-
28 Crit Rev Oral Biol Med 15(1):28-46 (2004)
Introduction
Several systemic factors are known to contribute to oral
dis-eases or conditions, and among those are the intake ofdrugs.
The pathogenesis of oral adverse reactions related tointake of
medications is not well-understood, and the preva-lence is not
known. They are, however, believed to be a rela-tively common
phenomenon, although medication-inducedoral reactions are often
regarded by the health profession astrivial complaints. According
to the current definitions andbasic requirements for the use of
terms for reporting adversedrug reaction disorders, "stomatitis"
and "ulcerative stomati-tis" are the terms proposed by the WHO in
cooperation withthe Council for International Organizations of
MedicalSciences (CIOMS, 1998).
To date, there is no consensus on the definition of anadverse
drug reaction (ADR), but Table 1 presents some of thedefinitions
proposed. It appears that the definitions becomemore qualitative
over time without clarifying the underlyingcausation of these
reactions. It is still an open question if it is theclinician or
the patient who defines if a drug has induced anadverse
reaction.
ADRs are seen in everyday practice, but estimates of thetrue
incidence of ADRs are difficult, since many of these reac-tions go
unreported. A French study of 2067 adults aged 20-67years attending
a health center for check-ups reported that14.7% gave reliable
histories of adverse reactions (Vervloet and
Durham, 1998). The estimated rate of medication-related visitsto
office-based physicians in the United States is 7.7 per
1000persons, but only 7% of these persons reported ADRs as
theirreason for the visit (Aparasu, 1999). The overall incidence
ofADRs is about 3 in 1000 patients, according to the
BostonCollaborative Drug surveillance program (Bigby et al., 1986).
Ina study based on outpatient referrals (2367 patients), the toptwo
adverse events reported by both male and female patientswere skin
disorders (49%) and allergic or immunological dis-turbances (14%)
(Tran et al., 1998).
As more drugs are marketed and with an increasing num-ber of the
elderly in the population, the number of drug pre-scriptions will
also likely increase (Gruchalla, 2000).Accordingly, it can be
predicted that the occurrence of ADR,including the oral ones, will
continue to increase. The preva-lence of oral drug reactions
(ODRs), however, is at presentunknown, but dentists must be
knowledgeable on the relationbetween medication intake and
ODRs.
Mechanisms Related to ADRPharmacological, immunological, and
genetic factors areinvolved in the pathogenesis of ADRs (Shapiro
and Shear, 1996;Zhou et al., 1996; Evans and Relling, 1999; Moore,
2001), andany drug can cause such reactions. As shown in Table 2,
somedrug reactions (e.g., drug overdose, drug interaction) can
occurin any individual (type A or predictable reactions),
whereas
ORAL ADVERSE DRUG REACTIONSTO CARDIOVASCULAR DRUGSLis Andersen
Torpet*Camilla KragelundJesper ReibelBirgitte Nauntofte
Department of Oral Medicine, Clinical Oral Physiology, Oral
Pathology & Anatomy, School of Dentistry, Faculty of Health
Sciences, University of Copenhagen, 20 Norre All, DK-2200
CopenhagenN, Denmark; *corresponding author, [email protected]
ABSTRACT: A great many cardiovascular drugs (CVDs) have the
potential to induce adverse reactions in the mouth. Theprevalence
of such reactions is not known, however, since many are
asymptomatic and therefore are believed to go unreport-ed. As more
drugs are marketed and the population includes an increasing number
of elderly, the number of drug prescriptionsis also expected to
increase. Accordingly, it can be predicted that the occurrence of
adverse drug reactions (ADRs), includingthe oral ones (ODRs), will
continue to increase. ODRs affect the oral mucous membrane, saliva
production, and taste. The patho-genesis of these reactions,
especially the mucosal ones, is largely unknown and appears to
involve complex interactions amongthe drug in question, other
medications, the patient's underlying disease, genetics, and
life-style factors. Along this line, thereis a growing interest in
the association between pharmacogenetic polymorphism and ADRs.
Research focusing on polymor-phism of the cytochrome P450 system
(CYPs) has become increasingly important and has highlighted the
intra- and inter-indi-vidual responses to drug exposure. This
system has recently been suggested to be an underlying candidate
regarding the patho-genesis of ADRs in the oral mucous membrane.
This review focuses on those CVDs reported to induce ODRs. In
addition, itwill provide data on specific drugs or drug classes,
and outline and discuss recent research on possible mechanisms
linkingADRs to drug metabolism patterns. Abbreviations used will be
as follows: ACEI, ACE inhibitor; ADR, adverse drug reaction;ANA,
antinuclear antigen; ARB, angiotensin II receptor blocker; BAB,
beta-adrenergic blocker; CCB, calcium-channel blocker;CDR,
cutaneous drug reaction; CVD, cardiovascular drug; CYP, cytochrome
P450 enzyme; EM, erythema multiforme; FDE,fixed drug eruption; I,
inhibitor of CYP isoform activity; HMG-CoA, hydroxymethyl-glutaryl
coenzyme A; NAT, N-acetyl-transferase; ODR, oral drug reaction;
RDM, reactive drug metabolite; S, substrate for CYP isoform; SJS,
Stevens-Johnson syn-drome; SLE, systemic lupus erythematosus; and
TEN, toxic epidermal necrolysis.
Key words. Oral mucous membrane, medication, CYP, drug
interaction, therapeutic classes.
-
others (e.g., allergic reaction, idiosyn-cratic reaction) occur
only in suscepti-ble patients (type B or unpredictablereactions).
Type B reactions are rare andevident only by spontaneous
reportingin case-population studies, or in largecohort studies
(Moore, 2001). A reactionmay reflect the drug's exacerbation
ofpre-existing disease, or, more frequent-ly, it represents an
idiosyncratic reac-tion to the drug.
PHARMACOLOGICAL FACTORSFactors that predispose to
pharmaco-logical ADRs include dose, drug for-mulation,
pharmacokinetic or pharma-codynamic abnormalities, and
druginteractions. The metabolic conversionof drugs to chemically
reactive prod-ucts is now established as a prerequi-site for many
idiosyncratic drug reac-tions. Increased levels of reactive
drugmetabolites (RDMs), their impaireddetoxification, or decreased
cellulardefense against reactive drug products appears to be an
impor-tant initiating factor (Pirmohamed et al., 1996; Hess and
Rieder,1997). Oxidative RDMs are found in organs and cells
preferen-tially affected by idiosyncratic drug reactions
(Gruchalla, 2000).
IMMUNOLOGICAL FACTORSThe immune events are
less-well-characterized (Shapiro andShear, 1996). Theories for the
induction of immune-mediatedevents to drugs, their metabolites, or
changes caused by thesesubstances include the 'hapten' and the
'danger' hypotheses(Uetrecht, 1999). The 'hapten' hypothesis
proposes that RDMsbind irreversibly to proteins or other
macromolecules that areperceived as foreign and then induce an
immune response.According to the 'danger' hypothesis, the immune
systemresponds with tolerance to most antigens, and a 'danger
signal'rather than the 'foreignness' of the antigen triggers an
immuneresponse. The exact nature and range of stimuli that can act
asdanger signals remain to be determined but are likely toinclude
cell damage (Uetrecht, 1999).
GENETIC FACTORSThere is a growing body of literature on the
possible associa-tion between pharmacogenetic polymorphism and
ADRs.Underlying the person-to-person (phenotypic) differences inthe
safety of a drug within a population are genotypic poly-morphisms
of key enzymes and proteins (Evans and Relling,1999;
Ingelman-Sundberg, 2001). In this context, pharmaco-genomics refers
to the entire spectrum of genes that determinedrug behavior and
sensitivity, whereas pharmacokinetics isused to define the narrower
spectrum of inherited differencesin drug metabolism and disposition
(Evans and Relling, 1999).There is genetic variability in drug
absorption, metabolism,and disposition, and in drug interactions
with receptors(Ozdemir et al., 2001). All of the major human
enzymes respon-sible for modification of functional groups by
oxidation,hydroxylation, etc. (classified as phase I reactions), or
conjuga-tion with endogenous constituents (classified as phase II
reac-
tionsglucoronidation, acetylation, demethylation, etc.),exhibit
common polymorphism at the genomic level (Evansand Relling, 1999).
Among the important enzyme families thattake part in the process
are CYPs and N-acetyltransferases(NATs) (see "Cardiovascular drug
metabolism").
Apart from the documented genetic risk factors for
thedevelopment of ADRs, other risk factors include a history
ofprevious adverse reaction, multiple medications, liver andrenal
disease, and female gender. Sex may influence pharma-cokinetics,
drug utilization, and susceptibility to and presenta-tion/detection
of ADRs. Factors that may explain the higheradverse event rate
observed in female patients include phar-macodynamic factors,
hormonal influences, reporting bias, andincreased use of
medications (Tran et al., 1998).
DIAGNOSTIC WORK-UP IN THE DENTAL OFFICEA detailed drug
historyincluding all prescription and non-prescription drugs,
herbal treatments, and other remedies(vitamins, minerals, and
homeopathic agents)should beobtained during the diagnostic work-up.
These supplementsmay cause unexpected toxicity by themselves or
through inter-action with drugs, resulting in increased or
decreased pharma-cological or toxicological effects of either
component (Fugh-Berman, 2000; Ozdemir et al., 2001). In addition,
the clinicianneeds to know the doses of all medications, timing of
medica-tion(s) as it relates to the onset of reaction, and
concurrent dis-eases (e.g., renal failure, hepatitis, bowel
disease) that couldlead to alteration in drug excretion,
absorption, or metabolism.Finally, it is important that the
clinician be familiar with thevarious types of adverse reactions
that a particular drug mayelicit. In many instances, this task is
not so simple, since a drugcan be responsible for causing a range
of reactions, some ofwhich can be attributed to its pharmacological
properties, andothers to its immunological properties (Gruchalla,
2000). Withregard to ODRs, the matter is complicated by the fact
that theyare not currently reported as a group per se, but rather
areincluded among several organ groups (e.g.,
gastrointestinal,dermatological, hematological, neurological).
15(1):28-46 (2004) Crit Rev Oral Biol Med 29
TABLE 1Definitions* of Adverse Drug Reactions (ADRs) Proposed
during theLast 30 Years
WHO, 1972 "Any noxious and unintended drug effect which occurs
at dosesemployed in man for prophylaxis, diagnosis or therapy."
FDA, 1995 "An undesirable effect, reasonably associated with the
use ofthe drug, that occurs as part of the pharmacological action
of adrug or may be unpredictable in its occurrence."
Laurence, 1998 "A harmful or significantly unpleasant effect
caused by a doseintended for therapeutic effect (or prophylaxis or
diagnosis)which warrants reduction of dose or withdrawal of the
drugand/or foretells hazard from future administration."
Edwards and Aronson, 2000 "An appreciably harmful or unpleasant
reaction, resulting froman intervention related to the use of a
medical product, whichpredicts hazard from future administration
and warrants preven-tion or specific treatments, or alteration of
the dosage, or with-drawal of the product."
* It appears that these definitions have become more qualitative
in nature over time.
