Pharmacogenetics

Inherited Variation and Polymorphism in DNA

August 3, 2017 Cytogenetics, Laboratory Medicine, Molecular Biology, Pharmacogenetics No comments

The original Human Genome Project and the subsequent study of now many thousands of individuals worldwide have provided a vast amount of DNA sequence information. With this information in hand, one can begin to characterize the types and frequencies of polymorphic variation found in the human genome and to generate catalogues of human DNA sequence diversity around the globe. DNA polymorphisms can be classified according to how the DNA sequence varies between the different alleles.

Single Nucleotide Polymorphisms

The simplest and most common of all polymorphisms are single nucleotide polymorphisms (SNPs). A locus characterized by a SNP usually has only two alleles, corresponding to the two different bases occupying that particular location in the genome. As mentioned previously, SNPs are common and are observed on average once every 1000 bp in the genome. However, the distribution of SNPs is uneven around the genome; many more SNPs are found in noncoding parts of the genome, in introns and in sequences that are some distance from known genes. Nonetheless, there is still a significant number of SNPs that do occur in genes and other known functional elements in the genome. For the set of protein-coding genes, over 100,000 exonic SNPs have been documented to date. Approximately half of these do not alter the predicted amino acid sequence of the encoded protein and are thus termed synonymous, whereas the other half do alter the amino acid sequence and are said to be nonsynonymous. Other SNPs introduce or change a stop codon, and yet others alter a known splice site; such SNPs are candidates to have significant functional consequences.

The significance for health of the vast majority of SNPs is unknown and is the subject of ongoing research. The fact that SNPs are common does not mean that they are without effect on health or longevity. What it does mean is that any effect of common SNPs is likely to involve a relatively subtle altering of disease susceptibility rather than a direct cause of serious illness.

Insertion-Deletion Polymorphisms

A second class of polymorphism is the result of variations caused by insertion or deletion (in/dels or simply indels) of anywhere from a single base pair up to approximately 1000 bp, although larger indels have been documented as well. Over a million indels have been described, numbering in the hundreds of thousands in any one individual’s genome. Approximately half of all indels are referred to as “simple” because they have only two alleles – that is, the presence or absence of the inserted or deleted segment.

Microsatellite Polymorphisms

Other indels, however, are multiallelic due to variable numbers of the segment of DNA that is inserted in tandem at a particular location, thereby constituting what is referred to as a microsatellite. They consist of stretches of DNA composed of units of two, three, or four nucleotides, such as TGTGTG, CAACAACAA, or AAATAAATAAAT, repeated between one and a few dozen times at a particular site in the genome. The different alleles in a microsatellite polymorphism are the result of differing numbers of repeated nucleotide units contained within any one microsatellite and are therefore sometimes also referred to as short tandem repeat (STR) polymorphisms. A microsatellite locus often has many alleles (repeat lengths) that can be rapidly evaluated by standard laboratory procedures to distinguish different individuals and to infer familial relationships. Many tens of thousands of microsatellite polymorphic loci are known throughout the human genome. Finally, microsatellites are a particularly useful group of indels. Determining the alleles at multiple microsatellite loci is currently the method of choice for DNA fingerprinting used for identity testing.

Mobile Element Insertion Polymorphisms

Nearly half of the human genome consists of families of repetitive elements that are dispersed around the genome. Although most of the copies of these repeats are stationary, some of them are mobile and contribute to human genetic diversity through the process of retrotransposition, a process that involves transcription into an RNA, reverse transcription into a DNA sequence, and insertion into another site in the genome. Mobile element polymorphisms are found in nongenic regions of the genome, a small proportion of them are found within genes. At least 5000 of these polymorphic loci have an insertion frequency of greater than 10% in various populations.

Coyp Number Variants

Another important type of human polymorphism includes copy number variants (CNVs). CNVs are conceptually related to indels and microsatellites but consist of variation in the number of copies of larger segments of the genome, ranging in size from 1000 bp to many hundreds of kilobase pairs. Variants larger than 500 kb are found in 5% to 10% of individuals in the general population, whereas variants encompassing more than 1 Mb are found in 1% to 2%. The largest CNVs are sometimes found in regions of the genome characterized by repeated blocks of homologous sequences called segmental duplications (or segdups).

