Option D: Medicinal Chemistry Flashcards
What do medicines and drugs do?
One of the following:
- Alter incoming sensory sensations
- Alter a person’s mood or emotions
- Alter the physiological state of the body including consciousness and coordination
Drug
A substance that causes a physiological change in the body
Pharmaceutical drugs
Used for the treatment or prevention of disease.
Medicines contain beneficial drugs.
Recreational drugs
Chemical substances taken for enjoyment or leisure purposes rather than for medical reasons
Example include alcohol, nicotine, cannabis and ecstasy
Therapeutic effect
The beneficial effect of a medicine
Methods of drug administration: Oral
Taken by mouth
e.g tables, capsules, pills
Methods of drug administration: Inhalation
Vapour breathed in or smoking
e.g asthma medication or drugs such as nicotine
Methods of drug administration: Skin patches
Absorbed through the skin into the blood
e.g hormone patches
Methods of drug administration: Suppositories
Inserted into the rectum
e.g laxatives for constipation
Methods of drug administration: Eye or ear drops
Liquids administered into eyes or ears
e.g treatment of eye or ear infections
Methods of drug administration: Injection (parenteral)
Injected into the muscle, blood, or under the skin
e.g vaccines and local anaesthetics
Parenteral methods of drug administration: intramuscular
Drug is injected directly into the muscle
Parenteral methods of drug administration: subcutaneous
Drug is injected directly under the skin into the subcutaneous tissue
Parenteral methods of drug administration: intravenous
Drug is injected directly into the blood stream.
This method has the most rapid effect as the drug is injected directly into the blood
Bioavailability
The fraction of the administered dosage of a drug that enters the bloodstream thereby accessing the site of action
Factors that effect the bioavailability
- The method of drug administration
- The polarity (solubility) of the drug
- The type of functional groups present in the drug
Bioavailability of drugs that are administered intravenously
Drugs that are administered intravenously have a bioavailability of 100% as they are delivered directly into the bloodstream
Bioavailability of drugs that are administered orally
Drugs that are administered orally are often broken down during digestion before reaching the bloodstream.
In general, an oral dose of a drug needs to be about four times higher than the dosage of the same drug that is administered intravenously.
How does the polarity of a drug affect its solubility
Very hydrophilic (polar_ drugs are soluble in aqueous body fluid but are poorly absorbed because of their inability to cross cell membranes (composed of lipids)
Very hydrophobic (non polar) drugs are also poorly absorbed because they are insoluble in aqueous fluids
For a drug to be readily absorbed it must be largely hydrophobic (non-polar) but also have some solubility in aqueous solutions.
How do functional groups affect solubility of a drug
A functional group’s ability to ionise and a functional group’s ability to form hydrogen bonds contribute to the water solubility of a functional group.
Carboxyl groups, hydroxyl groups and amine groups all have the ability to form hydrogen bonds with water molecules.
In addition, carboxyl groups are acid and amine groups are basic. Both of these groups can form ions therefore increasing the solubility of a drug.
Functional groups that enhance the lipid solubility of a drug
These functional groups are non-polar. They lack the ability to ionise or to form hydrogen bonds.
examples are phenyl groups and alkyl groups.
Bioavailability of aspirin
Aspirin is a largely non-polar molecule and therefore has low solubility in water
It has a carboxyl group, a phenyl group, and an ester group.
The solubility of aspirin can be increased by reacting it with aqueous NaOH to form an ionic salt (increasing bioavailability)
Bioavailability can be increased by administering aspirin intravenously.
Therapeutic window
The therapeutic window is a measure of the safety of a drug
The wider the therapeutic window, the safer the drug.
A wide therapeutic window means that there is a wide margin between doses that are effective and doses that are toxic.
A narrow therapeutic window means that only a small increase in the effective dose may produce toxic effects.
