Oral Adverse Drug Reactions to Cardiovascular Drugs

28 Crit Rev Oral Biol Med 15(1):28-46 (2004)

Introduction

Several systemic factors are known to contribute to oral dis-eases or conditions, and among those are the intake ofdrugs. The pathogenesis of oral adverse reactions related tointake of medications is not well-understood, and the preva-lence is not known. They are, however, believed to be a rela-tively common phenomenon, although medication-inducedoral reactions are often regarded by the health profession astrivial complaints. According to the current definitions andbasic requirements for the use of terms for reporting adversedrug reaction disorders, "stomatitis" and "ulcerative stomati-tis" are the terms proposed by the WHO in cooperation withthe Council for International Organizations of MedicalSciences (CIOMS, 1998).

To date, there is no consensus on the definition of anadverse drug reaction (ADR), but Table 1 presents some of thedefinitions proposed. It appears that the definitions becomemore qualitative over time without clarifying the underlyingcausation of these reactions. It is still an open question if it is theclinician or the patient who defines if a drug has induced anadverse reaction.

ADRs are seen in everyday practice, but estimates of thetrue incidence of ADRs are difficult, since many of these reac-tions go unreported. A French study of 2067 adults aged 20-67years attending a health center for check-ups reported that14.7% gave reliable histories of adverse reactions (Vervloet and

Durham, 1998). The estimated rate of medication-related visitsto office-based physicians in the United States is 7.7 per 1000persons, but only 7% of these persons reported ADRs as theirreason for the visit (Aparasu, 1999). The overall incidence ofADRs is about 3 in 1000 patients, according to the BostonCollaborative Drug surveillance program (Bigby et al., 1986). Ina study based on outpatient referrals (2367 patients), the toptwo adverse events reported by both male and female patientswere skin disorders (49%) and allergic or immunological dis-turbances (14%) (Tran et al., 1998).

As more drugs are marketed and with an increasing num-ber of the elderly in the population, the number of drug pre-scriptions 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 preva-lence of oral drug reactions (ODRs), however, is at presentunknown, but dentists must be knowledgeable on the relationbetween medication intake and ODRs.

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

ORAL ADVERSE DRUG REACTIONSTO CARDIOVASCULAR DRUGSLis Andersen Torpet*Camilla KragelundJesper ReibelBirgitte Nauntofte

Department of Oral Medicine, Clinical Oral Physiology, Oral Pathology & Anatomy, School of Dentistry, Faculty of Health Sciences, University of Copenhagen, 20 Norre All, DK-2200 CopenhagenN, Denmark; *corresponding author, [email protected]

ABSTRACT: A great many cardiovascular drugs (CVDs) have the potential to induce adverse reactions in the mouth. Theprevalence of such reactions is not known, however, since many are asymptomatic and therefore are believed to go unreport-ed. As more drugs are marketed and the population includes an increasing number of elderly, the number of drug prescriptionsis also expected to increase. Accordingly, it can be predicted that the occurrence of adverse drug reactions (ADRs), includingthe oral ones (ODRs), will continue to increase. ODRs affect the oral mucous membrane, saliva production, and taste. The patho-genesis of these reactions, especially the mucosal ones, is largely unknown and appears to involve complex interactions amongthe drug in question, other medications, the patient's underlying disease, genetics, and life-style factors. Along this line, thereis a growing interest in the association between pharmacogenetic polymorphism and ADRs. Research focusing on polymor-phism of the cytochrome P450 system (CYPs) has become increasingly important and has highlighted the intra- and inter-indi-vidual responses to drug exposure. This system has recently been suggested to be an underlying candidate regarding the patho-genesis of ADRs in the oral mucous membrane. This review focuses on those CVDs reported to induce ODRs. In addition, itwill provide data on specific drugs or drug classes, and outline and discuss recent research on possible mechanisms linkingADRs 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-acetyl-transferase; ODR, oral drug reaction; RDM, reactive drug metabolite; S, substrate for CYP isoform; SJS, Stevens-Johnson syn-drome; SLE, systemic lupus erythematosus; and TEN, toxic epidermal necrolysis.

Key words. Oral mucous membrane, medication, CYP, drug interaction, therapeutic classes.

others (e.g., allergic reaction, idiosyn-cratic reaction) occur only in suscepti-ble patients (type B or unpredictablereactions). Type B reactions are rare andevident only by spontaneous reportingin case-population studies, or in largecohort studies (Moore, 2001). A reactionmay reflect the drug's exacerbation ofpre-existing disease, or, more frequent-ly, it represents an idiosyncratic reac-tion to the drug.

PHARMACOLOGICAL FACTORSFactors that predispose to pharmaco-logical ADRs include dose, drug for-mulation, pharmacokinetic or pharma-codynamic abnormalities, and druginteractions. The metabolic conversionof drugs to chemically reactive prod-ucts is now established as a prerequi-site for many idiosyncratic drug reac-tions. Increased levels of reactive drugmetabolites (RDMs), their impaireddetoxification, or decreased cellulardefense against reactive drug products appears to be an impor-tant initiating factor (Pirmohamed et al., 1996; Hess and Rieder,1997). Oxidative RDMs are found in organs and cells preferen-tially affected by idiosyncratic drug reactions (Gruchalla, 2000).

IMMUNOLOGICAL FACTORSThe immune events are less-well-characterized (Shapiro andShear, 1996). Theories for the induction of immune-mediatedevents to drugs, their metabolites, or changes caused by thesesubstances include the 'hapten' and the 'danger' hypotheses(Uetrecht, 1999). The 'hapten' hypothesis proposes that RDMsbind irreversibly to proteins or other macromolecules that areperceived as foreign and then induce an immune response.According to the 'danger' hypothesis, the immune systemresponds with tolerance to most antigens, and a 'danger signal'rather than the 'foreignness' of the antigen triggers an immuneresponse. The exact nature and range of stimuli that can act asdanger signals remain to be determined but are likely toinclude cell damage (Uetrecht, 1999).

GENETIC FACTORSThere is a growing body of literature on the possible associa-tion between pharmacogenetic polymorphism and ADRs.Underlying the person-to-person (phenotypic) differences inthe safety of a drug within a population are genotypic poly-morphisms of key enzymes and proteins (Evans and Relling,1999; Ingelman-Sundberg, 2001). In this context, pharmaco-genomics refers to the entire spectrum of genes that determinedrug behavior and sensitivity, whereas pharmacokinetics isused to define the narrower spectrum of inherited differencesin drug metabolism and disposition (Evans and Relling, 1999).There is genetic variability in drug absorption, metabolism,and disposition, and in drug interactions with receptors(Ozdemir et al., 2001). All of the major human enzymes respon-sible for modification of functional groups by oxidation,hydroxylation, etc. (classified as phase I reactions), or conjuga-tion with endogenous constituents (classified as phase II reac-

tionsglucoronidation, acetylation, demethylation, etc.),exhibit common polymorphism at the genomic level (Evansand Relling, 1999). Among the important enzyme families thattake part in the process are CYPs and N-acetyltransferases(NATs) (see "Cardiovascular drug metabolism").

Apart from the documented genetic risk factors for thedevelopment of ADRs, other risk factors include a history ofprevious adverse reaction, multiple medications, liver andrenal disease, and female gender. Sex may influence pharma-cokinetics, drug utilization, and susceptibility to and presenta-tion/detection of ADRs. Factors that may explain the higheradverse event rate observed in female patients include phar-macodynamic factors, hormonal influences, reporting bias, andincreased use of medications (Tran et al., 1998).

DIAGNOSTIC WORK-UP IN THE DENTAL OFFICEA detailed drug historyincluding all prescription and non-prescription drugs, herbal treatments, and other remedies(vitamins, minerals, and homeopathic agents)should beobtained during the diagnostic work-up. These supplementsmay cause unexpected toxicity by themselves or through inter-action with drugs, resulting in increased or decreased pharma-cological or toxicological effects of either component (Fugh-Berman, 2000; Ozdemir et al., 2001). In addition, the clinicianneeds to know the doses of all medications, timing of medica-tion(s) as it relates to the onset of reaction, and concurrent dis-eases (e.g., renal failure, hepatitis, bowel disease) that couldlead to alteration in drug excretion, absorption, or metabolism.Finally, it is important that the clinician be familiar with thevarious types of adverse reactions that a particular drug mayelicit. In many instances, this task is not so simple, since a drugcan be responsible for causing a range of reactions, some ofwhich can be attributed to its pharmacological properties, andothers to its immunological properties (Gruchalla, 2000). Withregard to ODRs, the matter is complicated by the fact that theyare not currently reported as a group per se, but rather areincluded among several organ groups (e.g., gastrointestinal,dermatological, hematological, neurological).

15(1):28-46 (2004) Crit Rev Oral Biol Med 29

TABLE 1Definitions* of Adverse Drug Reactions (ADRs) Proposed during theLast 30 Years

WHO, 1972 "Any noxious and unintended drug effect which occurs at dosesemployed in man for prophylaxis, diagnosis or therapy."

FDA, 1995 "An undesirable effect, reasonably associated with the use ofthe drug, that occurs as part of the pharmacological action of adrug or may be unpredictable in its occurrence."

Laurence, 1998 "A harmful or significantly unpleasant effect caused by a doseintended for therapeutic effect (or prophylaxis or diagnosis)which warrants reduction of dose or withdrawal of the drugand/or foretells hazard from future administration."

Edwards and Aronson, 2000 "An appreciably harmful or unpleasant reaction, resulting froman intervention related to the use of a medical product, whichpredicts hazard from future administration and warrants preven-tion or specific treatments, or alteration of the dosage, or with-drawal of the product."

* It appears that these definitions have become more qualitative in nature over time.

Cardiovascular DrugsSeveral drug classes are used to treat hypertension and/orarrhythmias: diuretics (thiazides, loop diuretics, potassium-sparing diuretics), peripheral and central adrenergic inhibitors,alpha-adrenergic blockers, beta-adrenergic blockers (BAB),combined alpha- and beta-adrenergic blockers, direct vasodila-tors, calcium-channel blockers (CCB), ACE inhibitors (ACEI),angiotensin II receptor blockers (ARB), and hypolipidemicdrugs (e.g., statins).

Drugs used for the treatment of cardiovascular diseasewere implicated in ADRs by about 3% of the 2367 patients seenin an ADR clinic, and there were no significant differences inreports by male and female patients (Tran et al., 1998). In astudy of patients (n = 9210) who could not tolerate ACEIs, therewere significant sex-related differences in the use of CVDs(Shah et al., 2000). ACEIs, nitrates, aspirin, warfarin, and anti-arrhythmic 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 sexdifferences in consumption rates. Although women beganACEI treatment at similar rates of use as men, they receivedless sustained therapy because of a higher rate of side-effects.Cough, angioedema, and taste disturbance were among thereasons for discontinuing ACEIs in both men and women(Shah et al., 2000).

