As we learned in pharmacology, the drug upon reaching the site of action, it gives a certain response. However, what if that response varies among individuals in terms of potency, duration or even adverse effects. As an example, in 1950s it has been noticed that Caucasians show prolonged effects to suxamethoniun chloride where further investigations revealed that 1 in every 3500 Caucasians has a less efficient butyryltranseferase, that metabolizes suxamethonium chloride, thus showing prolonged half-life & slower recovery from surgical paralysis. This fact has led to the emergence of a very unfavourable term “especially to clinicians”, Idiosyncrasy, which means the abnormal response to drugs, food & toxic agents that is peculiar to an individual. However, understanding the basic underlying mechanisms that led to this variation, made the scientists realize that in this case,  the drug response is not only a matter of pharmacodynamic effects but is considered as a ring holding pharmacology at one side and the genetic make up (which is the DNA sequence of any protein dealing with the drug as receptors, carriers, metabolizing enzymes………, etc) at the other side. This understanding led the scientists to replace the old term of Idiosyncrasy with a better descriptive term known as pharmacogenetics.

image credit: www.medigenomix.de/

Variations in the genetic make up are diverse in types. The most common type is Single Nucleotide Polymorphisms (SNPs) which are single nucleotide substitutions that can be found in coding and non-coding regions in the DNA sequences of protein systems dealing with the drug. Another form of variation can be chromosomal aneuploidy as Trisomy, where an extra copy of a chromosome, carrying a gene coding for any protein system dealing with the drug, will in turn lead to response variation. As an example for that is in leukemic patients with down syndrome, since there is a third copy of chromosome 21 which bears Reduced folate Carrier gene that codes for the transmembrane Reduced Folate carrier system which is responsible for the of transport methotrexate inside the cell, thus having a third extra copy of this gene leads to the over expression of RFC & methotrexate toxicity due to high levels of intracellular methotrexate.                                

Now, with the fact that the genetic make up of an individual dictates the response has been laid down, the clinical application has become a consequent step. For example, regarding leukemic patients having down syndrome, as mentioned previously, they are highly predisposed to methotrexate toxicity & thus as a routine, these patients should be set on lower doses of methotrexate. This particular example is a little bit simple that is easily characterized by the well known phenotype of down syndrome patients. However, translating the basic knowledge of pharmacogenetics to useful clinical guidelines is a more complicated approach in terms of both characterizing the alteration in the genetic make up and the subsequent clinical decision regarding the choice of the drug, dose and the dosing schedule. For instance carrying out a SNP Genotyping for DNA sequencing and identification of SNPs is a difficult matter as SNPs are very scattered along the human genome, where it has been estimated that every 1,ooo base pair, one SNP is found. In addition, the functional characterization of this SNP on the protein level is a matter of complexity that requires well controlled studies (i.e. all other causes of response variation regarding the drug of interest are eliminated).

Inspite of the complexity of the investigations for clinical application, it is a productive promising approach that does have three positive impacts on the clinical application where upon the tailoring of the treatment protocol according to each patient genetic make up (individualized therapy), this will increase the efficiency of the medications, decrease side effects, adverse drug reactions, morbidities Image credit:& mortalities and thus reduce the finances of the clincal mangement of adverse drug reactions as well as toxicities that may be result from incompatibility of the drug with the genetic make up of the patient.

http://www.pharmacogeneticsinpsychiatry.com

Read the rest of this entry »