ORAL ADVERSE DRUG REACTIONS TO CARDIOVASCULAR DRUGS Lis Andersen Torpet* Camilla Kragelund Jesper Reibel Birgitte Nauntofte Department of Oral Medicine, Clinical Oral Physiology, Oral Pathology & Anatomy, School of Dentistry, Faculty of Health Sciences, University of Copenhagen, 20 Norre Allé, DK-2200 Copenhagen N, Denmark; *corresponding author, [email protected] ABSTRACT: A great many cardiovascular drugs (CVDs) have the potential to induce adverse reactions in the mouth. The prevalence of such reactions is not known, however, since many are asymptomatic and therefore are believed to go unreported. As more drugs are marketed and the population includes an increasing number of elderly, the number of drug prescriptions is also expected to increase. Accordingly, it can be predicted that the occurrence of adverse drug reactions (ADRs), including the oral ones (ODRs), will continue to increase. ODRs affect the oral mucous membrane, saliva production, and taste. The pathogenesis of these reactions, especially the mucosal ones, is largely unknown and appears to involve complex interactions among the drug in question, other medications, the patient's underlying disease, genetics, and life-style factors. Along this line, there is a growing interest in the association between pharmacogenetic polymorphism and ADRs. Research focusing on polymorphism of the cytochrome P450 system (CYPs) has become increasingly important and has highlighted the intra- and inter-individual responses to drug exposure. This system has recently been suggested to be an underlying candidate regarding the pathogenesis of ADRs in the oral mucous membrane. This review focuses on those CVDs reported to induce ODRs. In addition, it will provide data on specific drugs or drug classes, and outline and discuss recent research on possible mechanisms linking ADRs to drug metabolism patterns. Abbreviations used will be as follows: ACEI, ACE inhibitor; ADR, adverse drug reaction; ANA, antinuclear antigen; ARB, angiotensin II receptor blocker; BAB, beta-adrenergic blocker; CCB, calcium-channel blocker; CDR, cutaneous drug reaction; CVD, cardiovascular drug; CYP, cytochrome P450 enzyme; EM, erythema multiforme; FDE, fixed drug eruption; I, inhibitor of CYP isoform activity; HMG-CoA, hydroxymethyl-glutaryl coenzyme A; NAT, N-acetyltransferase; ODR, oral drug reaction; RDM, reactive drug metabolite; S, substrate for CYP isoform; SJS, Stevens-Johnson syndrome; SLE, systemic lupus erythematosus; and TEN, toxic epidermal necrolysis. Key words. Oral mucous membrane, medication, CYP, drug interaction, therapeutic classes.

Introduction

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everal systemic factors are known to contribute to oral diseases or conditions, and among those are the intake of drugs. The pathogenesis of oral adverse reactions related to intake of medications is not well-understood, and the prevalence is not known. They are, however, believed to be a relatively common phenomenon, although medication-induced oral reactions are often regarded by the health profession as trivial complaints. According to the current definitions and basic requirements for the use of terms for reporting adverse drug reaction disorders, "stomatitis" and "ulcerative stomatitis" are the terms proposed by the WHO in cooperation with the Council for International Organizations of Medical Sciences (CIOMS, 1998). To date, there is no consensus on the definition of an adverse drug reaction (ADR), but Table 1 presents some of the definitions proposed. It appears that the definitions become more qualitative over time without clarifying the underlying causation of these reactions. It is still an open question if it is the clinician or the patient who defines if a drug has induced an adverse reaction. ADRs are seen in everyday practice, but estimates of the true incidence of ADRs are difficult, since many of these reactions go unreported. A French study of 2067 adults aged 20-67 years attending a health center for check-ups reported that 14.7% gave reliable histories of adverse reactions (Vervloet and

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Durham, 1998). The estimated rate of medication-related visits to office-based physicians in the United States is 7.7 per 1000 persons, but only 7% of these persons reported ADRs as their reason for the visit (Aparasu, 1999). The overall incidence of ADRs is about 3 in 1000 patients, according to the Boston Collaborative Drug surveillance program (Bigby et al., 1986). In a study based on outpatient referrals (2367 patients), the top two adverse events reported by both male and female patients were skin disorders (49%) and allergic or immunological disturbances (14%) (Tran et al., 1998). As more drugs are marketed and with an increasing number of the elderly in the population, the number of drug prescriptions will also likely increase (Gruchalla, 2000). Accordingly, it can be predicted that the occurrence of ADR, including the oral ones, will continue to increase. The prevalence of oral drug reactions (ODRs), however, is at present unknown, but dentists must be knowledgeable on the relation between medication intake and ODRs.

