Adverse Drug Reactions - Essay Example

To reduce adverse drug reactions (ADRs), should patients be ed to genetic screening prior to the administration of a long-term drug therapy Summary: Project Aims and Outcomes Aims 1. To research and evaluate current literature on the affect genetic polymorphisms has on the frequency of ADRs. 2. To understand the importance of pharmacogenomics in the future of drug development and individualised medicine. 3. To make a substantial contribution to the growing field and significance of Pharmacogenomics. 4. To weigh up all social, ethical, scientific and economic considerations to make an informed decision about the use of genetic screening. Outcomes 1. Adverse drug reactions constitute a critical phenomenon in patient care, with significant effects on morbidity, mortality and healthcare costs. 2. Individual differences exist in the manifestation of ADRs to drug treatment, based on genetic causes among other reasons. These individual differences are rooted in genetic polymorphisms which affect drug metabolizing enzymes, transporters and receptors in people, and the differences can cause major undesirable events in the course of treatment. 3. Pharmacogenomics is an emerging science which seeks to identify the genetic peculiarities that influence disease susceptibility and drug response. It holds the promise of individualizing drug treatment and helping to predict and minimise ADRs caused by genetic variations. 4. There are significant merits to the prospect of using prior genetic screening to optimise drug treatment for patients on long-term therapy. However, there are also major drawbacks that are of concern to several parties involved in healthcare. 5. Prior genetic screening appears to be the way to go: but more time may be needed to lay the proper foundations. Table of Contents 1. Introduction 2. Adverse drug reactions 3. Overview of pharmacokinetics and pharmacodynamics a. Pharmacokinetic processes b. Pharmacodynamic processes 4. Pharmacogenetics, pharmacogenomics and adverse drug reactions a. Important definitions b. The role of genetic polymorphism in causing adverse drug reactions c. Genetic screening methods d. Benefits of genetic screening: the promise of pharmacogenomics e. Concerns and controversies: the drawbacks of pharmacogenomics f. Evaluation and appraisal 5. Conclusion Introduction This review addresses the topic of pharmacogenomics and the debate surrounding the prospects of using genetic screening to reduce the incidence of adverse drug reactions in patients on long-term drug therapy. The basic concepts of adverse drug reactions (ADRs), factors influencing interindividual variation in drug response, fate of administered drugs, and pharmacogenomics will be addressed initially, followed by a detailed look into how ADRs may be influenced by pharmacogenomics, and currently available techniques for genetic screening. Finally, issues that surround the prospects of generalized genetic screening will be discussed in terms of the inherent advantages and disadvantages. Adverse Drug Reactions An adverse drug reaction is defined as a negative and unintended consequence of taking a drug. These consequences are of two possible kinds: those resulting from an unwanted extension of the therapeutic action of the drug, and those unrelated to the therapeutic action of the drug. An example of the former would be daytime drowsiness caused by taking a tranquilizer at bedtime, while the latter may be exemplified by dry mouth caused by an antihistamine taken for allergy control. As will be shown later, both kinds of ADRs can be influenced by the genetic makeup of individual patients. Preventing ADRs is a crucial issue for patient drug treatment because a significant proportion of health care expenditure and time go into the management of conditions directly attributed to the ADRs caused by previous drug treatment (Beijer & Blaey, 2002; Moore, Lecointre, Noblet, & Mabille, 1998). Because a number of ADRs are influenced by genetic factors, it has lately become a matter of interest to health researchers, practitioners and policy makers as to if and how a kind of genetic screening approach should be taken to minimize ADRs that are determined by genetic factors. There are several factors that may influence interindividual differences in the occurrence of ADRs. These include the following: Physiological status of individual patients (age, weight, gender, disease status) Lifestyle choices (diet, smoking, alcohol consumption) Drug interactions with concomitantly administered medications, dietary components or environmental contaminants Genetic differences in terms of polymorphisms. The last factor is the focus of this research paper. Overview of Pharmacokinetics and Pharmacodynamics In order to understand how ADRs occur and the role of genetic modulation in ADR events, there has to be an understanding of the fate of drugs in the body after administration. This encompasses the dual disciplines of pharmacokinetics (what the body does to the drug) and pharmacodynamics (what the drug does to the body) (Neligan, 1999). Pharmacokinetics