OPTION D SL: MEDICINES AND DRUGS D 1. Pharmaceutical products D 1.1. List the effects of medicines and drugs on the functioning of the body.D 1.2. Outline the stages involved in the research, development and testing of new pharmaceutical products.D 1.3. Describe the different methods of administering drugs.D 1.4. Discuss the terms therapeutic window, tolerance and side-effects.

Effects of medicines and drugs on the functioning of the body

A medicine or drug is any chemical that does one or more of the following to the human body, for better or worse: alters the physiological state, including consciousness, activity level or coordination alters incoming sensory sensations alters mood or emotions

A medicine is a beneficial drug as it effects the body functions for the better. Each medicine has one (or sometimes more) intended beneficial physiological effect that is called its therapeutic effect.

Physiological = to do with the functions in living organisms; physiological effects = effect on the functioning of the living organism.

The types of medicines and drugs that we will study in this topic can be classified according to what process or part they target in the human body:

Medicines and drugs Target/aimAnalgesics, stimulants, depressants Nervous systems and brain; affect both sensory sensations and

moodAntacids Target metabolic processesAntibacterials, antivirals Assist body’s ability to fight diseases

Stages in the development of a drug

1. Identify disease, could be new disease.

2. Identify a molecular target e.g. enzyme or gene which is necessary for disease to progress or a receptor.

3. Identify ‘lead’ molecule that can act on gene/enzyme in the disease organism or host or on the receptor – has pharmaceutical activity. Isolate the ‘lead’ molecule (e.g. from plants) or manufacture it synthetically.

4. Preclinical trials : testing of ‘lead molecule’ in laboratory,

a. ‘in vitro’: the lead molecule is tested on animal/human cells and tissues which have been removed from the body and are kept in an artificial environment.

b. ‘in vivo’: testing in live animals (usually 3 different species) to establish ED50 or LD50 which is the amount which kills 50 % of the population.

5. Clinical trials

a. Testing of its effectiveness, its therapeutic window, tolerance and its side effects using the placebo effect. This is a ‘blind trial’ in which half of the people/patients involved are given the drug whilst the other half are given a similar substance that is not the drug (called ‘placebo’ but none of the patients (or even their administering doctors) know which half they are in.

b. Structural modifications likely to be made to, for instance, improve effectiveness or reduce side-effects.

6. Submission of reports on the drug and its trials to international or national regulatory bodies.

7. Monitoring of the drug after it has been launched; molecule might need further structural changes.

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Methods of administering drugs

Oral: taken in by the mouth e.g. tablets, syrups, capsules;

Advantages of taking it orally disadvantage Easily taken No specialist equipment needed

Can be destroyed by stomach acid Slow to have an effect Can cause stomach bleeding or vomiting Only small amount of drug is absorbed Patient needs to be conscious

Parenteral – i.e. by injection, used when fast delivery is necessary.o intravenous: into a vein of the blood stream – used for immediate impacts as it is the fastest

method; drug is immediately pumped around the body by the blood e.g. anaesthetics.o intramuscular i.e. into the muscles, e.g. many vaccines, antibiotics, usually used when a large

dose needs to be administered and it needs to act locally.o subcutaneous: in the layer of the skin directly below the cutis (dermis and epidermis) e.g. dental

injections, morphine, insulin. Slow absorption needed; also slow effect. Inhalation: e.g. medication for respiratory conditions such as asthma. Rectal: inserted into the rectum e.g. treatment for digestive illnesses, drug absorbed into the blood

stream. Transdermal:

o Skin patches: e.g. hormone treatments.o Topical – applied to the skin: e.g. creams or ointments, also includes eye and ear drops.

Terms

Dosing regime = the amount of drug used for each dose i.e. how much drug should be taken in and its frequency of administration e.g. three tablets every 4 hours. Therapeutic window =

The therapeutic window is the range in amount or concentration over which a drug can be safely administered to a typical population: The lowest level of concentration is the called the effective level (therapeutic level) or ED50; below this

level the drug loses its therapeutic effect. The highest level is the toxic or LD50 level (= the dose needed to kill 50 % of (animal) population)

above which adverse side-effects can occur.

wide therapeutic window

low effective dose (ED50) and larger lethal dose (LD50) as a result there is a big difference between effective and lethal dose.

for more common and minor diseasesnarrow therapeutic window

small difference between effective and lethal dose, usually because lethal dose is small; only used for serious conditions overdose is a high risk.

