Oral Adverse Drug Reactions To Cardiovascular Drugs

ORAL ADVERSE DRUG REACTIONS
TO CARDIOVASCULAR DRUGS
Lis Andersen Torpet*
Camilla Kragelund
Jesper Reibel
Birgitte Nauntofte
Department of Oral Medicine, Clinical Oral Physiology, Oral Pathology & Anatomy, School of Dentistry, Faculty of Health Sciences, University of Copenhagen, 20 Norre All, DK-2200 Copenhagen
N, Denmark; *corresponding author, la@odont.ku.dk
ABSTRACT: A great many cardiovascular drugs (CVDs) have the potential to induce adverse reactions in the mouth. The
prevalence of such reactions is not known, however, since many are asymptomatic and therefore are believed to go unreported. As more drugs are marketed and the population includes an increasing number of elderly, the number of drug prescriptions
is also expected to increase. Accordingly, it can be predicted that the occurrence of adverse drug reactions (ADRs), including
the oral ones (ODRs), will continue to increase. ODRs affect the oral mucous membrane, saliva production, and taste. The pathogenesis of these reactions, especially the mucosal ones, is largely unknown and appears to involve complex interactions among
the drug in question, other medications, the patient's underlying disease, genetics, and life-style factors. Along this line, there
is a growing interest in the association between pharmacogenetic polymorphism and ADRs. Research focusing on polymorphism of the cytochrome P450 system (CYPs) has become increasingly important and has highlighted the intra- and inter-individual responses to drug exposure. This system has recently been suggested to be an underlying candidate regarding the pathogenesis of ADRs in the oral mucous membrane. This review focuses on those CVDs reported to induce ODRs. In addition, it
will provide data on specific drugs or drug classes, and outline and discuss recent research on possible mechanisms linking
ADRs to drug metabolism patterns. Abbreviations used will be as follows: ACEI, ACE inhibitor; ADR, adverse drug reaction;
ANA, antinuclear antigen; ARB, angiotensin II receptor blocker; BAB, beta-adrenergic blocker; CCB, calcium-channel blocker;
CDR, cutaneous drug reaction; CVD, cardiovascular drug; CYP, cytochrome P450 enzyme; EM, erythema multiforme; FDE,
fixed drug eruption; I, inhibitor of CYP isoform activity; HMG-CoA, hydroxymethyl-glutaryl coenzyme A; NAT, N-acetyltransferase; ODR, oral drug reaction; RDM, reactive drug metabolite; S, substrate for CYP isoform; SJS, Stevens-Johnson syndrome; SLE, systemic lupus erythematosus; and TEN, toxic epidermal necrolysis.
Key words. Oral mucous membrane, medication, CYP, drug interaction, therapeutic classes.
Introduction
everal systemic factors are known to contribute to oral diseases or conditions, and among those are the intake of
drugs. The pathogenesis of oral adverse reactions related to
intake of medications is not well-understood, and the prevalence is not known. They are, however, believed to be a relatively common phenomenon, although medication-induced
oral reactions are often regarded by the health profession as
trivial complaints. According to the current definitions and
basic requirements for the use of terms for reporting adverse
drug reaction disorders, "stomatitis" and "ulcerative stomatitis" are the terms proposed by the WHO in cooperation with
the Council for International Organizations of Medical
Sciences (CIOMS, 1998).
To date, there is no consensus on the definition of an
adverse drug reaction (ADR), but Table 1 presents some of the
definitions proposed. It appears that the definitions become
more qualitative over time without clarifying the underlying
causation of these reactions. It is still an open question if it is the
clinician or the patient who defines if a drug has induced an
adverse reaction.
ADRs are seen in everyday practice, but estimates of the
true incidence of ADRs are difficult, since many of these reactions go unreported. A French study of 2067 adults aged 20-67
years attending a health center for check-ups reported that
14.7% gave reliable histories of adverse reactions (Vervloet and
28
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
Crit Rev Oral Biol Med
15(1):28-46 (2004)
others (e.g., allergic reaction, idiosyncratic reaction) occur only in susceptible patients (type B or unpredictable
reactions). Type B reactions are rare and
evident only by spontaneous reporting
in case-population studies, or in large
cohort studies (Moore, 2001). A reaction
may reflect the drug's exacerbation of
pre-existing disease, or, more frequently, it represents an idiosyncratic reaction to the drug.
PHARMACOLOGICAL FACTORS
TABLE 1
Definitions* of Adverse Drug Reactions (ADRs) Proposed during the
Last 30 Years
WHO, 1972
"Any noxious and unintended drug effect which occurs at doses