Mechanisms Related to ADR Pharmacological, immunological, and genetic factors are involved in the pathogenesis of ADRs (Shapiro and Shear, 1996; Zhou et al., 1996; Evans and Relling, 1999; Moore, 2001), and any drug can cause such reactions. As shown in Table 2, some drug reactions (e.g., drug overdose, drug interaction) can occur in any individual (type A or predictable reactions), whereas

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others (e.g., allergic reaction, idiosyncratic reaction) occur only in susceptible patients (type B or unpredictable reactions). Type B reactions are rare and evident only by spontaneous reporting in case-population studies, or in large cohort studies (Moore, 2001). A reaction may reflect the drug's exacerbation of pre-existing disease, or, more frequently, it represents an idiosyncratic reaction to the drug.

PHARMACOLOGICAL FACTORS

TABLE 1 Definitions* of Adverse Drug Reactions (ADRs) Proposed during the Last 30 Years WHO, 1972

"Any noxious and unintended drug effect which occurs at doses employed in man for prophylaxis, diagnosis or therapy." FDA, 1995 "An undesirable effect, reasonably associated with the use of the drug, that occurs as part of the pharmacological action of a drug or may be unpredictable in its occurrence." Laurence, 1998 "A harmful or significantly unpleasant effect caused by a dose intended for therapeutic effect (or prophylaxis or diagnosis) which warrants reduction of dose or withdrawal of the drug and/or foretells hazard from future administration." Edwards and Aronson, 2000 "An appreciably harmful or unpleasant reaction, resulting from an intervention related to the use of a medical product, which predicts hazard from future administration and warrants prevention or specific treatments, or alteration of the dosage, or withdrawal of the product."

Factors that predispose to pharmacological ADRs include dose, drug formulation, pharmacokinetic or pharmacodynamic abnormalities, and drug interactions. The metabolic conversion of drugs to chemically reactive prod* It appears that these definitions have become more qualitative in nature over time. ucts is now established as a prerequisite for many idiosyncratic drug reactions. Increased levels of reactive drug metabolites (RDMs), their impaired detoxification, or decreased cellular tions—glucoronidation, acetylation, demethylation, etc.), defense against reactive drug products appears to be an imporexhibit common polymorphism at the genomic level (Evans tant initiating factor (Pirmohamed et al., 1996; Hess and Rieder, and Relling, 1999). Among the important enzyme families that 1997). Oxidative RDMs are found in organs and cells preferentake part in the process are CYPs and N-acetyltransferases tially affected by idiosyncratic drug reactions (Gruchalla, 2000). (NATs) (see "Cardiovascular drug metabolism"). Apart from the documented genetic risk factors for the IMMUNOLOGICAL FACTORS development of ADRs, other risk factors include a history of previous adverse reaction, multiple medications, liver and The immune events are less-well-characterized (Shapiro and renal disease, and female gender. Sex may influence pharmaShear, 1996). Theories for the induction of immune-mediated cokinetics, drug utilization, and susceptibility to and presentaevents to drugs, their metabolites, or changes caused by these tion/detection of ADRs. Factors that may explain the higher substances include the 'hapten' and the 'danger' hypotheses adverse event rate observed in female patients include phar(Uetrecht, 1999). The 'hapten' hypothesis proposes that RDMs macodynamic factors, hormonal influences, reporting bias, and bind irreversibly to proteins or other macromolecules that are increased use of medications (Tran et al., 1998). perceived as foreign and then induce an immune response. According to the 'danger' hypothesis, the immune system DIAGNOSTIC WORK-UP IN THE DENTAL OFFICE responds with tolerance to most antigens, and a 'danger signal' rather than the 'foreignness' of the antigen triggers an immune A detailed drug history—including all prescription and nonresponse. The exact nature and range of stimuli that can act as prescription drugs, herbal treatments, and other remedies danger signals remain to be determined but are likely to (vitamins, minerals, and homeopathic agents)—should be include cell damage (Uetrecht, 1999). obtained during the diagnostic work-up. These supplements may cause unexpected toxicity by themselves or through interGENETIC FACTORS action with drugs, resulting in increased or decreased pharmacological or toxicological effects of either component (FughThere is a growing body of literature on the possible associaBerman, 2000; Ozdemir et al., 2001). In addition, the clinician tion between pharmacogenetic polymorphism and ADRs. needs to know the doses of all medications, timing of medicaUnderlying the person-to-person (phenotypic) differences in tion(s) as it relates to the onset of reaction, and concurrent disthe safety of a drug within a population are genotypic polyeases (e.g., renal failure, hepatitis, bowel disease) that could morphisms of key enzymes and proteins (Evans and Relling, lead to alteration in drug excretion, absorption, or metabolism. 1999; Ingelman-Sundberg, 2001). In this context, pharmacoFinally, it is important that the clinician be familiar with the genomics refers to the entire spectrum of genes that determine various types of adverse reactions that a particular drug may drug behavior and sensitivity, whereas pharmacokinetics is elicit. In many instances, this task is not so simple, since a drug used to define the narrower spectrum of inherited differences can be responsible for causing a range of reactions, some of in drug metabolism and disposition (Evans and Relling, 1999). which can be attributed to its pharmacological properties, and There is genetic variability in drug absorption, metabolism, others to its immunological properties (Gruchalla, 2000). With and disposition, and in drug interactions with receptors regard to ODRs, the matter is complicated by the fact that they (Ozdemir et al., 2001). All of the major human enzymes responare not currently reported as a group per se, but rather are sible for modification of functional groups by oxidation, included among several organ groups (e.g., gastrointestinal, hydroxylation, etc. (classified as phase I reactions), or conjugadermatological, hematological, neurological). tion with endogenous constituents (classified as phase II reac15(1):28-46 (2004)

