Option D.8 – Drug Action
D.8.1 – Describe the importance of geometrical isomerism in drug action.
Geometric isomers have different arrangements around a double bond and have two forms:
- cis– isomers are when the functional groups are found on the same side of the double bond
- trans– isomers are when the functional groups are found on different sides of the double bond
These isomers have different physical properties and can undergo different chemical reactions, giving them different pharmacological effects. Although the concept of geometric isomerism is discussed in the organic chemistry unit, it can also occur in inorganic complexes.
Cisplatin
This is an inorganic complex that acts as an anti-cancer drug, with the full name cis-diamminedichloroplatinum(II) – Pt(NH3)2Cl2. Since it is the cis– isomer, it is a polar compound, making it water soluble.
Cancer is when a mutation has occurred in the DNA of cells,causing them to replicate uncontrollably and form tumours. This drugs acts to form cross-links along the DNA strand, creating a bend in the chain, thereby preventing the replication of damaged DNA of a cancer cell. Although the drug will also affect normal cells, they can repair the damage. On the other hand, cancer cells will be destroyed by the immune system.
The drug reacts with water to form ions, then bind to the nucleic base guanine. Since the shape of the DNA molecule changes, the body recognises the problem and this activates the repair of the DNA.
The trans– isomer does not have the same effect on the DNA, which means that it is not effective for preventing cancer. This is because it needs to have the functional groups on the same side to be able to make the two bonds along the DNA helix.
D.8.2 – Discuss the importance of chirality in drug action.
Optical isomers are the mirror image of one another, so that their structures cannot be superimposed. These are called chiral molecules, and their different structures are called enantiomers. When optical isomers are present in solution, they can be sorted using plane-polarised light. The molecules receive the prefix dextro- or levo– depending on whether they cause the light to rotate to the right or left. This variation in structure affects the pharmaceutical action of the compound.
The difference in the action of optical isomers is often related to the binding of the drug to a certain sites. Given that their structure is slightly different, some of the isomers might not fit a receptor, thus having no effect. The body is therefore very specific in the production of such chemical, and will only produce on enantiomer. However, when drugs are synthetically produced, they will produce a range of racemates. Part of the research and development process will hence include analysing the other enantiomers to ensure that they are not detrimental to the body.
In some cases, one of the isomers is inactive and does not affect the patient at all. The drug can be sold as a racemic mixture because only one is active, and the other will not be harmful to the patient. However, the other enantiomers can sometimes have detrimental effects on the patient. If a drug is found to have a harmful isomer mixed into it, then it will not be allowed to be sold.
Thalidomide
This drug was sold to pregnant women to give relief from morning sickness. However, there are two enantiomers of the drug that were present in a racemic mixture – one that gives relief, and the other, which causes deformities in the limbs of the foetus, along with other birth defects.
However, further research into the action of the drug has shown that it has other applications, including suppressing cancer tumour growth and treatment of HIV and leprosy.
D.8.3 – Explain the importance of the beta-lactam ring action of penicillin
Penicillin contains a β-lactam ring. Being composed of only four atoms, the ring is unstable and very reactive. The bond angles are not the preferred ones, putting strain on the bonds and making them weaker. As a result, when the molecule comes into contact with bacteria, it will covalently bond with the enzyme that forms the cell wall of the bacteria, called transpeptidase, and blocks its action. The crosslinks cannot be formed properly. Over time, the cell wall will degrade until the cell bursts. Penicillin essentially acts as a non-competitive inhibitor to this enzyme.
Bacteria that are resistant to penicillin contain enzymes that open this ring, preventing the action of penicillin.
D.8.4 – Explain the increased potency of diamorphine (heroin) compared to morphine
Morphine and heroin both have similar action on the brain, acting as narcotics and analgesics. However, heroin is more potent than morphine, and much more addictive. Heroin is derived from morphine, and is formed when the polar hydroxyl groups of morphine are replaced with non-polar ester groups. The brain is protected by the blood-brain barrier, but the non-polar nature of heroin makes it lipid soluble, and able to cross the barrier. This easier access is the reason it is more powerful than morphine.
Essentially, heroin is more effective at getting to its receptors in the brain. Its structure is more suited for the conditions of the central nervous system. Heroin binds to the opiod receptors, preventing the brain from receiving pain signals. However, the increased effectiveness of heroin also leads to the higher likelihood of tolerance and addiction.
Before heroin can act on the brain, it is hydrolysed by enzymes called esterases, changing it back into the structure of morphine, thus acting the same way. So, heroin is really just the “package” that allows morphine to get into the brain faster and in higher concentrations