OPTION D: CORE ENVIRONMENTAL CHEMISTRY



OPTION D: MEDICINAL CHEMISTRY SL

D 1. Pharmaceutical products and drug action

E.I.: Medicines and drugs have a variety of different effects on the functioning of the body

Nature of science Risks and benefits – medicines and drugs go through a variety of tests to determine their effectiveness and safety before they are made commercially available. Pharmaceutical products are classified for their use and abuse potential (4.8)

|Understandings |

|D.1 U1 In animal studies, the therapeutic index is the lethal dose of a drug for 50% of the population (LD50) divided by the minimum effective dose for 50% |

|of the population (ED50). |

|D.1 U2 In humans, the therapeutic index is the toxic dose of a drug for 50% of the population (TD50) divided by the minimum effective dose for 50% of the |

|population (ED50). |

|D.1 U3 The therapeutic window is the range of dosages between the minimum amounts of the drug that produce the desired effect and a medically unacceptable |

|adverse effect. |

|D.1 U4 Dosage, tolerance, addiction and side effects are considerations of drug administration. |

|D.1 U5 Bioavailability is the fraction of the administered dosage that reaches the target part of the human body. |

|D.1 U6 The main steps in the development of synthetic drugs include identifying the need and structure, synthesis, yield and extraction. |

|D.1 U7 Drug–receptor interactions are based on the structure of the drug and the site of activity. |

|Applications and skills |

|D.1 AS1 Discussion of experimental foundations for therapeutic index and therapeutic window through both animal and human studies. |

|D.1 AS2 Discussion of drug administration methods. |

|D.1 AS3 Comparison of how functional groups, polarity and medicinal administration can affect bioavailability. |

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

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

The term ‘medicine’ is a more specific term as a medicine is a beneficial drug as it effects the body functions for the better; improves health. Each medicine has one (or sometimes more) intended beneficial physiological effect that is called its therapeutic effect.

How does a medicine have a physiological effect: Drug-receptor interaction.

A drug achieves its therapeutic effect as its molecular structure allows it to bind (through ionic bonding, hydrogen bonding or Van Der Waal’s forces) with a receptor e.g. a protein molecule such an enzyme or a cellular receptor such as a cell membrane. The binding prevents or inhibits the biological activity (e.g. enzyme activity) that allows the disease to develop. The receptor part in the molecule or cellular structure is referred to as the site of activity.

Methods of drug or medicinal administration

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

|Advantages of taking it orally |Disadvantage |

|Easily taken |Can be destroyed by stomach acid or changed by enzymes or metabolized by the |

|No specialist equipment needed |liver |

| |Slow to have an effect |

| |Can cause stomach bleeding or vomiting |

| |Only small amount of medicine reaches target in the body (low |

| |bioavailability) |

| |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 of a vapour: 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; from skin into blood.

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

Considerations of drug administration

Dosing regime = determined by:

• the amount of drug used for each dose i.e. how much drug should be taken e.g. number of tablets or spoonful

• how frequently e.g. three tablets every 4 hours.

The target of a dosing regime is to achieve constant, safe and effective levels of the medicine in blood.

Side-effects =

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.

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. Tolerance can also lead to addiction or dependence.

Addiction

Physical dependence. A condition that occurs when a person needs the drug just to live normally and shows withdrawal symptoms when not taking the drug.

Therapeutic window and therapeutic index

The therapeutic window is the range in the amount or concentration of the drug in the blood over which a drug can be safely administered to a typical population. It is the range of dosages between the minimum amount that produces the therapeutic affect and the maximum amount that produces a medically adverse effect.

The therapeutic window can be expressed as a ratio called the therapeutic index. This index can have a different definition depending on whether the it is obtained in an animal study or in humans trials.

• In animal studies, the therapeutic index is the dose of a drug that is lethal for 50% of the animal population (LD50) divided by the minimum effective dose for 50% of the population (ED50). TIanimals = LD50/ED50.

• In humans, the therapeutic index is the dose of a drug that is toxic (undesirable effect) for 50% of the human population (TD50) divided by the minimum dose that has the therapeutic effect (=effective dose) for 50% of the population (ED50). TIhumans = TD50/ED50.

|Large therapeutic index (=wide|Low effective dose (ED50) and larger toxic dose (TD50) as a result there is a big difference between effective and toxic |

|therapeutic window) |dose. |

| |For more common and minor diseases. |

| |Can be bought without doctor prescription. |

| |Safe to take in high doses |

| |Example: it TI is 50 then the patient can take 50 times more then the prescribed amount. |

|Low therapeutic index (=narrow|Small difference between effective (ED50) and toxic dose (TD50). |

|therapeutic window) |Usually because toxic dose is low. |

| |Correct dosage is important. |

| |Only used for serious conditions. |

| |Administered by qualified personnel. |

| |Overdose is a high risk/low margin of safety |

Main stages in the development of synthetic drugs




• Identification of a ‘need’: e.g. a disease, could be new disease.

• Identification of a molecular target (in the disease causing organism, pathogen) that has a receptor e.g. an enzyme or a cell structure that has a biological activity in the disease e.g ebola) and that needs to be inhibited.

• Identification of ‘lead’ molecule i.e. molecules with a molecular structure that can bind onto the receptor site. Such lead molecules could be found in plants or microorganisms but often will need to be modified to improve their chemical fit or their bioavailability. Alternatively a lead molecule is designed using the drug-receptor interactions approach; designing on computers a molecule with a structure that fits chemically into the receptor site and can bonds with it.

• Using the lead molecule, many different molecules or derivatives are synthesized and their therapeutic effect tested. During this process the intended molecules are extracted.

• Preclinical trials: testing of medicine in laboratory,

o ‘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.

o ‘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.

• Clinical trials

o 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.

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

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

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

Bioavailability of a drug

Bioavailability of a drug is the fraction of the administered dosage that reaches the target part in the human body (sometimes also just the blood). 


Bioavailability is affected by:

• Functional groups: e.g. acid or basic groups affect the pH of the environment and that can affect reactivity and solubility of the drug.

• Polarity of the drug molecule: polar molecules dissolve well in aqueous environments whilst more non-polar drug molecules dissolve better in lipids.

• Method of drug administration: e.g. intravenous is 100 % bioavailability whilst orally taken drugs could have a bioavailability of 40%.

D 2. Aspirin and penicillins

E.I.: Natural products with useful medicinal properties can be chemically altered to produce more potent or safer medicines.

Nature of science: Serendipity and scientific discovery—the discovery of penicillin by Sir Alexander Fleming. (1.4)


Making observations and replication of data—many drugs need to be isolated, identified and modified from natural sources. For example, salicylic acid from bark tree for relief of pain and fever. (1.8)

|Understandings |

|Aspirin |

|D.2 U1 Mild analgesics function by intercepting the pain stimulus at the source, often by interfering with the production of substances that cause pain, |

|swelling or fever. 
 |

|D.2 U2 Aspirin is prepared from salicylic acid. 
 |

|D.2 U3 Aspirin can be used as an anticoagulant, in prevention of the recurrence of heart attacks and strokes and as a prophylactic. 
 |

|Penicillin |

|D.2 U4 Penicillins are antibiotics produced by fungi. 
 |

|D.2 U5 A beta-lactam ring is a part of the core structure of penicillins. 
 |

|D.2 U6 Some antibiotics work by preventing cross-linking of the bacterial cell walls. 
 |

|D.2 U7 Modifying the side-chain results in penicillins that are more resistant to the penicillinase enzyme. 
 |

|Applications and skills |

|Aspirin |

|D.2 AS1 Description of the use of salicylic acid and its derivatives as mild analgesics. 
 |

|D.2 AS2 Explanation of the synthesis of aspirin from salicylic acid, including yield, purity 
by recrystallization and characterization using IR and melting|

|point. 
 |

|D.2 AS3 Discussion of the synergistic effects of aspirin with alcohol. 
 |

|D.2 AS4 Discussion of how the aspirin can be chemically modified into a salt to increase its aqueous solubility and how this facilitates its |

|bioavailability. 
 |

|Penicillin 
 |

|D.2 AS5 Discussion of the effects of chemically modifying the side-chain of penicillins. 
 |

|D.2 AS6 Discussion of the importance of patient compliance and the effects of the over- 
prescription of penicillin. 
 |

|D.2 AS7 Explanation of the importance of the beta-lactam ring on the action of penicillin. 
 |

Aspirin

Mild analgesics, such as salicylic acid and its derivatives and paracetamol, block the transmission of pain from source to brain as they intercept the pain stimulus at source i.e. the injured tissue by interfering with or suppressing the production of substances, such as prostaglandins, by the injured tissues. Prostaglandins stimulate pain receptors that send pain impulses to the brain. Prostaglandins are chemicals that send pain impulses to the brain and cause swelling or fever.

