urticarial, purpuric, blistering, lichenoid, Exanthematic (maculopapular) reactions, Exfoliative dermatitis, Anaphylaxis and anaphylactoid reactions, Drug rash with eosinophilia and systemic symptoms (DRESS) syndrome, Serum sickness, Fixed drug eruptions, Photosensitivity, Acute generalized exanthematous pustulosis (toxic pustuloderma)

1. Clinical patterns of adverse drug
reactions
Moderator- Dr Vijay Paliwal

2. INTRODUCTION
• An adverse reaction is a reaction which is noxious and
unintended and which occurs at dosages normally used in
man for prophylaxis, diagnosis or therapy of disease or for the
modification of physiological function.
• CADR found in 2-3 percent of hospitalised patients.
• Ranges from common transient and benign erythema
occurring 6–9 days after the introduction of a new drug, to
the most severe forms which affect fewer than 1/10 000
users.

3. Exanthematic (maculopapular)
reactions
• Most frequent of all cutaneous
reactions to drugs.
• Can occur after almost any drug
at any time up to 3 (but usually
2) weeks after administration.
• Clinical features are variable,
rash may be morbilliform or
scarlatiniform or rubelliform.
• Consist of profuse eruptions of
small papules or purpuric
lesions, which are usually
associated with severe pruritus.

4. • Distribution is also variable
– generally symmetrical.
– trunk and extremities are usually involved
– face may be spared
– relative sparing of pressure areas.
– Palmar and plantar lesions may occur, and sometimes the
eruption is generalized.
• Usually fades with desquamation, sometimes with postinflammatory hyperpigmentation.
• The main differential diagnosis is from viral rashes.

5. • Ampicillin, amoxycillin and sulphonamides are amongst the
most frequent causes.
• Other common drugs include phenytoin, carbamazepine,
NSAIDS and ciprofloxacin.
• Less common drugs: cephalosporins, barbiturates, thiazides.
INH, phenothiazines, naproxen and quinidine.

6. Purpura
• Several mechanisms may be involved.
– Altered coagulation
– Allergic and non-allergic thrombocytopenia
– Altered platelet function
– Vascular causes
• Cytotoxic drug therapy, Bleomycin (non allergic tcp)
• Quinine, quinidine and chlorothiazide, heparin (allergic tcp)
• Tissue plasminogen activator (alteplase) associated with
painful purpura
• Pigmented purpuric eruption/capillaritis -aspirin, carbromal,
glipizide, pefloxacin, lorazepam, paracetamol,polyvinyl
pyrrolidone, plasma expander, ciclosporin and griseofulvin.

7. Exfoliative dermatitis
• It may follow exanthematous eruptions or may develop as
erythema and exudation in the flexures, rapidly generalizing.
• Serious condition and can be life threatening in elderly
patients.
• Takes 4 to 6 weeks to subside even after withdrawal of drugs.
• Most frequently encountered drugs include sulfonamides,
antimalarials, penicillin, INH, thioacetazone and a variety of
homeopathic preparations.
• Recently incriminated drugs are Captopril, Cefoxitin and
Cimetidine.

9. Anaphylaxis and anaphylactoid
reactions
• A systemic reaction, usually develops within minutes to hours
(mainly within the first hour), is often severe and may be fatal.
• In less severe cases, there may be premonitory dizziness or
faintness, skin tingling and reddening of the bulbar
conjunctiva, followed by urticaria, angio-oedema,
bronchospasm, abdominal pain and vasomotor collapse.
• Usually develops on second exposure to a drug, but may
develop during the first treatment.
• Antibiotics (especially penicillin) and radiocontrast media are
the most common known causes.

11. Urticaria
• Second most common type of CADR.
• Occurs within 24–36 h of drug ingestion.
• Most commonly caused by penicillins, sulphonamides and
NSAIDs (aspirin).
• Urticaria manifests as severely pruritic circumscribed raised,
oedematous and erythematous wheals widely scattered on
the body.
• As a rule, single lesions last less than 24 h, although new
lesions may continue to arise.
• Seen in association with anaphylaxis, angio-oedema and
serum sickness.