Smaller CNVs in particular may have only two alleles (i.e., the presence or absence of a segment), similar to indels in that regard. Larger CNVs tend to have multiple alleles due to the presence of different numbers of copies of a segment of DNA in tandem. In terms of genome diversity between individuals, the amount of DNA involved in CNVs vastly exceeds the amount that differs because of SNPs. The content of any two human genomes can differ by as much as 50 to 100 Mb because of copy number differences at CNV loci.

Notably, the variable segment at many CNV loci can include one to as several dozen genes, that thusCNVs are frequently implicated in traits that involve altered gene dosage. When a CNV is frequent enough to be polymorphic, it represents a background of common variation that must be understood if alterations in copy number observed in patients are to be interpreted properly. As with all DNA polymorphism, the significance of different CNV alleles in health and disease susceptibility is the subject of intensive investigation.

Inversion Polymorphisms

A final group of polymorphisms to be discussed is inversions, which differ in size from a few base pairs to large regions of the genome (up to several megabase pairs) that can be present in either of two orientations in the genomes of different individuals. Most inversions are characterized by regions of sequence homology at the edges of the inverted segment, implicating a process of homologous recombination in the origin of the inversions. In their balanced form, inversions, regardless of orientation, do not involve a gain or loss of DNA, and the inversion polymorphisms (with two alleles corresponding to the two orientations) can achieve substantial frequencies in the general population.

Variability – Differ in Drug Response

April 13, 2017 Adverse Drug Reactions, Pharmacodynamics, Pharmacogenetics, Pharmacokinetics, Therapeutics No comments , , , , , , , , , , , , , ,

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Substantial differences in response to drugs commonly exist among patients. Such between or interindividual variability is often reflected by various marketed dose strengths of a drug. Because variability in response within a subject from one occasion to another (intraindividual variability) is generally smaller than interindividual variability, there is usually little need to subsequently adjust an individual’s dosage regimen, once well-established, unless the condition or treatment of the patient changes. Clearly, if intraindividual variability were large and unpredictable, finding and maintaining dosage for an individual would be an extremely difficult task, particularly for a drug with a low therapeutic index (e.g., warfarin).

Many patients stabilized on one medicine receive another for the treatment of the same or concurrent condition or disease. Sometimes, the second drug affects the response to the first. The change in response may be clinically insignificant for most of the patient population, with the recommendation that no adjustment in dosage be made. However, a few individuals may exhibit an exaggerated response, which could prove fatal unless the dosage of the first drug given to them is reduced. The lesson is clear: Average data are useful as a guide; but ultimately, information pertaining to the individual patient is all-important.

PS: Evidence for interindividual differences in drug response

  • Variability in the dosage required to produce a given response – daily dose of warfarin
  • Variability in pharmacokinetics – phenytoin’s wide scatter in plateau plasma concentration
  • Variability in pharmacodynamics – levels of endogenous agonists or antagonists

Clearly, variability exists in both pharmacokinetics and pharmacodynamics, and measurement of drug in plasma is a prerequisite for separating the two. The characterization of pharmacokinetic and pharmacodynamic variabilities within the population is called population pharmacokinetics and population pharmacodynamics, respectively.

The dependence on dose and time in the assignment of variability is minimized by expressing variability not in terms of observations but rather in terms of the parameter values defining pharmacokinetics and pharmacodynamics, that is, in F, ka, Cl, and V for pharmacokinetics, and in Emax, C50, and the factor defining the steepness of the concentration-response relationship for pharmacodynamics.

Why People Differ

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The reasons why people differ in their responsiveness to a given dose of a drug are manifold and include genetics, disease, age, gender, body weight, drugs given concomitantly, and various behavioral and environmental factors. Age, body weight, disease, and concomitantly administered drugs are important because they are measurable sources of variability that can be taken into account. Gender-linked differences in hormonal balance, body composition, and activity of certain enzymes manifest themselves in differences in both pharmacokinetics and responsiveness, but overall, the effect of gender is small. Although inheritance accounts for a substantial part of the differences in response among individuals for many drugs, much of this variability is still largely unpredictable, particularly in regard to pharmacodynamics.
 
Pharmaceutical formulation and the process used to manufacture a product can be important because both can affect the rate and extent of release, and hence entry, into the body. A well-designed formulation diminishes the degree of variability in the release characteristics of a drug in vivo.
 