Therapeutic index
The ratio between the dosage of a drug that causes a toxic effect and the dosage that causes a therapeutic effect
Therapeutic index in humans is calculated by dividing the median toxic dose by the median effective dose
Therapeutic index in animals is calculated by dividing the median lethal dose by the median effective dose
Drug development
Main stages of drug development:
- Drug is synthesised in lab
- The drug is tested on animals to determine the LD 50
- The drug is tested on humans - half of the group are given the real drug, the other half are given a placebo. This placebo contains none of the drug being tested.
- This is done double-blind
Placebo effect
When the body is fooled into healing itself naturally
Factors that must be determined during clinical drug trials
- Risk : benefit ratio - balance between the risks and benefits of the drug
- Unwanted side effects
- Drug tolerance - person needs to take ever larger qu’altistes of a drug to gain the original effect
Synthesis of aspirin
Aspirin is produced by reacting salicylic acid with ethanoic anhydride
Salicylic acid is converted to aspirin through esterification, which is a condensation reaction.
The catalyst in the reaction can be either concentrated sulphuric acid or phosphoric acid
Uses of aspirin
Aspirin is a mild analgesic.
Mild analgesics block the sensation of pain at the source. Aspirin works by blocking the action of the enzymes that produce prostaglandins.
Prostaglandins are involved in the transmission of pain impulses to the brain, as well of causing fever and swelling.
Aspirin prevents the prostaglandins from being synthesised, thereby reducing or eliminating the pain.
Aspirin is also used as an anticoagulant.
Anticoagulants are a class of drugs that work to prevent the blood from clotting.
They are effective in the prevention of the recurrence of heart attacks and strokes.
Due to its anti-inflammatory properties, aspirin is also taken for arthritis and rheumatism.
Side effects of aspirin
The most common side effect of aspirin is that it can cause bleeding of the lining of the stomach.
This effect is increased by drinking alcohol as the same time as taking aspirin, which is known as a synergistic effect.
Two drugs can have a synergistic effect if they increase each other’s effectiveness when taken together.
The synergistic effects of alcohol and aspirin can cause increased bleeding of the stomach lining.
Discover of penicillin
Penicillins are a group of antibiotics used to treat a range of bacterial infections.
They are derived from Penicillium fungi and can be taken orally or via injection.
Penicillin was discovered in 1928 by Sir Alexander Fleming, a Scottish microbiologist, whilst working with bacteria cultures.
He noticed that a fungus had contaminated some of his cultures and left a clear region where no bacteria colonies were growing.
Fleming came to the conclusion that something in the fungus was inhibiting the growth of the bacteria.
Despite Flemings’ discovery, it wasn’t until the 1940s that the true potential of penicillin was realised when it was used to save thousands of lives in WW2.
Penicillin mode of action.
Penicillins (beta-lactam antibiotics) are characterised by the presence of a beta-lactam ring.
The beta-lactam ring is the part of the molecule responsible for penicillin’s anti-bacterial properties.
Beta-lactam antibiotics interfere with cell wall formation in bacteria by inhibiting the enzymes responsible for creating cross-links in the cell wall.
When the beta-lactam ring comes into contact with the bacteria, the ring opens and binds irreversibly to the enzyme responsible for catalysing cross-linking in the cell wall of the bacteria.
Water enters the cell, increasing the osmotic pressure inside the cell, causing it to burst
Why are beta-lactam rings fragile?
In a beta-lactam ring:
- Two C atoms and the N atom are sp3 hybridised (bond angle of 109.5)
- One C atom in the ring is sp2 hybridised (bond angle of 120)
Then one angles in the ring are reduced to about 90 degrees, which puts a strain on the bonds. Due to the strain, it breaks relatively easily
Antibiotic resistance
The ability of bacteria to resist the effects of an antibiotic
Bacterial resistance is caused by the misuse or overuse of antibiotics
Examples of misuse include the over-prescription of penicillin for minor illnesses and the failure of patients to complete the course of antibiotics as prescribed by the doctor
How are side-chains used to reduce anti-bacterial resistance
Modified penicillins are able to withstand the action of the penicillinase enzyme.