-
Cardiovascular DrugsSeveral drug classes are used to treat
hypertension and/orarrhythmias: diuretics (thiazides, loop
diuretics, potassium-sparing diuretics), peripheral and central
adrenergic inhibitors,alpha-adrenergic blockers, beta-adrenergic
blockers (BAB),combined alpha- and beta-adrenergic blockers, direct
vasodila-tors, calcium-channel blockers (CCB), ACE inhibitors
(ACEI),angiotensin II receptor blockers (ARB), and
hypolipidemicdrugs (e.g., statins).
Drugs used for the treatment of cardiovascular diseasewere
implicated in ADRs by about 3% of the 2367 patients seenin an ADR
clinic, and there were no significant differences inreports by male
and female patients (Tran et al., 1998). In astudy of patients (n =
9210) who could not tolerate ACEIs, therewere significant
sex-related differences in the use of CVDs(Shah et al., 2000).
ACEIs, nitrates, aspirin, warfarin, and anti-arrhythmic medications
were used to a lesser extent by women,
while the opposite was true for diuretics. Digoxin, ARB,
BAB,lipid-lowering agents, and CCB showed non-significant
sexdifferences in consumption rates. Although women beganACEI
treatment at similar rates of use as men, they receivedless
sustained therapy because of a higher rate of side-effects.Cough,
angioedema, and taste disturbance were among thereasons for
discontinuing ACEIs in both men and women(Shah et al., 2000).
Cardiovascular Drug MetabolismResearch focusing on the
cytochrome P450 system (CYP) hasbecome increasingly important in
shedding light on the intra-and inter-individual responses to drug
exposure. CYP encom-passes a large gene superfamily that catalyzes
the metabolismof a wide range of xenobiotics (e.g., foreign
chemicals), inclu-ding most drugs. The isoforms CYP2C9, CYP2C19,
andCYP2D6 are polymorphic, and their allelic forms are distrib-
30 Crit Rev Oral Biol Med 15(1):28-46 (2004)
TABLE 2Classification of ADRs (reaction types A and B) and
Pathophysiological Mechanisms Behind theReactions
Drug-related Reactions Actions Mechanisms Actions
Patient-related Reactions(Type A reactions; predictable) (Type B
reactions; unpredictable)
Pharmaceutical Dosage- and formulation-related
Increased quantityEnhanced releaseDecompositionAdditives
Toxic reactions Pharmacokinetic Idiosyncratic reactions
Formation of RDMs
or oxygen species Biological factors
(age, disease states) Environmental factors (dietary,
drugs, other chemicals)
Pharmacogenetic GP of drug transporters GP of metabolizing
enzymes GP of drug targets/receptors
Drug interactions Pharmacodynamic Drug responsiveness Drug
intolerance
(Disease states)
Unknown
Immunologic Allergic/hypersensitivity reactions Antigen-specific
antibody reaction
Hapten/danger hypothesisParent drug/RDM
Drug-induced mediator release Pseudoallergic/anaphylactoid
reactions
* ADRs are presented in the context of actual knowledge in
molecular biology, pharmacology, and immunology. The Table is to be
read from the mid-paneltoward the side panels. The mid-panel
displays mechanisms with potential contributions to both reaction
types A (left panel) and B (right panel). Type Areactions also
include unwarranted side-effects and secondary effects, e.g.,
nosocomial infections (not represented). ADR, adverse drug
reaction; RDM,reactive drug metabolite; GP, genetic
polymorphism.
-
uted with pronounced inter-ethnic differences(Abernethy and
Flockhart, 2000; Ingelman-Sundberg,2001) (Table 3). The phenotypic
consequences of genet-ic variation are individuals with no, normal,
increased,and reduced or inactive enzyme activity, some ofwhich may
result in idiosyncratic pharmacologicalresponses to prescribed
medications (Smith et al., 1998;Ingelman-Sundberg, 2001). Great
inter-individual dif-ferences in the activity of CYP1A2 and CYP3A4
areknown, and individuals with the phenotype of lowactivity might
be at risk for the development of ADRs.Non-genetic factors and
as-yet-undetermined geneticcauses will likely contribute to these
inter-individualdifferences (Lamba et al., 2002). From now on, the
twoenzymes in question will be referred to as "non-poly-morphic".
Induction and inhibition of CYPs by xenobiotics,including
concomitant medication, may also result in treatmentfailure or
ADRs, respectively.
Table 4 illustrates several CVDs which are catabolized byCYPs.
Beta-adrenergic blockers, CCBs, ACEIs, ARBs, andstatins are all
metabolized via CYP-dependent pathways, andthe isoforms of
relevance are CYP1A2, CYP2C9, CYP2C19,CYP2D6, and CYP3A4.
Acetylation polymorphism (NAT-2) isalso important for some
anti-hypertensives and anti-arrhyth-mics (hydralazine,
procaineamide) (Evans and Relling, 1999).Most populations of
European origin are approximately equal-ly divided between rapid
and slow acetylators (Weber andHein, 1985). Individuals inheriting
mutant forms of more thanone drug-metabolizing enzyme have a higher
risk of drug-induced toxicity (Smith et al., 1998; Evans and
Relling, 1999).
Cutaneous and Oral Mucosal Adverse Reactionsto Cardiovascular
Drugs
CVDs have been estimated to account for at least 9% of
med-ication-related visits to office-based physicians
(Aparasu,1999). Cutaneous drug reactions (CDRs) undoubtedly
areamong the most frequent events in patients receiving
drugtherapy. The incidence of CDRs has been estimated to be about2%
(Bigby et al., 1986; Apaydin et al., 2000). Skin reactionsaccount
for up to 30% of all the adverse events, although over-reporting of
skin reactions per se or under-reporting of otherorgan reactions
should be borne in mind (Naldi et al., 1999).Since the skin reacts
with a few patterns to a variety of stimuli,different drugs may
induce identical cutaneous changes. About10% of drug-induced rashes
result from true allergy thatrequires prior exposure, and asthma
may exacerbate adversereactions to drugs (Vervloet and Durham,
1998). The morpho-logic reaction patterns frequently mimick
well-known skin andmucocutaneous lesions or disorders. Furthermore,
specificclasses of drugs are associated with specific clinical
presenta-tions (Table 5). CDRs to systemically administered
anti-hyper-tensives and anti-arrhythmics are reviewed elsewhere
(Sun etal., 1994; Caron and Libersa, 1997; Brosnan et al., 2000;
Svenssonet al., 2001).
Table 5 list several oral mucosal reaction patterns to
car-diovascular drug exposure. There is much less
informationavailable on ODRs than on CDRs, but the former may be
lessfrequent. However, some common reactions, such as drymouth,
taste disturbances, and aphthae, may be added to thespectrum of
ODRs. Although ODRs only rarely result in severemorbidity or death,
they may cause mild to substantial dis-comfort and, therefore,
influence the individual's quality of life
and oral health condition. As with the skin, the oral
mucousmembrane reacts with a few patterns to a variety of
stimuli,and different drug classes may induce identical
mucosalchanges. The following section is devoted to a brief
overview ofdifferent ODR patterns.
ORAL DRUG REACTION PATTERNSIn general, there are no clinical or
histopathological oral reac-tion patterns that can be specifically
related to drug usage.Neither is it possible by clinical or
histopathological presenta-tion alone to relate ODRs to any
specific drug. Many ODRsmimic oral lesions that are also seen in
the absence of drugusage. Thus, for a given reaction in the mouth
to be establishedas an ODR, the suspected offender drug should be
withdrawn,which should lead to disappearance of the reaction,
whichshould then re-appear on re-challenge. Such tests, however,
arenot always desirable or advisable. Furthermore, an
allergicreaction to additives should be ruled out. Below we
haveemphasized certain oral reactions commonly reported asODRs.
Dry mouth is one of the most common oral side-effects ofdrug
usage, although it is also commonly seen as part of
certaindiseases, such as Sjgren's syndrome, which are unrelated
todrug usage. A subjective feeling of dry mouth (xerostomia)does
not necessarily correlate with objective measures, such
assialometry, which can establish a pathologically decreasedwhole
saliva flow rate (hyposalivation). Vast numbers of car-diovascular
drugs are implicated in dry mouth (Sreebny andSchwartz, 1997).
Chronic hyposalivation has debilitating effectson the integrity of
the hard and soft tissues of the mouth, typi-cally leading to an
increase in dental caries incidence and yeastinfections
(candidosis) (Pedersen et al., 2002).
Taste disturbances are not uncommonly described as anODR. The
mechanisms by which the medications alter tastesensation are not
well-understood. One possibility is that theexcretion of the drug
or its metabolites into saliva may gener-ate an unpleasant taste.
Many chemosensory disorders affectboth taste and smell, and often
patients refer to a taste deficitthat is actually anosmia, e.g.,
inability to detect olfactory stimu-lants (Spielman, 1998). In
scalded mouth syndrome, sometimesincluded as an ODR, taste
perception is normal; however,patients complain of a burning
sensation comparable with hav-ing been scalded by a hot liquid
(Vlasses et al., 1982).
Various diseases of the oral mucous membrane, unrelat-ed to drug
usage, have been regarded as manifestations ofODR. The terms "oral
ulceration" and "aphthae" are common-ly used synonymously in
reports on ODR; however, aphthae
15(1):28-46 (2004) Crit Rev Oral Biol Med 31
TABLE 3Ethnic Variation in the Cytochrome P450 Enzymes (CYPs)in
an American Population (adapted from Abernethyand Flockhart,
2000)
Frequency (%)
Enzyme Absent White Asian African/African-American
CYP2D6 7 1 8CYP2C19 3 12-22 4-7CYP2C9 < 1 < 1 < 1
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usually commence in thesecond decade of life asrecurrent oral
ulcerationsand usually wane duringthe fourth decade (Porteret al.,
1998). In contrast,drug-induced ulcerationspresent mostly in
olderage groups and notalways as a recurrent pat-tern.
Oral manifestations ofsystemic diseases are notuncommon and may
berelated to drug usage.Ulcerations are seen asoral manifestations
ofhematological disorderssuch as agranulocytosisand neutropenia,
whereashemorrhagic bullae, petec-chias, ecchymoses, andbleeding are
oral featuresof thrombocytopenia. It iswell-known that CVDscan
cause agranulocytosisand thrombocytopenia(Wiholm and Emanuels-son,
1996). Drug-inducedautoantibodies affectplatelets more often
thanany other blood element(Aster, 2000).