Heavy cigarette smoking tends to reduce clinical and toxic effects of some drugs, including theophylline, caffeine, and olanzapine. The drug affected are extensively metabolized by hepatic oxidation catalyzed by CYP1A2; induction of this enzyme is the likely cause.
 
Although on average the body maintains homeostasis, many biological functions and many endogenous substances undergo temporal rhythms. The period of the cycle is often circadian, approximately 24 hr, although there may be both shorter and longer cycles upon which the daily one is superimposed. The menstrual cycle and seasonal variations in the concentrations of some endogenous substances are examples of cycles with a long period. Drug responses and pharmacokinetics may therefore change with time of the day, day of the month, or season of the year.
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How Pharmacogenetics Affects Drug Therapy

March 29, 2016 Pharmacogenetics No comments , , , ,

Polymorphisms of genes can affect drug therpay in three ways: polymorphisms in genes for drug-metabolizing enzymes, polymorphisms in genes encoding for drug transporters, and polymorphisms in genes encoding for drug targets.

Polymorphisms in Genes for Drug-Metabolizing Enzymes

Polymorphisms in the drug-metabolizing enzymes represent the first recognized and, so far, the most documented examples of genetic variants with consequences in drug response and toxicity. The major phase I enzymes are the CYP superfamily of isoenzymes. N-acetyltransferase, uridine diphosphate glucuronosyltransferase (UGT), and glutathione S-transferase are examples of phase II metabolizing enzymes that exhibit genetic polymorphisms. Thiopurine S-methyltransferase (TPMT) and dihydropyrimidine dehydrogenase (DPD) are examples of nucleotide base-metabolizing enzymes.

Polymorphisms in Drug Transporter Genes

Certain membrane-spanning protein facilitate drug transport across the gastrointestinal tract, drug excretion into the bile and urine, drug distribution across the blood-brain barrier, and drug uptake into target cells. Genetic variations for drug transport proteins may affect the distribution of drugs that are substrates for these proteins and alter drug concentrations at their therapeutic sites of action.

Polymorphisms in Drug Target Genes

Genetic polymorphisms occur commonly for drug target proteins, including receptors, enzymes, ion channels, and intracellular signaling proteins. Drug target genes may work in concert with genes that affect pharmacokinetic properties (i.e., genes for drug transporters and drug-metabolizing enzymes) to contribute to overall drug response. These drug targets include receptors, enzymes, intracellular signaling proteins, and ion channels.

Disease-Associated Genes

Numerous genes have been correlated with disease outcomes, and many of these have been found subsequently to influence response to pharmacologic disease management. These gene-drug response associations often occur despite the lack of a direct effect on pharmacokinetic or pharmacodynamic drug properties.

Polymorphisms in Pharmacotherapy

November 10, 2015 Pharmacodynamics, Pharmacogenetics, Pharmacokinetics, Pharmacotherapy, Therapeutics No comments

dna_istock_rustycloudPolymorphisms related to pharmacotherapy include polymorphisms in genes for drug-metabolizing enzymes, polymorphisms in drug transporter genes, and polymorphisms in drug target genes.

Polymorphisms in Genes for Drug-Metabolizing Enzymes

Polymorphisms in the drug-metabolizing enzymes represent the first recognized and, so far, the most documented examples of genetic variants with consequences in drug response and toxicity. eTable 6-1 lists examples of polymorphic metabolizing enzymes and corresponding drug substrates whose plasma concentrations and pharmacologic effects may be altered as a consequence of genetic variation.


Screen Shot 2015-11-10 at 2.38.46 PMPolymorphisms in the CYP2D6 gene are the best characterized among all polymorphisms in genes for drug-metabolizing enzymes. For example, the presence of two defective alleles coding for CYP2D6 in PM (poor metabolizer) results in significant impaired ability to metabolize CYP2D6-dependent substrates. Depending on the importance of the affected CYP2D6 pathway to overall drug metabolism and the drug's therapeutic index, clinically significant side effects may occur in PMs as a result of elevated drug concentrations.Screen Shot 2015-11-10 at 2.39.27 PM
Conversely, if the polymorphisms in CYP2D6 genes significantly enhance the activity of the drug-metabolizing enzyme, large amount of drugs will be metabolized and as a result the serum concentraton and pharmacologic effect of the drug would probablely be significantly lower.Screen Shot 2015-11-10 at 2.39.54 PM

The therapeutic implication of CYP2D6 polymorphism is different if the substrate in question is a prodrug. In this case, PMs would not be able to convert the drug into the therapeutically active metabolite (if low CPY2D6 activity).