For treating certain diseases like TB, a ‘cocktail’ of different types of antibiotics are required.
The bacteria that cause TB are extremely resistant to penicillin therefore a mixture of different antibiotics must be used.
How are side-chains used to reduce the effects of stomach acid
The side chan can also be modified to give increased resistance to breakdown by stomach acid, which means that the antibiotic can be taken orally.
Penicillin G had to be injected as it was broken down by stomach acid.
Ampicillin is a modified penicillin and can be taken orally.
Strong analgesics
Morphine and codeine are example of opiates and are used as strong analgesics.
Opiates are natural analgesics that are derived from opium- found in poppy seeds
Strong analgesics are given to relieve severe pain caused by injury, heart attacks, or diseases such as cancer
How do opiate analgesics work?
They work by temporarily bonding to receptor sites in the brain, preventing the transmission of pain impulses without depressing the central nervous system.
Opiate analgesics and side effects
Opiate analgesics can cause side effects and can lead to dependency and addiction.
For these reasons, they are only available on prescription and their usage is monitored through medical supervision.
Advantages of strong analgesics
- Strong analgesics provide relief for acute or extreme pain
- They have a wide therapeutic window
- They can relieve anxiety, induce relaxation, or improve the quality of life
- Because they are administered intravenously there is a faster distribution of the drug
Disadvantages of strong analgesics
- Users feel euphoria, a lack of self-control, and can indulge in dangerous behaviour
- Regular usage can lead to addiction, dependence, and withdrawal symptoms
- Users build up a tolerance to the drug with increased risk of overdose upon prolonged use
- Increased risks associated with intravenous drug administration
Blood-brain barrier
A layer of tightly packed cells that protect the brain by restricting the passage of substances from the bloodstream into the brain
It is largely composed of lipids which are non-polar, hydrophobic molecules
The blood-brain barrier is not easily crossed by polar, hydrophilic molecules
For a drug to penetrate the blood-brain barrier and enter the brain, it must be non-polar and lipid soluble
What do the analgesic properties of opiates depend on?
Their ability to move from the blood, where aqueous solubility is important, to the brain, where lipid solubility is important to cross the blood- brain barrier.
Opioid receptors
Once in the brain, opiates attach to opioid receptors. When opiates attach to the opioid receptors, they reduce the perception of pain.
Differences in structures of codeine, morphine, and diamorphine
Codeine has one hydroxyl group and morphine has two hydroxyl groups
Codeine has two ether groups whilst morphine and diamorphine only have one
Diamorphine has two ester groups whilst morphine and codeine have none
What are the implications of morphine having two hydroxyl groups
The presence of the two hydroxyl groups make it a polar molecule.
Polar molecules are more soluble in water, but less soluble in lipids which limits their ability to cross the blood-brain barrier
Synthesis of diamorphine
Diamorphine is produced from morphine in an esterification reaction in which both OH groups are converted into ester groups
In the reaction, morphine reacts with ethanoic acid or ethanoic anhydride to produce diamorphine
The two hydroxyl groups are turned into ester groups.
This makes the diamorphine less polar- making it more lipid soluble. This means that it is able to cross the blood-brain barrier more rapidly- as a result it is much more potent than morphine, but its effects do not last as long
Synthesis of codeine
Codeine is produced from morphine in a methylation reaction.
In the reaction, an OH is converted into a methoxy group.
This reaction makes codeine a less polar molecule than morphine and therefore more able to cross the blood-brain barrier
However this reaction also reduces the ability of codeine to bond at the opioid receptors, which makes codeine a weaker analgesic than morphine
Antacids
Used to reduce excess stomach acid.
The stomach contains HCl that kills bacteria in food and provides the optimum pH for digestive enzymes.
Excess stomach acid can cause health effects such as acid indigestion, heartburn, and stomach ulcers.
