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.
Introduction
Several 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 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 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
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 products is now established as a prerequisite for many idiosyncratic drug reactions. Increased levels of reactive drug metabolites (RDMs), their impaired detoxification, or decreased cellular defense against reactive drug products appears to be an important initiating factor (Pirmohamed et al., 1996; Hess and Rieder, 1997). Oxidative RDMs are found in organs and cells preferentially affected by idiosyncratic drug reactions (Gruchalla, 2000).
Immunological factors
The immune events are less-well-characterized (Shapiro and Shear, 1996). Theories for the induction of immune-mediated events to drugs, their metabolites, or changes caused by these substances include the ‘hapten’ and the ‘danger’ hypotheses (Uetrecht, 1999). The ‘hapten’ hypothesis proposes that RDMs bind irreversibly to proteins or other macromolecules that are perceived as foreign and then induce an immune response. According to the ‘danger’ hypothesis, the immune system responds with tolerance to most antigens, and a ‘danger signal’ rather than the ‘foreignness’ of the antigen triggers an immune response. The exact nature and range of stimuli that can act as danger signals remain to be determined but are likely to include cell damage (Uetrecht, 1999).
Genetic factors
There is a growing body of literature on the possible association between pharmacogenetic polymorphism and ADRs. Underlying the person-to-person (phenotypic) differences in the safety of a drug within a population are genotypic polymorphisms of key enzymes and proteins (Evans and Relling, 1999; Ingelman-Sundberg, 2001). In this context, pharmacogenomics refers to the entire spectrum of genes that determine drug behavior and sensitivity, whereas pharmacokinetics is used to define the narrower spectrum of inherited differences in 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 responsible for modification of functional groups by oxidation, hydroxylation, etc. (classified as phase I reactions), or conjugation with endogenous constituents (classified as phase II reactions—glucoronidation, acetylation, demethylation, etc.), exhibit common polymorphism at the genomic level (Evans and Relling, 1999). Among the important enzyme families that take part in the process are CYPs and N-acetyltransferases (NATs) (see “Cardiovascular drug metabolism”).
Apart from the documented genetic risk factors for the development of ADRs, other risk factors include a history of previous adverse reaction, multiple medications, liver and renal disease, and female gender. Sex may influence pharmacokinetics, drug utilization, and susceptibility to and presentation/detection of ADRs. Factors that may explain the higher adverse event rate observed in female patients include pharmacodynamic factors, hormonal influences, reporting bias, and increased use of medications (Tran et al., 1998).
Diagnostic work-up in the dental office
A detailed drug history—including all prescription and non-prescription drugs, herbal treatments, and other remedies (vitamins, minerals, and homeopathic agents)—should be obtained during the diagnostic work-up. These supplements may cause unexpected toxicity by themselves or through interaction with drugs, resulting in increased or decreased pharmacological or toxicological effects of either component (Fugh-Berman, 2000; Ozdemir et al., 2001). In addition, the clinician needs to know the doses of all medications, timing of medication(s) as it relates to the onset of reaction, and concurrent diseases (e.g., renal failure, hepatitis, bowel disease) that could lead to alteration in drug excretion, absorption, or metabolism. Finally, it is important that the clinician be familiar with the various types of adverse reactions that a particular drug may elicit. In many instances, this task is not so simple, since a drug can be responsible for causing a range of reactions, some of which can be attributed to its pharmacological properties, and others to its immunological properties (Gruchalla, 2000). With regard to ODRs, the matter is complicated by the fact that they are not currently reported as a group per se, but rather are included among several organ groups (e.g., gastrointestinal, dermatological, hematological, neurological).
Cardiovascular Drugs
Several drug classes are used to treat hypertension and/or arrhythmias: 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 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 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 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 intra- and 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 distributed with pronounced inter-ethnic differences (Abernethy and Flockhart, 2000; Ingelman-Sundberg, 2001) (Table 3). The phenotypic consequences of genetic variation are individuals with no, normal, increased, and reduced or inactive enzyme activity, some of which may result in idiosyncratic pharmacological responses to prescribed medications (Smith et al., 1998; Ingelman-Sundberg, 2001). Great inter-individual differences in the activity of CYP1A2 and CYP3A4 are known, and individuals with the phenotype of low activity might be at risk for the development of ADRs. Non-genetic factors and as-yet-undetermined genetic causes will likely contribute to these inter-individual differences (Lamba et al., 2002). From now on, the two enzymes in question will be referred to as “non-polymorphic”. Induction and inhibition of CYPs by xenobiotics, including concomitant medication, may also result in treatment failure or ADRs, respectively.
Table 4 illustrates several CVDs which are catabolized by CYPs. Beta-adrenergic blockers, CCBs, ACEIs, ARBs, and statins are all metabolized via CYP-dependent pathways, and the isoforms of relevance are CYP1A2, CYP2C9, CYP2C19, CYP2D6, and CYP3A4. Acetylation polymorphism (NAT-2) is also important for some anti-hypertensives and anti-arrhythmics (hydralazine, procaineamide) (Evans and Relling, 1999). Most populations of European origin are approximately equally divided between rapid and slow acetylators (Weber and Hein, 1985). Individuals inheriting mutant forms of more than one drug-metabolizing enzyme have a higher risk of drug-induced toxicity (Smith et al., 1998; Evans and Relling, 1999).
Cutaneous and Oral Mucosal Adverse Reactions to Cardiovascular Drugs
CVDs have been estimated to account for at least 9% of medication-related visits to office-based physicians (Aparasu, 1999). Cutaneous drug reactions (CDRs) undoubtedly are among the most frequent events in patients receiving drug therapy. The incidence of CDRs has been estimated to be about 2% (Bigby et al., 1986; Apaydin et al., 2000). Skin reactions account for up to 30% of all the adverse events, although over-reporting of skin reactions per se or under-reporting of other organ 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. About 10% of drug-induced rashes result from true allergy that requires prior exposure, and asthma may exacerbate adverse reactions to drugs (Vervloet and Durham, 1998). The morphologic reaction patterns frequently mimick well-known skin and mucocutaneous lesions or disorders. Furthermore, specific classes of drugs are associated with specific clinical presentations (Table 5). CDRs to systemically administered anti-hypertensives and anti-arrhythmics are reviewed elsewhere (Sun et al., 1994; Caron and Libersa, 1997; Brosnan et al., 2000; Svensson et al., 2001).
Table 5 list several oral mucosal reaction patterns to cardiovascular drug exposure. There is much less information available on ODRs than on CDRs, but the former may be less frequent. However, some common reactions, such as dry mouth, taste disturbances, and aphthae, may be added to the spectrum of ODRs. Although ODRs only rarely result in severe morbidity or death, they may cause mild to substantial discomfort and, therefore, influence the individual’s quality of life and oral health condition. As with the skin, the oral mucous membrane reacts with a few patterns to a variety of stimuli, and different drug classes may induce identical mucosal changes. The following section is devoted to a brief overview of different ODR patterns.
Oral drug reaction patterns
In general, there are no clinical or histopathological oral reaction patterns that can be specifically related to drug usage. Neither is it possible by clinical or histopathological presentation alone to relate ODRs to any specific drug. Many ODRs mimic oral lesions that are also seen in the absence of drug usage. Thus, for a given reaction in the mouth to be established as an ODR, the suspected offender drug should be withdrawn, which should lead to disappearance of the reaction, which should then re-appear on re-challenge. Such tests, however, are not always desirable or advisable. Furthermore, an allergic reaction to additives should be ruled out. Below we have emphasized certain oral reactions commonly reported as ODRs.
