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22.3.6 Fixed Drug Eruption
Fixed drug eruptions (FDEs) are characterised by recurrence at the same site with repeated exposure to a particular drug. It usually presents as a solitary reactive area associated with the initial
exposure, developing within 30 minutes to 8 hours after taking the drug. The size of the area
infected may increase with subsequent exposure to the drug, and on occasions, multiple sites of
involvement may develop(46).
The pathogenesis of FDE is still not fully elucidated; however, a number of factors including
antibody production, antibody- dependent cell- mediated cytotoxicity and serum properties have
been identified as contributors(47, 48).
+
T cells produce interferon γ, and by interacting with other inflammatory cells are thought
CD8
to be involved in the initial epidermal injury. The persistence in situ of CD8
+
memory T cells is
hypothesised to account for the recurrence of lesions at the same location with repeated exposure
to the offending drug. It has been suggested that cell- mediated hypersensitivity may play a role in
pathogenesis(48, 49).
Cutaneous lesions appear as a dusky red macule, usually involving the extremities, genital region
and lips. There may be an accompanying stinging or burning sensation. The lesions may be solitary
or multiple clusters of lesions which can progress to vesiculation following repeated exposure to
the inciting drug. These lesions will recur at the same anatomical location when the individual is
exposed to the same drug again. There are often signs of post- inflammatory melanosis. Intraoral
involvement of FDE is rare.
Management entails withdrawal of the inciting drug, topical application of corticosteroids and
systemic antihistamines. In severe cases, supportive therapy such as maintenance of fluid and
electrolyte balance and systemic corticosteroids may be indicated(50).
Drugs that have been implicated in FDE are listed in Table22.9.
Table22.9 Drugs associated withfixed drug eruption.
Drug group Examples
Sulphonamide antibiotics/sulphones Trimethoprim/sulfamethoxazole
Dapsone
Nitroimidazoles Metronidazole
Ornidazole
Tinidazole
Tetracyclines Tetracycline
Doxycycline
Quinolones Ciprofloxacin
Norfloxacin
Ofloxacin
Penicillins Penicillin
Amoxicillin
Macrolides Azithromycin
Clarithromycin
Glycopeptides Vancomycin
Cephalosporins Ceftriaxone
Cefixime
t.me/Dr_Mouayyad_AlbtousH
Table22.9 (Continued)
Drug group Examples
COX- 2inhibitors Etoricoxib
Celecoxib
Haemostatic drugs Tranexamic acid
Clopidogrel
Ticagrelor
Ticlopidine
Cardiovascular drugs Beta- blockers: atenolol, bisoprolol and propranolol
Statins: atorvastatin, rosuvastatin and simvastatin
Antihistamines Cetirizine
Loratadine
Antivirals Acyclovir
Valacyclovir
Famciclovir
Oral hypoglycaemics Dapagliflozin
Metformin
Sitagliptin
Proton pump inhibitors Esomeprazole
Rabeprazole
Omeprazole
Antifungals Fluconazole
Phosphodiesterase- 5inhibitors Tadalafil
Sildenafil
Immunomodulating agents Mycophenolate
Axitinib
Musculoskeletal drugs Allopurinol
Psychotropic drugs Modafinil
Chemotherapeutic drugs Paclitaxel
Capecitabine
Others Influenza vaccine
Covid vaccine
Herbal medicines
Iodine containing contrast
Multivitamins
389
Source: Adapted from McClatchy etal.(49).
22.3.7 Angioedema
Angioedema is characterised by rapid short- lived swelling of the skin, mucous membranes, or both
including the upper respiratory and intestinal epithelial linings. It is short- lived, resolving within
24–72 hours without visible sequelae. The swelling is non- pitting and may be erythematous and
slightly warm to touch. Pain is a variable symptom. When swelling occurs in the oropharynx and
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Table22.10 Drugs associated withangioedema.
IgE mediated Penicillins
Cephalosporins
Iodinated contrast media
Neuromuscular blocking agents
Pyrazoles
Quinolones
Intolerance NSAIDs
Iodinated contrast media
Neuromuscular blocking agents
Pyrazolones
Quinolones
Kinin- dependent ACEIs
Angiotensin II receptor blockers
Source: Adapted from Lerch etal.(51).
respiratory tract, it may be life- threatening. Gastrointestinal tract involvement may result in
abdominal pain, vomiting and diarrhoea.
Orofacial manifestations usually appear as rapid painless swelling of the lips, periorbital region
and tongue. In cases of drug- induced angioedema, this reaction is triggered by contact with a
specific drug in susceptible patients. The mechanism of drug- induced angioedema relates to
the direct action of certain medications on mast cells, causing degranulation and subsequent
inflammatory cytokine (histamine, serotonin and kinins) release(51).