12. • Angioedema - edema of the deep dermis or subcutaneous
and submucosal areas.
• Characterized by deep, skin-colored swelling, most commonly
of the lips or eyes, that may last for several days. It may occur
with urticarial lesions or arise independently. Eg- ACE
inhibitors.

13. Drug rash with eosinophilia and systemic
symptoms (DRESS) syndrome
• Synonymous to Drug hypersensitivity syndrome, Anticonvulsant
hypersensitivity syndrome.
• It is a severe idiosyncratic reaction, syndrome comprises of :1. Fever
2. Facial oedema with infiltrated papules, generalized papulopustular
or exanthematous rash which may extend to exfoliative dermatitis.
3. Lymphadenopathy
4. Haematological abnormalities (hypereosinophilia in 90% of cases,
atypical lymphocytes/mononucleosis in 40% of cases)
5. Organ involvement such as hepatitis, possible nephritis,
pneumonitis, myocarditis and hypothyroidism, and encephalitis.
• It usually develops 2-6 weeks after the drug is first administered.

14. • The drugs associated with this syndrome include antiepileptic
agents- phenytoin, carbamazepine, phenobarbital and
lamotrigine; dapsone; allopurinol, gold, trimethoprim–
sulfamethoxazole, minocycline, procarbazine,
terbinafine,abacavir and nevirapine and sorbinil.
• The mortality is of the order of 10%.
• The cutaneous histological pattern shows a lymphocytic infi
ltrate, sometimes mimicking a cutaneous lymphoma.
• Recovery is usually total but rash and hepatitis may persist for
weeks.
• Treatment with steroids has been widely advocated but
controlled studies are lacking.

15. Serum sickness
• Serum sickness, a type III immune complex-mediated reaction
• Occur between 5 days and 3 weeks after initial exposure.
• In its complete form, combines fever, urticaria, angio-oedema, joint
pain and swelling, lymphadenopathy, and occasionally nephritis or
endocarditis, with eosinophilia.
• In minor forms, fever, urticaria and transitory joint tenderness may
be the only manifestations.
• Drugs implicated include heterologous serum , immunoglobulin,
aspirin, antibiotics such as penicillin, amoxicillin , flucloxacillin ,
cefaclor , cefprozil , piperacillin, ciprofloxacin , cotrimoxazole,
streptomycin, sulphonamides and sulfasalazine , thiouracils,
intravenous streptokinase, Nacetylcysteine.

16. • Circulating immune complexes, low serum C4 and C3 levels,
and elevated plasma C3a anaphylatoxin levels are found.
• Direct immunofluorescence revealed the presence of
immunoreactants including IgM, C3, IgE and IgA in the walls of
dermal blood vessels.

17. Fixed drug eruptions
• Characteristically recurs in the same site or sites each time the
same drug is administered; with each exposure, however, the
number of involved sites may increase.
• Acute lesions usually develop 30 min to 8 h after drug
administration.
• Sharply marginated, round or oval itchy plaques of erythema
and oedema becoming dusky violaceous or brown, and
sometimes vesicular or bullous.
• Eruption may initially be morbilliform, scarlatiniform or
erythema multiforme-like.
• As healing occurs, crusting and scaling are followed by
pigmentation, which may be very persistent and occasionally
extensive, especially in pigmented individuals.

18. • Distribution
– the hands and feet, genitalia and perianal areas are
favoured sites.
– Perioral and periorbital lesions may occur.
– Genital and oral mucous membranes may be involved in
association with skin lesions, or alone.

21. Lichenoid eruptions
• May develop weeks or months after initiation of therapy.
• Morphology of lesions– similar to lichen planus
– eczematous papules and generalized eczematous skin
reactions with marked desquamation.
– lesions are symmetrical, larger, and psoriasiform and often
have a photo distribution.
– Mucosa is less commonly involved
• Long-lasting, deep hyperpigmentation, alopecia and skin
atrophy with anhidrosis due to sweat gland atrophy.
• Resolution of the skin eruption may be slow after cessation of
therapy, on average from 1 to 4 months, but up to 24 months
with gold.

