would be asked to stop taking their aspirin prior to surgery or childbirth to prevent
excessive bleeding.

Factors influencing the bioavailability of aspirin

Aspirin can be chemically modified to a salt to increase its solubility in aqueous solutions. By
dissolving the acetylsalicylic acid in sodium hydroxide, the hydrogen on the carboxyl functional
group is replaced by a sodium ion, as shown in the reaction below, to make sodium
acetylsalicylate, sometimes called soluble aspirin.

The sodium acetylsalicylate product is more soluble in water than the aspirin molecule, as ions
have a stronger attractive force to the dipoles in water molecules than the intermolecular forces
of the carboxyl functional group. Having a product with greater aqueous solubility means that
orally ingested sodium acetylsalicylate will reach the stomach more quickly. The bioavailability
of soluble aspirin, however, is almost the same as the insoluble form because the ionic salt reacts
with stomach acid to produce (insoluble) aspirin. One method of increasing the bioavailability of
aspirin is to administer the drug intravenously. As discussed in section D.1.2, this method of
administration produces the highest possible bioavailability.

Synergistic effects of aspirin and alcohol

Drug labels warn that drinking alcoholic beverages (those that contain ethanol) while taking
aspirin can cause an increased risk of stomach bleeding. Aspirin and alcohol have a synergistic
effect; that is, each drug has a higher medicinal effect when taken in combination than they
would when taken separately. People taking aspirin are advised to not consume alcohol to avoid
the increased risk of stomach bleeding or other toxic effects.

Case study
Alcohol also has a synergistic effect on other drugs such as tobacco, cocaine and depressants like
Valium. Even legal drugs, like morphine, can lead to respiratory failure when taken with alcohol.
Always be sure to follow the warning labels to avoid a drug overdose.

D.2 Aspirin and penicillin

Use of penicillin
Communicable diseases are generally spread via two routes – bacteria and viruses. Bacteria are
single-celled organisms that divide by binary fission within the organism that they have infected.
Some bacteria are harmful, such as the salmonella that causes food poisoning, while others are
harmless or even beneficial, such as the bacteria that live in your small intestine and produce
vitamin K in exchange for a place to live and nutrients. Bacterial infections can be treated with
antibiotics, such as penicillin, that stop the growth and reproduction of bacteria.
Viruses are small capsules of DNA (deoxyribonucleic acid, which is genetic material) that
require a host organism in order to replicate. Viruses are much smaller than bacteria and do not
contain the organelles necessary to divide on their own. Viral infections are difficult to treat and
there are many such infections that have no cure, such as HIV (human immunodeficiency virus).
The only course of treatment for a virus is prevention with an immunisation. In other cases, the
body's immune system will eventually fight off the virus, as with a cold or influenza.

Important
Only bacterial infections can be treated with antibiotics. Viruses are not affected by the presence
of antibiotics.

Synthesis of penicillin Penicillin production

In order to produce the quantities of penicillins that are required for a large population, growing
fungi in a Petri dish is not sufficient. Populations of fungi are fermented in large, stainless steel
tanks under controlled conditions in a sterile environment. Penicillin is produced when the fungi
are under stress, not under regular growth conditions. In order to produce a stressful
environment, scientists provide penicillin with lactose sugar, rather than glucose sugar that the
fungus prefers as a food source. The temperature, pH and other nutrients added to the batch also
ensure that the fungi are under stress.
 Figure 1. Production of penicillin.

Different strains of fungi produce different penicillin molecules. The core structure of the
penicillin molecule is shown below, with different options for side chains. The key feature of any
penicillin molecule is the beta-lactam ring. The beta-lactam ring is important for the action of
penicillin in preventing the growth of bacteria.
Different side chains for the R-group give rise to different penicillin structures and functions.
Penicillin G, also known as benzyl penicillin, is a very potent antibiotic that has been used
successfully to treat syphilis, meningitis and other bacterial infections. Notice that the benzene
ring is nonpolar and as a result, penicillin G must be injected to have an effect, as it is not
water-soluble enough to be absorbed by oral ingestion. Penicillin V, by contrast, contains an
oxygen before the benzene ring. This provides slightly more solubility in water and therefore
penicillin V is prescribed as an oral antibiotic to treat minor infections like tonsillitis.
 Figure 2. Different side chains result in different penicillin molecules.

Examiner Tip

The general structure for penicillin is in your data booklet on page 38. You are not required to
know specific penicillin molecules, but be sure to understand how the different R groups give
rise to differences in physical properties, such as polarity, and thus bioavailability and action.
Some penicillins are chemically modified by altering the side chain in order to give the antibiotic
enhanced medicinal effects or to improve the bioavailability. Penicillin G is not stable in the
acidic environment of the stomach, so it cannot be taken orally and must be injected to have
better bioavailability. Penicillin V is stable in acid, so it can be prescribed orally. Ampicillin is
produced by chemically modifying the R group to include an amino group. The presence of this
amino group allows ampicillin to better penetrate the cell walls of bacteria and thus has greater
action on stopping the growth of bacteria for respiratory infections. The amino group also allows
for greater solubility in water, so ampicillin is often prescribed orally, rather than intravenously.

Case study
It is estimated that about 10% of people report an allergic reaction to penicillin. The symptoms of
the reaction could be mild, such as a rash, itching or nausea, or severe, such as anaphylaxis
(constriction of the airway). The actual occurrence of a severe penicillin allergy is quite low, less
than 1%, but doctors will generally err on the side of caution and not prescribe a penicillin-based
medicine to a person who has reported an allergic reaction in the past.

How penicillin works

How the structure of penicillin allows for action

The beta-lactam ring is the core structure of all penicillin molecules. When bacteria divide by
binary fission to make two identical cells, new cell walls are required in order for the two cells to
separate and to have structure and protection. Cell walls are made with layers of peptidoglycan,
a polymer made of sugars and amino acids, also known as murein, that is sandwiched between
two lipid layers. Without a functioning cell wall, a bacterium would not have the rigid structure
required to function and would instead rupture, causing the death of the cell.
When the layers of peptidoglycan are made for the cell wall, they are cross-linked, which means
there are covalent bonds holding the layers together (this is common in polymers). This
cross-linking provides additional structure and rigidity for the cell wall. Cross-linking occurs by
the action of certain enzymes, known as transpeptidase, also known as the penicillin binding
protein (PBP). The beta-lactam ring effectively binds to transpeptidase (the penicillin binding
protein) and thus interferes with the action of the enzyme, therefore not allowing the cell wall to
be cross-linked. A cell wall that is missing the necessary cross-linking will eventually have too
much water entering the cell via osmosis, causing the cell to burst. Since animal cells do not
have a cell wall or transpeptidase, penicillins cannot bind, so they have no effect on animal cells.

