Drug Eruptions

Any drug can cause a skin reaction, but some classes of drugs are characteristically associated with certain types of reaction.

Not all dermatological problems produce visible signs. The skin may appear normal with marked pruritus. It may be difficult to decide if the drug is really the cause of the problem and to withdraw it, especially if it is providing important treatment. Early withdrawal of the offending drug may limit its adverse effects.

Many of these reactions are immunological in origin. Possibly the drug acts as a hapten and binds to proteins to form a structure that the immune system recognises as "not self".

Most immunologically mediated reactions can be allocated to one of the Gel and Coombs' classes of hypersensitivity:

• Type I is mediated by IgE and results in urticaria, angioedema, and anaphylaxis. They are often caused by proteins and especially insulin.
• Type II is a cytotoxic reaction which produces haemolysis and purpura. They are caused by penicillin, cephalosporins, sulphonamides, and rifampin.
• Type III is immune complex reactions, which result in vasculitis, serum sickness, and urticaria. They can be caused by salicylates, chlorpromazine and sulphonamides.
• Type IV is delayed-type reactions with cell-mediated hypersensitivity, which result in contact dermatitis, exanthematous reactions, and photoallergic reactions. These reactions are the most common and are usually caused by topical applications. Antibodies can be demonstrated in fewer than 5% of drug reactions, as the problem is cell-mediated. Type IV reactions are not dose-dependent. They usually begin one to three weeks after medication is started. This is significantly slower than most other reactions. There may be eosinophilia, and they may recur if other drugs that are chemically related are used.

Epidemiology
Adverse drug reactions occur in about 2-5% of patients in hospital and follow about 1% of prescriptions in the community. They are more common in women than men and more common in the elderly but the elderly also take more drugs.

Most are mild reactions and simply an inconvenience, although they may be very uncomfortable. About 1 in 1,000 in the hospital setting are rather more severe.

Notification of adverse drug reaction is on a voluntary basis through the Yellow Card scheme in the British National Formulary.

Diagnosis

• History and examination are as important here as in any field.¹
• Most drugs will cause a reaction fairly soon after they have started, although type IV reactions take longer than others. When a patient develops a dermatological problem it is often difficult to decide which, if any, drugs are responsible.²
• Take a careful history, avoiding being too ready to accept the patient's diagnosis of what is to blame, especially if they are on multiple medication. Take note of all medication including prescribed, over-the-counter (OTC), "alternative" and illicit drugs. It is not only prescription only medications (POMs) that can cause trouble and patients may be surprised to learn that OTCs, "natural therapies" and illegal drugs can also have adverse effects.
• Urticaria may not be due to a drug at all but the ingestion of strawberries or shellfish. There may be a viral infection. Has the patient had that drug before? Were there any problems then?

Associated drugs and rashes

Acneform lesions

These are different from acne vulgaris in that they tend to be over the upper body rather than the face and there are no comedomes.
Typical drugs are corticosteroids, halogens, haloperidol, hormones, isoniazid, lithium, phenytoin, and trazodone:

• The halogens are usually bromide or iodide.
• The hormones may be anabolic steroids taken illicitly by body builders or some athletes. Progestogens can also be a problem. This tends to be in low oestrogen, high progestogen oral contraceptive pills rather than progestogen-only pills or depot and implant contraceptives.

Acute generalised exanthematous pustulosis

• This is often abbreviated to AGEP. It produces an acute onset of fever and generalised scarlatiniform erythema with many small, sterile, nonfollicular pustules. It appears like pustular psoriasis.
• Most cases are caused by antibiotics, often in the first few days of administration.
• Some may be viral infections, mercury exposure, or UV radiation. They resolve spontaneously and rapidly, with fever and pustules lasting 7-10 days before desquamation over a few days.
• Typical drugs include beta-lactam antibiotics, macrolides, and less commonly, a wide variety of drugs including paracetamol, carbamazepine, tetracyclines, diltiazem, furosemide, hydrochlorothiazide, hydroxychloroquine, nifedipine, phenytoin, pseudoephedrine, ranitidine, sertraline, simvastatin, terbinafine and vancomycin.