employed in man for prophylaxis, diagnosis or therapy."
FDA, 1995
"An undesirable effect, reasonably associated with the use of
the drug, that occurs as part of the pharmacological action of a
drug or may be unpredictable in its occurrence."
Laurence, 1998
"A harmful or significantly unpleasant effect caused by a dose
intended for therapeutic effect (or prophylaxis or diagnosis)
which warrants reduction of dose or withdrawal of the drug
and/or foretells hazard from future administration."
Edwards and Aronson, 2000 "An appreciably harmful or unpleasant reaction, resulting from
an intervention related to the use of a medical product, which
predicts hazard from future administration and warrants prevention or specific treatments, or alteration of the dosage, or withdrawal of the product."
Factors that predispose to pharmacological ADRs include dose, drug formulation, pharmacokinetic or pharmacodynamic abnormalities, and drug
interactions. The metabolic conversion
of drugs to chemically reactive prod* It appears that these definitions have become more qualitative in nature over time.
ucts is now established as a prerequisite for many idiosyncratic drug reactions. Increased levels of reactive drug
metabolites (RDMs), their impaired
detoxification, or decreased cellular
tionsglucoronidation, acetylation, demethylation, etc.),
defense against reactive drug products appears to be an imporexhibit common polymorphism at the genomic level (Evans
tant initiating factor (Pirmohamed et al., 1996; Hess and Rieder,
and Relling, 1999). Among the important enzyme families that
1997). Oxidative RDMs are found in organs and cells preferentake part in the process are CYPs and N-acetyltransferases
tially affected by idiosyncratic drug reactions (Gruchalla, 2000).
(NATs) (see "Cardiovascular drug metabolism").
Apart from the documented genetic risk factors for the
IMMUNOLOGICAL FACTORS
development of ADRs, other risk factors include a history of
previous adverse reaction, multiple medications, liver and
The immune events are less-well-characterized (Shapiro and
renal disease, and female gender. Sex may influence pharmaShear, 1996). Theories for the induction of immune-mediated
cokinetics, drug utilization, and susceptibility to and presentaevents to drugs, their metabolites, or changes caused by these
tion/detection of ADRs. Factors that may explain the higher
substances include the 'hapten' and the 'danger' hypotheses
adverse event rate observed in female patients include phar(Uetrecht, 1999). The 'hapten' hypothesis proposes that RDMs
macodynamic factors, hormonal influences, reporting bias, and
bind irreversibly to proteins or other macromolecules that are
increased use of medications (Tran et al., 1998).
perceived as foreign and then induce an immune response.
According to the 'danger' hypothesis, the immune system
DIAGNOSTIC WORK-UP IN THE DENTAL OFFICE
responds with tolerance to most antigens, and a 'danger signal'
rather than the 'foreignness' of the antigen triggers an immune
A detailed drug historyincluding all prescription and nonresponse. The exact nature and range of stimuli that can act as
prescription drugs, herbal treatments, and other remedies
danger signals remain to be determined but are likely to
(vitamins, minerals, and homeopathic agents)should be
include cell damage (Uetrecht, 1999).
obtained during the diagnostic work-up. These supplements
may cause unexpected toxicity by themselves or through interGENETIC FACTORS
action with drugs, resulting in increased or decreased pharmacological or toxicological effects of either component (FughThere is a growing body of literature on the possible associaBerman, 2000; Ozdemir et al., 2001). In addition, the clinician
tion between pharmacogenetic polymorphism and ADRs.
needs to know the doses of all medications, timing of medicaUnderlying the person-to-person (phenotypic) differences in
tion(s) as it relates to the onset of reaction, and concurrent disthe safety of a drug within a population are genotypic polyeases (e.g., renal failure, hepatitis, bowel disease) that could
morphisms of key enzymes and proteins (Evans and Relling,
lead to alteration in drug excretion, absorption, or metabolism.
1999; Ingelman-Sundberg, 2001). In this context, pharmacoFinally, it is important that the clinician be familiar with the
genomics refers to the entire spectrum of genes that determine
various types of adverse reactions that a particular drug may
drug behavior and sensitivity, whereas pharmacokinetics is
elicit. In many instances, this task is not so simple, since a drug
used to define the narrower spectrum of inherited differences
can be responsible for causing a range of reactions, some of
in drug metabolism and disposition (Evans and Relling, 1999).
which can be attributed to its pharmacological properties, and
There is genetic variability in drug absorption, metabolism,
others to its immunological properties (Gruchalla, 2000). With
and disposition, and in drug interactions with receptors
regard to ODRs, the matter is complicated by the fact that they
(Ozdemir et al., 2001). All of the major human enzymes responare not currently reported as a group per se, but rather are
sible for modification of functional groups by oxidation,
included among several organ groups (e.g., gastrointestinal,
hydroxylation, etc. (classified as phase I reactions), or conjugadermatological, hematological, neurological).
tion with endogenous constituents (classified as phase II reac15(1):28-46 (2004)
29
Cardiovascular Drugs
Several drug classes are used to treat hypertension and/or
arrhythmias: diuretics (thiazides, loop diuretics, potassiumsparing diuretics), peripheral and central adrenergic inhibitors,
alpha-adrenergic blockers, beta-adrenergic blockers (BAB),
combined alpha- and beta-adrenergic blockers, direct vasodilators, calcium-channel blockers (CCB), ACE inhibitors (ACEI),
angiotensin II receptor blockers (ARB), and hypolipidemic
drugs (e.g., statins).
Drugs used for the treatment of cardiovascular disease
were implicated in ADRs by about 3% of the 2367 patients seen
in an ADR clinic, and there were no significant differences in
reports by male and female patients (Tran et al., 1998). In a
study of patients (n = 9210) who could not tolerate ACEIs, there
were significant sex-related differences in the use of CVDs
(Shah et al., 2000). ACEIs, nitrates, aspirin, warfarin, and antiarrhythmic medications were used to a lesser extent by women,
while the opposite was true for diuretics. Digoxin, ARB, BAB,
lipid-lowering agents, and CCB showed non-significant sex
differences in consumption rates. Although women began
ACEI treatment at similar rates of use as men, they received
less sustained therapy because of a higher rate of side-effects.
Cough, angioedema, and taste disturbance were among the
reasons for discontinuing ACEIs in both men and women
(Shah et al., 2000).
Cardiovascular Drug Metabolism

