Principle of Clinical Pharmacology (Part 2)

GENETIC DETERMINANTS OF THE RESPONSE TO DRUGS

Principles of Genetic Variation and Human Traits

Variants in the human genome resulting in variation in level of expression or function of molecules important for pharmacokinetics and pharmacodynamics are increasingly recognized. These may be mutations (very rare variants, often associated with disease) or polymorphisms, variants that are much more common in a population. Variants may occur at a single nucleotide [known as single nucleotide polymorphism (SNP)] or involve insertion or deletion of one or more nucleotides. They may be in the exons (coding regions) or introns (noncoding intervening sequences). Exonic polymorphisms may or may not alter the encoded protein, and variant proteins may or may not display altered function. Similarly, polymorphisms in intronic regions may or may not alter gene expression and protein level.

As variation in the human genome is increasingly well documented, associations are being described between polymorphisms and various traits (including response to drug therapy). Some of these rely on well-developed chains of evidence, including in vitro studies demonstrating variant protein function, familial aggregation of the variant allele with the trait, and association studies in large populations. In other cases, the associations are less compelling. Identifying "real" associations is one challenge that must be overcome before the concept of genotyping to identify optimal drugs (or dosages) in individual patients prior to prescribing can be considered for widespread clinical practice. Nevertheless, the appeal of using genomic information to guide therapy is considerable.

Rates of drug efficacy and adverse effects often vary among ethnic groups. Many explanations for such differences are plausible; genomic approaches have now established that functionally important variants determining differences in drug response often display differing distributions among ethnic groups. This finding may have importance for drug use among ethnic groups, as well as in drug development.

Genetically Determined Drug Disposition and Variable Effects

The concept that genetically determined variations in drug metabolism might be associated with variable drug levels, and hence effect, was advanced at the end of the nineteenth century, and the first examples of familial clustering of unusual drug responses due to this mechanism were noted in the mid-twentieth century. Clinically important genetic variants have been described in multiple molecular pathways of drug disposition (Table 1). A distinct multimodal distribution of drug disposition (as shown in Fig. 6) argues for a predominant effect of variants in a single gene in the metabolism of that substrate. Individuals with two alleles (variants) encoding for nonfunctional protein make up one group, often termed poor metabolizers (PM phenotype); many variants can produce such a loss of function, complicating the use of genotyping in clinical practice. Individuals with one functional allele make up a second (intermediate metabolizers) and may or may not be distinguishable from those with two functional alleles (extensive metabolizers, EMs). Ultra-rapid metabolizers with especially high enzymatic activity (occasionally due to gene duplication; Fig. 6) have also been described for some traits. Many drugs in widespread use can inhibit specific drug disposition pathways (Table 1), and so EM individuals receiving such agents can respond like PM patients (phenocopying). Polymorphisms in genes encoding drug uptake or drug efflux transporters may be another contributor to variability in drug delivery to target sites and, hence, drug effects. However, loss-of-function alleles in these genes have not yet been described.

Fig.6. A. CYP2D6 metabolic activity was assessed in 290 subjects by administration of a test dose of a probe substrate and measurement of urinary formation of the CYP2D6-generated metabolite. The heavy arrow indicates a clear antimode, separating poor metabolizer subjects (PMs, green), with two loss-of-function CYP2D6 alleles, indicated by the intron-exon structures below the bar chart. Individuals with one or two functional alleles are grouped together as extensive metabolizers (EMs, blue). Also shown are ultrarapid metabolizers (UMs), with 2–12 functional copies of the gene (red), displaying the greatest enzyme activity. (Adapted by permission from M-L Dahl et al: J Pharmacol Exp Ther 274:516, 1995.) B. These simulations show the predicted effects of CYP2D6 genotype on disposition of a substrate drug. With a single dose (left), there is an inverse "gene-dose" relationship between the number of active alleles and the areas under the time-concentration curves (smallest in UM subjects; highest in PM subjects); this indicates that clearance is greatest in UM subjects. In addition, elimination half-life is longest in PM subjects. The right panel shows that these single dose differences are exaggerated during chronic therapy: steady-state concentration is much higher in PM subjects (decreased clearance), as is the time required to achieve steady state (longer elimination half-life).

CYP Variants

CYP3A4 is the most abundant hepatic and intestinal CYP and is also the enzyme responsible for metabolism of the greatest number of drugs in therapeutic use. CYP3A4 activity is highly variable (up to an order of magnitude) among individuals, but the underlying mechanisms are not yet well understood. A closely related gene, encoding CYP3A5 (which shares substrates with CYP3A4), does display loss-of-function variants, especially in African-derived populations. CYP3A refers to both enzymes.

CYP2D6 is second to CYP3A4 in the number of commonly used drugs that it metabolizes. CYP2D6 is polymorphically distributed, with about 7% of European- and African-derived populations (but very few Asians) displaying the PM phenotype (Fig. 6). Dozens of loss-of-function variants in the CYP2D6 gene have been described; the PM phenotype arises in individuals with two such alleles. In addition, ultrarapid metabolizers with multiple functional copies of the CYP2D6 gene have been identified, particularly among northern Africans.