22. • Histopathology - focal parakeratosis; focal interruption of the
granular layer; cytoid bodies situated higher in the granular
and cornified layers; presence of a few eosinophils; exocytosis
of lymphoid cells into the upper epidermis; and a deeper
perivascular infiltrate.
Lichenoid photodermatitis occurring in a
patient with a long history of thiazide
ingestion.

24. Photosensitivity
• General term used to describe individuals that exhibit an increased
incidence of erythema upon exposure to ultraviolet radiation.
• This may be manifested as an inflammatory reaction upon exposure to
normally harmless levels of electromagnetic radiation or an exaggerated
response to inflammation-inducing levels.
• Eruptions on exposed areas
• Sparing of upper eyelids, submental and retroauricular areas
• May be phototoxic or photoallergic, cannot always be distinguished
clinically.
Phototoxic reactions
• Commoner than photoallergic reactions,
• Can be produced in almost all individuals given a high enough dose of drug
and sufficient light irradiation.
• Occur within 5–20 h of the first exposure, and resemble exaggerated
sunburn.
• Erythema, oedema, blistering, weeping, desquamation and residual
hyperpigmentation occur on exposed areas; photo-onycholysis.

25. Photoallergic reactions
• require a latent period during which sensitization occurs
• usually appear within 24 h of re-exposure to drug and light in a
sensitized individual
• may spread beyond irradiated areas.
• may occur as a result of local photocontact dermatitis to a topical
photoallergen, relatively common cause of photosensitivity,
accounting for 9% of cases.
• Topical photoallergens include antihistamines, chlorpromazine,
local anaesthetics, benzydamine, hydrocortisone, desoximetasone
(desoxymethasone) and sunscreens containing p-aminobenzoic
acid (PABA) and benzophenones.

27. Photorecall reactions
• A curious photorecall-like eruption, occurs, restricted to an
area of sunburn sustained previously, while on medication
with certain drugs.
• Cephazolin, gentamicin, piperacillin, tobramycin and ciprofl
oxacin, site of pelvic radiotherapy for carcinomas, and
Methotrexate.
Photo-onycholysis
• May be caused by tetracycline, psoralens and UVA (PUVA)
therapy, and the fluoroquinolone antibiotics, pefloxacin and
ofloxacin.

28. Pigmentation reactions
Hyperpigmentation
• Drug-induced alteration in skin colour may result from :
1.
2.
3.
4.
increased melanin synthesis
increased lipofuscin synthesis
cutaneous deposition of drug-related material
most commonly as a result of post-inflammatory hyperpigmentation
(e.g. fixed drug eruption).

30. Flagellate pigmentation from bleomycin
Minocycline pigmentation
Amiodarone pigmentation
Carotenemia due to anticonvulsants

31. Hypopigmentation
• Occupational exposure to monobenzyl ether of hydroquinone,
p-tertiary butylcatechol, p-tertiary-butylphenol, p-tertiary
amylphenol, monomethyl ether of hydroquinone and
hydroquinone
• Hypopigmentation may result from phenolic detergent
germicides and following use of diphencyprone for alopecia
areata .
• Depigmentation of the skin and hair occurred after a
phenobarbital-induced eruption.
• Photoleukomelanodermatitis occurred due to afloqualone for
cervical spondylosis

32. Acneiform and pustular eruptions
• Lesions are papulopustular but comedones are usually absent.
• ACTH, corticosteroids , dexamethasone in neurosurgical
patients, anabolic steroids for body-building , androgens (in
females), oral contraceptives, iodides and bromides may
produce acneiform eruptions.
• Isoniazid may induce acne, especially in slow inactivators of
the drug.
• Others include production of acneiform rashes include
dantrolene , danazol, quinidine , lithium and azathioprine.