Drug-induced lichenplanus, also referred to aslichenoid drug
eruptions,exhibits clinical featuressimilar to those of idio-pathic
lichen planus,which is a fairly commonoral mucosal
disease.Lichenoid drug eruptionsare more likely to be uni-lateral
and of the erythe-matous and ulcerativevariety; however, this isnot
well-substantiated(Lamey et al., 1995). Re-cently, it has been
suggest-ed that intake of medica-tions metabolized bypolymorphic
CYPs maybe implicated in lichenoiddrug eruptions (Krage-lund et
al., 2003). Clinicalmanifestations of otheroral mucosal
diseasessuch as erythema multi-forme (EM), Stevens-Johnson syndrome
(SJS),linear IgA disease/IgAbullous disease, lupus
32 Crit Rev Oral Biol Med 15(1):28-46 (2004)
TABLE 4Cytochrome P450 Enzymes Involved in Metabolism of
Cardiovascular Drugs(adapted from Rendic, 2002)
Drug Class/Drug CYP1A2 CYP2C9 CYP2C19 CYP2D6 CYP3A4
ACE inhibitors Captopril Enalapril
Angiotensin II inhibitors IrbesartanLosartan
Anti-coagulants Warfarin Warfarin Warfarin Warfarin Warfarin
Adrenergic neurone blockers DebrisoquineGuanoxan
Anti-arrhythmic drugs, Class I(sodium-channel blockers)
Disopyramide DisopyramideDofetilide
EncainideFlecainide
Lidocaine Lidocaine Lidocaine LidocaineMexilitine Mexiletine
Phenytoin Phenytoin PhenytoinProcainamide
Propafenone Propafenone PropafenoneSpartein
Quinidine Quinidine
Anti-arrhythmic drugs, Class III(potassium-channel blockers)
Amiodarone Amiodarone Amiodarone Amiodarone
Beta-adrenergic blockers AlprenololBisoprolol Bisoprolol
Bufuranol Bufuranol Bufuranol Bufuralol
BufuranolCarvediolLabetalol
Metoprolol MetoprololPropranolol Propranolol Propranolol
Timolol
Calcium-channel blockers AmlodipineDiltiazem Diltiazem
Diltiazem
FelodipineIsradipineMibefradil
Nicardipine Nicardipine NicardipineNifedipine Nifedipine
NimodipineNisoldipineNitrendipine
Verapamil Verapamil Verapamil Verapamil
Diuretics TorsemideTielinic acid
HMGCoA inhibitors (statins) AtorvastatinCerivastatin
Fluvastatin Fluvastatin FluvastatinLovastatinSimvastatin
Nitrates Isosorbidedinitrate
Platelet aggregation inhibitors Aspirin
-
e r y t h e m a t o s u s ,pemphigoid, andpemphigushave,at
times, been re-garded as ODRs.However, the crite-ria used in
diagno-sing these diseasesas ODRs are rarelygiven. Unlike
idio-pathic linear IgAdisease, mucosallesions appear lessfrequently
in thedrug-induced form,whereas the oppo-site is true for bul-lous
pemphigoid(Camilleri and Pace,1998; Vassileva,1998). Also,
angio-edema, fixed drugeruptions (FDEs),toxic epidermalnecrolysis
(TEN),drug hypersensitivity syndrome, oculo-mucocutaneous
syn-drome, and pigmentary disturbances have been regarded
asODRs.
A well-known adverse reaction to certain drugs such
ascyclosporins, calcium-channel blockers, and phenytoin is
gin-gival overgrowth, which is characterized by enlarged
gingiva.The condition usually involves the interproximal papilla
andmay present as a localized or generalized condition. This
over-growth can be associated with both natural teeth and
dentalimplants but does not appear to affect edentulous
areas.Proper dental prophylaxis and good oral hygiene may reduceor
prevent the overgrowth in some patients (Marshall andBartold,
1998).
Oral Drug Reactions from Major Therapeutic Classes of CVDs
The next section will deal with the wide spectrum of oral
reac-tion patterns in response to usage of CVDs (Table 6).
Thereview does not fully describe all possible reactions of
CVDs.The clinical evidence for ODRs will be linked to
drug-metabo-lizing enzymes relevant to the drugs implicated, to
illustratethe potential impact of genetic variability to the
reactions. Inthis context, we focus on CYP enzymes with known
variantalleles causing poor metabolism of drugs due to no, reduced,
orinactive enzymes (CYP2C9, 2C19, 2D6) and with great
inter-individual, non-polymorphic differences in the
activity(CYP1A2, 3A4), which are most relevant to the development
ofADRs. The potential contributions from drug interactions
bysubstrate competition or inhibition of these CYP enzymes arealso
addressed.
Substrate competition occurs with the concomitant
admin-istration of two substrates of a CYP. Each drug will compete
forthat enzyme and competitively inhibit the metabolism of theother
substrate. Owing to a lack of larger surveys investigatingsuch
aspects, we review here the available case reports withindications
of the CYP metabolism pathway for offending drugsand concurrent
medication (Rendic, 2002).
ADRENERGIC AGENTS
Alpha-adrenergic blockers
Alpha1-adrenergic agents may result in altered saliva
composi-tion and secretion rates. Furthermore, oral lichenoid
eruptionsand ulcerations may be seen.
Inhibitors of alpha1-adrenoreceptors (terazosin and pra-zosin)
have been reported to reduce saliva production due totheir effects
on salivary gland alpha1-adrenoreceptors.However, an
alpha2-adrenoreceptor agonist (clonidine) mayalso cause dry mouth
by both central and peripheral mecha-nisms (Sreebny and Schwartz,
1997; Baum et al., 2000). Othercentrally acting anti-hypertensive
drugs associated with drymouth include methyldopa, reserpine,
moxonidine, and ril-menidine.
Reports implicate the use of methyldopa, an alpha2-adre-nergic
agent, in the etiology of oral lichen planus. A patientwho had been
taking methyldopa and hydrochlorothiazide forseven years developed
multiple oral ulcerations in addition topruritic skin papules
collectively diagnosed as lichen planus.The oral lesions and
symptoms had been present for threemonths, and the patient had
experienced a previous episode oforal ulcerations one year earlier.
The lesions were refractory totreatment, but healed or improved
after withdrawal of methyl-dopa. No re-challenge was performed
(Brooks, 1982). Threecases of oral lichenoid eruptions, including
tongue ulcerations,that were deemed possibly linked to methyldopa
have beenreported. These patients had been taking methyldopa for
peri-ods of one year or "several years". In two out of the three
cases,tongue ulcerations resolved four to five months after
methyl-dopa was discontinued. The case reports do not provide
infor-mation on other medications the patients may have been
tak-ing, or on re-challenge attempts (Burry and Kirk, 1974). A
lar-ger series of 17 patients with oral mucosal reactions
associatedwith methyldopa has been reported (Hay and Reade,
1978).Most patients presented with erythematous or ulcerative
lichen
15(1):28-46 (2004) Crit Rev Oral Biol Med 33
TABLE 5Cutaneous and Oral Mucosal Diseases or Reaction Patterns
That May Occur inResponse to Cardiovascular Drug Exposures
Oral Mucosal and Syndromes with OralCutaneous and Cutaneous Oral
Mucosal and/or Diseases/Reactions Diseases/Reactions
Diseases/Reactions Cutaneous Involvements
Acneiform Angioedema Aphthae Drug hypersensitivity
syndromeEczematous Erythema multiforme Dry mouth Lupus
erythematosus-like
(xerostomia, hyposalivation) syndromeErythema nodosum Fixed drug
reaction Gingival overgrowth Oculo-mucocutaneous
syndromeExanthematous Hyperpigmentation Scalded mouth
syndromeExfoliative Lichenoid eruptions Taste
disturbancesMacular/maculopapular Linear IgA disease
UlcerationsPityriasis rosea-like PemphigoidPhotosensitive
PemphigusPsoriasis Stevens-Johnson syndromePurpura Toxic epidermal
necrolysisUrticariaVasculitis
-
34 Crit Rev Oral Biol Med 15(1):28-46 (2004)
TABLE 6Overview of Potential Oral Reaction Patterns, Diseases,
or Syndromes from Cardiovascular Drug Exposure*
Drug Class Type of ODR Type of Study Culprit Drug
Culpability
Alpha adrenergic blockersDry mouth Class effect
EstablishedLichen planus CR (4) CS (17) Methyldopa Possible
Beta adrenergic blockersAngioedema CS (11) Unspecified
EstablishedDry mouth Class effect EstablishedAphthae/Ulcerations CR
(1) CCS (13) Labetalol, unspecified ProbableThrombocytopenia CR (1)
Propranolol PossibleLichen planus CR (4) Atenolol, Oxprenolol
Possible
Practolol, PropranololOculo-mucocutaneous syndrome CR (4)
Practolol PossibleSJS CR (1) Carvediol PossibleMouth paresthesia CS
(7) Propranolol (sublingual) Possible
ACE inhibitorsAngioedema Class effect (Captopril, Enalapril,
Established
Lisinopril, Zofenapril, Omapatrilat)Aphthae/Ulcerations CR (2)
Captopril ProbableDry mouth Lisinopril
ProbableNeutropenia/agranulocytosis Class effect EstablishedLichen
planus CR (3) Captopril PossibleSloughing of epithelium CR (1)
Enalapril UncertainPemphigus CR (1) Captopril ProbableScalded Mouth
syndrome CR (6) Captopril, Enalapril, Lisinopril ProbableTaste
disturbances Captopril, Enalapril Established
Angiotensin II receptor blockersAngioedema CR (2), CS (9)
Losartan Probable
Anti-arrhythmics, Class I (sodium-channel blockers)Dry mouth
Class effect EstablishedFDE CR (2) Quinidine
PossibleThrombocytopenia SRS (16) Quinidine ProbableAgranulocytosis
CCS (5) Phenytoin ProbableHypersensitivity reaction syndrome
Phenytoin EstablishedSJS, TEN CCS (14) Phenytoin ProbableGingival
hyperplasia CR/CS (multiple) Phenytoin Established
Anti-arrhythmics, Class III (potassium-channel
blockers)Angioedema CR (1) Amiodarone ProbableTaste disturbances
Amiodarone Possible
Calcium-channel blockersAngioedema CR (3), CS (14) Nifedipine,
Diltiazem PossibleAphthae/Ulcerations CR (2) Diltiazem, Verapamil
PossibleGingival hyperplasia CR/CS (multiple) Class effect
EstablishedLichen planus CR (1) Amlodipine PossibleEM, SJS, TEN CR
(4) Diltiazem, Verapamil PossibleTaste disturbances Class effect
EstablishedDry mouth Class effect Established
DiureticsAngioedema SRS (11) Unspecified PossibleDry mouth Class
effect EstablishedEM, SJS, TEN (Sulphonamides) Furosemide,
Thiazides PossibleAgranulocytosis SRS (> 50) Amiloride,
Furosemide, Probable
ThiazidesThrombocytopenia SRS (> 100) Amiloride, Furosemide,
Probable
ThiazidesDrug hypersensitivity (Sulphonamides) Furosemide,
Thiazides Possible
syndromeLichen planus CR (2) Bendrofluazide
Uncertain/possible
Furosemide/SpironolactoneTaste disturbances Amiloride,
Spironolactone Probable
(continued on next page)
-
planus lesions. They had been taking the drug from six to
60months prior to the development of lesions and required up tofive
months for healing after drug cessation. Of the 17 patients,13 used
from one to six concurrent medications, including com-binations
with diuretics, NSAIDs [substrate (S) for CYP2C9,2C19; inhibitor of
activity (I) of CYP2C9, 3A4], sulfonylurea (Sfor CYP2C9; I of 3A4),
anti-arrhythmics (S for CYP2C9; I ofCYP2C9, 3A4), and
anti-depressants (S for and I of CYP1A2,2C9, 2C19, 2D6, 3A4) ((Hay
and Reade, 1978).
The association between methyldopa therapy and orallichen planus
has not been clearly established. The evidenceoriginates from case
reports or small case series that are inade-quate with regard to
information on co-morbidity, timingbetween presentation of lesions,
and start of co-medication,and re-challenges have rarely been
performed (Table 6). Mostindividuals were on multiple medications,
raising the possibil-ity of the reaction being linked to drugs
other than methyldopaor to drug-drug interactions by inhibition.