Antacids work by neutralising the excess acid in the stomach
They are weak bases such as calcium hydroxide, magnesium hydroxide, aluminium hydroxide, sodium carbonate, and sodium bicarbonate
Strong bases should not be used as they are harmful to the body.
Alginates
A group of medicines called alginates are found in some brands of antacid medication
They produce a neutralising layer which prevents acid in the stomach from rising into the oesophagus.
Stomach acid inhibitors
Stomach acid inhibitors inhibit the production of stomach acid.
Proton pump inhibitors (PPIs) and H2 receptor antagonists (H2 blockers) are both stomach acid inhibitors.
PPIs inhibit the proton pumps in the stomach.
H2 blockers work by blocking the histamine receptors in acid-producing cells in the stomach.
Proton pump
The gastric proton pump pumps protons into the stomach.
PPIs inhibit the proton pump which prevents the release of protons into the stomach
PPIs have a longer lasting effect (up to 3 days)
They are used to treat stomach ulcers and also provide relief from the symptoms of acid-reflux
H2 blockers
Reduce the amount of acid produced by the cells in the lining of the stomach.
Histamine stimulates the secretion of stomach acid by interacting at H2 receptors in the stomach lining.
H2 blockers compete with histamine for binding at the H2 receptors.
They block the interaction between histamine and the H2 receptors, preventing the release of stomach acid.
Comparing stomach acid inhibitors
Both PPIs and antacids relieve the symptoms of acid reflux, heartburn and indigestion.
PPIs inhibit the production of stomach acid and antacids neutralise the excess acid in stomach
PPIs have longer-lasting effects than antacids
Calculating concentration of buffer solution
Use the Henderson-Hasselbalch equation (found in section 1 of the data booklet)
Viruses
Viruses are sub-microscopic organisms that replicate inside the living cells of other organisms.
They have two main components- a protein coat, and nucleic acid (either DNA or RNA).
Viruses do not carry out metabolic processes and are considered to be non-living.
They derive their energy from the host cell.
Bacteria
Bacteria are single-called microorganisms
Unlike viruses, bacteria are self-reproducing units (they do not require a host to reproduce)
Bacteria contain various cell subunits together with a cell wall
Bacteria carry out metabolic processes and are considered to be living
Comparing viruses and bacteria
Bacteria are self-reproducing units while viruses need living hosts to multiply.
Bacteria carry out metabolic processes while viruses do not.
Bacteria contain organelles that perform specific functions while viruses consist only of generic material and a protein coat.
Bacteria are many times larger than viruses.
Antiviral drugs
Viruses lack a cell structure and so are more difficult to target with drugs than bacteria.
Antibiotics are effective against bacteria and work by disrupting the formation of the bacteria cell wall.
They are ineffective against viruses because they lack a cell wall.
Viral infections are treated buy medicines known as antivirals.
Reasons that viruses are more difficult to treat than bacteria
- Viruses mutate quickly so adapt to drugs
- Bacteria are more complex and can be targeted in more ways, whereas viruses lack subunits that can be targeted by antibacterials
- Bacteria can be killed by simple chemical agents but viruses must be targeted on a genetic level
How do antiviral drugs work
- Alter the cells genetic material so that the virus cannot use it to multiple
- Prevent viruses from multiplying by blocking enzyme activity within the host cell
- Bind to cellular receptors targeted by viruses
- Prevent or hinder the release of viruses from the cell
Oseltamivir and Zanamivir
Oseltamivir and Zanamivir are both used as antivirals to prevent the spread of the flu virus.
Zanamivir is taken by inhalation due to its low bioavailability when taken orally.
Oseltamivir can be taken orally as its bioavailability is not affected by this method of administration.
Comparing structures of Oseltamivir and Zanamivir
Oseltamivir has an alkenyl group, a carboxamide group, amine group, ester group, and ether group
Zanamivir has an alkenyl group, a carboxamide group, amine group, ether group, carboxyl group, 3 hydroxyl groups
The presence of the hydroxyl groups in Zanamivir makes it more soluble in polar solvents than Oseltamivir.