Figure 1. The action of penicillin on cell wall synthesis as an inhibitor.

This short video shows how penicillin works to inhibit cell wall synthesis.
Antibiotic resistance
Some bacterial infections do not respond to a course of antibiotics. This is because some bacteria
are capable of producing enzymes that destroy penicillin. These enzymes are known as
penicillinase or beta-lactamase. Penicillinase works to break the beta-lactam ring in the
penicillin molecule, thus rendering it ineffective in binding to transpeptidase (also known as the
penicillin binding protein).

Figure 2. The action of beta-lactamase that is produced by some bacteria, rendering

penicillin ineffective.

Important
The intact beta-lactam ring is essential for the action of penicillin.
Different R-groups on the beta-lactam ring make penicillin more resistant to the action of
penicillinase. For example, having a larger, bulkier R-group seems to make penicillin more
resistant to penicillinase, so naturally-occurring penicillins can be chemically modified to make
penicillin more effective at stopping the growth of bacteria.
Bacteria that produce penicillinase in large quantities are known to be penicillin-resistant. These
strains of bacteria are very difficult to treat and require potent antibiotics at a high dose. It is
believed that the overprescription of antibiotics has led to greater antibiotic resistance in recent
years, as bacteria have adapted to produce larger quantities of penicillinase as a survival
mechanism.
Another factor influencing antibiotic resistance is the course of the prescription. If a person does
not complete their entire prescribed dose, the weaker bacteria (those that produce lower
quantities of penicillinase) would have been effectively killed, but the stronger ones (the ones
producing more penicillinase) would still remain. These cells would then survive to reproduce,
thus making an entire population of cells that are resistant to the effects of penicillin.
This video outlines the some of the ideas that have led to antibiotic resistance.

Case study
In many countries, it is customary to be prescribed antibiotics, even if the cause of illness has not
been identified as bacterial. Methicillin is not even prescribed anymore because so many
infections of the bacterium staphyllococcus aureus are resistant (known as MRSA - methicillin
resistant staph aureus). According to the World Health Organization, antibiotics should only be
prescribed for bacterial infections and people should complete the full prescription, even if they
feel better.

D.3 Opiates

What you should know

At the end of this Subtopic D3 - Opiates, you should be able to:

● Understand that potent medical drugs can be prepared by chemical modification of

natural products which could be addictive and could be abused.
● Know that opiates are natural narcotic analgesics that are derived from the opium poppy.
● Compare the structures of morphine, codeine and diamorphine (heroin), using Section 37
of the data booklet, in terms of polarity of functional groups.
● Explain the synthesis of codeine and diamorphine from morphine.
● Explain why diamorphine is stronger than morphine due to its chemical structure and
ability to cross the blood-brain barrier.
● Explain why codeine is weaker than morphine due to its slow metabolism back into
morphine by the liver.
● Know that the ability of a drug to cross the blood-brain barrier depends on its chemical
structure (i.e. nonpolar functional groups) and solubility in water (blood) and lipids
(brain).
● Understand that opiates work by temporarily bonding to endorphin receptors in the brain,
preventing the transmission of pain impulses.
● Describe the medical uses for morphine, codeine and diamorphine.
● Explain the problem with opiate tolerance and the addictive properties of opiate
compounds.
● Discuss the side effects and risk of addiction to opiate compounds.

Essential idea: Potent medical drugs prepared by chemical modification of natural products can
be addictive and become substances of abuse.

The history of opium

Opium is the dried latex of the opium poppy, Papaver somniferum. Latex is the milky fluid
produced by some flowering plants and contains a mixture of polymers, sugars, oils and proteins.
Latex from plants can be used to make a variety of consumer products including balloons,
chewing gum and paint. Opium latex was observed to have medicinal properties as early as 5000
BC. In fact, somniferum means sleep.

Definition
Opiates generally refer to naturally occurring analgesics obtained from the opium poppy or
synthetic derivatives made from the naturally-sourced medicine. Examples include morphine,
codeine and diamorphine (heroin).
Opioids generally refer to synthetically produced drugs that mimic the action of naturally
occurring opiates. Examples include oxycodone and hydrocodone. These drugs have been under
a lot of legal and ethical scrutiny for their highly addictive nature.

Opium has a long history, originating in ancient Mediterranean cultures. It has been used as a
painkiller and for euthanasia, and smoked for recreational use. The opium trade brought poppies
all over the world and later started wars. The flower with the bright red petals and large seed
pods has had a very controversial history, but continues to be an important medicine worldwide.

The opium poppy, papaver somniferum, with its characteristic red petals, and seed pods with
morphine-containing latex.
Figure 1. The opium poppy, Papaver somniferum, with its characteristic red petals, and seed pods
with morphine-containing latex.
The cultivation of opium poppies
Turkey, England and India are some countries that currently cultivate poppies to produce opium
for pharmaceutical companies legally, as permitted by the United Nations. Illegal opium
cultivation for recreational drug use has occurred in the Golden Triangle region of Asia,
consisting of Myanmar, Thailand and Laos, since World War II and has grown in Afghanistan in
recent years. Afghanistan is the largest producer of illegal opium, where most of it is converted
to heroin and is exported to Europe and the United States.

The active medicinal ingredient in opium is morphine. Opium latex contains about 12%
morphine, so it must be refined to purify and make the sample more potent. Traditional poppy
cultivation for morphine involves making incisions in the seed pod and collecting the dried latex.
The latex is then processed to extract the morphine, which can then be taken intravenously or
orally. Morphine can also be processed to make codeine, an analgesic used to treat a
mild-to-moderate degree of pain, and heroin, a highly addictive analgesic, which is illegal in
many countries.

Latex on an opium seed pod. The pods are cut and the latex, known as "poppy tears", drips out
for collection and processing.
Figure 2. Latex on an opium seed pod. The pods are cut and the latex, known as "poppy tears",
drips out for collection and processing.