Polymorphisms in Drug Transporter Genes

Certain membrane-sparnning proteins facilitate drug transport across the gastrointestinal tract, drug excretion into the bile and urine, drug distribution across the blood-brain barrier, and drug uptake into target cells.

Absorption

Polymorphisms in drug transporters on gastrointestinal tract would affect the absorption of drugs. The role of drug transproters on gastrointestinal tract is to put the drug molecule back into GI lumen. So the activity of these drug transporters would significantly alter the bioavailability/absorption of the drug.

Distribution

Genetic variations for drug transport proteins may affect the distribution of drugs that are substrates for these proteins and alter drug concentrations at their therapeutic sites of action. P-glycoprotein is one of the most recognized of the drug transport proteins that exhibit genetic polymorphism.

Excretion

Some drug are transported into bile or urine by drug transporters. So the polymorphisms in these transporters which result in significant change of the activity of the drug transporters would enhance or weaken the ability of these drug transporters's ability to excret the drug.

Drug Uptake by Target Cells

Even the drug could reach the therapeutic sites of action, efflux pumps (drug transporters) available on the surface of target cells could put the drug molecules back into extracellular environment, which prevent the pharmacologic effect of the drug if the drug's target receptors are inside the target cells.

Polymorphisms in Drug Target Genes

Genetic polymorphisms occur commonly for durg target proteins, including receptors, enzymes, ion channels, and intracellular signaling proteins. Drugs could bind to enzymes, ion channels, and intracellular signaling proteins directly to produce pharmacologic effects, or they just only bind to the receptor and the after-binding (drug-receptor) process is altered by polymorphisms in enzymes, ion channels, and intracellular signaling proteins.

Receptor Genotypes and Drug Response

The beta1-adrenergic receptor gene (ADRB1) has been the primary focus of research into genetic determinants of responses to beta-adrenergic receptor antagonists in hypertension and cardiovascular disease. The polymorphisms in beta1-adregergic receptors causes pharmacologic (or even clinical) responses in different extent to its agonists and antagonists.

Enzyme Genes and Drug Response

Some drugs exert their clinical efficacy by affect enzymes which play some roles in the life of a cell. Polymorphisms in these enzymes therefore determine what degree of responsiveness they respond to these drugs. One example is the warfarin resistance, where there is a SNP in the VKORC1. Warfarin exerts its anticoagulant effects by inhibiting VKOR and thus preventing carboxylation of the vitamin K-dependent clotting factors II, VII, IX, and X. VKORC1 encodes for the warfarin-sensitive component of VKOR. Mutations in VKORC1 coding region cause rare case of warfarin resistance, with carriers of these mutations requiring either exceptionally high doses (>100 mg/wk) to achieve effective anticoagulation or failing to respond to warfarin at any dose (the mutated VKOR lose sensitivity to warfarin).

Genes For Intracellular Signaling Proteins, Ion Channels, and Drug Response

Cellular responses to many drugs are mediated through receptor-coupled guanosine diphosphate (GDP)-bound proteins also called G-proteins. Following receptor activation, the receptor couples to the G-protein, resulting in dissociation of GDP from the alpha subunit in exchange for guanosine triphosphate (GTP) and activation of the alpha, beta, and gamma subunits. The alpha subunit and beta-gamma subunit complex are released intracellularly and interact with various effectors to produce a cellular responses. Changes in the activity of G-proteins might influence response to agonists/antagonists which bind the receptors coupled with G-proteins.