Cardiovascular Drug MetabolismResearch focusing on the cytochrome P450 system (CYP) hasbecome increasingly important in shedding light on the intra-and inter-individual responses to drug exposure. CYP encom-passes a large gene superfamily that catalyzes the metabolismof a wide range of xenobiotics (e.g., foreign chemicals), inclu-ding most drugs. The isoforms CYP2C9, CYP2C19, andCYP2D6 are polymorphic, and their allelic forms are distrib-


TABLE 2Classification of ADRs (reaction types A and B) and Pathophysiological Mechanisms Behind theReactions

Drug-related Reactions Actions Mechanisms Actions Patient-related Reactions(Type A reactions; predictable) (Type B reactions; unpredictable)

Pharmaceutical Dosage- and formulation-related

Increased quantityEnhanced releaseDecompositionAdditives

Toxic reactions Pharmacokinetic Idiosyncratic reactions Formation of RDMs

or oxygen species Biological factors

(age, disease states) Environmental factors (dietary,

drugs, other chemicals)

Pharmacogenetic GP of drug transporters GP of metabolizing enzymes GP of drug targets/receptors

Drug interactions Pharmacodynamic Drug responsiveness Drug intolerance

(Disease states)

Unknown

Immunologic Allergic/hypersensitivity reactions Antigen-specific antibody reaction

Hapten/danger hypothesisParent drug/RDM

Drug-induced mediator release 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-paneltoward the side panels. The mid-panel displays mechanisms with potential contributions to both reaction types A (left panel) and B (right panel). Type Areactions 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.

uted with pronounced inter-ethnic differences(Abernethy and Flockhart, 2000; Ingelman-Sundberg,2001) (Table 3). The phenotypic consequences of genet-ic variation are individuals with no, normal, increased,and reduced or inactive enzyme activity, some ofwhich may result in idiosyncratic pharmacologicalresponses to prescribed medications (Smith et al., 1998;Ingelman-Sundberg, 2001). Great inter-individual dif-ferences in the activity of CYP1A2 and CYP3A4 areknown, and individuals with the phenotype of lowactivity might be at risk for the development of ADRs.Non-genetic factors and as-yet-undetermined geneticcauses will likely contribute to these inter-individualdifferences (Lamba et al., 2002). From now on, the twoenzymes in question will be referred to as "non-poly-morphic". Induction and inhibition of CYPs by xenobiotics,including concomitant medication, may also result in treatmentfailure or ADRs, respectively.

Table 4 illustrates several CVDs which are catabolized byCYPs. Beta-adrenergic blockers, CCBs, ACEIs, ARBs, andstatins are all metabolized via CYP-dependent pathways, andthe isoforms of relevance are CYP1A2, CYP2C9, CYP2C19,CYP2D6, and CYP3A4. Acetylation polymorphism (NAT-2) isalso important for some anti-hypertensives and anti-arrhyth-mics (hydralazine, procaineamide) (Evans and Relling, 1999).Most populations of European origin are approximately equal-ly divided between rapid and slow acetylators (Weber andHein, 1985). Individuals inheriting mutant forms of more thanone drug-metabolizing enzyme have a higher risk of drug-induced toxicity (Smith et al., 1998; Evans and Relling, 1999).

Cutaneous and Oral Mucosal Adverse Reactionsto Cardiovascular Drugs

CVDs have been estimated to account for at least 9% of med-ication-related visits to office-based physicians (Aparasu,1999). Cutaneous drug reactions (CDRs) undoubtedly areamong the most frequent events in patients receiving drugtherapy. The incidence of CDRs has been estimated to be about2% (Bigby et al., 1986; Apaydin et al., 2000). Skin reactionsaccount for up to 30% of all the adverse events, although over-reporting of skin reactions per se or under-reporting of otherorgan reactions should be borne in mind (Naldi et al., 1999).Since the skin reacts with a few patterns to a variety of stimuli,different drugs may induce identical cutaneous changes. About10% of drug-induced rashes result from true allergy thatrequires prior exposure, and asthma may exacerbate adversereactions to drugs (Vervloet and Durham, 1998). The morpho-logic reaction patterns frequently mimick well-known skin andmucocutaneous lesions or disorders. Furthermore, specificclasses of drugs are associated with specific clinical presenta-tions (Table 5). CDRs to systemically administered anti-hyper-tensives and anti-arrhythmics are reviewed elsewhere (Sun etal., 1994; Caron and Libersa, 1997; Brosnan et al., 2000; Svenssonet al., 2001).

Table 5 list several oral mucosal reaction patterns to car-diovascular drug exposure. There is much less informationavailable on ODRs than on CDRs, but the former may be lessfrequent. However, some common reactions, such as drymouth, taste disturbances, and aphthae, may be added to thespectrum of ODRs. Although ODRs only rarely result in severemorbidity or death, they may cause mild to substantial dis-comfort and, therefore, influence the individual's quality of life

and oral health condition. As with the skin, the oral mucousmembrane reacts with a few patterns to a variety of stimuli,and different drug classes may induce identical mucosalchanges. The following section is devoted to a brief overview ofdifferent ODR patterns.

ORAL DRUG REACTION PATTERNSIn general, there are no clinical or histopathological oral reac-tion patterns that can be specifically related to drug usage.Neither is it possible by clinical or histopathological presenta-tion alone to relate ODRs to any specific drug. Many ODRsmimic oral lesions that are also seen in the absence of drugusage. Thus, for a given reaction in the mouth to be establishedas an ODR, the suspected offender drug should be withdrawn,which should lead to disappearance of the reaction, whichshould then re-appear on re-challenge. Such tests, however, arenot always desirable or advisable. Furthermore, an allergicreaction to additives should be ruled out. Below we haveemphasized certain oral reactions commonly reported asODRs.

Dry mouth is one of the most common oral side-effects ofdrug usage, although it is also commonly seen as part of certaindiseases, such as Sjgren's syndrome, which are unrelated todrug usage. A subjective feeling of dry mouth (xerostomia)does not necessarily correlate with objective measures, such assialometry, which can establish a pathologically decreasedwhole saliva flow rate (hyposalivation). Vast numbers of car-diovascular drugs are implicated in dry mouth (Sreebny andSchwartz, 1997). Chronic hyposalivation has debilitating effectson the integrity of the hard and soft tissues of the mouth, typi-cally leading to an increase in dental caries incidence and yeastinfections (candidosis) (Pedersen et al., 2002).

Taste disturbances are not uncommonly described as anODR. The mechanisms by which the medications alter tastesensation are not well-understood. One possibility is that theexcretion of the drug or its metabolites into saliva may gener-ate an unpleasant taste. Many chemosensory disorders affectboth taste and smell, and often patients refer to a taste deficitthat is actually anosmia, e.g., inability to detect olfactory stimu-lants (Spielman, 1998). In scalded mouth syndrome, sometimesincluded as an ODR, taste perception is normal; however,patients complain of a burning sensation comparable with hav-ing been scalded by a hot liquid (Vlasses et al., 1982).

Various diseases of the oral mucous membrane, unrelat-ed to drug usage, have been regarded as manifestations ofODR. The terms "oral ulceration" and "aphthae" are common-ly used synonymously in reports on ODR; however, aphthae


TABLE 3Ethnic Variation in the Cytochrome P450 Enzymes (CYPs)in an American Population (adapted from Abernethyand Flockhart, 2000)

Frequency (%)

Enzyme Absent White Asian African/African-American

CYP2D6 7 1 8CYP2C19 3 12-22 4-7CYP2C9 < 1 < 1 < 1

usually commence in thesecond decade of life asrecurrent oral ulcerationsand usually wane duringthe fourth decade (Porteret al., 1998). In contrast,drug-induced ulcerationspresent mostly in olderage groups and notalways as a recurrent pat-tern.

Oral manifestations ofsystemic diseases are notuncommon and may berelated to drug usage.Ulcerations are seen asoral manifestations ofhematological disorderssuch as agranulocytosisand neutropenia, whereashemorrhagic bullae, petec-chias, ecchymoses, andbleeding are oral featuresof thrombocytopenia. It iswell-known that CVDscan cause agranulocytosisand thrombocytopenia(Wiholm and Emanuels-son, 1996). Drug-inducedautoantibodies affectplatelets more often thanany other blood element(Aster, 2000).

Drug-induced lichenplanus, also referred to aslichenoid drug eruptions,exhibits clinical featuressimilar to those of idio-pathic lichen planus,which is a fairly commonoral mucosal disease.Lichenoid drug eruptionsare more likely to be uni-lateral and of the erythe-matous and ulcerativevariety; however, this isnot well-substantiated(Lamey et al., 1995). Re-cently, it has been suggest-ed that intake of medica-tions metabolized bypolymorphic CYPs maybe implicated in lichenoiddrug eruptions (Krage-lund et al., 2003). Clinicalmanifestations of otheroral mucosal diseasessuch as erythema multi-forme (EM), Stevens-Johnson syndrome (SJS),linear IgA disease/IgAbullous disease, lupus


TABLE 4Cytochrome P450 Enzymes Involved in Metabolism of Cardiovascular Drugs(adapted from Rendic, 2002)

Drug Class/Drug CYP1A2 CYP2C9 CYP2C19 CYP2D6 CYP3A4

ACE inhibitors Captopril Enalapril

Angiotensin II inhibitors IrbesartanLosartan

Anti-coagulants Warfarin Warfarin Warfarin Warfarin Warfarin

Adrenergic neurone blockers DebrisoquineGuanoxan

Anti-arrhythmic drugs, Class I(sodium-channel blockers)

Disopyramide DisopyramideDofetilide

EncainideFlecainide

Lidocaine Lidocaine Lidocaine LidocaineMexilitine Mexiletine

Phenytoin Phenytoin PhenytoinProcainamide

Propafenone Propafenone PropafenoneSpartein

Quinidine Quinidine

Anti-arrhythmic drugs, Class III(potassium-channel blockers) Amiodarone Amiodarone Amiodarone Amiodarone

Beta-adrenergic blockers AlprenololBisoprolol Bisoprolol

Bufuranol Bufuranol Bufuranol Bufuralol BufuranolCarvediolLabetalol

Metoprolol MetoprololPropranolol Propranolol Propranolol

Timolol

Calcium-channel blockers AmlodipineDiltiazem Diltiazem Diltiazem

FelodipineIsradipineMibefradil

Nicardipine Nicardipine NicardipineNifedipine Nifedipine

NimodipineNisoldipineNitrendipine

Verapamil Verapamil Verapamil Verapamil

Diuretics TorsemideTielinic acid

HMGCoA inhibitors (statins) AtorvastatinCerivastatin

Fluvastatin Fluvastatin FluvastatinLovastatinSimvastatin

Nitrates Isosorbidedinitrate

Platelet aggregation inhibitors Aspirin

e r y t h e m a t o s u s ,pemphigoid, andpemphigushave,at times, been re-garded as ODRs.However, the crite-ria used in diagno-sing these diseasesas ODRs are rarelygiven. Unlike idio-pathic linear IgAdisease, mucosallesions appear lessfrequently in thedrug-induced form,whereas the oppo-site is true for bul-lous pemphigoid(Camilleri and Pace,1998; Vassileva,1998). Also, angio-edema, fixed drugeruptions (FDEs),toxic epidermalnecrolysis (TEN),drug hypersensitivity syndrome, oculo-mucocutaneous syn-drome, and pigmentary disturbances have been regarded asODRs.