Research focusing on the cytochrome P450 system (CYP) has
become increasingly important in shedding light on the intraand inter-individual responses to drug exposure. CYP encompasses a large gene superfamily that catalyzes the metabolism
of a wide range of xenobiotics (e.g., foreign chemicals), including most drugs. The isoforms CYP2C9, CYP2C19, and
CYP2D6 are polymorphic, and their allelic forms are distrib-
TABLE 2
Classification of ADRs (reaction types A and B) and Pathophysiological Mechanisms Behind the
Reactions
Drug-related Reactions
(Type A reactions; predictable)
Actions
Mechanisms
Actions
Patient-related Reactions
(Type B reactions; unpredictable)
Pharmaceutical
Dosage- and formulation-related
Increased quantity
Enhanced release
Decomposition
Additives
Toxic reactions
Pharmacokinetic
Formation of RDMs
or oxygen species
Biological factors
(age, disease states)
Environmental factors (dietary,
drugs, other chemicals)
Idiosyncratic reactions
Pharmacogenetic
GP of drug transporters
GP of metabolizing enzymes
GP of drug targets/receptors
Drug interactions
Pharmacodynamic
Drug responsiveness
(Disease states)
Drug intolerance
Unknown
Immunologic
Antigen-specific antibody reaction
Hapten/danger hypothesis
Parent drug/RDM
Drug-induced mediator release
*
30
Allergic/hypersensitivity reactions
Pseudoallergic/anaphylactoid reactions
ADRs are presented in the context of actual knowledge in molecular biology, pharmacology, and immunology. The Table is to be read from the mid-panel
toward the side panels. The mid-panel displays mechanisms with potential contributions to both reaction types A (left panel) and B (right panel). Type A
reactions also include unwarranted side-effects and secondary effects, e.g., nosocomial infections (not represented). ADR, adverse drug reaction; RDM,
reactive drug metabolite; GP, genetic polymorphism.
15(1):28-46 (2004)
uted with pronounced inter-ethnic differences