CYP2D6 represents the main metabolic pathway for a number of drugs (Table 1). Codeine is biotransformed by CYP2D6 to the potent active metabolite morphine, so its effects are blunted in PMs and exaggerated in ultrarapid metabolizers. In the case of drugs with beta-blocking properties metabolized by CYP2D6, including ophthalmic timolol and the sodium channel–blocking antiarrhythmic propafenone, PM subjects display greater signs of beta blockade (including bradycardia and bronchospasm) than EMs. Further, in EM subjects, propafenone elimination becomes zero-order at higher doses; so, for example, a tripling of the dose may lead to a tenfold increase in drug concentration. The oral hypoglycemic agent phenformin was withdrawn because it occasionally caused profound lactic acidosis; this likely arose as a result of high concentrations in CYP2D6 PMs. Ultrarapid metabolizers may require very high dosages of tricyclic antidepressants to achieve a therapeutic effect and, with codeine, may display transient euphoria and nausea due to very rapid generation of morphine. Tamoxifen undergoes CYP2D6-mediated biotransformation to an active metabolite, so its efficacy may be in part related to this polymorphism. In addition, the widespread use of selective serotonin reuptake inhibitors (SSRIs) to treat tamoxifen-related hot flashes may also alter the drug's effects since many SSRIs (fluoxetine, paroxetine) are also CYP2D6 inhibitors.

The PM phenotype for CYP2C19 is common (20%) among Asians and rarer (3–5%) in European-derived populations. The impact of polymorphic CYP2C19-mediated metabolism has been demonstrated with the proton pump inhibitor omeprazole, where ulcer cure rates with "standard" dosages were markedly lower in EM patients (29%) than in PMs (100%). Thus, understanding the importance of this polymorphism would have been important in developing the drug, and knowing a patient's CYP2C19 genotype should improve therapy.

There are common allelic variants of CYP2C9 that encode proteins with loss of catalytic function. These variant alleles are associated increased rates of neurologic complications with phenytoin and of hypoglycemia with glipizide. The angiotensin-receptor blocker losartan is a prodrug that is bioactivated by CYP2C9; as a result, PMs and those receiving inhibitor drugs may display little response to therapy.

Transferase Variants

One of the most extensively studied phase II polymorphisms is the PM trait for thiopurine S-methyltransferase (TPMT). TPMT bioinactivates the antileukemic drug 6-mercaptopurine. Further, 6-mercaptopurine is itself an active metabolite of the immunosuppressive azathioprine. Homozygotes for alleles encoding the inactive TPMT (1 in 300 individuals) predictably exhibit severe and potentially fatal pancytopenia on standard doses of azathioprine or 6-mercaptopurine. On the other hand, homozygotes for fully functional alleles may display less anti-inflammatory or antileukemic effect with the drugs.

N-acetylation is catalyzed by hepatic N-acetyl transferase (NAT), which represents the activity of two genes, NAT-1 and NAT-2. Both enzymes transfer an acetyl group from acetyl coenzyme A to the drug; NAT-1 activity is generally constant, while polymorphisms in NAT-2 result in individual differences in the rate at which drugs are acetylated and thus define "rapid acetylators" and "slow acetylators." Slow acetylators make up ~50% of European- and African-derived populations but are less common among Asians.

Slow acetylators have an increased incidence of the drug-induced lupus syndrome during procainamide and hydralazine therapy and of hepatitis with isoniazid. Induction of CYPs (e.g., by rifampin) also increases the risk of isoniazid-related hepatitis, likely reflecting generation of reactive metabolites of acetylhydrazine, itself an isoniazid metabolite.

Individuals homozygous for a common promoter polymorphism that reduces transcription of uridine diphosphate glucuronosyltransferase (UGT1A1) have benign hyperbilirubinemia. This variant has also been associated with diarrhea and increased bone marrow depression with the antineoplastic prodrug irinotecan, whose active metabolite is normally detoxified by this UGT1A1-mediated glucuronidation.

Variability in the Molecular Targets with Which Drugs Interact

As molecular approaches identify specific gene products as targets of drug action, polymorphisms that alter the expression or function of these drug targets—and thus modulate their actions in patients—are also being recognized. Multiple polymorphisms identified in the β₂-adrenergic receptor appear to be linked to specific phenotypes in asthma and congestive heart failure, diseases in which β₂-receptor function might be expected to determine prognosis. Polymorphisms in the β₂-receptor gene have also been associated with response to inhaled β₂-receptor agonists, while those in the β₁-adrenergic receptor gene have been associated with variability in heart rate slowing and blood pressure lowering (Fig. 5B ). In addition, in heart failure, a common polymorphism in the β₁-adrenergic receptor gene has been implicated in variable clinical outcome during therapy with the beta blocker bucindolol. Response to the 5-lipoxygenase inhibitor zileuton in asthma has been linked to polymorphisms that determine the expression level of the 5-lipoxygenase gene. Herceptin, which potentiates anthracycline-related cardiotoxicity, is ineffective in breast cancers that do not express the herceptin receptor; thus, "genotyping" the tumor is a mechanism to avoid potentially toxic therapy in patients who would derive no benefit.

