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Dermatitis Medicamentosa (Drug Eruption)

 

What is a drug reaction?

Dermatitis Medicamentosa is a term used to describe any of the group of those skin eruptions or changes which may occur as a result of the ingestion or parenteral administration, or contact with, virtually any drug. Please note that there is a difference between a true "drug allergy" and a "drug reaction." A drug reaction is better called a "side effect," while a true drug allergy is usually an immunologic reaction to a medication such as a rash due to penicillin. The overall incidence of drug eruptions is low (3 per 1000 drug courses). However, rates of reaction may vary greatly among different drugs (e.g., less than 1 per 1000 drug courses for chloral hydrate compared to more than 50 reactions per 1000 courses of ampicillin or trimethoprim-sulfamethoxazole). The exact biochemical sequence leading to most drug eruptions is conjectural. Some eruptions are, however, are clearly due to IgE-mediated histamine release, while others are the result of circulating antigen-antibody complexes. Nonimmunologic release of biochemical mediators, direct deposition in the skin of drug or metabolites, and activation of melanin production may also explain some drug eruptions. Drug reactions may be immunologically mediated, such as immediate hypersensitivity to penicillin. They can occur due to toxicity, as in the case of oral ulcerations from methotrexate use, or they may simply be side effects, such as the dark cutaneous striae which can develop following prolonged corticosteroid use. Some drugs may provoke idiosyncratic reactions; that is, reactions which are uncharacteristic, unexpected, and unpredictable, and do not depend upon the dosage of the drug used. For example, bromides (such as those utilized in Bromo-Seltzer) may on rare occasions cause pustular, vegetative plaques to form on the skin in such a manner. Antibiotics or immunosuppressive medications may bring about an alteration in the normal flora of the skin and mucous membranes and thus permit overgrowth of opportunistic organisms such as Candida albicans or of cutaneous fungi. Some drugs can cause alterations in the metabolism which can result in cutaneous changes. The drug Accutane has been reported to alter lipid metabolism in some patients to the extent that eruptive xanthomas (lipid deposits in the skin which resemble pustules) appear. Still, other medications may worsen preexisting skin diseases. A variety of drugs, such as beta-blockers, salicylates, and progesterone may worsen psoriasis. Lithium may also worsen both acne and psoriasis. A large group of medications are associated with photosensitivity reactions-- these include, but are not limited to, sulfonamides, oral sulfonylurea hypoglycemics such as Diabenese, tetracycline and its derivatives, griseofulvin, thiazide diuretics, phenothiazines such as thorazine and phenergan, and Psoralens. The above listed types of cutaneous drug reactions represent only a small portion of the large variety of different reactions that can occur. Virtually every morphologic type of generalized and localized skin reaction may occur as a result of almost any drug. Eruptions may exanthematous, eczematous, urticarial, or may be exfoliative or vasculitic. They may resemble virtually any generalized skin disease.

 

Is your rash drug related?

When attempting to decide whether a drug is responsible for a given skin rash, the following suggestive features should be looked for:

 

1. The skin eruption usually, but not always occurs closely (within 2 weeks) follows initial administration of the suspected drug.

2. The skin eruption is a known complication of the suspected drug.

3. The suspected drug is likely to cause skin eruptions.

4. The skin eruption reappears upon rechallenge.

5. Structurally similar compounds elicit, or elicited in the past, an identical or similar eruption.

6. The eruption follows administration of standard therapeutic doses.

 

Several, often misunderstood, features of drug eruptions are worth mentioning.

1. Even drugs administered for years may be the cause of a cutaneous reaction.

2. After a suspected inciting agent is stopped, the skin rash may persist for weeks or months.

3. Specific drug eruptions are the exception rather than the rule (some of these exceptions are listed in the following discussion). If a patient is receiving multiple medications, stopping just one on the basis of a recognizable rash is may or may not be advised.