Dry mouth is one of the most common oral side-effects of drug usage, although it is also commonly seen as part of certain diseases, such as Sjögren’s syndrome, which are unrelated to drug usage. A subjective feeling of dry mouth (xerostomia) does not necessarily correlate with objective measures, such as sialometry, which can establish a pathologically decreased whole saliva flow rate (hyposalivation). Vast numbers of cardiovascular drugs are implicated in dry mouth (Sreebny and Schwartz, 1997). Chronic hyposalivation has debilitating effects on the integrity of the hard and soft tissues of the mouth, typically leading to an increase in dental caries incidence and yeast infections (candidosis) (Pedersen et al., 2002).
Taste disturbances are not uncommonly described as an ODR. The mechanisms by which the medications alter taste sensation are not well-understood. One possibility is that the excretion of the drug or its metabolites into saliva may generate an unpleasant taste. Many chemosensory disorders affect both taste and smell, and often patients refer to a taste deficit that is actually anosmia, e.g., inability to detect olfactory stimulants (Spielman, 1998). In scalded mouth syndrome, sometimes included as an ODR, taste perception is normal; however, patients complain of a burning sensation comparable with having been scalded by a hot liquid (Vlasses et al., 1982).
Various diseases of the oral mucous membrane, unrelated to drug usage, have been regarded as manifestations of ODR. The terms “oral ulceration” and “aphthae” are commonly used synonymously in reports on ODR; however, aphthae usually commence in the second decade of life as recurrent oral ulcerations and usually wane during the fourth decade (Porter et al., 1998). In contrast, drug-induced ulcerations present mostly in older age groups and not always as a recurrent pattern.
Oral manifestations of systemic diseases are not uncommon and may be related to drug usage. Ulcerations are seen as oral manifestations of hematological disorders such as agranulocytosis and neutropenia, whereas hemorrhagic bullae, petecchias, ecchymoses, and bleeding are oral features of thrombocytopenia. It is well-known that CVDs can cause agranulocytosis and thrombocytopenia (Wiholm and Emanuelsson, 1996). Drug-induced autoantibodies affect platelets more often than any other blood element (Aster, 2000).
Drug-induced lichen planus, also referred to as lichenoid drug eruptions, exhibits clinical features similar to those of idiopathic lichen planus, which is a fairly common oral mucosal disease. Lichenoid drug eruptions are more likely to be unilateral and of the erythematous and ulcerative variety; however, this is not well-substantiated (Lamey et al., 1995). Recently, it has been suggested that intake of medications metabolized by polymorphic CYPs may be implicated in lichenoid drug eruptions (Kragelund et al., 2003). Clinical manifestations of other oral mucosal diseases—such as erythema multiforme (EM), Stevens-Johnson syndrome (SJS), linear IgA disease/IgA bullous disease, lupus erythematosus, pemphigoid, and pemphigus—have, at times, been regarded as ODRs. However, the criteria used in diagnosing these diseases as ODRs are rarely given. Unlike idiopathic linear IgA disease, mucosal lesions appear less frequently in the drug-induced form, whereas the opposite is true for bullous pemphigoid (Camilleri and Pace, 1998; Vassileva, 1998). Also, angioedema, fixed drug eruptions (FDEs), toxic epidermal necrolysis (TEN), drug hypersensitivity syndrome, oculo-mucocutaneous syndrome, and pigmentary disturbances have been regarded as ODRs.
A well-known adverse reaction to certain drugs such as cyclosporins, calcium-channel blockers, and phenytoin is gingival overgrowth, which is characterized by enlarged gingiva. The condition usually involves the interproximal papilla and may present as a localized or generalized condition. This overgrowth can be associated with both natural teeth and dental implants but does not appear to affect edentulous areas. Proper dental prophylaxis and good oral hygiene may reduce or prevent the overgrowth in some patients (Marshall and Bartold, 1998).
Oral Drug Reactions from Major Therapeutic Classes of CVDs
The next section will deal with the wide spectrum of oral reaction patterns in response to usage of CVDs (Table 6). The review does not fully describe all possible reactions of CVDs. The clinical evidence for ODRs will be linked to drug-metabolizing enzymes relevant to the drugs implicated, to illustrate the potential impact of genetic variability to the reactions. In this context, we focus on CYP enzymes with known variant alleles causing poor metabolism of drugs due to no, reduced, or inactive enzymes (CYP2C9, 2C19, 2D6) and with great inter-individual, non-polymorphic differences in the activity (CYP1A2, 3A4), which are most relevant to the development of ADRs. The potential contributions from drug interactions by substrate competition or inhibition of these CYP enzymes are also addressed.
Substrate competition occurs with the concomitant administration of two substrates of a CYP. Each drug will compete for that enzyme and competitively inhibit the metabolism of the other substrate. Owing to a lack of larger surveys investigating such aspects, we review here the available case reports with indications of the CYP metabolism pathway for offending drugs and concurrent medication (Rendic, 2002).
Adrenergic agents
Alpha-adrenergic blockers
Alpha1-adrenergic agents may result in altered saliva composition and secretion rates. Furthermore, oral lichenoid eruptions and ulcerations may be seen.
Inhibitors of alpha1-adrenoreceptors (terazosin and prazosin) have been reported to reduce saliva production due to their effects on salivary gland alpha1-adrenoreceptors. However, an alpha2-adrenoreceptor agonist (clonidine) may also cause dry mouth by both central and peripheral mechanisms (Sreebny and Schwartz, 1997; Baum et al., 2000). Other centrally acting anti-hypertensive drugs associated with dry mouth include methyldopa, reserpine, moxonidine, and rilmenidine.
Reports implicate the use of methyldopa, an alpha2-adrenergic agent, in the etiology of oral lichen planus. A patient who had been taking methyldopa and hydrochlorothiazide for seven years developed multiple oral ulcerations in addition to pruritic skin papules collectively diagnosed as lichen planus. The oral lesions and symptoms had been present for three months, and the patient had experienced a previous episode of oral ulcerations one year earlier. The lesions were refractory to treatment, but healed or improved after withdrawal of methyldopa. No re-challenge was performed (Brooks, 1982). Three cases of oral lichenoid eruptions, including tongue ulcerations, that were deemed possibly linked to methyldopa have been reported. These patients had been taking methyldopa for periods of one year or “several years”. In two out of the three cases, tongue ulcerations resolved four to five months after methyldopa was discontinued. The case reports do not provide information on other medications the patients may have been taking, or on re-challenge attempts (Burry and Kirk, 1974). A larger series of 17 patients with oral mucosal reactions associated with methyldopa has been reported (Hay and Reade, 1978). Most patients presented with erythematous or ulcerative lichen planus lesions. They had been taking the drug from six to 60 months prior to the development of lesions and required up to five months for healing after drug cessation. Of the 17 patients, 13 used from one to six concurrent medications, including combinations with diuretics, NSAIDs [substrate (S) for CYP2C9, 2C19; inhibitor of activity (I) of CYP2C9, 3A4], sulfonylurea (S for CYP2C9; I of 3A4), anti-arrhythmics (S for CYP2C9; I of CYP2C9, 3A4), and anti-depressants (S for and I of CYP1A2, 2C9, 2C19, 2D6, 3A4) ((Hay and Reade, 1978).