TABLE 3
(Abernethy and Flockhart, 2000; Ingelman-Sundberg,
Ethnic Variation in the Cytochrome P450 Enzymes (CYPs)
2001) (Table 3). The phenotypic consequences of genetin an American Population (adapted from Abernethy
ic variation are individuals with no, normal, increased,
and Flockhart, 2000)
and reduced or inactive enzyme activity, some of
Frequency (%)
which may result in idiosyncratic pharmacological
responses to prescribed medications (Smith et al., 1998;
Enzyme Absent
White
Asian
African/African-American
Ingelman-Sundberg, 2001). Great inter-individual differences in the activity of CYP1A2 and CYP3A4 are
CYP2D6
7
1
8
known, and individuals with the phenotype of low
CYP2C19
3
12-22
4-7
activity might be at risk for the development of ADRs.
CYP2C9
<1
<1
<1
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-polyand oral health condition. As with the skin, the oral mucous
morphic". Induction and inhibition of CYPs by xenobiotics,
membrane reacts with a few patterns to a variety of stimuli,
including concomitant medication, may also result in treatment
and different drug classes may induce identical mucosal
failure or ADRs, respectively.
changes. The following section is devoted to a brief overview of
Table 4 illustrates several CVDs which are catabolized by
different ODR patterns.
CYPs. Beta-adrenergic blockers, CCBs, ACEIs, ARBs, and
statins are all metabolized via CYP-dependent pathways, and
ORAL DRUG REACTION PATTERNS
the isoforms of relevance are CYP1A2, CYP2C9, CYP2C19,
In general, there are no clinical or histopathological oral reacCYP2D6, and CYP3A4. Acetylation polymorphism (NAT-2) is
tion patterns that can be specifically related to drug usage.
also important for some anti-hypertensives and anti-arrhythNeither is it possible by clinical or histopathological presentamics (hydralazine, procaineamide) (Evans and Relling, 1999).
tion alone to relate ODRs to any specific drug. Many ODRs
Most populations of European origin are approximately equalmimic oral lesions that are also seen in the absence of drug
ly divided between rapid and slow acetylators (Weber and
usage. Thus, for a given reaction in the mouth to be established
Hein, 1985). Individuals inheriting mutant forms of more than
as an ODR, the suspected offender drug should be withdrawn,
one drug-metabolizing enzyme have a higher risk of drugwhich should lead to disappearance of the reaction, which
induced toxicity (Smith et al., 1998; Evans and Relling, 1999).
should then re-appear on re-challenge. Such tests, however, are
Cutaneous and Oral Mucosal Adverse Reactions
not always desirable or advisable. Furthermore, an allergic
to Cardiovascular Drugs
reaction to additives should be ruled out. Below we have
CVDs have been estimated to account for at least 9% of medemphasized certain oral reactions commonly reported as
ication-related visits to office-based physicians (Aparasu,
ODRs.
1999). Cutaneous drug reactions (CDRs) undoubtedly are
Dry mouth is one of the most common oral side-effects of
among the most frequent events in patients receiving drug
drug usage, although it is also commonly seen as part of certain
therapy. The incidence of CDRs has been estimated to be about
diseases, such as Sjgren's syndrome, which are unrelated to
2% (Bigby et al., 1986; Apaydin et al., 2000). Skin reactions
drug usage. A subjective feeling of dry mouth (xerostomia)
account for up to 30% of all the adverse events, although overdoes not necessarily correlate with objective measures, such as
reporting of skin reactions per se or under-reporting of other
sialometry, which can establish a pathologically decreased
organ reactions should be borne in mind (Naldi et al., 1999).
whole saliva flow rate (hyposalivation). Vast numbers of carSince the skin reacts with a few patterns to a variety of stimuli,
diovascular drugs are implicated in dry mouth (Sreebny and
different drugs may induce identical cutaneous changes. About
Schwartz, 1997). Chronic hyposalivation has debilitating effects
10% of drug-induced rashes result from true allergy that
on the integrity of the hard and soft tissues of the mouth, typirequires prior exposure, and asthma may exacerbate adverse
cally leading to an increase in dental caries incidence and yeast
reactions to drugs (Vervloet and Durham, 1998). The morphoinfections (candidosis) (Pedersen et al., 2002).
logic reaction patterns frequently mimick well-known skin and
Taste disturbances are not uncommonly described as an
mucocutaneous lesions or disorders. Furthermore, specific
ODR. The mechanisms by which the medications alter taste
classes of drugs are associated with specific clinical presentasensation are not well-understood. One possibility is that the
tions (Table 5). CDRs to systemically administered anti-hyperexcretion of the drug or its metabolites into saliva may genertensives and anti-arrhythmics are reviewed elsewhere (Sun et
ate an unpleasant taste. Many chemosensory disorders affect
al., 1994; Caron and Libersa, 1997; Brosnan et al., 2000; Svensson
both taste and smell, and often patients refer to a taste deficit
et al., 2001).
that is actually anosmia, e.g., inability to detect olfactory stimuTable 5 list several oral mucosal reaction patterns to carlants (Spielman, 1998). In scalded mouth syndrome, sometimes
diovascular drug exposure. There is much less information
included as an ODR, taste perception is normal; however,
available on ODRs than on CDRs, but the former may be less
patients complain of a burning sensation comparable with havfrequent. However, some common reactions, such as dry
ing been scalded by a hot liquid (Vlasses et al., 1982).
mouth, taste disturbances, and aphthae, may be added to the
Various diseases of the oral mucous membrane, unrelatspectrum of ODRs. Although ODRs only rarely result in severe
ed to drug usage, have been regarded as manifestations of
morbidity or death, they may cause mild to substantial disODR. The terms "oral ulceration" and "aphthae" are commoncomfort and, therefore, influence the individual's quality of life
ly used synonymously in reports on ODR; however, aphthae
15(1):28-46 (2004)
31
TABLE 4
Cytochrome P450 Enzymes Involved in Metabolism of Cardiovascular Drugs
(adapted from Rendic, 2002)
Drug Class/Drug
CYP1A2
CYP2C9
CYP2C19
ACE inhibitors
Angiotensin II inhibitors
Anti-coagulants
CYP2D6
CYP3A4
Captopril
Enalapril
Warfarin
Warfarin
Irbesartan
Losartan
Warfarin
Warfarin
Warfarin
Adrenergic neurone blockers
Debrisoquine
Guanoxan
Anti-arrhythmic drugs, Class I