This is the study of the time course of a drug in the body. Four processes together make up the pharmacokinetics of a drug: absorption, distribution, metabolism and excretion (Creasey, 1979). Absorption: Absorption is defined as the movement of a drug from the site of administration into the systemic circulation, for example in the diffusion of orally administered drugs across the villi of the small intestine into the hepatic portal circulation, or the diffusion of an intramuscularly administered drug from the muscles into the capillaries of the systemic circulation. Absorption may occur by passive diffusion across a concentration gradient, active transport, or facilitated passive diffusion. Distribution: this is the movement of the drug from the site of absorption, through the circulatory system, to the site of action. It involves binding of the drug to plasma proteins which facilitate the distribution process. Also, part of the distribution process is mediated by proteins known as transporters, especially at effector organs. Metabolism: Drug metabolism describes the enzyme-mediated chemical transformation of the drug molecules at sites of metabolism into different chemical entities with altered properties which generally facilitate the termination of their pharmacological effect and promote the process of removal from the body (Gibson & Skett, 2001). The most important site of drug metabolism is the liver, although the process occurs in various other organs including the skin, lungs, pancreas, small intestines and the brain. Drug metabolism reactions generally fall into two phases: Phase I (functionalisation reactions) and Phase II (conjugation reactions). Phase I reactions serve to prepare the drug molecule for the Phase II reactions which actually deactivate the drug and make it water soluble, hence facilitating its excretion from the body through urine or the bile. Phase I metabolic reactions include oxidation, reduction, hydrolysis, hydration, deacetylation and isomerization. These are mediated by several enzymes, by far the most important of which are the cytochrome P450 family of enzymes. The list below shows common CYP 450 enzymes involved in Phase I reactions and examples of the drug substrates they act upon (Rendic & Di Carlo, 1997): CYP1A1: R-warfarin CYP1A2: R-warfarin, paracetamol, caffeine, phenacetin CYP2A6: cyclophosphamide, zidovudine, halothane CYP2B6: cyclophosphamide, testosterone CYP2C8, 9: tolbutamide, diclofenac, S-warfarin, phenytoin, hexobarbital CYP2C18, 19: diazepam, omeprazole, S-mephenytoin CYP2D6: codeine, debrisoquin, dextromethorphan, sparteine CYP3A4, 5: carbamazepine, erythromcycin, diazepam, cortisol, midazolam, testosterone, nifedipine, dapsone, omeprazole Phase II reactions involve conjugation with endogenous molecules in the presence of high energy cofactors. They include glucuronidation, glycosidation, sulfation, acetylation, methylation, amino acid conjugation, glutathione conjugation and fatty acid conjugation. Enzymes involved in Phase II reactions and examples of their drug substrates include (Gibson & Skett, 2001): UDP-glucuronosyl transferase: morphine, chloramphenicol, salicylic acid Sulfotransferases: isoprenaline, metronidazole, paracetamol Methyl transferases: desmethylimipramine, thiouracil N-acetyltransferases: isoniazid, sulfanilamide Excretion is the removal of the metabolized or unchanged drug from the body. This takes place mainly through the kidneys, but other organs involved include the skin and the lungs. Three processes are involved in excretion of drugs: glomerullar filtration, active tubular secretion, and passive reabsorption. It is important to note that protein transporters are crucial players in the excretory process, and as will be shown later on, genetic variations involving these transporters could play an active role in causation of ADRs. Pharmacodynamics This is the study of the effects of drugs on tissues and organs (Teitelbaum et al., 2005). It explains interaction of drugs with the sites of action in the body that leads to the eliciting of drug action. Basically, it involves the interaction of drug molecules with complex proteins known as receptors. Again, because proteins are involved, the possibilities for genetic variations leading to unexpected physiological responses exist (Weber, 2005). Pharmacogenetics, Pharmacogenomics and Adverse Drug Reactions Important Definitions Pharmacogenomics: this is a science that examines the inherited variations in genes that dictate drug response, and explores the ways these variations can be used to predict if a patient to whom a drug is administered will have a good response, a bad response or no response to the drug. It encompasses the study of the role of the entire genome in both disease susceptibility and drug response, in an attempt to identify specific genes that are associated with specific diseases and that may be targets for new drugs (Werner Kalow, 2005; U. A. Meyer, 2002). Pharmacogenetics: this is the study of variability in drug responses due to heredity (Werner Kalow, 2005). Allele and allelic variants: An