Professor Ihab Younis, M.D

Professor Ihab Younis, M.D.

Etiology• It occurs in approximately 2-5% of inpatients

and in greater than 1% of outpatients • Most estimates of the incidence of drug

eruptions are inaccurate, because many mild and transitory eruptions are not recorded, and because skin disorders are sometimes falsely attributed to drugs

• Elderly patients have an increased prevalence of adverse drug reactions

• It may be divided into immunologically and nonimmunologically mediated reactions

A - Immunologically mediated reactions

The 4 types of hypersensitivity occur:

Type I (IgE-Dependant)

• The drug or protein conjugates with two or more specific IgE molecules, then gets fixed to sensitized mast cells or circulating basophil. This triggers the cell to release a variety of chemical mediators e.g.histamine and cytokines

• Clinically, this may produce pruritus, urticaria, bronchospasm, laryngeal edema and in severe cases anaphylactic shock with hypotension and possible death

• Immediate reactions occur within minutes of drug administration; accelerated reactions may occur within hours or days, and are generally urticarial but may involve laryngeal oedema

• Penicillins are the commonest cause of IgE-dependent drug eruptions

Type II (Antibody Mediated)

• An immune complex is formed from: The drug + a cell + Ig G antibodies with subsequent

complement

fixation

• Example:thrombo-

cytopenic purpura

that may result

from antibodies to quinidine

Type III (Immune Complex Reaction)

• Soluble immune complexes are formed from Ig G class antibodies & a soluble antigen (not attached to the organ involved)

• Example:Vasculitis induced

by antibiotics results from

deposition of immune

complexes on vascular

endothelium resulting in

activation of the

complement cascade

Type IV (Delayed or cell-mediated)

• First,sensitization to the drug occurs when Langerhans' cells take up and process antigen, and migrate to regional lymph nodes, where they activate T cells with the consequent production of memory T cells, which end up in the dermis. On consequent exposure to the drug T cells & keratinocytes release cytokines causing inflammation

• Example:Contact dermatitis to neomycin

B- Nonimmunologically- mediated reactions

1-Accumulation: e.g. argyria (blue-gray discoloration of skin and nails) observed with use of silver nitrate nasal sprays

2-Side effects: unwanted or toxic effects, which are not separable from the desired pharmacological action of the drug e.g. the drowsiness induced by antihistamines

3-Direct release : The direct release of mast cell mediators is a dose-dependent phenomenon that does not involve antibodies. For example, aspirin and other NSAIDs cause a shift in leukotriene production, which triggers the release of histamine and other mast-cell mediators

4-Idiosyncrasy: a response, not predictable from animal experiments, and its cause is often unknown, but genetic variation in metabolic pathways may be involved e.g. dapsone induced hemolysis due to glucose-6-phosphate dehydrogenase deficiency

5-Intolerance:The characteristic effects of the drug are produced to an exaggerated extent by an abnormally small dose. This may simply represent an extreme within normal biological variation or may occur in patients with altered metabolism. For example, individuals who are slow acetylators of the enzyme N-acetyltransferase are more likely than others to develop drug-induced lupus in response to procainamide

6-Imbalance of endogenous flora: may occur when antimicrobial agents preferentially suppress the growth of one species of microbe, allowing other species to grow vigorously. For example, candidiasis frequently occurs with antibiotic therapy

7-Overdosage: is an exaggerated response to an increased amount of a medication. For example, increased doses of anticoagulants may result in purpura

8-Jarisch-Herxheimer phenomenon: is a reaction due to bacterial endotoxins and microbial antigens that are liberated by the destruction of microorganisms. The reaction is characterized by fever, tender lymphadenopathy, arthralgias, transient macular or urticarial eruptions, and exacerbation of preexisting cutaneous lesions. The reaction is not an indication to stop treatment because symptoms resolve with continued therapy. This reaction can be seen with penicillin therapy for syphilis, griseofulvin or ketoconazole therapy for dermatophyte infections

9-Metabolic effects: Drugs may induce cutaneous changes by their effects on metabolism e.g. isotretinoin may cause xanthomas by increasing lipoproteins

