Over-the-Counter Medications: Toxic
Effects and Adverse Reactions: Part I
Richard Y. Wang, DO,
FACEP, FACMT
Daren D. Girard, MD
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 (Please see Table 1.) While the
majority of these produced no serious harm, some OTC exposures resulted in
significant morbidity and mortality. (Please see Table 2.)
The recent withdrawal of phenylpropan- olamine-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 chapter 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.
Dermatologic Preparations:
Topical Products
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. (Please see Table 3.) 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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