ADVERSE DRUG REACTIONS OF ORAL CAVITY

ADVERSE DRUG REACTION

An appreciably harmful or unpleasant reaction, resulting from an intervention related to the use of a medicinal product, which predicts hazard from future administration and warrants prevention or specific treatment, or alteration of the dosage regimen, or withdrawal of the product

Edwards and Aronson 2000

ADVERSE DRUG REACTION

“Adverse drug event” includes

(1) harm caused by a drug (commonly

known as adverse drug reaction)

(2) harm caused by appropriate drug use

(usually referred to as a side effect)

(3) medication errors

BURDEN OF ADR

DRUG INDUCED ORAL REACTIONS

Hyposalivation/ hypersalivation Lichenoid reactions/lichen planus Apthous like ulcers Bullous disorders Pigmentation Fibrovascular hyperplasia Keratosis/epithelial hyperplasia Dysesthesia Osteonecrosis of jaw Infection Angioedema Malignancy

HYPOSALIVATION/XEROSTOMIA

Dry mouth is listed as an adverse effect for over 500 medications-Femiano etal 2011

The most frequently reported medication classes are

1. Antidepressants2. Antipsychotics3. Antihistamines4. Muscarinic receptor and a-receptor antagonists5. Antihypertensives (e.g., diuretics, b-blockers,

and angiotensin-converting enzyme [ACE] inhibitors)

6. Bronchodilators7. Skeletal muscle relaxants.

PERSISTENT HYPOSALIVATION CAUSES

SIALADENITIS

DENTAL CARIES

GLOSSO DYNIAGLOSSOPYROSIS

SIALORRHOEA Increased saliva Droling Increased swallowing Drugs responsible-

Alprazolam Xanax AmiodaroneClozapine Digoxin Galantamine Lamotrigine Levodopa Nifedipine

LICHENOID REACTION/ LICHEN PLANUSOral lichen planus (OLP) is a chronic

inflammatory disease that affects the mucus membrane of the oral cavity. It is a T-cell mediated autoimmune disease in which the cytotoxic CD8+ T cells trigger apoptosis of the basal cells of the oral epithelium.

Oral LP presents as white striations or papules often associated with erythema or erosion and ulcers, most commonly in a bilaterally symmetric manner, often on the buccal mucosa, tongue, and gingiva.

PATHOGENESIS OF OLPKeratinocyte antigen expression or unmasking of an antigen

 T cells (mostly CD8+, and some CD4+ cells) migrate into the epithelium

 Migrated CD8+ cells are activated directly by antigen binding to major histocompatibility complex (MHC)-1 on keratinocyte 

Subsequent antigen presentation to CD4+ cells and Interleukin (IL)-12 activates CD4 + T helper cells which activate CD8+ T cells through receptor interaction, interferon γ (INF - γ) and IL-2

Wickham striae

LICHENOID HYPERSENSITIVITY REACTIONS The two classes of medications

historically associated with oral LHRs are

Nonsteroidal anti-inflammatory drugs (NSAIDs) and antihypertensive agents

Sulfonylurea antidiabetic medications (e.g., tolbutamide and glipizide)

Antifungals (e.g., ketoconazole)

Anticonvulsants (e.g.carbamazepine)

Immunomodulatory drugs (e.g. gold salts and penicillamine)

Sulfasalazine Allopurinol, and lithium have

been reported to elicit oral LHRs

Fixed drug eruptions (FDEs) in the oral cavity are lesions that recur at the same site each time the offending medication is taken

The presentation can range from bullous to erosive, hyperpigmented, pruitic, or erythematous lesions

First and second generation antihistamines are known to cause FDE

Fluconazole has caused lesions of the palatal mucosa and oral bullae

Naproxen and oxicams have caused lesions on the lips

APTHOUS LIKE ULCERS

ovoid to round ulcers usually 1 cm or less with a yellowish fibrinous membrane and surrounding erythema

NSAIDs were one of the earliest classes of drugs

associated with the development of aphthous-like

ulcers in the oral cavity

Piroxicam, in particular, was shown to cause such

ulcers

Naproxen,trimethoprim-sulfamethoxazole,

cyclooxygenase-2 inhibitors (e.g., refecoxib), and the

angiotensin receptor blocker losartan have been

implicated in the development of aphthous like

ulcers

5-fluorouracil CisplatinMethotrexate Hydroxyurea,

Stomatotoxic drugs

BULLOUS DISORDERSThe development of simultaneous oral and

cutaneous pemphigus vulgaris has been noted with the use of thiol radicale containing drugs, such as penicillamine and NSAIDs