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Cardiovascular Drugs Several drug classes are used to treat hypertension and/or arrhythmias: diuretics (thiazides, loop diuretics, potassiumsparing diuretics), peripheral and central adrenergic inhibitors, alpha-adrenergic blockers, beta-adrenergic blockers (BAB), combined alpha- and beta-adrenergic blockers, direct vasodilators, calcium-channel blockers (CCB), ACE inhibitors (ACEI), angiotensin II receptor blockers (ARB), and hypolipidemic drugs (e.g., statins). Drugs used for the treatment of cardiovascular disease were implicated in ADRs by about 3% of the 2367 patients seen in an ADR clinic, and there were no significant differences in reports by male and female patients (Tran et al., 1998). In a study of patients (n = 9210) who could not tolerate ACEIs, there were significant sex-related differences in the use of CVDs (Shah et al., 2000). ACEIs, nitrates, aspirin, warfarin, and antiarrhythmic medications were used to a lesser extent by women,

while the opposite was true for diuretics. Digoxin, ARB, BAB, lipid-lowering agents, and CCB showed non-significant sex differences in consumption rates. Although women began ACEI treatment at similar rates of use as men, they received less sustained therapy because of a higher rate of side-effects. Cough, angioedema, and taste disturbance were among the reasons for discontinuing ACEIs in both men and women (Shah et al., 2000).

Cardiovascular Drug Metabolism Research focusing on the cytochrome P450 system (CYP) has become increasingly important in shedding light on the intraand inter-individual responses to drug exposure. CYP encompasses a large gene superfamily that catalyzes the metabolism of a wide range of xenobiotics (e.g., foreign chemicals), including most drugs. The isoforms CYP2C9, CYP2C19, and CYP2D6 are polymorphic, and their allelic forms are distrib-

TABLE 2 Classification of ADRs (reaction types A and B) and Pathophysiological Mechanisms Behind the Reactions Drug-related Reactions (Type A reactions; predictable)

Actions

Mechanisms

Actions

Patient-related Reactions (Type B reactions; unpredictable)

Pharmaceutical • Dosage- and formulation-related Increased quantity Enhanced release Decomposition Additives Toxic reactions

Pharmacokinetic • Formation of RDMs or oxygen species • Biological factors (age, disease states) • Environmental factors (dietary, drugs, other chemicals)

Idiosyncratic reactions

Pharmacogenetic • GP of drug transporters • GP of metabolizing enzymes • GP of drug targets/receptors Drug interactions

Pharmacodynamic • Drug responsiveness (Disease states)

Drug intolerance

Unknown Immunologic • Antigen-specific antibody reaction Hapten/danger hypothesis Parent drug/RDM • Drug-induced mediator release *

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Allergic/hypersensitivity reactions

Pseudoallergic/anaphylactoid reactions

ADRs are presented in the context of actual knowledge in molecular biology, pharmacology, and immunology. The Table is to be read from the mid-panel toward the side panels. The mid-panel displays mechanisms with potential contributions to both reaction types A (left panel) and B (right panel). Type A reactions also include unwarranted side-effects and secondary effects, e.g., nosocomial infections (not represented). ADR, adverse drug reaction; RDM, reactive drug metabolite; GP, genetic polymorphism.

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uted with pronounced inter-ethnic differences TABLE 3 (Abernethy and Flockhart, 2000; Ingelman-Sundberg, Ethnic Variation in the Cytochrome P450 Enzymes (CYPs) 2001) (Table 3). The phenotypic consequences of genetin an American Population (adapted from Abernethy ic variation are individuals with no, normal, increased, and Flockhart, 2000) and reduced or inactive enzyme activity, some of Frequency (%) which may result in idiosyncratic pharmacological responses to prescribed medications (Smith et al., 1998; Enzyme Absent White Asian African/African-American Ingelman-Sundberg, 2001). Great inter-individual differences in the activity of CYP1A2 and CYP3A4 are CYP2D6 7 1 8 known, and individuals with the phenotype of low CYP2C19 3 12-22 4-7 activity might be at risk for the development of ADRs. CYP2C9