How do oseltamivir and zanamivir work?
By inhibiting the enzyme neuraminidase by binding to its active site.
Neuraminidase is an enzyme found on the surface of the influence virus that enables the virus to be released from the host cell.
By inhibiting this enzyme, the virus is prevented from leaving the host cell and cannot infect other cells.
The difficulties associated with treating HIV
- HIV destroys T-cells (the cells that protect the body from infection)
- HIV can mutate rapidly
- HIV uses host cells to replicate
- Drugs used to treat HIV may also harm the host cell
- High price of antiretroviral drugs
Sociocultural factors related to the AIDS problem
- Condom use (the availability, cost, or cultural resistance)
- Cultural factors (ignorance, misinformation, social stigma)
- Illegal activities (drug use, prostitution)
- Resources / medical factors (availability of medical services, cost of drugs)
Radioactive waste
Can be classified as low-level, intermediate-level or high-level waste.
High-level waste gives off large amounts of ionising radiation for a long time (long half-life).
Low-level waste gives off small amounts of ionising radiation for a short time (short half-life).
Low-level waste: examples and disposal methods
Examples:
- Gowns / protective clothing
- Shoe covers
- Tissues / needles
- Mops
Disposal method:
- Stored in shielded containers until the isotopes have decayed and then disposed of as non-radioactive waste
Intermediate-level waste: examples and disposal methods
Example:
- Radioactive sources (cobalt-60 and caesium-137)
Disposal method:
- Stored in shielded containers in underground repositories
Antibiotic waste
Antibiotics are released into the environment in three ways:
- The use of antibiotics in animal feeds (carry antibiotics into the soil and ground water)
- Improper disposal of antibiotic medicines by hospitals and households
- Antibiotics excreted in human urine (enter the sewage system at low concentrations. Then they can end up in the drinking water supply)
Solvent waste
The majority of medicines and drugs are produced by chemical synthesis.
The production of these medicines and drugs requires multiple steps such as reaction, separation, and purification to form the end product.
Solvents are used as reaction media and in product recovery and purification
These solvents must be disposed of carefully to avoid causing harm to the environment
Green Chemistry solvent guide:
Preferred solvents: (white people eat my eggs)
- Water
- Propan-1-ol
- Ethyl ethanoate
- Methanol
- Ethanol
Useable: (certain objects end every morning)
- Cyclohexane
- Octane
- Ethanenitrile
- Ethanoic acid
- Methyl benzene
Undesirable: (people dont do their chores)
- Pentane
- Dichloromethane
- Dichloroethane
- Trichloromethane
- Carbon tetrachloride
VOCs
Many undesirable solvents are VOCs
VOCs are used as solvents due to their high volatility (easy to remove by evaporation)
They have the potential to cause nose and throat discomfort, nausea and fatigue.
They can also result in the formation of low level ozone and smug
Principles of green chemistry
- Prevent waste
- Maximise atom economy
- Design less hazardous chemical syntheses
- Design safer chemicals and products
- Use safer solvents and reaction conditions
- Increase energy efficiency
- Use renewable feedstocks
- Avoid chemical derivatives
- Use catalysts, not stoichiometric reagents
- Design chemicals and products to degrade after use
- Analyse in real time to prevent pollution
- Minimise the potential for accidents
Green chemistry: problems associated with the production of oseltamivir
Oseltamivir is used as an antiviral to prevent the spread of the flue.
The synthesis requires shikimic acid- extracted from star anise pods
Star anise has a limited worldwide supply- in 2005 a shortage was caused by its use in the productive of the drug.
Another shortage in 2009 caused by the swine-flu outbreak caused the price of star anise to increase dramatically
The synthesis requires a complex ten-step process. The time required for its production is between 6-8 months. 30kg of star anise produces only 1 kg of shikimic acid.
Green chemistry: advancements to the production of oseltamivir
- The production of shikimic acid from the fermentation of genetically engineered bacteria
- The extraction of shikimic acid from pine needles