33. Acute generalized exanthematous
pustulosis (toxic pustuloderma)
• A distinct reaction pattern commonly caused by β-lactam and
macrolide antibiotics.
• Especially ampicillin/amoxicillin + clavulanic acid, pristinamycin,
quinolones, (hydroxy)chloroquine, anti-infective sulphonamides,
terbinafine, diltiazem, carbamazepine and spiramycin,
metronidazole.
• Characterized by non-follicular based pustules on an erythematous
background that arise within 2 weeks of drug exposure
• The eruption usually begins on the face or intertriginous areas and
spreads rapidly to affect the entire body.
• In contrast to pustular psoriasis, polymorphous lesions, including
EM-like lesions and purpura, are common
• Fever and leukocytosis are also clinical clues to the diagnosis
• Histology characteristically demonstrates an intraepidermal
spongiform pustule with eosinophils.

35. Eczematous eruptions
• A patient initially sensitized to a drug by way of allergic contact
dermatitis may develop an eczematous reaction when the same, or
a chemically related, substance is subsequently administered
systemically - ‘systemic contact-type dermatitis medicamentosa’.
• The eruption tends to be symmetrical, and may involve first, or
most severely, the site(s) of the original dermatitis, before
becoming generalized.
• ‘baboon syndrome’ denotes a characteristic pattern of systemic
allergic contact dermatitis, in which there is diffuse erythema of the
buttocks, upper inner thighs and axillae, provoked by penicillin,
ampicillin, amoxicillin, nickel, heparin, mercury (including that
found in a homeopathic medicine) , terbinafine and hydroxyurea.

37. Erythema multiforme, Stevens–Johnson
syndrome and toxic epidermal necrolysis
• Widely accepted that EM minor, EM major, Stevens Johnson
syndrome (SJS) and toxic epidermal necrolysis (TEN) were all
part of a single “EM spectrum”.
• Recently a consensus clinical classification was proposed,
based on the pattern of skin lesions and the extent of
epidermal detachment.
• EM (minor or major) is mainly caused by herpes virus
infection and other infectious diseases, but rarely, if ever by
drugs.
• SJS, TEN and overlap (SJS/TEN) are probably severe variants of
a single disorder mainly caused by drugs.

38. • Diagnostic criteria for EM:
– an acute self-limiting illness
– Duration of episode less than four weeks
– Symmetrically and acrally distributed lesions, typical or raised atypical
target lesions.
– Absent or limited mucosal involvement.
– Recurrent episodes.
• Stevens Johnson Syndrome
– serious mucocutaneous illness with systemic symptoms and signs with
significant mortality.
– characterized by the presence of flat atypical target lesions or purpuric
macules with blisters that are distributed mainly on the trunk or
widespread
– epidermal detachment <10% of body surface area (BSA).
– Two or more mucosal sites can be involved.

39. • Toxic Epidermal Necrolysis –
– life threatening illness characterized by high fever and confluent
erythema followed by necrolysis
– epidermal detachment is >30% of BSA. Patients with this condition
may also have flat atypical target lesions (TEN with spots).
– Rarely extensive epidermal necrosis occurs without any discrete
target lesion (TEN without Spots)
• In the overlap category (SJS/TEN) the area of epidermal
detachment, is between 10 and 30% of the BSA.
• Typically begin 1-3weeks after the initiation of therapy.
• Suspected drug should be avoided lifelong.

41. Bullous eruptions
Bullous eruption in drug overdosage
• overdosage with barbiturates, methadone, meprobamate,
imipramine, nitrazepam or glutethimide.
• Bullae at pressure areas, usually in comatose patients.
Drug-induced porphyria
• excess destruction of haem or inhibition of haem synthesis by
certain drugs exacerbate the acute hepatic porphyrias.
Pseudoporphyria
• porphyria-like blistering of exposed areas on the extremities
occurs in the absence of abnormal porphyrin metabolism.

