Drug eruptions

 

Drug eruptions

 

introduction

 

Cutaneous drug eruptions cause a great deal of consternation and confusion. Is the eruption you are viewing possibly related to a medication; is it likely to be due to a medication; and if so what is the probable culprit? The problem of diagnosis is intensified by the patient taking many drugs, particularly if the drug history is clouded or incomplete. It is essential to obtain a full history of all drug use. This includes prescribed and nonprescription medication and drugs that are ingested, inhaled, injected, inserted or applied (as either drops, creams or patches).

 

Medications that are often overlooked by the patient unless specifically questioned about are: drugs used intermittently (eg ibuprofen for dysmenorrhoea); homoeopathic and herbal remedies; medications stopped prior to the rash developing – the importance of this is illustrated by the exanthem due to a semisynthetic penicillin, which may begin 1 to 4 weeks after the penicillin course is completed.

Some medications produce a characteristic eruption, either clinically (thiazide-induced photosensitivity) or histologically (a lichenoid reaction due to gold). More often, however, a particular eruption can be produced by many different drugs, and one is left to consider what the most likely culprit is. Remember that almost any drug can produce any rash.

This diagnosis is made by: assessment of the clinical features of the rash; the temporal relationship between drug contact and the commencement of the rash; the histological features on biopsy (when this is appropriate).

After the eruption has subsided, it is vital that the patient and family are advised of what medication caused the rash. The generic name and the range of trade names for this drug must be written down for the patient and recorded prominently in the medical notes. If the drug cross-reacts with any other drugs, this must also be noted for the patient.

Rechallenge with a suspected drug may be performed if the clinical indications for continued use of the drug are significant and the rash was not serious or life threatening. For example, it is reasonable to confirm a suspected drug by rechallenge if it caused a fixed drug reaction, but not if the reaction was toxic epidermal necrolysis or Stevens-Johnson syndrome.

Special considerations for drug eruptions

 

The time of onset of the rash relative to the ingestion of medication is important when considering the type of eruption, see Figure 1. For instance, if the drug eruption is urticarial it is most likely due to a recently commenced medication. Anaphylaxis will occur from minutes to hours after contact with the allergen (usually <1 hour). Similarly, urticaria/angioedema usually presents within a few hours, but when caused by nonsteroidal anti-inflammatory drugs (NSAIDs) it may be delayed 1 to 7 days, and urticaria/angioedema in response to angiotensin converting enzyme (ACE) inhibitors occurs within 4 weeks.

Exanthems typically have a sudden onset 7 to 14 days after drug commencement, with the exanthem associated with semisynthetic penicillins developing 2 weeks after the first dose. Exfoliative dermatitis can develop abruptly several weeks after initiation of the drug or can progress from an exanthem. Stevens-Johnson syndrome and toxic epidermal necrolysis more commonly develop 1 to 3 weeks after initial drug administration. Fixed drug eruptions occur 30 minutes to 8 hours after rechallenge. Lichenoid eruptions typically take months to develop.

Drug eruptions may temporarily worsen and extend after cessation of the causative drug and can occasionally begin after the causative medication has been stopped. Very delayed reactions can occur, even after years of drug ingestion. This may be caused by a change in drug bioavailability due to a drug interaction, dosage change, general health of the patient, or environmental factors, eg lifestyle changes producing more solar exposure. While these intervals are a guide, they cannot be totally relied on. Previous exposure may reduce reaction times.

 

It is important to recognise when a drug-induced cutaneous eruption is becoming serious. Some of the cutaneous features that may indicate the development of conditions such as Stevens-Johnson syndrome, toxic epidermal necrolysis or the severe hypersensitivity syndromes are facial confluent erythema, facial oedema and involvement of the central part of the face, skin pain, palpable purpura, skin necrosis, blisters or epidermal detachment, mucous membrane erosions and swelling of the tongue or angioedema. The systemic features that indicate a serious drug reaction include high fever, enlarged lymph nodes, arthralgias and wheezing or shortness of breath or hypertension. In these more serious drug reactions, it is imperative that there is evaluation for internal organ involvement, particularly if the latter systemic features are present.

An individual sensitive to one drug may react to other drugs in that group. The most common example is the penicillins; hypersensitivity to any penicillin should be assumed to imply sensitivity to all penicillins. Between 3 and 6% of all patients hypersensitive to penicillin experience cross-reactions to cephalosporins. The use of the latter in individuals with a history of early IgE mediated reactions to penicillins is contraindicated.

Phenytoin is metabolised by the cytochrome P450 enzyme system into toxic intermediates; these are then detoxified by the enzyme epoxide hydrolase. Phenobarbitone and carbamazepine (aromatic anticonvulsants) are metabolised to similar potentially toxic arene oxides. Patients who develop a hypersensitivity to one of these agents have a 75% chance of reacting to other aromatic anticonvulsants. It is estimated that up to 25% of these patients’ relatives are at risk of similar hypersensitivity syndromes if they encounter the drugs.