(sodium-channel blockers)
Disopyramide
Lidocaine
Mexilitine
Encainide
Flecainide
Lidocaine
Mexiletine
Lidocaine
Phenytoin
Phenytoin
Quinidine
Anti-arrhythmic drugs, Class III
(potassium-channel blockers)
Amiodarone
Amiodarone
Bufuranol
Bufuranol
Metoprolol
Propranolol
Propranolol
Amiodarone
Alprenolol
Bisoprolol
Bufuralol
Carvediol
Labetalol
Metoprolol
Propranolol
Timolol
Calcium-channel blockers
Verapamil
Diuretics
Diltiazem
Diltiazem
Nicardipine
Nicardipine
Nifedipine
Verapamil
Verapamil
Fluvastatin
Fluvastatin
Nitrates
32
Amiodarone
Bisoprolol
Bufuranol
Amlodipine
Diltiazem
Felodipine
Isradipine
Mibefradil
Nicardipine
Nifedipine
Nimodipine
Nisoldipine
Nitrendipine
Verapamil
Torsemide
Tielinic acid
HMGCoA inhibitors (statins)
Platelet aggregation inhibitors
Propafenone
Quinidine
Beta-adrenergic blockers
Bufuranol
Lidocaine
Phenytoin
Procainamide
Propafenone
Spartein
Propafenone
Disopyramide
Dofetilide
Atorvastatin
Cerivastatin
Fluvastatin
Lovastatin
Simvastatin
Isosorbide
dinitrate
Aspirin
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), StevensJohnson syndrome (SJS),
linear IgA disease/IgA
bullous disease, lupus
15(1):28-46 (2004)
erythematosus,
TABLE 5
pemphigoid, and
Cutaneous and Oral Mucosal Diseases or Reaction Patterns That May Occur in
pemphigushave,
Response to Cardiovascular Drug Exposures
at times, been regarded as ODRs.
Oral Mucosal and
Syndromes with Oral
However, the criteCutaneous
and Cutaneous
Oral
Mucosal and/or
ria used in diagnoDiseases/Reactions
Diseases/Reactions
Diseases/Reactions
Cutaneous Involvements
sing these diseases
as ODRs are rarely
Acneiform
Angioedema
Aphthae
Drug hypersensitivity syndrome
given. Unlike idioEczematous
Erythema multiforme
Dry mouth
Lupus erythematosus-like
pathic linear IgA
(xerostomia,
hyposalivation)
syndrome
disease,
mucosal
Erythema
nodosum
Fixed
drug
reaction
Gingival
overgrowth
Oculo-mucocutaneous
lesions appear less
syndrome
frequently in the
Exanthematous
Hyperpigmentation
Scalded mouth syndrome
drug-induced form,
Exfoliative
Lichenoid eruptions
Taste disturbances
whereas the oppoMacular/maculopapular Linear IgA disease
Ulcerations
site is true for bulPityriasis rosea-like
Pemphigoid
lous pemphigoid
Photosensitive
Pemphigus
(Camilleri and Pace,
Psoriasis
Stevens-Johnson syndrome
1998;
Vassileva,
Purpura
Toxic epidermal necrolysis
1998). Also, angioUrticaria
edema, fixed drug
Vasculitis
eruptions (FDEs),
toxic
epidermal
necrolysis (TEN),
drug hypersensitivity syndrome, oculo-mucocutaneous synADRENERGIC AGENTS
drome, and pigmentary disturbances have been regarded as
ODRs.
Alpha-adrenergic blockers
A well-known adverse reaction to certain drugs such as
Alpha
1-adrenergic agents may result in altered saliva composicyclosporins, calcium-channel blockers, and phenytoin is gintion
and
secretion rates. Furthermore, oral lichenoid eruptions
gival overgrowth, which is characterized by enlarged gingiva.
and
ulcerations
may be seen.
The condition usually involves the interproximal papilla and
Inhibitors
of
alpha1-adrenoreceptors (terazosin and pramay present as a localized or generalized condition. This overzosin) have been reported to reduce saliva production due to
growth can be associated with both natural teeth and dental
their effects on salivary gland alpha1-adrenoreceptors.
implants but does not appear to affect edentulous areas.
However, an alpha2-adrenoreceptor agonist (clonidine) may
Proper dental prophylaxis and good oral hygiene may reduce
also
cause dry mouth by both central and peripheral mechaor prevent the overgrowth in some patients (Marshall and
nisms (Sreebny and Schwartz, 1997; Baum et al., 2000). Other
Bartold, 1998).
centrally acting anti-hypertensive drugs associated with dry
Oral Drug Reactions from
mouth include methyldopa, reserpine, moxonidine, and rilMajor Therapeutic Classes of CVDs
menidine.
The next section will deal with the wide spectrum of oral reacReports implicate the use of methyldopa, an alpha2-adretion patterns in response to usage of CVDs (Table 6). The
nergic agent, in the etiology of oral lichen planus. A patient
review does not fully describe all possible reactions of CVDs.
who had been taking methyldopa and hydrochlorothiazide for
The clinical evidence for ODRs will be linked to drug-metaboseven years developed multiple oral ulcerations in addition to
lizing enzymes relevant to the drugs implicated, to illustrate
pruritic skin papules collectively diagnosed as lichen planus.
the potential impact of genetic variability to the reactions. In
The oral lesions and symptoms had been present for three
this context, we focus on CYP enzymes with known variant
months, and the patient had experienced a previous episode of
alleles causing poor metabolism of drugs due to no, reduced, or
oral ulcerations one year earlier. The lesions were refractory to
inactive enzymes (CYP2C9, 2C19, 2D6) and with great intertreatment, but healed or improved after withdrawal of methylindividual, non-polymorphic differences in the activity
dopa. No re-challenge was performed (Brooks, 1982). Three
(CYP1A2, 3A4), which are most relevant to the development of
cases of oral lichenoid eruptions, including tongue ulcerations,
ADRs. The potential contributions from drug interactions by
that were deemed possibly linked to methyldopa have been
substrate competition or inhibition of these CYP enzymes are
reported. These patients had been taking methyldopa for perialso addressed.
ods of one year or "several years". In two out of the three cases,
Substrate competition occurs with the concomitant admintongue ulcerations resolved four to five months after methylistration of two substrates of a CYP. Each drug will compete for
dopa was discontinued. The case reports do not provide inforthat enzyme and competitively inhibit the metabolism of the
mation on other medications the patients may have been takother substrate. Owing to a lack of larger surveys investigating
ing, or on re-challenge attempts (Burry and Kirk, 1974). A larsuch aspects, we review here the available case reports with
ger series of 17 patients with oral mucosal reactions associated
indications of the CYP metabolism pathway for offending drugs
with methyldopa has been reported (Hay and Reade, 1978).
and concurrent medication (Rendic, 2002).
Most patients presented with erythematous or ulcerative lichen
15(1):28-46 (2004)
33
TABLE 6
Overview of Potential Oral Reaction Patterns, Diseases, or Syndromes from Cardiovascular Drug Exposure*
Drug Class
Type of ODR
Alpha adrenergic blockers

