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Authors: Richard Y. Wang, DO, FACEP, FACMT, Director, Division of Medical Toxicology, Rhode Island Hospital, Brown University School of Medicine; Daren D. Girard, MD, Department of Emergency Medicine, Rhode Island Hospital, Brown University School of Medicine; Alfred Aleguas, PharmD, College of Pharmacy, University of Rhode Island.
Peer Reviewers: Chuck Seamens, MD, FACEP, Assistant Professor of Emergency Medicine, Vanderbilt University Medical Center, Nashville, TN; and Stephen Ernest, PharmD, Retail Pharmacist, PharMor, Terre Haute, IN.
Recent advances in consumer marketing have fueled the creation of a proliferation of self-treatment products. These products, known as "over-the-counter" or OTC agents, include traditional remedies, new formulations, and combinations, as well as reduced-strength versions of prescription medications. Examples of OTC formulations of prescription drugs include cimetidine, nonsteroidal anti-inflammatory drugs (NSAIDs), and antihistamines.
In 1998, the American Association of Poison Control Centers Toxic Exposure Surveillance System (AAPCC TESS) registered more than 500,000 exposures to OTC formulations.1 (See Table 1.)
Table 1. Incidence of OTC Exposures in 19981
|OVER- THE- COUNTER PREPARATION||
Cosmetics and personal
Cough and cold formulations
Topicals (dermal, nasal, ocular,
oral, rectal, vaginal)
|Vitamins and iron supplements||
(antacids, antidiarrheals, laxatives)
While the majority of these produced no serious harm, some OTC exposures resulted in significant morbidity and mortality. (See Table 2.)
Table 2. OTC Agents with Reported Clinical Toxicity
|AGENT||OTC APPLICATION||CLINICAL MANIFESTATION|
|Acetaminophen||Analgesic, Antipyretic||Hepatic failure|
|Antihistamine (H1 receptor)
Altered mental status
Depressed mental status
naphazoline, oxymetazoline, Xylometazoline)
|Topical decongestant|| Depressed mental status
Alteration of blood pressure
aluminum, sodium bicarbonate)
|Iodine (Povidone-iodine)|| Antiseptic/Germicide
| Nausea, vomiting
Gastrointestinal tract burns
|Iron salts (e.g., ferrous sulfate, ferrous gluconate, etc.)||Mineral supplement||
Nausea, vomiting, abdominal pain
Decreased mental status
|Local anesthetics (benzocaine, dibucaine, dyclonine, lidocaine)||Topical analgesic||
Depressed mental status
Depressed mental status
|Nonsteroidal anti-inflammatory agents (ibuprofen, ketoprofen, naproxen)||
| Gastrointestinal distress
|Quartenary ammonium compounds (alkyldimehtylbenzylammonium chlorides)||Antiseptic/Germicide|| Nausea, vomiting
Gastrointestinal tract burns
Altered mental status
Mixed acid/base disorder
(ephedrine, psuedoephedrine, phenylephrine,
The recent withdrawal of phenylpropanolamine-containing flu remedies suggests increasing vigilance in review of OTC products to prevent toxicity. As a result, it is important that emergency health care providers be familiar with these agents so they can optimize care for their patients. With these issues in focus, this detailed review outlines the clinical manifestations and management of important OTC exposures caused by various routes of administration. Part I of this two-part series will review topical preparations.— The Editor
Dermatologic preparations include formulations of creams, ointments, gels, liquids, and aerosols; the principal difference among these products is the base or vehicle. Vehicles determine the rate of absorption at the site of action. Creams are water-in-oil emulsions and permit absorption into the subdermal and subcutaneous layers. Ointments are hydrophobic mixtures, usually hydrocarbon based (e.g., petrolatums), and are intended to remain at the site of application, with minimal absorption. Gels are water-based vehicles, allowing rapid dissolution and absorption.
Inadvertent ingestion of any of the vehicles may produce toxic effects similar to mild anionic and nonionic surfactants (e.g., soaps), which produce both emetic and laxative effects. Although toxicity is unusual during therapeutic use, applying these agents to large areas of abraded or denuded skin increases the amount of vehicle absorbed, as well as the potential for symptoms.2 Increasing absorption with occlusive dressings, repeat application, or application to a large percentage of body surface area also may lead to toxicity.