Certain patient groups, including the elderly and those with acquired immunodeficiency syndrome (AIDS), are at increased risk of drug reactions. Sixty per cent of AIDS patients have reactions to cotrimoxazole, and the risk of toxic epidermal necrolysis is increased by 1000-fold. Human immunodeficiency virus (HIV) -infected patients have a systemic glutathione deficiency, which results in a decreased ability to scavenge toxic hydroxylamine derivatives of sulfonamides and may partially explain the phenomenon. Ampicillin exanthems are more common in patients with lymphocytic leukemia, and occur in nearly all patients during acute Epstein-Barr virus and cytomegalovirus infections.

descriptions, causes and management

 

These are typically maculopapular or morbilliform rashes that are the most common of all drug rashes. Small erythematous macules or barely raised papules begin on the trunk and may coalesce. Slight pruritus is typical. The drugs most commonly associated with a drug exanthem are ampicillin, amoxycillin, cotrimoxazole, carbamazepine, cefaclor and gold. Management involves withdrawal of the drug and the use of simple emollients. Occasionally, moderately potent topical corticosteroids,  may be needed to relieve pruritus.

This is the second most common pattern of drug eruption and is manifested by pruritic erythematous wheals. This may be associated with angioedema of the lips or eyelids. The most common causes of drug-induced urticaria are antibiotics, particularly penicillins, captopril and other ACE inhibitors, NSAIDs including aspirin, and quinine. Treatment involves immediate cessation of the causative agent, and the use of an antihistamine. For more persistent cases or if there is significant angioedema

prednisolone 0.5 to 1mg/kg orally, daily for 7 days may be warranted.

 

This is rare and is manifest by a pruritic erythroderma, characterised by generalised erythema and scale. It may begin as a maculopapular erythema that progresses, generalises, persists and worsens. This can be associated with malaise, fever and lymphadenopathy.

Drugs causing erythroderma include allopurinol, antimalarials, carbamazepine, penicillins and sulfonamides. Erythroderma due to drugs needs to be managed by the immediate withdrawal of the offending agent and institution of therapy as for erythroderma of any other cause, see Emergencies: Exfoliate dermatitis (erythroderma). These patients require adequate nursing care to ensure that heat, fluid and protein loss through the skin is minimised. Systemic involvement, most commonly manifest by hepatitis, may further complicate management. Any suspicious drugs should be withdrawn. Pruritus and cutaneous inflammation may be reduced with

emollients (see Control of xerosis)

OR

moderately potent topical corticosteroids.

 

Drugs that photosensitise (NSAIDs, ciprofloxacin, nalidixic acid, phenothiazines, tetracyclines, griseofulvin, amiodarone, sulfonamides and thiazides) cause the skin to become abnormally sensitive to light, usually solar radiation. This can occur with either topically applied medications, eg sunscreen formulations, or systemically ingested medications. These reactions can be either phototoxic or photoallergic, phototoxic reactions being far more common.

Phototoxic reactions are dependent on both the dose of radiation and the dose of medication. They can therefore occur at the time of commencement of therapy, or at a later date due to an increase in dose of medication or increase in sun exposure, as happens seasonally or when travelling to sunnier climes. Photoallergic reactions indicate an immunological reaction involving the skin and drug. They are not dose-related, and require a latent period of 24 to 48 hours for the sensitisation to occur.

The eruption will be prominent on the face (sparing deep creases, the area under the point of the chin and behind the ears), the dorsum of the hands and the ‘V’ of the neck. With continued exposure, the eruption can eventually extend to involve sun-protected areas as well as the sun-exposed sites.

Some mild photosensitive eruptions, eg due to thiazides, are very common and may not necessitate the cessation of the drug. It is, however, important to stress increased solar protection, ie sun avoidance, adequate clothing including hats, and a broad-spectrum sunscreen. The photosensitivity to some agents such as thiazides can take many months to resolve and consequently prolonged photoprotection may be necessary.

Local irritation may be controlled with emollients (see Control of xerosis) and moderately potent topical corticosteroids)

Erythema multiforme is characterised by ‘target’ lesions involving the skin with occasional involvement of the mucosal surfaces, see Erythema multiforme - Mouth ulcers. Only 10% of cases are due to drugs. On the other hand, the severe form, Stevens-Johnson syndrome, is usually a drug reaction. It is marked by extensive and sometimes exclusive involvement of mucosal surfaces (oral, ocular, genital and others) with cutaneous target lesions variably present, and this is very likely the result of a drug reaction.

Drugs associated with erythema multiforme and Stevens-Johnson syndrome include allopurinol, carbamazepine, phenytoin, gold, NSAIDs, sulfonamides and tetracyclines. Stevens-Johnson syndrome is a serious and occasionally life threatening condition. The drug must be stopped and expert care given to the affected mucous membranes. If the disease is recognised early in its course (within the first 72 hours), use

prednisolone 0.5 to 1mg/kg orally, daily until lesions cease cropping then reduce the dose and cease over 1 week.