Dry mouth
Lichen planus
Beta adrenergic blockers
Angioedema
Dry mouth
Aphthae/Ulcerations
Thrombocytopenia
Lichen planus
Oculo-mucocutaneous syndrome
SJS
Mouth paresthesia
Type of Study
Culprit Drug
Culpability
CR (4) CS (17)
Class effect
Methyldopa
Established
Possible
Unspecified
Class effect
Labetalol, unspecified
Propranolol
Atenolol, Oxprenolol
Practolol, Propranolol
Practolol
Carvediol
Propranolol (sublingual)
Established
Established
Probable
Possible
Possible
CS (11)
CR (1) CCS (13)
CR (1)
CR (4)
CR (4)
CR (1)
CS (7)
Possible
Possible
Possible
ACE inhibitors
Angioedema
Aphthae/Ulcerations
CR (2)
Dry mouth
Neutropenia/agranulocytosis
Lichen planus
CR (3)
Sloughing of epithelium
CR (1)
Pemphigus
CR (1)
Scalded Mouth syndrome
CR (6)
Taste disturbances
Angiotensin II receptor blockers
Angioedema
CR (2), CS (9)
Anti-arrhythmics, Class I (sodium-channel blockers)
Dry mouth
FDE
CR (2)
Thrombocytopenia
SRS (16)
Agranulocytosis
CCS (5)
Hypersensitivity reaction syndrome
SJS, TEN
CCS (14)
Gingival hyperplasia
CR/CS (multiple)
Anti-arrhythmics, Class III (potassium-channel blockers)
Angioedema
CR (1)
Taste disturbances
Calcium-channel blockers
Angioedema
CR (3), CS (14)
Aphthae/Ulcerations
CR (2)
Gingival hyperplasia
CR/CS (multiple)
Lichen planus
CR (1)
EM, SJS, TEN
CR (4)
Taste disturbances
Dry mouth
Diuretics
Angioedema
SRS (11)
Dry mouth
EM, SJS, TEN
(Sulphonamides)
Agranulocytosis
SRS (> 50)
Thrombocytopenia
SRS (> 100)
Drug hypersensitivity
syndrome
Lichen planus
(Sulphonamides)
Taste disturbances
CR (2)
Class effect (Captopril, Enalapril,