Theoretically, a con-tribution from genetic variation in metabolism
of methyldopais a further candidate as a risk factor for the
adverse reaction.There is a large individual variation in levels of
activity of theenzyme catechol O-methyltransferase that catalyzes
methyl-dopa, and genotype frequencies of 25% with low activity of
thisenzyme have been demonstrated in Caucasian populations(Ameyaw
et al., 2000).
Beta-adrenergic blockers (BABs) (anti-arrhythmics Class II)
BABs have been linked with various ODRs, includingangioedema,
dry mouth, oral ulcerations, lichenoid drug erup-tions, lupus
erythematosus, SJS, oculo-mucocutaneous syn-drome, and
manifestations of hematological disorders.
In a study of 72 patients with oro-facial angioedema
pre-cipitated by anti-hypertensives, 11 cases were linked to
BABs.An expert panel excluded triggering events other than
BABs.Most reactions occurred within the first week after initiation
oftherapy, and symptoms resolved when therapy was discontin-ued
(Hedner et al., 1991).
Dry mouth has been reported in about 20% of hyperten-sives
treated with BABs alone, and BABs may decrease the total
protein content of whole-mouth saliva (Baum et al., 2000).Oral
ulcerations are among the reactions to BAB (Petrie et
al., 1976). In a case report, use of labetalol (200 mg a day; S
forCYP2D6), a combined alpha- and beta-adrenergic blocker,
wasimplicated in oral ulcerations that resolved following
drugwithdrawal and relapsed at re-challenge (Pradalier et al.,
1982).A recent case-control study suggests a statistically
significantlink between BABs and aphthous ulcers (P = 0.002,
multivari-ate paired analysis) (Boulinguez et al., 2000).
A patient presenting with pruritic oral and cutaneouslesions may
constitute a case of secondary thrombocytopeniacaused by
medication. The patient had been taking a combina-tion of
propranolol and disulfiram for less than a month priorto onset of
the lesions. Following withdrawal of both drugs,propranolol (S for
CYP1A2, 2C9, 2D6) alone could be resumedwithout eliciting any
reaction. The authors suggested that thereaction was due to an
overdose achieved by the combinedusage of the two drugs or from
disulfiram (I of CYP1A2, 2C9,2D6, 3A4) subsequent to prior
sensitizing exposure to this drug(Thompson et al., 1982). A
contribution from drug interactionsby inhibition of any of the
three implicated CYP enzymesmight have been involved in the
presumed toxic reaction.Agranulocytosis is also among the adverse
reactions to BAB(Petrie et al., 1976). Hence, oral ulcerations are
a possible ADR.
BAB-induced lichen planus is a well-established phenom-enon in
the dermatological literature. Since it is a mucocuta-neous
disease, involvement of the oral mucous membrane canbe expected.
However, there are only a few case reports on oneor two patients
that implicate the usage of BABs with the devel-opment of oral
lichen planus lesions in these individuals.Cutaneous as well as
oral lesions have been reported in apatient taking propranolol
(Hawk, 1980). In this patient, thera-py including propranolol (240
mg a day; S for CYP1A2, 2C9,2D6) and furosemide (80 mg a day) was
initiated 21 monthsprior to the onset of reaction. Allopurinol (300
mg a day) wascommenced the same year and before the development of
skineruptions. Propranolol and furosemide were discontinued,
andmethyldopa (1000 mg a day) was substituted. The reticular
andulcerative oral lesions almost resolved within four months
afterdiscontinuance of drugs, whereas the cutaneous lesions
turned
15(1):28-46 (2004) Crit Rev Oral Biol Med 35
Drug Class Type of ODR Type of Study Culprit Drug
Culpability
Direct-acting peripheral vasodilatorLupus erythematosus CR (2)
Hydralazine Probable
HMG-CoA reductase inhibitors (statins)Cheilitis CR (2)
Simvastatin PossibleLichen planus CR (1) Simvastatin Possible
Platelet aggregation inhibitorsAngioedema CR (1) Aspirin
PossibleFDE CR (2) Aspirin Probable
Potassium-channel openerAphthae/Ulcerations CR/CoS (multiple)
Nicorandil Probable
* Criteria for causality assessment include type of study and
response to de- and re-challenge as follows: possible = case report
(CR)/case series (CS) andpositive de-challenge; probable = CR/CS
with positive re-challenge, case-control study (CCS), spontaneous
reporting (SRS), or cohort study (CoS); estab-lished = substantial
evidence from CRs, CCS, SRS, and/or CoS. Class effect: Multiple
reports stating subjective and/or objective adverse reaction to
thedrug class. With regard to type of study, the number in
parenthesis indicates the number of cases reviewed. For further
details, see text. EM, erythemamultiforme; FDE, fixed drug
reaction; SJS, Stevens-Johnson syndrome; TEN, toxic epidermal
necrolysis.
(continued from previous page)
-
into hyper-pigmented areas. A patient with Ferguson-Smithdisease
developed asymptomatic oral lichen planus two weeksafter therapy
with oxprenolol (I of CYP2D6), and cyclopenthi-azide was initiated
(Wiesenfeld et al., 1982). A switch fromoxprenolol to methyldopa
resulted in the disappearance of thecutaneous and the oral white
reticular and plaque-type lesionswithin two months, but both oral
and cutaneous lesionsrecurred a month later. Methyldopa was
replaced by prazosin,and after six months the oral lesions resolved
completely andthe cutaneous lesions improved. Another patient was
reportedas having lichenoid skin eruptions and oral lesions typical
oflichen planus associated with the intake of practolol (with-drawn
from the market). The duration of treatment (400 mg aday) before
the onset of rash was one month. It is possible thatthe patient was
on concurrent medication(s), since most of thereported 21 patients
with cutaneous and ocular reactions topractolol were taking
combinations of other drugs (diuretics,
tranquilizers, antihypertensives; Felix et al., 1974). A
patientpresented with a one-year history of asymptomatic
reticularand erosive oral lichen planus. The medication regimen
inclu-ded atenolol (100 mg a day) for six months,
chlorpropamide(100 mg and increased to 200 mg daily for the last
eightmonths) for 18 months, and salbutamol (6 mg a day; I
ofCYP3A4). The patient was thought to represent a case of
drug-induced lichen planus, and no alternative drug therapies
wereattempted (Lamey et al., 1990). Chlorpropamide, a
sulfonylureaagent, is known to cause drug-induced oral lichen
planus(Thompson and Skaehill, 1994). None of the four
patientsreferred to above was clearly established as having
BAB-induced lichen planus by re-challenge, and the outcomes
ofsubstitution by drugs other than BABs were variable andincluded
relapses. A delay ranging from weeks to monthsbetween the
presentation of oral lesions and the start of thera-py does not
exclude the incriminated BABs, provided that the
36 Crit Rev Oral Biol Med 15(1):28-46 (2004)
TABLE 7Potential Adverse Drug Reactions from Cardiovascular Drug
Exposure Exemplified by MedicationCatabolized by the P450 Enzyme
System*
Drug-related Reaction Mode of Action Mechanisms Mode of Action
Patient-related Reaction
PharmacokineticToxic reactions Formation of RDMs
Biotransformation of drugs Formation of RDMs Idiosyncratic
reactions
(mainly CYPs) including haptens or antigens Biological
factors
Impaired drug elimination Organ-specific diseases Impaired drug
elimination(liver, kidney) Environmental factors
Inhibition of drug Concurrent drug exposure(s)metabolism Phase I
metabolism, mainly by
CYPs (1A2, 2C9, 2C19, 2D6, 3A4)Interactions Other
constituents
Increased plasma and undergoing phase Itissue drug concentration
metabolism: dietary (CYP 1A2,
2E1, 3A4), tobacco (CYP 1A2);alcohol (CYP 2E1); herbalmedication
(CYP1A2, 2C9);dental materials (CYP1A2)
Pharmacogenetic GP of drug transporters
Affects drug absorption P-glycoprotein Affects drug
absorptionDrug-metabolizer GP of drug-metabolizing
Drug-metabolizer
phenotypes enzymes (interethnic/-racial
phenotypesvariation)Phase I: CYPs (1A2, 2C9,
Increased, decreased, 2C19, 2D6) (3A4?)#; ADH; ... Increased,
decreased,abnormal or no Phase II: NAT1, NAT2 abnormal or no
metabolism metabolismAffects drug sensitivity? GP of drug
targets Affects drug sensitivity Allergic/hypersensitivity
Receptors (beta-adrenergic, reactionsangiotensin
IIT1,sulfonylurea), enzymes (ACE),proteins
* The panel design from Table 2 is maintained. Modes of action
behind type A (left panel) or type B reactions (right panel) are
extended and imply effectson CYP expression, activity, and outcome,
e.g., type of adverse drug reaction. CYP, cytochrome P450 enzyme;
GP, genetic polymorphism;
# Polymorphically in specific populations?
-
drugs metabolized into RDMs and such metabolites are impli-cated
in the pathophysiological mechanism.
Some BABs (acebutolol, labetalol, practolol, and propra-nolol)
have been linked to drug-induced lupus erythematosusmanifesting as
skin eruptions (S for CYP1A2, 2C19, 2D6) (Sunet al., 1994).
Labetalol and practolol may also cause the oculo-mucocutaneous
syndrome (Wright, 1975; Sun et al., 1994). Acase series of 27
patients with this syndrome was linked to theadministration of
practolol (Wright, 1975). Nineteen of thesepatients were also
taking diuretics, cardiac glycosides, or anti-coagulants.
Anti-nuclear antibodies (ANAs) were positive inall patients, and a
circulating antibody capable of binding toepithelial tissue was
found in 25 patients. No other evidence ofdrug-induced systemic
lupus erythematosus (SLE) was found.Recurrent ulcerations of the
oral mucous membrane occurredas part of the syndrome in four of the
patients. Three of thesepatients showed improvement in symptoms and
signs over aperiod of four months to more than a year; one patient
devel-oped a progressive disorder suggestive of an atypical
drug-induced SLE (Wright, 1975). Hence, a long-term follow-up
isconsidered crucial before a final diagnosis of drug-induced
SLEand/or oculo-mucocutaneous syndrome can be made.
SJS with oral manifestations associated with carvediol,
aselective beta1-blocker, has been reported (Kowalski and
Cody,1997). The rash included macules, blisters, and target
lesionsinvolving the entire skin surface and the oral mucous
mem-brane. The symptoms developed four weeks after initiation
oftherapy and following dosage reduction (initially 6.25
mg,titrated to 25 mg and reduced to 12.5 mg a day). At the
timecarvediol (S for CYP2C9, CYP2D6) was initiated, the patientwas
on stable long-term doses of hydralazine (I of CYP3A4),captopril (S
for CYP2D6), digoxin, furosemide, warfarin (S forCYP1A2, 2C9, 2C19,
2D6, 3A4; I of CYP2C9, 2C19), allopurinol,famotidine, and aspirin
(S for CYP2C9). Following cessation ofcarvediol therapy, complete
resolution occurred within twoweeks. The patient was not
re-challenged (Kowalski and Cody,1997).
'Mouth paresthesia' is the main adverse effect observedafter
sublingual administration of propranolol (Mansur et al.,1998).