The therapeutic window depends on: The type of drug Age, sex and weight of the patient Diet Environment

Tolerance

Tolerance refers to the body’s reduced response to a drug i.e. its therapeutic effect is less than what it is intended, usually as a result of taking the drug over a long period of time. As a result more of the drug needs to be taken to achieve the same initial physiological effect with the danger of exceeding the lethal dose. Side-effects =

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Side-effects are physiological effects which are not intended and therefore undesired (intended = therapeutic effects); these could be: beneficial e.g. protect against heart disease like aspirin. benign e.g. causing drowsiness, nausea constipation. adverse i.e. causing damage to other organs.The extent of side effects determines who and when a medicine should be administered. Medicines with severe side-effects should only be administered by qualified staff in medical emergencies.

Placebo effect

The placebo effect occurs when a person experiences a positive therapeutic (in particular with pain killers) effect because they believe they have been given a medicine although the substance given is not a medicine, instead a ‘placebo’ has been administered; the human body is fooled into healing itself naturally. Placebo is used as a control to measure the real effectiveness of the drug which is the difference between the effects experienced by the patients who took the drug and those patients who did not. Patients and administrators do not know which patients have taken the placebo.

D 2. AntacidsD 2.1 State and explain how excess acidity in the stomach can be reduced by the use of different bases.

Acid indigestion (discomfort in stomach) and heartburn (acid rising into oesaphagus) are conditions that arise when excess hydrochloric acid is produced by the gastric glands in the walls of the stomach. The acid, which creates an acidic environment of pH 0.3 to 1.2, is needed to:

kill any bacteria in the food ingested and provide the optimum pH environment for the digestive enzymes which act in the stomach.

Action of antacids

Antacids are substances (usually weak bases) which are used to neutralize excess hydrochloric acid in the stomach so the pH level returns to the desired level. Aluminium hydroxide, magnesium hydroxide, magnesium carbonate and sodium hydrogencarbonate are commonly used as active ingredients in such antacids as they are weak bases. Aluminium hydroxide is the most effective as it has 3 OH- per formula unit an can therefore neutralize three times as many H+ than sodium hydrogen carbonate.Sodium hydroxide or potassium hydroxide are not used as antacids because they are strong alkalis and are too corrosive to the body tissue.

Equations Al(OH)3 (s) + 3HCl (aq) AlCl3 (aq) + 3H2O (l) Mg(OH)2 (s) + 2HCl (aq) MgCl2 (aq) + 2H2O (l) NaHCO3(s) + HCl (aq) NaCl (aq) + H2O (l) + CO2(g) MgCO3(s) + 2HCl (aq) MgCl2 (aq) + H2O (l) + CO2(g)

Alginates

Some antacids also contain compounds called ‘alginates’ which prevent heartburn by producing a neutralizing layer on top of stomach contents and preventing acid in the stomach from rising into the oesophagus and causing heartburn (inflammation and

pain).

Anti-foaming agents

Antacids which use carbonates will also contain anti- foaming agents such as dimethicone which reduce the bloating of the stomach as a result of the carbon dioxide production.D 3. Analgesics

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D 3.1 Describe and explain the different ways that analgesics prevent pain.D 3.2 Describe the use of derivatives of salicylic acid as mild analgesics, and compare the advantages and disadvantages of using aspirin and paracetamol (acetaminophen).D 3.3 Compare the structures of morphine, codeine and diamorphine (heroin, a semi-synthetic opiate).D 3.4 Discuss the advantages and disadvantages of using morphine and its derivatives as strong analgesics.

Analgesics reduce pain.

How do analgesics prevent pain?

Mild analgesics, such as aspirin and paracetamol, function by stopping the transmission of pain from source to brain as they intercept the pain stimulus at the source. They do this by interfering with or suppressing the production of substances by injured tissues, such as prostaglandins, that stimulate pain receptors that send pain impulses to the brain. Prostaglandins also cause pain, swelling or fever.

