Pharmacogenetics_The science of personalized medicine

One of the Pharma Literati interns for 2018 is involved in writing blog articles for us. Here comes the first of the series on Pharmacogenetics.

PHARMACOGENETICS

The man, all sweaty and troubled asks the pharmacist, "I did not have any of the listed side effects. Should I be worried?"

The pharmacists' composed reply, "You're unique!"

The retort, "Am I?" The man was all boiling.

My question, "Is he unique?"

Well let’s find out!

Pharmacogenetics is the study of inherited genetic differences in drug metabolic pathways which can affect individual responses to drugs, both in terms of therapeutic effect as well as adverse effects. The idea shadowed is that a person's genes influence their responses to medicinal drugs.

The term, pharmacogenetics can be interchanged with the term pharmacogenomics. This relatively new field allows us to combine pharmacology and genomics to develop effective and safe medication dosages which are specific to an individual’s DNA makeup. Wow!

It is hence, concluded that the tailoring of the drug treatments to an individual genetic make up, a form of personalized medicine.

The boon: Minimalization of the side effects from the drugs.

The study of pharmacogenetics originated in the mid-20th century. In those days, primaquine-induced haemolysis was associated with glucose-6-phosphate dehydrogenase (G6PD) deficiency. In this deficiency, the pentose phosphate cascade in erythrocytes is blocked, resulting in a reduction in the synthesis of reduced glutathione. Reduced glutathione protects erythrocytes against several drug-induced oxidation reactions, thereby preventing haemolysis. A decrease in the availability of reduced gluthation increases the risk of haemolysis, especially in the presence of certain drugs such as primaquine.

Before technology allowed the determination of individual genetic variation, pharmacogenetics was mainly based on gross ethnic variation. Primaquine-induced haemolysis was particularly prominent among African Americans and people originating from the Mediterranean area with G6PD deficiency and diagnosed by means of enzymatic assays.

With the introduction of the polymerase chain reaction (PCR), isolation of individual genetic variations became possible. One of the first examples was the discovery of different subtypes of the enzyme N-acetyl transferase-2 (NAT-2); this is a phase-II enzyme that is relevant in the metabolic pathway of the antituberculosis drug, isoniazid. In some patients, known as “slow acetylators”, sustained high plasma levels of isoniazid with a “normal” dosage causes peripheral neuropathy and liver toxicity. The difference in isoniazid-metabolising capacity between normal acetylators and slow acetylators was found to be the result of differences in base sequence within the DNA segment encoding for the synthesis of NAT-2.

Let us direct ourselves towards the evidences, and the witnesses too.

1. The beautiful tale of Vitamin E.

It has been lit that vitamin E can be used, in certain genotypes, to lower the risk of cardiovascular disease in patients with diabetes, but in the same patients with another genotype, vitamin E can raise the risk of cardiovascular disease. A study was carried out, showing vitamin E is able to increase the function of HDL in those with the genotype haptoglobin 2-2 who suffer from diabetes. HDL is a lipoprotein that removes cholesterol from the blood and is associated with a reduced risk of atherosclerosis and heart disease. However, if you have the misfortune to possess the genotype haptoglobin 2-1, the study shows that this same treatment can drastically decrease your HDL function and cause cardiovascular disease.

The Pharmacogenetic Tool assists in predicting which drugs will be effective in various patients.

2. The drug Plavix blocks platelet reception and is the second best selling prescription drug in the world, however, it is known to warrant different responses among patients.

In toto, be-aware and beware of your own self!

The human genome contains all the hereditary information and is encoded in DNA- embedded macromolecules called chromosomes. Each human cell contains a total of 23 pairs of large linear nuclear chromosomes, giving a total diploid number of 46 per cell (23 originating from the father and 23 from the mother). DNA includes both a functional and a non-coding sequence (99% of the human DNA is not functional, as far as we know). The functional part of DNA, which codes for the synthesis of a protein, is called a gene. A difference in base sequence within DNA is referred to as a mutation. Most mutations are clinically irrelevant because they do not lie within the functional part of DNA. The field of pharmacogenetics is only concerned with mutations affecting gene function. Because of mutations, several variations called alleles, exist for each gene. If mutant alleles are prevalent in more than 1% of the normal population, they are called polymorphisms. Because of this, mutant alleles, as a consequence of spontaneous mutations, are excluded from the definition “polymorphism”. The most elementary polymorphism is called a single nucleotide polymorphism (SNP [pronounced SNIP]). SNPs are single mutations that differ by only one base pair from the most prevalent allele called “wild type”.

Pharmacogenetics focuses in particular on polymorphisms encoding for:

1. Proteins affecting pharmacokinetic parameters (drug metabolising enzymes or transporter proteins)

2. Proteins affecting pharmacodynamic parameters (receptors or ion channels)

3. Proteins affecting the pathogenesis of disease.

Much of current clinical interest is at the level of pharmacogenetics, involving variation in genes involved in drug metabolism with a particular emphasis on improving drug safety. The wider use of pharmacogenetic testing is viewed by many as an outstanding opportunity to improve prescribing safety and efficacy. As pharmacogenetics continues to gain acceptance in clinical practice, when to utilize pharmacogenetics will be of importance in advancing patient care.

However, a coin has two sides.

Pharmacogenetics has become a controversial issue in the area of bioethics. There are three main ethical issues that have risen.

Pharmacogenetics is believed to account for inter-ethnic differences (e.g., between patients of Asian, Caucasian and African descent) in adverse events and efficacy profiles of many widely used drugs in cancer chemotherapy.

The pharmacogenetic motto!

The Right Drug for

The Right Patient and

The Right Dosage!

With Genes, Mutations happen.

Genes load the Gun, while the Environment pulls the trigger.