Rubefacients. Rubefacient preparations are intended to produce mild local irritation, creating an increase in blood flow, and subsequently, erythema. The result of this process is the sensation of warmth. Camphor and menthol combinations are traditional formulations that have been around for decades. (See Table 3.)
Table 3. Topical OTC Preparations and Their Ingredients
|OTC PREPARATION||ACTIVE AGENTS|
|Acne||Benzoyl peroxide, sulfur, salicylic acid|
Bacitracin, polymyxin B, neomycin,
Benzalkonium choride, benzoyl peroxide,
chlorhexidine, ethanol, povidine iodine,
salicylic acid, sulfur
|Local anesthetics||Benzocaine, tetracaine, dibucaine, lidocaine, pramoxine|
Lotions (e.g., sunscreens,
skin Softeners, scalp care)
|PABA, kaolin, lanolin, mineral oil|
Essential and volatile oils (e.g., camphor,
capsaicin, chamomile, eucalyptus, menthol, wormwood)
|Miscellaneous (diaper rash,
|Zinc oxide, calamine, local anesthetics, essential oils, diphenhydramine|
|DERMAL (LIQUIDS, POWDERS)|
|Antiperspirant||Aluminum chloride, talc|
|Antiseptics, Germicides||Iodide, inorganic mercury, quarternary ammonium chloride, chlorhexidine gluconate|
|Pediculocide, scabicide||Pyrethrin, piperonyl butoxide|
|VAGINAL AND RECTAL|
|Analgesics||Acetaminophen, local anesthetics, salicylate|
|Antifungal||Clotriamazole, miconazole, butoconazole|
A druggist’s handbook, circa 1877, identifies 10 different formulas using various combinations.3 Typically, camphor and menthol are mixed together to form an eutectic mixture that is then incorporated into a vehicle, commonly petrolatum. The concentrations of camphor and menthol range from 2% to 5% and 1% to 16%, respectively.4 Camphor is still available, however, in a solid, block form, usually in a 1-ounce size.4
Toxicity is characterized initially by gastrointestinal (GI) symptoms, including: nausea, vomiting, and abdominal distress. More significant exposures may demonstrate such central nervous system (CNS) effects as delirium, excitement, and seizures. Onset of symptoms usually occurs within 5-20 minutes and peaks within 90 minutes. Camphor is readily absorbed, and death has occurred from ingestion of as little as 1 gram.5
Menthol is the major constituent of peppermint oil. It also causes such gastrointestinal symptoms as nausea, vomiting, and abdominal pain. After a significant exposure (i.e., pure peppermint oil or a large ingestion of high concentration product), CNS effects, including ataxia, drowsiness, or coma, may be seen.6 Acute toxic effects from ingestion of small amounts are unlikely given the available formulations, but significant toxicity may occur with ingestion of even a small amount of either agent in its pure form. Trivial (a mouthful or less) ingestions of the combination forms are treated by dilution, in conjunction with observation for local oral and GI irritant effects.
Capsaicin. Another counter irritant ingredient approved for OTC use is capsaicin. Previously available in prescription strengths of 0.025% and 0.075%, it was converted to OTC status in 1990.7 Used in combination with camphor and menthol in 0.025% concentrations, capsaicin is derived from capsicum oleoresin, the irritant oil from the pepper plants of the Solanacae family. The clinical effects range from a feeling of warmth to burning, depending on the concentration applied.8 Ingestion of the agent causes nausea and vomiting secondary to gastric irritation. Treatment consists of dilution or irrigation; symptoms abate after 30-60 minutes.
Ingredients in various rubefacient products include eucalyptol, thymol, cajput oil, and turpentine. They are present in very low concentrations and their toxicity is limited to minor irritation in the amounts available.