The evidence implicating the use of BABs with ODRderives from
single case reports, and verification by re-chal-lenge has seldom
been performed (Table 6). Hence, BAB-induced oral ulcerations reach
a causality level of only 'possi-ble', as evidenced by a
case-control study. Some of the offend-ing BABs in question are
metabolized by polymorphic CYPenzymes, implying abnormal
metabolizing as a risk factor forODRs. Most case patients were on
multiple drugs, raising thepossibility of the reaction being linked
to drugs other than theincriminated BABs or to drug-drug
interactions.
ANGIOTENSIN-CONVERTING ENZYME INHIBITORS(ACEIS)
ACEIs evoke a relatively low incidence of ADRs, with coughand
nausea being the more common adverse effects (Lawton etal., 1992;
Vleeming et al., 1998). Reports on ODRs have includedangioedema,
dry mouth, ulcerations, lichenoid eruptions, man-ifestations of
hematological disturbances, loss of taste, and'scalded mouth
syndrome'.
Hundreds of cases of angioedema related to the usage ofACEIs
have been reported (Roberts and Wuerz, 1991; Maier,1995; Vleeming
et al., 1998; Messerli and Nussberger, 2000).
Angioedema occurs regardless of the chemical structure
(e.g.,sulphhydryl compoundscaptopril, zofenapril;
carboxyalkyl-dipeptideenalapril, lisinopril; and phosphoric acid
com-poundsfosinopril) (Vleeming et al., 1998). The majority of
thereactions occur in the first week after the initiation of
ACEinhibitor therapy, but a significant number occur after
pro-longed therapy (Vleeming et al., 1998; Agostoni and
Cicardi,2001). In a review of 72 patients with angioedema
precipitatedby anti-hypertensives, 36 cases were due to ACEIs
(Hedner etal., 1991). Angioedema has been estimated to occur in one
tofive in 1000 patients using ACEIs, but if long-term therapy
andlate onset are taken into account, the risk may be as high as
1%after 10 years of treatment (Vleeming et al., 1998). ACEI-induced
angioedema has a predilection for the head and neckregion, and most
occurrences manifest as edema of the tongueand lips (Slater et al.,
1988; Roberts and Wuerz, 1991; Rees andGibson, 1997; Vleeming et
al., 1998; Agostoni and Cicardi,2001). Immunological processes and
several mediator systems(bradykinin, substance P, and
prostaglandins) have been sug-gested to be involved in the
pathogenesis, but to date there isno conclusive evidence for an
immune-mediated pathogenesis(Sabroe and Black, 1997; Vleeming et
al., 1998; Agostoni andCicardi, 2001). In addition, ACE gene
polymorphism may beinvolved in the development of angioedema
(Vleeming et al.,1998). Angioedema occurs in a wide dosage range
and withoutsex preference (Slater et al., 1988; Lawton et al.,
1992; Vleeminget al., 1998; Agostoni and Cicardi, 2001). Ethnic
differencesappear to be the most important predisposing risk
factor. Thus,Blacks are at greater risk than Whites, regardless of
dose, spe-cific ACEI, or concurrent medications (Vleeming et al.,
1998).The vasopeptidase inhibitor omapatrilate (a dual ACEI
andneural enolase inhibitor) may also carry a risk for
angioedema(Messerli and Nussberger, 2000). The overall incidence
basedon controlled clinical trials is about 0.5% in non-Black and
2%in Black patients (Weber, 2001). A pharmacogenetic polymor-phism
would be a likely candidate underlying these ethnic
dif-ferences.
Tongue ulcerations preceded by loss of taste have beenreported
as a complication of captopril therapy (Nicholls et al.,1981) (S
for CYP2D6). A patient underwent a treatment regi-men that included
digoxin, furosemide, prazosin, andhydralazine (I of CYP3A4) in
addition to captopril (S forCYP2D6). The ulcerations appeared after
the patient hadreceived captopril (300 or 450 mg a day) for three
months,healed two weeks after the drug was withdrawn, and
re-appeared two to three weeks after captopril therapy was
re-introduced. Another case report of ulcers due to
captopriloccurred in a patient suffering from both hypertension and
dia-betes mellitus and treated by propranolol (S for CYP1A2,
2C9,2D6) and chlorpropamide, respectively (Seedat, 1979).
Theulcerations developed two month after the initiation of
capto-pril therapy (300 mg a day) and reduction in propranolol (S
forCYP1A2, 2C19, 2D6) dosage. Ulcerations recurred within twodays
upon re-challenge and resolved with discontinuance ofcaptopril.
Oral mucosal ulcerations following an increase in thedosage of
captopril (from 25 mg to 100 mg a day) have beenreported in a
further case. In this case, other medicationsincluding furosemide
(40 mg), dinitrate isosorbide (30 mg; S forCYP3A4), and digoxin
(0.125 mg)were taken at unchangeddoses. Laboratory investigations
revealed a slight leukopeniaand thrombocytopenia. Ulcerations and
abnormal blood cellcounts resolved after two weeks and two months,
respectively
15(1):28-46 (2004) Crit Rev Oral Biol Med 37
-
(Corone et al., 1987). A recent case-control study did not
identi-fy ACEIs as inducers of aphthous ulcers (Boulinguez et
al.,2000). In three of the four patients referred to above, the
associ-ation between ACEIs and oral ulcerations was established
byre-challenge (Table 6). Captopril is metabolized by a
polymor-phic CYP enzyme, implying that abnormal drug
metabolismcould be a risk factor for oral ulceration. Accumulation
of drugmetabolites or their impaired detoxification products
mightaccount for the delay in clinical presentation of the
reactions.All case patients were on multiple medications, implying
drug-drug interaction by the inhibition of CYP enzymes as
anotherrisk factor.
The administration of ACEIs may cause dry mouth. Forexample,
lisinopril has been shown to reduce salivary flow rate(Sreebny and
Schwartz, 1997; Baum et al., 2000).
ODRs as manifestations of ACEI-induced hematologicalreactions
may occur (Plosker and McTavish, 1995; Langtry andMarkham, 1997).
There are isolated reports of neutropenia andagranulocytosis
associated with captopril usage in certain sub-sets of patients
(e.g., those with renal insufficiency and auto-immune disease).
However, with reduced dosage, only neutro-penia is encountered
(Jaffe, 1986).
Two cases of long-term usage of ACEIs have been associat-ed with
oral lichen planus (Firth and Reade, 1989). A patientwith a
three-month history of oral pain and treated with multi-ple
medications [allopurinol, colchicine (S for CYP3A4) fourmonths
before and quinethazone, potassium, and enalapril (Sfor CYP3A4) one
month before the onset of oral symptoms]presented with
manifestations of the reticular, erosive, andulcerative type of
lichen planus. The latter two manifestationsimproved with
discontinuance of enalapril and quinethazone.Three months later,
quinethazone was re-introduced withoutrecurrence of ulcerations.
The second patient had a six-monthhistory of oral and cutaneous
lichen planus lesions. One monthprior to the onset of lesions, the
patient was being treated withseveral drugs [nifedipine (S for
CYP3A4, 2D6; I of CYP1A2,2C9, 2D6, 3A4), captopril (S for CYP2D6),
digoxin,nitrazepam]. Captopril was discontinued, and a month
laterthere was considerable clinical improvement: fewer oral
ulcer-ations and partial resolution of skin lesions. Enalapril and
cap-topril were considered as drugs with a potential to
amplifyand/or induce oral lichenoid lesions (Firth and Reade,
1989).An additional patient with suggestive captopril-induced
oraland cutaneous lichen planus has been reported (Cox et
al.,1989). The patient had been on intermittent hemodialysis for
ayear, and medications included isosorbide nitrate (S forCYP3A4),
erythromycin (S for CYP3A4; I of CYP3A4), flu-cloxacillin (S for
CYP3A4), and captopril (S for CYP2D6; 50-75mg a day for four
months). The eruptions resolved within twomonths after captopril
was discontinued and healed withresidual macular pigmentation. The
three cases of lichenplanus linked to the use of ACEIs referred to
above occurred inpatients on multiple medications with an
interaction potentialvia CYP enzyme inhibition. None of the
patients was subjectedto re-challenge (Table 6). The metabolism of
ACEIs by CYPenzymes with either genetic polymorphism (CYP2D6) or
greatinter-individual, non-polymorphic variation in
activity(CYP3A4) could have contributed to the pathophysiology
ofthe reaction.
A patient developed a skin rash and minor oral bleeding asa
consequence of sloughing of the superficial layers of the lipsand
gingiva one month after enalapril therapy (S for CYP3A4)
was initiated. This patient was also on digoxin, procainamide(S
for CYP2D6), and furosemide (Kubo and Cody, 1984). Alllesions
resolved within a week following withdrawal ofenalapril, and no
re-challenge was performed (Table 6).Captopril (S for CYP2D6)
therapy was initiated without recur-rence of the symptoms. From a
diagnostic point of view, theclinical findings presented might as
well be those observed asreactions to a variety of ingredients in
dentifrices or mouthrin-ses.
There is a report of a single case with
captopril-inducedpemphigus with oral manifestations (Pinto et al.,
1992). Thepatient presented with a five-month history of painful
erosionsin the mouth, perineum, and groin, and had been
medicatedfor 18 months (50 g daily). The diagnosis was confirmed
byskin and oral mucosal biopsies and by resolution of lesions
andnormalization of serum IgG titer following discontinuation ofthe
offending drug (Table 6). Non-thiol drugs and a variety ofother
agents have also been implicated in drug-induced pem-phigus
(Brenner et al., 1998). The mechanism behind the drug-induced
acantholytic lesions is unclear, but may involve specif-ic
circulating and/or tissue-bound autoantibodies (Korman etal.,
1991).
'Scalded mouth syndrome' is reported as a rare adverseeffect of
ACEIs (Vlasses et al., 1982; Savino and Haushalter,1992). The
symptom is unrelated to taste abnormalities associ-ated with ACEIs
and is possibly a class effect, since it has beennoted with the use
of three chemically different ACEIs (e.g.,lisinopril, enalapril,
and captopril) (Vlasses et al., 1982; Savinoand Haushalter, 1992).
The potential to induce the scaldedmouth syndrome apparently
differs between drugs within thedrug class, i.e., symptoms may
decrease when the medication ischanged and the syndrome appears to
be dosage-related(Savino and Haushalter, 1992; Brown et al., 1997).
The conditionoccurs in some patients following increase in daily
dosage ofcaptopril and enalapril. Four out of the six cases of this
syn-drome were on concurrent medication: BABsatenolol,nadolol,
propranolol (S for CYP1A2, 2C19, 2D6), thiazidediuretics,
nitroglycerine, isosorbide dinitrate (S for CYP3A4), oraspirin (S
for CYP 2C9). The six cases reported so far fulfill, tosome extent,
the criteria on timing of medication as it relates toonset of
reaction and absence of symptoms following cessationand/or relapse
of symptoms by re-challenge (Table 6). In addi-tion, clinical and
medical information that allows for differenti-ation from other
causes of painful conditions without clinicalmanifestations (e.g.,
burning mouth syndrome) is not consis-tently provided. The latency
in onset of scalded mouth syn-drome in a patient after 7 years'
continued use of captopril(Brown et al., 1997) remains unexplained,
but could involveinteraction with agents other than prescribed
drugs easilymissed during history-taking.