Synthesis of aspirin

|Aspirin is a derivative (a derivative = a new compound obtained from another compound) of salicylic acid or |[pic] |

|2-hydroxybenzoic acid (structure to the left). Salicylic acid was used as an analgesic in the past but was | |

|unpleasant to take as it had a bitter taste and, because of its acidity, was irritating to the stomach and even | |

|damaged the membranes in the mouth, gullet and stomach. Because of these reasons the 2-hydroxybenzoic acid was | |

|converted into aspirin, 2-ethanoyloxybenzoic acid or C9H8O4, by esterification using ethanoic anhydride, | |

|CH3COOCOCH3, as shown by the equation below: | |

|C6H4(OH)COOH + CH3COOCOCH3 → C6H4(OCOCH3)COOH + CH3COOH | |

|Method |[pic] |

|The 2-hydroxybenzoic acid and ethanoic anhydride are warmed gently with concentrated sulphuric or phosphoric acid | |

|as a catalyst. The mixture is diluted with water and allowed to cool down so that aspirin crystals form as aspirin | |

|has a low solubility in water. The aspirin crystals are removed using filtration (Buchner filter) | |

| | |

|Purification of the aspirin crystals: recrystallization | |

|To increase the yield, the impure crystals are removed using filtration and then dissolved in hot ethanol to make a| |

|saturated solution. This solution is cooled slowly and the aspirin crystalizes again (or recrystallizes) out first | |

|(lower solubility of aspirin in ethanol than the impurities) and is removed using filtration (Buchner filter). | |

Characterization of aspirin as product using IR and determination of purity using melting point.

The identity of the product from the above synthesis can be determined using IR spectroscopy whilst the purity (and therefore the yield) is determined using melting point determination.

The aspirin IR spectrum is different from salicylic acid at the following wavenumbers:

• The ester group in aspirin produces an absorption at 1700 to 1750 cm-1 which is not there in salicylic acid as salicylic acid does not have an ester group.

• The absence of hydroxyl group in aspirin means that there is no peak at 3200 to 3600 cm-1.

Both the aspirin and salicylic acid IR spectrum show:

• A strong C-O peak from 1050 to 1410 cm-1 in alcohols and esters.

• A strong peak at 1700 -1750 cm-1 for C=O in carboxylic acid group.

• A strong, broad O-H peak at 3200 - 3600 cm-1 in carboxylic acid.

The purity of the synthesized aspirin is determined using the determination of the melting point of the crystals obtained.

Worked example of calculation of yield

Using the reaction below, two aspirin samples were prepared as shown by the details in the table below:

C6H4(OH)COOH + CH3COOCOCH3 → C6H4(OCOCH3)COOH + CH3COOH

|Sample |Masses of reactants and products (g) |Melting point of product |Product isolation |

| | |(0C) | |

| |Salicylic acid |Ethanoic anhydride |Aspirin | | |

|1 |2.57 |2.85 |2.11 |134-135 |Filtering, recrystallization from |

| | | | | |ethanol, and drying for 24 hours |

|2 |2.06 |4.49 |3.42 |124-126 |Filtering, washing with water and |

| | | | | |drying for 10 minutes |

a) Calculate the amounts, in mol, of reactants used in both samples and deduce the limiting reactant in each sample.

b) Calculate the theoretical yields, in g, of aspirin in both samples.

c) Calculate the percentage yield of each sample.

d) The melting point of pure aspirin is 136 0C. Deduce, referring to percentage yields and melting points, which sample of aspirin to be more pure. How does the melting point of impure aspirin compare to the melting point of pure aspirin.

Beneficial side effects of aspirin

Aspirin also:

• Acts as an anticoagulant as it reduces blood clotting

• Prevents the recurrence of heart attacks and strokes as it thins the blood.

• Aspirin also seems to prevent colon cancer. Medicines taken for preventative measures are also referred to as a prophylactic.

Synergetic effect of aspirin with ethanol

Ethanol produces a synergic effect with a number of drugs including aspirin, this means that the effect of the drug is enhanced in the presence of alcohol which can be dangerous e.g. aspirin and ethanol together can increase risk of stomach bleeding.

Improving bioavailability of aspirin: chemical modification to Improve aqueous solubility of aspirin

Many medicines are either non-polar or relatively non-polar molecules. If their target area in the body is in an aqueous environment their low solubility in water, as a result of their non-polarity or limited polarity, will make their uptake slow and also give them low bioavailability.

However, if the polarity of the medicine molecule can be modified (without altering its pharmaceutical activity) then so can its distribution around the body and its bioavailability and therefore its effectiveness.

In the case of molecules with either acidic (carboxylic acid) or basic (amine) groups, the polarity can be increased by converting them into ionic salts/compounds such as chlorides by adding either an alkali or an acid. Ionic salts dissolve in water because of the ion-dipole interactions between the salts and water that cause the salt crystal to break up and the salt ions to disperse in the water increasing bioavailability.

Examples of such chemical modifications:

|Aspirin: adding sodium hydroxide |

| |

|Aspirin, which has very low solubility in water and has a carboxylic acid group, can be made into an ionic salt by reacting it with a strong alkali such |

|sodium hydroxide to form a soluble sodium salt, sodium 2-ethanoyloxybenzenecarboxylate, as shown by the equation below: |

|C6H4(OCOCH3)COOH + NaOH → C6H4(OCOCH3)COO- Na+ + H2O |

| |

|The structure of aspirin in the data booklet is the structure of the insoluble aspirin. The molecule can still act as an analgesic. The ionic salts forms |

|ion-dipole interactions with water. |

|Once in the stomach the conjugate base in the aspirin reacts with the H+ in the stomach acid to reform the acidic aspirin molecule. |

|C6H4(OCOCH3)COO- + H+ → C6H4(OCOCH3)COOH |

|fluoxetine hydrochloride: adding an acid |

| |

|In the case of fluoxetine hydrochloride (Prozac®) the structure in the data booklet is the structure of the soluble ionic salt, hydrogen chloride salt, and|

|this is usually the form in which it is administered or prescribed. |

| |

|[pic] |

|Fluoxetine hydrochloride (Prozac®) is produced by reacting a strong acid such as hydrochloric acid with the secondary amine group in fluoxetine (see |

|structure to the left). This reaction is similar to the reaction between ammonia and hydrochloric acid, a reaction you are very familiar with. In both |

|reactions the nitrogen atom donates its non-bonding pair to the hydrogen ion forming a basic cation to which the chloride ion is attracted. |

| |

| |

|Use the structure above to write an equation for the formation of fluoxetine hydrochloride from fluoxetine. |

| |

|F3C(C6H4)OCH(C6H5)CH2CH2NHCH3 + HCl → F3C(C6H4)OCH(C6H5)CH2CH2N+H2CH3Cl- |

Penicillin

Antibacterials are drugs that kill or inhibit the growth of bacteria that cause infectious diseases. An example of antibacterials are penicillins.