Alopecia

It may occur with ACE inhibitors, allopurinol, anticoagulants, azathioprine, bromocriptine, beta blockers, cyclophosphamide, hormones - especially those with androgenic effects, indinavir, non-steroidal anti-inflammatory drugs (NSAIDs), phenytoin, methotrexate, retinoids, and valproate. It is usual with cylcophosphamide therapy but is quite rare with the other medications.

Bullous pemphigoid

Lesions like bullous pemphigoid may occur with penicillamine, captopril, chloroquine, ciprofloxacin, enalapril, furosemide, neuroleptics, penicillins, PUVA, sulfasalazine, and terbinafine

Erythema nodosum

See separate article Erythema Nodosum. Lesions most often occur with oral contraceptives but can occur with halogens, penicillin, sulphonamides, and tetracyclines.

Erythroderma

This is a diffuse redness of the skin. Offending drugs include allopurinol, anticonvulsants, captopril, chloroquine, chlorpromazine, cimetidine, diltiazem, lithium, nitrofurantoin, omeprazole, phenytoin, St John's wort and sulphonamides.

Fixed drug eruptions

• These are when lesions recur in the same area when the same drug is given.
• Plaques are circular, violaceous and oedematous and they resolve with macular hyperpigmentation. The latent period is half an hour to eight hours after taking the drug. Perioral and periorbital lesions may occur, but the hands, feet, and genitalia are the usual sites to be involved.
• Fixed drug eruptions are well-recognised with many drugs including anticonvulsants, aspirin and NSAIDs, benzodiazepines, cetirizine, ciprofloxacin, clarithromycin, doxycycline, fluconazole, hydroxyzine, lamotrigine, loratadine, metronidazole, oral contraceptives, penicillins, phenytoin, sulphonamides, tetracyclines and zolmitriptan.

Fig. 1. A generalised fixed drug eruption.

Fig. 2. The same - closer.

Hypersensitivity syndromes

True allergy may occur with allopurinol, amitriptyline, carbamazepine, lamotrigine, minocycline, NSAIDs, olanzapine, phenytoin, spironolactone, and zidovudine.

Lichenoid reactions

Lesions are similar in appearance to lichen planus and there may be marked pruritus.
They can accompany amlodipine, antimalarials, beta blockers, captopril, diflunisal (now withdrawn), diltiazem, enalapril, furosemide, glimepiride, gold, leflunomide, penicillamine, phenothiazine, proton pump inhibitors, sildenafil, tetracycline, thiazides, and ursodeoxycholic acid.

Lupus drug reactions

Unlike other drug reactions, lupus tends to require a long period of exposure.³ It produces symptoms like systemic lupus erythematosus
(SLE) but with skin findings being uncommon, or drug-induced subacute cutaneous lupus erythematosus (SCLE), which is characterised by annular psoriasiform, nonscarring lesions in a typical pattern for photosensitivity.
For SLE effects, hydralazine and minocycline are best known. For SCLE, hydrochlorothiazide is the most common.

Photosensitivity

The most common offenders are ACE inhibitors, amiodarone, amlodipine, celecoxib, chlorpromazine and other phenothiazines, diltiazem, furosemide, lovastatin, nifedipine, quinolones, sulphonamides, tetracyclines, and thiazides.

Urticaria

The most likely drugs are bupropion, carbamazepine, chlordiazepoxide, fluoxetine, imipramine, lamotrigine, lithium, paroxetine, and trazodone.

Vasculitis

This is most likely with fluoxetine, paroxetine, and trazodone.

There are many other well-known reactions that are associated with drugs used in cancer chemotherapy and cytokine therapy. A list of such problems plus a more comprehensive list of other drug reaction may be found in the emedicine link at the end.

Potentially fatal drug eruptions

Most drug eruptions are unpleasant rather than potentially life-threatening. There are two that are worthy of special mention.

Stevens-Johnson syndrome

See related separate article Stevens-Johnson syndrome. This is a much more serious drug eruption.⁴ It may be the result of malignancy in adults or viral infection in children but drugs should be considered as the potential culprit. It may be associated with allopurinol, anticonvulsants, aspirin and NSAIDS, carbamazepine, cimetidine, ciprofloxacin, codeine, diltiazem, erythromycin, furosemide, griseofulvin, indinavir, nitrogen mustard, penicillin, phenothiazines, phenytoin, ramipril, rifampicin, sulphonamides including co-trimoxazole, and tetracyclines. Of these, sulphonamides are most often implicated.