ACEI as a drug class is associated with taste
disturbances.Captopril is linked with increased taste detection and
recogni-tion thresholds; and enalapril, with metallic, sweet, salt
dys-geusia, and taste loss (Mott et al., 1993). There may be
somevariability in the extent of this potential side-effect
amongdrugs. Incidence rates for taste disturbances between 2 and
5%or up to 7% with captopril have been reported (Plosker
andMcTavish, 1995; Langtry and Markham, 1997). As with
othercaptopril-related ADRs, the altered taste sensation responds
todose reduction (Weber, 1988).
The ODRs reviewed above were associated with use ofeither
captopril or enalapril, and case reports suggest a dose-
38 Crit Rev Oral Biol Med 15(1):28-46 (2004)
-
related response. Metabolism of these two drugs is mediatedby a
polymorphic enzyme (CYP2D6) or an enzyme (CYP3A4)with great
inter-individual, non-polymorphic variation inactivity; hence,
reduced detoxification of the drugs mightserve as a risk factor for
the development of ADRs. The dif-ference in metabolic pathways
between the two drugs mightalso explain why mutual drug
substitution can occur withoutrelapse of the reaction.
ANGIOTENSIN II RECEPTOR BLOCKERS (ARBS)Rare cases of angioedema
have been reported with intake ofARBs, and some of the individuals
have a previous history ofACEI-induced angioedema (Agostoni and
Cicardi, 2001). In 13patients, the diagnosis of angioedema was
linked to the use oflosartan (S for CYP2D6, 3A4; I of CYP1A2, 2C9,
2C19, 3A4). Thereactions occurred from 24 hours to 16 months after
the initia-tion of therapy (25-100 mg a day). Three patients had
previ-ously experienced angioedema during treatment with ACEIs.Lips
and/or tongue was involved in nine out of the 13 cases.There was
co-medication in three of the patients, and regimensconsisted of
two or three drugs, including diuretics, dexfenflu-ramide (S for
CYP2D6, 1A2), estradiol (S for CYP1A2, 2C9,2C19, 3A4; I of CYP1A2,
3A4), progesterone (S for CYP2C9,3A4), and metoprolol (S for
CYP2C9, 2D6; I of CYP2D6). In allcases, the causal relation between
losartan therapy andangioedema was considered to be at least
'probable' (vanRijnsoever et al., 1998). A patient experienced
swelling of thelips and face with losartan. In this patient,
captopril (S forCYP2D6) had previously been discontinued because of
coughand substituted with bisoprolol-hydrochlorothiazide and
tera-zosin. Bisoprolol-hydrochlorothiazide (bisoprolol: S
forCYP2D6, 3A4) was, in turn, substituted by losartan, and
theangioedema occurred within 30 minutes after a single dose
(50-mg) of losartan (Acker and Greenberg, 1995). Both quinapril-and
losartan-induced facial and palatal angioedema has beenreported in
a patient who had no history of urticaria, angioede-ma, or other
drug allergies (Boxer, 1996).
The association between ARBs (e.g., losartan) andangioedema is
based upon case reports and cases from sponta-neous reporting
systems (Table 6). Onset and resolution of mostreactions occurred
within hours to a few weeks, indicating anallergic or
pseudo-allergic mechanism. Abnormal metabolismby a polymorphic
enzyme (CYP2D6) and/or interactions bysubstrate competition or
inhibition from concurrent drugs arepotential risk factors that
might contribute to the pathophysi-ology of the reaction.
ANTI-ARRHYTHMICS, CLASS I (SODIUM-CHANNEL BLOCKERS)
ODRs associated with Class I anti-arrhythmics include drymouth,
fixed drug eruptions, oral manifestations of hemato-logic
disorders, lupus erythematosus, gingival overgrowth,SJS, TEN, and
oral manifestations of the hypersensitivity syn-drome (Table
6).
Dry mouth is a result of an anticholinergic effect thatoccurs
with drugs like quinidine (S for CYP2C9, 3A4; I ofCYP2C9, 2D6,
3A4), disopyramide (S for CYP2C9, 3A4), fle-cainide (S for CYP2D6;
I of CYP2D6), cibenzoline (S forCYP2D6, 3A4), and moricizine
(Sreebny and Schwartz, 1997).Whether an effect per se or a
consequence of dry mouth, a bit-ter or metallic taste has been
reported with propafenone ther-
apy (S for CYP1A2, 2D6, 3A4; I of CYP1A2, 2D6) (Caron
andLibersa, 1997).
FDEs from cardiovascular drugs have been reported forphenytoin
and quinidine (Korkij and Soltani, 1984; Sun et al.,1994). Two
cases of oral pigmentation associated with quini-dine therapy
(Birek and Main, 1988) (S for CYP2C9, 3A4; I ofCYP2C9, 2D6, 3A4)
may represent FDEs. Both patients werereceiving long-term therapy
(five or 10 years) and presentedwith palatal pigmentations of
unknown duration. One of thepatients who was on monotherapy also
had a melanotic areaon the right ankle, and the palatal lesion
became darker andmore extensive during the subsequent three years.
The otherpatient ingested multiple drugs: digoxin, verapamil (S
forCYP1A2, 2C9, 2C19, 3A4; I of CYP2C9, 2D6, 3A4), and warfarin(S
for CYP1A2, 2C9, 2C19, 2D6, 3A4; I of CYP2C9, 2C19). Nodrug
withdrawal or re-challenge test was performed (Table 6).Quinidine
has a high drug-drug interaction potential andmetabolizes into
RDMs.
Oral manifestations of hematological disorders may occurin rare
cases of class I anti-arrhythmic therapy (Caron andLibersa, 1997).
Drugs commonly suspected to cause thrombo-cytopenia include
quinidine (Wiholm and Emanuelsson, 1996).
Procainamide (S for CYP2D6), hydralazine (I of CYP3A4),and
quinidine (S for CYP2C9, 3A4; I of CYP2C9, 2D6, 3A4) maycause
drug-induced lupus erythematosus (Brosnan et al., 2000).A patient
presented with cutaneous and oro-genital ulcerationsas well as
arthritis and a photodistributed rash after initiationof therapy
with hydralazine (a direct-acting vasodilator;reviewed in this
section because its metabolism is similar tothat of procainamide).
ANA- and DNA-binding tests were pos-itive. All clinical
manifestations disappeared on withdrawal ofthe offending drug
(Neville et al., 1981). A further case has beenreported with
hydralazine-induced Sjgren's syndrome andassociated with features
of SLE in terms of rheumatoid-arthri-tis-like symptoms and a
positive ANA. The patient was treatedfor four years with
hydralazine (150 mg a day). Joint symptomsresolved after
hydralazine was discontinued, and salivary andlacrimal gland flow
returned to normal over the following year(Darwaza et al., 1988)
(Table 6). The polymorphic enzymeNAT2 metabolizes both hydralazine
and procainamide, andthe slow acetylator phenotype appears to be a
significant riskfactor for drug-induced lupus. The drug- or
metabolite-proteincomplex is recognized as 'foreign' by the immune
system(Hofstra, 1994).
Hydantoin and its derivatives may interfere with
folateabsorption or metabolism and thus mediate potential
manifes-tations of oral ulcerations, cheilitis, and glossitis
(Wintroub andStern, 1985). Mucocutaneous reactions including
gingival over-growth are part of the broad spectrum of ADRs to
phenytointherapy (Table 6). Details on clinical presentation and
patho-genesis of phenytoin-induced gingival overgrowth arereviewed
in detail elsewhere (Brown et al., 1991; Marshall andBartold, 1998;
Rees, 1998; Hallmon and Rossmann, 1999).Phenytoin may also induce
facial changes such as coarse facies,including enlargement of the
lips and nose and thickening ofthe face and scalp. The mechanism of
gingival and facialenlargement is unknown but may involve RDMs.
Metabolismof phenytoin by CYP2C9 is the major route of elimination
ofthis drug (other S for CYP2C9, 2C19, 3A4; I of CYP2C9),
andphenotyping studies have identified individuals with
impairedcapacity to metabolize the substrate (Smith et al., 1998).
It is alsoknown that both healthy and hyperplastic gingival tissues
con-
15(1):28-46 (2004) Crit Rev Oral Biol Med 39
-
tain a significant amount of the active metabolite
5-hydroxy-phenyl-5-phenylhydantoin and express CYP2C9 that
catalyzesthe formation of this metabolite (Zhou et al., 1996).
Phenytoinintake also carries a relative risk of borderline
significance tocause hematological disorders such as
agranulocytosis(Kaufman et al., 1996).
Phenytoin is among the common agents that can
causehypersensitivity reactions (Daoud et al., 1998). A small
propor-tion of patients (from one in 1000 to one in 10,000) exposed
toanti-convulsants will develop the 'drug hypersensitive' syn-drome
(Lawton et al., 1992; Knowles et al., 2000) that was origi-nally
called the 'anti-convulsant hypersensitivity' syndrome.Oral
ulcerations may occur as a manifestation of the widerange of skin
diseases, including EM, SJS, and TEN, that,together with fever and
internal organ involvement, character-izes the syndrome. A further
clinical feature of this syndrome is'strawberry tongue' (Sun et
al., 1994; Hebert and Ralston, 2001).The syndrome is associated
with a relative excess of RDMs andinsufficient detoxification of a
reactive arene oxide metabolitethat may contribute to the formation
of the antigen that triggersan immune reaction (Hebert and Ralston,
2001).
SJS and TEN are associated with short-term therapy withphenytoin
(Wintroub and Stern, 1985; Crowson and Magro,1999; Rzany et al.,
1999). The period of increased risk is largelyconfined to the first
eight weeks of treatment. The associationbetween anti-epileptics
and SJS and TEN has been substantiat-ed by a recent case-control
study that also took into accountpotential co-factors that might
confound or modify the risk(Rzany et al., 1999).
The association between the use of anti-arrhythmics class Iand
ODR mostly derives from case reports, and only some ofthe reactions
have been validated by re-challenge (Table 6). Anarrow therapeutic
index, metabolism into RDMs, and a highdrug-drug interaction
potential by CYP enzymes are risk fac-tors underlying the
development of ADR from anti-arrhyth-mics. Non-genetic or genetic
variation in metabolism pheno-type might also have contributed to
the pathogenesis.
ANTI-ARRHYTHMICS, CLASS III (POTASSIUM-CHANNEL BLOCKERS)
CDRs from amiodarone (S for CYP1A2, 2C19, 2D6, 3A4; I ofCYP1A2,
2D6, 3A4) therapy are common, and photosensitivityoccurs in about
5-20% of patients and a blue-gray discoloringof skin in 1-7%. A
patient was symptom-free upon withdrawalof amiodarone, and a
positive double-blind oral re-challengewith this drug confirmed
angioedema of the facial regioninduced by amiodarone (Burches et
al., 2000) (Table 6). Thepatient had been taking corticosteroid (S
for CYP3A4) for eightyears prior to amiodarone therapy for cardiac
rhythm abnor-mality.
A possible association between amiodarone and bretyliumtherapy
may cause taste abnormality and salty taste, respec-tively
(McGovern et al., 1983; Mott et al., 1993).
