Abstract: Cutaneous adverse reactions may be dangerous from transitory exanthematous rash ( It is the most frequent of all cutaneous reactions to drugs and may occur with almost any drug at any time upto three weeks (but usually two) after administration) to the potentially fatal Toxic Epidermal Necrolysis (TEN). An adverse reaction is noxious and unintentionally occurs at dosages normally used in people for prophylaxis, diagnosis or therapy of disease or for the modification of physiological function. Here in this poster presentation various types of cutaneous drug reaction will be presenting on basis of theoretical aspect and already experimented data to create awareness of cutaneous drug reactions and some basic concept of drug allergy, mechanism of drug absorption through skin layers to clear concept of over dose associated with right dosage regimen of pharmaceutically prepared chemically synthesized and herbal formulation.

1. Poster presentation on Adverse drug reaction of drugs used in skin diseases.
Presented by Miss Sudipta Roy
Designation: Assistant Professor
Place: Department of pharmaceutics, Northern Institute of Pharmacy and Research, Alwar,
Rajasthan, India
Abstract:
Cutaneous adverse reactions may be dangerous from transitory exanthematous rash ( It is the
most frequent of all cutaneous reactions to drugs and may occur with almost any drug at any time
upto three weeks (but usually two) after administration) to the potentially fatal Toxic Epidermal
Necrolysis (TEN). An adverse reaction is noxious and unintentionally occurs at dosages normally
used in people for prophylaxis, diagnosis or therapy of disease or for the modification of
physiological function. Here in this poster presentation various types of cutaneous drug reaction
will be presenting on basis of theoretical aspect and already experimented data to create awareness
of cutaneous drug reactions and some basic concept of drug allergy, mechanism of drug absorption
through skin layers to clear concept of over dose associated with right dosage regimen of
pharmaceutically prepared chemically synthesized and herbal formulation.
Aim and objective:
To create awareness about adverse drug reactions of drugs related to skin diseases.
Introduction:
Drug toxicity is the most common type of adverse case in hospitalised patients. Adverse drug
reactions may be of Immunological or nonimmunological mechanisms (which may be predictable
(type A) or unpredictable (type B)) .
* Type A(predictable) reactions: its a known pharmacological actions of the drugs and usually
dose related, predictable drug reactions include toxicity or overdose, side effects, drug interactions
and secondary effects.
* Type B (unpredictable) reactions: it's a Unpredictable reactions that are dose independent,
exempted from the pharmacological actions of the drug and may be on genetic basi, divided into
three categories: intolerance (an expected drug reaction at lower dose) , idiosyncratic reaction and
hypersensitivity reaction are qualitatively abnormal unexpected responses.
* Type C reactions include those associated with prolonged therapy e.g. analgesic nephropathy.
* Type D reactions consist of delayed reactions e.g. carcinogenesis and teratogenesis.

2. What is adverse drug reaction?
When drug metabolism is temporarily inhibited by disorder or by another drug. An unwanted
effect caused by the administration of a drug. The onset of the adverse reaction may be sudden or
develop over time, also called adverse drug event or adverse drug reaction or adverse effect.
General classification of adverse drug reaction:
This is classified into six types.These are following:
Dose related (Augmented)
Non dose related (Bizarre)
Dose related and time related (chronic)
Time related (Delayed)
Withdrawal (End of use)
Failure of therapy (failure)
What is drug toxicity?
Drug toxicity describes adverse effects of a drug that occurs because the dose or plasma
concentration has risen above the therapeutic range, either unintentionally or intentionally (Drug
over dose).
What is drug abuse?.
Drug abuse is the misuse of recreational or therapeutic drugs that may lead to addiction or
dependence.
What is pharmacovigilence?
The science and activities relating to the detection, assessment, understanding and prevention of
adverse drug reactions.
What is photosensitivity?
Cutaneous reaction results from drug induced sensitisation of skin to UV radiation. Drug of its
metabolic accumulates in skin absorbs lights and undergoes a photochemical reaction followed by
a photobiological reaction resulting in tissue damage (sunburn). That is odema, erythema,
blistering followed by hyperpigmentation and desquamation.
What is alopecia?
Alopecia is a common autoimmune skin disease, causing hair loss on the scalp, face and
sometimes on other areas of the body.
Alopecia areata is a common auto immune skin disease causing hair loss on the scalp, face, and
sometimes on the other areas of the body.