Topical Analgesics. Topical analgesics are used for muscle or joint pain. Like rubefacients, these agents are counter irritants, stimulating circulation and a feeling of warmth. Topical analgesics usually contain methyl salicylate (e.g., oil of wintergreen), or other salt forms of salicylate (e.g., trolamine salicylate). Commonly used in combination with other ingredients, especially camphor and menthol, the concentration of methyl salicylate may be as high as 35%.9 Oil of wintergreen contains approximately 98 gm/100 mL of methyl salicylate, and the purified oil can be highly toxic; in fact, an ingestion of as little as 7 gm (7.5 mL) has produced significant morbidity in a 2-year-old child.10 Since methyl salicylate is the methyl ester form of salicylate, symptoms of salicylate intoxication can be seen with ingestion or chronic application of more concentrated products.
Keratolytics. Other formulations that use concentrated salicylates include the keratolytics. These agents produce desquamation of the skin and are used as wart and corn removers. These products contain salicylic acid in concentrations ranging from 17% to 40% in liquid, solution, gel, patch, plaster, and cream form. The creams utilize the higher concentrations, with the liquid, gel, and solution products limited to less than 30%.11 The liquid formulations commonly use flexible collodion (e.g., nitrocellulose) as a vehicle. These products can produce oral irritation, or potentially a burn if they have prolonged contact with skin. Nitrocellulose is water resistant and may cause adherence to mucus membranes. Due to the high concentrations of salicylate available in these OTC formulations, significant or chronic misuse can result in intoxication. Patient management includes monitoring serum salicylate levels, initiating urinary alkalinization, and hemodialysis, as would be indicated in salicylate poisoning.
Local Anesthetics. Topical anesthetics are used for local analgesia on intact dermis and to treat pruritic conditions such as insect bites, plant poisonings, eczema, and minor burns. These agents interrupt nerve impulse conduction by altering cell membrane ion flux, and as a result, produce an anesthetic effect. Most local anesthetic agents are poorly absorbed through intact dermis, but readily absorbed through the mucous membranes. Abraded skin augments the effectiveness of local anesthetics by increasing absorption. Anesthetic agents are classified according to their structure. Most agents belong to one of two classes: 1) benzoate esters; or 2) amides. Benzoate esters include benzocaine, tetracaine, and butamben picrate. The amides are dibucaine and lidocaine. Another topical anesthetic agent, pramoxine, is structurally unique.
Adverse effects of local anesthetics during therapeutic use include local irritation, burning, sloughing, interaction between other drugs, and hypersensitivity reactions.12,13 The toxicity of these agents affects the cardiovascular, neurologic, and hematologic systems. Cardiac dysrhythmias, seizures, and coma can be seen with severe toxicity. Additionally, benzocaine and lidocaine can produce methemoglobinemia.14
Lidocaine is available in gel, cream, ointment, liquid, and spray formulations. OTC preparations are limited to concentrations of 2.5% or less. Oral ingestions of 5-30 mL of a 2-4% viscous lidocaine solution have resulted in seizures in children.15-17 Lidocaine has the potential to produce systemic effects, and repeated applications can lead to accumulation of the drug and its metabolites. It should be used with caution in patients who are taking Class I antiarrhythmic agents (e.g., tocainanide, mexilitene), due to a potential for synergism.
Lidocaine is readily absorbed if ingested, and it may accumulate in patients with hepatic impairment. Systemic effects, which can be seen with toxic plasma levels, include seizures, metabolic acidosis, heart block, bradycardia, hypotension, and methemoglobinemia. Very young patients, as well as patients with G6PD-deficiency, are more susceptible to methemoglobinemia.18 General treatment is supportive; methylene blue is used to treat methemoglobinemia.
Benzocaine is available in creams, ointments, lotions, sprays, and liquids in concentrations ranging from 0.5% to 20%. It also is available in several combination products with menthol, phenol, camphor, alcohol, and antiseptic agents. Benzocaine’s principal toxic effect is methemoglobinemia. It does not produce the CNS or cardiovascular effects observed with lidocaine.19 Methemoglobinemia may be dose-related or idiosyncratic. Onset is usually within 20-60 minutes of application. Clinical symptoms of methemoglobinemia are related to the percentage of hemoglobin involved; dyspnea and tachycardia are present at high methemoglobin levels.20 Methemoglobinemia is treated with methylene blue.