A well-known adverse reaction to certain drugs such ascyclosporins, calcium-channel blockers, and phenytoin is gin-gival overgrowth, which is characterized by enlarged gingiva.The condition usually involves the interproximal papilla andmay present as a localized or generalized condition. This over-growth can be associated with both natural teeth and dentalimplants but does not appear to affect edentulous areas.Proper dental prophylaxis and good oral hygiene may reduceor prevent the overgrowth in some patients (Marshall andBartold, 1998).

Oral Drug Reactions from Major Therapeutic Classes of CVDs

The next section will deal with the wide spectrum of oral reac-tion patterns in response to usage of CVDs (Table 6). Thereview does not fully describe all possible reactions of CVDs.The clinical evidence for ODRs will be linked to drug-metabo-lizing enzymes relevant to the drugs implicated, to illustratethe potential impact of genetic variability to the reactions. Inthis context, we focus on CYP enzymes with known variantalleles causing poor metabolism of drugs due to no, reduced, orinactive enzymes (CYP2C9, 2C19, 2D6) and with great inter-individual, non-polymorphic differences in the activity(CYP1A2, 3A4), which are most relevant to the development ofADRs. The potential contributions from drug interactions bysubstrate competition or inhibition of these CYP enzymes arealso addressed.

Substrate competition occurs with the concomitant admin-istration of two substrates of a CYP. Each drug will compete forthat enzyme and competitively inhibit the metabolism of theother substrate. Owing to a lack of larger surveys investigatingsuch aspects, we review here the available case reports withindications of the CYP metabolism pathway for offending drugsand concurrent medication (Rendic, 2002).

ADRENERGIC AGENTS

Alpha-adrenergic blockers

Alpha1-adrenergic agents may result in altered saliva composi-tion and secretion rates. Furthermore, oral lichenoid eruptionsand ulcerations may be seen.

Inhibitors of alpha1-adrenoreceptors (terazosin and pra-zosin) have been reported to reduce saliva production due totheir effects on salivary gland alpha1-adrenoreceptors.However, an alpha2-adrenoreceptor agonist (clonidine) mayalso cause dry mouth by both central and peripheral mecha-nisms (Sreebny and Schwartz, 1997; Baum et al., 2000). Othercentrally acting anti-hypertensive drugs associated with drymouth include methyldopa, reserpine, moxonidine, and ril-menidine.

Reports implicate the use of methyldopa, an alpha2-adre-nergic agent, in the etiology of oral lichen planus. A patientwho had been taking methyldopa and hydrochlorothiazide forseven years developed multiple oral ulcerations in addition topruritic skin papules collectively diagnosed as lichen planus.The oral lesions and symptoms had been present for threemonths, and the patient had experienced a previous episode oforal ulcerations one year earlier. The lesions were refractory totreatment, but healed or improved after withdrawal of methyl-dopa. No re-challenge was performed (Brooks, 1982). Threecases of oral lichenoid eruptions, including tongue ulcerations,that were deemed possibly linked to methyldopa have beenreported. These patients had been taking methyldopa for peri-ods of one year or "several years". In two out of the three cases,tongue ulcerations resolved four to five months after methyl-dopa was discontinued. The case reports do not provide infor-mation on other medications the patients may have been tak-ing, or on re-challenge attempts (Burry and Kirk, 1974). A lar-ger series of 17 patients with oral mucosal reactions associatedwith methyldopa has been reported (Hay and Reade, 1978).Most patients presented with erythematous or ulcerative lichen


TABLE 5Cutaneous and Oral Mucosal Diseases or Reaction Patterns That May Occur inResponse to Cardiovascular Drug Exposures

Oral Mucosal and Syndromes with OralCutaneous and Cutaneous Oral Mucosal and/or Diseases/Reactions Diseases/Reactions Diseases/Reactions Cutaneous Involvements

Acneiform Angioedema Aphthae Drug hypersensitivity syndromeEczematous Erythema multiforme Dry mouth Lupus erythematosus-like

(xerostomia, hyposalivation) syndromeErythema nodosum Fixed drug reaction Gingival overgrowth Oculo-mucocutaneous

syndromeExanthematous Hyperpigmentation Scalded mouth syndromeExfoliative Lichenoid eruptions Taste disturbancesMacular/maculopapular Linear IgA disease UlcerationsPityriasis rosea-like PemphigoidPhotosensitive PemphigusPsoriasis Stevens-Johnson syndromePurpura Toxic epidermal necrolysisUrticariaVasculitis


TABLE 6Overview of Potential Oral Reaction Patterns, Diseases, or Syndromes from Cardiovascular Drug Exposure*

Drug Class Type of ODR Type of Study Culprit Drug Culpability

Alpha adrenergic blockersDry mouth Class effect EstablishedLichen planus CR (4) CS (17) Methyldopa Possible

Beta adrenergic blockersAngioedema CS (11) Unspecified EstablishedDry mouth Class effect EstablishedAphthae/Ulcerations CR (1) CCS (13) Labetalol, unspecified ProbableThrombocytopenia CR (1) Propranolol PossibleLichen planus CR (4) Atenolol, Oxprenolol Possible

Practolol, PropranololOculo-mucocutaneous syndrome CR (4) Practolol PossibleSJS CR (1) Carvediol PossibleMouth paresthesia CS (7) Propranolol (sublingual) Possible

ACE inhibitorsAngioedema Class effect (Captopril, Enalapril, Established

Lisinopril, Zofenapril, Omapatrilat)Aphthae/Ulcerations CR (2) Captopril ProbableDry mouth Lisinopril ProbableNeutropenia/agranulocytosis Class effect EstablishedLichen planus CR (3) Captopril PossibleSloughing of epithelium CR (1) Enalapril UncertainPemphigus CR (1) Captopril ProbableScalded Mouth syndrome CR (6) Captopril, Enalapril, Lisinopril ProbableTaste disturbances Captopril, Enalapril Established

Angiotensin II receptor blockersAngioedema CR (2), CS (9) Losartan Probable

Anti-arrhythmics, Class I (sodium-channel blockers)Dry mouth Class effect EstablishedFDE CR (2) Quinidine PossibleThrombocytopenia SRS (16) Quinidine ProbableAgranulocytosis CCS (5) Phenytoin ProbableHypersensitivity reaction syndrome Phenytoin EstablishedSJS, TEN CCS (14) Phenytoin ProbableGingival hyperplasia CR/CS (multiple) Phenytoin Established

Anti-arrhythmics, Class III (potassium-channel blockers)Angioedema CR (1) Amiodarone ProbableTaste disturbances Amiodarone Possible

Calcium-channel blockersAngioedema CR (3), CS (14) Nifedipine, Diltiazem PossibleAphthae/Ulcerations CR (2) Diltiazem, Verapamil PossibleGingival hyperplasia CR/CS (multiple) Class effect EstablishedLichen planus CR (1) Amlodipine PossibleEM, SJS, TEN CR (4) Diltiazem, Verapamil PossibleTaste disturbances Class effect EstablishedDry mouth Class effect Established

DiureticsAngioedema SRS (11) Unspecified PossibleDry mouth Class effect EstablishedEM, SJS, TEN (Sulphonamides) Furosemide, Thiazides PossibleAgranulocytosis SRS (> 50) Amiloride, Furosemide, Probable

ThiazidesThrombocytopenia SRS (> 100) Amiloride, Furosemide, Probable

ThiazidesDrug hypersensitivity (Sulphonamides) Furosemide, Thiazides Possible

syndromeLichen planus CR (2) Bendrofluazide Uncertain/possible

Furosemide/SpironolactoneTaste disturbances Amiloride, Spironolactone Probable

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planus lesions. They had been taking the drug from six to 60months prior to the development of lesions and required up tofive months for healing after drug cessation. Of the 17 patients,13 used from one to six concurrent medications, including com-binations with diuretics, NSAIDs [substrate (S) for CYP2C9,2C19; inhibitor of activity (I) of CYP2C9, 3A4], sulfonylurea (Sfor CYP2C9; I of 3A4), anti-arrhythmics (S for CYP2C9; I ofCYP2C9, 3A4), and anti-depressants (S for and I of CYP1A2,2C9, 2C19, 2D6, 3A4) ((Hay and Reade, 1978).

The association between methyldopa therapy and orallichen planus has not been clearly established. The evidenceoriginates from case reports or small case series that are inade-quate with regard to information on co-morbidity, timingbetween presentation of lesions, and start of co-medication,and re-challenges have rarely been performed (Table 6). Mostindividuals were on multiple medications, raising the possibil-ity of the reaction being linked to drugs other than methyldopaor to drug-drug interactions by inhibition. Theoretically, a con-tribution from genetic variation in metabolism of methyldopais a further candidate as a risk factor for the adverse reaction.There is a large individual variation in levels of activity of theenzyme catechol O-methyltransferase that catalyzes methyl-dopa, and genotype frequencies of 25% with low activity of thisenzyme have been demonstrated in Caucasian populations(Ameyaw et al., 2000).

Beta-adrenergic blockers (BABs) (anti-arrhythmics Class II)

BABs have been linked with various ODRs, includingangioedema, dry mouth, oral ulcerations, lichenoid drug erup-tions, lupus erythematosus, SJS, oculo-mucocutaneous syn-drome, and manifestations of hematological disorders.

In a study of 72 patients with oro-facial angioedema pre-cipitated by anti-hypertensives, 11 cases were linked to BABs.An expert panel excluded triggering events other than BABs.Most reactions occurred within the first week after initiation oftherapy, and symptoms resolved when therapy was discontin-ued (Hedner et al., 1991).