Types of opiates

General structure of opiates

Morphine is the active medicinal ingredient in the latex extracted from the opium seed pod. The
morphine extracted can be used directly or be processed to make two other drugs, codeine and
diamorphine, the latter commonly known as heroin. All three drugs work as analgesics, but the
minor differences in their chemical structures result in a change of potency and bioavailability.
Opiates must travel to the brain, where they interfere with nerve impulses. Since blood is polar,
there must be sufficient polar functional groups to keep the drug soluble. The brain, however, is
surrounded by a layer of lipids, or fats, which are highly nonpolar. In order for the drug to pass
from the blood and into the brain, there must also be sufficient nonpolar functional groups.
 Figure 1. The structures of morphine, diamorphine (heroin) and codeine.

Morphine contains two hydroxyl functional groups, which add polarity and water solubility to
the structure. Morphine is prescribed orally in a tablet or liquid or by intramuscular or
intravenous injection. The bioavailability of morphine taken orally is approximately 30%.
Codeine has one hydroxyl functional group substituted with an O bonded to a methyl alkyl
functional group, which forms an ether and therefore slightly decreasing the polarity and water
solubility, when compared to morphine. As a result codeine can pass into the brain more easily.
However, codeine is less effective at binding to receptors in the brain and therefore has 1/10 the
strength of morphine, so it is only suitable for mild to moderate pain.
Diamorphine has the two hydroxyl functional groups substituted with O bonded to an acetyl side
chains, which forms 2 ester groups and greatly reduces the polarity and solubility in water
compared to morphine and codeine. The bioavailability of diamorphine is less than 35% when
taken orally. As a result, diamorphine is generally not taken orally, but is injected intravenously.
With the decrease in polarity, diamorphine can pass into the brain much more easily than both
morphine or codeine. It also binds to the receptors in the brain more effectively than both
morphine and codeine, making diamorphine have 4-5 times the strength of morphine. It is rarely
used medically and only for severe pain due to its highly addictive nature. Diamorphine is used
recreationally, but is regarded as an illegal drug in many countries.
Important
For opiates, as polarity decreases (from morphine to codeine to diamorphine), the ability to pass
from the blood to the brain increases.

Exam tip
The structures of morphine, codeine and diamorphine are in your databooklet in Section 37.
There is no need to memorise these structures, but you should be able to discuss the differences
in functional groups and polarity.

Morphine derivatives

Codeine
Opium latex does naturally contain about 3% codeine, but most codeine is made synthetically
from morphine through a chemical reaction. Codeine is sometimes referred to as
methylmorphine since one hydroxyl functional group is replaced with a methyl alkyl group via
a methylation reaction. This makes an ether linkage. This reaction is actually reversed in the
liver when the body is breaking down the codeine for elimination.

Figure 2. Synthesis of codeine from morphine by a methylation reaction.

Exam tip
You are not required to know the specific chemical reaction details or the mechanism for the
synthesis of codeine from morphine. You should understand that a hydroxyl functional group is
replaced with a methyl functional group, which slightly decreases the polarity of the molecule,
but greatly increases the ability to cross the blood-brain barrier, increasing the overall
bioavailability.

Diamorphine (heroin)
Unlike morphine and codeine, diamorphine is not naturally found in the opium latex and it is
only made synthetically by reacting morphine with ethanoic acid in an esterification reaction.
The hydroxyl functional groups on the morphine molecule each react by a condensation reaction
with the carboxylic functional group on the ethanoic acid. The result is an ester linkage and the
elimination of water.

Figure 3. Synthesis of diamorphine from morphine by an esterification reaction.

How opiates work

How pain is perceived

When the body experiences a trauma, a chemical pathway occurs with the end result being the
production of prostaglandins. Prostaglandins can increase the body's temperature, causing a
fever, and are also part of producing the sensation of pain. The sensation of pain is caused by the
direct action of prostaglandins on the nerve endings locally at the site of the trauma or by acting
on the perception of pain in the central nervous system in the brain. Some analgesics, such as
aspirin, work to interfere with prostaglandin production and treat pain (and the associated
trauma) locally. Other analgesics, like opiates, work to interfere with the sensation of pain in the
brain (and do not address the trauma).
When the central nervous system receives a pain stimulus from the nerve endings at the site of a
trauma, the pain signal is transmitted through the nerve cells, called neurons, to the spinal cord
and then the brain. Neurons can communicate to one another using chemicals called
neurotransmitters, to transmit the signal faster and across small gaps between neurons, called
synapses, where they interact with receptors on the neuron on the other side of the synapse.
Specific parts of the brain are then stimulated to give the sensation of pain.

Opiates and pain

Opiates work by interfering with the neurotransmitters and receptors in the transmission of the
pain signal across. Your body produces substances called endorphins that work as natural pain
relievers. Endorphins are produced when we are in pain, but also during stress and extreme
physical exercise. The word "endorphin" comes from the two words 'endogenous morphine',
which means naturally occurring morphine.
 Figure 1. The structures of an endorphin, the body's natural pain reliever, and morphine, the
pain reliever produced by poppies. Note the similarity in structure.

Endorphins bind to endorphin receptors (also called opioid or opiate receptors) in brain cells to
intercept the pain signal. Opiates also bind to the same endorphin receptors, since they share a
similar chemical structure. As the endorphin receptors cannot tell the difference between a
natural endorphin and an opiate, the pain signal is interrupted centrally for the body.

Figure 2. The binding of endorphin and morphine to the receptors in the brain.
Endorphins and opiates often cause a feeling of euphoria, not just from the relief of pain, but also
because of chemical changes that occur in the brain when opiates are present. For example,
dopamine is a neurotransmitter that is produced when the endorphin receptor binds to a natural
endorphin or to an opiate. The release of dopamine causes feelings of pleasure, which adds to the
addictive nature of opiates.

The action of opiates and opioids in the brain., image

Figure 3. The action of opiates and the release of dopamine in the brain to produce the euphoric
effect. Note that more dopamine is released when the opiate is binding to the opiate receptor.
Watch this video to learn more about how opiates work.

Comparison of opiates
There are three types of endorphin receptors in the brain. All three receptors respond with
analgesia (pain relief), but each one also produces other side-effects, ranging from hallucinations
and anxiety to respiratory depression, nausea and constipation. These side-effects are the result
of chemical changes that occur in the body in response to the binding of the opiate or endorphin
to the endorphin receptor.

Figure 4. The structures of morphine, diamorphine (heroin) and codeine.