Dibucaine is available in cream or ointment forms in 0.5% or 1% concentrations. It is a potent amide-type anesthetic and can cause seizures and dysrhythmias in children, leading to fatality.21 Photosensitivity and allergic dermatitis also have occurred with therapeutic use.22,23 Pramoxine is available in creams, lotions, gels, and a spray, all of which are available in a 1% concentration. Its reported systemic toxicity is low, and the incidence of hypersensitivity reactions to pramoxine is less than that of other local anesthetics.13
Topical Anti-Infectives. Topical anti-infective agents include antibiotics such as neomycin, polymixin B, and bacitracin zinc; and antifungal agents such as clotrimazole, miconazole, undecyclenic acid derivatives, tolnaftate, and gentian violet. Anti-infective agents are available in formulations that include creams, ointments, gels, lotions, and powders. They are used to treat various minor infections. The relative toxicity of any of these agents is low; toxic effects from ingestion are limited to the GI tract, principally diarrhea, especially with the non-absorbable antibiotics. Hypersensitivity reactions are always possible, although the incidence of systemic reactions from ingestion is very low.
Corticosteroid. Topical corticosteroids are used for treatment of inflammatory and pruritic conditions. They are used alone or in combination with an antibiotic or antifungal agent. The only available OTC topical corticosteroid is hydrocortisone. It is available in creams, ointments, and lotions in 0.5% and 1% concentrations. The relative toxicity of hydrocortisone, even when large amounts (a mouthful) are ingested, is minimal. Dermal absorption occurs with topical application and hypothalamic-pituitary-adrenal axis suppression is possible, especially if an occlusive dressing is applied over a large surface area, or with chronic application over large areas of abraded skin.24
Soaps. Soaps for personal use are comprised almost entirely of anionic and nonionic surfactants. The balance of ingredients depends upon the particular form (liquid, bar, shampoo, etc.), and may include such additives as perfumes, stabilizers, and antibacterial agents. Used for personal cleaning and disinfecting, the number and variety of products available are staggering. Fortunately, the toxicity of soaps, whether liquid or solid, is very low. However, they are irritating to all mucus membranes—nasal, ocular, oral, rectal, and vaginal. Ingestion of even small amounts usually produces immediate emesis.25 Treatment is symptomatic, with irrigation of exposed, irritated areas. Dilution is recommended with ingestion, and resolution of symptoms occur within minutes.
Lotions. Hand and body lotions are comprised of emulsions of oil in water or water in oil. As such, their toxic potential is low. High viscosity, a desirable property in a lotion, minimizes the aspiration potential on ingestion. Ingestion of significant amounts can cause emesis and also can have a laxative effect similar to that of other emollient laxatives (e.g., mineral oil or glycerine). Additives, such as perfumes, preservatives, stabilizers, emulsifiers, and thickeners, are present in negligible amounts. Ocular exposures cause irritation and conjunctival inflammation, and treatment should include dilution and irrigation, with ophthalmologic referral if prolonged or significant irritation occurs.
Acne Preparations. Acne preparations use benzoyl peroxide or sulfur as antibacterial agents. Benzoyl peroxide also has keratolytic and irritant effects and is available in creams, gels, or lotions in concentrations ranging from 2.5% to 20%. Likewise, sulfur has a keratolytic effect and is commonly available as either precipitated sulfur or colloidal sulfur in concentrations of 0.5-10%. Patient tolerance may limit the concentration of product applied.
The relative toxicity of acne preparations is low. Ocular and GI irritation can occur with significant exposures to either benzoyl peroxide or sulfur compounds.26 Superficial corneal opacification may occur with benzoyl peroxide in concentrations greater than 5%.27 Irrigation and dilution are recommended for these exposures, with ophthalmologic referral for persistent eye irritation. Make up or cosmetic products include mascaras, lipsticks, facial cremes, blushes, eye shadows, etc. Although multiple ingredients are involved, they are considered non-toxic.