Dry mouth has been reported in about 20% of hyperten-sives treated with BABs alone, and BABs may decrease the total

protein content of whole-mouth saliva (Baum et al., 2000).Oral ulcerations are among the reactions to BAB (Petrie et

al., 1976). In a case report, use of labetalol (200 mg a day; S forCYP2D6), a combined alpha- and beta-adrenergic blocker, wasimplicated in oral ulcerations that resolved following drugwithdrawal and relapsed at re-challenge (Pradalier et al., 1982).A recent case-control study suggests a statistically significantlink between BABs and aphthous ulcers (P = 0.002, multivari-ate paired analysis) (Boulinguez et al., 2000).

A patient presenting with pruritic oral and cutaneouslesions may constitute a case of secondary thrombocytopeniacaused by medication. The patient had been taking a combina-tion of propranolol and disulfiram for less than a month priorto onset of the lesions. Following withdrawal of both drugs,propranolol (S for CYP1A2, 2C9, 2D6) alone could be resumedwithout eliciting any reaction. The authors suggested that thereaction was due to an overdose achieved by the combinedusage of the two drugs or from disulfiram (I of CYP1A2, 2C9,2D6, 3A4) subsequent to prior sensitizing exposure to this drug(Thompson et al., 1982). A contribution from drug interactionsby inhibition of any of the three implicated CYP enzymesmight have been involved in the presumed toxic reaction.Agranulocytosis is also among the adverse reactions to BAB(Petrie et al., 1976). Hence, oral ulcerations are a possible ADR.

BAB-induced lichen planus is a well-established phenom-enon in the dermatological literature. Since it is a mucocuta-neous disease, involvement of the oral mucous membrane canbe expected. However, there are only a few case reports on oneor two patients that implicate the usage of BABs with the devel-opment of oral lichen planus lesions in these individuals.Cutaneous as well as oral lesions have been reported in apatient taking propranolol (Hawk, 1980). In this patient, thera-py including propranolol (240 mg a day; S for CYP1A2, 2C9,2D6) and furosemide (80 mg a day) was initiated 21 monthsprior to the onset of reaction. Allopurinol (300 mg a day) wascommenced the same year and before the development of skineruptions. Propranolol and furosemide were discontinued, andmethyldopa (1000 mg a day) was substituted. The reticular andulcerative oral lesions almost resolved within four months afterdiscontinuance of drugs, whereas the cutaneous lesions turned


Drug Class Type of ODR Type of Study Culprit Drug Culpability

Direct-acting peripheral vasodilatorLupus erythematosus CR (2) Hydralazine Probable

HMG-CoA reductase inhibitors (statins)Cheilitis CR (2) Simvastatin PossibleLichen planus CR (1) Simvastatin Possible

Platelet aggregation inhibitorsAngioedema CR (1) Aspirin PossibleFDE CR (2) Aspirin Probable

Potassium-channel openerAphthae/Ulcerations CR/CoS (multiple) Nicorandil Probable

* Criteria for causality assessment include type of study and response to de- and re-challenge as follows: possible = case report (CR)/case series (CS) andpositive de-challenge; probable = CR/CS with positive re-challenge, case-control study (CCS), spontaneous reporting (SRS), or cohort study (CoS); estab-lished = substantial evidence from CRs, CCS, SRS, and/or CoS. Class effect: Multiple reports stating subjective and/or objective adverse reaction to thedrug class. With regard to type of study, the number in parenthesis indicates the number of cases reviewed. For further details, see text. EM, erythemamultiforme; FDE, fixed drug reaction; SJS, Stevens-Johnson syndrome; TEN, toxic epidermal necrolysis.

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into hyper-pigmented areas. A patient with Ferguson-Smithdisease developed asymptomatic oral lichen planus two weeksafter therapy with oxprenolol (I of CYP2D6), and cyclopenthi-azide was initiated (Wiesenfeld et al., 1982). A switch fromoxprenolol to methyldopa resulted in the disappearance of thecutaneous and the oral white reticular and plaque-type lesionswithin two months, but both oral and cutaneous lesionsrecurred a month later. Methyldopa was replaced by prazosin,and after six months the oral lesions resolved completely andthe cutaneous lesions improved. Another patient was reportedas having lichenoid skin eruptions and oral lesions typical oflichen planus associated with the intake of practolol (with-drawn from the market). The duration of treatment (400 mg aday) before the onset of rash was one month. It is possible thatthe patient was on concurrent medication(s), since most of thereported 21 patients with cutaneous and ocular reactions topractolol were taking combinations of other drugs (diuretics,

tranquilizers, antihypertensives; Felix et al., 1974). A patientpresented with a one-year history of asymptomatic reticularand erosive oral lichen planus. The medication regimen inclu-ded atenolol (100 mg a day) for six months, chlorpropamide(100 mg and increased to 200 mg daily for the last eightmonths) for 18 months, and salbutamol (6 mg a day; I ofCYP3A4). The patient was thought to represent a case of drug-induced lichen planus, and no alternative drug therapies wereattempted (Lamey et al., 1990). Chlorpropamide, a sulfonylureaagent, is known to cause drug-induced oral lichen planus(Thompson and Skaehill, 1994). None of the four patientsreferred to above was clearly established as having BAB-induced lichen planus by re-challenge, and the outcomes ofsubstitution by drugs other than BABs were variable andincluded relapses. A delay ranging from weeks to monthsbetween the presentation of oral lesions and the start of thera-py does not exclude the incriminated BABs, provided that the


TABLE 7Potential Adverse Drug Reactions from Cardiovascular Drug Exposure Exemplified by MedicationCatabolized by the P450 Enzyme System*

Drug-related Reaction Mode of Action Mechanisms Mode of Action Patient-related Reaction

PharmacokineticToxic reactions Formation of RDMs Biotransformation of drugs Formation of RDMs Idiosyncratic reactions

(mainly CYPs) including haptens or antigens Biological factors

Impaired drug elimination Organ-specific diseases Impaired drug elimination(liver, kidney) Environmental factors

Inhibition of drug Concurrent drug exposure(s)metabolism Phase I metabolism, mainly by

CYPs (1A2, 2C9, 2C19, 2D6, 3A4)Interactions Other constituents

Increased plasma and undergoing phase Itissue drug concentration metabolism: dietary (CYP 1A2,

2E1, 3A4), tobacco (CYP 1A2);alcohol (CYP 2E1); herbalmedication (CYP1A2, 2C9);dental materials (CYP1A2)

Pharmacogenetic GP of drug transporters

Affects drug absorption P-glycoprotein Affects drug absorptionDrug-metabolizer GP of drug-metabolizing Drug-metabolizer

phenotypes enzymes (interethnic/-racial phenotypesvariation)Phase I: CYPs (1A2, 2C9,

Increased, decreased, 2C19, 2D6) (3A4?)#; ADH; ... Increased, decreased,abnormal or no Phase II: NAT1, NAT2 abnormal or no

metabolism metabolismAffects drug sensitivity? GP of drug targets Affects drug sensitivity Allergic/hypersensitivity

Receptors (beta-adrenergic, reactionsangiotensin IIT1,sulfonylurea), enzymes (ACE),proteins

* The panel design from Table 2 is maintained. Modes of action behind type A (left panel) or type B reactions (right panel) are extended and imply effectson CYP expression, activity, and outcome, e.g., type of adverse drug reaction. CYP, cytochrome P450 enzyme; GP, genetic polymorphism;

# Polymorphically in specific populations?

drugs metabolized into RDMs and such metabolites are impli-cated in the pathophysiological mechanism.

Some BABs (acebutolol, labetalol, practolol, and propra-nolol) have been linked to drug-induced lupus erythematosusmanifesting as skin eruptions (S for CYP1A2, 2C19, 2D6) (Sunet al., 1994). Labetalol and practolol may also cause the oculo-mucocutaneous syndrome (Wright, 1975; Sun et al., 1994). Acase series of 27 patients with this syndrome was linked to theadministration of practolol (Wright, 1975). Nineteen of thesepatients were also taking diuretics, cardiac glycosides, or anti-coagulants. Anti-nuclear antibodies (ANAs) were positive inall patients, and a circulating antibody capable of binding toepithelial tissue was found in 25 patients. No other evidence ofdrug-induced systemic lupus erythematosus (SLE) was found.Recurrent ulcerations of the oral mucous membrane occurredas part of the syndrome in four of the patients. Three of thesepatients showed improvement in symptoms and signs over aperiod of four months to more than a year; one patient devel-oped a progressive disorder suggestive of an atypical drug-induced SLE (Wright, 1975). Hence, a long-term follow-up isconsidered crucial before a final diagnosis of drug-induced SLEand/or oculo-mucocutaneous syndrome can be made.

SJS with oral manifestations associated with carvediol, aselective beta1-blocker, has been reported (Kowalski and Cody,1997). The rash included macules, blisters, and target lesionsinvolving the entire skin surface and the oral mucous mem-brane. The symptoms developed four weeks after initiation oftherapy and following dosage reduction (initially 6.25 mg,titrated to 25 mg and reduced to 12.5 mg a day). At the timecarvediol (S for CYP2C9, CYP2D6) was initiated, the patientwas on stable long-term doses of hydralazine (I of CYP3A4),captopril (S for CYP2D6), digoxin, furosemide, warfarin (S forCYP1A2, 2C9, 2C19, 2D6, 3A4; I of CYP2C9, 2C19), allopurinol,famotidine, and aspirin (S for CYP2C9). Following cessation ofcarvediol therapy, complete resolution occurred within twoweeks. The patient was not re-challenged (Kowalski and Cody,1997).

'Mouth paresthesia' is the main adverse effect observedafter sublingual administration of propranolol (Mansur et al.,1998).

The evidence implicating the use of BABs with ODRderives from single case reports, and verification by re-chal-lenge has seldom been performed (Table 6). Hence, BAB-induced oral ulcerations reach a causality level of only 'possi-ble', as evidenced by a case-control study. Some of the offend-ing BABs in question are metabolized by polymorphic CYPenzymes, implying abnormal metabolizing as a risk factor forODRs. Most case patients were on multiple drugs, raising thepossibility of the reaction being linked to drugs other than theincriminated BABs or to drug-drug interactions.

ANGIOTENSIN-CONVERTING ENZYME INHIBITORS(ACEIS)

ACEIs evoke a relatively low incidence of ADRs, with coughand nausea being the more common adverse effects (Lawton etal., 1992; Vleeming et al., 1998). Reports on ODRs have includedangioedema, dry mouth, ulcerations, lichenoid eruptions, man-ifestations of hematological disturbances, loss of taste, and'scalded mouth syndrome'.