Strong analgesics such as morphine and diamorphine (heroin) work by temporarily bonding to receptor sites to pain impulses in the brain or other parts of the central nervous system such as the spinal cord. This prevents the transmission of pain impulses i.e. blocking the signal without depressing the central nervous system.

Structures of some analgesics

Mild analgesics

Functional groups present in some mild analgesics:

aspirin paracetamol ibuprofen phenyl/aromatic benzene ester carboxylic acid

phenyl/aromatic benzene hydroxyl amide carbonyl

phenyl/aromatic benzene carboxylic acid

Some mild analgesics such as aspirin are derivatives of salicylic acid that was used as an analgesic in the past but which was unpleasant to take and damaged the membranes in the mouth, gullet and stomach. The structure of salicylic acid is shown below. A derivative = a new compound obtained from another compound.

To convert salicylic acid into aspirin the hydrogen atom of the OH group is replaced by a COCH3 group to form an ester functional group which makes the compound less irritating to the stomach and therefore easier to take.

Strong analgesics (opiates)

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Functional groups present in some strong analgesics:

morphine diamorphine/heroin codeine benzene ring hydroxyl (2) ether; tertiary amine; double bond/alkene;

benzene ring tertiary amine alkene ester (2) ether

benzene ring hydroxyl/alcohol ether (2) alkene tertiar y amine

All three compounds are derived from opium which is an extract from poppy seeds. Both codeine and diamorphine are derived from morphine and are called semi-synthetic opiate. An opiate is any chemical that has the same physiological effect as morphine. As the structures above show, heroin’s structure is only slightly different from morphine. Both the hydroxyl or alcohol groups in morphine have been replaced with ester groups. This is achieved by reacting the morphine with ethanoic acid; as a result an esterification occurs during which also water is produced.The amine in morphine, diamorphine and codeine is a tertiary amine as the nitrogen atom has three alkyl groups bonded onto it.

Comparison of aspirin and paracetamol as mild analgesics

analgesic advantage disadvantageaspirin reduces fever more effectively –

antipyretic (=drug which reduces fever) beneficial side-effects:

o preventing the recurrence of heart attacks and strokes

o thins the bloodo reduces blood clottingo also anti-inflammatory – reduces

inflammation or swelling

ulceration stomach bleeding due to its acidic

properties allergic reactions Reye’s syndrome in children (a

potentially fatal liver and brain disorder) so not suitable for children

paracetamol does not irritate stomach wall suitable for children allergic reactions rare can be made in liquid form

can, in rare cases, cause blood disorders and kidney damage.

easier to overdose and overdosage can lead to serious liver damage, brain damage and even death.

not a good anti-inflammatory

Aspirin has more side-effects.

Advantages and disadvantages of using morphine and its derivatives

advantage disadvantage strong analgesics and

therefore can relieve extreme pain

wide therapeutic window

relieves anxiety induces relaxation

euphoria, lack of self-control even dangerous behaviour kidney failure. addiction or physical dependence which leads to withdrawal

symptoms when drug is not taken e.g. restlessness, sweating, fever, cramping, …

tolerance can become an issue with this type of drug as more of the drug needs to be taken to achieve the same effect; in order to

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can be administered intravenously which results in faster distribution of drug

achieve the desired effect heroin users may take doses which exceed the lethal dose

Social: o heroin users are more likely to commit crimes to pay for

gradually increasing doses of the drugo diversion of energy and money; loss of jobo when administered intravenously can lead to transmission of

dangerous infections e.g. AIDS.o prostitution

D 4. Depressants

D 4.1 Describe the effects of depressants.D 4.2 Discuss the social and physiological effects of the use and abuse of ethanol.D 4.3 Describe and explain the techniques used for the detection of ethanol in the breath, the blood and urine.D 4.4. Describe the synergistic effects of ethanol with other drugs.D 4.5. Identify other commonly used depressants and describe their structures.

Depressants are often described as antidepressants (act against depression) because they relieve the symptoms of (mental) depression by depressing (decreasing the activity of) the central nervous system. They calm and relax the nervous system as they slow down the action of the brain, heart and other organs.