The association between methyldopa therapy and oral lichen planus has not been clearly established. The evidence originates from case reports or small case series that are inadequate with regard to information on co-morbidity, timing between presentation of lesions, and start of co-medication, and re-challenges have rarely been performed (Table 6). Most individuals were on multiple medications, raising the possibility of the reaction being linked to drugs other than methyldopa or to drug-drug interactions by inhibition. Theoretically, a contribution from genetic variation in metabolism of methyldopa is a further candidate as a risk factor for the adverse reaction. There is a large individual variation in levels of activity of the enzyme catechol O-methyltransferase that catalyzes methyldopa, and genotype frequencies of 25% with low activity of this enzyme 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, including angioedema, dry mouth, oral ulcerations, lichenoid drug eruptions, lupus erythematosus, SJS, oculo-mucocutaneous syndrome, and manifestations of hematological disorders.
In a study of 72 patients with oro-facial angioedema precipitated 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 of therapy, and symptoms resolved when therapy was discontinued (Hedner et al., 1991).
Dry mouth has been reported in about 20% of hypertensives 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 for CYP2D6), a combined alpha- and beta-adrenergic blocker, was implicated in oral ulcerations that resolved following drug withdrawal and relapsed at re-challenge (Pradalier et al., 1982). A recent case-control study suggests a statistically significant link between BABs and aphthous ulcers (P = 0.002, multivariate paired analysis) (Boulinguez et al., 2000).
A patient presenting with pruritic oral and cutaneous lesions may constitute a case of secondary thrombocytopenia caused by medication. The patient had been taking a combination of propranolol and disulfiram for less than a month prior to onset of the lesions. Following withdrawal of both drugs, propranolol (S for CYP1A2, 2C9, 2D6) alone could be resumed without eliciting any reaction. The authors suggested that the reaction was due to an overdose achieved by the combined usage 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 interactions by inhibition of any of the three implicated CYP enzymes might 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 phenomenon in the dermatological literature. Since it is a mucocutaneous disease, involvement of the oral mucous membrane can be expected. However, there are only a few case reports on one or two patients that implicate the usage of BABs with the development of oral lichen planus lesions in these individuals. Cutaneous as well as oral lesions have been reported in a patient taking propranolol (Hawk, 1980). In this patient, therapy including propranolol (240 mg a day; S for CYP1A2, 2C9, 2D6) and furosemide (80 mg a day) was initiated 21 months prior to the onset of reaction. Allopurinol (300 mg a day) was commenced the same year and before the development of skin eruptions. Propranolol and furosemide were discontinued, and methyldopa (1000 mg a day) was substituted. The reticular and ulcerative oral lesions almost resolved within four months after discontinuance of drugs, whereas the cutaneous lesions turned into hyper-pigmented areas. A patient with Ferguson-Smith disease developed asymptomatic oral lichen planus two weeks after therapy with oxprenolol (I of CYP2D6), and cyclopenthiazide was initiated (Wiesenfeld et al., 1982). A switch from oxprenolol to methyldopa resulted in the disappearance of the cutaneous and the oral white reticular and plaque-type lesions within two months, but both oral and cutaneous lesions recurred a month later. Methyldopa was replaced by prazosin, and after six months the oral lesions resolved completely and the cutaneous lesions improved. Another patient was reported as having lichenoid skin eruptions and oral lesions typical of lichen planus associated with the intake of practolol (withdrawn from the market). The duration of treatment (400 mg a day) before the onset of rash was one month. It is possible that the patient was on concurrent medication(s), since most of the reported 21 patients with cutaneous and ocular reactions to practolol were taking combinations of other drugs (diuretics, tranquilizers, antihypertensives; Felix et al., 1974). A patient presented with a one-year history of asymptomatic reticular and erosive oral lichen planus. The medication regimen included atenolol (100 mg a day) for six months, chlorpropamide (100 mg and increased to 200 mg daily for the last eight months) for 18 months, and salbutamol (6 mg a day; I of CYP3A4). The patient was thought to represent a case of drug-induced lichen planus, and no alternative drug therapies were attempted (Lamey et al., 1990). Chlorpropamide, a sulfonylurea agent, is known to cause drug-induced oral lichen planus (Thompson and Skaehill, 1994). None of the four patients referred to above was clearly established as having BAB-induced lichen planus by re-challenge, and the outcomes of substitution by drugs other than BABs were variable and included relapses. A delay ranging from weeks to months between the presentation of oral lesions and the start of therapy does not exclude the incriminated BABs, provided that the drugs metabolized into RDMs and such metabolites are implicated in the pathophysiological mechanism.
Some BABs (acebutolol, labetalol, practolol, and propranolol) have been linked to drug-induced lupus erythematosus manifesting as skin eruptions (S for CYP1A2, 2C19, 2D6) (Sun et al., 1994). Labetalol and practolol may also cause the oculo-mucocutaneous syndrome (Wright, 1975; Sun et al., 1994). A case series of 27 patients with this syndrome was linked to the administration of practolol (Wright, 1975). Nineteen of these patients were also taking diuretics, cardiac glycosides, or anti-coagulants. Anti-nuclear antibodies (ANAs) were positive in all patients, and a circulating antibody capable of binding to epithelial tissue was found in 25 patients. No other evidence of drug-induced systemic lupus erythematosus (SLE) was found. Recurrent ulcerations of the oral mucous membrane occurred as part of the syndrome in four of the patients. Three of these patients showed improvement in symptoms and signs over a period of four months to more than a year; one patient developed a progressive disorder suggestive of an atypical drug-induced SLE (Wright, 1975). Hence, a long-term follow-up is considered crucial before a final diagnosis of drug-induced SLE and/or oculo-mucocutaneous syndrome can be made.
SJS with oral manifestations associated with carvediol, a selective beta1-blocker, has been reported (Kowalski and Cody, 1997). The rash included macules, blisters, and target lesions involving the entire skin surface and the oral mucous membrane. The symptoms developed four weeks after initiation of therapy and following dosage reduction (initially 6.25 mg, titrated to 25 mg and reduced to 12.5 mg a day). At the time carvediol (S for CYP2C9, CYP2D6) was initiated, the patient was on stable long-term doses of hydralazine (I of CYP3A4), captopril (S for CYP2D6), digoxin, furosemide, warfarin (S for CYP1A2, 2C9, 2C19, 2D6, 3A4; I of CYP2C9, 2C19), allopurinol, famotidine, and aspirin (S for CYP2C9). Following cessation of carvediol therapy, complete resolution occurred within two weeks. The patient was not re-challenged (Kowalski and Cody, 1997).
‘Mouth paresthesia’ is the main adverse effect observed after sublingual administration of propranolol (Mansur et al., 1998).
The evidence implicating the use of BABs with ODR derives from single case reports, and verification by re-challenge has seldom been performed (Table 6). Hence, BAB-induced oral ulcerations reach a causality level of only ‘possible’, as evidenced by a case-control study. Some of the offending BABs in question are metabolized by polymorphic CYP enzymes, implying abnormal metabolizing as a risk factor for ODRs. Most case patients were on multiple drugs, raising the possibility of the reaction being linked to drugs other than the incriminated BABs or to drug-drug interactions.
Angiotensin-converting enzyme inhibitors (ACEIs)
ACEIs evoke a relatively low incidence of ADRs, with cough and nausea being the more common adverse effects (Lawton et al., 1992; Vleeming et al., 1998). Reports on ODRs have included angioedema, dry mouth, ulcerations, lichenoid eruptions, manifestations of hematological disturbances, loss of taste, and ‘scalded mouth syndrome’.