10-Teratogenicity and other effects on the fetus:Thalidomide, retinoids and cytotoxic drugs are proven teratogens and tetracyclines are deposited in developing bones and cause discoloration and enamel hypoplasia of teeth

11-Effects on spermatogenesis: A number of drugs cause oligospermia e.g. estrogens, androgens, cyproterone acetate, colchicine, most monoamine oxidase inhibitors, ketoconazole. Conception should also be avoided after griseofulvin for 3 months as it potentially can damage sperm

Clinically

• They usually begin 7-20 days after the medication is started

• They may involve blood or tissue eosinophilia

• They may recur if drugs chemically related to the causative agent are administered

During history taking note and detail the following:• All prescription and over-the-counter drugs,

including topical agents, vitamins, herbal, laxatives, oral contraceptives, vaccines, homeopathic medicines, etc. as these may not be volunteered as medications

• The interval between the introduction of a drug and onset of eruption

• Route, dose, duration, and frequency of drug administration

• Any improvement after drug withdrawal and any reaction with readministration

• Determining the morphology of drug eruptions can help the clinician determine the causative medication :

EruptionCommon drugs

1- Morbilliform (exanthematous(:

•It is the most common pattern

•Lesions are symmetric, with confluent erythematous macules and papules that spare the palms and soles

•It typically develops within 2 weeks after the onset of therapy

Ampicillin,penicillin,

phenylbutazone,sulpho-namides, gold, genta-mycin, cephalosporins,

barbit-

urates,

thia-

zides


2- Urticaria:

•It is the 2 nd most common eruption

•Occurs as small wheals that may coalesce or have cyclical or gyrate forms

•Lesions appear within 36h of intake and resolve rapidly when the drug is withdrawn

ACEI ,aspirin/NSAIDs,blood products,cephalosporins, cetirizine, dextran, infliximab, inhaled steroids, opiates, penicillin, radiologic contrast material, ranitidine, tetra-cycline, vaccines, zidovudine


3- Purpura:

•Can occur alone or as a component of vasculitis

Aspirin, cephalosporins, cytotoxics,heparin


4- Pityriasis rosea-like:

•Eruption is similar to PR

•Itching is severe not responding to antihist-amines

•There is no tendency of spontaneous remission

Gold,ACE inhibitors, thiazides, bismuth, barbiturates, griseofulvine,

metro-

nidazole


5-Erythroderma:It is a scaling erythematous dermatitis involving 90% or more of the cutaneous surface

Allopurinol,sulphonamides,antico-nvulsants, aspirin, barbiturates, captopril, cefoxitin, chloroquine, chlorpro-

mazine,

cimetidine,

griseofulvin ,

lithium,

nitrofurantoin


6- Serum sickness:

•Cutaneous signs begin with erythema on the sides of the fingers, hands, and toes and progress to a widespread eruption (most often morbilliform or urticarial)

• Viscera may be involved, and fever, arthralgia, and arthritis are common

Antithymocyte globulin for bone marrow failure, human rabies vaccine, penicillin and vaccines containing horse serum, aspirin


7- Erythema multiforme minor:

It is characterized by target lesions distributed

predominantly on the extremities. Mucous membrane involvement may occur but is not severe. Patients with EM minor recover fully, but relapses are common

Sulphonamides,cephalo-sporins,penicillins,tetra-cyclines, phenytoin, barbiturates, aspirin, NSAID,thiazides


8-Stevens Johnson synd.

•Bloody bullae, eroded, bloody or crusted lips, stomatitis and genitals mucosal ulceration

•Conjunctivitis

•Extensive EM on limbs

•Sloughing of >10% of skin

• Constitutional symptoms

•Lymphadenopathy

As EM


9-Toxic epidermal necrolysis:

•Starts with a burning morbilliform eruption accompanied by systemic flu-like symptoms

•This is quickly followed by rapid, widespread, full-thickness skin sloughing affecting 30% or more the total body surface area

As EM


10- Fixed drug eruptions:

• Lesions recur in the same area ½ -8 h after the drug is reused

•Circular, violaceous, edematous plaques that resolve with macular hyperpigmentation