4. A person is never allergic to something the first time they use it. It takes many repeated exposures before the body can develop a true allergy to a substance. Often, a person will say, “Dr. Jacobs, I can’t understand how I can be allergic to my perfume, I have been using it for 10 years.” Dr. Jacobs explains that the person has used the perfume for 10 years, and has finally acquired an allergy due to repeated exposure. The same holds true for allergic reactions to drugs. A person needs to be exposed to a substance repeatedly before allergy can occur.

 

How do drug eruptions present?

Drug eruptions can present in a variety of ways from mild to wild. Perhaps the most severe drug reaction is that known as Toxic Epidermal Necrolysis, a condition characterized by a prodrome of malaise, mild fever, and sore throat for 2 to 3 days, followed by widespread, erythematous, flaccid bullae which rupture and are sloughed easily, both from skin and mucosal areas, and which leave behind them a denuded, painful, and infection-susceptible dermis which is also subject to large losses of electrolytes and fluids. Many of the antibiotics have been implicated in this fortunately rare condition, which has a 25-50% mortality rate. The diagnosis of cutaneous eruptions due to drug reactions may, in some patients, be fairly straightforward, but may also be quite difficult, particularly in those patients who are on several medications. The keys to diagnosis are a careful medication history and clinical suspicion. Any rather generalized skin condition, particularly one of recent onset, should raise questions concerning use of oral or parenteral drugs. Frequently, a chronological relationship can be established between the initiation of a particular drug and the occurrence of the skin eruption, but often this may be ambiguous. The only reasonable approach to diagnosis is to eliminate, if at all possible, those drugs which are the more likely offenders based upon the type of presenting eruption and the statistical possibilities. Nonessential medications may be discontinued without replacement. Those which are essential may frequently be replaced by a chemically unrelated substitute. This method of discerning the etiology for a drug reaction is also, of course, pivotal in successful treatment-- that is, the removal of the offending agent. In some cases a relatively mild exanthematous eruption may be so asymptomatic that a patient may accept its presence if removal of the suspected drug were to prove too difficult. This approach is obviously not practical with drugs causing widespread urticaria, vasculitis, or exfoliation. Further treatment of drug eruptions, once the offending drug has been eliminated, may be accomplished in mild eruptions through the use of topical corticosteroids, oral antihistamines, and emollients. Reactions involving severe urticaria may necessitate large doses of antihistamines, epinephrine, or systemic steroids. Much controversy surrounds the treatment of severe erythema multiforme or toxic epidermal necrolysis when these are clearly caused by a drug such as phenytoin that has been discontinued. There is argument that the drugs used to attenuate the acute inflammatory response may also inhibit healing and re-epithelialization. Studies have been performed which seem to indicate that, indeed, patients with these conditions who were treated with systemic corticosteroids tended to have a longer course and more complications than untreated patients. This is particularly important in patients who present in the early stages of the disease. It is also clear that any patient who has suffered widespread loss of skin from a severe drug reaction is best served by management in a burn intensive care unit. The course of drug eruptions depends upon many factors, such as the type of drug, type and severity of the reaction, general health of the patient, and the effectiveness of therapy. Exanthematous, eczematous, or mild urticarial reactions that do not involve anaphylaxis tend to have a good prognosis. Exfoliative, bullous, or purpuric skin eruptions tend to have a much more serious prognosis and protracted course.

 

How are drug reactions treated?

In general, drug reactions are first treated in the way that best eliminates any possible severe complications, for example, a severe anaphylactic reaction to penicillin is first treated with life saving epinephrine to keep the air ways open. The second step in therapy is to, of course, stop the offending drug. When initially assessing a probable drug eruption or counseling a patient following an episode, always consider over-the-counter laxatives, cold remedies, sedatives, vitamin supplements and eye, ear, or nose drops. The patient should be carefully taught what agent (if known) was responsible for a drug eruption and what other medications might result in a similar complication. Therapy: Discontinuation of an offending medication is paramount. Symptomatic therapy for itch may be offered. Systemic steroids are reserved for severe reactions, although their efficacy has never been scientifically documented. Oral antihistamines work best in urticarial eruptions. The patient with toxic epidermal necrolysis is treated with the same intensive supportive measures given to a burn patient.