Drugs may also interact with genetic pathways of disease, to elicit or exacerbate symptoms of the underlying conditions. In the porphyrias, CYP inducers are thought to increase the activity of enzymes proximal to the deficient enzyme, exacerbating or triggering attacks. Deficiency of glucose-6-phosphate dehydrogenase (G6PD), most often in individuals of African or Mediterranean descent, increases risk of hemolytic anemia in response to primaquine and a number of other drugs that do not cause hemolysis in patients with normal amounts of the enzyme. Patients with mutations in the ryanodine receptor, which controls intracellular calcium in skeletal muscle and other tissues, may be asymptomatic until exposed to certain general anesthetics, which trigger the syndrome of malignant hyperthermia. Certain antiarrhythmics and other drugs can produce marked QT prolongation and torsades des pointes, and in some patients this adverse effect represents unmasking of previously subclinical congenital long QT syndrome.

Polymorphisms that Modulate the Biologic Context Within Which the Drug-Target Interactions Occur

The interaction of a drug with its molecular target is translated into a clinical action in a complex biologic milieu that is itself often perturbed by disease. Thus, polymorphisms that determine variability in this biology may profoundly influence drug response, although the genes involved are not themselves directly targets of drug action. Polymorphisms in genes important for lipid homeostasis (such as the ABCA1 transporter and the cholesterol ester transport protein) modulate response to 3-hydroxymethylglutaryl-CoA (HMG-CoA) reductase inhibitors, "statins." In one large study, the combination of diuretic use combined with a variant in the adducin gene (encoding a cytoskeletal protein important for renal tubular sodium absorption) decreased stroke or myocardial infarction risk, while neither factor alone had an effect. Common polymorphisms in ion channel genes that are not themselves the target of QT-prolonging drugs may nevertheless influence the extent to which those drugs affect the electrocardiogram and produce arrhythmias. These findings not only point to new mechanisms for understanding drug action, but also can be used for drug development. For example, a set of polymorphisms in the gene encoding 5-lipoxygenase activating protein (FLAP) has been identified as a risk factor for myocardial infarction in an Icelandic population, and an initial clinical trial of a FLAP inhibitor was conducted only in subjects with the high risk allele.

Multiple Variants Modulating Drug Effects

As this discussion makes clear, for each drug with a defined mechanism of action and disposition pathways, a set of "candidate genes," in which polymorphisms may mediate variable clinical responses, can be identified. Indeed, polymorphisms in multiple genes have been associated with variability in the effect of a single drug. CYP2C9 loss-of-function variants are associated with a requirement for lower maintenance doses of the vitamin K antagonist anticoagulant warfarin. In rarer (<2%)>CYP2C9, variants in the promoter region of VKORC1, encoding a vitamin K epoxide reductase, predict warfarin dosages; these promoter variants are in tight linkage disequilibrium , i.e. genotyping at one polymorphic site within this haplotype block provides reliable information on the identity of genotypes at other linked sites. Thus, variability in response to warfarin can be linked to both coding region polymorphisms in CYP2C9 and promoter haplotypes in the warfarin target VKORC1.

As genotyping technologies improve and data sets of patients with well-documented drug responses are accumulated, it is becoming possible to interrogate hundreds of polymorphisms in dozens of candidate genes. This approach has been applied to implicate linked noncoding polymorphisms in the HMG-CoA reductase gene as predicting efficacy of HMG-CoA reductase inhibitors, and in variants in the gene-encoding corticotrophin-releasing hormone receptor 1 as predicting efficacy of inhaled steroids in asthma.

Technologies are now evolving to interrogate hundreds of thousands of SNPs across the genome, or to rapidly resequence each patient's genome. These approaches, which have been applied to identify new genes modulating disease susceptibility, may be applicable to the problem of identifying genomic predictors of variable drug effects.

Prospects for Incorporating Genetic Information into Clinical Practice

The examples of associations between specific genotypes and drug responses raise the tantalizing prospect that patients will undergo routine genotyping for loci known to modulate drug levels or response prior to receiving a prescription. Indeed, clinical tests for some of the polymorphisms described above, including those in TPMT, UGT1A1, CYP2D6, and CYP2C19, have been approved by the U.S. Food and Drug Administration (FDA). The twin goals are to identify patients likely to exhibit adverse effects and those most likely to respond well. Obstacles that must be overcome before this vision becomes a reality include replication of even the most compelling associations, demonstrations of cost-effectiveness, development of readily useable genotyping technologies, and ethical issues involved in genotyping. While these barriers seem daunting, the field is very young and evolving rapidly. Indeed, one major result of understanding of the role of genetics in drug action has been improved screening of drugs during the development process to reduce the likelihood of highly variable metabolism or unanticipated toxicity (such as torsades des pointes).