Zinc Oxide. Zinc oxide is used for the treatment of diaper rash, abrasions, burns, and minor skin irritations. When used for the treatment of diaper rash, it forms a protective barrier against further irritation. It is available as an ointment in concentrations of 20% and is very often combined with other ingredients (e.g., zinc oxide and calamine for the treatment of poison ivy). Its systemic toxicity is low and needs no GI decontamination other than dilution.28
Poison Ivy Products. There are numerous products available for the symptomatic treatment of poison ivy exposure. These are all combination products, with the relative toxicity of each determined by its specific ingredients. They employ astringent agents such as calamine and zinc oxide, local anesthetic agents (e.g., benzocaine, pramoxine), antipruritic agents (e.g., diphenhydramine), and counterirritants (e.g., menthol, phenol, and camphor). They come in creams, ointments, and lotions. Their relative toxicity is low. Diphenhydramine in combination with calamine has caused severe anticholinergic toxicity in children and is no longer available OTC.29,30
Pediculocides/Scabicides. These products are used for the treatment of Sarcoptes scabiei (scabies) and Pediculus capitus, pubis, and humanus (head, pubic, or body lice, respectively), and their nits or eggs. The OTC products available for these conditions contain pyrethrins or permethrin, a synthetic pyrethroid, and piperonyl butoxide. Pyrethrins are obtained from the chrysanthemum plant, and are extremely effective against many insects. Hypersensitivity to the chrysanthemum plant, or any member of the Asteracaea (daisy) family, is a contraindication to the use of pyrethrin/pyrethroid-containing products. Permethrin is available as a 5% prescription cream for the treatment of scabies or a 1% cream rinse for the treatment of lice. Combination products containing pyrethrins and piperonyl butoxide are available OTC in concentrations ranging from 0.1% to 0.3%, and 2% to 4%, respectively. These are formulated into liquids, gels, and shampoos.
The relative toxicity of pyrethrins and pyrethroids is low; hypersensitivity is the primary concern.31 Serious systemic hypersensitivity reactions are rare.32 A fatality attributed to an asthma attack that was precipitated by the use of a pyrethrin-based dog shampoo has been reported.32 CNS symptoms have occurred, especially in children exposed to the more potent pyrethroids.33 It has been suggested that children are less able to metabolize pyrethrins efficiently, making them more susceptible to symptoms of toxicity, especially with application to large areas of skin. CNS depression and stimulation and dizziness, as well as periorbital paresthesias and dysesthesias have been reported.33,34 Seizures have occurred with accidental and intentional exposure to products containing higher concentrations of pyrethrins/pyrethroids. No case reports could be found in the primary literature documenting these CNS effects after exposure to the OTC-strength topical products.35
Ocular exposure with subsequent corneal damage can result from the use of shampoo containing pyrethrin.36 Irritation and contact dermatitis can be seen, especially with chronic, prolonged exposure; severe allergic reactions have been reported.37 Treatment is primarily symptomatic and supportive. Thorough irrigation is indicated for dermal and ocular exposures. Fluorescein staining to assess corneal patency is indicated if there is continued eye pain after adequate irrigation.
Antiseptics and Germicidals. Antiseptics and germicidals are used to clean and disinfect cuts and abrasions and to cleanse an area prior to a medical procedure, such as intravenous catheter insertion or phlebotomy. OTC products available for this use are identical to those used in the hospital setting, with the exception of hexachlorophene. The use of this agent has declined with the discovery of its neurotoxic potential. Products available OTC for antisepsis and disinfection comprise agents containing mercury and iodine compounds, quaternary ammonium compounds, and chlorhexidine gluconate.
When mercury is used, it is in the organic form of merbromin or thiomerosal. Mercurochrome contains 2% merbromin, which is 24-27% mercury and 18-22% bromine. It is available as an aqueous solution and has very limited bacteriostatic activity. Thiomerosal (merthiolate) is comprised of 49% organically bound mercury. Although more effective than merbromin, thimerosal shares the disadvantage of poor tissue penetration and tissue fixation and therefore has limited bacteriostatic activity.38 Thiomersal is available in solutions, tinctures (with a vehicle containing as much as 50% alcohol), and sprays.
The toxicity of mercury compounds is low with normal or recommended use. Ingestion of merbromin (mercurochrome) or thimerosal (merthiolate) causes nausea and vomiting. Serious poisoning is unlikely, due to the small volumes available in OTC formulations and the relatively low mercury content. Applications to large areas of abraded skin or frequent or prolonged use could potentially lead to absorption and mercury poisoning (mercurialism). This syndrome is characterized by acrodynia (pain and erythema of the palms and soles), polyneuritis, irritability, diaphoresis, and GI symptoms, especially anorexia.39 The most common toxicity from application of these OTC preparations is sensitization, either from the mercury or thio radical (in merthiolate). This is evidenced by erythematous, papular, and vesicular lesions where applied.