3. Structure of skin and mechanism of drug absorption through skin layers:
The skin layers consist of three layers.
The epidermis.
The dermis.
The subcutaneous tissue.
The epidermis consists of a multilayered, keratinising, stratified, squamous epithelium.
The dermis is thick, highly vascular layer made up of ground substance, fibroblast and collagen
fibres together with the appendages of the skin,
Sweat glands and pilosebaceous follicles embeded in it.
The subcutaneous tissue is a Fibro fatty layer with varying quantities of adipose tissue in different
regions of the body.
Mechanism of drug absorption through skin layers:
Absorption of drugs into the skin is slow and incomplete. It depends upon following factors:
The lipid solubility of the preparation.
The state of hydration of the stratum corneum-increased hydration increases the drug penetration.
Drug concentration in the vehicle.
Thickness of the skin (the thicker the skin, the lower the drug penetration.)
Quantity of the preparation applied, which varies with the extent of the skin lesion.
The presence of inflamed skin which allows higher penetration of drug.
The use of an occlusive dressing that increases the drug penetration into the skin.
An absorbed drug may be stored in the skin for prolonged periods, e. g. Atopical glucocorticoid
applied to the skin under occlusion for 24h eastablishing a reservoir for up to 2 weeks.
Different types of skin lesion related
to understand skin diseases:

4. Macule is a flat, coloured lesion, less than 2 cm in diameter that is not raised above the surface of
the surrounding skin.
A macule larger than 2 cm is called a patch.
Papule is a small solid lesion with diameter less than 1 cm, raised above the surface of the
surrounding skin.
Nodule: A raised lesion larger than 1 cm which is firm and easily palpable.
Vesicle: When the vesicle is filled with leucocytes, it is designated as a pustule.
Bulla: A raised fluid-filled lesion more than 1 cm in diameter.
Cyst:A soft, raised, encapsulated lesion which contains semisolid or liquid materials.
Wheal: A raised erythematous papule that is usually due to short lived dermal oedema.
How to examine skin diseases primarily?
The type of primary lesion.
The shape of the individual lesion.
Their arrangement.
The distribution of the eruption.
Presence of itching.
In vivo Testing.
i) Rechallenge (Test Dosing): A positive rechallenge is generally accepted as strong evidence
for causality. Reexposure should not be performed after a serious reaction.
ii) Patch Testing: It is a well-known method of rechallenging the skin in conditions when cell
mediated immunity is suspected viz-maculopapular eruptions, FDE, exfoliative dermatitis and
lichenoid dermatitis.
iii) Dechallenge: Most adverse reactions to drugs should remit with dechallenge i.e. withdrawal
of the drugs.
In Vitro Testing
Immunoassays such as radioallergosorbent lest (RAST) and Enzyme linked Immunosorbent
Assays (ELISA) are in varying stages of development for the detection of IgE to aminoglycosides,
penicillin, sulfonamides, ACTH etc.
Other tests include Lymphocyte Transformation Test (LTT), Macrophage Migration Inhibition
Factor Test (MIF), Lymphocyte Toxicity Assay (LTA), Basophil Degranulation Test, Histamine
Release Test, Haemagglutination Assays 108 and flowcytometry.
Management of cutaneous drug reactions.
* Stop the offending drug or all drugs
* Assess the type of rash.
* Symptomatic treatment (antihistamines) for minor reactions.