INTERACTIONS BETWEEN DRUGS

Drug interactions can complicate therapy by increasing or decreasing the action of a drug; interactions may be based on changes in drug disposition or in drug response in the absence of changes in drug levels. Interactions must be considered in the differential diagnosis of any unusual response occurring during drug therapy. Prescribers should recognize that patients often come to them with a legacy of drugs acquired during previous medical experiences, often with multiple physicians who may not be aware of all the patient's medications. A meticulous drug history should include examination of the patient's medications and, if necessary, calls to the pharmacist to identify prescriptions. It should also address the use of agents not often volunteered during questioning, such as over-the-counter (OTC) drugs, health food supplements, and topical agents such as eye drops. Lists of interactions are available from a number of electronic sources. While it is unrealistic to expect the practicing physician to memorize these, certain drugs consistently run the risk of generating interactions, often by inhibiting or inducing specific drug elimination pathways. Examples are presented below and in Table 2. Accordingly, when these drugs are started or stopped, prescribers must be especially alert to the possibility of interactions.

Table 2 Drugs with a High Risk of Generating Pharmacokinetic Interactions

Drug Mechanism Examples Antacids Bile acid sequestrants Reduced absorption Antacids/tetracyclines Cholestryamine/digoxin Proton pump inhibitors H2-receptor blockers Altered gastric pH Ketoconazole absorption decreased Rifampin Carbamazepine Barbiturates Phenytoin St. John's wort Glutethimide Induction of hepatic metabolism Decreased concentration and effects of warfarin quinidine cyclosporine losartan oral contraceptives methadone Tricyclic antidepressants Fluoxetine Quinidine Inhibitors of CYP2D6 Increased β-blockade Decreased codeine effect Cimetidine Inhibitor of multiple CYPs Increased concentration and effects of warfarin theophylline phenytoin Ketoconazole, itraconazole Erythromycin, clarithromycin Calcium channel blockers Ritonavir Inhibitor of CYP3A Increased concentration and toxicity of some HMG-CoA reductase inhibitors cyclosporine cisapride, terfenadine (now withdrawn) Increased concentration and effects of indinavir (with ritonavir) Decreased clearance and dose requirement for cyclosporine (with calcium channel blockers) Allopurinol Xanthine oxidase inhibitor Azathioprine and 6-mercaptopurine toxicity Amiodarone Inhibitor of many CYPs and of P-glycoprotein Decreased clearance (risk of toxicity) for warfarin, digoxin, quinidine Gemfibrazol (and other fibrates) CYP3A inhibition Rhabdomyolysis when co-prescribed with some HMG-CoA reductase inhibitors Quinidine Amiodarone Verapamil Cyclosporine Itraconazole Erythromycin P-glycoprotein inhibition Risk of digoxin toxicity Phenylbutazone Probenecid Salicylates Inhibition of renal tubular transport Salicylates -> increased risk of methotrexate toxicity

Pharmacokinetic Interactions Causing Decreased Drug Effects

Gastrointestinal absorption can be reduced if a drug interaction results in drug binding in the gut, as with aluminum-containing antacids, kaolin-pectin suspensions, or bile acid sequestrants. Drugs such as histamine H₂ receptor antagonists or proton pump inhibitors that alter gastric pH may decrease the solubility and hence absorption of weak bases such as ketoconazole.

Expression of some genes responsible for drug elimination, notably CYP3A and MDR1, can be markedly increased by "inducing" drugs, such as rifampin, carbamazepine, phenytoin, St. John's wort, and glutethimide and by smoking, exposure to chlorinated insecticides such as DDT (CYP1A2), and chronic alcohol ingestion. Administration of inducing agents lowers plasma levels over 2–3 weeks as gene expression is increased. If a drug dose is stabilized in the presence of an inducer that is subsequently stopped, major toxicity can occur as clearance returns to preinduction levels and drug concentrations rise. Individuals vary in the extent to which drug metabolism can be induced, likely through genetic mechanisms.

Interactions that inhibit the bioactivation of prodrugs will similarly decrease drug effects. The analgesic effect of codeine depends on its metabolism to morphine via CYP2D6. Thus, the CYP2D6 inhibitor quinidine reduces the analgesic efficacy of codeine in EMs.

Interactions that decrease drug delivery to intracellular sites of action can decrease drug effects: tricyclic antidepressants can blunt the antihypertensive effect of clonidine by decreasing its uptake into adrenergic neurons. Reduced CNS penetration of multiple HIV protease inhibitors (with the attendant risk of facilitating viral replication in a sanctuary site) appears attributable to P-glycoprotein-mediated exclusion of the drug from the CNS; indeed, inhibition of P-glycoprotein has been proposed as a therapeutic approach to enhance drug entry to the CNS (Fig. 5A ).