allele is one of two or more alternative forms of a gene at the same locus in each of a pair of chromosomes, which determine alternative characters in inheritance. For drug metabolizing enzymes, the standard nomenclature is to use a suffix in the form *1 (the wild-type), *2, and so forth; for example, CYP2D6*1, CYP2D6*2 (Mansmann, 2002). An allelic variant results from a genetic variation that is of secondary importance to a more dominant gene variation, e.g. CYP2D6*4A, 2D6*4C, 2D6*4E. The B, C, D and E variants are secondary to the same dominant mutation that prevents any of them from being expressed. Genetic polymorphism: this describes the existence of two or more alternative forms of a given gene. It is defined as the inheritance of a genetic trait controlled by a single gene locus with two alleles in which the least common allele has a frequency of about 1% or greater. To be an allele, the enzyme should contain nucleotide changes that have been shown to affect either of transcription, mRNA splicing, translation, post-transcriptional or post-translational modifications, and have resulted in at least one amino acid change (Meyer, 1991). Variations may be monogenic or polygenic (Gaussian distribution type). Monogenic variations manifest as an all-or-none function in the affected gene, and is typified by the CYP2D6 variations which produce "slow" and "fast" metabolizers (Werner Kalow, 2005). Polygenic distributions are those in which the affected gene shows a range of function defined by an ED50 (Werner Kalow, 2005)and involves multiple gene variation. Polygenic variation accounts for the majority of variations in drug response. Polymorphisms have been known to lead to enzyme-mediated differences in drug response. Examples of enzymes that have displayed polymorphisms include the following: cytochrome P450 enzymes N-acetyl transferases, pseudocholinesterases, thiopurine methyl transferase, alcohol dehydrogenase, dihydropyrimidine dehydrogenase, serum paroxonase, trimethylamine N-oxidase, glutathione-S-transferase, UDP-glucuronyl transferase. The most important polymorphisms in terms of clinical implications are observed with CYP2D6 (Rendic & Di Carlo, 1997) and thiopurine S-methyltransferase (TMPT) (Otterness, 1997). The polymorphisms of the largest class of metabolizing enzymes (cytochrome P450 enzymes) are due to either single nucleotide polymorphisms resulting in altered functional activity or altered transcriptional/post-transcriptional regulation; gene deletions resulting in loss of functional activity; or gene duplications resulting in the incidence of ultra-rapid metabolizers (Werner Kalow, 2005). Single nucleotide polymorphisms: by far the most important types of genetic polymorphisms are the single nucleotide polymorphisms (SNPs) (McCarthy, 2002). They are arbitrarily distinguished from mutations in that while mutations occur in less than 1% of the population, gene polymorphisms occur in over 1% of the populations. SNPs occur in every 1900 bases, which translate to about 3 million in the entire genome. In terms of racial differences (W. Kalow & Bertilsson, 1994), the descending order of number of variants is Africans, Asians and Caucasians (evolutionally reflecting the length of time these races have been on earth) (W. Kalow, 1991; Wood, 1998). SNPs may be classified as coding or non-coding (depending on whether it leads to coding changes or not); synonymous or non-synonymous (depending on whether there is a change in the type of amino acid coded or not); and conservative or non-conservative (depending on whether the region of variation is one that is critical to function or not). Specific examples of SNPs within some drug metabolizing enzymes are listed below: CYP2A6: in the 2A6*2 allele, there is a single amino acid change (Leu 160 to His) which leads to loss of activity. Homozygous carriers of this variant are unable to metabolize coumarin, while heterozygous carriers have a metabolic capacity at 50-60% of the maximum rate. About 10-20% of Caucasians and Asians carry this allele, but it has a much lower frequency in African Americans. CYP2C: About 12-23% of Southeast Asian populations are display the poor metaboliser phenotype with this enzyme. CYP2D6: this has a well-characterized polymorphism (Michelson, 2007), as typified by variations in the metabolism of debrisoquine and sparteine (Bertilsson, Dahl, Dalen, & Al-Shurbaji, 2002). Perhexiline induced liver injury and neurotoxicity in some patients has been associated with polymorphisms of this enzyme. N-acetyltransferase: NAT2 is polymorphic, and while slow metabolisers are at risk of urinary bladder carcinogenesis because of the prevalence of the alternative metabolic pathway of N-oxidation, fast metabolisers may also be at risk of colorectal cancer from the O-acetylation of N-hydroxy arylamine metabolites (U. A. Meyer & Flockhart, 2005). Clinically relevant polymorphisms manifests as a multi-modal frequency distribution of enzyme activity, typically yielding two phenotypes: the poor metabolisers and the extensive metabolizers (duplication or amplification may rarely result in