Since morphine, codeine and diamorphine have similar structures, they are all capable of binding
to endorphin receptors. Morphine is capable of binding very well to one type of receptor and also
has been shown to interfere with the action of other two types, producing an analgesic effect.
Codeine, although less polar and more capable of passing into the brain than morphine, is only
about 1/10 the strength of morphine. This is because morphine has a much greater affinity for the
endorphin receptors in the brain compared to codeine. About 10% of codeine is metabolised in
the liver into morphine, although this can vary between individuals. For this reason, codeine is
known as a prodrug; a drug that is converted to a more active form once inside the human body.
However, this conversion is quite slow and other products are also made, which have no
medicinal effect.
Diamorphine contains more nonpolar functional groups than morphine or codeine, so it is faster
at crossing into the lipid layer that surrounds the brain. Diamorphine can only bind to one
receptor, so the effect of diamorphine is immediate, but does not last long.

D.3 Opiates

What you should know

At the end of this Subtopic D3 - Opiates, you should be able to:

● Understand that potent medical drugs can be prepared by chemical modification of

natural products which could be addictive and could be abused.
● Know that opiates are natural narcotic analgesics that are derived from the opium poppy.
● Compare the structures of morphine, codeine and diamorphine (heroin), using Section 37
of the data booklet, in terms of polarity of functional groups.
● Explain the synthesis of codeine and diamorphine from morphine.
● Explain why diamorphine is stronger than morphine due to its chemical structure and
ability to cross the blood-brain barrier.
● Explain why codeine is weaker than morphine due to its slow metabolism back into
morphine by the liver.
● Know that the ability of a drug to cross the blood-brain barrier depends on its chemical
structure (i.e. nonpolar functional groups) and solubility in water (blood) and lipids
(brain).
● Understand that opiates work by temporarily bonding to endorphin receptors in the brain,
preventing the transmission of pain impulses.
● Describe the medical uses for morphine, codeine and diamorphine.
● Explain the problem with opiate tolerance and the addictive properties of opiate
compounds.
● Discuss the side effects and risk of addiction to opiate compounds.
Use of opiates

Morphine Codeine Diamorphine

Most common Oral tablet or liquid Oral ingestion (90% Oral ingestion (35%
method(s) of (30% bioavailability). bioavailability).
administration bioavailability). Intravenous
Intramuscular or injection (100%
intravenous injection bioavailability).
(100%
bioavailability).

Relative strength 1 0.1 4-5

Common Quick moderate to Mild pain. Severe pain.

medicinal uses severe pain. Cough suppressant for
Sedation for minor non-productive cough
surgical procedures. (one that does not clear
mucus from the airways).

Advantages Quickly relieves Suitable for mild pain. Very quick relief
pain. Drug is slowly from pain.
Mild side effects. metabolised, so fewer
Option for doses are required.
convenient Convenient
administration (oral administration.
ingestion).

Moderately Addiction is possible. Highly addictive.

Disadvantages addictive. Must be injected.
Withdrawal if taken Withdrawal if taken
for extended periods. for extended
periods.
Drug metabolises
quickly, so frequent
doses are required.

Morphine is used for moderate to severe pain, such as following surgery, during childbirth or
after breaking a bone. Morphine can also be used effectively for sedation in minor surgical
procedures, such as during wisdom tooth surgery.
Strong analgesics are required in many circumstances. Codeine, the mildest opiate, is prescribed
for minor pain, such as a headache, but is also used as a cough suppressant. Codeine is
metabolised slowly by the liver back into morphine, making it useful as a long-lasting analgesic
for low levels of pain. Some people, however, are able to metabolise codeine very quickly,
converting it to morphine at a dangerous speed, so codeine cannot be prescribed for all people.
The use of diamorphine as a treatment for severe pain is controversial, due to its highly addictive
nature. Since it is a stronger analgesic than morphine, it can be administered at lower doses. It is
effective in alleviating severe chronic pain, such as for patients in end-of-life stages (palliative
care)
suffering from terminal illnesses. It is also used for pain relief following childbirth by caesarian
section and even in children suffering from severe post-operative pain.

Side effects and addiction

Unlike aspirin, which acts at the local site of trauma, morphine affects the body's central pain
response in the brain, so there are more side effects. Common side effects that are mild include
feeling dizzy, drowsiness, constipation and weight loss. More serious side effects include blurred
vision, chest pains and difficulty breathing. Symptoms of an overdose can include constricted
pupils, fever, muscle pain or spasms and severe sleepiness.
For people taking opiates for an extended period of time, their bodies build a tolerance to the
drug. The tolerance is due to the opiate receptors undergoing changes to become less sensitive to
the opiates. For people taking opiates for extended periods of time, higher doses of the drug are
required to have the same medicinal effect. Doctors must be careful when prescribing opiates for
patients long term because of desensitisation.

Definition
Tolerance is decreased medicinal effect of a drug that occurs with extended use of the same
dosage. Certain medicines cause a physiological response in the body, making the same dosage
of the medicine not as effective. In order to achieve the same medicinal effect, the dosage must
be increased with time.
Since patients require higher and higher doses of opiates to maintain the same medicinal effect,
opiates can become habit-forming, or addictive, with extended use. When patients have become
accustomed to the medication they can experience physiological addiction and withdrawal to
the medication if removed suddenly. Doctors will generally wean a patient off an opiate by
gradually decreasing the dose to avoid withdrawal. Symptoms of withdrawal include sweating,
vomiting, muscle aches and psychological distress.

In 2014, nearly 250,000 people died from drug overdoses (United Nations). Diamorphine
(heroin) and other opiate addiction is thought to be responsible for half of all drug-related deaths
worldwide. What responsibility do local governments, scientists, doctors and pharmaceutical
companies share to ensure the safety of the public from opiates? The World Health Organisation
produces a "List of Essential Medicines" that it recommends to countries cost-effective, essential
medicines that should be used in most health care systems. Codeine and morphine are on this list,
but not diamorphine.
See the World Health Organisation's List of Essential Medicines, which includes morphine and
codeine, but not diamorphine.
Methadone treatment
Opiates can produce a euphoric sensation at high doses, which results in illegal use and
addiction.Methadone is an opiate derivative that can bind to the opiate receptors but does not
produce the euphoric effects of morphine. Methadone is an effective treatment option to help
with tolerance, addiction and withdrawal symptoms.

Figure 1. Structures of morphine, diamorphine (heroin) and methadone.