The following three main categories of drug- induced angioedema are recognised:
1) Immediate hypersensitivity reaction to beta- lactam antibiotics.
This is the most frequent allergic reaction and is mediated by IgE. Iodinated contrast
media, pyrazolones, quinolones and neuromuscular blockers may also cause angioedema
byIgE- mediated pathways(52).
2) Aspirin and other NSAID- induced angioedema are generally considered to be an intolerance
rather than a true allergic reaction. Cyclooxygenase inhibition results in alterations in
arachidonic acid metabolism, with overproduction of cysteinyl leukotrienes(53).
3) ACEI can elicit angioedema, which, although rarely occurring, can be life- threatening due to
upper airway obstruction. This reaction is caused by inhibition of bradykinin degradation(54).
Drugs most commonly implicated in angioedema are listed in Table22.10.
22.3.8 Mucosal Pigmentation
Certain drugs may induce oral mucosal pigmentation. This may be either extrinsic (non- melanocytic)
or intrinsic (melanocytic) in origin. Drug- induced oral pigmentation usually appears as a widespread
alteration in colour. There is a direct relationship between exposure to an inciting drug and the
development of mucosal pigmentation. The timing of this is variable, with some cases noted soon
after administration of the drug and others appearing days, weeks or years after(55).
The exact mechanism by which certain drugs induce oral mucosal pigmentation is not fully
understood. It has been observed that some medications cause an increase in the number of
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melanocytes in the epithelium, others increase melanin synthesis, and some pigmentation is the
result of deposition of drug metabolites in the tissues (56–58). Certain drugs may also cause a
change in colour of the alveolar bone and tooth substance.
The drugs most frequently associated with melanocytic mucosal pigmentation are the antineoplastic agents, followed by the antimalarial medications. There appears to be a dose- dependent
relationship between the intensity and extension of pigmentation. Lesions usually regress when
the offending drug is withdrawn(58, 59).
Drug- induced intrinsic pigmentation has a variable presentation, ranging from grey–blue to
brown macular lesions on the oral mucosa. These may be focal or multiple, localised or diffuse.
The most frequent sites to be affected are the hard palate, gingival tissues and buccal mucosa.
Drugs most commonly associated with oral mucosal pigmentation are listed in Table22.11.
Additionally, some drugs such as iron, chlorhexidine, antibiotics and bismuth have been noted
to cause temporary yellow–brown discolouration of the tissues, particularly the dorsal surface of
the tongue.
Table22.11 Drugs associated withoral mucosa pigmentation.
Drug Pigmentation colour
Amiodarone Blue
Aminophenazone Brown
Amodiaquine Black, grey
Arsenic
Bismuth Blue, yellow–brown, black
Busulphan Brown
Chlorhexidine Yellow, brown
Chloroquine Blue, grey
Clofazimine Brown
Copper Green
Cyclophosphamide
Doxorubicin Brown
Fluorouracil Brown
Fluoxetine Grey
Gold
Heroin Brown
Hormone replacement therapy Brown
Hydroxychloroquine Grey
Iron
Ketoconazole Brown
Lead Grey
Manganese
Mepacrine Blue
Methyldopa Black
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(Continued)
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392
Table22.11 (Continued)
Drug Pigmentation colour
Minocycline Blue, brown, black
Oral contraceptives Brown
Phenolphthalein Brown
Phenothiazines
Propranolol Brown
Quinacrine
Quinidine Blue
Silver Blue, Grey
Sulphasalazine Blue
Thallium
Tin Grey
Vanadium
Zidovudine Brown
Zinc Grey
Source: Scully etal.(33)/with permission of International & American
Associations for Dental Research.
22.3.9 Drug- Induced Gingival Enlargement
Drug- induced gingival enlargement is a well- documented adverse effect of certain medications(60).
Many of these drugs are broadly categorised into three groups: calcium channel blockers,
anticonvulsants and immunosuppressants(61).
This reaction is thought to occur in genetically susceptible patients in the presence of dental
plaque or gingival inflammation(62), with painless overgrowth of both epithelium and connective
tissues developing between one and three months after treatment has been instigated. The most
common appearance is generalised fibrotic enlargement of the interdental papilla, usually affecting the anterior teeth before the posterior teeth. The hyperplastic tissue may encroach on the teeth,
making oral hygiene difficult. The severity of the enlargement is proportionate to the duration of
therapy, the drug dose, as well as the amount of bacterial plaque build- up.