5. * Steroids for major reactions like SJS, TEN and exfoliative dermatitis.
 Short courses of steroids have been advocated in severe maculopapular reactions,
erythema multiforme and Stevens Johnson or overlap syndromes especially early in the
disease (within 48 hours of the onset of the disease). The rationale for the use of steroids
is based on the concept that TEN is due to a delayed hypersensitivity reaction or antibody
dependent cytotoxicity and also their inhibitory action against the secretion of Tumour
necrosis factor.
 Anti-viral therapy in case of HSV induced EM.
 Monitoring of vitals.
 Fluid and electrolyte maintenance Desensitization: when no alternative drug is available,
it is possible to induce a state of antigen specific mast cell unresponsiveness in patients
with Type 1 IgE mediated reactions especially to penicillin.
Elaboration of cutaneous drug reactions based on eastablished clinical data references:
Drug reactions in children and adolescent:
The common drug reaction patterns include maculopapular rash, fixed drug eruption and erythema
multiforme and the commonly implicated drugs are antibiotics, antiepileptics drugs, antiemetics,
bronchodilators, vaccines, antipyretic, analgesics and drugs used for preanaesthetic medication.
The frequency of drug rash is low in the younger age group, probably because of less cumulative
drug exposure, rapid dissipation of IgE compared to adults and poorly developed
immunopathologic mechanisms like impaired T cell reactivation, diminished production of
lymphokines, decreased chemotactic activity of macrophages and less functional competence of
NK cells.
Drug induced pigmentation:
This is due to increased melanin synthesis, increased lipofuscin synthesis, cutaneous deposition
of drug related material or most commonly as a result of post inflammatory hyperpigmentation.
Drugs causing pigmentation: oral contraceptives, minocycline, antimalarials (chloroquine and
mepacrine), chlorpromazine, clofazimine, gold and lead.
Miscellaneous reactions:
Other reactions include photosensitivity, pruritus, hypertrichosis, photoonycholysis, bullous
eruptions, alopecia, erythema nodosum, allergic eczematous dermatitis, systemic eczematous
"contact type" dermatitis and pityriasis rosea like eruptions.
Lichenoid drug reactions (LDE):
skin eruptions caused by certain drugs and compounds can be identical or similar to lichen planus.
An LDE may have eczematous papules and generalized eczematous skin reactions with marked
desquamation. The lesions are symmetrical, larger, and psoriasiform and often have a photo

6. distribution. Mucosae are less commonly involved.
Responsible drugs:
Inducers of LDE, gold salts, antimalarials, diuretics, calcium channel blockers, heavy metals etc.
Exanthematous (maculopapular) rash:
It is the most frequent of all cutaneous reactions to drugs and may occur with almost any drug at
any time upto three weeks (but usually two) after administration. They may consist of profuse
eruptions of small papules or purpuric lesions, which are usually associated with severe pruritus.
The distribution is generally bilaterally symmetrical involving trunk and extremities.
Responsible drugs:
Ampicillin, amoxycillin and sulphonamides are amongst the most frequent causes, other common
drugs indlude phenytoin carbamazepine, NSAIDS and ciprofloxacin
. Less common drugs: cephalosporins, barbiturates, thiazides. INK phenothiazines, naproxen and
quinidine.
Fixed Drug eruption (FDE):
FDE are characterized by a single or a few sharply demarcated erythematous lesions, which
resolve promptly but the local hyperpigmentation remains. Face, genitalia and the extremities are
commonly affected.
Responsible drug: sulfonamides especially cotrimoxazole, NSAIDS, phenolphthalein,
tetracyclines and ciprofloxacin.
Urticaria/angioedemalanaphylaxis:
Immediate hypersensitivity reactions can produce a range of cutaneous findings from simple
urticaria to angioedema or fatal anaphylaxis. Most urticarial and angioedema reactions caused by
antibiotics are I9E mediated with the exception of polymyxin B and vancomycin, which directly
release histamine from mast cells and basophils.
Responsible drug: Penicillin is the most common drug but other antibiotics including
sulphonamides, cephalosporins and tetracyclines, as well as diuretics, tranquilizers, analgesics,
muscle relaxants and anti hypertensives may be responsible. Morphine, codeine, doxorubicin,
certain muscle relaxants like d-tubocurarine, and ionic radiocontrast dyes all cause mast cell
degranulation. Urticaria and angioedema due to aspirin and other cyclooxygenase inhibitors is
probably due to an imbalance between prostaglandin and leukotriene production.
Stevens Johnson Syndrome:
It is a serious mucocutaneous illness with systemic symptoms and signs with significant mortality,