Erythema multiforme (EM), major or minor, can affect both the skin and mucous membranes

EM of the skin and oral mucous membranes has been reported with the administration of infliximab and adalimumab

EM due to intake of diclofenac sodium

SJS and TEN almost always involve the mucous membranes of the mouth, eye, and genitalia, sometimes extensively

pigmentationMetabolites of such medications as the

tetracyclines, minocyclines, antimalarial drugs and phenazine dyes (e.g., clofazimine) may be deposited in the oral mucosa

Drug metabolites chelate with

Iron and melanin

pigmentation

Tetracycline stains

Zidovudine pigmentation

Drugs implicated in pigmentationTetracycline, minocycline

Imatinab

Zidovudine

Oral contraceptives

Chemotherapy agents

Antimalarials

Fibrovascular hyperplasiaCalcium channel blockers, in particular,

nifedipine and amlodipine, are antihypertensive agents that induce hyperplasia of the gingival tissue

Decreased cellular folic acid

Decreased activity of MMP

Failure to activate collagenase

Suggested mechanism

Gingival enlargement

Nifidipine induced Cyclosporin induced

Phenytoin induced

Dysesthesia

Oral dysesthesias,such as sensitivity, burning, dysgeusia, and other altered sensations without clinical signs, may be caused by medications

Salivary gland dysfunction

Low production of saliva

No solution for binding of chemoreceptors on taste buds over the tongue

Drugs causing Dysesthesia

Macrolides-such as clarithromycin (17%); antimycotics,-such as terbinafine (9%)

Fluoroquinolones (8%), Protein kinase inhibitors, ACE-inhibitors, Statins, Proton pump inhibitors

STOMATITIS WITH BMS

AGEUSIA-LOSS OF TASTE

Amitriptyline Angiotensin II Receptor

Blockers Aspirin Atorvastatin Clopidigral Enalapril Fluoxetine Indomethacin Phenytoin Spironolactone

DYSGEUSIA- TASTE DISTURBANCE

ACE Inhibitors Allopurinol

Alprazolam Aspirin Atorvastatin Baclofen Benztropine Diclofenac Cardizem

OSTEONECROSIS OF THE JAWBisphosphonates and denosumab are

antiresorptive medications that markedly slow bone turnover and remodeling and therefore increase bone density

Used to treat postmenopausal osteoporosis and reduce skeletal-related events during cancer therapy

Osteonecrosis is an ADE presenting as either exposed bone or a nonhealing extraction socket

Bisphosphonate induced osteonecrosis

INFECTION

psuedomembranous candidiasis in immunosuppresant therapy

Herpes simplex - methotrexate

omeprazoleinhaled steroidsolanzapine

CANDIDIASIS

BLACK HAIRY TONGUE

Amitriptyline Cephalosporins

Clarithromycin Corticosteroids Prednisone

Clonazepam Lansoprazole Methyldopa Nortriptyline Penicillins

ANGULAR CHELITIS

Atorvastatin Methyldopa Prochlorperazine Simvastatin Sulfasalazine Tetracyclines Vitamin A

AngioedemaAntihypertensive

agents, such as angiotensin receptor blockers

Calcium channel blockers, hydrochlorothiazide

Antiplatelet agents, such as thienopyridine and clopidogrel

Abrupt-onset swelling of the orofacial region and lips can compromise the airway and be life-threatening.

MALIGNANCYA number of chemotherapy and

immunomodulating agents have been shown to increase the risk of lymphoproliferative disorders and neoplasms

Squamous cell carcinoma may develop in patients with oral LP treated with tacrolimus ointment

The issue of drug-induced malignancy is still controversial, and it is difficult to remove confounding factors from studies that show an association

Identification of the underlying pathogenesis of an ADR together with the severity of the reaction will have profound implications on continuation of drug therapy after an ADR

However, because the majority of ADRs is dose-dependent and therefore preventable, individualization of pharmacotherapy may have a major impact on reducing such events

ther umsch 2000