Hundreds of cases of angioedema related to the usage ofACEIs have been reported (Roberts and Wuerz, 1991; Maier,1995; Vleeming et al., 1998; Messerli and Nussberger, 2000).

Angioedema occurs regardless of the chemical structure (e.g.,sulphhydryl compoundscaptopril, zofenapril; carboxyalkyl-dipeptideenalapril, lisinopril; and phosphoric acid com-poundsfosinopril) (Vleeming et al., 1998). The majority of thereactions occur in the first week after the initiation of ACEinhibitor therapy, but a significant number occur after pro-longed therapy (Vleeming et al., 1998; Agostoni and Cicardi,2001). In a review of 72 patients with angioedema precipitatedby anti-hypertensives, 36 cases were due to ACEIs (Hedner etal., 1991). Angioedema has been estimated to occur in one tofive in 1000 patients using ACEIs, but if long-term therapy andlate onset are taken into account, the risk may be as high as 1%after 10 years of treatment (Vleeming et al., 1998). ACEI-induced angioedema has a predilection for the head and neckregion, and most occurrences manifest as edema of the tongueand lips (Slater et al., 1988; Roberts and Wuerz, 1991; Rees andGibson, 1997; Vleeming et al., 1998; Agostoni and Cicardi,2001). Immunological processes and several mediator systems(bradykinin, substance P, and prostaglandins) have been sug-gested to be involved in the pathogenesis, but to date there isno conclusive evidence for an immune-mediated pathogenesis(Sabroe and Black, 1997; Vleeming et al., 1998; Agostoni andCicardi, 2001). In addition, ACE gene polymorphism may beinvolved in the development of angioedema (Vleeming et al.,1998). Angioedema occurs in a wide dosage range and withoutsex preference (Slater et al., 1988; Lawton et al., 1992; Vleeminget al., 1998; Agostoni and Cicardi, 2001). Ethnic differencesappear to be the most important predisposing risk factor. Thus,Blacks are at greater risk than Whites, regardless of dose, spe-cific ACEI, or concurrent medications (Vleeming et al., 1998).The vasopeptidase inhibitor omapatrilate (a dual ACEI andneural enolase inhibitor) may also carry a risk for angioedema(Messerli and Nussberger, 2000). The overall incidence basedon controlled clinical trials is about 0.5% in non-Black and 2%in Black patients (Weber, 2001). A pharmacogenetic polymor-phism would be a likely candidate underlying these ethnic dif-ferences.

Tongue ulcerations preceded by loss of taste have beenreported as a complication of captopril therapy (Nicholls et al.,1981) (S for CYP2D6). A patient underwent a treatment regi-men that included digoxin, furosemide, prazosin, andhydralazine (I of CYP3A4) in addition to captopril (S forCYP2D6). The ulcerations appeared after the patient hadreceived captopril (300 or 450 mg a day) for three months,healed two weeks after the drug was withdrawn, and re-appeared two to three weeks after captopril therapy was re-introduced. Another case report of ulcers due to captopriloccurred in a patient suffering from both hypertension and dia-betes mellitus and treated by propranolol (S for CYP1A2, 2C9,2D6) and chlorpropamide, respectively (Seedat, 1979). Theulcerations developed two month after the initiation of capto-pril therapy (300 mg a day) and reduction in propranolol (S forCYP1A2, 2C19, 2D6) dosage. Ulcerations recurred within twodays upon re-challenge and resolved with discontinuance ofcaptopril. Oral mucosal ulcerations following an increase in thedosage of captopril (from 25 mg to 100 mg a day) have beenreported in a further case. In this case, other medicationsincluding furosemide (40 mg), dinitrate isosorbide (30 mg; S forCYP3A4), and digoxin (0.125 mg)were taken at unchangeddoses. Laboratory investigations revealed a slight leukopeniaand thrombocytopenia. Ulcerations and abnormal blood cellcounts resolved after two weeks and two months, respectively


(Corone et al., 1987). A recent case-control study did not identi-fy ACEIs as inducers of aphthous ulcers (Boulinguez et al.,2000). In three of the four patients referred to above, the associ-ation between ACEIs and oral ulcerations was established byre-challenge (Table 6). Captopril is metabolized by a polymor-phic CYP enzyme, implying that abnormal drug metabolismcould be a risk factor for oral ulceration. Accumulation of drugmetabolites or their impaired detoxification products mightaccount for the delay in clinical presentation of the reactions.All case patients were on multiple medications, implying drug-drug interaction by the inhibition of CYP enzymes as anotherrisk factor.

The administration of ACEIs may cause dry mouth. Forexample, lisinopril has been shown to reduce salivary flow rate(Sreebny and Schwartz, 1997; Baum et al., 2000).

ODRs as manifestations of ACEI-induced hematologicalreactions may occur (Plosker and McTavish, 1995; Langtry andMarkham, 1997). There are isolated reports of neutropenia andagranulocytosis associated with captopril usage in certain sub-sets of patients (e.g., those with renal insufficiency and auto-immune disease). However, with reduced dosage, only neutro-penia is encountered (Jaffe, 1986).

Two cases of long-term usage of ACEIs have been associat-ed with oral lichen planus (Firth and Reade, 1989). A patientwith a three-month history of oral pain and treated with multi-ple medications [allopurinol, colchicine (S for CYP3A4) fourmonths before and quinethazone, potassium, and enalapril (Sfor CYP3A4) one month before the onset of oral symptoms]presented with manifestations of the reticular, erosive, andulcerative type of lichen planus. The latter two manifestationsimproved with discontinuance of enalapril and quinethazone.Three months later, quinethazone was re-introduced withoutrecurrence of ulcerations. The second patient had a six-monthhistory of oral and cutaneous lichen planus lesions. One monthprior to the onset of lesions, the patient was being treated withseveral drugs [nifedipine (S for CYP3A4, 2D6; I of CYP1A2,2C9, 2D6, 3A4), captopril (S for CYP2D6), digoxin,nitrazepam]. Captopril was discontinued, and a month laterthere was considerable clinical improvement: fewer oral ulcer-ations and partial resolution of skin lesions. Enalapril and cap-topril were considered as drugs with a potential to amplifyand/or induce oral lichenoid lesions (Firth and Reade, 1989).An additional patient with suggestive captopril-induced oraland cutaneous lichen planus has been reported (Cox et al.,1989). The patient had been on intermittent hemodialysis for ayear, and medications included isosorbide nitrate (S forCYP3A4), erythromycin (S for CYP3A4; I of CYP3A4), flu-cloxacillin (S for CYP3A4), and captopril (S for CYP2D6; 50-75mg a day for four months). The eruptions resolved within twomonths after captopril was discontinued and healed withresidual macular pigmentation. The three cases of lichenplanus linked to the use of ACEIs referred to above occurred inpatients on multiple medications with an interaction potentialvia CYP enzyme inhibition. None of the patients was subjectedto re-challenge (Table 6). The metabolism of ACEIs by CYPenzymes with either genetic polymorphism (CYP2D6) or greatinter-individual, non-polymorphic variation in activity(CYP3A4) could have contributed to the pathophysiology ofthe reaction.

A patient developed a skin rash and minor oral bleeding asa consequence of sloughing of the superficial layers of the lipsand gingiva one month after enalapril therapy (S for CYP3A4)

was initiated. This patient was also on digoxin, procainamide(S for CYP2D6), and furosemide (Kubo and Cody, 1984). Alllesions resolved within a week following withdrawal ofenalapril, and no re-challenge was performed (Table 6).Captopril (S for CYP2D6) therapy was initiated without recur-rence of the symptoms. From a diagnostic point of view, theclinical findings presented might as well be those observed asreactions to a variety of ingredients in dentifrices or mouthrin-ses.

There is a report of a single case with captopril-inducedpemphigus with oral manifestations (Pinto et al., 1992). Thepatient presented with a five-month history of painful erosionsin the mouth, perineum, and groin, and had been medicatedfor 18 months (50 g daily). The diagnosis was confirmed byskin and oral mucosal biopsies and by resolution of lesions andnormalization of serum IgG titer following discontinuation ofthe offending drug (Table 6). Non-thiol drugs and a variety ofother agents have also been implicated in drug-induced pem-phigus (Brenner et al., 1998). The mechanism behind the drug-induced acantholytic lesions is unclear, but may involve specif-ic circulating and/or tissue-bound autoantibodies (Korman etal., 1991).

'Scalded mouth syndrome' is reported as a rare adverseeffect of ACEIs (Vlasses et al., 1982; Savino and Haushalter,1992). The symptom is unrelated to taste abnormalities associ-ated with ACEIs and is possibly a class effect, since it has beennoted with the use of three chemically different ACEIs (e.g.,lisinopril, enalapril, and captopril) (Vlasses et al., 1982; Savinoand Haushalter, 1992). The potential to induce the scaldedmouth syndrome apparently differs between drugs within thedrug class, i.e., symptoms may decrease when the medication ischanged and the syndrome appears to be dosage-related(Savino and Haushalter, 1992; Brown et al., 1997). The conditionoccurs in some patients following increase in daily dosage ofcaptopril and enalapril. Four out of the six cases of this syn-drome were on concurrent medication: BABsatenolol,nadolol, propranolol (S for CYP1A2, 2C19, 2D6), thiazidediuretics, nitroglycerine, isosorbide dinitrate (S for CYP3A4), oraspirin (S for CYP 2C9). The six cases reported so far fulfill, tosome extent, the criteria on timing of medication as it relates toonset of reaction and absence of symptoms following cessationand/or relapse of symptoms by re-challenge (Table 6). In addi-tion, clinical and medical information that allows for differenti-ation from other causes of painful conditions without clinicalmanifestations (e.g., burning mouth syndrome) is not consis-tently provided. The latency in onset of scalded mouth syn-drome in a patient after 7 years' continued use of captopril(Brown et al., 1997) remains unexplained, but could involveinteraction with agents other than prescribed drugs easilymissed during history-taking.

ACEI as a drug class is associated with taste disturbances.Captopril is linked with increased taste detection and recogni-tion thresholds; and enalapril, with metallic, sweet, salt dys-geusia, and taste loss (Mott et al., 1993). There may be somevariability in the extent of this potential side-effect amongdrugs. Incidence rates for taste disturbances between 2 and 5%or up to 7% with captopril have been reported (Plosker andMcTavish, 1995; Langtry and Markham, 1997). As with othercaptopril-related ADRs, the altered taste sensation responds todose reduction (Weber, 1988).