42. Drug-induced bullous pemphigoid
• Clinically drug induced bullous pemphigoid usually resembles
classic bullous pemphigoid with urticaria (hive)-like patches
and tense clear blisters that do not break easily.
• They usually appear suddenly.
• Sometimes it can look more like erythema multiforme .
• Rarely affects the mucous membranes.
• Generally it occurs in a younger age group than classic
idiopathic bullous pemphigoid, which is a disease of old age.
• The skin biopsy histopathology and direct immunofluoresence
is the same as for the classic disease.

43.  Drugs reported to cause this reaction include:
• Analgesics
• Antibiotics– including penicillins
• Captopril
• Diuretics – especially frusemide/furosemide, also
spironolactone
• Gold
• D-penicillamine
• Potassium iodide
• Sulfasalazine

44. Drug-induced pemphigus
• A number of drugs have been implicated in drug-induced
pemphigus, usually of foliaceus type, although the
erythematosus, herpetiformis and urticaria-like forms also
occur; drug-induced pemphigus vulgaris is rare.
• The skin lesions are flaccid blisters which break easily and
often only erosions +/- crusting are seen. The Nikolsky sign
can be positive.
• In drug-induced pemphigus, mucous membranes are only
involved in 10-15% of cases .
• The onset of drug related pemphigus can be weeks to
months after the drug was started.
• Resolution occurs after drug withdrawal in drug-induced
pemphigus but not if drug-triggered.

45.  Drug-induced pemphigus is caused by drugs with a thiol
group such as:
• D-penicillamine
• Captopril
• Gold sodium thiomalate
• Pyritinol
 Drug-triggered pemphigus follows nonthiol drug use
including:
• Antibiotics especially betalactams, rifampicin
• Pyrazolone derivatives
• Nifedipine
• Propranolol
• Piroxicam
• Phenobarbital

46. Tense subepithelial blisters
Well-demarcated crusted lesions scattered over the
chest

47. Linear IgA disease
• The drug related form usually resembles the idiopathic type
with tense small and large blisters often in ring-shaped
arrangements on the body, arms and legs.
• It may involve the palms and soles and rarely mucous
membranes. Rarely it may be more severe and resemble toxic
epidermal necrolysis.
• Skin biopsy shows the same histopathology and direct
immunofluoresence (DIF) features as in the idiopathic form.
• The reaction begins 1-2 weeks after starting the drug (range
24 hours to 15 days).

48. • When the offending drug is ceased, new blisters stop
appearing 1-3 days later and the rash has usually cleared by 3
weeks.
• Rechallenge with the drug results in a more severe reaction
with a shorter latency time and longer time to clearance.
• The most common drug associated with this reaction is
vancomycin.
• Others-amiodarone,ampicillin, atorvastatin , captopril ,
carbamazepine ,cefamandole (cephamandole), diclofenac,
furosemide , glibenclamide, IFN-γ, iodine, lithium, penicillin,
phenytoinand somatostatin, as well as tea-tree oil.

49. Lupus erythematosus-like syndrome
• 5% of cases of SLE are drug induced.
• Cutaneous involvement in drug-induced SLE may be vasculitic, bullous,
erythema multiforme-like or resemble pyoderma gangrenosum.
• Photosensitivity may be prominent, Constitutional symptoms may be
present, and there may be evidence of Raynaud’s disease, arthritis or
polyserositis.
• Differenting features include –
– occurs in an older age group
– renal and central nervous system involvement are infrequent
– antihistone antibodies are frequent
– anti-DNA antibodies are absent and serum complement is normal.
– deposition of immunoreactants in uninvolved skin is rare.
• The condition usually, but not always, resolves after discontinuation of the
drug.

51. • Commonly -Hydralazine ,procainamide, sulpha drugs
• less commonly- β- blockers, methyldopa, isoniazid, most
anticonvulsants in clinical use including phenytoin, carbamazepine,
ethosuximide, trimethadione, primidone and valproate (but not
phenobarbital or benzodiazepines) and quinidine.
• Subacute LE with positive Ro/SSA antibodies has been reported in
association with a number of drugs, including phenytoin, thiazide
diuretics such as hydrochlorothiazide , ACE inhibitors, calcium
channel blockers, terbinafine, griseofulvin , piroxicam, oxprenolol,
interferons and statins.
• A number of drugs may exacerbate pre-existing SLE, such as
griseofulvin, β-blockers, sulphonamides, testosterone and
oestrogens.

