Pharmacogenetics

Pharmacogenetics studies the contribution of genetic variation to the variation in response to pharmacotherapy. Interest lies both with desired therapeutic effects and with the range and severity of adverse events. When a given drug is administered to different patients for whom, based on the best available diagnostic evidence, it is appropriate, many of them will safely experience a therapeutic benefit. However, there are other possible outcomes that may be experienced by a relatively small number of patients  

While other factors (e.g., existing disease, concomitant medication, nutrition, and use of tobacco and alcohol) can influence why different people respond differently to a given drug, the predominant factor is genetic variation, specifically variation in the structure of the target receptor and in pharmacokinetics (Primrose and Twyman, 2006). 

We have discussed both target receptors and pharmacokinetics in this book. Protein manufacture is under direct genetic control, and two factors are of particular relevance here. First, the precise structure and function of protein macromolecules (receptors) targeted by a specific drug molecule will vary in different individuals. Since the structure and function of the protein are directly related to how the drug molecule will interact with that protein, individuals responses to the drug will vary. Second, there are genetic variations in metabolic enzymes (proteins) and hence metabolism. Both of these processes fall neatly into the domain of pharmacoproteomics (see Section 14.8). 

Ferkol et al. (2005) listed three major mechanisms by which genetic variation can produce variation in individual responses to drugs  

Until quite recently, X-ray crystallography was the technique used almost exclusively to resolve the three-dimensional structure of proteins. As well as itself being technically challenging, a major limitation of X-ray crystallography is the requirement for the target protein to be in crystalline form. It has thus far proven difficult/impossible to induce the majority of proteins to crystallize. NMR is an analytical technique that can also be used to determine the three-dimensional structure of a molecule, and without the necessity for crystallization. For many years, even the most powerful NMR machines could resolve the three-dimensional structure of only relatively small proteins (less than 20-25 kDa). However, recent analytical advances now render it possible to analyse much larger proteins by this technique successfully. 

The ultimate goal of structural genomics is to provide a complete three-dimensional description of any gene product. Also, as the structures of more and more proteins of known function are elucidated, it should become increasingly possible to link specific functional attributes to specific structural attributes. As such, it may prove ultimately feasible to predict protein function if its structure is known, and vice versa. 

Different people respond differently to any given drug, even if they present with essentially identical disease symptoms. Optimum dose requirements, for example, can vary significantly. Furthermore, not all patients respond positively to a specific drug (e.g. IFN-P is of clinical benefit to only one in three multiple sclerosis patients see Chapter 8). The range and severity of adverse effects induced by a drug can also vary significantly within a patient population base. 

The identification and characterization of SNPs within the human genomes is, therefore, of both academic and applied interest. Several research groups continue to map human SNPs, and over 1.5 million have thus far been identified. 

Different people respond differently to any given drug, even if they present with essentially identical disease symptoms, e.g. optimum dose requirements can vary significantly. 

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In all work on enzyme inhibitors, it must be remembered that individuals do not necessarily possess the same content of enzymes as the population as a whole. Thus many people, particularly in Africa and the Middle East, have a deficiency of glucose 6-phosphate dehydrogenase, a biochemical lesion which 

The same inheritance controls the acetylation (deactivation) of the antibacterial sulfonamides, the anti-arrhythmic cardiac drug, procainamide (7.56) (Woosley et aL, 1978), the blood-pressure-lowering drug, hydralazine 11.47), and the amine derived by metabolism of the sedative, nitrazepam (12.98). In each case, rapid acetylation reduces the effect of the drug, but slow acetylators of hydralazine are unfortunate for they are prone to develop systemic lupus erythematosis, with arthritis-like symptoms (Batchelor a/., 1980). 

Another pharmacogenetic effect is the unwelcome rise in intraocular pressure when glucocorticoids are placed in the eye. A sampled Caucasian population showed 5% of responders. This effect was found to run in families, as does the presence of atypically weak plasma cholinesterase in those patients who find difficulty in hydrolysing suxamethonium (7.29) at the end of an operation (Kalow, 1962). 

For further reading on pharmocogenetics, see Kalow (1962,1980) and World Health Organization (1973b). 

In all work on enzyme inhibitors, it must be remembered that individuals do not necessarily possess the same content of enzymes as the population as a whole. Thus many people, particularly in Africa and the Middle East, have a deficiency of glucose 6-phosphate dehydrogenase, a biochemical lesion which does them no harm imtil they are prescribed the antimalarial drug, primaquine (5.27). These patients quickly develop haemol5rtic anaemia, due to their biochemical lesion which is inherited on an incompletely dominant sex-linked gene (Beutler, 1959). The anaemia is caused by the haemolytic quinone formed in the first stage of metabolism the enzyme which should destroy the quinone is missing. 

Other such enzyme deficiencies have been revealed through an individual s adverse reaction to drugs. More than 90% of Orientals are genetically rapid N-acetylators of isoniazid (6.12), whereas only 40% of black or white citizens of the United States showed this trait (Kalow, 1962). Rapid acetylators produce acetylhydrazine, which can cause liver damage. The same inheritance controls the acetylation (deactivation) of the sulphonamide antibacterials. The rise of intraocular pressure when glucocorticoids are placed in the eye is another pharmacogenetic effect. Low and high responses are shown by 66% and 5%, respectively, of a sample white population. 

2 Differences in ionization that can bring about selectivity. 338 

3 Substances that are more biologically active when ionized. 344 

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Pharmacogenetics the responses to dmgs may be significantiy different according to heritable factors that can modulate pharmacodynamic or pharmacogenetic factors (118). Atypical cholinesterase occurs in about 1 in 2000 Caucasians and is associated with a markedly reduced sensitivity to hydrolysis of the muscle-relaxant cholinesterase. Similarly, the reduced sensitivity to the anticoagulant warfarin is associated with a reduced receptor affinity. 

Bioinformatics Gene Expression Analysis Microarray Technology Pharmacogenetics Proteomics... 

Malignant hyperthermia (MH) is an autosomal-dominant pharmacogenetic disorder that is triggered by exposure to inhalation of general anesthetics, such as halothane. In susceptible individuals, these drugs can induce tachycardia, a greatly increased body metabolism, muscle contracture and an elevated body temperature (above 40°C) with a rapid rate of increase. Many cases of MH are linked to a gene for type 1 ryanodine receptor (RyRl). 

Essential to the definition of Pharmacogenetics is the term genetic polymorphism. It is extrapolated that there are at least three million genetic polymorphisms in the human genome. Historically, a genetic polymorphism was defined as a genetic variation with a population frequency of 1% and above, but the larger inter-ethnic variation of population frequencies makes a strict definition based on such frequencies impractical. The most common molecular type of polymorphism is the... 

Pharmacogenetics. Figure 1 Relationship between Pharmacogenetics and other disciplines illustrated using a Venn diagram. 

Pharmacogenetics. Table 1 Selected genetic polymorphisms and their medical impact... 

Pharmacogenetics as a Compound Selection Tool in Drug Development... 

Pharmacogenetics as a Discoveiy Tool for Mechanisms of Diseases and New Therapentic Principles... 

Pharmacogenetics and Pharmacogenomics (2000) Recent Conceptual and Technical Advances. Pharmacology 61(3) (the entire issue)... 

Weber WW (1997) Pharmacogenetics. Oxford University Press, Oxford... 

The reader is also referred to a number of journals specifically devoted to this field of research Pharmacogenetics published by Lippincott Williams and Wilkins Pharmacogenomics published by Ashley Publications Ltd. American Journal of Pharmacogenomics published by ADIS international The Pharmacogenomics Journal published by Nature Publishing group... 

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