Effects of depressants

dose effectlow may exert little or no effect.moderate may induce sedation, soothing, reduction of anxiety, relaxes muscles, impaired

judgement, lowers heart rate,high may induce sleep, unconsciousness, slurred speech, altered perception extremely high may cause organ failure, coma or death

Social and physiological effect of the use and abuse of ethanol

Social Physiological increased risk when driving or

operating machinery involvement in violence or crime relationship problems taking time off work as a result of

sickness or death associated with alcohol abuse

loss of income hospital costs lower economical production cost of medical treatment to society

Short term: reduces tension, anxiety and inhibitions impairs function of central nervous system dehydration high dose can cause vomiting, unconsciousnessLong term: liver damage/cirrhosis – liver disease increased blood pressure heart disease or stroke miscarriage and fetal abnormalities tolerance and physical dependence

Synergetic effect of ethanol with other drugs

Ethanol produces a synergic effect with other drugs i.e. their effect is enhanced in the presence of alcohol which can be dangerous e.g. with aspirin it can increase risk of stomach bleeding. In the case of sleeping tablets and other sedatives it can cause coma or death.

Techniques used for the detection of alcohol

Using potassium dichromate

Only used for detection in breath. Ethanol is sufficiently volatile to pass into the lungs from the bloodstream which

is why it can be detected using a breathalyzer which contains potassium dichromate(VI).

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In a positive result (i.e. presence of alcohol) the potassium dichromate changes form orange to green when ethanol is present as the potassium dichromate is reduced and the ethanol oxidized to ethanoic acid.

Equations:

oxidation: C2H5OH + H2O → CH3COOH + 4H+ + 4e−

reduction: Cr2O7 2− + 14H+ + 6e− → 2Cr3+ +7H2O

Overall: 3C2H5OH + 16H+ + 2Cr2O7 2− → 3CH3COOH + 2Cr3+ + 11H2O

intoximeter Used for breath, blood and urine. Infrared radiation is passed through breath, blood or urine. The C–H bond in

ethanol causes radiation to be absorbed at a specific wavenumber (a wave property proportional to frequency/energy) which is 2950 cm-1. The intoximeter measures the amount of absorption at 2950 cm-1 which depends on the amount of ethanol in the breath i.e. the more ethanol there is present the more IR is absorbed. The concentration of ethanol is determined from the area under the peak of the graph.

A fuel cell can also be used. Ethanol is oxidized to CO2 and H2O; the energy released during this oxidation is converted into a voltage which can be used to measure the concentration.

chromatography Used for blood and urine samples. Ethanol is separated from the blood or urine using gas-liquid chromatography. Accurate; area under ethanol peak on chromatogram indicates amount of

ethanol in blood or urine

Other commonly used depressants prescribed for stress relief: (see table 20 in data booklet)

depressant Structure: functional groupsFluoxetine hydrochloride (Prozac®) aromatic benzene, ether, fluorine, secondary amine, chloride

iondiazepam/Valium®; amide

aromatic benzene secondary amine chlorine atom

nitrazepam/Mogadon®; amide aromatic benzene secondary amine NO2

D 5. Stimulants

D 5.1 List the physiological effects of stimulants.D 5.2 Compare amphetamines and epinephrine (adrenaline).D 5.3 Discuss the short- and long-term effects of nicotine consumption.D 5.4 Describe the effects of caffeine and compare its structure with that of nicotine.

Stimulants are drugs that act on the central nervous system as they increase the activity of the brain by increasing the levels of neurotransmitters. They are the opposite to depressants.

Examples of stimulants

Caffeine, nicotine, amphetamines (synthetic drugs e.g. in diet pills). The intention of these drugs is to have similar effects to adrenaline which is a natural stimulant that is released in times of stress e.g. pain, cold, fear. The effects of adrenaline are increased heart beat, increased blood pressure, increased blood flow to brain and muscles, increased air flow to lungs all resulting in an increased alertness to allow the organism to deal with the stress or “fight or flight”.