•Hands, feet&genitalia are the most common sites but perioral and periorbital lesions may occur

Sulfonamides,penicillin, tetracyclines, aspirin/NSAID, barbiturates, cetirizine, ciprofloxacin, dapsone, fluconazole, hydroxyzine, loratadine, metronidazole, oral contraceptives, phenytoin, vancomycin


11- Lichenoid:

•May develop weeks or months after initiation of therapy

•Lesions are more extensive, more itchy and psoriasi-form than in idiopathic lichen

•Oral lesions are rare

•Resolution may take 1-4 months or more

Antimalarials, gold, diuretics,antihypertensives,

hypoglycaemicagents, NSAI,antituberculous,tetra-cyclines, allopurinol, phenytoin


12- Phototoxic dermatitis

•Min. to h. after sun exposure

•Exaggerated sunburn

•Vesicles& bullae in severe cases

•Burning is the main symptom

•Limited to sun-exposed skin

Photoallergic dermatitis

•1-3 days after sun exposure

•Lesions are eczematous

•Pruritus is the main symptom

•May spread to non-exposed area

Chlorpromazine, psoralens,sulphona-mides,tetracyclines, NSAI, thiazides


13- Acneiform:

•Characterized by inflammatory papules or pustules that have a follicular pattern

•Localized primarily on the upper body

•In contrast to acne vulgaris, comedones are absent

Corticosteroid, anabolic steroids, oral contraceptives,halogens, isoniazid, lithium, phenytoin


14- Pseudoporphyria:

•Blistering and skin fragility that is clinically and pathologically identical to that of porphyria cutanea tarda, but hypertrichosis and sclerodermoid changes are absent and urine and serum porphyrin levels are normal

Frusemide, cyclosporine, dapsone, etretinate, 5-fluoro-uracil,thiazides,isotretinoin, NSAIDs, oral contraceptives, tetracyclines


15 - Bullous pemphigoid:

•Patients tend to be younger

•Tissue-bound and circulating anti-basement-membrane zone IgG antibodies may be absent

Frusemide, penicillamine, penicillins, sulphasalazine, PUVA


16- Pemphigus:

•Pemphigus folliacius &erythematosus may occur but pemphigus vulgaris is rare

•Most patients have tissue and serum autoantibodies as in idiopathic pemphigus

Captopril, D-penicillamine, captopril, gold, penicillins


17- Leukocytoclastic vasculitis:

•It is the most common severe drug eruption

•There are blanching erythematous macules quickly followed by palpable purpura

• Fever, myalgias, arthritis, abdominal pain may occur

• It appears 7-21 days after the onset of therapy

Sulphonamides, frusemide, aspirin /NSAIDs, cimetidine, gold, hydralazine,mino-cycline, penicillins,

phenytoin,

quinolones,

sulfonamide,

tetracycline,

thiazides


18 -Erythema nodosum:

•Tender, red, subcutaneous nodules

•Appear on the anterior aspect of the legs

•Lesions do not suppurate or become ulcerated

Oral contraceptives (most common), halogens, penicillin, sulfonamides, tetracy-

clines


19- Sweet syndrome (acute febr. neutrophilic dermatosis):

•Tender erythematous papules and plaques occur most often on the face, neck, upper trunk, and extremities

•The surface of the lesions may become vesicular or pustular

•Systemic findings are common and include fever, arthritis, conjunctivitis, oral ulcers

Retinoic acid, nitrofurantoin, oral contraceptives, tetracyclines,trimetho-primsulfamethoxazole


20- Acral erythema:

•It is a relatively common reaction to chemotherapy

•There is symmetric tenderness, edema, and erythema of the palms and soles thought to be a direct toxic effect on skin

•It resolves 2-4 weeks after chemotherapy withdrawal

Cytotoxic

drugs


21- Acute generalized exanthematous pustulosis : Acute-onset fever and generalized scarlatiniform erythema occur with many small, sterile, nonfollicular pustules. The clinical presentation is similar to pustular psoriasis