The pathophysiology of drug- induced gingival enlargement appears to be common amongst
these three categories of drugs, with the key feature being inhibition of cation influx (particularly sodium and calcium) into cells. The decrease of cation- dependent folic acid active transport within gingival fibroblasts results in a reduction of folic acid uptake by the cells. This
alters matrix metalloproteinase metabolism and causes an inability to activate collagenase.
This relative lack of collagenase results in increased accumulation of connective tissue and
collagen(62).
Drugs most commonly associated with this type of reaction are listed in Table22.12.
Management of drug- induced gingival enlargement entails conservative measures such as
consideration of altering the drug regimen and adequate plaque control in the first instance. In
some cases, surgical debulking of the affected tissue may be indicated to facilitate oral hygiene
or improve cosmesis.
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22.4 Hard Tissue Involvement
Table22.12 Drugs commonly associated withgingival enlargement.
Calcium channel blockers Amlodipine
Diltiazem
Felodipine
Lacidipine
Nifedipine
Verapamil
Anticonvulsants Phenytoin
Immunosuppressants Cyclosporin
Source: Scully etal.(33)/with permission of International & American
Associations for Dental Research.
22.4 Hard Tissue Involvement
22.4.1 Medication- Related Osteonecrosis of the Jaws (MRONJ)
Medication- related osteonecrosis of the jaws (MRONJ) is a well- documented adverse effect associated with various bone modifying (such as bisphosphonates) and antiangiogenic drugs. These
medications are commonly used to manage osteoporosis or malignancy. Drugs commonly associated with MRONJ are listed in Table22.13.
The diagnosis of MRONJ requires:
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1) Previous or current treatment with a bone- modifying agent or angiogenesis inhibitor;
2) Exposed bone or bone that can be probed through an intra- oral or extra- oral fistula in the maxil-
lofacial region that has persisted for longer than eight weeks; and
3) No history of radiation therapy of the jaws or metastatic disease of the jaws(64).
The pathogenesis of MRONJ is not clear; however, there are several hypotheses, which are as
follows:
Unique jaw characteristics:
Medications implicated in MRONJ affect osteoclastic function within the entire skeletal system,
and it is thought that several characteristics that are unique to the jaw bones predispose them to
this condition.
● High calcium concentration in the mandible, increasing the absorption of bisphosphonates
compared with other bones(65).
● Relationship between the teeth and the jawbone provides a route of entry for microorganisms
from the oral cavity.
● A major risk factor for the development of MRONJ is tooth extraction or dentoalveolar
surgery(65).
● Bisphosphonates have been found to be more effective on craniofacial bone cells than elsewhere
in the body(66).
● Mandibular mesenchymal stem cells proliferate at a higher rate than other bone stem cells(67).
● Bisphosphonates induce reactive oxygen species production, which in turn inhibit proliferation
and migration of oral fibroblasts(68).
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394
Table22.13 Drugs commonly associated withMRONJ.
Drug class Examples Indications
Bisphosphonates Oral–alendronate
and risedronate
Intravenous–
Zoledronate
Monoclonal
antibodies
Denosumab
Bevacizumab
Adalimumab
Osteoporosis, osteopenia, Paget’s disease,
hypercalcaemia of malignancy, skeletal- related
events of malignancy, bone metastases, multiple
myeloma.
Osteoporosis, rheumatoid arthritis, psoriatic
arthritis, ankylosing spondylitis, inflammatory
bowel disease.
Infliximab
Rituximab
Romosozumab
Tyrosine kinase
inhibitors
Sunitinib
Imatinib
Sorafenib
Haematological malignancy, renal cell carcinomas,
gastrointestinal stromal tumours, soft tissue
sarcomas, neuroendocrine tumours.
Panzopanib
Axitinib
Regorafenib
Cabozantanib
Mammalian target of
rapamycin inhibitors
Variant fusion
proteins
Disease- modifying
anti- rheumatic drugs
Everolimus
Temsirolimus
Aflibercept
Etanercept
Renal cell cancer, neuroendocrine cancer, breast
cancer, lymphoma, solid organ transplantation.
Renal cell carcinoma, macular degeneration,
macular oedema.
Methotrexate Rheumatoid arthritis, psoriatic arthritis,
inflammatory bowel disease.
Corticosteroids Prednisolone Numerous
Source: Adapted from King etal.(63).
Osteoblasts and osteoclast balance alteration in bone remodelling:
● Bisphosphonate medications can increase apoptosis of osteoclasts. Antiresorptive medications
may inhibit differential and function of osteoclasts. These changes may lead to a reduction in
bone resorption and remodelling(69).