The ODRs reviewed above were associated with use ofeither captopril or enalapril, and case reports suggest a dose-


related response. Metabolism of these two drugs is mediatedby a polymorphic enzyme (CYP2D6) or an enzyme (CYP3A4)with great inter-individual, non-polymorphic variation inactivity; hence, reduced detoxification of the drugs mightserve as a risk factor for the development of ADRs. The dif-ference in metabolic pathways between the two drugs mightalso explain why mutual drug substitution can occur withoutrelapse of the reaction.

ANGIOTENSIN II RECEPTOR BLOCKERS (ARBS)Rare cases of angioedema have been reported with intake ofARBs, and some of the individuals have a previous history ofACEI-induced angioedema (Agostoni and Cicardi, 2001). In 13patients, the diagnosis of angioedema was linked to the use oflosartan (S for CYP2D6, 3A4; I of CYP1A2, 2C9, 2C19, 3A4). Thereactions occurred from 24 hours to 16 months after the initia-tion of therapy (25-100 mg a day). Three patients had previ-ously experienced angioedema during treatment with ACEIs.Lips and/or tongue was involved in nine out of the 13 cases.There was co-medication in three of the patients, and regimensconsisted of two or three drugs, including diuretics, dexfenflu-ramide (S for CYP2D6, 1A2), estradiol (S for CYP1A2, 2C9,2C19, 3A4; I of CYP1A2, 3A4), progesterone (S for CYP2C9,3A4), and metoprolol (S for CYP2C9, 2D6; I of CYP2D6). In allcases, the causal relation between losartan therapy andangioedema was considered to be at least 'probable' (vanRijnsoever et al., 1998). A patient experienced swelling of thelips and face with losartan. In this patient, captopril (S forCYP2D6) had previously been discontinued because of coughand substituted with bisoprolol-hydrochlorothiazide and tera-zosin. Bisoprolol-hydrochlorothiazide (bisoprolol: S forCYP2D6, 3A4) was, in turn, substituted by losartan, and theangioedema occurred within 30 minutes after a single dose (50-mg) of losartan (Acker and Greenberg, 1995). Both quinapril-and losartan-induced facial and palatal angioedema has beenreported in a patient who had no history of urticaria, angioede-ma, or other drug allergies (Boxer, 1996).

The association between ARBs (e.g., losartan) andangioedema is based upon case reports and cases from sponta-neous reporting systems (Table 6). Onset and resolution of mostreactions occurred within hours to a few weeks, indicating anallergic or pseudo-allergic mechanism. Abnormal metabolismby a polymorphic enzyme (CYP2D6) and/or interactions bysubstrate competition or inhibition from concurrent drugs arepotential risk factors that might contribute to the pathophysi-ology of the reaction.

ANTI-ARRHYTHMICS, CLASS I (SODIUM-CHANNEL BLOCKERS)

ODRs associated with Class I anti-arrhythmics include drymouth, fixed drug eruptions, oral manifestations of hemato-logic disorders, lupus erythematosus, gingival overgrowth,SJS, TEN, and oral manifestations of the hypersensitivity syn-drome (Table 6).

Dry mouth is a result of an anticholinergic effect thatoccurs with drugs like quinidine (S for CYP2C9, 3A4; I ofCYP2C9, 2D6, 3A4), disopyramide (S for CYP2C9, 3A4), fle-cainide (S for CYP2D6; I of CYP2D6), cibenzoline (S forCYP2D6, 3A4), and moricizine (Sreebny and Schwartz, 1997).Whether an effect per se or a consequence of dry mouth, a bit-ter or metallic taste has been reported with propafenone ther-

apy (S for CYP1A2, 2D6, 3A4; I of CYP1A2, 2D6) (Caron andLibersa, 1997).

FDEs from cardiovascular drugs have been reported forphenytoin and quinidine (Korkij and Soltani, 1984; Sun et al.,1994). Two cases of oral pigmentation associated with quini-dine therapy (Birek and Main, 1988) (S for CYP2C9, 3A4; I ofCYP2C9, 2D6, 3A4) may represent FDEs. Both patients werereceiving long-term therapy (five or 10 years) and presentedwith palatal pigmentations of unknown duration. One of thepatients who was on monotherapy also had a melanotic areaon the right ankle, and the palatal lesion became darker andmore extensive during the subsequent three years. The otherpatient ingested multiple drugs: digoxin, verapamil (S forCYP1A2, 2C9, 2C19, 3A4; I of CYP2C9, 2D6, 3A4), and warfarin(S for CYP1A2, 2C9, 2C19, 2D6, 3A4; I of CYP2C9, 2C19). Nodrug withdrawal or re-challenge test was performed (Table 6).Quinidine has a high drug-drug interaction potential andmetabolizes into RDMs.

Oral manifestations of hematological disorders may occurin rare cases of class I anti-arrhythmic therapy (Caron andLibersa, 1997). Drugs commonly suspected to cause thrombo-cytopenia include quinidine (Wiholm and Emanuelsson, 1996).

Procainamide (S for CYP2D6), hydralazine (I of CYP3A4),and quinidine (S for CYP2C9, 3A4; I of CYP2C9, 2D6, 3A4) maycause drug-induced lupus erythematosus (Brosnan et al., 2000).A patient presented with cutaneous and oro-genital ulcerationsas well as arthritis and a photodistributed rash after initiationof therapy with hydralazine (a direct-acting vasodilator;reviewed in this section because its metabolism is similar tothat of procainamide). ANA- and DNA-binding tests were pos-itive. All clinical manifestations disappeared on withdrawal ofthe offending drug (Neville et al., 1981). A further case has beenreported with hydralazine-induced Sjgren's syndrome andassociated with features of SLE in terms of rheumatoid-arthri-tis-like symptoms and a positive ANA. The patient was treatedfor four years with hydralazine (150 mg a day). Joint symptomsresolved after hydralazine was discontinued, and salivary andlacrimal gland flow returned to normal over the following year(Darwaza et al., 1988) (Table 6). The polymorphic enzymeNAT2 metabolizes both hydralazine and procainamide, andthe slow acetylator phenotype appears to be a significant riskfactor for drug-induced lupus. The drug- or metabolite-proteincomplex is recognized as 'foreign' by the immune system(Hofstra, 1994).

Hydantoin and its derivatives may interfere with folateabsorption or metabolism and thus mediate potential manifes-tations of oral ulcerations, cheilitis, and glossitis (Wintroub andStern, 1985). Mucocutaneous reactions including gingival over-growth are part of the broad spectrum of ADRs to phenytointherapy (Table 6). Details on clinical presentation and patho-genesis of phenytoin-induced gingival overgrowth arereviewed in detail elsewhere (Brown et al., 1991; Marshall andBartold, 1998; Rees, 1998; Hallmon and Rossmann, 1999).Phenytoin may also induce facial changes such as coarse facies,including enlargement of the lips and nose and thickening ofthe face and scalp. The mechanism of gingival and facialenlargement is unknown but may involve RDMs. Metabolismof phenytoin by CYP2C9 is the major route of elimination ofthis drug (other S for CYP2C9, 2C19, 3A4; I of CYP2C9), andphenotyping studies have identified individuals with impairedcapacity to metabolize the substrate (Smith et al., 1998). It is alsoknown that both healthy and hyperplastic gingival tissues con-


tain a significant amount of the active metabolite 5-hydroxy-phenyl-5-phenylhydantoin and express CYP2C9 that catalyzesthe formation of this metabolite (Zhou et al., 1996). Phenytoinintake also carries a relative risk of borderline significance tocause hematological disorders such as agranulocytosis(Kaufman et al., 1996).

Phenytoin is among the common agents that can causehypersensitivity reactions (Daoud et al., 1998). A small propor-tion of patients (from one in 1000 to one in 10,000) exposed toanti-convulsants will develop the 'drug hypersensitive' syn-drome (Lawton et al., 1992; Knowles et al., 2000) that was origi-nally called the 'anti-convulsant hypersensitivity' syndrome.Oral ulcerations may occur as a manifestation of the widerange of skin diseases, including EM, SJS, and TEN, that,together with fever and internal organ involvement, character-izes the syndrome. A further clinical feature of this syndrome is'strawberry tongue' (Sun et al., 1994; Hebert and Ralston, 2001).The syndrome is associated with a relative excess of RDMs andinsufficient detoxification of a reactive arene oxide metabolitethat may contribute to the formation of the antigen that triggersan immune reaction (Hebert and Ralston, 2001).

SJS and TEN are associated with short-term therapy withphenytoin (Wintroub and Stern, 1985; Crowson and Magro,1999; Rzany et al., 1999). The period of increased risk is largelyconfined to the first eight weeks of treatment. The associationbetween anti-epileptics and SJS and TEN has been substantiat-ed by a recent case-control study that also took into accountpotential co-factors that might confound or modify the risk(Rzany et al., 1999).

The association between the use of anti-arrhythmics class Iand ODR mostly derives from case reports, and only some ofthe reactions have been validated by re-challenge (Table 6). Anarrow therapeutic index, metabolism into RDMs, and a highdrug-drug interaction potential by CYP enzymes are risk fac-tors underlying the development of ADR from anti-arrhyth-mics. Non-genetic or genetic variation in metabolism pheno-type might also have contributed to the pathogenesis.

ANTI-ARRHYTHMICS, CLASS III (POTASSIUM-CHANNEL BLOCKERS)

CDRs from amiodarone (S for CYP1A2, 2C19, 2D6, 3A4; I ofCYP1A2, 2D6, 3A4) therapy are common, and photosensitivityoccurs in about 5-20% of patients and a blue-gray discoloringof skin in 1-7%. A patient was symptom-free upon withdrawalof amiodarone, and a positive double-blind oral re-challengewith this drug confirmed angioedema of the facial regioninduced by amiodarone (Burches et al., 2000) (Table 6). Thepatient had been taking corticosteroid (S for CYP3A4) for eightyears prior to amiodarone therapy for cardiac rhythm abnor-mality.

A possible association between amiodarone and bretyliumtherapy may cause taste abnormality and salty taste, respec-tively (McGovern et al., 1983; Mott et al., 1993).

PLATELET AGGREGATION INHIBITORS (ASPIRIN)Topical application of aspirin (acetylsalicylic acid; S forCYP2C9) in the oral cavity causes aspirin or acid burn of theoral mucous membrane (Kawashima et al., 1975; Dellinger andLivingston, 1998). The drug may also induce angioedema. Themechanism for this disorder may be an inhibition ofprostaglandin synthesis with overproduction of leukotrienes

(Vervloet and Durham, 1998). Interestingly, a recent case-con-trol study showed that aspirin played no significant role in theoccurrence of aphthous ulcers (Boulinguez et al., 2000).