Pharmacokinetic Interactions Causing Increased Drug Effects

The most common mechanism here is inhibition of drug elimination. In contrast to induction, new protein synthesis is not involved, and the effect develops as drug and any inhibitor metabolites accumulate (a function of their elimination half-lives). Since shared substrates of a single enzyme can compete for access to the active site of the protein, many CYP substrates can also be considered inhibitors. However, some drugs are especially potent as inhibitors (and occasionally may not even be substrates) of specific drug-elimination pathways, and so it is in the use of these agents that clinicians must be most alert to the potential for interactions (Table 2). Commonly implicated interacting drugs of this type include cimetidine, erythromycin and some other macrolide antibiotics (clarithromycin but not azithromycin), ketoconazole and other azole antifungals, the antiretroviral agent ritonavir, and high concentrations of grapefruit juice (Table 2). The consequences of such interactions will depend on the drug whose elimination is being inhibited; high-risk drugs are those for which alternate pathways of elimination are not available and for which drug accumulation increases the risk of serious toxicity (see "The Concept of High-Risk Pharmacokinetics," above). Examples include CYP3A inhibitors increasing the risk of cyclosporine toxicity or of rhabdomyolysis with some HMG-CoA reductase inhibitors (lovastatin, simvastatin, atorvastatin), and P-glycoprotein inhibitors increasing risk of digoxin toxicity.

Phenytoin, an inducer of many systems, including CYP3A, inhibits CYP2C9. CYP2C9 metabolism of losartan to its active metabolite is inhibited by phenytoin, with potential loss of antihypertensive effect.

The antiviral ritonavir is a very potent CYP3A4 inhibitor that has been added to anti-HIV regimens, not because of its antiviral effects but because it decreases clearance, and hence increases efficacy, of other anti-HIV agents. Grapefruit (but not orange) juice inhibits CYP3A, especially at high doses; patients receiving drugs where even modest CYP3A inhibition may increase the risk of adverse effects (e.g., cyclosporine, some HMG-CoA reductase inhibitors) should therefore avoid grapefruit juice.

CYP2D6 is markedly inhibited by quinidine, a number of neuroleptic drugs (chlorpromazine and haloperidol), and the SSRIs fluoxetine and paroxetine. Clinical consequences of fluoxetine's interaction with CYP2D6 substrates may not be apparent for weeks after the drug is started, because of its very long half-life and slow generation of a CYP2D6-inhibiting metabolite.

6-Mercaptopurine, the active metabolite of azathioprine, is metabolized not only by TPMT but also by xanthine oxidase. When allopurinol, a potent inhibitor of xanthine oxidase, is administered with standard doses of azathioprine or 6-mercaptopurine, life-threatening toxicity (bone marrow suppression) can result.

A number of drugs are secreted by the renal tubular transport systems for organic anions. Inhibition of these systems can cause excessive drug accumulation. Salicylate, for example, reduces the renal clearance of methotrexate, an interaction that may lead to methotrexate toxicity. Renal tubular secretion contributes substantially to the elimination of penicillin, which can be inhibited (to increase its therapeutic effect) by probenecid. Similarly, inhibition of the tubular cation transport system by cimetidine decreases the renal clearance of dofetilide and of procainamide and its active metabolite NAPA.

Drug Interactions Not Mediated by Changes in Drug Disposition

Drugs may act on separate components of a common process to generate effects greater than either has alone. Antithrombotic therapy with combinations of antiplatelet agents (glycoprotein IIb/IIIa inhibitors, aspirin, clopidogrel) and anticoagulants (warfarin, heparins) are often used in the treatment of vascular disease, although such combinations carry an increased risk of bleeding.

Nonsteroidal anti-inflammatory drugs (NSAIDs) cause gastric ulcers, and in patients treated with warfarin, the risk of bleeding from a peptic ulcer is increased almost threefold by concomitant use of an NSAID.

Indomethacin, piroxicam, and probably other NSAIDs antagonize the antihypertensive effects of β-adrenergic receptor blockers, diuretics, ACE inhibitors, and other drugs. The resulting elevation in blood pressure ranges from trivial to severe. This effect is not seen with aspirin and sulindac but has been found with the cyclooxygenase 2 (COX-2) inhibitor celecoxib.

Torsades des pointes during administration of QT-prolonging antiarrhythmics (quinidine, sotalol, dofetilide) occur much more frequently in patients receiving diuretics, probably reflecting hypokalemia. In vitro, hypokalemia not only prolongs the QT interval in the absence of drug but also potentiates drug block of ion channels that results in QT prolongation. Also, some diuretics have direct electrophysiologic actions that prolong QT.

The administration of supplemental potassium leads to more frequent and more severe hyperkalemia when potassium elimination is reduced by concurrent treatment with ACE inhibitors, spironolactone, amiloride, or triamterene.

The pharmacologic effects of sildenafil result from inhibition of the phosphodiesterase type 5 isoform that inactivates cyclic GMP in the vasculature. Nitroglycerin and related nitrates used to treat angina produce vasodilation by elevating cyclic GMP. Thus, coadministration of these nitrates with sildenafil can cause profound hypotension, which can be catastrophic in patients with coronary disease.