ultra-rapid metabolizers). However, this may be a simplistic classification from the genotypic perspective, as genetic variability is more complex within each phenotypic group, with allelic variants that often express less different levels of enzyme activity. In addition to drug metabolizing enzymes, transporter enzymes involved in absorption, distribution, metabolism and renal excretion, as well as receptors at effector organs, are also subject to polymorphisms, creating a whole plethora of potential variations in drug absorption, distribution, metabolism and excretion which ultimately confound patient therapy and make a strong case for individualized patient therapy (Marzolini, Tirona, & Kim, 2005; Weber, 2005). Historical Background of Pharmacogenomics Inherited differences in drug metabolism were first discovered following clinical observations of marked interindividual differences in drug response, as in the pronounced hypotension following debrisoquin therapy in some patients (Werner Kalow, 2005). Such clinical observations were followed by population studies to define the frequency in populations (racial, ethnic or geographic). Although initial tests were simple affairs involving chromatography for cytochrome P450 enzymes, later work attempted to elucidate the molecular basis of the genetic defect responsible for the phenotypes. This took place in the 1980s. The inherited differences in individual metabolizing enzymes exhibiting monogenic traits like CYP2D6 were studied by cloning of polymorphs, while differences in pharmacological response which usually involved polygenic traits were determined by genetic differences in genes encoding proteins involved in metabolic and disposition processes. Polygenic traits are rather more difficult to elucidate clinically, but present effort is focused on understanding polygenic determinants of drug response. The 2000 sequencing of the human genome marked a watershed in the history of pharmacogenomics (Broder, Subramanian, & Venter, 2002). Prior to that time, the approach was more drug-centred, in which genetic polymorphisms were compared in phenotypic groups. However, the post-genomic era, the emphasis is on a genotype-centred approach, in which phenotypes are compared in genotypic groups. With the sequencing of the human genome, a large variation in the genome has been brought to light. Current scientific thought hypothesizes that the variations in the genome account for the observed interindividual responses to drugs. The ultimate goal of pharmacogenomics is to define the contributions of genetic differences in drug disposition or drug targets to drug response to improve drug safety and efficacy using genetically guided, individualized treatment. The Role of Genetic Polymorphism in Causing Adverse Drug Reactions Ultimately, the genetic variations that form the focus of pharmacogenomics play out in the form of individual differences in response to drug therapy. These differences will be looked into, both from the perspective of enzymatic causes as well as that of clinical effects, with an emphasis on the ones that influence ADRs. Clinical Consequences of Genetic Variations The practical implications of the aforementioned polymorphisms are multifarious, but all inevitably stem from the fact that recommended drugs of choice, doses and dosage regimens are all derived from studies in general populations and are inherently based on the assumption that every patient's body will handle and respond to drugs in very much the same way as the average person tested during clinical trials. Given what is now known in pharmacogenomics, nothing could be further from the truth. Generally speaking, the following aberrations could occur after standard drug therapy as a result of relevant polymorphisms (U. A. Meyer & Flockhart, 2005): a) Drug levels may reach toxic levels in the body after a "normal" dose, leading to problems of artificial overdosing. Symptoms that would present will be akin to an exacerbation of the pharmacological action of the drug. This would occur if either of the following happens: A patient has a polymorphism of transporters involved in active transport at the site of absorption, which results in excessive uptake transporter functioning, or poor efflux transporter activity. In either case, more than the expected fraction of administered drug will be absorbed and the drug may reach toxic levels in the blood. There is a polymorphism which results in impaired metabolism, hence the inactivation or chemical modification of the molecule does not take place at all, or does not take place fast enough. Apparently the drug will accumulate in the body with each successive dosing. With drugs excreted largely unchanged through the renal system, there could be a polymorphism involving transporters in the kidney which may manifest either an inadequacy of efflux transport activity during active tubular secretion, or overexpression of activity in renal reuptake. In either case, with a standard dose of the drug, the drug does not get out of the body in these patients adequately, and subsequently accumulates, leading