Toxic epidermal necrolysis

See separate article Toxic Epidermal Necrolysis. Responsible agents include allopurinol, anticonvulsants, aspirin and NSAIDs, isoniazid, penicillins, phenytoin, prazosin, sulphonamides including co-trimoxazole, tetracyclines and vancomycin. Both Stevens-Johnson syndrome and toxic epidermal necrolysis are often caused by infections, especially herpes simplex virus but, when caused by drugs, it is usually penicillins or sulphonamides.⁵

Clinical features are similar in all causes:

• The reaction often starts with fever, sore throat, chills, headache, arthralgia, vomiting and diarrhoea and malaise.
• Lesions may occur anywhere, but most commonly affect the palms, soles, dorsum of hands and extensor surfaces. The rash may be confined to any one area of the body, most often the trunk. There is no pruritus.
• Mouth involvement may be severe enough that patients may not be able to eat or drink.
• Genitourinary involvement result in dysuria or an inability to pass urine
• The rash can begin as macules that develop into papules, vesicles, bullae, urticarial plaques, or confluent erythema.
• The typical lesion has the appearance of a target, which is considered pathognomonic.
• As stated above, toxic epidermal necrolysis is similar but more severe. Mucocutaneous detachment is more marked and a greater area is usually involved.
• Both conditions require admission to hospital if not already there. The skin loss of toxic epidermal necrolysis is best managed in a burns unit.
• Both, but especially toxic epidermal necrolysis may result in scarring, blindness and even death.

Investigations

• Usually no specific investigation is undertaken other than removing the suspected drug or even several drugs and monitoring for improvement.
• FBC may show leukopenia, thrombocytopenia, and eosinophilia in patients with serious drug eruptions.
• In the severe forms of reactions, LFTs and renal function should be monitored. In vasculitis, CXR and urinalysis are required.
• In lupus-type responses, autoantibodies may be positive. Antihistone antibodies are often found in drug-induced SLE, whilst anti-Ro/SS-A antibodies are typical of drug-induced SCLE.
• Prick testing can be dangerous and patch testing is often of little value. it must be interpreted with caution.⁶
• Oral provocation tests may be regarded as the "gold standard" but they have to be conducted under strict supervision.
• In chronic cases, biopsy may be helpful.

Associated diseases
Although compromise of the immune system dampens the immune response it may increase the risk of adverse reactions, and patients with HIV have 10 times the average risk of drug reactions. The risk of serious adverse reactions such as Stevens-Johnson syndrome is even higher.

Common causes of nonimmunological reactions

Not all drug reactions are immunological in origin.

• The Jarisch-Herxheimer reaction classically occurs on starting penicillin for syphilis. It is due to the rapid destruction of spirochetes and the release of endotoxins from these organisms. It may occur with rickettsial illness such as Lyme disease as the organisms are similar. It may occur if penicillin is given for another condition and it was not known that the patient had syphilis. If the reaction is to be anticipated, the diagnosis of syphilis having been made, it is usual to start steroids at a dose such as prednisolone 20 mg a day, a day before the first injection of penicillin and to tail off quite rapidly over the next few days. It is important to make the diagnosis and not to mistake it for allergy to penicillin and stop the antibiotic or syphilis will remain inadequately treated. This reaction may sometimes be seen with griseofulvin or ketoconazole given for dermatophyte infections, and diethylcarbamazine treatment of onchocerciasis.
• Photosensitivity is not an immunological reaction. It may be caused by production of free radicals or reactive oxygen species. There is an excessive sensitivity to sunburn. The phenothiazines and doxycycline are often involved.
• Antimetabolites almost invariably cause certain adverse effects such as hair loss with cyclophosphamide.
• Argyria is the accumulation of silver from silver nitrate nasal sprays. It causes blue-grey discoloration of skin and nails.
• Aspirin and other NSAIDs can act on mast cells directly and cause release of histamine and other mediators without any immunological reaction. Other drugs that may do do include X-ray contrast media, cimetidine, quinine, hydralazine, atropine, vancomycin, tubocurarine, opiates, cytokines and even alcohol.
• Idiosyncratic reactions are unpredictable. In slow acetylators, drugs such as isoniazid may accumulate and cause peripheral neuropathy. If a patient with infectious mononucleosis is given ampicillin or amoxycillin there will almost invariably be a rash and the patient will probably be incorrectly labelled as allergic to penicillin. Penicillin V is the drug of choice for streptococcal sore throat and amoxycillin must not be given for throat infections, especially in young people.