D.4 pH regulation of the stomach

What you should know
At the end of this Subtopic D4 - pH regulation of the stomach, you should be able to:

● Recall that excess stomach acid is a common problem that can be alleviated by
compounds that increase the stomach pH either by neutralisation or by reducing acid
production and secretion.
● Explain that antacids are bases that neutralise excess stomach acid.
● Write a balanced reaction equation between a given antacid and hydrochloric acid.
● Solve stoichiometric calculations involving antacids.
● Explain how the pH of the stomach is buffered between pH 1 and 3 using carbonic acid
and hydrogen carbonate ions.
● Use the Henderson-Hasselbalch equation to solve problems involving buffers.
● Explain how H2 receptor antagonists, such as ranitidine, bind to the histamine receptor in
the cells of the stomach to inhibit stomach acid production.
● Explain how proton pump inhibitors, such as omeprazole, bind irreversibly with a
covalent bond to the proton pump to suppress acid secretion into the stomach.

Essential idea: Excess stomach acid is a common problem that can be alleviated by compounds
that increase the stomach pH by neutralizing or reducing its secretion.
You may have experienced the symptoms before – a burning sensation in your chest, abdominal
pain or even vomiting – following a meal of spicy or acidic foods. That feeling is generally
described as having 'indigestion', a 'sour stomach' or 'heartburn', but it has nothing to do with
your heart. Excess stomach acid, or hyperchlorhydria, is a problem that affects some people only
when certain foods are eaten, and other people on a daily basis regardless of their diet. Excess
stomach acid can rise upward into the oesophagus in a process known as 'acid reflux'. It is
estimated that one in four people are affected by excess stomach acid every day worldwide.
When experienced as a chronic problem, gastroesophageal reflux disorder, or GERD, is the
diagnosis.
The stomach produces hydrochloric acid (HCl) in order to help with the digestion of proteins and
carbohydrates (sugars). It is also helpful in killing any bacteria that might be consumed in
slightly spoiled food, protecting you from a potentially dangerous bout of food poisoning. When
the stomach produces too much acid, however, discomfort is often the result. In extreme cases,
stomach acid can cause damage to the stomach lining, oesophagus, mouth and teeth.

Certain lifestyle factors can put people more at risk of excess stomach acid production. A diet
high in spicy, fatty or acidic foods, such as chilli peppers, coffee, citrus fruits and alcohol, can
increase stomach acid production. Stress, lack of sleep or certain medical conditions can also
increase stomach acid production. Eating very large meals, lying down after eating or even
excess pressure on the stomach during pregnancy can push the stomach contents, including acid,
up into the oesophagus, causing the same symptoms.

In order to combat excess stomach acid, there are two main routes for treatment – either to
neutralise the excess acid or to decrease the production in the stomach. Traditional treatments for
excess stomach acid include baking soda (sodium hydrogen carbonate), aloe vera juice or ginger
root tea to neutralise the acid. Apple cider vinegar, also acidic, has proven effective in decreasing
stomach acid production. Currently, medicines offer quick and effective relief, either by
neutralisation or by decreasing acid production.

D.4 pH regulation of the stomach

Decreasing acid secretion. How stomach acid is produced

Rather than neutralising excess stomach acid, like antacids, some medicines work to stop the
production of excess acid in the first place. There are two main factors to stomach acid
production – synthesis of the acid and the release of the acid into the stomach. Drugs can work
on either factor to reduce the amount of acid that makes it way to the stomach.
In the stomach, acid is produced in specialised cells, called parietal cells, which then release the
acid when required. The acid is made and released on demand, otherwise the acid could cause
damage to the stomach lining. The stimulus to release acid can be triggered by eating food, stress
or a increase in the pH of the stomach contents.
There are three receptors in the parietal cells that must all be activated to produce and release
stomach acid. They are called the histamine receptor, gastrin receptor and acetylcholine
receptors. Interfering with the action of any of these receptors will stop acid production and
release.

H2 receptor antagonists
Drugs can act to either increase or decrease a process in the body by interacting with targeted
receptors. An agonist is a substance that binds to a receptor and fully activates it, while an
antagonist binds to a receptor and blocks it or prevents the action of other agonists. An example
of an agonist are opiates, such as morphine, that bind to opiate receptors to activate them in their
action of pain relief. An example of an antagonist is aspirin, which binds to cyclooxygenase
receptors to prevent their action in the pain response to trauma.
One method to decrease acid release into the stomach is with an H2 receptor antagonist drug.
One example of an H2 receptor antagonist is ranitidine. This drug interferes with the histamine
receptor and blocks its action (the 'H' in H2 antagonist stands for histamine). The result is that
acid will not be produced by the cells where ranitidine interferes with the histamine receptor,
since all three receptors are required to be activated in order to produce acid.
Like many drugs, ranitidine must first be processed by the liver before the drug can have the
desired medicinal effect. The active metabolite is the form of the drug after it has been
processed by the body. Ranitidine, therefore does not have as immediate an effect on stomach
acid as antacids do because there is a time delay for the liver to metabolise the drug before it is
active.

Figure 1. Structure of ranitidine.

Exam tip
The structure for ranitidine is in your data booklet. You should be able to identify the various
functional groups.
The chemical structure of ranitidine has ionic charges, allowing it to dissolve very well in water,
making it able to be well absorbed by oral ingestion (40-80% bioavailability), so it is generally
swallowed as a tablet or as granules dissolved in water. Ranitidine has a low incidence of side
effects: generally headaches are reported, and very few serious side effects have been noted. The
drug is effective for about 4-6 hours after ingestion, so it is generally taken twice a day. There are
different doses available, depending on the severity of the symptoms.
Proton pump inhibitors
Another option for decreasing acid in the stomach is to restrict the release of the acid. The
hydrogen ions (H+) are produced in the parietal cells and released through a proton pump, while
the chloride ions (Cl-) are released from a separate pump, into the stomach. The release of
hydrogen ions into the stomach goes against the concentration gradient, so the proton pump is
required to actively transport H+ from low to high concentration, the opposite of diffusion (when
substances naturally move from high to low concentration).
Proton pump inhibitors (PPIs), such as omeprazole or esomeprazole, work by irreversibly
binding to the proton pump with a covalent bond, preventing it from pumping hydrogen ions into
the stomach. As a result, PPIs are much more effective than H2 receptor antagonists at relieving
the symptoms of excess stomach acid.

Figure 2. The structure of omeprazole, a proton pump inhibitor.