Factors Contributing to Drug-Induced Diseases

May 28, 2015 Adverse Drug Reactions, Pharmacoeconomics, Pharmacogenetics, Pharmacokinetics, Pharmacology No comments , ,

470px-Emblem_of_the_United_NationsPharmacokinetic and pharmacodynamic factors

Toxic or exaggerated responses to normal drug doses can lead to drug-induced diseases and other adverse events for two reasons. First, excessively high concentrations of unbound drug or metabolite at the site of action may occur as a result of unusual pharmacokinetics (absorption, distribution, metabolism, excretion) of the drug or metabolites. Second, response to a given concentration of unbound drug or metabolite at the site of action (pharmacodynamics) may be exaggerated or unusual because of many factors, including changes in the number and/or binding affinity of target receptors as well as alternations in signal-transduction pathways. The pharmacokinetic and pharmacodynamic behaviours of drug may be influenced by factors related to concurrent diseases, physiologic status, concomitantly administered drugs or food, lifestyle, and genetic variability.

Concurrent Diseases

The effects of disease on pharmacokinetics have been extensively reviewed. For drugs or drug metabolites that are highly dependent on the kidney or liver for elimination, usual does produce higher-than-normal serum drug concentrations in patients with kidney or liver disease respectively. This results in an exaggerated response, particularly for drugs with narrow therapeutic index.

Cardiovascular diseases, such as acute myocardial infarction or heart failure, may reduce hepatic and/or renal blood flow and decrease the elimination of drugs that are normally highly extracted by the liver. Serum concentrations and response are increased if such drugs are administered intravenously.

Hypothyroidism may be associated with a decrease in both hepatic and renal drug clearances.

Many diseases can also decrease the serum protein binding of drugs. For example, kidney and liver diseases have been associated with decreased albumin binding of some drugs. These changes generally do not result in an altered clinical response, however, because the concentration of unbound drug is unaffected. Nevertheless, misinterpretation of total serum drug concentrations of highly protein-bound drugs that are routinely monitored may lead a clinician to inappropriately increase the dose, thus resulting in toxicity.

Concurrent diseases may also be associated with enhanced pharmacodynamic responses to drugs for a variety of reasons. For example, the incidence of skin rashes and serious dermatologic adverse effects such as Stevens-Johnson syndrome is increased in patients with human immunodeficiency virus (HIV) infection who are taking trimethoprim-sulfamethoxazole. Patients with cytomegalovirus infection who are taking ampicillin are also at increased risk for skin rashes. Although the precise mechanisms are unkown, desensitisation procedures generally reduce the severity of the adverse effect if rechallenge with the drug is necessary.

Physiologic Conditions

The pharmacokinetics of a drug may be affect by age, pregnancy, and sex. In general, the rate of elimination of a drug is impaired in premature newborns, increases in early childhood to more efficient rates than those in adults, and then progressively declines with advancing age. In addition, early patients may also suffer from decreased mental status or diminished physical function. When these physiologic conditions are compounded by decreased elimination of some drugs, the patient is more susceptible to drug-induced falls or physical injury (i.e., benzodiazepines). A variety of physiologic changes during pregnancy may affect the pharmacokinetics of drugs, but no consistent patterns have been identified. The higher serum concentrations of digoxin reported in pregnant patients may be caused by increased bioavailability resulting from decreased gastric emptying time. Women have a higher risk of drug-induced adverse events as compared with men, which has been attributed to the fact that they take more drugs than men, have lower activity of drug-metabolising enzymes, and have estrogen-related effects on drug receptors, as in the case of drug-induced torsades de pointes.

DDIs

Drug-drug interactions may cause altered pharmacokinetics (bioavailability, distribution, clearance) or altered pharmacodynamics by additive or antagonistic effects. Such interactions have been extensively reviewed and are more often a predictable and preventable cause of morbidity and mortality. By far the most frequent contributing factors to drug-induced disease resulting from drug interactions are those that affect bioavailability and drug elimination. A large number of important interactions occur in the liver and gastrointestinal tract because of decreases in the rate of a drug’s metabolism or transport caused by other drugs that are inhibitors of these system.

P-glycoprotein, a transporter protein expressed on the luminal surfaces of intestinal epithelial cells, biliary hepatocytes, and renal tubular cells, transports drug from within the cell to the intestine, bile, or urine, respectively. Inhibition of P-glycoprotein can therefore increase the bioavailability and decrease renal and biliary excretion of affected drugs, thus increasing their serum concentrations. Other interaction mechanisms that may result in reduced renal excretion include reduction of the glomerular filtration rate and increased reabsorption of drug into blood from the renal tubule.