to toxicity. b) Drug levels in the body may be much lower than anticipated after standard dosing, leading to possible therapeutic failure. An outcome like this may occur with the following scenarios: Due to a polymorphic variation transporters involved in absorption, there is inadequate absorption and the bioavailability of the drug in the affected patients becomes a fraction of the expected literature value. Enzyme variations resulting in faster-than-normal metabolic activity could occur, leading to a highly accelerated inactivation and removal of the drug from the body. In this case, blood levels between successive doses consistently fail to reach the therapeutic targets With drugs excreted in their active forms through the kidney, excessive efflux activity or inadequate reuptake activity resulting from transporter polymorphisms will lead to rapid removal of the drug from the body; hence blood levels will be below expected normal values. c) Alternate metabolic pathways may take over, leading to the production of harmful metabolites. When a standard metabolic path is saturated (which could happen due to a polymorphism which causes impaired enzyme function), the body often responds by taking an alternative chemical transformation pathway for the drug molecule. However, this alternative pathway may be one that leads to metabolites with deleterious activity, and this will ultimately result in a new pathology occurring with the patient. Such diseases (caused by administered drugs) are known as iatrogenic diseases, and may cause carcinomas and other types of organ damage. d) Drug therapy with prodrugs may fail, due to the shutdown or compromise of a bioactivation pathway. A number of drugs are not biologically active until they have been activated by metabolism in the body to their pharmacologically active metabolites (the metabolites themselves are not manufactured as drugs because of problems associated with formulation or absorption). These kinds of drugs are known as prodrugs. A recently studied example is that of the antithrombotic drug clopidogrel (Beitelshees, 2006). It follows therefore that if there is a polymorphism that compromises the functioning of the bioactivation reaction, the predicted profile of bioactivation can no longer be guaranteed, and the outcome will inevitably be therapeutic failure or the emergence of adverse drug reactions from the unchanged parent drug circulating in the body. For example, opiate analgesics require activation by CYP2D6. In patients who are poor metabolizers, there may be failure of treatment using standard dosing, whereas attempts to increase the dose may lead to the exacerbation of the side effects of opiates like constipation and nausea, which do not rely on the bioactivation to happen. e) Drug-drug interactions may occur inadvertently, or to an unforeseen degree, leading to iatrogenic ADRs. Some ADRs are caused by interactions between two or more co-administered drugs, or between drugs and dietary components, or between drugs and environmental toxicants. These kinds of ADRs are all the more common in patients on long-term treatment because the treatment of most diseases requiring long-term therapy involves the use of multiple drugs. Although most standard interactions are predictable, the exceptional cases that arise from genetic polymorphisms cannot in any way be planned for or avoided except by prior knowledge of the patient's genetic profile. An example is the inhibition of tricyclic antidepressants by the selective serotonin reuptake inhibitors (SSRIs), which takes place in the presence of CYP2D6 (Okey, 2005). In an individual with a polymorphism which attenuates the expression of the enzyme, the inhibition will not occur significantly, and any design of dosage regimens which factored in the interaction will fail, leading to unwanted ADRs. f) Adverse events may occur due to altered drug pharmacodynamics (Weber, 2005). In addition to ADRs that may occur from pharmacokinetic processes due to genetic variations, there may also be adverse events from genetically altered receptor function. Given that drugs are administered based on their predicted interactions with receptors from laboratory testing (and corroborated by clinical evaluations), a genetic variation that makes one or more receptors to interact with a drug in an unexpected manner will inevitably cause an unwanted reaction in the patient. The two main pharmacodynamic outcomes that may result in ADRs are: Altered sensitivity to the drug leading to toxic effects (although the blood levels of the drug are within normal values). An example is the neurotoxicity caused by propafenone (an antiarrythmic) drug. Because the pharmacological activity is due to its hydroxylated metabolite, poor metabolisers (with genetically suppressed expression of CYP2D6) may compensate for decreased levels of the active drug by an increase in the sensitivity of their receptors. This situation muddles up the classical dose-response relationship on which propafenone dosing is predicated upon (Roden, 2005). There may also be changes in drug response at the