The structure of omeprazole has many polar functional groups, ensuring high bioavailability
when taken orally. Omeprazole, like ranitidine, must be metabolised by the liver before the
active metabolite can have an effect on acid secretion. Omeprazole can sometimes take up to 24
hours to have an effect, due to the slow metabolism. The active metabolite, however, binds
covalently to the proton pump, resulting in a longer-lasting effect compared to ranitidine;
sometimes 1-3 days for a single dose. This makes PPIs provide much longer and more permanent
relief compared to antacids or H2 receptor antagonists.
Omeprazole would generally be prescribed for chronic stomach acid problems, not for
occasional issues. When excess stomach acid is regularly released, it can cause damage to the
stomach lining, leading to ulcers. Side-effects to omeprazole are rare and generally mild, but can
include fever, stomach pain, nausea and headaches. Omeprazole is on the World Health
Organisation's List of Essential Medicines for its effective relief of stomach acid discomfort.
 Figure 4. Comparison of H2 antagonist and proton pump inhibitor.

D.5 Antiviral medications

Important
Bacterial infections can be treated with the use of antibiotics. Viral infections can be treated with
antiviral drugs.

How viruses reproduce

The reason why viruses are so hard to stop is because of their small size and method of action.
Viruses are extremely small, nearly 1000 times smaller than a human body cell. They are made
up of a protein capsule containing genetic material (deoxyribonucleic acid, known as DNA, or
sometimes ribonucleic acid, known as RNA), but no other organelles, as we typically see with
other living things made up of cells. As a result, viruses do not have their own ability to undergo
typical processes required of life, such as growth and reproduction. Rather, they require a host
cell to reproduce and make more viruses. Viruses identify and attach themselves to a specific
host cell and inject their DNA (or RNA). The host cell is then taken over by the virus to use the
host cell's resources to make more viruses. The host cell bursts, releasing the newly made viruses
and dying itself.
 Figure 1. The life cycle of a virus. Note that the host cell's organelles have been omitted.

Viruses are selective in the type of cell they can infect. They recognise the specific cell type by
special proteins, called antigens, on the surface of the cell. The virus requires interaction with
specific antigens on the surface of the cell in order to infect the cell and use it as a host for
reproduction. For example, the rhinovirus, which is responsible for the common cold, can only
infect a type of cell in the airway. Therefore, to 'catch a cold', the virus must be inhaled. A cold
virus present on food that is eaten will not result in a successful infection because it cannot
interact with the cells of the digestive tract.
Conversely, bacteria are single-celled organisms that grow and reproduce. They contain
organelles that perform a variety of cell functions and they do not require a host cell to perform
those functions. When a bacterium infects a host organism, like a person or an animal, the
bacterium rapidly divides by binary fission, using the host organism's nutrients, but does not
attack the cells directly, like viruses do.
 Figure 2. The life cycle of a bacterium.

Bacteria require a constant supply of oxygen, nutrients and water to perform cellular functions,
so some bacteria cannot live long outside of a host organism on surfaces of objects and are easily
killed with cleaning products containing ethanol or bleach. Viruses do not perform cellular
functions, so they do not have the same requirements as bacteria for water, nutrients or oxygen.
Therefore, some viruses are more robust and can live on surfaces outside of a host organism for
much longer than bacteria and are not easily killed with cleaning products.

Case study
Some hand soaps are labelled as 'antibacterial' because they contain the antibiotic triclosan.
Triclosan is also found in some toothpastes, deodorants and pesticides. The hand soaps have
been under investigation recently as they have been shown in studies to not be any more
effective at killing bacteria during hand washing than regular soap. The risk of having more
antibiotics in wastewater can create further problems with antibiotic resistance.

How the body fights viral infections

For mild viral infections, time is all that is required to fight off the infection because the body has
an immune response, a series of processes designed to fight infection. When a virus attacks a
healthy host cell, proteins called antigens on the outside of the cell change. Other cells, called
T-cells, recognise that the infected cell is abnormal by the presence of these antigens and the
T-cells attack the abnormal cell. In order to stop the viral infection, the T-cells must kill the
abnormal host cells before the viruses are formed and released. The body quickly makes more
T-cells to stop the continued growth of the virus, which can take a few days. In time, all of the
T-cells will have killed all of the host cells and the virus does not have a chance to reproduce.

Figure 3. The immune response to a virus-infected cell.

The body has a 'memory' for some previous infections and will quickly act to destroy the virus if
infected again. While the T-cells are actively seeking and killing infected host cells, other cells
called B cells work to recognise the antigens present on the surface of the host cells. The B cells
quickly make antibodies that bind to the antigens. When the virus is present, the antibodies
surround the virus and macrophages, a type of white blood cell, swallow and destroy the cluster
of antibodies and virus.
 Figure 4. The action of B cells in making 'immunity memory' with antibodies.

Some antibodies are made continually, so a second exposure to a virus does not result in a
successful infection because the antibodies quickly surround the virus and it is destroyed.
Reinfection with the same exact virus does not occur because the body now has lifelong
immunity to that virus. Varicella, commonly known as the chicken pox virus, is an example of a
viral infection that generally only happens once per lifetime. Other viruses, like the common cold
or influenza, have different strains of the same virus, so you can be reinfected with a variation of
the same virus over and over again.

Creating immunity with vaccines

When a vaccine is administered containing a heat-killed or live attenuated virus (a virus which
has had some of its genetic material removed), the same immune response occurs, but the
inactivated virus is not able to cause an infection. The B cells work to produce antigens, so
immunity is present if the virus were to enter the body.
 Figure 5. How vaccines work to create immunity.

Some vaccines are only required once to create enough lifelong immunity, while others must
have a 'booster' dose to ensure that the body continues to make antibodies. The tetanus vaccine
must be given approximately every 10 years, while the smallpox vaccine only requires a single
dose for lifelong immunity.

Case study
Vaccines are sometimes too expensive or not available in developing countries, putting people at
risk of infection from illnesses that are preventable. In developed countries where vaccines are
easily available and affordable, there has been a movement to refuse vaccination for religious or
ethical reasons or even for misguided notions about vaccines being dangerous. As a result, there
have been outbreaks of diseases that were once thought to be eliminated by the effective use of
vaccines, such as measles and rubella, which can affect those with compromised immune
systems or infants that are too young to receive a vaccination. What responsibility do people
have to the human population to protect themselves, and others, from preventable diseases by
receiving vaccinations?