52. Vasculitis
• Vasculitis of various morphological types can be caused by
drug ingestion.
• The clinical pattern is usually that of a superficial small vessel
cutaneous leukocytoclastic vasculitis but other patterns,
including systemic vasculitis, occur.
• Drug-induced leukocytoclastic vasculitis presents with
palpable purpura, petechiae, necrosis and urticarial lesions,
indistinguishable from other causes of this pattern of
vasculitis.
• In the serum sickness-like reaction, the initial rash may be
acral, with urticaria or purpura, followed by more generalized
annular urticarial lesions. There may be fever, arthralgia,
haematuria or proteinuria, lymphadenopathy and decreased
complement.

53. • The patterns of polyarteritis nodosa, Henoch– Schönlein
vasculitis and hypocomplementaemic vasculitis are not seen
commonly with drugs.
• Indistinguishable clinically from the same clinical picture
occurring due to other causes.
– Timing of the eruption in relation to starting a new drug
may be informative.
– Blood eosinophilia and tissue eosinophilia is found in
almost 80% of patients.
– Drug caused ANCA-associated vasculitides (cocaine)
generally mimic the WG but with less systemic features,
has multiple ANCA specificities or anti-HLE, rather than the
more usual anti-MPO or anti-PR3 ANCA.

54. • Those most frequently implicated are penicillins,
sulphonamides, quinolones, analgesics (including nonsteroidal anti-inflammatory drugs), thiazides and other
diuretics, anticonvulsants, phenothiazines, allopurinol, and
colony-stimulating factors.
• Less commonly used drugs, but with a significant risk of
causing vasculitis, include hydralazine, quinidine, thiouracils
and various biological agents.
• Suspected drug should be avoided.

55. Pseudolymphomatous drug
hypersensitivity syndrome
• Should be differentiated from DRESS, which has a more acute
onset.
• Develops between 2 weeks and 5 years after starting drug
therapy, but usually within 7 weeks.
• Skin involvement consist of erythematous plaques, multiple
infiltrative papules or solitary nodules; there may be facial
oedema.
• Histopathologically, there is epidermotropism of atypical
lymphocytes, often with Pautrier’s microabscess-like
structures
• Misdiagnosed as cutaneous lymphoma.

56. • Causative drugs - Phenytoin especially, but also
phenobarbitone and carbamazepine, mephenytoin,
trimethadione and sodium valproate.
• Usually responds to drug withdrawal.

57. Pityriasis rosea-like reactions
• The best-known drug cause of a pityriasiform rash is gold
therapy but several other drugs have been implicated.
• Includes metronidazole,aspirin , captopril , isotretinoin and
omeprazole , angiotensin converting enzyme inhibitors, alone
or in combination with hydrochlorothiazide, followed by one
case each for hydrochlorothiazide plus sartan, allopurinol,
nimesulide, and acetylsalicylic acid.

59. Psoriasiform eruptions
• Psoriasiform eruptions are similar to idiopathic psoriasis and
typically consist of erythematous plaques surmounted by
large dry silvery scales.
• The time course between initiation of the causative agent and
exacerbation or formation of the eruption varies between
drugs, from less than 1 month to more than 3 months.
• One definite trigger is lithium, others are Terbinafine,
chloroquine and hydroxychloroquine , beta-blockers.
• Drug-associated or -exacerbated psoriasis is typically resistant
to treatment indicated for idiopathic psoriasis. The causative
agent should ideally be stopped or the dose reduced.

61. Widespread erythematous papulosquamous
lesions on (a) the trunk and buttocks, and (b) both
legs by lithium.

62. Widespread erythematous papulosquamous lesions on (a) the trunk
and buttocks, and (b) both legs by lithium.