receptor level, independent of pharmacokinetic effects (Okey, 2005). An example is the altered insulin sensitivity that occurs in certain people with non-insulin dependent diabetes mellitus (NIDDM), who have been found to possess insulin receptor polymorphisms. It is also postulated that the extreme sedation in response to antihistamines experienced in some individuals may be due to receptor polymorphisms. g) Idiosyncratic drug reactions have occurred years after a drug has been certified safe for use. The history of drug development is replete with drugs that have been hailed as blockbuster medicines for years, and suddenly a few patients suffer deadly ADRs that could not have been predicted from early stage laboratory testing, nor were discovered in early clinical trials. Such reactions are typically not related to the normal pharmacology of the drug, and are described as idiosyncratic reactions. While the exact mechanisms by which these reactions occur are not yet fully elucidated, their rarity lends credence to the view that they are manifestations of aberrant genetic polymorphisms which make the affected individuals susceptible to the unusual deleterious effects. Examples of drugs that have suffered such withdrawals include the nonsteroidal anti-inflammatory drug alcofenac (hypersensitivity reaction), benoxaprofen (hepatotoxicity and neurotoxicity), fenclofenax (epidermal necrolysis), ibufenac (hepatotoxicity), the antidiabetic phenformin (lactic acidosis), and the antibiotic temafloxacin (hepatotoxicity, haemolysis). Genetic Screening Methods A number of methods are in development for the assessment of genetic profiles, which may help in determining the presence of pharmacogenomically relevant polymorphisms and predict their effect on drug therapy (Grant, 2005; Lee, 2005). DNA sequencing: this is used for qualitative characterization of mutations. Hybridization based methods (target amplification or signal amplification): this employs the polymerase chain reaction, and they are quantitative and highly sensitive. Microarray: this method screens broad patterns of sequences, and is both quantitative and qualitative. Restriction and conformational analysis: these methods are used for polymorphism detection and analysis. Single base primer extension: this is a high throughput method for SNP detection and confirmation, which is adaptable to generic formats. Benefits of Genetic Screening: The Promise of Pharmacogenomics From the discussion above, it is not difficult to see why it is such a tantalizing idea to have the genetic profile of a patient on hand at the point of initiating long-term therapy. The benefits are multi-pronged and have been extensively reviewed (Iqbal & Fareed, 2006; U. A. Meyer, 2002; Ozdemir & Lerer, 2005). The first advantage is in the promise of individualizing patient treatment at a level of precision not seen today in clinical practice. With the knowledge of a patient's genetic profile, the polymorphisms in the patient's genes can be evaluated against what is known about the pharmacology of a drug, and the potential for potentially disastrous interactions may be foreseen at the outset. With this knowledge, a rational decision can be made to choose or discard a potential drug treatment. With an array of therapeutic choices available for many conditions today, it should be possible to make a scientific choice for each individual, which will translate into much better outcomes, rather than using a one-solution-fits-all approach from clinical guidelines, or making random choices. It is not only in the choice of drugs that an advantage may be obtained: the dosage for individual patients can also be optimized, leading to the speedy attainment of therapeutic blood levels. A patient's unusual genetic profile may not necessarily contra-indicate the drug in question, it may just mean that the blood levels that will be obtained with standard doses (based on age, weight or body surface area) could be unduly high (or low). The clinician can then use her judgment to devise a patient-specific dosage schedule, rather than relying on laboratory blood level monitoring after the fact to adjust doses. Apparently, several cases of toxicity-induced ADRs or death from idiosyncratic drug reactions will be prevented, using this approach. Pre-treatment genetic screening can also guide the prescriber from using drugs or formulations that are inappropriate for certain patients. For example, codeine preparations will be avoided for patients with CYP2D6 defects, and sustained release metoprolol will not be used if it is known that the patient is a poor metabolizer (U. A. Meyer & Flockhart, 2005). It is believed that therapeutic costs will be brought down with this approach, at least for a number of patients. This will happen as a result of the avoidance of drug-induced ADRs that lead to hospitalizations or doctor visits, as well as the elimination of treatment cost duplication that will otherwise happen with therapies that are found to be ineffective after the fact. Concerns and Controversies: The Drawbacks of Pharmacogenomics Pharmacogenomics and its