Penicillins are a group of compounds that are produced by fungi and kill harmful micro-organisms; they are therefore called antibiotics.

How do all penicillins work? The beta-lactam ring

Structure of the first penicillin to be used, penicillin G or C16H18O4N2S is shown in the IB Data booklet. The main part of the structure is the beta-lactam ring.

Penicillins prevent the growth of bacteria. In some penicillins the beta-lactam ring deactivates the enzyme transpeptidase 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 that causes the cell to burst. Bacteria constantly replace cell walls.

Increased resistance in bacteria to penicillins

As a result of genetic mutations, bacteria have become resistant to penicillins because of the misuse of anitbacterials by patients and farmers. Resistant bacteria produce an enzyme, penicillinase, which causes the break up of the penicillin molecule as penicillinase makes the beta lactam ring break open; these bacteria then reproduce and pass on their resistance to succeeding generations. The more bacteria are exposed to antibacterials, the more opportunities there are for the mutation into antibiotic resistant bacteria.

Examples of misuse of penicillins include:

|1. Patient compliance |

| |

|Patient compliance refers to patients not completing the full course of penicillins and this results 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 penicillins |

| |

|Many doctors are too quick to prescribe penicillins. 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 of harmless bacteria in the alimentary canal and destroyed bacteria |

|might be replaced by more harmful bacteria. |

|3. Use of penicillins in animal feedstock as growth promotors |

| |

|Some penicillins are also effective in animals but they are more often administered without the animals having any disease; they are administered as a |

|prophylactic to prevent the animals from developing any disease that could affect their growth. In most cases these penicillins are passed by the animals |

|into the environment and eventually ending 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.

|penicillin |ampicillin |

|[pic] |[pic] |

Such modifications to the side-chain bring advantages such as:

• Reducing the occurrence 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 that cause the breakdown 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.

• Produce penicillin that do not cause allergic reactions to some patients.

D3 Opiates

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

Nature of science: Data and its subsequent relationships—opium and its many derivatives have been used as a painkiller in a variety of forms for thousands of years. One of these derivatives is diamorphine. (3.1)

|Understandings |

|D.3 U1 The ability of a drug to cross the blood–brain barrier depends on its chemical structure and solubility in water and lipids. 
 |

|D.3 U2 Opiates are natural narcotic analgesics that are derived from the opium poppy. 
 |

|D.3 U3 Morphine and codeine are used as strong analgesics. Strong analgesics work by temporarily bonding to receptor sites in the brain, preventing the |

|transmission of pain impulses without depressing the central nervous system. 
 |

|D.3 U4 Medical use and addictive properties of opiate compounds are related to the presence of opioid receptors in the brain. 
 |

|Applications and skills |

|D.3 AS1 Explanation of the synthesis of codeine and diamorphine from morphine. 
 |

|D.3 AS2 Description and explanation of the use of strong analgesics. 
 |

|D.3 AS3 Comparison of the structures of morphine, codeine and diamorphine (heroin). 
 |

|D.3 AS4 Discussion of the advantages and disadvantages of using morphine and its derivatives as strong analgesics. 
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|D.3 AS5 Discussion of side effects and addiction to opiate compounds. 
 |

|D.3 AS6 Explanation of the increased potency of diamorphine compared to morphine 
based on their chemical structure and solubility. 
 |

Action of opiates

Opiates, such as morphine, diamorphine (heroin) and codeine, are natural strong analgesics as they reduce severe pain by temporarily bonding to receptor sites (these receptor sites are called opioid receptors) in the brain or other parts of the central nervous system, CNS, such as the spinal cord. This prevents the brain and the CSN receiving any pain impulses and therefore prevents the perception of pain in the CNS but without depressing the CNS.

To be able to bond with the opioid receptors the opiates need to cross the blood-brain barrier and how well they do this depends on their solubility in water (blood) and lipids (brain) and on their chemical structure.

Opiates are also called narcotics as they act on the brain, are potent analgesics, cause changes in mood and behaviour and can result in addiction.

Structures of morphine, diamorphine and codeine

|morphine |diamorphine/heroin |codeine |

|benzene ring |benzene ring |benzene ring |

|hydroxyl (2) |tertiary amine |hydroxyl/alcohol |

|ether; |alkene |ether (2) |

|tertiary amine; |ester (2) |alkene |

|double bond/alkene; |ether |tertiary amine |

| |[pic] | |

|[pic] | |[pic] |

Synthesis of opiates

Opiates compounds are derived from opium which is an extract obtained from the seeds of a poppy plant. Morphine is the main drug extracted from opium and codeine and diamorphine are derived from morphine and are called semi-synthetic opiate.

Esterification of morphine to obtain heroin

As the structures above show, diamorphine’s structure is only slightly different from morphine. Both the hydroxyl groups in the morphine molecule have been converted into ester groups. This is achieved by reacting the morphine with ethanoic acid; as a result an esterification occurs during which also water is produced. This action makes diamorphine more soluble in lipids and therefore more potent as a pain killer but also more addictive.

Methylation of morphine to obtain codeine

In the synthesis of codeine from morphine one of the hydroxyl groups on the morphine is converted into a methyl ether group through a process called methylation. This also makes codeine less polar but more lipid soluble although it results in less binding with the opioid receptors – weaker analgesic.

Advantages and disadvantages of using morphine and its derivatives as strong analgesics

|Advantage |Disadvantage |

|Strong analgesics and therefore can relieve extreme pain |Addictive/habit-forming or physical dependence which leads to withdrawal symptoms – see |

|Fast acting as can be administered intravenously |below. |

|Wider therapeutic window/wider safety margin |As heroin is often taken by injections many addicts get infections such as HIV and |

|Relieves anxiety |hepatitis as a result of sharing needles. |

|Induces relaxation/feeling of well-being. |Tolerance can become an issue with this type of drug as more of the drug needs to be taken|

|High bioavailability. |to achieve the same effect; in order to achieve the desired effect heroin users may take |

| |doses which exceed the lethal dose. |

| |See side effects below. |

Side-effects and addiction

Addiction leads to withdrawal symptoms.

|Side-effects |Withdrawal symptoms of opiates |

|Constipation, loss of sex drive, poor appetite, induce sleep, addictive, |Perspiration, diarrhoea, cramps, acute feelings of distress, fever. |

|constriction of pupil in the eye, depression, kidney and liver disorder, … | |

Increased potency of diamorphine

Diamorphine has greater potency as a painkiller than morphine and also gives a greater feeling of euphoria. This is because diamorphine is less polar than morphine as it does not have two polar hydroxyl group anymore as they have been replaced by two less polar ester groups.

As a result diamorphine (heroin) cannot form any hydrogen bonds and is therefore less soluble in polar substances such as water but more soluble in non-polar fatty tissue which makes up the central nervous system. As a result diamorphine can cross the blood-brain barrier faster/more easily than morphine.

Lower polarity in diamorphine makes it more soluble in fatty tissue and ensure a more rapid uptake.

Increased polarity makes a medicine more soluble in water and less so in fatty tissue.

D4 pH regulation in stomach

E.I.: Excess stomach acid is a common problem that can be alleviated by compounds that increase the stomach pH by neutralizing or reducing its secretion.