Treatment depends on the extent of poisoning. Dermal reactions are managed supportively and resolve after discontinuation of use. More serious systemic poisonings may require chelation with British Anti-Lewisite (BAL, dimercaprol), dimercaptosuccinic acid (DMSA), or D-penicillamine after initial stabilization.40 This degree of poisoning is not expected with common misuse of OTC mercurials and requires consultation with a regional poison control center or medical toxicologist.
Iodine. Iodine is an effective and inexpensive germicidal, with low tissue toxicity. Iodine compounds include solutions, tinctures, and povidone-iodine, a water soluble complex. The solutions of iodine contain free-iodine and potassium iodide for increased solubility. The tinctures are composed of free-iodine, potassium iodide, sodium iodide for increased miscibility, and alcohol. Tinctures come in strengths of 2% and 7% iodine. Povidone-iodine complexes contain 9-12% iodine and are available as 5% creams; 10% gels; 4-10% ointment; 10% solutions in aerosols, perineal washes, saturated gauze pads, and swabs; and a 0.5% mouthwash.
Iodine’s toxicity is related to its corrosive nature. Local inflammatory reactions can occur secondary to the application of strong tincture to wounds. Upon ingestion, symptoms of vomiting, hypotension, and circulatory collapse can occur, though death is rare following acute exposure.41 Iodine is rapidly inactivated by the presence of food in the stomach, particularly starches. In the vomiting patient, iodine ingestion is suggested by a blue colored emesis (due to the conversion of iodine to iodide). Serious systemic symptoms have occurred after irrigation of wounds with iodine compounds.42 These include hypothyroidism, renal failure, metabolic acidosis, leukopenia, and hemolysis.43 Estimates of the mean lethal dose range from 2 to 4 grams of free iodine.44
Treatment is primarily symptomatic and supportive. Induction of emesis is, and lavage may be, contraindicated with ingestion of concentrated solutions, due to iodine’s corrosive nature. Although iodine is adsorbed by activated charcoal, the presence of charcoal in the gut limits the endoscopist’s ability to assess the extent of caustic injury.45 Cornstarch (15 gm/ 500 mL water) is a better alternative for limiting gut iodine absorption. Starch converts iodine to iodide and then binds to the iodide salt. Further evaluation of the corrosive injury must be performed, including timely esophagoscopy.
Quaternary ammonium compounds are cationic surfactants comprised of mixtures of alkyldimethylbenzylammonium chlorides with alkyl chains varying in length from C8H17 to C18H37. The aqueous solutions are used for cleansing of skin, mucous membranes, and wounds; irrigation of bladder, urethra, body cavity; and vaginal douching. Quaternary ammonium compounds are effective against bacteria, some viruses, protozoa, and fungi and have a sustained duration of action.46 Composition of product is usually expressed in percentages of alkyl chain length, but this is less important than the concentration of the mixture. Concentrations of greater than 7% are potentially corrosive.
At lower concentrations, local irritation is the only adverse effect.47 Dilute solutions used for irrigation and antisepsis can be more irritating to inflamed or abraded skin and sensitization has occurred.48 Nausea, vomiting, and diarrhea are expected after trivial ingestions of even dilute solutions. Gastrointestinal tract burns have been reported with small volume ingestions of concentrated solutions.49 CNS depression progressing to coma, seizures, and shock also have been reported after ingestion of concentrated solutions.50 Serious corneal injury may occur with ocular exposure to concentrated solutions.51
Treatment depends on the concentration and circumstances of the exposure. Ingestion of small amounts of dilute solutions is managed with dilution and observation alone; more concentrated solutions are diluted and evaluated in a health care facility for potential GI tract burns. Emesis is contraindicated, as is gastric lavage, due to the caustic nature of this agent and the potential for pulmonary aspiration from rapid CNS deterioration and loss of protective airway reflexes. Treatment consists of dilution, supportive care, and hospital admission as needed for esophagoscopy.
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