Drugs that displace other drugs from serum protein-binding sites without affecting their metabolism cause only transient increases in unbound drug concentration, and hence do not generally result in adverse effects. Displacement of drugs such as warfarin (long half-life, small volume of distribution, and narrow therapeutic range) can be clinical important, however, and necessitate a temporary reduction in the dose of the affected drug.

Serious drug-drug interactions may also occur when drugs produce additive effects through different mechanisms. Examples include: 1.the combined blood-pressure-lowering effects of calcium channel-blockers and β-blockers; 2.the increased risk of gastrointestinal bleeding resulting from non steroidal anti-inflammatory drug (NSAID)-omdiced gastric erosion in patients taking warfarin; and 3.exaggerated cyclic guanine monophosphate (cGMP)-mediated smooth-muscle relaxation caused by the combination of sildenafil (which inhibits cGMP degradation) and nitrates (which increase GMP production), leading to potentially serious hypotension. An example of a drug-drug interaction involving active or toxic metabolites is the potentiation of acetaminophen hepatotoxicity in patients receiving enzyme inducer such as rifampin, presumably by increasing the formation of toxic acetaminophen metabolites.

Drug-Food Interactions

Drug-food interactions have been extensively reviewed. One of the most serious drug-food interactions occurs with first generation nonselective monoamine oxidase inhibitors and tyramine, an amino acid found in aged or fermented foods and beverages. The suppressed metabolism of large amounts of tyramine may result in hypertensive-crisis, the so-called cheese reaction (tyramine, dopamine, norepinephrine and epinephrine are all monoamines). A large dietary intake of tyramine (or a dietary intake of tyramine while taking MAO inhibitors) can cause the tyramine pressor response, which is defined as an increase in systolic blood pressure of 30 mmHg or more. The displacement of norepinephrine (noradrenaline) from neuronal storage vesicles by acute tyramine ingestion is thought to cause the vasoconstrictionand increased heart rate and blood pressure of the pressor response. In severe cases, adrenergic crisis can occur (from wiki at http://en.wikipedia.org/wiki/Tyramine).

Components of grapefruit juice are known to suppress the presystemic elimination of certain drugs that are either metabolised in the intestinal wall by the cytochrome P-450 isozyme CYP3A4, are substrates for P-glycoprotein, or both, resulting in increased bioavailability. Drugs for which bioavailability increases dramatically when taken with grapefruit juice include lovastatin, simvastatin, buspirone, and amiodarone.

In general, an increase in drug bioavailability caused by food intake is not a problem if doses throughout the course of treatment are taken consistently at a fixed time relative to a meal. However, a clinically important drug-food interaction was reported for a particular once-daily theophylline product, which has since been reformulated. When taken with high-fat meals, a sudden, rapid release of a large amount of theophylline occurred, leading to excessively hight serum theophylline concentrations.

The salt, protein, or vitamin content of the diet also may affect the renal excretion of drugs. For example, a patient taking lithium who initiates a low-salt diet for treatment of hypertension or heart failure excretes less lithium, resulting in higher serum lithium concentrations and potential toxicity, given this drug’s narrow therapeutic range. A low-protein diet is associated with decreased renal clearance of oxypurinol, apparently through enhanced reabsorption efficiency by the uric acid transporter system.

Lifestyle Factors

Alcohol and caffeine consumption can affect both the pharmacokinetics and the pharmacodynamics of other drugs, leading to serious drug-induced diseases. There are many examples of alcohol exaggerating the central nervous system depressant effects of drugs, including benzodiazepines, phenothiazines, tricyclic antidepressants, opiates, and anthistamines. Caffeine has an additive and potentially dangerous stimulant effect when taken with ephedrine in herbal weight-loss and athletic performance-enhancing supplements.

Genetic Variability

As a result of the rapidly evolving field of pharmacogenomics, interindividual differences in drug related toxicity and therapeutic response are not always considered to be “idiosyncratic” responses. Rther, it is widely recognized that genetic makeup is responsible for a significant portion of drug-induced diseases. Many genes that encode metabolic enzymes or drug transporters are polymorphic, meaning that some groups of patients with certain gene variants have relatively inactive enzymes or transporters, while others have unusually active forms. In addition, the proportion of patients with active or inactive forms may differ among racial groups.