 

Toxic epidermal necrolysis is a rare and potentially fatal condition that is usually precipitated by drugs. The rash often begins with a morbilliform eruption. This rapidly progresses to result in skin that is easily detached, with large sheets separating at the dermoepidermal junction. This resembles a second-degree burn in a patient who is acutely ill, often with a high fever. The mucosa is often extensively involved, especially the eyes. Here it can produce significant scarring sequelae in those patients who survive. Toxic epidermal necrolysis is a medical emergency. Previously, mortality rates were as high as 60% but have steadily declined to around 20% because of improved medical and nursing care.

Drugs causing toxic epidermal necrolysis include allopurinol, ampicillin, amoxycillin, carbamazepine, phenytoin, lamotrigine, nevirapine, barbiturates, sulfonamides, cephalosporins and NSAIDs.

Patients need intensive care or burns unit care to avoid the systemic complications of renal failure and electrolyte imbalance, as well as reverse barrier nursing to reduce the risk of sepsis. Specific treatment of this condition is still controversial; some patients have apparently responded to agents such as cyclosporin and prednisolone. Urgent referral to specialist care is essential.

Drug-induced vasculitis may not only cause the typical ‘palpable purpura’ but may also involve internal organs, including the kidneys, liver and heart. Drugs associated with vasculitis include ACE inhibitors, NSAIDs, sulfonamides and thiazide diuretics. Assessment of a patient with a drug-induced vasculitis requires investigations to exclude other causes of the vasculitis and to assess any systemic involvement.

These eruptions are so-called because they resemble lichen planus. There are clinical differences between idiopathic lichen planus and drug-induced lichenoid eruptions. Drug-induced cases have a tendency to be more severe and generalised, may show a photoexacerbation of lesions, and may be associated with some dermatitis-like areas and less mucosal involvement. These typically begin weeks or months after commencement of the drug and will often take several weeks to resolve after drug cessation.

Drugs commonly causing lichenoid eruptions include beta-blockers, ACE inhibitors, antimalarials, frusemide, thiazides, chlorpropamide, methyldopa, gold, phenothiazines and quinidine. Treatment of a lichenoid eruption involves cessation of the drug and photoprotection, if relevant, together with

emollients (see Control of xerosis) AND a moderately potent to potent topical corticosteroid.

 

Fixed drug eruptions characteristically recur in the same site(s) with each administration of the causative agent. They are seen particularly with drugs that are ingested episodically, such as those for night cramps, dysmenorrhoea or constipation. The lesion is typically a single, well-demarcated, erythematous plaque, a few millimetres to many centimetres in diameter, and may be surmounted by a bulla. It develops 30 minutes to 8 hours after administration of the drug and is typically associated with burning rather than itch. If the drug is continued, multiple lesions can develop. Common sites affected are the face, hands, feet, genitalia (especially the glans penis) and the perianal area. When the drug is ceased the lesion resolves, leaving a well-demarcated patch of macular hyperpigmentation.

Common culprits in fixed drug eruptions include tetracyclines, sulfonamides, NSAIDs, paracetamol, phenolphthalein and barbiturates. Management involves taking a full and exhaustive history of drug ingestion, remembering that causative agents are often not considered to be drugs by the patient. The drug should be stopped.

For symptomatic relief, use

a moderately potent to potent topical corticosteroid.

 

If the reaction is severe or there is extensive mucosal involvement, use

prednisolone 0.5 to 1mg/kg orally, each morning for 3 to 7 days.

 

To confirm a clinically suspicious drug, a small dose of the agent could be taken as a rechallenge. This would be ill advised if the previous reaction had been severe, extensive or with significant mucosal involvement.

This severe reaction is manifest by fever, skin rash and hepatitis. It typically begins 2 to 3 weeks after initiation of therapy and may continue or worsen for weeks after the drug is ceased. Other signs include lymphadenopathy, leukocytosis with atypical lymphocytes, and nephritis. The skin rash is predominantly morbilliform, but erythroderma and toxic epidermal necrolysis have been reported. The outcome is variable, but the syndrome may be fatal, usually due to liver involvement.

Expert medical and nursing care is needed to assist recovery after the drug is stopped. Systemic corticosteroids are used to hasten resolution. There is a high risk of cross-reaction between aromatic anticonvulsants (phenytoin, carbamazepine, phenobarbitone), which means that other anticonvulsants need consideration. Other drugs can produce a similar hypersensitivity syndrome.

Many drugs have been implicated in either precipitating or aggravating a variety of cutaneous diseases. The worsening of psoriasis and acne vulgaris by lithium is the best recognised example, but the exacerbation of psoriasis has also been reported with beta-blockers and antimalarials. If a rash is believed to have been responsible for worsening or indeed precipitating a dermatosis, consideration should be given to ceasing the drug in question. Assessment of the progression of the rash after cessation of the drug is then required. Rash aggravation by a medication may not necessarily preclude the use of this medication at a future time by the same patient. The withdrawal of a drug may also be responsible for the aggravation of a rash, eg the worsening of psoriasis on withdrawal of oral corticosteroids.