 

 

The following is a list of particular drugs and their reactions

 

Drugs Commonly Causing Skin Eruptions

Penicillin and related medications (ampicillin, cephalosporins), Sulfonamides and related medications (thiazide diuretics, trimethoprim-sulfamethoxazole), Barbiturate sedatives, Quinidine, Diazepam and related compounds, Phenytoin, Isoniazid

 

Drugs Relatively Unlikely to Cause Skin Eruptions

Digitalis preparations, Acetaminophen, Aspirin, Narcotic analgesics, Insulin, Propanolol, Vitamins and minerals, Aminophyline

 

Acneiform Eruptions

Acnelike drug eruptions may be seen with corticosteroids and actinomycin D, iodide, bromides, and lithium.

 

Coumarin Necrosis

Coumarin necrosis is a rare, but identifiable reaction to anticoagulants of the coumarin family (e.g., Dicoumarol and Coumadin). This reaction begins between the third and tenth day of therapy. The reaction begins as petechiae, develops into hemorrhagic bullae, and may progress to necrosis. Sites of predilection include breasts, thighs, and buttocks.

 

Exanthematous Eruptions

Often referred to as morbiliform (measles like) and maculopapular (flat and raised), exanthematous eruptions are widespread, symmetric, and blanchable, and may be accompanied by pruritus or fever. Ampicillin is a frequent offender, especially if the patient is taking allopurinol or has concomitant mononucleosis, cytomegalovirus infection, or lymphocytic leukemia. This is the most common but nonspecific pattern of drug eruption.

 

Fixed Drug Eruption

Fixed drug eruption begins as a well-defined circular to ovoid area of dusky erythema which may be covered by a bulla. the initial area fades in 2 weeks or less, but leaves a brown to purple, residual macular discoloration. Reexposure to the inciting agent leads to recurrence of the eruption at the same site (thus the fixed nature). The glans penis is a common location for this reaction pattern. Fixed drug eruption are usually due to barbiturates, phenolphthalein-containing laxatives, sulfonamides, and tetracyclines.

 

Lupus Erythematosus

A rash resembling lupus (sometimes with systemic complaints and positive blood studies) may accompany administration of hydralazine, isoniazid, procainamide, and phenytoin.

 

Pigmentation

Hyperpigmentation may accompany certain chemotherapeutic agents as well as exposure to heavy metals (silver, mercury, arsenic, or gold) and antimalarial and phenothiazine compounds.

 

Photosensitivity

Exaggerated sunburn reactions (phototoxic) and eczematous reactions in sun-exposed areas (photoallergic) may be encountered with various medications. Doxycycline, minocycline, and tetracycline are each known for there potential photosensitivity... So is Retin A topical medication for acne. It is important to understand that tanning beds can also bring on these reactions.

 

Toxic Epidermal Necrolysis

Toxic epidermal necrolysis is severe, life threatening cutaneous drug eruption that begins as widespread, tender erythema. Ultimately, flaccid bullae develop and large portions of the epidermis slide off the underlying dermis. Mucous membrane erosions are frequent. Death may result from fluid and electrolyte disturbances, concomitant renal failure, or bacterial septicemia. Common causal agents include antibiotics, anticonvulsants, and allopurinol.

 

Urticaria

Hives may be the manifestation of drug reactions to a wide variety of medications.  While antibiotics are often implicated, this pattern is nonspecific.

 

Photos of Drug Rashes:

 

 
Ken Alpern, M.D. Charity Morris, PAC Eleni Litras,
PAC

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Hello, and welcome to our dermatology office. My name is Randy Jacobs, MD, FAAD. Some people are blessed with the most beautiful skin, and it’s all natural. Others have to work at it. Healthy skin is lovely to behold, comfortable to live in, and a pleasure to touch.
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