Sometimes, combining drugs can increase overall efficacy and/or reduce drug-specific toxicity. Such therapeutically useful interactions are described in chapters dealing with specific disease entities, elsewhere in this text.

ADVERSE REACTIONS TO DRUGS

The beneficial effects of drugs are coupled with the inescapable risk of untoward effects. The morbidity and mortality from these untoward effects often present diagnostic problems because they can involve every organ and system of the body; these may be mistaken for signs of underlying disease.

Adverse reactions can be classified in two broad groups. One type results from exaggeration of an intended pharmacologic action of the drug, such as increased bleeding with anticoagulants or bone marrow suppression with antineoplastics. The other type of adverse reactions ensues from toxic effects unrelated to the intended pharmacologic actions. The latter effects are often unanticipated (especially with new drugs) and frequently severe and result from recognized as well as undiscovered mechanisms.

Drugs may increase the frequency of an event that is common in a general population, and this may be especially difficult to recognize; the increase in myocardial infarctions with the COX-2 inhibitor rofecoxib is an excellent example. Drugs can also cause rare and serious adverse effects, such as hematologic abnormalities, arrhythmias, or hepatic or renal dysfunction. Prior to regulatory approval and marketing, new drugs are tested in relatively few patients who tend to be less sick and to have fewer concomitant diseases than those patients who subsequently receive the drug therapeutically. Because of the relatively small number of patients studied in clinical trials and the selected nature of these patients, rare adverse effects are generally not detected prior to a drug's approval, and physicians therefore need to be cautious in the prescription of new drugs and alert for the appearance of previously unrecognized adverse events.

Elucidating mechanisms underlying adverse drug effects can assist development of safer compounds or allow a patient subset at especially high risk to be excluded from drug exposure. National adverse reaction reporting systems, such as those operated by the FDA (suspected adverse reactions can be reported online at http://www.fda.gov/medwatch/report/hcp.htm) and the Committee on Safety of Medicines in Great Britain, can prove useful. The publication or reporting of a newly recognized adverse reaction can in a short time stimulate many similar such reports of reactions that previously had gone unrecognized.

Occasionally, "adverse" effects may be exploited to develop an entirely new indication for a drug. Unwanted hair growth during minoxidil treatment of severely hypertensive patients led to development of the drug for hair growth. Sildenafil was initially developed as an antianginal, but its effects to alleviate erectile dysfunction not only led to a new drug indication but also to increased understanding of the role of type 5 phosphodiesterase in erectile tissue. These examples further reinforce the concept that prescribers must remain vigilant to the possibility that unusual symptoms may reflect unappreciated drug effects.

Some 25–50% of patients make errors in self-administration of prescribed medicines, and these errors can be responsible for adverse drug effects. Similarly, patients commit errors in taking OTC drugs by not reading or following the directions on the containers. Physicians must recognize that providing directions with prescriptions does not always guarantee compliance.

In hospital, drugs are administered in a controlled setting, and patient compliance is, in general, ensured. Errors may occur nevertheless—the wrong drug or dose may be given or the drug may be given to the wrong patient—and improved drug distribution and administration systems are addressing this problem.

Epidemiology

Patients receive, on average, 10 different drugs during each hospitalization. The sicker the patient, the more drugs are given, and there is a corresponding increase in the likelihood of adverse drug reactions. When <6>15 drugs are given, the probability is >40%. Retrospective analyses of ambulatory patients have revealed adverse drug effects in 20%. Serious adverse reactions are also well recognized with "herbal" remedies and OTC compounds: examples include kava-associated hepatotoxicity, L-tryptophan-associated eosinophilia-myalgia, and phenylpropanolamine-associated stroke, each of which has caused fatalities.

A small group of widely used drugs accounts for a disproportionate number of reactions. Aspirin and other NSAIDs, analgesics, digoxin, anticoagulants, diuretics, antimicrobials, glucocorticoids, antineoplastics, and hypoglycemic agents account for 90% of reactions, although the drugs involved differ between ambulatory and hospitalized patients

Toxicity Unrelated to a Drug's Primary Pharmacologic Activity

Cytotoxic Reactions

Drugs or more commonly reactive metabolites generated by CYPs can covalently bind to tissue macromolecules (such as proteins or DNA) to cause tissue toxicity. Because of the reactive nature of these metabolites, covalent binding often occurs close to the site of production, typically the liver.

The most common cause of drug-induced hepatotoxicity is acetaminophen overdosage. Normally, reactive metabolites are detoxified by combining with hepatic glutathione. When glutathione becomes exhausted, the metabolites bind instead to hepatic protein, with resultant hepatocyte damage. The hepatic necrosis produced by the ingestion of acetaminophen can be prevented or attenuated by the administration of substances such as N-acetylcysteine that reduce the binding of electrophilic metabolites to hepatic proteins. The risk of acetaminophen-related hepatic necrosis is increased in patients receiving drugs such as phenobarbital or phenytoin that increase the rate of drug metabolism or ethanol that exhaust glutathione stores. Such toxicity has even occurred with therapeutic dosages, so patients at risk through these mechanisms should be warned.