Hundreds of cases of angioedema related to the usage of ACEIs 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 compounds—captopril, zofenapril; carboxyalkyldipeptide—enalapril, lisinopril; and phosphoric acid compounds—fosinopril) (Vleeming et al., 1998). The majority of the reactions occur in the first week after the initiation of ACE inhibitor therapy, but a significant number occur after prolonged therapy (Vleeming et al., 1998; Agostoni and Cicardi, 2001). In a review of 72 patients with angioedema precipitated by anti-hypertensives, 36 cases were due to ACEIs (Hedner et al., 1991). Angioedema has been estimated to occur in one to five in 1000 patients using ACEIs, but if long-term therapy and late 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 neck region, and most occurrences manifest as edema of the tongue and lips (Slater et al., 1988; Roberts and Wuerz, 1991; Rees and Gibson, 1997; Vleeming et al., 1998; Agostoni and Cicardi, 2001). Immunological processes and several mediator systems (bradykinin, substance P, and prostaglandins) have been suggested to be involved in the pathogenesis, but to date there is no conclusive evidence for an immune-mediated pathogenesis (Sabroe and Black, 1997; Vleeming et al., 1998; Agostoni and Cicardi, 2001). In addition, ACE gene polymorphism may be involved in the development of angioedema (Vleeming et al., 1998). Angioedema occurs in a wide dosage range and without sex preference (Slater et al., 1988; Lawton et al., 1992; Vleeming et al., 1998; Agostoni and Cicardi, 2001). Ethnic differences appear to be the most important predisposing risk factor. Thus, Blacks are at greater risk than Whites, regardless of dose, specific ACEI, or concurrent medications (Vleeming et al., 1998). The vasopeptidase inhibitor omapatrilate (a dual ACEI and neural enolase inhibitor) may also carry a risk for angioedema (Messerli and Nussberger, 2000). The overall incidence based on controlled clinical trials is about 0.5% in non-Black and 2% in Black patients (Weber, 2001). A pharmacogenetic polymorphism would be a likely candidate underlying these ethnic differences.
Tongue ulcerations preceded by loss of taste have been reported as a complication of captopril therapy (Nicholls et al., 1981) (S for CYP2D6). A patient underwent a treatment regimen that included digoxin, furosemide, prazosin, and hydralazine (I of CYP3A4) in addition to captopril (S for CYP2D6). The ulcerations appeared after the patient had received 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 captopril occurred in a patient suffering from both hypertension and diabetes mellitus and treated by propranolol (S for CYP1A2, 2C9, 2D6) and chlorpropamide, respectively (Seedat, 1979). The ulcerations developed two month after the initiation of captopril therapy (300 mg a day) and reduction in propranolol (S for CYP1A2, 2C19, 2D6) dosage. Ulcerations recurred within two days upon re-challenge and resolved with discontinuance of captopril. Oral mucosal ulcerations following an increase in the dosage of captopril (from 25 mg to 100 mg a day) have been reported in a further case. In this case, other medications—including furosemide (40 mg), dinitrate isosorbide (30 mg; S for CYP3A4), and digoxin (0.125 mg)—were taken at unchanged doses. Laboratory investigations revealed a slight leukopenia and thrombocytopenia. Ulcerations and abnormal blood cell counts resolved after two weeks and two months, respectively (Corone et al., 1987). A recent case-control study did not identify ACEIs as inducers of aphthous ulcers (Boulinguez et al., 2000). In three of the four patients referred to above, the association between ACEIs and oral ulcerations was established by re-challenge (Table 6). Captopril is metabolized by a polymorphic CYP enzyme, implying that abnormal drug metabolism could be a risk factor for oral ulceration. Accumulation of drug metabolites or their impaired detoxification products might account 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 another risk factor.
The administration of ACEIs may cause dry mouth. For example, lisinopril has been shown to reduce salivary flow rate (Sreebny and Schwartz, 1997; Baum et al., 2000).
ODRs as manifestations of ACEI-induced hematological reactions may occur (Plosker and McTavish, 1995; Langtry and Markham, 1997). There are isolated reports of neutropenia and agranulocytosis associated with captopril usage in certain subsets of patients (e.g., those with renal insufficiency and autoimmune disease). However, with reduced dosage, only neutropenia is encountered (Jaffe, 1986).
Two cases of long-term usage of ACEIs have been associated with oral lichen planus (Firth and Reade, 1989). A patient with a three-month history of oral pain and treated with multiple medications [allopurinol, colchicine (S for CYP3A4) four months before and quinethazone, potassium, and enalapril (S for CYP3A4) one month before the onset of oral symptoms] presented with manifestations of the reticular, erosive, and ulcerative type of lichen planus. The latter two manifestations improved with discontinuance of enalapril and quinethazone. Three months later, quinethazone was re-introduced without recurrence of ulcerations. The second patient had a six-month history of oral and cutaneous lichen planus lesions. One month prior to the onset of lesions, the patient was being treated with several drugs [nifedipine (S for CYP3A4, 2D6; I of CYP1A2, 2C9, 2D6, 3A4), captopril (S for CYP2D6), digoxin, nitrazepam]. Captopril was discontinued, and a month later there was considerable clinical improvement: fewer oral ulcerations and partial resolution of skin lesions. Enalapril and captopril were considered as drugs with a potential to amplify and/or induce oral lichenoid lesions (Firth and Reade, 1989). An additional patient with suggestive captopril-induced oral and cutaneous lichen planus has been reported (Cox et al., 1989). The patient had been on intermittent hemodialysis for a year, and medications included isosorbide nitrate (S for CYP3A4), erythromycin (S for CYP3A4; I of CYP3A4), flucloxacillin (S for CYP3A4), and captopril (S for CYP2D6; 50–75 mg a day for four months). The eruptions resolved within two months after captopril was discontinued and healed with residual macular pigmentation. The three cases of lichen planus linked to the use of ACEIs referred to above occurred in patients on multiple medications with an interaction potential via CYP enzyme inhibition. None of the patients was subjected to re-challenge (Table 6). The metabolism of ACEIs by CYP enzymes with either genetic polymorphism (CYP2D6) or great inter-individual, non-polymorphic variation in activity (CYP3A4) could have contributed to the pathophysiology of the reaction.
A patient developed a skin rash and minor oral bleeding as a consequence of sloughing of the superficial layers of the lips and 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). All lesions resolved within a week following withdrawal of enalapril, and no re-challenge was performed (Table 6). Captopril (S for CYP2D6) therapy was initiated without recurrence of the symptoms. From a diagnostic point of view, the clinical findings presented might as well be those observed as reactions to a variety of ingredients in dentifrices or mouthrinses.
There is a report of a single case with captopril-induced pemphigus with oral manifestations (Pinto et al., 1992). The patient presented with a five-month history of painful erosions in the mouth, perineum, and groin, and had been medicated for 18 months (50 g daily). The diagnosis was confirmed by skin and oral mucosal biopsies and by resolution of lesions and normalization of serum IgG titer following discontinuation of the offending drug (Table 6). Non-thiol drugs and a variety of other agents have also been implicated in drug-induced pemphigus (Brenner et al., 1998). The mechanism behind the drug-induced acantholytic lesions is unclear, but may involve specific circulating and/or tissue-bound autoantibodies (Korman et al., 1991).