PLATELET AGGREGATION INHIBITORS (ASPIRIN)Topical application of
aspirin (acetylsalicylic acid; S forCYP2C9) in the oral cavity
causes aspirin or acid burn of theoral mucous membrane (Kawashima
et al., 1975; Dellinger andLivingston, 1998). The drug may also
induce angioedema. Themechanism for this disorder may be an
inhibition ofprostaglandin synthesis with overproduction of
leukotrienes
(Vervloet and Durham, 1998). Interestingly, a recent
case-con-trol study showed that aspirin played no significant role
in theoccurrence of aphthous ulcers (Boulinguez et al., 2000).
In a series of 25 cases of oral FDEs, two were associatedwith
the intake of aspirin (Jain et al., 1991). Withdrawal ofaspirin
resulted in a remission of the lesions. Both patients
werere-challenged, and the lesions recurred at the previous
siteswithin 24-48 hours (Table 6).
Based on a case-control study, it was found that dipyri-damole
carried a relative risk of borderline significance for
thedevelopment of agranulocytosis (Kaufman et al.,
1996).Dipyridamole has also been linked to altered taste
('bizarre'taste) (Mott et al., 1993).
CALCIUM-CHANNEL BLOCKERS (CCBS) (ANTI-ARRHYTHMICS, CLASS IV)
Reported ODRs include taste disturbances, angioedema,
oralulceration, lichenoid drug eruptions, SJS, TEN, and
gingivalovergrowth (Table 6).
The reported adverse effect profile tends to hold true fordrug
class and is observed in ADRs associated with benzo-thiazepine
derivatives (diltiazem), phenylalkylamine deriva-tives (verapamil),
and dihydropyridine derivatives (nifedipineand amlodipine) (Dougall
and McLay, 1996).
Two patients developed angioedema of the tongue or lipsshortly
after the initiation of nifedipine therapy (50 mg a day)(Sauve et
al., 1999). Peri-orbital and lip angioedema occurred ina patient
one month after starting diltiazem. Patch-testing tocosmetic agents
was negative, and the reactions resolved with-in 48 hours after the
drug was discontinued (Sadick et al., 1989).In a series of 72
patients with drug-induced oro-facialangioedema, 14 cases were
precipitated by CCBs. An expertpanel excluded triggering events
other than CCBs. Most reac-tions occurred within the first week of
therapy, and symptomsresolved when therapy was discontinued (Hedner
et al., 1991).
Two cases with recalcitrant oral ulcerations caused by
dil-tiazem (S for CYP 3A4) have been reported (Cohen et al.,
1999).One of the cases had no previous history of aphthous ulcers
butdeveloped tongue ulceration within two months after initiationof
diltiazem therapy (240 mg a day). This patient was also
con-comitantly taking other medications, including losartan (50 mga
day; S for CYP2C9, 3A4, I of CYP1A2, 2C9, 2C19, 3A4),lorazepam,
terazosin, and hydrochlorothiazide. The ulcerationhealed within
weeks after diltiazem therapy was discontinued(Cohen et al., 1999).
A possible association between diltiazemtherapy and oral
ulcerations has not been validated by re-chal-lenge.
Non-polymorphic variation (CYP3A4) in metabolismphenotype or
interaction by substrate competition/inhibition(CYP3A4) is a
candidate risk factor in the ulceration pathogen-esis. The second
case with tongue ulceration had been treatedwith captopril (200 mg
a day; S for CYP2D6) and verapamil (Sfor CYP1A2, 2C9, 2C19, 3A4; I
of CYP2C9, 2D6, 3A4) for at leastfive years and in gradually
increasing dosages (from 180 to 240mg a day). Other medications
that this patient had been takingincluded oxazepam, metoclopramide,
estrogen (S for CYP1A2,2C9, 2C19, 3A4; I of CYP2C9, 2D6, 3A4),
thyroxine, and aspirin(S for CYP2C9). Discontinuance of captopril
therapy followedby decreased dosage of verapamil resulted in
gradual healingover a four-month period. Verapamil was finally
discontinued,and complete healing occurred in two weeks. A
re-challengetest with another CCB, diltiazem, a month later
resulted inulceration at the initial site, implying that the
ulceration was a
40 Crit Rev Oral Biol Med 15(1):28-46 (2004)
-
case of FDE. This lesion healed one month after cessation of
dil-tiazem administration (Cohen et al., 1999). In this case, an
asso-ciation between CCB therapy and oral ulcerations appears
like-ly. The finding that substitution of verapamil by
diltiazemoccurred uneventfully may indicate that drug-drug
interac-tions mediated via CYP enzymes (CYP1A2, 2C9, or 2C19)
couldplay a role in ulcer pathogenesis. CCBs did not cause a
problemin a case-control study on aphthous ulcers (Boulinguez et
al.,2000). So far, the association between CCB therapy and
oralulcerations remains presumptive (Table 6).
Drug-induced gingival overgrowth is a well-documentedand widely
recognized ADR to CCB usage (for a recent review,see Marshall and
Bartold, 1998; Hallmon and Rossmann, 1999)(Table 6). Incidence
rates of gingival overgrowth vary consid-erably, and most reported
cases have been associated withnifedipine. Gingival overgrowths
occur in as many as 38% ofpatients after three months' therapy with
nifedipine, as com-pared with 21% of patients taking diltiazem and
19% of thosetaking verapamil. The prevalence is unknown but appears
tobe relatively low when one considers that these drugs in
par-ticular are widely prescribed throughout the world (Marshalland
Bartold, 1998). There are also well-documented reports ongingival
overgrowth occurring with other CCBs (lacidipine,felodipine,
amlodipine, isradipine, nicardipine, and nitrendi-pine) (Marshall
and Bartold, 1998; Hallmon and Rossmann,1999). Although this
side-effect with these latter CCBs occursless frequently, it seems
likely that this is merely a reflection ofthe smaller number of
patients who are treated with these morerecently introduced drugs.
Regression of the overgrowth mayoccur in some patients following
switch to a CCB of the sameor a different chemical composition
(Westbrook et al., 1997).There is no clear relationship between
dosage and CCB-induced gingival overgrowth (Bullon et al., 1994).
The patho-genesis of CCB-induced gingival overgrowth remains
unclear(Marshall and Bartold, 1998). Genetic predisposition and
phar-macokinetic variables are among the factors implicated in
itspathogenesis (Seymour et al., 1994; Marshall and Bartold,
1998).Seventeen percent of a Dutch population is
phenotypicallydeficient in the first step of nifedipine
metabolism(Kleinbloesem et al., 1984). Alternatively, RDMs may be
pro-duced as the CYP3A4 gene catalyzes the formation of
suchmetabolites in both healthy and hyperplastic gingival
tissuesfrom patients receiving cyclosporine and nifedipine
therapy(Zhou et al., 1996).
A case of amlodipine-associated lichen planus has recentlybeen
reported (Swale and McGregor, 2001). The patient pre-sented with
widespread cutaneous lichenoid eruptions andWickham's striae in the
oral cavity two weeks following initia-tion of amlodipine therapy
(S for CYP3A4; I of CYP2C9, 2D6,3A4). The patient had a history of
non-insulin-dependent dia-betes mellitus (treated with metformin)
and as such representsa case of the triad of oral lichen planus,
hypertension, and dia-betes mellitus known as Grinspan's syndrome.
A possible asso-ciation between amlodipine therapy and lichen
planus was notvalidated by re-challenge (Table 6).
The proportions of serious adverse reactions, including SJSand
TEN, are similar in any of the three chemical groups ofCCBs (Stern
and Khalsa, 1989; Knowles et al., 1998). The reac-tions developed
within two weeks after drug therapy was ini-tiated. Clinical
details have been provided for three of thecases: One patient
developed EM after 10 days of therapy withverapamil (S for CYP1A2,
2C9, 2C19 3A4; I of CYP2C9, 2D6,
3A4), recovered when the drug was withdrawn, and presentedwith
relapse when re-challenged; a second patient was diag-nosed with
SJS after about 12 days' therapy with verapamil(160 mg a day) and
recovered after the drug was discontinued,but was not
re-challenged; a third patient suffering from obesi-ty,
hypothyroidism, asthma, angina, and hypertension devel-oped TEN
possibly secondary to diltiazem therapy. Otherdrugs taken by two
out of the three patients included levothy-roxine, metoproterenol,
nitroglycerin, theophylline (S forCYP1A2, 3A4), and warfarin (S for
CYP1A2, 2C9, 2C19, 2D6,3A4; I of CYP2C9, 2C19) (Stern and Khalsa,
1989). A patientwho was taking nitroglycerin presented with
multiple oralulcerations, without skin manifestations, two weeks
followingthe initiation of diltiazem therapy (90 mg a day). The
conditiondiagnosed as EM resolved two weeks after diltiazem was
with-drawn. No re-challenge test was performed (Brown et al.,
1989).The exposure with an incriminated CCB, along with a
correla-tion between onset and resolution of the disease patterns
andstart of administration and withdrawal of the drug(s), suggestsa
causal association (Table 6). Diltiazem is partly metabolizedby a
polymorphic CYP enzyme, implying that abnormalmetabolism could be a
risk factor. For the two patients on ver-apamil, the activity level
of the highly variable CYP3A4enzyme might be implicated in the
pathogenesis of the ODRs.Finally, two of the cases occurred in
patients on multiple drugswith an interaction potential via CYP
enzymecompetition/inhibition.
CCBs may cause taste disturbances. Diltiazem may causehypogeusia
and hyposmia, and nifedipine, taste and smell dis-tortion (Mott et
al., 1993; Spielman, 1998). In animal experi-ments, CCBs such as
verapamil and nifedipine have beenreported to inhibit saliva output
and reduce the protein contentof the secretion (Baum et al.,
2000).
DIURETICSODRs related to diuretics include dry mouth, taste
distur-bances, angioedema, and oral manifestations of
hematologicdisorders, drug hypersensitive syndrome, lichenoid drug
erup-tions, and lupus erythematosus-like eruptions (Table
6).According to a recent case-control study (Boulinguez et
al.,2000), diuretics do not seem to play a significant role as
indu-cers of aphthous ulcers.
In a series of 72 patients with oro-facial angioedema
pre-cipitated by anti-hypertensives, diuretics could have induced
areaction in 11 of these cases (Hedner et al., 1991). An
expertpanel excluded triggering events other than diuretics.
Mostreactions occurred within the first week after the initiation
oftherapy, and symptoms resolved when the therapy was dis-continued
(Table 6). Information on intake of other medicationswas not
provided (Hedner et al., 1991).
Diuretics may contribute to dry mouth by causing dehy-dration,
and thereby salivary gland hypofunction (Sreebny andSchwartz, 1997;
Baum et al., 2000).
In Sweden, diuretics (furosemide, amiloride, and thi-azides) are
among the commonly reported offenders suspectedto cause
agranulocytosis and thrombocytopenia (Wiholm andEmanuelsson, 1996).