Lisinopril, Zofenapril, Omapatrilat)
Captopril
Lisinopril
Class effect
Captopril
Enalapril
Captopril
Captopril, Enalapril, Lisinopril
Captopril, Enalapril
Established
Probable
Probable
Established
Possible
Uncertain
Probable
Probable
Established
Losartan
Probable
Class effect
Quinidine
Quinidine
Phenytoin
Phenytoin
Phenytoin
Phenytoin
Established
Possible
Probable
Probable
Established
Probable
Established
Amiodarone
Amiodarone
Probable
Possible
Nifedipine, Diltiazem
Diltiazem, Verapamil
Class effect
Amlodipine
Diltiazem, Verapamil
Class effect
Class effect
Possible
Possible
Established
Possible
Possible
Established
Established
Unspecified
Class effect
Furosemide, Thiazides
Amiloride, Furosemide,
Thiazides
Amiloride, Furosemide,
Thiazides
Furosemide, Thiazides
Possible
Established
Possible
Probable
Bendrofluazide
Furosemide/Spironolactone
Amiloride, Spironolactone
Uncertain/possible
Probable
Possible
Probable
(continued on next page)
34
15(1):28-46 (2004)
(continued from previous page)

Drug Class
Type of ODR
Direct-acting peripheral vasodilator

Lupus erythematosus
HMG-CoA reductase inhibitors (statins)
Cheilitis
Lichen planus
Platelet aggregation inhibitors
Angioedema
FDE
Potassium-channel opener
Aphthae/Ulcerations
*
Type of Study
Culprit Drug
Culpability
CR (2)
Hydralazine
Probable
CR (2)
CR (1)
Simvastatin
Simvastatin
Possible
Possible
CR (1)
CR (2)
Aspirin
Aspirin
Possible
Probable
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) and
positive de-challenge; probable = CR/CS with positive re-challenge, case-control study (CCS), spontaneous reporting (SRS), or cohort study (CoS); established = substantial evidence from CRs, CCS, SRS, and/or CoS. Class effect: Multiple reports stating subjective and/or objective adverse reaction to the
drug class. With regard to type of study, the number in parenthesis indicates the number of cases reviewed. For further details, see text. EM, erythema
multiforme; FDE, fixed drug reaction; SJS, Stevens-Johnson syndrome; TEN, toxic epidermal necrolysis.
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
15(1):28-46 (2004)
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
35
TABLE 7
Potential Adverse Drug Reactions from Cardiovascular Drug Exposure Exemplified by Medication
Catabolized by the P450 Enzyme System*
Drug-related Reaction
Toxic reactions
Mode of Action
Formation of RDMs
Impaired drug elimination
Inhibition of drug
metabolism
Interactions
Increased plasma and
tissue drug concentration
Affects drug absorption

Drug-metabolizer
phenotypes
Increased, decreased,
abnormal or no
metabolism
Affects drug sensitivity?
*
#
Mechanisms
Patient-related Reaction
Pharmacokinetic
Biotransformation of drugs
Formation of RDMs
Idiosyncratic reactions
(mainly CYPs)
including haptens or antigens
Biological factors
Organ-specific diseases
Impaired drug elimination
(liver, kidney)
Environmental factors
Concurrent drug exposure(s)
Phase I metabolism, mainly by
CYPs (1A2, 2C9, 2C19, 2D6, 3A4)
Other constituents
undergoing phase I
metabolism: dietary (CYP 1A2,
2E1, 3A4), tobacco (CYP 1A2);
alcohol (CYP 2E1); herbal
medication (CYP1A2, 2C9);
dental materials (CYP1A2)
Pharmacogenetic
GP of drug transporters
P-glycoprotein
GP of drug-metabolizing
enzymes (interethnic/-racial
variation)
Phase I: CYPs (1A2, 2C9,
2C19, 2D6) (3A4?)#; ADH; ...
Phase II: NAT1, NAT2
GP of drug targets
Receptors (beta-adrenergic,
angiotensin IIT1,
sulfonylurea), enzymes (ACE),
proteins
Affects drug absorption