Polymorphisms in metabolising enzymes have been extensively reviewed. Patients with low N-acetyltransferase activities, known as “slow acetylators,” are more likely to suffer from peripheral nerve damage when administered standard isoniazid doses as compared with fast acetylators. Likewise, slow acetylators of hydrazine are more likely to suffer from hydaralazine-induced lupus erythematosus. At least four of the major cytochrome P-450 isozymes (CYP2A6, CYP2C9, CYP2C19, CYP2D6) responsible for oxidative drug metabolism are polymorphic in nature. Patients with gene variants that produce low-activity enzymes for the metabolism of warfarin experience a higher risk of serious bleeding events. Severe and potentially fatal hematologic toxicity occurs in the small percentage of patients receiving azathioprine or mercaptopurine who have a genetic deficiency in the thiopurine methyltransferase enzyme.

Polymorphisms in receptors, ion channels, or other proteins involved in drug response also occur. These result in widely variable pharmacodynamic responses among patients despite similar concentrations of the drug at the site of action. Examples include the polymorphisms in: 1.dopamine receptors, which affect the risk of drug induced tardive dyskinesia; 2.skeletal-muscle ryanodine receptors, which affect the risk of anesthesia-induced malignant hyperthermia; 3.potassium or sodium channels, which affect the risk of potentially fatal tornadoes de points when certain antiarrhythmic drugs are administered; 4.glucose-6-phosphate dehydrogenase, which if deficient, leads to red-cell homeless in patients who take drugs with a high redox potential, such as aspirin, nitrofurantoin, sulfonamides, and quinidine; and 5.the major histocompatibility complex, which mediates hypersensitivity reactions to drugs such as abacavir and nevirapine.


Adherence To Prescribed Therapy

Noncompliance implies that the patient is intentionally or willfully not following directions for medication use, which may or may not be the case. For this reason, some prefer the term non adherence, because it places no blame on either the patient or the health care professional. Common causes of non adherence are listed in Table 1. Regardless of the cause, non adherence can lead to drug-induced disease. Patients may take more or less drug than prescribed or recommended, modify medications in an inappropriate fashion (e.g., crush a sustained-release tablet), or continue to take a prescribed drug even though the underlying medical condition for which the drug was originally prescribed has resolved. Any of these actions can put patients at increased risk for drug-induced disease.

Screen Shot 2015-05-28 at 5.01.13 PMIt is estimated that the prevalence of medication non adherence is 40% to 70%. McDonnell and Jacobs analyzed the cause for hospital admissions from preventable adverse drug reactions. Of 158 drug-related hospital admissions over an 1-month period, patient non adherence with a prescribed medication regimen was the identified cause of 33% of these admissions. Unfortunately, health care providers typically are unable to identify patients at risk for non adherence. Patient age, sex, race, intelligence, and educational background have not been shown to be predictive of adherence or non adherence to a prescribed drug regimen.

Until the most effective strategy or strategies to improve adherence can be identified, it is recommended that healthcare professionals keep drug regimens simple, provide clear and complete instructions, encourage medication adherence by scheduling regular appointments, respond clearly and promptly to patients’ questions and concerns, and reinforce adherence with the prescribed regimen at every opportunity.


Medication Errors

Medication errors contribute significantly to the problem of drug-induced disease. These errors can include a variety of problems involving any step in the drug-use process. In an study, 67% of hospital admissions caused by adverse drug reactions were attributed to inadequate patient monitoring (e.g., failure to order appropriate laboratory tests to monitor drug response or failure to respond appropriately to abnormal laboratory-test results) and 51% were caused by inappropriate drug doses.

Fortunately, not all medication errors result in clinically significant problems. In one study of hospitalized patients, only 7 to 100 medication errors were thought to be serious enough to cause harm (all adverse effects are harm and might not be preventable, whereas all medication errors are preventable and do not necessarily cause harm). However, in a view of the overall frequency of medication errors that occur each year, a 7% proportion of serious medication errors may result in many affected lives.

Medication errors and drug-induced diseases may result from the limitations of an individual practitioner, from problems latent in the system or setting in which the practitioner operates, or from a combination of the above. In most cases, medication errors are caused by system-related problems including the absence of redundancies and system defenses needed to detect and counter an error in an individual’s judgment before the medication reaches the patient.