In a series of 25 cases of oral FDEs, two were associatedwith the intake of aspirin (Jain et al., 1991). Withdrawal ofaspirin resulted in a remission of the lesions. Both patients werere-challenged, and the lesions recurred at the previous siteswithin 24-48 hours (Table 6).

Based on a case-control study, it was found that dipyri-damole carried a relative risk of borderline significance for thedevelopment of agranulocytosis (Kaufman et al., 1996).Dipyridamole has also been linked to altered taste ('bizarre'taste) (Mott et al., 1993).

CALCIUM-CHANNEL BLOCKERS (CCBS) (ANTI-ARRHYTHMICS, CLASS IV)

Reported ODRs include taste disturbances, angioedema, oralulceration, lichenoid drug eruptions, SJS, TEN, and gingivalovergrowth (Table 6).

The reported adverse effect profile tends to hold true fordrug class and is observed in ADRs associated with benzo-thiazepine derivatives (diltiazem), phenylalkylamine deriva-tives (verapamil), and dihydropyridine derivatives (nifedipineand amlodipine) (Dougall and McLay, 1996).

Two patients developed angioedema of the tongue or lipsshortly after the initiation of nifedipine therapy (50 mg a day)(Sauve et al., 1999). Peri-orbital and lip angioedema occurred ina patient one month after starting diltiazem. Patch-testing tocosmetic agents was negative, and the reactions resolved with-in 48 hours after the drug was discontinued (Sadick et al., 1989).In a series of 72 patients with drug-induced oro-facialangioedema, 14 cases were precipitated by CCBs. An expertpanel excluded triggering events other than CCBs. Most reac-tions occurred within the first week of therapy, and symptomsresolved when therapy was discontinued (Hedner et al., 1991).

Two cases with recalcitrant oral ulcerations caused by dil-tiazem (S for CYP 3A4) have been reported (Cohen et al., 1999).One of the cases had no previous history of aphthous ulcers butdeveloped tongue ulceration within two months after initiationof diltiazem therapy (240 mg a day). This patient was also con-comitantly taking other medications, including losartan (50 mga day; S for CYP2C9, 3A4, I of CYP1A2, 2C9, 2C19, 3A4),lorazepam, terazosin, and hydrochlorothiazide. The ulcerationhealed within weeks after diltiazem therapy was discontinued(Cohen et al., 1999). A possible association between diltiazemtherapy and oral ulcerations has not been validated by re-chal-lenge. Non-polymorphic variation (CYP3A4) in metabolismphenotype or interaction by substrate competition/inhibition(CYP3A4) is a candidate risk factor in the ulceration pathogen-esis. The second case with tongue ulceration had been treatedwith captopril (200 mg a day; S for CYP2D6) and verapamil (Sfor CYP1A2, 2C9, 2C19, 3A4; I of CYP2C9, 2D6, 3A4) for at leastfive years and in gradually increasing dosages (from 180 to 240mg a day). Other medications that this patient had been takingincluded oxazepam, metoclopramide, estrogen (S for CYP1A2,2C9, 2C19, 3A4; I of CYP2C9, 2D6, 3A4), thyroxine, and aspirin(S for CYP2C9). Discontinuance of captopril therapy followedby decreased dosage of verapamil resulted in gradual healingover a four-month period. Verapamil was finally discontinued,and complete healing occurred in two weeks. A re-challengetest with another CCB, diltiazem, a month later resulted inulceration at the initial site, implying that the ulceration was a


case of FDE. This lesion healed one month after cessation of dil-tiazem administration (Cohen et al., 1999). In this case, an asso-ciation between CCB therapy and oral ulcerations appears like-ly. The finding that substitution of verapamil by diltiazemoccurred uneventfully may indicate that drug-drug interac-tions mediated via CYP enzymes (CYP1A2, 2C9, or 2C19) couldplay a role in ulcer pathogenesis. CCBs did not cause a problemin a case-control study on aphthous ulcers (Boulinguez et al.,2000). So far, the association between CCB therapy and oralulcerations remains presumptive (Table 6).

Drug-induced gingival overgrowth is a well-documentedand widely recognized ADR to CCB usage (for a recent review,see Marshall and Bartold, 1998; Hallmon and Rossmann, 1999)(Table 6). Incidence rates of gingival overgrowth vary consid-erably, and most reported cases have been associated withnifedipine. Gingival overgrowths occur in as many as 38% ofpatients after three months' therapy with nifedipine, as com-pared with 21% of patients taking diltiazem and 19% of thosetaking verapamil. The prevalence is unknown but appears tobe relatively low when one considers that these drugs in par-ticular are widely prescribed throughout the world (Marshalland Bartold, 1998). There are also well-documented reports ongingival overgrowth occurring with other CCBs (lacidipine,felodipine, amlodipine, isradipine, nicardipine, and nitrendi-pine) (Marshall and Bartold, 1998; Hallmon and Rossmann,1999). Although this side-effect with these latter CCBs occursless frequently, it seems likely that this is merely a reflection ofthe smaller number of patients who are treated with these morerecently introduced drugs. Regression of the overgrowth mayoccur in some patients following switch to a CCB of the sameor a different chemical composition (Westbrook et al., 1997).There is no clear relationship between dosage and CCB-induced gingival overgrowth (Bullon et al., 1994). The patho-genesis of CCB-induced gingival overgrowth remains unclear(Marshall and Bartold, 1998). Genetic predisposition and phar-macokinetic variables are among the factors implicated in itspathogenesis (Seymour et al., 1994; Marshall and Bartold, 1998).Seventeen percent of a Dutch population is phenotypicallydeficient in the first step of nifedipine metabolism(Kleinbloesem et al., 1984). Alternatively, RDMs may be pro-duced as the CYP3A4 gene catalyzes the formation of suchmetabolites in both healthy and hyperplastic gingival tissuesfrom patients receiving cyclosporine and nifedipine therapy(Zhou et al., 1996).

A case of amlodipine-associated lichen planus has recentlybeen reported (Swale and McGregor, 2001). The patient pre-sented with widespread cutaneous lichenoid eruptions andWickham's striae in the oral cavity two weeks following initia-tion of amlodipine therapy (S for CYP3A4; I of CYP2C9, 2D6,3A4). The patient had a history of non-insulin-dependent dia-betes mellitus (treated with metformin) and as such representsa case of the triad of oral lichen planus, hypertension, and dia-betes mellitus known as Grinspan's syndrome. A possible asso-ciation between amlodipine therapy and lichen planus was notvalidated by re-challenge (Table 6).

The proportions of serious adverse reactions, including SJSand TEN, are similar in any of the three chemical groups ofCCBs (Stern and Khalsa, 1989; Knowles et al., 1998). The reac-tions developed within two weeks after drug therapy was ini-tiated. Clinical details have been provided for three of thecases: One patient developed EM after 10 days of therapy withverapamil (S for CYP1A2, 2C9, 2C19 3A4; I of CYP2C9, 2D6,

3A4), recovered when the drug was withdrawn, and presentedwith relapse when re-challenged; a second patient was diag-nosed with SJS after about 12 days' therapy with verapamil(160 mg a day) and recovered after the drug was discontinued,but was not re-challenged; a third patient suffering from obesi-ty, hypothyroidism, asthma, angina, and hypertension devel-oped TEN possibly secondary to diltiazem therapy. Otherdrugs taken by two out of the three patients included levothy-roxine, metoproterenol, nitroglycerin, theophylline (S forCYP1A2, 3A4), and warfarin (S for CYP1A2, 2C9, 2C19, 2D6,3A4; I of CYP2C9, 2C19) (Stern and Khalsa, 1989). A patientwho was taking nitroglycerin presented with multiple oralulcerations, without skin manifestations, two weeks followingthe initiation of diltiazem therapy (90 mg a day). The conditiondiagnosed as EM resolved two weeks after diltiazem was with-drawn. No re-challenge test was performed (Brown et al., 1989).The exposure with an incriminated CCB, along with a correla-tion between onset and resolution of the disease patterns andstart of administration and withdrawal of the drug(s), suggestsa causal association (Table 6). Diltiazem is partly metabolizedby a polymorphic CYP enzyme, implying that abnormalmetabolism could be a risk factor. For the two patients on ver-apamil, the activity level of the highly variable CYP3A4enzyme might be implicated in the pathogenesis of the ODRs.Finally, two of the cases occurred in patients on multiple drugswith an interaction potential via CYP enzymecompetition/inhibition.

CCBs may cause taste disturbances. Diltiazem may causehypogeusia and hyposmia, and nifedipine, taste and smell dis-tortion (Mott et al., 1993; Spielman, 1998). In animal experi-ments, CCBs such as verapamil and nifedipine have beenreported to inhibit saliva output and reduce the protein contentof the secretion (Baum et al., 2000).

DIURETICSODRs related to diuretics include dry mouth, taste distur-bances, angioedema, and oral manifestations of hematologicdisorders, drug hypersensitive syndrome, lichenoid drug erup-tions, and lupus erythematosus-like eruptions (Table 6).According to a recent case-control study (Boulinguez et al.,2000), diuretics do not seem to play a significant role as indu-cers of aphthous ulcers.

In a series of 72 patients with oro-facial angioedema pre-cipitated by anti-hypertensives, diuretics could have induced areaction in 11 of these cases (Hedner et al., 1991). An expertpanel excluded triggering events other than diuretics. Mostreactions occurred within the first week after the initiation oftherapy, and symptoms resolved when the therapy was dis-continued (Table 6). Information on intake of other medicationswas not provided (Hedner et al., 1991).

Diuretics may contribute to dry mouth by causing dehy-dration, and thereby salivary gland hypofunction (Sreebny andSchwartz, 1997; Baum et al., 2000).

In Sweden, diuretics (furosemide, amiloride, and thi-azides) are among the commonly reported offenders suspectedto cause agranulocytosis and thrombocytopenia (Wiholm andEmanuelsson, 1996). Furosemide, amiloride, and thiazidediuretics are all sulphonamides and may, on re-exposure, causeallergic hematological manifestations of thrombocytopenia insusceptible patients (Vervloet and Durham, 1998).Sulphonamides have also been linked to the development ofEM and SJS (Brown et al., 1989; Gruchalla, 2000), and a dose-


independent reaction to sulphonamides is a common cause ofTEN (Becker, 1998). The drug hypersensitivity syndromeoccurs with thiazide diuretics and furosemide. The syndromeis thought to be initiated via effects of a reactive metabolite,hence the term "reactive metabolite syndrome".Sulphonamides can be metabolized to reactive metabolites,which may elicit both direct cytotoxicity and immune respon-ses (Gruchalla, 2000; Knowles et al., 2000).