Drug-metabolizer
phenotypes
Increased, decreased,
abnormal or no
metabolism
Affects drug sensitivity
Allergic/hypersensitivity
reactions
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 effects
on CYP expression, activity, and outcome, e.g., type of adverse drug reaction. CYP, cytochrome P450 enzyme; GP, genetic polymorphism;
Polymorphically in specific populations?
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,
36
Mode of Action
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 druginduced 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 BABinduced 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
15(1):28-46 (2004)
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 oculomucocutaneous 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 anticoagulants. 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 druginduced 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, BABinduced 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).
15(1):28-46 (2004)
Angioedema occurs regardless of the chemical structure (e.g.,

sulphhydryl compoundscaptopril, zofenapril; carboxyalkyldipeptideenalapril, lisinopril; and phosphoric acid compoundsfosinopril) (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). ACEIinduced 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 reappeared two to three weeks after captopril therapy was reintroduced. 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
37
(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 drugdrug 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)
38
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 druginduced 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: BABsatenolol,
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-
15(1):28-46 (2004)
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 (50mg) of losartan (Acker and Greenberg, 1995). Both quinapriland 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 ther15(1):28-46 (2004)
apy (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 Sjgren'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 con-
39
tain 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
40
(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
15(1):28-46 (2004)
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 CCBinduced 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,
15(1):28-46 (2004)
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-
41
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 sixmonth 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).
42
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 threemonth 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% (MarquartElbaz 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
15(1):28-46 (2004)
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 biotransformation (Abernethy and Flockhart, 2000). Pharmacokinetic drug interactions are known to occur with many drug
combinations. Administration of several drugsincluding
BABs, anti-arrhythmics, anti-convulsants, and hypnosedativestogether 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 conse15(1):28-46 (2004)
quence 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-druginduced 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.
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ORAL ADVERSE DRUG REACTIONS

Durham, 1998). The estimated rate of medication-related visits

Mechanisms Related to ADR

Crit Rev Oral Biol Med

"Any noxious and unintended drug effect which occurs at doses

Crit Rev Oral Biol Med

Cardiovascular Drug Metabolism

Crit Rev Oral Biol Med

uted with pronounced inter-ethnic differences

Crit Rev Oral Biol Med

Adrenergic neurone blockers

Anti-arrhythmic drugs, Class I

HMGCoA inhibitors (statins)

Platelet aggregation inhibitors

usually commence in the

Crit Rev Oral Biol Med

Alpha adrenergic blockers

SRS (> 100)

Class effect (Captopril, Enalapril,

(continued on next page)

Crit Rev Oral Biol Med

(continued from previous page)

Direct-acting peripheral vasodilator

Beta-adrenergic blockers (BABs)

protein content of whole-mouth saliva (Baum et al., 2000).

Crit Rev Oral Biol Med

Affects drug absorption

Affects drug absorption

into hyper-pigmented areas. A patient with Ferguson-Smith

tranquilizers, antihypertensives; Felix et al., 1974). A patient

Crit Rev Oral Biol Med

ANGIOTENSIN-CONVERTING ENZYME INHIBITORS

Angioedema occurs regardless of the chemical structure (e.g.,

Crit Rev Oral Biol Med

was initiated. This patient was also on digoxin, procainamide

Crit Rev Oral Biol Med

related response. Metabolism of these two drugs is mediated

ANGIOTENSIN II RECEPTOR BLOCKERS (ARBS)

apy (S for CYP1A2, 2D6, 3A4; I of CYP1A2, 2D6) (Caron and

Crit Rev Oral Biol Med

ANTI-ARRHYTHMICS, CLASS III

PLATELET AGGREGATION INHIBITORS (ASPIRIN)

CALCIUM-CHANNEL BLOCKERS (CCBS)

Crit Rev Oral Biol Med

3A4), recovered when the drug was withdrawn, and presented

Crit Rev Oral Biol Med

independent reaction to sulphonamides is a common cause of

A case of simvastatin-induced lichenoid eruptions with

POTASSIUM-CHANNEL OPENERS (NICORANDIL)

Crit Rev Oral Biol Med

large individual variation in levels of activity of the enzyme

quence might be an idiosyncratic pharmacological response to

Crit Rev Oral Biol Med

Baum B, Ferguson M, Fox P, Johansson I, Marmary Y, Nauntofte B,

Crit Rev Oral Biol Med

E, et al. (1999). Cutaneous reactions to drugs. An analysis of

Crit Rev Oral Biol Med

Amlodipine-induced gingival overgrowth. J Clin Periodontol

cial. Clin Dermatol 16:379-387.

Crit Rev Oral Biol Med

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