● Jaw osteoclasts are more sensitive to drugs implicated in MRONJ compared to osteoclasts in
long bones.
● High levels of bisphosphonate accumulation in the bones impact the survival of osteoblasts and
their precursor cells(70).
● RANK ligand inhibitors (e.g. denosumab) decrease bone resorption by blocking RANK/RANKL
interaction. The overall effect is inhibition of osteoclastic activity and reduction in the bone
turnover(71).
Infection and the immune response:
● Oral infections, including dental caries, periodontal disease, and periapical infections, increase
the risk of patients developing MRONJ(72, 73).
● Dental extraction in areas of periodontal or periapical infection increases the risk of developing
MRONJ(74).
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22.4 Hard Tissue Involvement
● pH changes due to dentoalveolar infection or inflammation have been associated with develop-
ment of MRONJ(75).
● Some nitrogen- containing bisphosphonates have been shown to impair neutrophil activity and
thus normal wound healing. Macrophages have also been shown to have reduced viability when
exposed to these drugs(76, 77)
● RANK ligand inhibitors have been shown to alter the function and survival of macrophages and
monocytes(78).
Angiogenesis:
● Zoledronic acid has an inhibitory effect on angiogenesis, thus impairing healing after an oral
surgical procedure(79).
● Antiangiogenic medications used to prevent cancer metastasis may result in ischaemia and pre-
dispose patients to MRONJ(80).
Soft tissue toxicity:
● Several medications implicated in MRONK have been shown to inhibit oral fibroblasts and are
thought to predispose patients to mucosal breakdown and impaired wound healing(68).
Other factors:
● Medical comorbidities and genetic factors are also thought to play a role in the pathogenesis of
MRONJ(81, 82).
395
Clinical staging has been used to categorise patients with MRONJ, ranging from no clinical
evidence of necrotic bone but present with non- specific symptoms or clinical and radiographic
findings (stage 0) to exposed and necrotic bone or a fistula that probes to bone in patients with
pain, infection and one or more of the following: exposed necrotic bone extending beyond the
region of alveolar bone, pathologic fracture, extraoral fistula, oral antral/oral nasal communication, osteolysis extending to the inferior border of the mandible or sinus floor (stage 3).
Management ranges from conservative measures to extensive surgical intervention.
22.4.2 Tetracycline Staining
Tetracycline and its derivatives are well documented to cause intrinsic staining of dental hard tissues due to their affinity for calcified tissues. This results in binding of the drug to calcium, forming tetracycline–calcium orthophosphate complex. The quicker the rate of mineralisation of the
tissues, the more tetracycline is deposited(83).
Tetracycline- stained calcified tissues exhibit yellow fluorescence when exposed to UV light.
Minocycline has been associated with pigmentation of a number of tissues including skin, nails,
teeth, bone, thyroid, sclera, conjunctiva and tongue. Affected calcified tissues do not fluoresce under
UV light. Bone pigmentation is most noticeable beneath the alveolar mucosa of the maxilla and
mandible, as well as the hard palate, with the incidence rising with prolonged exposure of thedrug.
Up to 10% of patients taking this medication for over 12months develop black bone pigmentation
in the oral cavity. The incidence rises to up to 20% after four years of continued exposure(83, 84).
Intrinsic discolouration and enamel hypoplasia of primary and permanent teeth occur if exposure
to tetracycline occurs during tooth development. This can occur during utero as tetracycline may
cross the placental barrier. The amount of tetracycline deposited in tooth substance depends on the
dosage, duration of therapy and stage of tooth development. The distribution of tooth discolouration
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396
corresponds with the stage of tooth development at the time of exposure. It is permanent, varying
from yellow to grey or brown. Once the tooth has erupted and is exposed to light, the discolouration
changes slowly from a fluorescent yellow to a non- fluorescent brown as a result of a light- induced
oxidation product of tetracycline. Minocycline tooth staining appears as a band- like blue–grey
discolouration of the tooth crown and a green or black appearance of the roots of the teeth.
There are three theories of the pathophysiology of minocycline discolouration, which are as
follows(85, 86):
1) Iron theory– Minocycline is absorbed from the gastrointestinal tract, chelating with iron to
form insoluble complexes which is thought to incite tooth discolouration.
2) Extrinsic theory–Minocycline is excreted in the gingival fluid in high concentrations and may
mineralise enamel. This allows the drug to discolour the enamel by diffusing through the pulp
or affecting tooth development.