Nature of science Collecting data through sampling and trialling—one of the symptoms of dyspepsia is the overproduction of stomach acid. Medical treatment of this condition often includes the prescription of antacids to instantly neutralize the acid, or H2-receptor antagonists or proton pump inhibitors which prevent the production of stomach acid. (2.8)

|Understandings |

|D.4 U1 Non-specific reactions, such as the use of antacids, are those that work to reduce the excess stomach acid. 
 |

|D.4 U2 Active metabolites are the active forms of a drug after it has been processed by the body. 
 |

|Applications and skills |

|D.4 AS1 Explanation of how excess acidity in the stomach can be reduced by the use of different bases. 
 |

|D.4 AS2 Construction and balancing of equations for neutralization reactions and the stoichiometric application of these equations. 
 |

|D.4 AS3 Solving buffer problems using the Henderson–Hasselbalch equation. 
 |

|D.4 AS4 Explanation of how compounds such as ranitidine (Zantac) can be used to 
inhibit stomach acid production. 
 |

|D.4 AS5 Explanation of how compounds like omeprazole (Prilosec) and esomeprazole (Nexium) can be used to suppress acid secretion in the stomach. 
 |

Excess acid in stomach

The term dyspepsia refers to conditions that cause pain and discomfort in the upper digestive tract such as the stomach.

Acid indigestion (discomfort in stomach) and heartburn (acid from the stomach rising into oesophagus-reflux- that causes inflammation) are conditions that arise when excess hydrochloric acid is produced by the gastric glands in the walls of the stomach making the gastric juice too acidic as it can have a pH of less than 1. Optimum pH in the stomach is between 1.0 and 2.0. The acid in the stomach is needed to:

• Kill any bacteria that were ingested with the food.

• Provide the optimum pH environment for the digestive enzymes that act in the stomach (different parts of the digestive tract needs a different pH environment).

A pH of less than 1.0 can also cause ulceration or damage (breaking down of tissue) to the lining of the stomach walls.

Dyspepsia or acid indigestion and heartburn can be prevented either by:

• Reducing the effect of the excess acid after it has been released in the stomach by using antacids to neutralize some of the excess acid

• Preventing the production of the excess acid by using H2 –receptor antagonists or proton pump inhibitors.

Action of antacids (weak bases)

Antacids are usually weak bases that are used to neutralize excess hydrochloric acid in the stomach so the pH level returns to the desired level i.e. pH 1.0 to 2.0.

Aluminium hydroxide, magnesium hydroxide, magnesium carbonate, sodium carbonate and sodium hydrogencarbonate (sodium bicarbonate) 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 and can therefore neutralize three times as many H+ than sodium hydrogen carbonate as shown by the equations below.

Sodium hydroxide or potassium hydroxide are not used as antacids because they are strong alkalis and are too corrosive to the body tissue.

Equations to show the neutralizing action of antacids

• 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)

• Na2CO3 (s) + 2HCl (aq) 2NaCl (aq) + H2O (l) + CO2(g)

• MgCO3(s) + 2HCl (aq) (( MgCl2 (aq) + H2O (l) + CO2(g)

• Al(OH)2NaCO3(s) + 4HCl (aq) (( AlCl3 (aq) + NaCl (aq) + 3H2O (l) + CO2(g)

Ionic equations:

• OH- (aq) + H+ (aq) (( H2O (l)

• CO32- (aq) + 2H+ (aq) (( H2O (l) + CO2(g)

• HCO3 + H+ (( 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 (refluxing) 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.

Calculation of the pH of an acid buffer

As antacids are usually weak bases that are added to a strong acid in the stomach a buffer is created.

An acid buffer consists of the following systems together:

acid: HA ( H+ + A- ( = conjugate base)

salt/conjugate base: MA ( M+ + A- (= conjugate base)

The equilibrium constant expression for such an acid buffer is

|Ka = |[H+] [A- ] |or Ka = [H+] x |[A-] |

| |[HA] | |[HA] |

Remember that all the above concentrations should be concentrations at equilibrium that are difficult to measure, but we can make the following assumptions:

|[conjugate base]equilibrium = [salt]initial (either added or formed) as the salt is by far the largest supplier of A- as opposed to the weak acid |

|[HA]equilibrium = [HA]initial (same assumption as with weak acids) |

Because of these assumptions the equilibrium expression above can then be rewritten in terms of the initial concentrations which are known:

|Ka = |[H+] [salt/conjugate base ]initial |and expressed in terms of hydrogen concentration: |[H+] = Ka x |[acid]initial |

| |[acid]initial | | |[conj b]initial |

The above expression tells us that the [H+] and therefore the pH of a buffer depends on:

|Ka of the acid; |

|ratio beween acid and salt concentration. Therefore, the dilution of a buffer solution does not affect its pH as the ratio [salt/acid] itself is not |

|changed by the dilution |

The above expression can also be rewritten in its log form and then becomes

|pH = pKa - log |[acid]initial |or |pH = pKa + log |[salt ]initial |

| |[conj b/salt ]initial | | |[acid/conj base]initial |

The expression to the right is called the Henderson-Hasselbalch equation.

Calculation of the pH of an alkali buffer

alkali: MOH ( OH- + M+ ( = conjugate acid)

salt (fully ionised) MA ( A- + M+ (= conjugate acid)

|Example: NH3/NH4+ buffer (ammonia solution/ammonium ion buffer) |

|alkali: NH3 + H2O ( OH- + NH4+ (equation that defines alkali buffer) |

|salt/conjugate acid: NH4Cl ( Cl - + NH4 + |

The conjugate acid can come from:

• a soluble salt of the weak alkali that is added to the weak alkali

• the incomplete reaction between the weak alkali and a strong acid which produces some salt but leaves excess alkali unionized.

Equilibrium constant expression for an alkali buffer is

|Kb = |[OH-] [M+ or conj acid/salt ]eqm |= [OH-] x |[conj base/salt]eqm |

| |[MOH]eqm | |[MOH]eqm |

Remember that all the above concentrations are concentrations at equilibrium, but we can make the following assumptions:

|[M+]equilibrium = [salt]initial and |

|[MOH]equilibrium = [MOH]initial |

Because of these assumptions the equilibrium expression can then be rewritten in terms of the initial concentrations which are known

|Kb = |[OH-] [salt ]initial |

| |[base]initial |

|and in terms of hydroxide ion concentration: |[OH-] = Kb x |[base ]initial e.g. |

| | |[NH3] |

| | |[salt]initial e.g. |

| | |[NH4+] |

The above expression can also be rewritten in its log form and then becomes

|pOH = pKb - log |[base]initial |or |pOH = pKb + log |[conj acid/salt ]initial |

| |[conj acid/salt ]initial | | |[base]initial |

Exercises (calculating pH after an acid/alkali has been added is an extension)

1. (a) Calculate the pH of a buffer system containing 1.0 mol dm-3 CH3COOH and 1.0 mol dm-3

CH3COONa.

b) What is the pH of the buffer system after the addition of 0.1 mole of gaseous HCl to 1dm3 of the solution. (no change in volume assumed)

2. (a) Calculate the pH of the 0.3 mol dm-3 NH3 (=NH4OH) and 0.36 mol dm-3 NH4Cl buffer system.

b) What is the pH after the addition of 20.0 cm3 of 0.050 mol dm-3 NaOH to 80.0 cm3 of the buffer solution?

3. (a) Calculate the pH of a solution containing 0.2 mol dm-3 CH3COOH and 0.3 mol dm-3 CH3COONa.

(b) What would be the pH of a 0.2 mol dm-3 CH3COOH if no salt were present?

4. A buffer was prepared by mixing exactly 200 cm3 of a 0.6 mol dm-3 NH3 solution and 300 cm3 of 0.3

NH4Cl solution. Kb of NH3 = 1.8 x 10- 5.

a) What is the pH of this buffer, if we assume a final volume of 500 cm3?