Fighting infection with antiviral medicines

Antiviral medicines are a new class of drugs that fight viral infections, but do not use the same
pathway of action as vaccines. Antiviral medicines work to fight the virus after infection occurs,
whereas vaccines must be given before an infection occurs. Since antiviral medicines are given
after a positively diagnosed infection, they are useful in decreasing the severity and duration of
the illness, but are not effective in preventing the illness from occurring in the first place, like
vaccines.
Antiviral medicines are given for a variety of reasons. Some people with compromised immune
systems, such as the elderly or those with cancer or HIV, might not be able to fight a viral
infection on their own. Antiviral medicines can decrease the severity and shorten the duration of
the illness, preventing further complications. For example, influenza in an otherwise healthy
adult may take up to one week for recovery, but in a person with a compromised immune system,
illness can last for weeks or can make the person more susceptible to other infections while their
system is so weak.
Another reason antivirals are used would be for 'accidental' exposure to a virus. Healthcare
workers occasionally are exposed to blood-borne viruses, like HIV or hepatitis, by an accidental
prick with a needle that has been used on an infected patient. When this occurs, antiviral
medicines can be quite effective in reducing the transmission of the virus if taken immediately
after exposure.
There are a few different ways that antiviral medicines work.

Blocking the virus from entering the cell

One method is to block the binding of the virus to the host cell. Viruses identify appropriate host
cells by binding and docking to specific receptors on the cell membrane. Drugs can be used that
either mimic the virus to bind to the cell receptors or that mimic the cell receptors to bind to the
virus. Designing effective molecules to interfere with the virus-receptor binding action is a
challenge.
Another method is to block the entry of the genetic material from the virus into the host cell.
Once the virus docks to the receptor, it must inject its genetic material into the host cell, which
requires some help from the host cell to allow foreign material to enter. Cell membranes are
selectively permeable to allow needed nutrients into the cell and to maintain a barrier for the
protection of the cell against damaging material. Drugs that interfere with the ability of the viral
genetic material to enter the host cell are effective at preventing the virus from reproducing.

Interfering with the replication of the virus

The virus uses the host cell's machinery to reproduce, so some antiviral medicines can interfere
with this process, producing incomplete viruses. Some drugs introduce inactive genetic building
blocks into infected host cells. When used to make new viruses, inactivated genetic building
blocks then produce viruses which are ineffective. Other medicines interfere with the host's
ability to generate the protein capsule for the virus, so that the newly made viruses do not have
the structure and protection of that outer capsule.

Interfering with the release of the newly-formed viruses

Once the assembled viruses are ready to be released, the host cell must activate certain proteins
to allow the viruses out. Drugs can be used to block the action of these 'release molecules'. The
newly made viruses are then trapped inside the host cell and are not able to be released to infect
other healthy cells.
 Figure 6. Different modes of action for antiviral drugs.

Influenza

The 'flu'
Influenza is a common virus that affects nearly everyone at least once in their lives. Influenza
affects approximately 5-10% of adults each year and 20-30% of children worldwide, resulting in
250,000 to 500,000 deaths per year (World Health Organisation). Individuals who are otherwise
healthy are able to battle the flu and return to normal health, but the elderly or those with
compromised immune systems are most at risk of influenza-related complications or death.
Common influenza prevention includes regular hand washing and minimising contact with
infected individuals, but also annual vaccines are available. When a case of influenza is
particularly severe, antiviral medicines can be given to shorten the duration and reduce the risk
severity.
 Figure 1. Symptoms of influenza.

Two antiviral medicines have been used effectively for the treatment of severe influenza cases.
One drug is called oseltamivir, known by the trade name Tamiflu, and the other is zanamivir,
known as Relenza. Note that there are some similarities in the structures of the two antivirals.
Attached to the ring structures of both molecules are the following functional groups: a
carboxamide group, an amino group and an ether group. Both rings also contain a carbon-carbon
double bond. Zanamivir has a carboxyl group and multiple hydroxyl groups which make it more
soluble in polar solvents than oseltamivir.

Figure 2. Structures of zanamivir (Relenza) and oseltamivir (Tamiflu). Note that these structures
are rotated from the ones in the data booklet to better show the similarities in structure.
These antiviral medicines work by blocking the exit of the newly-made viruses from the host
cell. In order for the virus to leave the host cell, an enzyme on the virus, called neuraminidase,
cuts through the host's cell membrane. When this occurs, the newly-made viruses go on to attack
other cells and the host cell is left with a hole in the membrane, which generally means death for
the cell. Oseltamivir and zanamivir are referred to as neuraminidase inhibitors, since they both
work to inactivate neuraminidase, so the virus is not able to leave or detach itself from the host
cell.

Figure 3. The action of oseltamivir and zanamivir on the life cycle of the influenza virus.
The use of antivirals for the treatment of influenza is limited. Healthy individuals can fight the
flu, generally in 3-7 days with no additional health risks, so antivirals are usually not required.
Small children, the elderly or those with compromised immune systems (cancer or HIV/AIDS
patients) are most at risk for a longer battle with the flu or for the risk of a secondary infection,
such as pneumonia. In these cases, antivirals would be recommended.
There are some side-effects, such as nausea or headaches, but these would be considered to be
minor in comparison to the severity of the influenza infection itself. Antivirals must be taken
within 48 hours of the first appearance of symptoms or the viral infection would have progressed
beyond the capacity of the drug to combat the virus, making the drug ineffective.
Antivirals have also been used as a prophylactic (to prevent contracting influenza) in individuals
that have come in close contact with an infected person. For example, if a family member
acquires influenza and there are also small children, pregnant women or elderly family members
in the same household that are at certain risk of exposure to the virus, oseltamivir has been
shown to be 92% effective at stopping the transmission of the virus, compared to a placebo.
Regular use of antivirals as a prophylactic for influenza is not recommended, as receiving an
influenza vaccine is more effective at preventing the flu.
 Oseltamivir Zanamivir

Recommended for Post-infection: any age Post-infection: 7 years and over

Prophylactic: 3 months and over Prophylactic: 5 years and over

Not recommended None Individuals with respiratory

for problems (e.g. asthma) or milk
allergy

Method of Oral tablet Oral inhalation

administration

Effectiveness Studies show to be more Studies show to be more effective

effective against influenza A against influenza B strain
strain

Vaccines for influenza

As introduced earlier, the vaccine for influenza is provided annually and considered to be the
most effective method of combating the virus. The reason for this is that there are more than 300
known variations of the virus and the virus keeps mutating and changing all the time, so one
vaccine cannot provide protection against all known and future variations of the virus. When an
influenza vaccine is made, doctors and scientists work together to predict the three most likely
variations that pose the greatest risk of infection. Some years, the predictions are good and those
who receive a vaccination are protected, but other years, the predictions are wrong and even
those vaccinated become infected with a different variation of the virus.