Immunologic Mechanisms

Most pharmacologic agents are small molecules with low molecular weights (<2000)>

Drug stimulation of antibody production may mediate tissue injury by several mechanisms. The antibody may attack the drug when the drug is covalently attached to a cell and thereby destroy the cell. This occurs in penicillin-induced hemolytic anemia. Antibody-drug-antigen complexes may be passively adsorbed by a bystander cell, which is then destroyed by activation of complement; this occurs in quinine- and quinidine-induced thrombocytopenia. Heparin-induced thrombocytopenia arises when antibodies against complexes of platelet factor 4 peptide and heparin generate immune complexes that activate platelets; thus, the thrombocytopenia is accompanied by "paradoxical" thrombosis and is treated with thrombin inhibitors. Drugs or their reactive metabolites may alter a host tissue, rendering it antigenic and eliciting autoantibodies. For example, hydralazine and procainamide (or their reactive metabolites) can chemically alter nuclear material, stimulating the formation of antinuclear antibodies and occasionally causing lupus erythematosus. Drug-induced pure red cell aplasia is due to an immune-based drug reaction. Red cell formation in bone marrow cultures can be inhibited by phenytoin and purified IgG obtained from a patient with pure red cell aplasia associated with phenytoin.

Serum sickness results from the deposition of circulating drug-antibody complexes on endothelial surfaces. Complement activation occurs, chemotactic factors are generated locally, and an inflammatory response develops at the site of complex entrapment. Arthralgias, urticaria, lymphadenopathy, glomerulonephritis, or cerebritis may result. Foreign proteins (vaccines, streptokinase, therapeutic antibodies) and antibiotics are common causes. Many drugs, particularly antimicrobial agents, ACE inhibitors, and aspirin, can elicit anaphylaxis with production of IgE, which binds to mast cell membranes. Contact with a drug antigen initiates a series of biochemical events in the mast cell and results in the release of mediators that can produce the characteristic urticaria, wheezing, flushing, rhinorrhea, and (occasionally) hypotension.

Drugs may also elicit cell-mediated immune responses. Topically administered substances may interact with sulfhydryl or amino groups in the skin and react with sensitized lymphocytes to produce the rash characteristic of contact dermatitis. Other types of rashes may also result from the interaction of serum factors, drugs, and sensitized lymphocytes.

Diagnosis and Treatment of Adverse Drug Reactions

The manifestations of drug-induced diseases frequently resemble those of other diseases, and a given set of manifestations may be produced by different and dissimilar drugs. Recognition of the role of a drug or drugs in an illness depends on appreciation of the possible adverse reactions to drugs in any disease, on identification of the temporal relationship between drug administration and development of the illness, and on familiarity with the common manifestations of the drugs. Many associations between particular drugs and specific reactions have been described, but there is always a "first time" for a novel association, and any drug should be suspected of causing an adverse effect if the clinical setting is appropriate.

Illness related to a drug's intended pharmacologic action is often more easily recognized than illness attributable to immune or other mechanisms. For example, side effects such as cardiac arrhythmias in patients receiving digitalis, hypoglycemia in patients given insulin, and bleeding in patients receiving anticoagulants are more readily related to a specific drug than are symptoms such as fever or rash, which may be caused by many drugs or by other factors.

Electronic sources of adverse drug reactions can be useful. However, exhaustive compilations often provide little sense of perspective in terms of frequency and seriousness, which can vary considerably among patients.

Eliciting a drug history from patients is important for diagnosis. Attention must be directed to OTC drugs and herbal preparations as well as to prescription drugs. Each type can be responsible for adverse drug effects, and adverse interactions may occur between OTC drugs and prescribed drugs. Loss of efficacy of oral contraceptives or cyclosporine by concurrent use of St. John's wort are examples. In addition, it is common for patients to be cared for by several physicians, and duplicative, additive, counteractive, or synergistic drug combinations may therefore be administered if the physicians are not aware of the patients' drug histories. Every physician should determine what drugs a patient has been taking, for the previous month or two ideally, before prescribing any medications. Medications stopped for inefficacy or adverse effects should be documented to avoid pointless and potentially dangerous reexposure. A frequently overlooked source of additional drug exposure is topical therapy; for example, a patient complaining of bronchospasm may not mention that an ophthalmic beta blocker is being used unless specifically asked. A history of previous adverse drug effects in patients is common. Since these patients have shown a predisposition to drug-induced illnesses, such a history should dictate added caution in prescribing drugs.

Laboratory studies may include demonstration of serum antibody in some persons with drug allergies involving cellular blood elements, as in agranulocytosis, hemolytic anemia, and thrombocytopenia. For example, both quinine and quinidine can produce platelet agglutination in vitro in the presence of complement and the serum from a patient who has developed thrombocytopenia following use of this drug. Biochemical abnormalities such as G6PD deficiency, serum pseudocholinesterase level, or genotyping may also be useful in diagnosis, often after an adverse effect has occurred in the patient or a family member.

Once an adverse reaction is suspected, discontinuation of the suspected drug followed by disappearance of the reaction is presumptive evidence of a drug-induced illness. Confirming evidence may be sought by cautiously reintroducing the drug and seeing if the reaction reappears. However, that should be done only if confirmation would be useful in the future management of the patient and if the attempt would not entail undue risk. With concentration-dependent adverse reactions, lowering the dosage may cause the reaction to disappear, and raising it may cause the reaction to reappear. When the reaction is thought to be allergic, however, readministration of the drug may be hazardous, since anaphylaxis may develop. Readministration is unwise under these conditions unless no alternative drugs are available and treatment is necessary.

If the patient is receiving many drugs when an adverse reaction is suspected, the drugs likeliest to be responsible can usually be identified; this should include both potential culprit agents as well as drugs that alter their elimination. All drugs may be discontinued at once or, if this is not practical, discontinued one at a time, starting with the ones most suspect, and the patient observed for signs of improvement. The time needed for a concentration-dependent adverse effect to disappear depends on the time required for the concentration to fall below the range associated with the adverse effect; that, in turn, depends on the initial blood level and on the rate of elimination or metabolism of the drug. Adverse effects of drugs with long half-lives or those not directly related to serum concentration may take a considerable time to disappear.

SUMMARY

Modern clinical pharmacology aims to replace empiricism in the use of drugs with therapy based on in-depth understanding of factors that determine an individual's response to drug treatment. Molecular pharmacology, pharmacokinetics, genetics, clinical trials, and the educated prescriber all contribute to this process. No drug response should ever be termed idiosyncratic; all responses have a mechanism whose understanding will help guide further therapy with that drug or successors. This rapidly expanding understanding of variability in drug actions makes the process of prescribing drugs increasingly daunting for the practitioner. However, fundamental principles should guide this process: The benefits of drug therapy, however defined, should always outweigh the risk. The smallest dosage necessary to produce the desired effect should be used. The number of medications and doses per day should be minimized. Although the literature is rapidly expanding, accessing it is becoming easier; tools such as computers and hand-held devices to search databases of literature and unbiased opinion will become increasingly commonplace. Genetics play a role in determining variability in drug response and may become a part of clinical practice. Prescribers should be particularly wary when adding or stopping specific drugs that are especially liable to provoke interactions and adverse reactions. Prescribers should use only a limited number of drugs, with which they are thoroughly familiar. FURTHER READINGS Bailey DG, Dresser GK: Interactions between grapefruit juice and cardiovascular drugs. Am J Cardiovasc Drugs 4:281, 2004 [PMID: 15449971] Chasman DI et al: Pharmacogenetic study of statin therapy and cholesterol reduction. JAMA 291:2821, 2004 [PMID: 15199031] Eichelbaum M et al: Pharmacogenomics and individualized drug therapy. Annu Rev Med 57:119, 2006 [PMID: 16409140] Gurwitz JH: Serious adverse drug effects—Seeing the trees through the forest. N Engl J Med 354:1413, 2006 [PMID: 16510740] Hakonarson H et al: Effects of a 5-lipoxygenase-activating protein inhibitor on biomarkers associated with risk of myocardial infarction: a randomized trial. JAMA 293:2245, 2005 [PMID: 15886380] Johnson JA, Turner ST: Hypertension pharmacogenomics: Current status and future directions. Curr Opin Mol Ther 7:218, 2005 [PMID: 15977418] Kim RB: Transporters and drug discovery: Why, when, and how. Mol Pharm 3:26, 2006 [PMID: 16686366] Liggett SB et al: A polymorphism within a conserved β1-adrenergic receptor motif alters cardiac function and β-blocker response in human heart failure. Proc Natl Acad Sci USA 103:11288–11293, 2006 [PMID: 16844790] Navarro VJ, Senior JR: Drug-related hepatotoxicity. N Engl J Med 354:731, 2006 [PMID: 16481640] Pirmohamed M et al: Adverse drug reactions as cause of admission to hospital: Prospective analysis of 18,820 patients. Br Med J 329:15, 2004 [PMID: 15231615] Rieder MJ et al: Effect of VKORC1 haplotypes on transcriptional regulation and warfarin dose. N Engl J Med 352:2285, 2005 [PMID: 15930419] Roden DM: Drug-induced prolongation of the QT Interval. N Engl J Med 350:1013, 2004 [PMID: 14999113] ——— et al: Pharmacogenomics: challenges and opportunities. Ann Intern Med, 145:745, 2006 Shu Y et al: Evolutionary conservation predicts function of variants of the human organic cation transporter, OCT1. Proc Natl Acad Sci USA 100:5902, 2003 [PMID: 12719534] Weiss ST et al: Asthma steroid pharmacogenetics: A study strategy to identify replicated treatment responses. Proc Am Thorac Soc 1:364, 2004 [PMID: 16113459]