(b) What will be the pH after 0.02 dm3 of 1 mol dm-3 HCl is added?

5. Determine the pH of a solution formed when adding 50.0 cm3 of 1.00 mol dm-3 ethanoic acid,

CH3COOH, to 50.0 cm3 of a 0.40 mol dm-3 sodium hydroxide solution.

Prevention of stomach acid production

There are 2 different types of actions and therefore drugs that can prevent stomach acid production:

H2-receptor antagonists:

HCl in the stomach is normally only produced when needed and this process involves hormones (such as histamine) that interact with H2-receptors in the parietal cells in the gastric glands and this stimulates the production of the acid that is released in the lumen (the hollow part of the stomach that holds the juices) of the stomach. Drugs called H2-receptor antagonists, such as ranitidine (Zantac), can be used to prevent the histamine from interacting with the H2-receptor and therefore inhibiting acid production. The drug competes with the hormones to interact with the H2-receptors. The H refers to different Histamine.

Proton pump inhibitors:

After the acid has been produced its secretion into the stomach involves a transfer of H+ ions (protons) into the lumen of the stomach and this is balanced out by a movement of K+ in the opposite direction to balance the charges in the lumen. The H+ ions are transferred or pumped into the lumen by the parietal cells; these cells are therefore referred to as proton pumps.

This proton pumping requires energy that is provided by the hydrolysis of ATP and this requires an enzyme referred to as H+/K+ ATPase or a gastric proton pump. Compounds such omeprazole (Prilosec) and esomeprazole (Nexium) inhibit the action of the enzyme and therefore the release of the acid into the stomach.

Active metabolites

An active metabolite is an active form of a drug that has been administered in an inactive form because of a number of reasons. The inactive form is then metabolized by the body into its active form (bioactivated) that has a greater therapeutic effect than the inactive form.

Possible reasons for using an inactive form include:

• Has greater bioavailability because it is more soluble or is absorbed faster.

• Easier to administer.

• More selective in its interaction with healthy cells.

• Has fewer side effects linked to the administration.

• Can be stored longer.

• Can withstand different storage conditions.

An example where active metabolites are used are the proton pump inhibitors esomeprazole and omeprazole. They are administered in their inactive form as it allows the drugs to, once in the body, easily cross the cell membranes of the parietal cells (giving the drug a higher bioavailability). In the inactive form they cannot interact with the gastric proton pump. However, the hydrochloric acid in the parietal cells causes both the esomeprazole and omeprazole to change from its inactive into an active form that can interact with the gastric proton pump and inhibit its action.

D5 Antiviral medications

E.I.: Antiviral medications have recently been developed for some viral infections while others are still being researched.

Nature of science Scientific collaboration—recent research in the scientific community has improved our understanding of how viruses invade our systems. (4.1)

|Understandings |

|D.5 U1 Viruses lack a cell structure and so are more difficult to target with drugs than bacteria. 
 |

|D.5 U2 Antiviral drugs may work by altering the cell’s genetic material so that the virus cannot use it to multiply. Alternatively they may prevent the |

|viruses from multiplying by blocking enzyme activity within the host cell. 
 |

|Applications and skills |

|D.5 AS1 Explanation of the different ways in which antiviral medications work. 
 |

|D.5 AS2 Description of how viruses differ from bacteria. 
 |

|D.5 AS3 Explanation of how oseltamivir (Tamiflu) and zanamivir (Relenza) work as a preventative agent against flu viruses. 
 |

|D.5 AS4 Comparison of the structures of oseltamivir and zanamivir. 
 |

|D.5 AS5 Discussion of the difficulties associated with solving the AIDS problem. 
 |

Differences between viruses and bacteria

|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 |viruses consist only of genetic material and protective coating, no cell |

|all perform specific functions |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 |

As viruses lack the same cell structures as bacteria, antibacterials are ineffective; in addition viruses also live inside host cells they are also more difficult to target by drugs.

Action of antiviral medication

As viruses do not have the essential cell structures and genetic material to make new viral particles they need to use the structures in host cells. Antiviral drugs all aim to interfere with the life cycle of the virus they target by preventing the virus to use the cell’s structures and genetic material in the host cell to make new viral particles.

There are number of different ways in which antivirals achieve this:

• Blocking the virus from entering the host cell by causing changes in the cell membrane of the host cell.

• Altering the host cell’s genetic material so it cannot be used by the virus to multiply e.g. prevents the transcription of the viral RNA into the host cell DNA.

• Preventing the virus from multiplying by blocking enzyme activity in the host cell.

• Preventing the new viral particles from leaving the host cell.

Examples of antiviral medication: Tamiflu and Relenza

The flu virus has an enzyme called neuraminidase that binds with the active site in a substrate molecule called sialic acid that is part of the cell membrane. This provides a pathway with a lower activation energy for a reaction that allows new viral particles (after multiplication) to leave the host cell and infect the rest of the body.

Some antiviral drugs target the neuraminidase enzyme and inhibit its action by preventing from binding with the sialic acid. Two of these neuraminidase inhibitors are oseltamivir (Tamiflu) and zanamivir (Relenza) as they each have a similar structure to the sialic acid in the cell membrane and can therefore also bond with the active site on the neuraminidase of the virus preventing it from bonding with the sialic acid in the cell membrane.

Structures of Tamiflu and Relenza

|Oseltamivir (Tamiflu) |Zanamivir (Relenza) |

|alkenyl |alkenyl |

|ether |ether |

|primary amine |primary amine |

|carboxyamide |carboxyamide |

|ester |carboxylic acid |

| |hydroxyl (3) |

|Some bacterial resistance |More bacterial resistance |

|Oral |Inhalation |

AIDS virus

HIV invades white blood cells or CD4+ T cells and causes the disease AIDS that causes the failure of the immune system but this also allows other life-threatening diseases such as pneumonia and cancer to affect the person carrying the HIV. The HIV uses its genetic information in the form of RNA to instruct the while blood cell’s DNA to produce new viral particles.

Antiretroviral drugs

As any antiviral drugs, antiretroviral drugs aim to interfere in HIV’s life cycle and achieve by doing one of the following:

• Preventing the virus from binding to the receptor on the CD4+ T cell membrane and by doing so preventing the virus from entering the CD4+ T cell.

• Interfering in the reverse transcription process of the viral RNA into viral DNA. 


• Interfering in the integration of the viral DNA into the CD4+ T cell’s chromosome.

• Interrupting the release of new viral particles from the CD4+ T cell’s surface.

Difficulties associated with solving the AIDS problems

• HIV viruses can mutate rapidly even within a HIV carrier.

• As HIV targets white blood cells, any antiretroviral drug needs to target white blood cells that 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.

D6 Environmental impact of some medications

E.I.: The synthesis, isolation, and administration of medications can have an effect on the environment.

Nature of science Ethical implications and risks and problems—the scientific community must consider both the side effects of medications on the patient and the side effects of the development, production and use of medications on the environment (i.e. disposal of nuclear waste, solvents and antibiotic waste. (4.8)

|Understandings |

|D.6 U1 High-level waste (HLW) is waste that gives off large amounts of ionizing radiation for a long time. 
 |

|D.6 U2 Low-level waste (LLW) is waste that gives off small amounts of ionizing radiation for a short time. 
 |

|D.6 U3 Antibiotic resistance occurs when micro-organisms become resistant to antibacterials. 
 |

|Applications and skills |

|D.6 AS1 Describe the environmental impact of medical nuclear waste disposal. 
 |

|D.6 AS2 Discussion of environmental issues related to left-over solvents. 
 |

|D.6 AS3 Explanation of the dangers of antibiotic waste, from improper drug disposal and animal waste, and the development of antibiotic resistance. 
 |

|D.6 AS4 Discussion of the basics of green chemistry (sustainable chemistry) processes. 
 |

|D.6 AS5 Explanation of how green chemistry was used to develop the precursor for Tamiflu (oseltamivir). 
 |

Green chemistry in the pharmaceutical industry

Green chemistry or sustainable chemistry is an approach to carrying out chemical processes such as the manufacture, administration and disposal of pharmaceuticals that involves some of the following:

• Considering the atom economy in the manufacturing process – making the processes as effective as possible by maximizing raw materials.

