1. Professor Ihab Younis, M.D.

2. 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

3. A - Immunologically mediated reactions
The 4 types of hypersensitivity occur:

4. 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

5. 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

6. 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

7. 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

8. 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

9. 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

10. 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

11. 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

12. 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

13. 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

14. 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

15. 11-Effects on spermatogenesis: A number of drugs cause oligospermia e
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

16. 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

17. 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

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

19. Common drugs
Eruption
Ampicillin,penicillin,
phenylbutazone,sulpho-namides, gold, genta-mycin, cephalosporins,
barbit-
urates,
thia-
zides
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

20. It is the 2 nd most common eruption
Common drugs
Eruption
ACEI ,aspirin/NSAIDs,blood products,cephalosporins, cetirizine, dextran, infliximab, inhaled steroids, opiates, penicillin, radiologic contrast material, ranitidine, tetra-cycline, vaccines, zidovudine
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

21. Aspirin, cephalosporins, cytotoxics,heparin 3- Purpura:
Common drugs
Eruption
Aspirin, cephalosporins, cytotoxics,heparin
3- Purpura:
Can occur alone or as a component of vasculitis

22. Common drugs
Eruption
Gold,ACE inhibitors, thiazides, bismuth, barbiturates, griseofulvine,
metro-
nidazole
4- Pityriasis rosea-like:
Eruption is similar to PR
Itching is severe not responding to antihist-amines
There is no tendency of spontaneous remission

23. Common drugs
Eruption
Allopurinol,sulphonamides,antico-nvulsants, aspirin, barbiturates, captopril, cefoxitin, chloroquine, chlorpro-
mazine,
cimetidine,
griseofulvin,
lithium,
nitrofurantoin
5-Erythroderma:It is a scaling erythematous dermatitis involving 90% or more of the cutaneous surface

24. Common drugs
Eruption
Antithymocyte globulin for bone marrow failure, human rabies vaccine, penicillin and vaccines containing horse serum, aspirin
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

25. Common drugs
Eruption
Sulphonamides,cephalo-sporins,penicillins,tetra-cyclines, phenytoin, barbiturates, aspirin, NSAID,thiazides
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

26. Common drugs
Eruption
As EM
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

27. 9-Toxic epidermal necrolysis:
Common drugs
Eruption
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

28. Common drugs
Eruption
Sulfonamides,penicillin, tetracyclines, aspirin/NSAID, barbiturates, cetirizine, ciprofloxacin, dapsone, fluconazole, hydroxyzine, loratadine, metronidazole, oral contraceptives, phenytoin, vancomycin
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

30. Common drugs
Eruption
Antimalarials, gold, diuretics,antihypertensives,
hypoglycaemicagents, NSAI,antituberculous,tetra-cyclines, allopurinol, phenytoin
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

31. Common drugs
Eruption
Chlorpromazine, psoralens,sulphona-mides,tetracyclines, NSAI, thiazides
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

32. Common drugs
Eruption
Corticosteroid, anabolic steroids, oral contraceptives,halogens, isoniazid, lithium, phenytoin
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

33. Common drugs
Eruption
Frusemide, cyclosporine, dapsone, etretinate, 5-fluoro-uracil,thiazides,isotretinoin, NSAIDs, oral contraceptives, tetracyclines
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

34. Common drugs
Eruption
Frusemide, penicillamine, penicillins, sulphasalazine, PUVA
15 - Bullous pemphigoid:
Patients tend to be younger
Tissue-bound and circulating anti-basement-membrane zone IgG antibodies may be absent

35. Common drugs
Eruption
Captopril, D-penicillamine, captopril, gold, penicillins
16- Pemphigus:
Pemphigus folliacius &erythematosus may occur but pemphigus vulgaris is rare
Most patients have tissue and serum autoantibodies as in idiopathic pemphigus

36. Common drugs
Eruption
Sulphonamides, frusemide, aspirin /NSAIDs, cimetidine, gold, hydralazine,mino-cycline, penicillins,
phenytoin,
quinolones,
sulfonamide,
tetracycline,
thiazides
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

37. Common drugs
Eruption
Oral contraceptives (most common), halogens, penicillin, sulfonamides, tetracy-
clines
18- Erythema nodosum:
Tender, red, subcutaneous nodules
Appear on the anterior aspect of the legs
Lesions do not suppurate or become ulcerated

38. Common drugs
Eruption
Retinoic acid, nitrofurantoin, oral contraceptives, tetracyclines,trimetho-primsulfamethoxazole
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

39. Common drugs
Eruption
Cytotoxic
drugs
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

40. Common drugs
Eruption
Beta-lactam antibiotics, macrolides, and mercury
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

41. Common drugs
Eruption
Cytotoxic drugs, anticoagulants, anticonvulsants, levodopa,
antithyroids
22- Hair loss:

42. Common drugs
Eruption
Androgens, corticosteroids, minoxidil, phenytoin, penicillamine, cyclosporin, psoralens ,streptomycin
23 - Hypertichosis:

43. Nail changes

44. Cytotoxics: Beau’s lines
Minocycline: blue nails
Silver : lunula discoloration
D-penicillamine: Yellow nail

45. 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%

46. Drugs that commonly cause serious reactions
Allopurinol
Anticonvulsants
NSAIDs
Sulfa drugs
Bumetanide
Captopril
Furosemide
Penicillamine
Thiazide diuretics

47. Drugs unlikely to cause skin reactions
Tetracycline
Morphine
Regular insulin
Warfarin
Folic acid
Methyldopa
Chlorpromazine
Serotonin-specific reuptake inhibitors
Digoxin
Acetaminophen
Diphenhydramine
Aspirin
Aminophylline
Prochlorperazine
Ferrous sulfate
Prednisone
Codeine

48. 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

49. 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

50. 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

51. 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

52. 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

53. 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

54. 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

55. Management of anaphlyaxis
Stop drug administration
Give i.m ml 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.