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Amphetamines are synthetic drugs that have similar structures to epinephrine/adrenaline and therefore mimic its effects of which is to stimulate the sympathetic nervous system. They are therefore known as sympathomimetic drugs. Physiological effects of stimulants

Short term Long term Increased brain activity increased heart rate, increase breathing rate, increased alertness and concentration decreased appetite shakes sleeplessness

increased risk of heart disease increased blood pressure coronary thrombosis (blood clots in blood vessels) stomach ulcers. tolerance: which leads to increased use as increased

amounts needed to produce same effect; increasing amounts cause damage/death/overdose/lethal dose

Differences between amphetamines and epinephrine

Both have the phenylethylamine structure, C6H5CH2CH2-. Highlight this structure on the molecule of amphetamine.

amphetamines epinephrine

Functional groups: benzene ring primary amine

Functional groups: benzene ring secondary amine hydroxyl (3) can form more hydrogen bonds

and is therefore more soluble in water

Short and long term effects of nicotine consumption

A nicotine molecule contains the following functional groups: a tertiary amine in one ring, ring structures with nitrogen atoms in them, and double bonds (alkene functional group). Label these groups on the structure below.

Short term effects Long term effects increased heart rate increased blood pressure reduced urine output increased concentration

increased risk of cancer or stroke heart disease / thrombosis stomach ulcers emphysema bronchitis shortage of breath coughing bad breath yellowing of teeth or fingers adverse effect on pregnancy addiction to tobacco reduction in capacity of blood to carry oxygen; withdrawal symptoms / weight gain (on quitting);

Caffeine

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Caffeine is a stimulant. When consumed in large amounts it can cause anxiety, irritability and sleeplessness. It is a weak diuretic (=causes increase in urine output).Its structure is similar to nicotine as shown on the right; in this structure highlight in blue the functional groups which both nicotine and caffeine have: benzene ring and tertiary amine (caffeine has three of those) and in red the group which caffeine has but not nicotine i.e. the amide group. It could also be considered that caffeine has 2 amide groups – circle them in green.

D 6. Antibacterials

D 6.1 Outline the historical development of penicillins.D 6.2 Explain how penicillins work and discuss the effects of modifying the side-chain.D 6.3 Discuss and explain the importance of patient compliance and the effect of penicillin overprescription.

Antibacterials are drugs that kill or inhibit the growth of bacteria that cause infectious diseases. Penicillins are a group of compounds that are produced by micro-organisms and kill harmful micro-organisms; they are therefore called antibiotics.

Examples of infectious diseases caused by bacteria: tuberculosis, syphilis, cholera, salmonella, bronchitis, anthrax, meningitis, gonorrhea, chlamydia.

Historical development of penicillins

Alexander Fleming, Howard Florey and Ernst Chain shared the Nobel Prize for “the discovery of penicillin and its curative effect in various infectious diseases”.

Scientist Contribution to development of penicillinAlexander Fleming Discovered by chance that penicillin inhibited growth or killed bacteria;

Fleming had left a bacteria culture and later found a clear zone in the culture in which bacteria had been killed. That zone had been contaminated by a mould called Penicillium notatum..

Howard Florey and Ernst Chain overcame the problems associated with isolating and concentrating penicillin as Penicillin G = main contribution

showed that penicillin is harmless and effective on mice; first to use penicillin on a human; grew penicillin in large amounts; grew strains of penicillin in corn-steep liquor.

How do penicillins work?

Structure of the first penicillin to be used, penicillin G or C16H18O4N2S, is shown below.

Label functional groups A and B and any other functional groups you recognize. Circle the side chain which is the benzene ring and CH2 to the left of the carbonyl group of the amide.

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Penicillins prevent the growth of bacteria. They do this by deactivating (the beta-lactam group does that) the enzymes in the bacteria that are involved in developing cross-links in the cell wall of bacteria. As a result the bacterial cell absorbs too much water which causes the cell to burst. Bacteria constantly replace cell walls.

Administering of penicillins

There are two types of antibiotics: broad-spectrum antibiotics that are effective against a wide range of bacteria. They are administered

against bacteria that might be or have shown resistance to one or even two (less likely) antibacterials. Broad-spectrum but can therefore also kill useful bacteria.

narrow-spectrum only attack a limited range of bacteria, usually administered when doctor has identified type of infectious bacteria after taking samples of blood, urine, …

With some diseases, e.g. tuberculosis (TB), it is important to administer a “cocktail” of different antibacterials because bacteria that cause TB are usually extremely resistant to penicillins so a mixture of different antibiotics is used.