Skin reactions including photodistributed and non-photo-distributed lichen planus eruptions induced by thiazides havebeen well-documented in the dermatological literature (Daoudet al., 1998). In a case report, symmetrical white buccal plaqueswere linked to bendrofluazide. In this patient, a diagnosis oforal lichen planus was supported by biopsy (Lamey et al.,1990). The patient had a four-year history of diabetes mellitus,which was initially treated with glibenclamide (S for CYP2C9,3A4; I of CYP3A4) and diet, but soon changed to metformin.Hypertension was controlled by bendrofluazide (5 mg a day)and debrisoquine (20 mg daily; S for CYP2D6). This patient isanother example of the triad of hypertension, diabetes mellitus,and lichen planus referred to as Grinspan's syndrome.Alteration of drug regimen was unsuccessful. An additionalpatient presented with oral lichen planus as part of Grinspan'ssyndrome (Lamey et al., 1990). For this patient, medicationsincluded glipizide (5 mg a day; S for CYP2C9), spironolactone(100 mg a day; S for CYP3A4), furosemide (40 mg a day), anddigoxin (125 or 250 mg on alternate days). For these two cases,a causal association between the use of diuretics and lichenplanus remains uncertain (Table 6). Except for exposure, therewas a lack of correlation between the development of lesionsand drug administration and withdrawal, as well as re-chal-lenge. Theoretically, the lesions might as well have been associ-ated with the concurrent medications that are metabolized by apolymorphic enzyme (CYP2C9, 2D6) or by an enzyme(CYP3A4) with great inter-individual, non-polymorphic varia-tion in activity.

Amiloride intake has been linked with decreased thresholdfor salt taste, and spironolactone with taste loss (Mott et al.,1993).

HYDROXYMETHYL-GLUTARYL CO-ENZYME A(HMG-COA) REDUCTASE INHIBITORS (STATINS)

Statins are, in general, well-tolerated if they are the only med-ication an individual is taking (Bernini et al., 2001). Known der-matological ADRs for statins include angioedema. Two patientsexperienced cheilitis after beginning treatment with simvastatin(Mehregan et al., 1998). One of the patients presented with aone-month history of skin rash and an extensive desquamationand crusting of the upper and lower lips. Therapy with simva-statin (S for CYP3A4; I of CYP2C9, 2C19, 2D6, 3A4) was initiat-ed four months before the rash appeared, and an unspecifiedBAB (S for mainly CYP2D6) and warfarin (S for CYP1A2, 2C9,2C19, 2D6, 3A4; I of CYP2C9, 2C19) were started one year priorto the onset of the rash. The second patient presented with a six-month history of cracking lips that appeared approximately sixmonths after initial therapy with simvastatin. Both patients'cheilitis resolved within three weeks following the discontinua-tion of simvastatin. Neither re-challenge nor patch test was per-formed. One could speculate that the lip lesions in these twopatients might represent photodistributed eruption to statinsanalogous to the scaly cheilitis reported in persons withlichenoid photoeruptions (West et al., 1990).

A case of simvastatin-induced lichenoid eruptions withskin and mucosal involvement has been reported (Roger et al.,1994). The patient presented with reticular manifestations onthe buccal mucosa, but no vaginal, scalp, or nail changes werenoted. The patient had been on simvastatin for four months (10mg a day), was not taking any other drug, and gave a three-month history of cutaneous lesions. The offending drug wasdiscontinued, and the cutaneous lesions began to resolve with-in four weeks. No new lesions appeared; however, the mucosallesions persisted for six months. The patient refused patch-test-ing and re-challenge. Thus, the diagnosis of lichenoid drugeruption remains presumptive.

A possible association between simvastatin therapy andthe sporadic cases of ODR has not been verified by re-challenge(Table 6). Hovever, most statins are prescribed for individualswho are on multiple medications, and a mechanism involvingpotential interaction by substrate competition or inhibition viathe CYP3A4 appears likely. The non-polymorphic variation inactivity of this enzyme may also represent a risk factor for thedevelopment of ODRs. The latency in timing between initiationof drug therapy and presentation of lesions favors a contribu-tion from RDMs.

POTASSIUM-CHANNEL OPENERS (NICORANDIL)Several case reports published in recent years link nicorandilwith ulcers or aphthae affecting the tongue, gingival, labial, orbuccal mucosa, hard palate, and fauces (Scully et al., 2001). Theestimated prevalence of this adverse reactions is 5% (Marquart-Elbaz et al., 1999). However, a recent case-control study whichinvestigated a possible association between drug exposure andaphthous ulcers showed that none of the cases (80 individuals)was on nicorandil therapy (Boulinguez et al., 2000). The age ofthe patients exhibiting ADRs to vasodilators ranges from 60 to90 years, with an even sex distribution. The ulcers present with-in 10 months following the initiation of drug therapy, and com-plete healing occurs weeks after drug withdrawal. In one out ofnine patients, a positive re-challenge was reported (Scully et al.,2001). A past history of aphthae could increase the risk forADRs in some patients. In a recent observational cohort studyof 13,260 patients over a minimum observation period of sixmonths of nicorandil treatment, there were 55 cases of mouthulcers (Dunn et al., 1999). In 49 patients, the ulcers developedduring treatment, while three patients developed the ulcersafter treatment had stopped, one patient had ulcers pre-datingtreatment, and for two patients it was uncertain whether theywere still taking nicorandil when the ulcers developed. Mostulcers developed more than 60 days after the start of treatment.The dosage of the drug covered a wide range, from 10 to 80 mga day, but there was no dose-response effect. The crude ratio ofmouth ulcers associated with nicorandil to all the comparabledrugs combined was 2.03 (95% CI, 1.48-2.74), indicating acausal association.

A possible association between nicorandil therapy and oralulcerations has been substantiated by both case reports and acohort study. Validation by re-challenge has been performed ina few cases (Table 6). Some lesions may be linked to drugs otherthan nicorandil, since some of the individuals were reported tobe on multiple drug regimens, including medication with apotential to induce oral ulcerations. The fact that ulcerationspresent weeks to months following the initiation of therapyindicates that nicorandil metabolites rather than the parentdrug are implicated in the development of ulcers. There is a


large individual variation in levels of activity of the enzymenicotinamide N-methyltransferase that catalyzes the methyl-conjugation of nicotinamide, an intermediate formed by de-nitration of nicorandil (Weinshilboum et al., 1999). The trait oflow levels of activity of this enzyme could be another risk fac-tor in the pathophysiology of oral ulcerations.

Concluding RemarksThe quality of evidence presented for oral reactions beingdrug-induced is variable. As presented in this review, informa-tion on ODRs is largely based on case reports or small series ofcases and was gathered before we entered the post-genomicera. Data on incidence rates are sparse and mostly derived fromstudies of selected populations in hospital or university set-tings. Thus, epidemiological studies with appropriate case andcontrol groups and racially matched populations are needed ifwe are to obtain more reliable information on the incidence ofODRs. The association between a drug and an ODR is mostlybased on the disappearance of the reactions following discon-tinuance of the offending drug. Some ODRs have been verifiedby re-challenge or laboratory tests. A few are documented bywell-controlled case-control studies. In patients on multipledrugs, most authors consider the latest-introduced drug as theoffending drug. When considering ADRs linked to CVDs thatare primarily catabolized by CYPs, as are xenobiotics in gener-al, it is important that one evaluate possible contributions fromboth endogenous and exogenous factors, such as concomitantdrugs, diet, and other chemicals. Table 7 presents mechanismsof potential ADRs due to CVDs, and below we discuss somedrug classes in which the influence of endogenous and exoge-nous factors on drug safety has been documented.

The pharmacokinetic behavior of drug-metabolizingenzymes should be considered as factors that can influencedrug safety along with geno- and phenotypes. Many pharma-cokinetic drug interactions with a potential for ADRs fromCVDs are associated with CYP-mediated phase I drug bio-transformation (Abernethy and Flockhart, 2000). Pharmaco-kinetic drug interactions are known to occur with many drugcombinations. Administration of several drugsincludingBABs, anti-arrhythmics, anti-convulsants, and hypnoseda-tivestogether with CCBs can significantly alter the pharma-cokinetics of those drugs. Some interactions are well-docu-mented, whereas other potential interactions await furtherinvestigation (Rosenthal and Ezra, 1995). BABs may furtherinteract with inotropic agents, anti-arrhythmics, NSAIDs, psy-chotropic drugs, anti-ulcer medications, statins, warfarin, andoral hyperglycamics (Blaufarb et al., 1995). In general, manypotential interactions can be predicted with anti-arrhythmics,quinidine and amiodarone in particular. These agents oftenhave a narrow therapeutic window. Accordingly, small increas-es in serum concentrations may lead to toxicity (Trujillo andNolan, 2000). Attention has to be paid to possible confoundingeffects due to an underlying and or concomitant disease. Todate, molecular genetics of underlying cardiovascular diseasesas they relate to genes that determine the responsiveness to agiven drug has recently been reviewed, and the data appearequivocal (Nakagawa and Ishizaki, 2000).

There is increasing knowledge on the genetic polymor-phism of CYP2C9, CYP2C19, and CYP2D6. For most patientswith a "poor metabolizer" phenotype, there is limited metabo-lism of the drug substrate unless another major metabolic path-way, involving other enzymes, exists. Thus, a clinical conse-

quence might be an idiosyncratic pharmacological response toa prescribed medication (Ingelman-Sundberg, 2001). For somedrugs, an extensive metabolizing phenotype may turn into apoorly metabolizing type, provided that the patient is con-comitantly exposed to an inhibitor of a particular medication, aphenomenon termed "phenocopy" (Brinn et al., 1986). Amongthe cases that have been reviewed, some drug combinationsincluded agents that are known inhibitors of CYP enzymes ofrelevance to CVDs. The isoforms CYP3A4 and CYP1A2 havehighly variable expressions across the population, even in theabsence of concurrent ingestion of an inhibiting drug. Mostindividuals have an intermediate level of enzyme activity, andsome individuals have very low or very high activity(Abernethy and Flockhart, 2000).

CYPs are expressed predominantly in the liver but also inextra-hepatic tissues, e.g., the gastrointestinal tract, the skin,and oral mucous membrane (Zhou et al., 1996; Janmohamed etal., 2001;

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Oral Adverse Drug Reactions to Cardiovascular Drugs