3) Intrinsic theory– Minocycline is bound to plasma proteins during absorption and then distrib-
uted to various body tissues. Tooth dentine, cementum, pulp and alveolar bone, by virtue of
their high collagen content, have an affinity for minocycline, which then undergoes oxidisation
and transformation to a pigmented metabolite.
Tetracycline and minocycline- induced tooth discolouration is permanent, and when the
secondary dentition is affected, there maybe aesthetic and psychological concerns for which
patients may seek dental advice.
22.5 Non- specific Reactions
22.5.1 Drug- Induced Taste Disorders (DITD)
Disturbance of taste has been reported to be associated with a large number of commonly
prescribed medications. The precise pathophysiology of DITD is not completely understood, and
there may be various between individuals which may be a result of polypharmacy, differences in
dosage and genetic factors(87, 88).
A number of drugs have been reported to cause a metallic or bitter taste. These medications
affect the taste buds after oral exposure, by dissolution in the saliva, gastrointestinal absorption or
intravenous administration, or by accumulation within the taste buds when used over a protracted
period of time. DITD may occur months–years after the initial exposure.
Some drugs are known to affect smell and taste signals for salt and sweet, resulting in the
perception of a bitter or sour taste(88).
Drugs that affect the quantity and quality of saliva may also induce taste changes. Taste receptor cells
are protected by saliva in the oral cavity, with this acting as a solvent and transport medium for taste
substances(89). Many drugs that are known to cause oral dryness are also associated with DITD.
Drugs commonly associated with DITD are listed in Table22.14.
22.5.2 Drug- Related Halitosis
Drug- related halitosis has been reported to occur with a number of drugs including dimethyl
sulfoxide, nitrates and nitrites, and penicillamine(87, 90, 91). Drugs commonly associated with
halitosis are listed in Table22.15.
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22.5 Non-specific Reactions
Table22.14 Drugs implicated intaste disorders.
Acarbose Acetazolamide Allopurinol Amiloride Amitriptyline
Amphetamines Amphotericin Amrinone Aspirin Atorvastatin
Auranofin Aurothiomalate Azathioprine Azelastine Aztreonam
Baclofen Biguanides Bleomycin Bretylium Calcitonin
Captopril Carbamazepine Carbimazole Carboplatin Cetirizine
Cephamandole Chlormezanone Cisplatin Clarithromycin Clidinium
Clofibrate Clomipramine Cocaine Diazoxide Dicyclomine
Diltiazem Dipyridamole Enalapril Ethambutol Ethionamide
Etidronate Fluoxetine Flurazepam 5- Fluorouracil Fluvoxamine
Glycopyrrolate Griseofulvin Hydrochlorothiazide Hydrocortisone Indomethacin
Interferon gamma Iodine Isotretinoin L- dopa Levamisole
Levodopa Lincomycin Lisinopril Lithium Losartan
Lovastatin Methotrexate Methylthiouracil Metronidazole Nifedipine
Nitroglycerin Omeprazole Penicillamine Pentamidine Phenformin
Phenindione Phenylbutazone Phenytoin Procaine penicillin Propafenone
Propranolol Propylthiouracil Quinapril Ramipril Rifabutin
Rivastigmine Selegiline Sodium lauryl sulphate Spironolactone Sulfasalazine
Terbinafine Tetracycline Thiamazole Tocainide Topiramate
Trandolapril Triazolam Venlafaxine Zopiclone
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Source: Scully etal.(33)/with permission of International & American Associations for Dental Research.
Table22.15 Drugs commonly associated withhalitosis.
Chloral hydrate Paraldehyde
Cysteamine Penicillamine (penicillin)
Dimethyl sulfoxide 3 Phenothiazine
Disulfiram Suplatast tosilate
Nitrates and nitrites (isosorbide dinitrate)
Source: Adapted from Torzten etal.(90).
Dimethyl sulfoxide may cause a garlic- like odour and taste in the mouth. This is transported
from the blood into the alveolar air, then into the breath(92).
Drugs containing nitrates are reduced to nitrites by anaerobic bacteria residing in the crypts at
the tongue base in the process of respiration. Further reduction to nitric oxide and reaction with
foul- smelling volatile organosulfur compounds contribute to halitosis(93, 94).
Penicillamine, a degradation product of penicillin, is structurally similar to the sulphurcontaining amino acid cysteine. Both penicillamine and cysteine can be degraded by microbes
within the biofilm on the tongue, with this reaction raising the pH and favouring growth of
Gram- negative bacteria. Enzymes such as serine protease, which is involved in the putrefaction
process, are activated and contribute to halitosis(95).
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