PHARMACOGENETICS

Introduction

• Individuals have always differed in how they respond to drugs. The ways in which patients respond to a particular drug is too often unpredictable; responses range from little or no therapeutic benefit to harmful adverse drug reactions.

Introduction

• The advent of molecular genetics and the dramatic development of genomic technologies have made it possible to consider the effect of a patient’s underlying genetic makeup on drug response.

• This is true despite the massive complexity of the human genome, which has more than three billion gene coding letters. However, neither the term pharmacogenetics nor the field it represents are recent phenomena.

History• The term itself was coined in

1959 by Vogel, a German geneticist, 94 years after an Augustinian priest, Gregor Johann Mendel, first described the laws that govern the inheritance of simple traits in pea plants.

• Archibald E. Garrod, coined the term ‘chemical individuality’ in 1934, which resulted into several studies which is directed towards pharmacogenetics.

• Sir Archibald Garrod, who postulated in his book Inborn Errors of Metabolism, stated that a mutation in a gene coding for an enzyme may be responsible for human differences in the metabolism of drugs and environmental chemicals.

First test to study Pharmacogenetic Variation

• The first large-scale study documenting human variation in response to a chemical was conducted by L. H. Snyder.

• Snyder investigated over 750 families and showed that “taste blindness,” the inability of some individuals to taste the chemical phenylthiocarbamide, was inherited as an autosomal-recessive trait.

Early studies• One of the first documented “pharmacogenetic stories”

was isoniazid, first synthesized in 1912, which became the first line of treatment for tuberculosis in the 1950s.

• These complications were attributed to the interaction of the drug with pyridoxine, or vitamin B6—specifically, the depletion of vitamin B6. By 1954, the complications were found to be specifically associated with patients exhibiting deficiencies of a specific enzyme, N-acetyltransferase. Patients with genetic deficiencies of N-acetyltransferase-2 exhibited a low ability to degrade isoniazid to acetylisoniazid and were termed “slow acetylators.”

Early Studies

• Ultimately it was found that approximately 50% of African Americans and Caucasians are slow acetylators, whereas rapid acetylators are more common among Asians.

Fast AcetylatorsSlow Acetylators

Pharamacogenetics

• the study of the effects of genetic differences between individuals in their response to medicines. These differences may or may not be related to the disease being treated.

Pharamacogenomics

• pharmacogenomics’ is not distinctly differentiated from pharmacogenetics, but implies the examination of whole genomes or substantial numbers of genes in order, or the study of genomics and proteomics for identifying new drug targets and their mechanism of action.

The CYP2D6 Paradigm

• In 1975, at St.Mary’s Hospital Medical School in London, Robert L. Smith, the laboratory director, ingested 32 mg of debrisoquine, a SYMPATHICOLYTIC antihypertensive drug, as did some of his co-workers.His later account of his adverse response to the drug states:“Within two hours severe orthostatic hypotension set in with blood pressure dropping to 70/50 mm Hg, hypotensive symptoms persisted for up to two days after the dose…”.

THE CYP2D6 Paradigm

• His colleagues who had ingested a similar dose had no significant cardiovascular effects. Analysis of 4-hydroxydebrisoquine in the urine of the volunteers revealed that the extreme sensitivity was associated with the inability to form this metabolite. A later study of 94 medical students and 3 families who were given a dose of 10 mg of debrisoquine led to the description of this genetic polymorphism of drug oxidation with two phenotypes, the ‘poor’ and the ‘extensive’metabolizers.