‘Scalded mouth syndrome’ is reported as a rare adverse effect of ACEIs (Vlasses et al., 1982; Savino and Haushalter, 1992). The symptom is unrelated to taste abnormalities associated with ACEIs and is possibly a class effect, since it has been noted with the use of three chemically different ACEIs (e.g., lisinopril, enalapril, and captopril) (Vlasses et al., 1982; Savino and Haushalter, 1992). The potential to induce the scalded mouth syndrome apparently differs between drugs within the drug class, i.e., symptoms may decrease when the medication is changed and the syndrome appears to be dosage-related (Savino and Haushalter, 1992; Brown et al., 1997). The condition occurs in some patients following increase in daily dosage of captopril and enalapril. Four out of the six cases of this syndrome were on concurrent medication: BABs—atenolol, nadolol, propranolol (S for CYP1A2, 2C19, 2D6), thiazide diuretics, nitroglycerine, isosorbide dinitrate (S for CYP3A4), or aspirin (S for CYP 2C9). The six cases reported so far fulfill, to some extent, the criteria on timing of medication as it relates to onset of reaction and absence of symptoms following cessation and/or relapse of symptoms by re-challenge (Table 6). In addition, clinical and medical information that allows for differentiation from other causes of painful conditions without clinical manifestations (e.g., burning mouth syndrome) is not consistently provided. The latency in onset of scalded mouth syndrome in a patient after 7 years’ continued use of captopril (Brown et al., 1997) remains unexplained, but could involve interaction with agents other than prescribed drugs easily missed during history-taking.
ACEI as a drug class is associated with taste disturbances. Captopril is linked with increased taste detection and recognition thresholds; and enalapril, with metallic, sweet, salt dysgeusia, and taste loss (Mott et al., 1993). There may be some variability in the extent of this potential side-effect among drugs. Incidence rates for taste disturbances between 2 and 5% or up to 7% with captopril have been reported (Plosker and McTavish, 1995; Langtry and Markham, 1997). As with other captopril-related ADRs, the altered taste sensation responds to dose reduction (Weber, 1988).
The ODRs reviewed above were associated with use of either captopril or enalapril, and case reports suggest a dose-related response. Metabolism of these two drugs is mediated by a polymorphic enzyme (CYP2D6) or an enzyme (CYP3A4) with great inter-individual, non-polymorphic variation in activity; hence, reduced detoxification of the drugs might serve as a risk factor for the development of ADRs. The difference in metabolic pathways between the two drugs might also explain why mutual drug substitution can occur without relapse of the reaction.
Angiotensin II receptor blockers (ARBs)
Rare cases of angioedema have been reported with intake of ARBs, and some of the individuals have a previous history of ACEI-induced angioedema (Agostoni and Cicardi, 2001). In 13 patients, the diagnosis of angioedema was linked to the use of losartan (S for CYP2D6, 3A4; I of CYP1A2, 2C9, 2C19, 3A4). The reactions occurred from 24 hours to 16 months after the initiation of therapy (25–100 mg a day). Three patients had previously 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 regimens consisted of two or three drugs, including diuretics, dexfenfluramide (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 all cases, the causal relation between losartan therapy and angioedema was considered to be at least ‘probable’ (van Rijnsoever et al., 1998). A patient experienced swelling of the lips and face with losartan. In this patient, captopril (S for CYP2D6) had previously been discontinued because of cough and substituted with bisoprolol-hydrochlorothiazide and terazosin. Bisoprolol-hydrochlorothiazide (bisoprolol: S for CYP2D6, 3A4) was, in turn, substituted by losartan, and the angioedema 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 been reported in a patient who had no history of urticaria, angioedema, or other drug allergies (Boxer, 1996).
The association between ARBs (e.g., losartan) and angioedema is based upon case reports and cases from spontaneous reporting systems (Table 6). Onset and resolution of most reactions occurred within hours to a few weeks, indicating an allergic or pseudo-allergic mechanism. Abnormal metabolism by a polymorphic enzyme (CYP2D6) and/or interactions by substrate competition or inhibition from concurrent drugs are potential risk factors that might contribute to the pathophysiology of the reaction.
Anti-arrhythmics , Class I (sodium-channel blockers )
ODRs associated with Class I anti-arrhythmics include dry mouth, fixed drug eruptions, oral manifestations of hematologic disorders, lupus erythematosus, gingival overgrowth, SJS, TEN, and oral manifestations of the hypersensitivity syndrome (Table 6).
Dry mouth is a result of an anticholinergic effect that occurs with drugs like quinidine (S for CYP2C9, 3A4; I of CYP2C9, 2D6, 3A4), disopyramide (S for CYP2C9, 3A4), flecainide (S for CYP2D6; I of CYP2D6), cibenzoline (S for CYP2D6, 3A4), and moricizine (Sreebny and Schwartz, 1997). Whether an effect per se or a consequence of dry mouth, a bitter or metallic taste has been reported with propafenone therapy (S for CYP1A2, 2D6, 3A4; I of CYP1A2, 2D6) (Caron and Libersa, 1997).
FDEs from cardiovascular drugs have been reported for phenytoin and quinidine (Korkij and Soltani, 1984; Sun et al., 1994). Two cases of oral pigmentation associated with quinidine therapy (Birek and Main, 1988) (S for CYP2C9, 3A4; I of CYP2C9, 2D6, 3A4) may represent FDEs. Both patients were receiving long-term therapy (five or 10 years) and presented with palatal pigmentations of unknown duration. One of the patients who was on monotherapy also had a melanotic area on the right ankle, and the palatal lesion became darker and more extensive during the subsequent three years. The other patient ingested multiple drugs: digoxin, verapamil (S for CYP1A2, 2C9, 2C19, 3A4; I of CYP2C9, 2D6, 3A4), and warfarin (S for CYP1A2, 2C9, 2C19, 2D6, 3A4; I of CYP2C9, 2C19). No drug withdrawal or re-challenge test was performed (Table 6). Quinidine has a high drug-drug interaction potential and metabolizes into RDMs.
Oral manifestations of hematological disorders may occur in rare cases of class I anti-arrhythmic therapy (Caron and Libersa, 1997). Drugs commonly suspected to cause thrombocytopenia 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) may cause drug-induced lupus erythematosus (Brosnan et al., 2000). A patient presented with cutaneous and oro-genital ulcerations as well as arthritis and a photodistributed rash after initiation of therapy with hydralazine (a direct-acting vasodilator; reviewed in this section because its metabolism is similar to that of procainamide). ANA- and DNA-binding tests were positive. All clinical manifestations disappeared on withdrawal of the offending drug (Neville et al., 1981). A further case has been reported with hydralazine-induced Sjögren’s syndrome and associated with features of SLE in terms of rheumatoid-arthritis-like symptoms and a positive ANA. The patient was treated for four years with hydralazine (150 mg a day). Joint symptoms resolved after hydralazine was discontinued, and salivary and lacrimal gland flow returned to normal over the following year (Darwaza et al., 1988) (Table 6). The polymorphic enzyme NAT2 metabolizes both hydralazine and procainamide, and the slow acetylator phenotype appears to be a significant risk factor for drug-induced lupus. The drug- or metabolite-protein complex is recognized as ‘foreign’ by the immune system (Hofstra, 1994).
Hydantoin and its derivatives may interfere with folate absorption or metabolism and thus mediate potential manifestations of oral ulcerations, cheilitis, and glossitis (Wintroub and Stern, 1985). Mucocutaneous reactions including gingival overgrowth are part of the broad spectrum of ADRs to phenytoin therapy (Table 6). Details on clinical presentation and pathogenesis of phenytoin-induced gingival overgrowth are reviewed in detail elsewhere (Brown et al., 1991; Marshall and Bartold, 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 of the face and scalp. The mechanism of gingival and facial enlargement is unknown but may involve RDMs. Metabolism of phenytoin by CYP2C9 is the major route of elimination of this drug (other S for CYP2C9, 2C19, 3A4; I of CYP2C9), and phenotyping studies have identified individuals with impaired capacity to metabolize the substrate (Smith et al., 1998). It is also known that both healthy and hyperplastic gingival tissues contain a significant amount of the active metabolite 5-hydroxyphenyl-5-phenylhydantoin and express CYP2C9 that catalyzes the formation of this metabolite (Zhou et al., 1996). Phenytoin intake also carries a relative risk of borderline significance to cause hematological disorders such as agranulocytosis (Kaufman et al., 1996).