Beta-lactam antibiotics, macrolides, and mercury


22- Hair loss:Cytotoxic drugs, anticoagulants, anticonvulsants, levodopa,

antithyroids


23 - Hypertichosis:Androgens, corticosteroids, minoxidil, phenytoin, penicillamine, cyclosporin, psoralens ,streptomycin

Nail changes

Silver : lunula discoloration

D-penicillamine: Yellow nail

Cytotoxics: Beau’s lines

Minocycline: blue nails

Rates of reactions to commonly used drugs

• Amoxicillin - 5.1% • Trimethoprim sulfamethoxazole - 4.7% • Ampicillin - 4.2% • Semisynthetic penicillin - 2.9% • Blood (whole human) - 2.8% • Penicillin G - 1.6% • Cephalosporins - 1.3% • Quinidine - 1.2% • Gentamicin sulfate - 1%

Drugs that commonly cause serious reactions

• Allopurinol • Anticonvulsants • NSAIDs • Sulfa drugs • Bumetanide • Captopril • Furosemide • Penicillamine • Thiazide diuretics

Drugs unlikely to cause skin reactions

•Digoxin

•Acetaminophen

•Diphenhydramine

•Aspirin

•Aminophylline

•Prochlorperazine

•Ferrous sulfate

•Prednisone

•Codeine

•Tetracycline

•Morphine

•Regular insulin

•Warfarin

•Folic acid

•Methyldopa

•Chlorpromazine

•Serotonin-specific reuptake inhibitors

Investigations• If history and physical examination are not

sufficient for diagnosis, the following investigations may help:– Biopsy e.g. by showing eosinophils in

morbilliform eruptions or numerous neutrophils without vasculitis in persons with Sweet syndrome

– CBC count with differential may show leukopenia, thrombocytopenia, and eosinophilia in patients with serious drug eruptions

– Special attention should be paid to the electrolyte balance and renal and/or hepatic function indices in patients with severe reactions such as SJS, TEN, or vasculitis

– Urinalysis, stool guaiac tests (for occult blood), and chest radiography are important for patients with vasculitis

– Drug reactions, apart from fixed drug eruption, have non-specific clinical features, and it is often impossible to identify the offending chemical with certainty, especially when a patient with a suspected reaction is receiving many drugs simultaneously

Treatment• Once the offending drug has been identified, it

should be promptly stopped. Failure of a rash to subside on drug withdrawal does not necessarily exonerate it, since traces of the drug may persist for long periods, and some reactions, once initiated, continue for many days without reexposure to the drug

• Patients with morbilliform eruptions can continue medication even in presence of rash as the eruption often resolves, especially if the individual is being treated for a serious disease

• Treatment of a drug eruption depends on the specific type of reaction

-Therapy for exanthematous drug eruptions is supportive in nature. First-generation antihistamines are used with mild topical steroids (e.g. hydrocortisone( and moisturizing lotions, especially during the late desquamative phase

• Oral antihistamines • A drying antipruritic lotion (calamine with or

without 0.25% menthol and/or 1% phenol) or lubricating antipruritic emollients will help relieve the pruritus. Lotions with phenol should not be given to pregnant women

• Topical steroids may provide some relief

• If signs and symptoms are severe, a 2-week course of systemic corticosteroids (prednisone, starting at 60 mg) will usually stop the symptoms and prevent further progression of the eruption within 48 hours of the onset of therapy

• Treatment of erythroderma : maintenance of body temperature and fluid and electrolyte balance, treatment of cardiac failure by use of digitalization and diuretics and administration of intravenous albumin for hypoalbuminaemia

• The management of TEN is perhaps best carried out on an intensive care or burns unit

Management of anaphlyaxis• Stop drug administration• Give i.m. 0.5-1ml 1:1000 adrenaline immediately• Check airway and give oxygen• Antihistamines:Chlorpheniramine maleate 1020 mg i.v.• Corticosteroids:Hydrocortisone 250mg i.v. and 100mg

6 hourly + Prednisolone 40mg/day for 3 d• I.V. Saline or glucose 5%• Monitor BP and pulse• For bronchospasm:aminophylline 250mg i.v. over 5

mins and 250mg in 500ml saline over 6 h.

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Professor Ihab Younis, M.D