Management
In uncomplicated cases, remove the offending drug and, if the condition resolves as expected, make notes to the effect that the patient has an adverse reaction to that drug. It may not be possible to be conclusive about which drug, if any was responsible and, whilst caution is prudent, it is inappropriate to be too eager to label patients as allergic to any specific drug. Many people have probably been wrongly labelled as allergic to penicillin over the years and denied this very safe and effective treatment but failure to note allergy can even be fatal.

Provided that they are not thought to be part of the problem, antihistamines may give some symptomatic relief.

Prognosis
Most cases resolve without complications but it may take 10 to 14 days for the rash to disappear. Patients with exanthematous eruptions will have mild desquamation as the rash resolves.

The Stevens Johnson syndrome has a mortality of around 5% whilst toxic epidermal necrolysis carries a mortality of 20-30%

Summary
This is a vast but very important area:

• Drug reactions are iatrogenic and hence contravene the principle of primum non nocere - 'first do no harm'.
• Patients are often too eager to attribute adverse reactions to prescribed medication but they may be correct. The doctor must keep an open and self-critical mind.
• History and examination are very important and ask about OTC, "alternative" and illicit medication.
• Most drug reactions are minor and self-limiting but certain red flags must be noted:
  • If the patient is systemically unwell this is serious.
  • If the rash is extensive, it could progress to a serious exfoliative dermatitis.
  • Detachment of the skin is serious.
  • Involvement of mucous membranes including eyes and genitalia may suggest Stevens-Johnson syndrome.
• The doctor must appreciate the protean nature of many adverse reactions and have a low threshold for stopping the drug, although if it is an essential drug this will require more circumspection.
• Accurate record-keeping is important to prevent a patient from being given a drug after an adverse reaction to it. On the other hand it is important not to be too eager to label a patient as allergic on tenuous and unsatisfactory grounds. It is a matter of looking at the evidence and balancing the risks.

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Document references

1. Daoud MS, Schanbacher CF, Dicken CH; Recognizing cutaneous drug eruptions. Reaction patterns provide clues to causes.; Postgrad Med. 1998 Jul;104(1):101-4, 107-8, 114-5. [abstract]
2. Nigen S, Knowles SR, Shear NH; Drug eruptions: approaching the diagnosis of drug-induced skin diseases.; J Drugs Dermatol. 2003 Jun;2(3):278-99. [abstract]
3. Rubin RL; Drug-induced lupus.; Toxicology. 2005 Apr 15;209(2):135-47. [abstract]
4. Hazin R, Ibrahimi OA, Hazin MI, et al; Stevens-Johnson syndrome: pathogenesis, diagnosis, and management. Ann Med. 2008;40(2):129-38. [abstract]
5. Forman R, Koren G, Shear NH; Erythema multiforme, Stevens-Johnson syndrome and toxic epidermal necrolysis in children: a review of 10 years' experience.; Drug Saf. 2002;25(13):965-72. [abstract]
6. Barbaud A; Drug patch testing in systemic cutaneous drug allergy.; Toxicology. 2005 Apr 15;209(2):209-16. [abstract]

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Internet and further reading

• Blume JE; Drug eruptions; emedicine January 2009
• Vervleot D, Durham S; Adverse drug reactions. Clinical review; BMJ 1998;316:1511-1514 ( 16 May ) Good pictures too.

Acknowledgements EMIS is grateful to Dr Hayley Willacy for writing this article. The final copy has passed scrutiny by the independent Mentor GP reviewing team. ©EMIS 2011.
Document ID: 1117
Document Version: 27
Document Reference: bgp2356
Last Updated: 14 Dec 2009
Planned Review: 13 Dec 2012