Phenytoin is among the common agents that can cause hypersensitivity reactions (Daoud et al., 1998). A small proportion of patients (from one in 1000 to one in 10,000) exposed to anti-convulsants will develop the ‘drug hypersensitive’ syndrome (Lawton et al., 1992; Knowles et al., 2000) that was originally called the ‘anti-convulsant hypersensitivity’ syndrome. Oral ulcerations may occur as a manifestation of the wide range of skin diseases, including EM, SJS, and TEN, that, together with fever and internal organ involvement, characterizes 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 and insufficient detoxification of a reactive arene oxide metabolite that may contribute to the formation of the antigen that triggers an immune reaction (Hebert and Ralston, 2001).
SJS and TEN are associated with short-term therapy with phenytoin (Wintroub and Stern, 1985; Crowson and Magro, 1999; Rzany et al., 1999). The period of increased risk is largely confined to the first eight weeks of treatment. The association between anti-epileptics and SJS and TEN has been substantiated by a recent case-control study that also took into account potential co-factors that might confound or modify the risk (Rzany et al., 1999).
The association between the use of anti-arrhythmics class I and ODR mostly derives from case reports, and only some of the reactions have been validated by re-challenge (Table 6). A narrow therapeutic index, metabolism into RDMs, and a high drug-drug interaction potential by CYP enzymes are risk factors underlying the development of ADR from anti-arrhythmics. Non-genetic or genetic variation in metabolism phenotype might also have contributed to the pathogenesis.
Anti-arrhythmics , Class III (potassium-channel blockers )
CDRs from amiodarone (S for CYP1A2, 2C19, 2D6, 3A4; I of CYP1A2, 2D6, 3A4) therapy are common, and photosensitivity occurs in about 5–20% of patients and a blue-gray discoloring of skin in 1–7%. A patient was symptom-free upon withdrawal of amiodarone, and a positive double-blind oral re-challenge with this drug confirmed angioedema of the facial region induced by amiodarone (Burches et al., 2000) (Table 6). The patient had been taking corticosteroid (S for CYP3A4) for eight years prior to amiodarone therapy for cardiac rhythm abnormality.
A possible association between amiodarone and bretylium therapy may cause taste abnormality and salty taste, respectively (McGovern et al., 1983; Mott et al., 1993).
Platelet aggregation inhibitors (aspirin)
Topical application of aspirin (acetylsalicylic acid; S for CYP2C9) in the oral cavity causes aspirin or acid burn of the oral mucous membrane (Kawashima et al., 1975; Dellinger and Livingston, 1998). The drug may also induce angioedema. The mechanism for this disorder may be an inhibition of prostaglandin synthesis with overproduction of leukotrienes (Vervloet and Durham, 1998). Interestingly, a recent case-control study showed that aspirin played no significant role in the occurrence of aphthous ulcers (Boulinguez et al., 2000).
In a series of 25 cases of oral FDEs, two were associated with the intake of aspirin (Jain et al., 1991). Withdrawal of aspirin resulted in a remission of the lesions. Both patients were re-challenged, and the lesions recurred at the previous sites within 24–48 hours (Table 6).
Based on a case-control study, it was found that dipyridamole carried a relative risk of borderline significance for the development 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, oral ulceration, lichenoid drug eruptions, SJS, TEN, and gingival overgrowth (Table 6).
The reported adverse effect profile tends to hold true for drug class and is observed in ADRs associated with benzothiazepine derivatives (diltiazem), phenylalkylamine derivatives (verapamil), and dihydropyridine derivatives (nifedipine and amlodipine) (Dougall and McLay, 1996).
Two patients developed angioedema of the tongue or lips shortly after the initiation of nifedipine therapy (50 mg a day) (Sauve et al., 1999). Peri-orbital and lip angioedema occurred in a patient one month after starting diltiazem. Patch-testing to cosmetic agents was negative, and the reactions resolved within 48 hours after the drug was discontinued (Sadick et al., 1989). In a series of 72 patients with drug-induced oro-facial angioedema, 14 cases were precipitated by CCBs. An expert panel excluded triggering events other than CCBs. Most reactions occurred within the first week of therapy, and symptoms resolved when therapy was discontinued (Hedner et al., 1991).
Two cases with recalcitrant oral ulcerations caused by diltiazem (S for CYP 3A4) have been reported (Cohen et al., 1999). One of the cases had no previous history of aphthous ulcers but developed tongue ulceration within two months after initiation of diltiazem therapy (240 mg a day). This patient was also concomitantly taking other medications, including losartan (50 mg a day; S for CYP2C9, 3A4, I of CYP1A2, 2C9, 2C19, 3A4), lorazepam, terazosin, and hydrochlorothiazide. The ulceration healed within weeks after diltiazem therapy was discontinued (Cohen et al., 1999). A possible association between diltiazem therapy and oral ulcerations has not been validated by re-challenge. Non-polymorphic variation (CYP3A4) in metabolism phenotype or interaction by substrate competition/inhibition (CYP3A4) is a candidate risk factor in the ulceration pathogenesis. The second case with tongue ulceration had been treated with captopril (200 mg a day; S for CYP2D6) and verapamil (S for CYP1A2, 2C9, 2C19, 3A4; I of CYP2C9, 2D6, 3A4) for at least five years and in gradually increasing dosages (from 180 to 240 mg a day). Other medications that this patient had been taking included oxazepam, metoclopramide, estrogen (S for CYP1A2, 2C9, 2C19, 3A4; I of CYP2C9, 2D6, 3A4), thyroxine, and aspirin (S for CYP2C9). Discontinuance of captopril therapy followed by decreased dosage of verapamil resulted in gradual healing over a four-month period. Verapamil was finally discontinued, and complete healing occurred in two weeks. A re-challenge test with another CCB, diltiazem, a month later resulted in ulceration at the initial site, implying that the ulceration was a case of FDE. This lesion healed one month after cessation of diltiazem administration (Cohen et al., 1999). In this case, an association between CCB therapy and oral ulcerations appears likely. The finding that substitution of verapamil by diltiazem occurred uneventfully may indicate that drug-drug interactions mediated via CYP enzymes (CYP1A2, 2C9, or 2C19) could play a role in ulcer pathogenesis. CCBs did not cause a problem in a case-control study on aphthous ulcers (Boulinguez et al., 2000). So far, the association between CCB therapy and oral ulcerations remains presumptive (Table 6).
Drug-induced gingival overgrowth is a well-documented and 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 considerably, and most reported cases have been associated with nifedipine. Gingival overgrowths occur in as many as 38% of patients after three months’ therapy with nifedipine, as compared with 21% of patients taking diltiazem and 19% of those taking verapamil. The prevalence is unknown but appears to be relatively low when one considers that these drugs in particular are widely prescribed throughout the world (Marshall and Bartold, 1998). There are also well-documented reports on gingival overgrowth occurring with other CCBs (lacidipine, felodipine, amlodipine, isradipine, nicardipine, and nitrendipine) (Marshall and Bartold, 1998; Hallmon and Rossmann, 1999). Although this side-effect with these latter CCBs occurs less frequently, it seems likely that this is merely a reflection of the smaller number of patients who are treated with these more recently introduced drugs. Regression of the overgrowth may occur in some patients following switch to a CCB of the same or 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 pathogenesis of CCB-induced gingival overgrowth remains unclear (Marshall and Bartold, 1998). Genetic predisposition and pharmacokinetic variables are among the factors implicated in its pathogenesis (Seymour et al., 1994; Marshall and Bartold, 1998). Seventeen percent of a Dutch population is phenotypically deficient in the first step of nifedipine metabolism (Kleinbloesem et al., 1984). Alternatively, RDMs may be produced as the CYP3A4 gene catalyzes the formation of such metabolites in both healthy and hyperplastic gingival tissues from patients receiving cyclosporine and nifedipine therapy (Zhou et al., 1996).