applications are not without problems, which form the basis for the opposition by certain individuals and interest groups to the idea of widespread genetic screening (Foster, 2003). Firstly, in more ways than one, it is currently more like a shot in the dark. The gene variations that influence drug response, and the mechanisms by which they do so, are not yet fully elucidated. Hence, it is argued that it is pretty immature at this time to attempt a universal individualization of drug therapy. The issue of immediate cost to the healthcare delivery system is another point of concern. Genetic technologies are pricey, and it is a matter of debate as to whether the burdens that would be added onto healthcare budgets with the introduction of routine genetic screening will be practical in terms of implementation. A related issue is that of preferential allocation of resources (Reeder & Dickson, 2003). There are those who feel that the financial investment that will go into screening technologies represents a misallocation of resources that would better be expended on providing basic healthcare, food or potable water for poorer nations. Also, it is argued that, even if genetic tests show a drug is may pose problems to a patient, in many cases there is still not a wide variety of alternatives to choose from, given that there is a complex interplay of factors that go into the initial choice of a drug for treatment (e.g. patient's co-morbid conditions, concurrent drug therapy, lifestyle peculiarities). Hence the cost of genetic screening may not be justified if the patient still has to be treated with the same drug eventually. There is also the problem of the disincentive innovative drug discovery and development. Given the high costs of research and development to the pharmaceutical industry, will companies be willing to develop multiple drugs for the same condition just to satisfy the needs of minorities who are genetic variants Certainly it will be difficult to assume that the costs of development will be recouped, especially when the variations in question are only pertinent to ethnic or racial groups with more limited economic resources (Nsiah-Jefferson, 2003). A case in point is that of drug discovery for a disease like tuberculosis, which affects people mostly in the developing world. The pharmaceutical industry has not committed significant efforts into new antitubercular drugs because the majority of beneficiaries cannot pay. Another point of concern is that of confidentiality. A patient's genetic profile is confidential information (probably of greater importance than most other kinds of personal information). Will issues arise that will threaten confidentiality of these records What will happen with malpractice lawsuits that result in court orders for release of treatment records What about health insurers and employers interested in cutting costs who wish to access genetic information Lastly, we are working under the assumption that the knowledge of genetic profiles and the power of individualized medicine will be harnessed ethically. This is an assumption that may fail under exceptional circumstances. Ethicists are concerned that this may also be an issue of controversy in future. Evaluation and Appraisal Apparently the controversies are far-reaching, and convincing arguments are to be heard from both sides. One thing both sides are agreed upon is that the patient must have the best treatment at the most reasonable cost, and with the least possible hassles. In my opinion, there may have to be a compromise. On one hand, genetic testing protagonists may need to appreciate the concerns of their opponents, and be willing to wait for scientific development, healthcare policymaking and interdisciplinary collaboration among the healthcare professions to lay the proper foundations for the implementations of future use of pharmacogenomics in individualizing patient treatment (Davis, 2006). On the other hand, the antagonists of the idea have to realize that the wind of change is coming, and like every other wind of change in history, it can only be delayed, not denied. As the essayist Francis Bacon put it: "the mind of man, once expanded by knowledge, can never return to its original dimensions". The concerns of each side need to be addressed, but pharmacogenomics is here to stay, and patient screening for individualisation of drug therapy is not a matter of if, but a matter of when. Conclusion This review has examined the debate surrounding the prospects of screening patients genetically prior to long-term drug administration. The foundation concepts of adverse drug reactions, pharmacokinetics, and pharmacodynamics were explained, as well as the basic concepts of pharmacogenetics and pharmacogenomics. The influence of genetic polymorphisms on the causation of ADRs were looked into, both from the enzymatic and clinical dimensions. Finally, the prospects and problems associated with genetic screening were evaluated, and a conclusive appraisal made on them to point a way forward into the future of pharmacogenomics in patient care. References Read More