Furosemide, amiloride, and thiazidediuretics are all sulphonamides
and may, on re-exposure, causeallergic hematological manifestations
of thrombocytopenia insusceptible patients (Vervloet and Durham,
1998).Sulphonamides have also been linked to the development ofEM
and SJS (Brown et al., 1989; Gruchalla, 2000), and a dose-
15(1):28-46 (2004) Crit Rev Oral Biol Med 41
-
independent reaction to sulphonamides is a common cause ofTEN
(Becker, 1998). The drug hypersensitivity syndromeoccurs with
thiazide diuretics and furosemide. The syndromeis thought to be
initiated via effects of a reactive metabolite,hence the term
"reactive metabolite syndrome".Sulphonamides can be metabolized to
reactive metabolites,which may elicit both direct cytotoxicity and
immune respon-ses (Gruchalla, 2000; Knowles et al., 2000).
Skin reactions including photodistributed and
non-photo-distributed lichen planus eruptions induced by thiazides
havebeen well-documented in the dermatological literature (Daoudet
al., 1998). In a case report, symmetrical white buccal plaqueswere
linked to bendrofluazide. In this patient, a diagnosis oforal
lichen planus was supported by biopsy (Lamey et al.,1990). The
patient had a four-year history of diabetes mellitus,which was
initially treated with glibenclamide (S for CYP2C9,3A4; I of
CYP3A4) and diet, but soon changed to metformin.Hypertension was
controlled by bendrofluazide (5 mg a day)and debrisoquine (20 mg
daily; S for CYP2D6). This patient isanother example of the triad
of hypertension, diabetes mellitus,and lichen planus referred to as
Grinspan's syndrome.Alteration of drug regimen was unsuccessful. An
additionalpatient presented with oral lichen planus as part of
Grinspan'ssyndrome (Lamey et al., 1990). For this patient,
medicationsincluded glipizide (5 mg a day; S for CYP2C9),
spironolactone(100 mg a day; S for CYP3A4), furosemide (40 mg a
day), anddigoxin (125 or 250 mg on alternate days). For these two
cases,a causal association between the use of diuretics and
lichenplanus remains uncertain (Table 6). Except for exposure,
therewas a lack of correlation between the development of
lesionsand drug administration and withdrawal, as well as
re-chal-lenge. Theoretically, the lesions might as well have been
associ-ated with the concurrent medications that are metabolized by
apolymorphic enzyme (CYP2C9, 2D6) or by an enzyme(CYP3A4) with
great inter-individual, non-polymorphic varia-tion in activity.
Amiloride intake has been linked with decreased thresholdfor
salt taste, and spironolactone with taste loss (Mott et
al.,1993).
HYDROXYMETHYL-GLUTARYL CO-ENZYME A(HMG-COA) REDUCTASE INHIBITORS
(STATINS)
Statins are, in general, well-tolerated if they are the only
med-ication an individual is taking (Bernini et al., 2001). Known
der-matological ADRs for statins include angioedema. Two
patientsexperienced cheilitis after beginning treatment with
simvastatin(Mehregan et al., 1998). One of the patients presented
with aone-month history of skin rash and an extensive
desquamationand crusting of the upper and lower lips. Therapy with
simva-statin (S for CYP3A4; I of CYP2C9, 2C19, 2D6, 3A4) was
initiat-ed four months before the rash appeared, and an
unspecifiedBAB (S for mainly CYP2D6) and warfarin (S for CYP1A2,
2C9,2C19, 2D6, 3A4; I of CYP2C9, 2C19) were started one year
priorto the onset of the rash. The second patient presented with a
six-month history of cracking lips that appeared approximately
sixmonths after initial therapy with simvastatin. Both
patients'cheilitis resolved within three weeks following the
discontinua-tion of simvastatin. Neither re-challenge nor patch
test was per-formed. One could speculate that the lip lesions in
these twopatients might represent photodistributed eruption to
statinsanalogous to the scaly cheilitis reported in persons
withlichenoid photoeruptions (West et al., 1990).
A case of simvastatin-induced lichenoid eruptions withskin and
mucosal involvement has been reported (Roger et al.,1994). The
patient presented with reticular manifestations onthe buccal
mucosa, but no vaginal, scalp, or nail changes werenoted. The
patient had been on simvastatin for four months (10mg a day), was
not taking any other drug, and gave a three-month history of
cutaneous lesions. The offending drug wasdiscontinued, and the
cutaneous lesions began to resolve with-in four weeks. No new
lesions appeared; however, the mucosallesions persisted for six
months. The patient refused patch-test-ing and re-challenge. Thus,
the diagnosis of lichenoid drugeruption remains presumptive.
A possible association between simvastatin therapy andthe
sporadic cases of ODR has not been verified by re-challenge(Table
6). Hovever, most statins are prescribed for individualswho are on
multiple medications, and a mechanism involvingpotential
interaction by substrate competition or inhibition viathe CYP3A4
appears likely. The non-polymorphic variation inactivity of this
enzyme may also represent a risk factor for thedevelopment of ODRs.
The latency in timing between initiationof drug therapy and
presentation of lesions favors a contribu-tion from RDMs.
POTASSIUM-CHANNEL OPENERS (NICORANDIL)Several case reports
published in recent years link nicorandilwith ulcers or aphthae
affecting the tongue, gingival, labial, orbuccal mucosa, hard
palate, and fauces (Scully et al., 2001). Theestimated prevalence
of this adverse reactions is 5% (Marquart-Elbaz et al., 1999).
However, a recent case-control study whichinvestigated a possible
association between drug exposure andaphthous ulcers showed that
none of the cases (80 individuals)was on nicorandil therapy
(Boulinguez et al., 2000). The age ofthe patients exhibiting ADRs
to vasodilators ranges from 60 to90 years, with an even sex
distribution. The ulcers present with-in 10 months following the
initiation of drug therapy, and com-plete healing occurs weeks
after drug withdrawal. In one out ofnine patients, a positive
re-challenge was reported (Scully et al.,2001). A past history of
aphthae could increase the risk forADRs in some patients. In a
recent observational cohort studyof 13,260 patients over a minimum
observation period of sixmonths of nicorandil treatment, there were
55 cases of mouthulcers (Dunn et al., 1999). In 49 patients, the
ulcers developedduring treatment, while three patients developed
the ulcersafter treatment had stopped, one patient had ulcers
pre-datingtreatment, and for two patients it was uncertain whether
theywere still taking nicorandil when the ulcers developed.
Mostulcers developed more than 60 days after the start of
treatment.The dosage of the drug covered a wide range, from 10 to
80 mga day, but there was no dose-response effect. The crude ratio
ofmouth ulcers associated with nicorandil to all the
comparabledrugs combined was 2.03 (95% CI, 1.48-2.74), indicating
acausal association.
A possible association between nicorandil therapy and
oralulcerations has been substantiated by both case reports and
acohort study. Validation by re-challenge has been performed ina
few cases (Table 6). Some lesions may be linked to drugs otherthan
nicorandil, since some of the individuals were reported tobe on
multiple drug regimens, including medication with apotential to
induce oral ulcerations. The fact that ulcerationspresent weeks to
months following the initiation of therapyindicates that nicorandil
metabolites rather than the parentdrug are implicated in the
development of ulcers. There is a
42 Crit Rev Oral Biol Med 15(1):28-46 (2004)
-
large individual variation in levels of activity of the
enzymenicotinamide N-methyltransferase that catalyzes the
methyl-conjugation of nicotinamide, an intermediate formed by
de-nitration of nicorandil (Weinshilboum et al., 1999). The trait
oflow levels of activity of this enzyme could be another risk
fac-tor in the pathophysiology of oral ulcerations.
Concluding RemarksThe quality of evidence presented for oral
reactions beingdrug-induced is variable. As presented in this
review, informa-tion on ODRs is largely based on case reports or
small series ofcases and was gathered before we entered the
post-genomicera. Data on incidence rates are sparse and mostly
derived fromstudies of selected populations in hospital or
university set-tings. Thus, epidemiological studies with
appropriate case andcontrol groups and racially matched populations
are needed ifwe are to obtain more reliable information on the
incidence ofODRs. The association between a drug and an ODR is
mostlybased on the disappearance of the reactions following
discon-tinuance of the offending drug. Some ODRs have been
verifiedby re-challenge or laboratory tests. A few are documented
bywell-controlled case-control studies. In patients on
multipledrugs, most authors consider the latest-introduced drug as
theoffending drug. When considering ADRs linked to CVDs thatare
primarily catabolized by CYPs, as are xenobiotics in gener-al, it
is important that one evaluate possible contributions fromboth
endogenous and exogenous factors, such as concomitantdrugs, diet,
and other chemicals. Table 7 presents mechanismsof potential ADRs
due to CVDs, and below we discuss somedrug classes in which the
influence of endogenous and exoge-nous factors on drug safety has
been documented.
The pharmacokinetic behavior of drug-metabolizingenzymes should
be considered as factors that can influencedrug safety along with
geno- and phenotypes. Many pharma-cokinetic drug interactions with
a potential for ADRs fromCVDs are associated with CYP-mediated
phase I drug bio-transformation (Abernethy and Flockhart, 2000).
Pharmaco-kinetic drug interactions are known to occur with many
drugcombinations. Administration of several drugsincludingBABs,
anti-arrhythmics, anti-convulsants, and hypnoseda-tivestogether
with CCBs can significantly alter the pharma-cokinetics of those
drugs. Some interactions are well-docu-mented, whereas other
potential interactions await furtherinvestigation (Rosenthal and
Ezra, 1995). BABs may furtherinteract with inotropic agents,
anti-arrhythmics, NSAIDs, psy-chotropic drugs, anti-ulcer
medications, statins, warfarin, andoral hyperglycamics (Blaufarb et
al., 1995). In general, manypotential interactions can be predicted
with anti-arrhythmics,quinidine and amiodarone in particular. These
agents oftenhave a narrow therapeutic window. Accordingly, small
increas-es in serum concentrations may lead to toxicity (Trujillo
andNolan, 2000). Attention has to be paid to possible
confoundingeffects due to an underlying and or concomitant disease.
Todate, molecular genetics of underlying cardiovascular diseasesas
they relate to genes that determine the responsiveness to agiven
drug has recently been reviewed, and the data appearequivocal
(Nakagawa and Ishizaki, 2000).
There is increasing knowledge on the genetic polymor-phism of
CYP2C9, CYP2C19, and CYP2D6. For most patientswith a "poor
metabolizer" phenotype, there is limited metabo-lism of the drug
substrate unless another major metabolic path-way, involving other
enzymes, exists. Thus, a clinical conse-
quence might be an idiosyncratic pharmacological response toa
prescribed medication (Ingelman-Sundberg, 2001). For somedrugs, an
extensive metabolizing phenotype may turn into apoorly metabolizing
type, provided that the patient is con-comitantly exposed to an
inhibitor of a particular medication, aphenomenon termed
"phenocopy" (Brinn et al., 1986). Amongthe cases that have been
reviewed, some drug combinationsincluded agents that are known
inhibitors of CYP enzymes ofrelevance to CVDs. The isoforms CYP3A4
and CYP1A2 havehighly variable expressions across the population,
even in theabsence of concurrent ingestion of an inhibiting drug.
Mostindividuals have an intermediate level of enzyme activity,
andsome individuals have very low or very high activity(Abernethy
and Flockhart, 2000).
CYPs are expressed predominantly in the liver but also
inextra-hepatic tissues, e.g., the gastrointestinal tract, the
skin,and oral mucous membrane (Zhou et al., 1996; Janmohamed etal.,
2001;