Viruses can mutate, or change, as they replicate. This generally occurs by mistake since the virus
reproduces quickly, but it can make a new strain of virus that is not recognised by the immune
system or by antiviral medicines, ensuring greater survival for the virus. There are two methods
of mutation. One is antigenic drift, where small mistakes are made in the reproduction process,
resulting in changes to the proteins on the outside of the virus, making a new strain. When this
occurs, the immune system does not recognise the virus any more and it can infect host cells,
even if immunity to a different strain of the virus had already been established. The other method
of mutation is antigenic shift, where two or more different strains of the virus infect the same
cell, producing a new hybrid strain. The hybrid strain now contains a combination of different
proteins on the outside of the virus, which the immune system is not able to recognise and fight.
Adaptations of viruses.

Figure 4. Adaptations of viruses.

Case study
Antigenic shift occurs when viruses from different species combine and 'jump' from animal to
human. For example, in 2009 a new influenza strain emerged that was a combination of human,
avian (bird) and swine (pig) influenza viruses that led to a worldwide pandemic known as the
'swine flu'. This new virus was capable of infecting humans and was not recognised by the
immune system nor protected by the annual influenza vaccine, causing over 14,000 deaths
worldwide (World Health Organisation). A special vaccine was later made and distributed to help
generate immunity and to control the spread of the virus. International travelling, schools and
workplaces were closed or were under quarantine to help with the spread of the virus. Although
eating pork products from an infected pig could not cause the disease, some countries
slaughtered pigs as a misguided prevention strategy.

Scientists collaborate around the world to keep people safe. International travel can quickly take
a small, infected group of individuals and spread it worldwide in a matter of days. Scientists,
doctors, pharmacists and other health care workers must collaborate to keep small outbreaks
from becoming larger epidemics or even worldwide pandemics.

HIV

Mysterious illness
It was in the late 1970s and early 1980s that doctors started to notice an increase in the number
of otherwise healthy individuals developing severe immune deficiencies resulting in death. The
condition seemed to be transmitted from person to person, but the means of transmission and the
source of the illness was not well understood. There was a global panic and fear of this
mysterious illness, causing people to reduce even casual contact, like shaking hands, with
strangers.
Nearly forty years later, we have a better understanding of this illness and much better treatment
options for managing the infection. The human immunodeficiency virus, or HIV, attacks the
cells that make up the body's immune system. If left untreated, HIV develops into acquired
immune deficiency syndrome, or AIDS. In the past, an HIV diagnosis was certainly a death
sentence, but today HIV-positive individuals can live long and relatively healthy lives with the
right combination of medicines, the most powerful drugs being antivirals.

HIV can only be transmitted by certain bodily fluids, such as blood, breast milk, vaginal fluids or
semen, where the virus is in higher concentration. It can be spread during sexual contact with an
infected person, by sharing unsterilised needles or other surgical equipment, by receiving a blood
transfusion with infected blood products or from mother to baby during pregnancy or
breastfeeding. It cannot be transmitted by casual contact, such as shaking hands or sharing a
glass of water, or through saliva or nasal secretions. The viral load in these secretions is too low
and the virus does not survive well outside of an infected person.
The HIV virus attacks a type of T-cells that contain a CD4 antigen (sometimes called CD4 cells)
to reproduce and make more viruses. CD4 cells, like all T-cells, are part of the body's immune
response, so the problem with an HIV infection is that over time, the CD4 cells that are involved
in producing more viruses are killed when the CD4 cell bursts open, releasing the newly-made
viruses. Depleting the body's immune system response weakens it, leaving the body susceptible
to any form of infection. In time, when nearly all the CD4 cells are gone, the patient would be
diagnosed with AIDS and even a common cold virus could result in death.
 Figure 2. Progression of HIV infection as shown by changes in blood sample.

HIV is classified as a retrovirus, a special type of virus that contains slightly different genetic
material than a traditional virus (it contains a single strand of RNA compared to a double strand
of DNA in a traditional virus). Antivirals used to treat retroviruses are called antiretroviral
medicines, and these are a new hope in the management and prevention of HIV. The replication
of the virus includes an additional step of converting RNA to DNA, so this makes the virus more
prone to mutation (mistakes in the genetic code). Mutations can result in a virus that is constantly
changing so much that the medicines designed to combat it are ineffective
Most patients on antiretroviral treatment (ART) take a 'cocktail', or mixture of different
antiretroviral drugs to target the different stages of the retrovirus life cycle. This helps to ensure
that the virus life cycle can be more effectively stopped. Taking ART can be very effective at
reducing the patient's viral load, the concentration of virus in a blood sample, to undetectable
levels in the blood, ensuring a longer, healthier life and reducing the risk of transmission to other
people.

Figure 3. Antiretroviral medicines interfere with HIV replication.

Antiretroviral drugs can also be effective at stopping the transmission of HIV if exposed. If ART
drugs are taken immediately after exposure, such as after a prick from an infected needle,
between sexual partners or from mother to unborn baby, the rate of transmission is greatly
reduced.

Vaccines for HIV

Vaccines for HIV have been under development for many years, but there are currently no
vaccines that have been shown to offer enough protection from HIV. The difficulty in developing
an effective HIV vaccine is due to many factors. It would be unwise to use a heat-killed virus, as
some vaccines use, because of the risk that not all of the viruses were killed and the vaccine
could actually cause HIV infection. Many vaccine studies start with animal studies, but HIV does
not affect animals the same way as humans, so the clinical trial process is challenging. Finding
human test subjects is difficult because it would be unethical to knowingly infect a person with
HIV to test the effectiveness of the vaccine. Clinical trials in humans would have to involve
individuals who are at a high risk of contracting HIV anyway, such as intravenous drug users,
workers in the sex trade or the sexual partners of HIV-positive individuals.
Another issue is that HIV is a retrovirus and there are currently no vaccines that have been
developed for any retroviruses. Since a retrovirus contains RNA, which is then converted to
DNA and incorporated into the host cell's own genetic material, the HIV viral DNA can remain
dormant (inactive) in the host cell for years before it begins to produce viruses and the person
shows symptoms of the illness. Since the virus can remain inactive, the presentation of illness
may be delayed and therefore the efficacy of the vaccine may be difficult to measure.
Here is a video that explains the difficulty of stopping HIV/AIDS: