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Oral manifestation of Systemic Drugs

Many commonly prescribed medications are capable of causing adverse drug reactions. It is important for the dentist to have knowledge about these reactions to arrive at a proper diagnosis.

Effects of Drugs on Oral Mucosa and Tongue

Oral mucosal membranes may be the sole site of involvement or they may be a part of a more generalised skin reaction to the offending drug. The main type of hypersensitivity reaction that affects oral mucosa is a delayed reaction mediated by sensitized T- lymphocyte. Stomatitis medicamentosa or fixed drug eruption, occurs with systemic drug usage and stomatitis venenata appears with contact hypersensitivity. Lesions associated with fixed drug eruption are erythematous in mild cases and appear ulcerated in severe cases. The reactions usually appear in 24 hours post- ingestion of the drug. Delayed reaction (up to two weeks) has been noted after use of ampicillin. Withdrawal of the causative drug results in resolution of the lesions.

Compounds with potential to cause Fixed drug eruptions
Barbiturates Lidocaine
Chlorhexidine Penicillinamine
Gold Salicylates
Indomethacin Sulphonamides

Contact stomatitis

Contact stomatitis is a local reaction of the mucosa after repeated contact with the causative agent. Reactions can be seen as erythematous to ulcerative lesions. The patient may complain of a burning sensation in the mouth together with xerostomia. The reaction may develop from days to years post-exposure to the causative agent.

Compounds with potential to cause Contact stomatitis
Antibiotics Iodine
Antiseptic lozenges Topical anaesthesia
Chewing gums Topical steroids
Dental materials (amalgam, steel wires, berylium, platinium and acrylic compounds)

Aphthous Stomatitis

Aphthous stomatitis (canker sores) is commonly observed and is mediated by the immune system. Lesions usually appear as painful, tiny, discrete or grouped papules and vesicles. These lesions are small in diameter with round, shallow ulcerations predominantly seen over the labial and buccal mucosa. The reactions heal without scarring in 10-14 days, however, recurrence is common.

Drugs with potential to cause Aphthous stomatitis
Azathiopurine Interferons
Losartan Penicillinamine
Captopril Sulphonamides
Fluoxetine NSAIDs
Indinavir Gold compounds
Olanzepine Sertraline

Burning Mouth Syndrome

This syndrome may occur due to psychogenic factors, hormonal withdrawal, folate, iron, pyridoxine deficiency or hypersensitivity reactions to the materials utilised in dental prosthesis. The mechanism of ACE-inhibitor “scalded mouth” is uncertain, but it may be a subclinical manifestation of lichen planus.


Glossitis is inflammation of the tongue that is characterised by swelling and intense pain that may be referred to the ear area. Salivation, fever and enlarged regional lymph nodes may develop during an infectious disease or after a burn or other injury.

Drugs with potential to cause Glossitis
Atrovastatin Etidronate Olanzepine
Benzodiazepines Fluoxetine Penicillinamine
Captopril Fluvoxamine Penicillin
Chlorhexidine Gabapentin Rivastigmine
Cyclosporine Gold Sulfonamides
Chloramphenicol Imipenem Sertaraline
Cephalosporines Mefenemic acid Tacrine
Clarithromycin Metronidazole Tetracycline
Enalapril Methotrxate Triamterene
Doxepin Mercaptopurine Tricyclic antidepressants
NSAID's Venlafaxine

Erythema Multiforme (Stevens–Johnson Syndrome)

Erythema muultiforme, in severe cases termed as Stevens–Johnson Syndrome, is a mucocutaneous disorder characterised by various clinical types of lesions. Young male adults are predominantly affected. The lips are swollen, crusted and bleed. Widespread erythema can be seen within the mouth. The oral lesions disappear within 14 days of drug withdrawal. Only 4% of erythema reactions are caused by drugs, however, 80% of cases occur in Stevens– Johnson Syndrome.

Drugs with potential to cause Erythema multiforme
Allopurinol Ginseng Phenytoin
Barbiturates Gold Rifampicil
Carbamazepine Iodine containing mouthwash Tetracycline
Chlorpropamide Sulphonamides Tolbutamide
Clindamycin Minoxidil Verapamil
Combination of antimalarial drugs Penicillin NASIDs
Estrogens/Progestins Penicillinamine
Ethambutol Phenothiazines

Oral Ulceration

A number of chemicals used by dental surgeons can cause “burns” of the oral mucosa, i.e. trichloroacetic acid used in the treatment of pericoronitis.

Drugs with potential to cause Local irritation of the mouth
Anticancer drugs Isoproterenol Tetracycline
Aspirin Lithium Tooth ache solution (menthol, phenol, clove oil)
Cocaine NSAIDs
Ergotamine tartarate Pancreatin
Hydrogen peroxide Paraquat
Drugs with potential to cause Oral ulceration
Alendronate Enalapril Mitomycin
Alprozolam Erythromycin Naproxen
Allopurinol Flucanazole Penicillinamine
Atrovastatin Fluoxetine Penicillin
Azathiopurine Ganciclovir Phenytoin
Barbiturates Gold compounds Promethazine
Bleomycin Hydralazine Propanolol
Captopril Hydroxyurea Propylthiouracil
Chlorambucil Ibuprofen Ritonavir
Chloramphenicol Imipramine Saquinavir
Chloroquine Indomethacin Streptomycin
Cisplatin Lamotrigine Sulfonamides
Chlorpromazine Levamisol Tetracycline
Cloofibrate Lithium Terbutaline
Clonazepam Melphalan Vincristine
Codeine Methimazole Warfarin
Cyclosporine Metronidazole Zidovudine
Doxorubicin Methotrxate

Vesiculo–Bullous Lesions

The exact mechanism of this reaction is unclear, but it seems to be the consequence of a direct irritant effect. Patients using steroid inhalers for more than 5 years are more prone to the development of oral blistering. This type of reaction has also been reported for naproxen and penicillamine.

Lichenoid Eruptions

Unlike true lichen planus, drug-induced lichenoid eruptions disappear after drug withdrawal. Lichenoid drug eruptions rarely affect the buccal mucosa. A characteristic white lace pattern may be present. It is thought that drugs causing lichenoid reactions only uncover the latent disease of lichen planus or amplify a previous disorder, rather than inducing the disease de novo.

Drugs with potential to cause Lichenoid reactions
Allopurinol Methyldopa
ACE inhibitors NSAIDs
Arsenic compounds Penicillinamine
Beta-blockers Phenothiazines
Bismuth Propanolol
Chloroquine Quinidine
Chlorpropamide Streptomycin
Furosemide Tetracycline
Gold compounds Thiazides
Hyroxychloroquine Tolbutamide
Lithium Mercury

Colour Changes of Oral Mucosa and Teeth

Discolouration can occur after direct contact with or following systemic absorption of a drug. Historically, exposure to metals like silver, bismuth, gold, lead, mercury, zinc and copper were the main causative agents of tissue discolouration. Colour changes are typically seen along the gingival margins and are caused by the formation of metallic sulphides as a result of reactions with plaque products in gingival pockets.

Drugs and chemicals with potential to cause Oral pigmentation
Drug/Chemical Colour Site
Amalgam grey gingiva
Amalgam brown tongue
Amodiaquine black-brown palate
Arsenic brown tongue
Aspirin white gingiva/mucosa
Bismuth blue-grey and  blue- black/brown gum lines/ mucosa/ tongue
Bromine brown tongue
Chlorhexidine white tongue
Copper salts blue-green gum lines
Gold purple gingiva
Iron slate grey to brown palate/ gingiva
Chloroquine blue-grey hard palate/ lip/ gingiva
Oral contraceptives dark brown mucosa
Methyl dopa darkening tongue
Phenothiazines blue-grey mucosa
Silver salts grey gingiva
Zidovudine dark lip/gingiva/tongue/soft palate
Drugs and chemicals with potential to cause Discoloration of teeth
Drug/Chemical Colour
Cadmium yellow ring
Chlorhexidine yellow-brown
Chlortetracycline grey-brown
Ciprofloxacin green
Copper salts green
Other tetracycline brown-yellow
Oxy tetracycline yellow
Tetracycline yellow
Tobacco yellow-brown
Iron+ tea brown
Minocycline grey-black

Black Hairy Tongue (Lingua villosa nigra)

In this condition there is an elongation of the filiform papillae of the tongue to form hair-like overgrowth that becomes stained brown or black due to proliferation of chromogenic microorganisms. Black hairy tongue can be seen with the administration of oral antibiotics, poor dental hygiene and excessive smoking in adults.

Drugs and chemicals with potential to cause Black tongue
Amitriptyline Griseofluvin
Benzotropine Methyl dopa
Cephalosporins Lansoprazole
Chloramphenicol Streptomycin
Clarithromycin Sulfonamides
Clonazepam Tetracyclines
Corticosteroids Tobacco

Postmortem Pink–Red Coloration

Tooth colouration of this nature is due to hemolysis and exudation of hemoglobin to dental pulp and is enhanced in the presence of moisture and increased venous pressure. Specific conditions of death associated with this phenomenon include drowning, aspiration pneumonitis and suffocation. Overdoses with barbiturates and carbon monoxide also demonstrate similar findings.

Effects of Drugs on Gingiva and Salivary glands

Drug Induced Gingival Hyperplasia

The growth starts as a painless, beadlike enlargement of the interdental papilla and extends to the facial and lingual gingival margin. The enlargement is usually generalised throughout the mouth but is more severe in the maxillary and mandibular anterior regions. Plaque removal and good oral hygiene may benefit in a fast recovery and limits the severity of the lesion but the lesion does not get completely cured. It is hypothesized that in noninflamed gingiva, fibroblasts are less active or even quiescent and do not respond to circulating drugs; fibroblasts within inflamed tissue are in an active state as a result of inflammatory mediators and the endogenous growth factors.

Drugs  with potential to cause Gingival hyperplasia
Phenytoin Ketoconazole
Cyclosporine Phenobarbital
Nifedipine  Sodium valproate
Amlodipine Primidone
Diltiazem Topiramate
Nitrendipine Ethosuximide
Cotrimoxazole  Erythromycin

Salivary Glands

The salivary glands are under control of the autonomic nervous system, mainly the parasympathetic division. Salivary gland function can be affected by a variety of drugs that can produce xerostomia.

Altered salivary flow rate and levels of secretory proteins or enzymes may cause destructive effects on oral and dental health and wound healing. Systemic drug therapy can also produce pain and swelling of the salivary glands.

Drugs  with potential to cause Gingival hyperplasia
Phenytoin Ketoconazole
Cyclosporine Phenobarbital
Nifedipine  Sodium valproate
Amlodipine Primidone
Diltiazem Topiramate
Nitrendipine Ethosuximide
Cotrimoxazole  Erythromycin
Drugs and chemicals with potential to cause Dryness of mouth
Amphetamine  Omeprazole
Anticholinergics  Ondansetron
Antihistamines Thiabendazole
Antineoplastic drugs Tramadol
Anti-HIV Protease inhibitors Tricyclic antidepressants
Drugs that can cause Sialorrhea
Alprazolam Levodopa
Amiodarone  Mefenemic acid
Bethanechol Niridazole
Diazoxise Pilocarpine
Edrophonium  Risperidone
Gentamycin Rivastigmine
Imipenem Succinyl choline
Iodides Tobramycin
Kanamycin  Venlafexine
Ketamine Zaleplon
Drugs that have potential to cause Swelling and/or pain in salivary gland
Bretylium Naproxen
Catecholamine inhalation  Nifedipine
Chlorhexidine  Nitrofuratoin
Cimetidine  Phenytoin
Clonidine Ranitidine
Doxycycline Sulfonamides
Famotidine  Warfarin
Methyl dopa

Muscular and Neurological Disorders and Taste Disturbance

Drugs reported to cause sensation of Numbness, tingling or burning in the face or mouth
Acetazolamide Nicotinic acid
Amitriptyline Nitrofurantoin
Chlorpropamide  Pentamidine
Ergotamine Polymixin B
Gonadotropin releasing hormone analouges  Propanolol
Isoniaszid Streptomycin
Nalidixic acid Tolbutamide

Taste Disturbance

Many drugs induce abnormalities of taste by processes not yet fully understood. The alteration in taste may be simply a blunting or decreased sensitivity in taste perception (hypogeusia), a total loss of the ability to taste (ageusia) or a distortion in perception of the correct taste of a substance for example, sour or sweet (dysgeusia). A wide range of drugs give rise to dysgeusia or hypogeusia either by interfering in chemical composition or flow of saliva or more specifically, affecting taste receptor function or signal transduction. Sulfhydryl compounds are a common cause of taste disturbance. Drugs with the potential for affecting taste are listed below.

Drugs with the potential to cause Aguesia
Acarbose Cocaine  Losartan
Acetazolamide Diaoxide  Methimazole
Amitriptyline Dicyclomine  Penicillamine
Aspirin Enalapril  Pentamidine
Atrovostatin Etidronate  Phenytoin
Captopril Fluoxetine Propythiouracil
Ceftrizine  Fluvoxamine Rifambutin
Clomipramine  Indomethacin Ritonavir
Levadopa  Rivastigmine Spironolactone
Sulfadoxine  Topiramate
Drugs with the potential to cause Dysguesia
Acetazolamide Diclofenac  Lisinopril Tacrine
Acetaminophen  Dicyclomine Lovastatin Terbutaline
Acyclovir  Diltiazam Losartan Timolol
Amitriptyline Dihydroergotamine Metformin Tolazamide
Alprozolam Dipyridamole  Methamphetamine Topiramate
Albuterol  Donepezil Methimazole Tramadol
Amiodarone Doxycycline Methotrexate  Triamterene
Amoxicillin  Enalapril Metaprolol Ursdiol
Aspirin  Etidronate Metronidazole Vancomycin
Atrovostatin  Famotidine Midazolam Vinblastine
Atropine  sulfate Fentanyl Minoxidil Venlafexine
Baclofen  Fluorouracil Nifedipine Vincristine
Benztropine  Fenfluramine Ofloxacin Zidovudine
Busulfan  Fluconazole Omeprazole
Calcitonin  Flurazepam Penicillinamine
Captopril  Fluvastin Penicillin
Cephalosporinse  Gancyclovir Pentazocine
Celecoxib  Griseofluvin Pergolide
Chlorhexidine  Hydrochlorthiazide Pilocarine
Chlorthiazide  Hydrochloroquinine Propanolol
Clarithromycin  Imipenem Propylthiouracil
Ciprofloxacin  Indinavir Procainamide
Clindamycin  Interferon Quinidine
Clofibrate  Ketoprofen Ranitidine
Clonazepam  Ketorolac Ribavirin
Clonidine  Labetolol Rivastigmine
Cotrimoxazole  Lamotrigine Saccharin
Cromolyn Lansoprazole  Sulfonamides
Dantrolene  Levasoda Sumatriptan

Oral Infections Induced or Aggravated by Drugs

Many types of systemic drug therapy can alter oral flora and therefore, predispose the mouth to bacterial or fungal infection. Drugs that have been implicated in this problem include corticosteroids, antimicrobials, anticancer drugs, immunosuppressive agents and oral contraceptives. Drugs causing xerostomia may also potentiate the initiation of oral infections.

Drugs with potential to cause Oral candidiasis
Cephalosporins  Olanzepine
Clarithromycin  Omeprazole
Ciprofloxacin  Penicillin
Griseofluvan  Riluzole
Mesalamine  Tacrolimus

Facial Edema/Angioedema

Facial edema is often a manifestation of drug induced hypersensitivity reactions and angiotensin converting enzyme inhibitors (ACEIs) are the most common cause. It seems that angioedema arises as a consequence of an alternation in bradykinin metabolism in susceptible patients. The most common ACEIs implicated in this reaction are captopril, lisinopril and enalapril. Angioedema usually occurs within hours or at most weeks after starting the ACEI and reverses within hours of stopping. However, it can develop after longterm therapy.

Drugs that can cause Facial edema
Adrenomimetic Bronchodilators Intravenous Clindamycin
Captopril Lisinopril
Enalapril Mianserin


Stomatodynia is pain in the mouth and can be a consequence of drug reactions.

Drugs with the potential to cause Stomatodynia
Benzotropine Triamterene
Griseofluvan Vitamin A
Lithium Potassium iodide


Cheilitis is an abnormal condition of the lips characterized by inflammation and cracking of the skin.

Drugs with the potential to cause Cheilitis
Atrovastatin Ritonavir
Clofazimine Saquinavir
Cyanocobalamine Streptomycin
Gold compound Sulfasalazine
Indinavir Tetracycline
Methyl dopa Vitamin A
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