• Reducing the amount of waste or avoiding waste all together.

• Reduce amount of hazardous waste e.g. reduce use of radioisotopes for instance in diagnostic medicine by using alternatives such as dyes.

• Safe disposal of waste.

• Using solvents safely in the manufacture or extraction.

• Considering implications to human health of the synthesis and extraction processes.

• Reducing the impact of the pharmaceutical industry on the environment.

Use and disposal of solvents

The synthesis and extraction of drugs often involves the use of solvents as they can provide a medium in which the synthesis occurs or they are used to extract the product. (e.g. using solubility) that need to be disposed off at the end of the synthesis or extraction.

Issues with the use of solvents concern:

• Health issues of the solvent itself to the workers e.g. is the solvent carcinogenic or toxic.

• Safety issue with the synthesis or extraction process in which the solvent is used e.g. solvent can be explosive or could form toxic by-products as a result of the process.

• Environmental impact of solvent use and disposal e.g. emissions in the air and water of chlorinated solvents. Some are toxic to animals and plants. Greenhouse effect. Flammable.

Possible solutions to green use of solvents:

• Modify the synthesis or extraction so less solvent is used.

• Use an alternative safer solvent or one with zero environmental impact.

• Reuse and recycle solvents.

Antibiotic waste

As explained earlier in this option when discussing resistance to penicillins many bacteria have become antibiotic resistant as a result of the misuse of most available antibacterials not just penicillins.

This means that many antibiotics are now less or even no longer effective against bacteria. Antibiotic resistant bacteria have genes that carry this resistant characteristic and pass on these resistant genes.

The spread of antibiotic resistance is promoted as a result of increased exposure of the bacteria to antibiotics as a result of the misuse described in D3.

In addition, the following practices also increase exposure:

• The use of broad-spectrum antibacterials (effective against a wide range of bacteria but overall less effective against any of the bacteria) has also provided opportunities for bacteria to genetically mutate and allow resistant bacteria to reproduce.

• The improper disposal of antibiotics by patients and pharmaceutical companies also allows antibiotics to enter the environment and into the food chain providing opportunities to develop genetic resistance.

Nuclear waste

Nuclear chemistry is used often in the diagnosis and treatment of diseases and this approach often produces hazardous radioactive waste that needs to be disposed off. Ionizing radiation is the hazardous radiation emitted by radioactive materials. Radioactive materials are also environmental pollutants.

| |High-level waste |Low-level waste |

|Amount of |Emit large amounts of ionizing radiation/high activity. |Small amounts of ionizing radiation emitted/low activity. |

|radiation/level of |High environmental impact |Limited environmental impact |

|activity | | |

|Time |Radioactive for a long time and release heat |Radioactive for a short time |

|Half life |Long half life |Short half life |

|Examples |Radioisotopes such as Co-60 that have been used for |Contaminated clothing, materials such as gloves, coats, paper, tools, |

| |diagnosis. These isotopes remain radioactive for a longer |towels, syringes, injection needles which have become radioactive because|

| |time; also the decay products might still be radioactive. |they have been exposed to radiation in activities such as sterilizing |

| |Some of these diagnostic radioisotopes are also toxic. |equipment in hospitals, radiotherapy, … |

|Disposal |High-level waste is stored under water in reinforced |Low levels waste is initially stored in sealed containers until the |

| |cooling ponds for a long time until radiation levels have |radiation has decreased to a safe limit and then compacted and placed in |

| |decreased substantially and then it is sealed in heavy |landfills or released in the sewage system. |

| |steel containers or vitrified and buried underground in | |

| |granite rock or in deep mines. | |

Green chemistry in the development of Tamiflu

Shikimic acid or shikimate is the precursor (= a chemical from which a more active chemical is produced) in the production of Tamiflu and is found in low concentrations in a variety of plants. Its extraction from plants is a long chemical process with low yields. Alternative and more effective sources and processes have been developed:

• Shikimate can also be produced by fermenting genetically engineered bacteria; process has a much higher yield and less waste.

• Extraction of shikimate acid from different natural sources such as pine trees that have a greater concentration so less raw material needs to be used.

• Less expensive extraction of shikimate from suspension cultures of the Indian sweetgum tree. 


D7 Taxol

E.I.: Chiral auxiliaries allow the production of individual enantiomers of chiral molecules.

Nature of science Advances in technology—many of these natural substances can now be produced in laboratories in high enough quantities to satisfy the demand. (3.7)

Risks and problems—the demand for certain drugs has exceeded the supply of natural substances needed to synthesize these drugs. (4.8)

|Understandings |

|D.7 U1 Taxol is a drug that is commonly used to treat several different forms of cancer. 
 |

|D.7 U2 Taxol naturally occurs in yew trees but is now commonly synthetically 
produced. 
 |

|D.7 U3 A chiral auxiliary is an optically active substance that is temporarily incorporated into an organic synthesis so that it can be carried out |

|asymmetrically with the selective formation of a single enantiomer. 
 |

|Applications and skills |

|D.7 AS1 Explanation of how taxol (paclitaxel) is obtained and used as a chemotherapeutic agent. 
 |

|D.7 AS2 Description of the use of chiral auxiliaries to form the desired enantiomer. 
 |

|D.7 AS3 Explanation of the use of a polarimeter to identify enantiomers. 
 |

Taxol (or paclitaxel) is a common anti-cancer drug, a chemotherapeutic drug (=a chemical that is used to control a disease such as cancer- chemotherapy) that was first extracted from the bark of yew trees.

However, the isolation of taxol from natural sources was very wasteful as it used a lot of bark some of trees that were threatened. A semi-synthetic method was developed that used a natural precursor, 10-deacetylbaccatin, (hence semi-synthetic) from different but more common and faster-growing trees.

Issues with chirality in drugs

Molecules of most semi-synthetic or synthetic drugs are chiral molecules (they have an asymmetrical carbon). During the synthesis of the drug the other enantiomer is also formed usually yielding a racemate or racemic mixture (a mixture in which both enantiomers are equimolar).

Taxol is such an enantiomer that is obtained during its synthesis from the natural precursor.

Both enantiomers of a chiral drug have the same chemical properties apart from that they react differently with other chiral compounds such as many enzymes and can have therefore different physiological effects; some of which will intended whilst other effects could be harmful. It is because of this reason that the physiological effect of each enantiomer needs to be tested. Usually only one of the enantiomers has the desired therapeutic effect and, after synthesis of the drug molecule, this enantiomer needs to be isolated from the racemic mixture that is obtained. Occasionally both enantiomers have the desired effect and the drug can be administered as a racemic mixture.

Using chiral auxiliaries in asymmetric synthesis of taxol

As the extraction of an enantiomer form a racemic mixture is a wasteful process (see green chemistry) asymmetric synthesis is often used as an alternative approach. This approach synthesizes the desired enantiomer directly by preventing the synthesis of the other enantiomer and involves the use of a chiral auxiliary.

A chiral auxiliary is an enantiomer (optically active substance) and is used to convert a non-chiral reacting molecule into just one enantiomer i.e. the enantiomer with the desired pharmaceutical effect. It does that by attaching itself to the non-chiral molecule to create the stereochemical conditions necessary to force the reaction to follow a certain path i.e. the path that will yield the desired enantiomer and not the other enantiomer.

Once the new desired molecule has been formed, the auxiliary can be taken off and recycled.

Action of Taxol

Taxol is an inhibitor that is effective against solid tumour cancers as it interferes with the cell division of the cells in the tumor and can therefore stop its growth. Taxol does this by bonding covalently with a protein called tubulin (taxol’s target) that makes up cellular structures called microtubules. The binding with the tubulin gives the microtubules stability preventing them from being broken down which is an essential step in the mitosis process and stops any cell division in the tumour.

D8 Nuclear medicine

E.I.: Nuclear radiation, whilst dangerous owing to its ability to damage cells and cause mutations, can also be used to both diagnose and cure diseases.

Nature of science

|Understandings |

|D.8 U1 Alpha, beta, gamma, proton, neutron and positron emissions are all used for medical treatment. |

|D.8 U2 Magnetic resonance imaging (MRI) is an application of NMR technology. 
 |

|D.8 U3 Radiotherapy can be internal and/or external. 
 |

|D.8 U4 Targeted Alpha Therapy (TAT) and Boron Neutron Capture Therapy (BNCT) are two methods which are used in cancer treatment. 
 |

|Applications and skills |

|D.8 AS1 Discussion of common side effects from radiotherapy. 
 |

|D.8 AS2 Explanation of why technetium-99m is the most common radioisotope used in 
nuclear medicine based on its half-life, emission type and chemistry. 
 |

|D.8 AS3 Explanation of why lutetium-177 and yttrium-90 are common isotopes used for radiotherapy based on the type of radiation emitted. 
 |

|D.8 AS4 Balancing nuclear equations involving alpha and beta particles. 
 |

|D.8 AS5 Calculation of the percentage and amount of radioactive material decayed and remaining after a certain period of time using the nuclear half-life |

|equation. 
 |

|D.8 AS6 Explanation of TAT and how it might be used to treat diseases that have spread throughout the body. 
 |

Radiotherapy

Radiotherapy concerns the use of ionizing radiation as emitted by radionuclides to treat diseases such as cancer by destroying the cancer cells. It can also be used to provide detailed information in the form of images about internal organs to diagnose any disease.

Radioisotopes have an unstable nucleus that spontaneously decay into a more stable form by emitting radiation either in the form of subatomic particles or energy.

Radiotherapy can be:

• Internal: radionuclides are placed in the human body to target a particular cancerous tissue or groups of receptors. Internal radionuclides are taken in orally as a solid or as a liquid or as an implant. Liquids could also be injected.

• External: radiation source remains outside the human body and the beams of radiation (beta or gamma rays, photons or neutrons) target specific cancerous tissues in the body. A commonly used nuclide for this approach is Co-60.

Effect of radiation on cells

Nuclear radiation is also referred to as ionizing radiation as it removes electrons from atoms in biological molecules converting them into ions that form reactive radicals that interfere with physiological processes. This causes:

• Changes to the structure of the DNA within the genes of cells (genetic damage) (mutations).

• A reduced ability of cells to repair DNA damage.

• Limited growth and regeneration of the cells/tissue

Effect on cancerous cells

Same as above but cancerous cells are affected more by radiation than normal cells so targeted radiotherapy (internal or external) is on obvious choice for the treatment of cancer.

Side effects

Ionizing radiation also affects normal cells but some cells more than others in particular cells that divide rapidly such as hair follicle cells, sex cells and cells in the skin causing more damage to the DNA and reducing growth.

Side effects:

• Hair loss

• Damage to skin and nails

• Nausea

• Fatigue

• Sterility

The different types of ionizing radiation used in radiotherapy:

• Alpha radiation involves the emission of particle equivalent to a helium nucleus as it consists of 2 protons and 2 neutrons and therefore has a charge of +2 and a relative mass of 4. As a result of this decay the radioisotope becomes an element with a decrease of 2 atomic number as shown by the nuclear equation below:

[pic]

• Beta emissions occur when a neutron in the nucleus splits into a proton and an electron. The electron is emitted and the proton remains in the nucleus increasing the atomic number by one unit changing the radioisotope into a nuclide of a different element as shown below:

[pic]

• Gamma is the emission of energy or photons of high frequency as part of the electromagnetic spectrum. Often also happens during alpha and beta radiation.

• Emission of protons.

• Emissions of neutrons.

• Positron (positively charged electrons) radiation occurs when a proton changes into a neutron and a positron is emitted.

Exercises on nuclear equations

Write nuclear equations for the following:

1. Alpha decay of Pb-212

2. Beta decay of Y-90

3. Beta decay of Lu-177

4. Alpha decay of Ac-255

Some types of radiotherapy

Targeted alpha therapy (TAT)

Used for treating leukemia and other dispersed cancers; these are cancers in which the cells have spread throughout the body from the original tumour. As alpha particles have the greatest charge and therefore the greatest ionizing ability, they are the most destructive type of emission. Alpha particles can only penetrate tissue, and therefore cause cellular damage, over a very short range of 0.05 mm-0.1 mm. This also means that not too many healthy cells should be effected.

The radioisotopes emitting the alpha radiation are directed to antibodies and bind themselves onto them. The antibody then carries the alpha-emitted to the cancer where the alpha radiation will destroy the cells without too much damage to the surrounding healthy cells.

Boron Neutron Capture Therapy (BNCT)

This therapy uses a beam of neutrons to produce alpha particles only at the site of the cancer. The target of the external neutron radiation are B-10 atoms that have been taken to the site of the cancer. There the B-10 atoms capture (absorb) the neutrons from the beam and then change into B-11 nucleii; these then immediately decay emitting alpha particles that destroy the surrounding cancerous cells. The B-10 nucleii are administered using intravenous injections in the form of a compound such as boronophenylalanine. This compound tends to accumulate in brain tumours. When the compound has been absorbed by the tumour cells the site is radiated by a neutron beam.

Diagnosis of diseases using radiation: radiodiagnostics

This often involves the use of a radioactive tracer (a radionuclide) that is attached to a biologically active molecule to form a radiopharmaceutical that is then ingested or injected and that can be traced used detection equipment that uses for instance gamma rays producing an image on a scan.

Commonly used tracers are Tc-99m (most common) and I-131. Different traces accumulate in different parts of the body e.g. I-131 in the thyroid gland which is why it is used in the diagnosis and treatment (higher dose than for diagnostic purposes) of thyroid cancer.

Common radioisotope: Tc-99m

The ‘m’ indicates that the nucleus is metastable and only exists over a short period of time.

Why is Tc-99m commonly used as a diagnostic nuclide?

• Emits gamma radiation:

o Must emit gamma radiation of sufficient energy as the source of the emission is inside the patient body but can only be detected if the radiation can escape the body.

o Easily traced using X-ray equipment: When Tc-99m decays it emits gamma radiation that can be detected using X-rays.

• Versatile and easily administered: Can be used to diagnose and treat cancer in different organs and tissues as it can bind onto a number of different biological carrier. Each type of tissue has its own biologically active molecule that accumulates there. Can easily be administered to specific areas in the body.

• Patient is only exposed to a minimum amount of radiation:

o Emission of low energy beta radiation.

o Half life is 6 hours and most Tc-99m will have decayed after 2 days. This amount of time is just sufficient to allow for preparation of the radiopharmaceutical, administer it and detect it.

o Low energy radiation so less hazardous to the patient: energy of photons in the gamma rays is low so patient only affected by a low dose.

Lutetium-177 and Yttrium-90

Both types of nuclides emit both beta and gamma radiation

Rate of decay

Rate of decay is the number of nuclides that decay or emit radiation per second. The unit is Bequerel or Bq.