A case of amlodipine-associated lichen planus has recently been reported (Swale and McGregor, 2001). The patient presented with widespread cutaneous lichenoid eruptions and Wickham’s striae in the oral cavity two weeks following initiation of amlodipine therapy (S for CYP3A4; I of CYP2C9, 2D6, 3A4). The patient had a history of non-insulin-dependent diabetes mellitus (treated with metformin) and as such represents a case of the triad of oral lichen planus, hypertension, and diabetes mellitus known as Grinspan’s syndrome. A possible association between amlodipine therapy and lichen planus was not validated by re-challenge (Table 6).
The proportions of serious adverse reactions, including SJS and TEN, are similar in any of the three chemical groups of CCBs (Stern and Khalsa, 1989; Knowles et al., 1998). The reactions developed within two weeks after drug therapy was initiated. Clinical details have been provided for three of the cases: One patient developed EM after 10 days of therapy with verapamil (S for CYP1A2, 2C9, 2C19 3A4; I of CYP2C9, 2D6, 3A4), recovered when the drug was withdrawn, and presented with relapse when re-challenged; a second patient was diagnosed 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 obesity, hypothyroidism, asthma, angina, and hypertension developed TEN possibly secondary to diltiazem therapy. Other drugs taken by two out of the three patients included levothyroxine, metoproterenol, nitroglycerin, theophylline (S for CYP1A2, 3A4), and warfarin (S for CYP1A2, 2C9, 2C19, 2D6, 3A4; I of CYP2C9, 2C19) (Stern and Khalsa, 1989). A patient who was taking nitroglycerin presented with multiple oral ulcerations, without skin manifestations, two weeks following the initiation of diltiazem therapy (90 mg a day). The condition diagnosed as EM resolved two weeks after diltiazem was withdrawn. No re-challenge test was performed (Brown et al., 1989). The exposure with an incriminated CCB, along with a correlation between onset and resolution of the disease patterns and start of administration and withdrawal of the drug(s), suggests a causal association (Table 6). Diltiazem is partly metabolized by a polymorphic CYP enzyme, implying that abnormal metabolism could be a risk factor. For the two patients on verapamil, the activity level of the highly variable CYP3A4 enzyme might be implicated in the pathogenesis of the ODRs. Finally, two of the cases occurred in patients on multiple drugs with an interaction potential via CYP enzyme competition/inhibition.
CCBs may cause taste disturbances. Diltiazem may cause hypogeusia and hyposmia, and nifedipine, taste and smell distortion (Mott et al., 1993; Spielman, 1998). In animal experiments, CCBs such as verapamil and nifedipine have been reported to inhibit saliva output and reduce the protein content of the secretion (Baum et al., 2000).
Diuretics
ODRs related to diuretics include dry mouth, taste disturbances, angioedema, and oral manifestations of hematologic disorders, drug hypersensitive syndrome, lichenoid drug eruptions, 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 inducers of aphthous ulcers.
In a series of 72 patients with oro-facial angioedema precipitated by anti-hypertensives, diuretics could have induced a reaction in 11 of these cases (Hedner et al., 1991). An expert panel excluded triggering events other than diuretics. Most reactions occurred within the first week after the initiation of therapy, and symptoms resolved when the therapy was discontinued (Table 6). Information on intake of other medications was not provided (Hedner et al., 1991).
Diuretics may contribute to dry mouth by causing dehydration, and thereby salivary gland hypofunction (Sreebny and Schwartz, 1997; Baum et al., 2000).
In Sweden, diuretics (furosemide, amiloride, and thiazides) are among the commonly reported offenders suspected to cause agranulocytosis and thrombocytopenia (Wiholm and Emanuelsson, 1996). Furosemide, amiloride, and thiazide diuretics are all sulphonamides and may, on re-exposure, cause allergic hematological manifestations of thrombocytopenia in susceptible patients (Vervloet and Durham, 1998). Sulphonamides have also been linked to the development of EM and SJS (Brown et al., 1989; Gruchalla, 2000), and a dose-independent reaction to sulphonamides is a common cause of TEN (Becker, 1998). The drug hypersensitivity syndrome occurs with thiazide diuretics and furosemide. The syndrome is 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 responses (Gruchalla, 2000; Knowles et al., 2000).
Skin reactions including photodistributed and non-photodistributed lichen planus eruptions induced by thiazides have been well-documented in the dermatological literature (Daoud et al., 1998). In a case report, symmetrical white buccal plaques were linked to bendrofluazide. In this patient, a diagnosis of oral 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 is another example of the triad of hypertension, diabetes mellitus, and lichen planus referred to as Grinspan’s syndrome. Alteration of drug regimen was unsuccessful. An additional patient presented with oral lichen planus as part of Grinspan’s syndrome (Lamey et al., 1990). For this patient, medications included glipizide (5 mg a day; S for CYP2C9), spironolactone (100 mg a day; S for CYP3A4), furosemide (40 mg a day), and digoxin (125 or 250 mg on alternate days). For these two cases, a causal association between the use of diuretics and lichen planus remains uncertain (Table 6). Except for exposure, there was a lack of correlation between the development of lesions and drug administration and withdrawal, as well as re-challenge. Theoretically, the lesions might as well have been associated with the concurrent medications that are metabolized by a polymorphic enzyme (CYP2C9, 2D6) or by an enzyme (CYP3A4) with great inter-individual, non-polymorphic variation in activity.
Amiloride intake has been linked with decreased threshold for 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 medication an individual is taking (Bernini et al., 2001). Known dermatological ADRs for statins include angioedema. Two patients experienced cheilitis after beginning treatment with simvastatin (Mehregan et al., 1998). One of the patients presented with a one-month history of skin rash and an extensive desquamation and crusting of the upper and lower lips. Therapy with simvastatin (S for CYP3A4; I of CYP2C9, 2C19, 2D6, 3A4) was initiated four months before the rash appeared, and an unspecified BAB (S for mainly CYP2D6) and warfarin (S for CYP1A2, 2C9, 2C19, 2D6, 3A4; I of CYP2C9, 2C19) were started one year prior to the onset of the rash. The second patient presented with a six-month history of cracking lips that appeared approximately six months after initial therapy with simvastatin. Both patients’ cheilitis resolved within three weeks following the discontinuation of simvastatin. Neither re-challenge nor patch test was performed. One could speculate that the lip lesions in these two patients might represent photodistributed eruption to statins analogous to the scaly cheilitis reported in persons with lichenoid photoeruptions (West et al., 1990).
A case of simvastatin-induced lichenoid eruptions with skin and mucosal involvement has been reported (Roger et al., 1994). The patient presented with reticular manifestations on the buccal mucosa, but no vaginal, scalp, or nail changes were noted. The patient had been on simvastatin for four months (10 mg a day), was not taking any other drug, and gave a three-month history of cutaneous lesions. The offending drug was discontinued, and the cutaneous lesions began to resolve within four weeks. No new lesions appeared; however, the mucosal lesions persisted for six months. The patient refused patch-testing and re-challenge. Thus, the diagnosis of lichenoid drug eruption remains presumptive.