Increased resistance in bacteria to antibacterials

As a result of mutations, bacteria have become resistant to penicillins because of their misuse by patients. Resistant bacteria produce an enzyme, penicillinase, which causes the break up of the penicillin molecule (the beta lactam ring to break open); these bacteria then reproduce and pass on their resistance to succeeding generations.

Examples of misuse of antibiotics include:

1. Patient compliance

Refers to patients not completing the full course of antibiotics and this resuts in prolonging the disease as not all bacteria are killed. By allowing the bacteria to live longer there can be more mutations eventually producing bacteria with resistance. Patient compliance also allows disease to spread as bacteria are not all killed.

2. Overprescription of antibacterials

Many doctors are too quick to prescribe antibiotics. Patients should be encouraged to fight an infection using their own immune system. Problems associated with overprescriptions: allergic reactions by the patients, the wiping out harmless bacteria in the alimentary canal and destroyed bacteria might be replaced by more harmful bacteria..

3. Use of antibacterials in animal feedstock

Some antibiotics are also effective in animals but these antibiotics are sometimes administered without the animals having any disease. These antibiotics end up in the food chain.

Modifying the side-chain of penicillin G to develop new semi-synthetic penicillins

Modern or semi-synthetic penicillins, such as ampicillin, are penicillin molecules that have been modified by replacing the side-chain with other atoms or groups of atoms. For instance, in the case of ampicillin, the side chain now still contains a benzene or C6H5 ring but has a hydrogen atom and an amine (-NH2) group instead of the CH2 group that was there.

Such modifications to the side-chain bring advantages such as: Reducing the occurence of penicillin resistant bacteria as the modified penicillins are able to

withstand the action of the enzyme, penicillinase, which is an enzyme produced by penicillin-resistant bacteria and which causes the break down of penicillin.

Resistance to breakdown or deactivation by stomach acid (so can be taken orally, e.g. ampicillin); penicillin G had to be administered by injection because it was decomposed by stomach acid.

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Produce penicillin that do not cause allergic reactions to some patients.D 7. Antivirals

D 7.1. State how viruses differ from bacteria.D 7.2 Describe the different ways in which antiviral drugs work.D 7.3 Discuss the difficulties associated with solving the AIDS problem.

Examples of diseases caused by viruses: AIDS, influenza, rabies, common cold, small pox, measles, …

Difference between bacteria and viruses

Bacteria Viruses – need a host cell bacteria are self-reproducing i.e. by cell division

– do not need a host viruses are not self-reproducing as they need a

host cell to multiply; viruses insert DNA into host cells – after reproduction the host cell dies

bacteria are able to grow, feed and excrete viruses lack any metabolic functions so they do not grow, feed or excrete

bacteria contain organelles such as cytoplasm, cell wall and a nucleus which all perform specific functions

viruses consist only of genetic material and protective coating, no cell wall, no nucleus and no cytoplasm

bacteria are (many times) larger than viruses viruses are smaller than bacteria bacteria have more complex DNA viruses have simpler DNA bacteria mutate/multiply slower than viruses; viruses mutate/multiply (much) faster than

bacteria

Ways in which antiviral drugs work

preventing viruses from entering host cell as it changes the cell membrane of the host cell preventing the viruses from multiplying in the host cell:

o by blocking enzyme activity within the host cell.o by altering genetic material in the host cell

preventing the release of viruses after reproduction from the cell

Viral infections are harder to treat than bacterial because

viruses mutate much more quickly so:o they can adapt to drugs or o they can evade human immune system response

bacteria are more complex and thus can be targeted in more ways - viruses lack subunits/functions which are normally targeted by antibacterials;

bacteria can be killed or their actions reduced by simple chemical agents but viruses cannot be killed and must be targeted on genetic level

different types of bacteria employ similar metabolic processes and thus can be targeted by common antibacterials whilst each kind of virus usually requires special drugs.

The treatment of AIDS by antiviral drugs is problematic because

HIV invades white blood cells or T4 cells.

HIV viruses can mutate rapidly antiretroviral drug target white blood cells which are meant to protect us against other pathogens HIV lies dormant for a while socioeconomic: high price of antiretroviral drugs, cost to state, access to drugs, cultural issues: discrimination, stigma high price of antiretroviral drugs

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