Half life

Half life, t1/2 ,is the time it takes for:

• Half the initial amount or concentration of a radionuclide to decay

• The activity or rate of decay to decrease by half

Half life is independent of the concentration or starting amount of the nuclide, temperature or pressure but is dependent on the identity of the nuclide i.e. each nuclide has own half life.

The longer the half- life, the more slowly a radionuclide decays, the lower the activity (Inverse relationship between half life and activity), the lower the doses of radiation emitted.

As radioactive decay only involves 1 reacting species it follows first order reaction kinetics i.e. rate = k[N].

This expression can be used to convert the half life value into a decay constant, k, that can be used for calculations such as to determine how long a radioisotope will remain active after administration.

The expression k = 0.63/ t1/2 also indicates that, just like the half life, the decay constant is independent of the concentration or starting amount of the nuclide or the temperature and that it remains constant throughout the decay process.

The decay constant can then be used to calculate how much radioisotope will be left or has decayed after a certain amount of time has elapsed. This amount can also be expressed as a percentage.

The expression to be used is ������t= ������0(0.5)t/k (see also IB data booklet page 2)

Nt = amount/concentration/activity after time t

N0 = initial amount/concentration/activity

t= time

k = decay constant (k = 0.693/t1/2 )

Exercises

MRI

MRI uses the same principles as NMR as the scans use very powerful magnets to detect not just H-1 but also C-13, Na-23, He-3 and P-31 nuclei and also use low frequency radio waves that are not ionizing. The radiowaves absorbed by the nuclei are detected and used by computers to produce 2D or 3D images of internal organs or body parts.

D9 Drug detection and analysis

E.I.: A variety of analytical techniques is used for detection, identification, isolation and analysis of medicines and drugs.

Nature of science Advances in instrumentation—advances in technology (IR, MS and NMR) have assisted in drug detection, isolation and purification. (3.7)

|Understandings |

|D.9 U1 Organic structures can be analysed and identified through the use of infrared spectroscopy, mass spectroscopy and proton NMR. 
 |

|D.9 U2 The presence of alcohol in a sample of breath can be detected through the use of either a redox reaction or a fuel cell type of breathalyser. 
 |

|Applications and skills |

|D.9 AS1 Interpretation of a variety of analytical spectra to determine an organic structure including infrared spectroscopy, mass spectroscopy and proton |

|NMR. 
 |

|D.9 AS2 Description of the process of extraction and purification of an organic product. Consider the use of fractional distillation, Raoult’s law, the |

|properties on which extractions are based and explaining the relationship between organic structure and solubility. 
 |

|D.9 AS3 Description of the process of steroid detection in sport utilizing chromatography and mass spectroscopy. 
 |

|D.9 AS4 Explanation of how alcohol can be detected with the use of a breathalyser. 
 |

Analysis of organic structures using chromatography, IR, mass spectroscopy and 1H NMR

IR, mass spectrometry and 1H NMR can be used to detect banned or illegal chemicals such as steroids in sport as they function as performance-enhancing drugs.

Gas chromatography

Gas chromatography can be used to separate and identify the components in a mixture such as blood and urine. This technique relies on the different components in the mixture (blood, urine, …) having different affinities for two different phases, a mobile phase (a gas medium) and a stationary phase (made up of a liquid). The affinity of a component towards the mobile phase and towards the stationary phase depends on its boiling point/volatility and its solubility in both the gas and the liquid and determines the rate at which it passes through the stationary phase.

The mixture sample is heated (boiling point) and mixed with the gas phase (solubility) and injected in the gas chromatography column. Each component travels though the column at a rate depending on their volatility and solubility in both phases.

A detector measures the time that is called the retention time; this is amount of time between injection time (t=0 on the gas chromatogram) and the time a component is eluted. The retention time is recorded as peak on the gas chromatogram. The area underneath the peak indicates the concentration of the component

The retention times for a variety of compounds are known and the component can therefor be identified although identification can also be completed using the fragmentation pattern obtained using mass spectrometry. (see 11.3)

Extraction and purification of organic products

Differences in solubility in different solvents and different boiling points are two physical properties that are often used in the extraction of a pure drug from a mixture produced as a result of a synthesis.

Order of increasing boiling points/decreasing volatility in different classes of organic compounds

Comparison of boiling points of compounds of corresponding or very similar mass.

The main factor is the strength of the intermolecular forces BETWEEN the molecules. The weaker the intermolecular forces, the lower the boiling point and the more volatile a compound is.

|Homologous series |Type of intermolecular force |

|Lowest boiling points |ALKENES |Non-polar molecules |

| | |Weak Van der Waals’ forces |

| | | |

| | | |

| | | |

| | | |

| | | |

|Least volatile/highest boiling point | | |

| |ALKANES | |

| |HALOGENOALKANES |Polar molecules |

| | |dipole-dipole attraction) |

| | | |

| |ALKANALS | |

| |KETONES | |

| |AMINES |HYDROGEN BONDING |

| | |(INCREASED POLARITY OF HYDROGEN) |

| |ALCOHOLS | |

| |CARBOXYLIC ACIDS | |

As alkanes and alkenes are non-polar their intermolecular forces are weak and as a result their melting and boiling points are low for their molar mass. Halogenoalkanes, esters and aldehydes and ketones (less than aldehydes) have a greater degree of polarity.

In the other functional groups hydrogen bonds are responsible for a greater attraction between the molecules; although there are differences in the number and magnitude of the hydrogen bonds. Carboxylic acids have stronger hydrogen bonds than amines and alcohols as each acid molecule has 2 sites to make hydrogen bonds; they also tend to form dimers.

Differences in solubility between the different classes of organic compounds

Polarity of the structure of molecules determines their solubility in polar and non-poar solvents. Non-polar molecules have very low solubility in water but higher solubility in other non-polar solvents.

Molecules with a polar structure are very soluble in water but have low solubility in non-polar solvents. Molecules that can hydrogen bond have the highest solubility in polar solvents.

|low solubility |soluble |high solubility |

|(non-polar molecules) |(dipoles) |(hydrogen bonding) |

|alkanes/alkenes |aldehydes/ketones |alcohols |

| | |carboxylic acids |

| |halogenoalkanes |amines |

Solubility generally decreases as molecules get longer; this is because the non-polar alkane ends cancel out the effect of dipole or hydrogen bonds.

Solvent extraction uses difference in solubility in different solvents

Examples of solvent extraction:

• Extraction of aspirin using ethanol

• Extraction of penicillin using trichloromethane.

The separation can be carried out using a separating funnel.

Fractional distillation uses differences in volatility

See information sheet on Fractional distillation and Raoult’s Law or pages 918 to 921 in your textbook.

Detection of ethanol using a breathalyzer

• Only used for detection of ethanol 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 acidified potassium dichromate(VI), an oxidizing agent.

• There is a direct relationship between the alcohol content in exhaled air and the alcohol content in the blood.

• In a positive result (i.e. presence of ethanol) the potassium dichromate changes form orange (Cr VI or +6) to green (Cr III or =3) as the chromium in the potassium dichromate is reduced by the ethanol and the ethanol (C= -2) itself oxidized to ethanal (C= -1) and ethanoic acid (C= 0). The extent of the colour change corresponds to a particular ethanol concentration.

• Equations:

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

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

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

Detection of ethanol using a fuel cell

A fuel cell is an electrochemical that consists of 2 platinum electrodes and an acid electrolyte and can also be used to measure the ethanol concentration.

The breath is blown over the cell and any ethanol is oxidized to ethanoic acid and H2O at the anode releasing electrons that produce an electrical current to the cathode where oxygen is reduced to water as shown by the overall equation: C2H5OH + O2 → CH3COOH + H2O

The voltage of the current can be used to measure the concentration.

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