A possible association between simvastatin therapy and the sporadic cases of ODR has not been verified by re-challenge (Table 6). Hovever, most statins are prescribed for individuals who are on multiple medications, and a mechanism involving potential interaction by substrate competition or inhibition via the CYP3A4 appears likely. The non-polymorphic variation in activity of this enzyme may also represent a risk factor for the development of ODRs. The latency in timing between initiation of drug therapy and presentation of lesions favors a contribution from RDMs.
Potassium-channel openers (Nicorandil )
Several case reports published in recent years link nicorandil with ulcers or aphthae affecting the tongue, gingival, labial, or buccal mucosa, hard palate, and fauces (Scully et al., 2001). The estimated prevalence of this adverse reactions is 5% (Marquart-Elbaz et al., 1999). However, a recent case-control study which investigated a possible association between drug exposure and aphthous ulcers showed that none of the cases (80 individuals) was on nicorandil therapy (Boulinguez et al., 2000). The age of the patients exhibiting ADRs to vasodilators ranges from 60 to 90 years, with an even sex distribution. The ulcers present within 10 months following the initiation of drug therapy, and complete healing occurs weeks after drug withdrawal. In one out of nine patients, a positive re-challenge was reported (Scully et al., 2001). A past history of aphthae could increase the risk for ADRs in some patients. In a recent observational cohort study of 13,260 patients over a minimum observation period of six months of nicorandil treatment, there were 55 cases of mouth ulcers (Dunn et al., 1999). In 49 patients, the ulcers developed during treatment, while three patients developed the ulcers after treatment had stopped, one patient had ulcers pre-dating treatment, and for two patients it was uncertain whether they were still taking nicorandil when the ulcers developed. Most ulcers developed more than 60 days after the start of treatment. The dosage of the drug covered a wide range, from 10 to 80 mg a day, but there was no dose-response effect. The crude ratio of mouth ulcers associated with nicorandil to all the comparable drugs combined was 2.03 (95% CI, 1.48–2.74), indicating a causal association.
A possible association between nicorandil therapy and oral ulcerations has been substantiated by both case reports and a cohort study. Validation by re-challenge has been performed in a few cases (Table 6). Some lesions may be linked to drugs other than nicorandil, since some of the individuals were reported to be on multiple drug regimens, including medication with a potential to induce oral ulcerations. The fact that ulcerations present weeks to months following the initiation of therapy indicates that nicorandil metabolites rather than the parent drug are implicated in the development of ulcers. There is a large individual variation in levels of activity of the enzyme nicotinamide N-methyltransferase that catalyzes the methylconjugation of nicotinamide, an intermediate formed by denitration of nicorandil (Weinshilboum et al., 1999). The trait of low levels of activity of this enzyme could be another risk factor in the pathophysiology of oral ulcerations.
Concluding Remarks
The quality of evidence presented for oral reactions being drug-induced is variable. As presented in this review, information on ODRs is largely based on case reports or small series of cases and was gathered before we entered the post-genomic era. Data on incidence rates are sparse and mostly derived from studies of selected populations in hospital or university settings. Thus, epidemiological studies with appropriate case and control groups and racially matched populations are needed if we are to obtain more reliable information on the incidence of ODRs. The association between a drug and an ODR is mostly based on the disappearance of the reactions following discontinuance of the offending drug. Some ODRs have been verified by re-challenge or laboratory tests. A few are documented by well-controlled case-control studies. In patients on multiple drugs, most authors consider the latest-introduced drug as the offending drug. When considering ADRs linked to CVDs that are primarily catabolized by CYPs, as are xenobiotics in general, it is important that one evaluate possible contributions from both endogenous and exogenous factors, such as concomitant drugs, diet, and other chemicals. Table 7 presents mechanisms of potential ADRs due to CVDs, and below we discuss some drug classes in which the influence of endogenous and exogenous factors on drug safety has been documented.
The pharmacokinetic behavior of drug-metabolizing enzymes should be considered as factors that can influence drug safety along with geno- and phenotypes. Many pharmacokinetic drug interactions with a potential for ADRs from CVDs are associated with CYP-mediated phase I drug bio-transformation (Abernethy and Flockhart, 2000). Pharmacokinetic drug interactions are known to occur with many drug combinations. Administration of several drugs—including BABs, anti-arrhythmics, anti-convulsants, and hypnosedatives—together with CCBs can significantly alter the pharmacokinetics of those drugs. Some interactions are well-documented, whereas other potential interactions await further investigation (Rosenthal and Ezra, 1995). BABs may further interact with inotropic agents, anti-arrhythmics, NSAIDs, psychotropic drugs, anti-ulcer medications, statins, warfarin, and oral hyperglycamics (Blaufarb et al., 1995). In general, many potential interactions can be predicted with anti-arrhythmics, quinidine and amiodarone in particular. These agents often have a narrow therapeutic window. Accordingly, small increases in serum concentrations may lead to toxicity (Trujillo and Nolan, 2000). Attention has to be paid to possible confounding effects due to an underlying and or concomitant disease. To date, molecular genetics of underlying cardiovascular diseases as they relate to genes that determine the responsiveness to a given drug has recently been reviewed, and the data appear equivocal (Nakagawa and Ishizaki, 2000).
There is increasing knowledge on the genetic polymorphism of CYP2C9, CYP2C19, and CYP2D6. For most patients with a “poor metabolizer” phenotype, there is limited metabolism of the drug substrate unless another major metabolic pathway, involving other enzymes, exists. Thus, a clinical consequence might be an idiosyncratic pharmacological response to a prescribed medication (Ingelman-Sundberg, 2001). For some drugs, an extensive metabolizing phenotype may turn into a poorly metabolizing type, provided that the patient is concomitantly exposed to an inhibitor of a particular medication, a phenomenon termed “phenocopy” (Brinn et al., 1986). Among the cases that have been reviewed, some drug combinations included agents that are known inhibitors of CYP enzymes of relevance to CVDs. The isoforms CYP3A4 and CYP1A2 have highly variable expressions across the population, even in the absence of concurrent ingestion of an inhibiting drug. Most individuals have an intermediate level of enzyme activity, and some individuals have very low or very high activity (Abernethy and Flockhart, 2000).
CYPs are expressed predominantly in the liver but also in extra-hepatic tissues, e.g., the gastrointestinal tract, the skin, and oral mucous membrane (Zhou et al., 1996; Janmohamed et al., 2001; Vondracek et al., 2001). Their relevance and importance for ODRs at the tissue level remain to be clarified. Expression and biological activity of CYP could play a role in detoxification or elicit an ODR and/or CDR by CYP-mediated activation of RDMs. CYP substrates and/or inhibitors might contribute to the more chronic pattern seen in oral-drug-induced lichen planus compared with that of skin. Oral tissues are continuously exposed to chemicals in the food chain, beverages, microbes, dental materials, and dentifrices that may influence the pathogenesis of ODRs by inhibition of CYPs and/or by action as substrates. For ODRs, it is also relevant that saliva may contain a certain concentration of drugs or drug metabolites. Hence, an exposure of the mucosal surface to either of these may play a role in the pathogenesis of ODRs.
Taken together, there is evidence that CVDs can precipitate ODRs, either alone or in concert with concurrent CVDs or other drugs. Both the patient and the medical consultant need to be aware of these ADRs. Within the field of odontology, this awareness has been minimal, possibly due to the complex diagnostic work-up. The post-genomic era presents new and interesting challenges to unveil the relevance of genotype and phenotype in the prediction and possibly prevention of some ADRs, including ODRs.