7. characterized by the presence of flat atypical target lesions or purpuric macules with blisters that
are distributed mainly on the trunk or widespread and the epidermal detachment being less than
ten percent of body surface area (BSA). Two or more mucosalsites can be involved.
Toxic Epidermal Necrolysis:
It is a life threatening illness characterized by high fever and confluent erythema followed by
necrolysis. The epidermal detachment is more than 30 per cent of BSA. Patients with this
condition may also have flat atypical target lesions (TEN with spots). Extensive epidermal
necrosis occurs without any discrete target lesion (TEN without Spots).
In the overlap category (SJS/TEN) the area of epidermal detachment, which is often much less
than the area of erythema, is between 10 and 30% of the BSA.
Drug induced SJS and TEN typically begin one to three weeks after the initiation of therapy.
Responsible drug:
Thioacetazone Allopurinol, Isoniaid Barbiturates, Diphenylhydantoin, Chlorpromazine,
Carbamazepine, Erythromycin, Phenylbutazone, Rifampicin, Cotrimoxazole , NSAIDs
Ampicillin, Salicylates, Oxytetracycline, Oxyphenbutazone, Phenylbutazone, Piroxicam, Pyritinol,
Diltiazam.
Exfoliative Dermatitis:
It may follow exanthematous eruptions or may develop as erythema and exudation in the flexures,
rapidly generalizing. It is a serious condition and can be life threatening in elderly patients. It takes
4 of 6 weeks to subside even after withdrawalof drugs.
Responsible drugs: sulfonamides, antimalarials, penicillin, INK thioacetazone and a variety of
homeopathic preparations. Recently incriminated drugs are Captopril, Cefoxitin and Cimetidine.
Pseudolymphomatous eruptions:
The pseudolymphoma syndrome is associated with a number of anticonvulsant drugs and is
characterized by fever, generalized rash, lymphadenopathy, hepatosplenomegaly, abnormal liver
function tests, arthralgia, eosinophilia and dyscrasias. This condition usually responds to drug
withdrawal.
Responsible drugs: Phenytoin, Mepheloin, Trimethadione and Phenobarbitone.
Vasculitis:
It is characterized by inflammation and necrosis of small vessel walls, having multiple etiologies
and drugs cause about 10 percent of cases of acute cutaneous vasculitis. It usually develops 7-21

8. days after a new drug is begun and is clinically characterized by palpable purpura predominantly
of the lower extremities. The other less common manifestations include erythematous macules,
haemorrhagic vesicles, papules, wheals, blisters, ecchymoses and large palpable nodules. It may
involve other organs including kidneys, liver, joints, CNS and pericardium. Histologically there is
swelling of endothelial cells, fibrinoid necrosis, neutrophilic infiltrate within and around the blood
vessel and nuclear dust.
Responsible drug: allopurinol, penicillin. aminopenicillins, sulphonamides, thiazides, pyrazolones,
hydantoin, propylthiouracil, streptomycin, phenothiazine. aminosalicylic acids, vitamins,
tamoxifen and oral contraceptive pills.
Serum sickness:
It is a type 3 hypersensitivity reaction mediated by the depositions of immune complexes in small
vessels, activation of complement and recruitment of granulocytes. Serum sickness in its usual
form is characterised by fever, urticaria (lasting for more than 24 hours), angioedema, arthralgia
and/or arthritis and lymphadenopathy. About half the cases of serum sickness, have visceral
involvement. In serum sickness C3 and C4 complement levels are markedly decreased.
Responsible drugs: like penicillin, streptomycin, sulphonamides, thiouracil, diphenyil hydantoin
and aminosalicylic acid.
Hypersensitivity syndrome:
It is a severe idiosyncratic reaction characterized by skin rash and fever, often associated with
hepatitis, arthralgia, lymphadenopathy or haematological abnormalities. It usually develops two to
six weeks after the drug is first administered.
Responsible drugs: antiepileptic agents, dapsone, allopurinol, gold and sorbinil. Recovery is
usually total but rash and hepatitis may persist for weeks. Treatment with steroids has been widely
advocated but controlled studies are lacking.
Conclusion:
Drug reactions are considered to be rare in infants and children. Though allergic reactions are
considered to be less common in aged people due to dampening of Immunological
responsiveness[8], adverse drug reactions occur frequently with increasing age, especially in those
above 65 years. Factors which may predispose elderly to adverse drug reactions, includes
polypharmacyage associated changes in pharmacokinetics and pharmacodynamics, altered
homeostasis, multiple pathology and use of drugs with a narrow therapeutic margin.Cutaneous
reactions are more frequent among women. Presence of infectious mononucleosis increases the
risk of hypersensitivity skin rash to ampicillin or its analogues.Human Immunodeficiency Virus

9. (HIV) increases the propensity for sulfonamide rash. Pre-existing diseases(impaired hepatic and
renal function) increase the risk of development of drug rashes.Multiple drugs: Use of multiple
drugs is associated with higher incidence of drug reactions as observed with increased frequency
in hospitalised patients. Drugs: Certain drugs are associated with higher incidence of drug reaction
eg. amoxycillin in 5.1 %, ampicillin in 3.3% and cotrimoxazole in 3.2%.
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