managament of drug reactions

MANAGEMENT OF DRUG REACTIONS

DIAGNOSIS

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

INVESTIGATIONS• With mild asymptomatic eruptions, the history &

physical examination are often sufficient for diagnosis

• With severe or persistent eruptions, further testing may be required as follows:

1. Biopsy

2. Complete blood count with differential

3. Serum electrolytes

4. Antibody or immunoserology studies

5. Urinalysis, chest radiography for vasculitis

Approach to a drug reaction

• The assessment of a potential drug adverse effect includes :

1. Taking a careful history & proper clinical examination

2. May involve a trial of:• drug elimination• Skin tests• In vitro tests• Challenge by re exposure(drug provocation

tests)

Drug History • Review the patient’s complete medication list ,

including prescription & OTC drugs• Any previous adverse reactions to drugs/food• Consider alternative etiologies (viral exanthems,

bacterial infections)• Note any concurrent infections, metabolic

disorders, or immunocomprimise• Note the interval between introduction of a drug

& onset of the eruption

Drug Elimination

• Resolution of a reaction on withdrawal of a drug is supportive incriminatory evidence but not diagnostic

• Failure of a rash to subside on drug withdrawal does not necessarily eliminates the possibility, as traces of the drug may persist for long periods & some reactions ,once initiated, may continue for many days without re exposure to the same drug

Skin Testing

• Skin testing should be performed 6 weeks- 6 months after complete resolution of the reaction

• There are 3 types of skin testing:

1. PRICK TESTS- immediate hypersensitivity reactions

2. PATCH TESTS- delayed hypersensitivity reactions

3. INTRA DERMAL TESTS- immediate & delayed hypersensitivity reactions

PRICK TESTS

• Performed on the skin of the volar aspects of forearm with the commercialized form of the drug, but with sequential dilutions

• Test reports are read at 20 mins and at 24 hours

PATCH TESTS

• Commercialized form of the drug should be tested at 30% in petroleum jelly/water at the site most effected in the initial reaction

• Use lower concentrations in severe adverse drug reactions

• Read the test at day 2, 4 and preferably also at 1 week

INTRADERMAL TESTS

• They are performed with sequential dilutions (10-4,10-3,10-

2,10-1) of 0.04 ml of a pure sterile/injectable form of the drug

• The test is read at 20 mins and at 24 hours

Advantages • Prick & Intradermal tests may be useful in

identification of patients who present with immediate IgE hypersensitivity reactions to certain drugs & thus may prevent anaphylaxis (ex: penicillin & other beta lactam antibiotics etc.)

• Drug Patch Tests are positive in 32-50% of patients with a drug eruption, particularly of value in maculopapular rashes , AGEP & FDE

• Patch test are of occasional use in SJS/TEN

RESULTS FALSE POSITIVE

• Can be due to an excipient ( surfactant polysorbate, emulsion stabilizer, carboxy methyl cellulose)

FALSE NEGATIVE

• Poor absorption through skin

• Test is done too soon after a reaction or too late

• A metabolite rather than the substance administered in the test is the sensitizing antigen

LIMITATIONS• Usefulness of skin testing is limited by the fact

that the significant antigenic determinants are unknown for most drugs

• Skin testing in not always safe as testing :

1. May induce a generalization of the drug reaction

2. May lead to anaphylactic response

3. May lead to exfoliative dermatitis

IN VITRO TESTS• They are in trial stage and are not routinely used

for clinical purposes• Various available tests are:

1. Basophil degranulation test

2. Histamine release test

3. Radioallergosorbent test

4. Leukocyte migration test

5. Lymphocyte transformation test

DRUG PROVOCATION TESTS

• Defn: It is the controlled administration of a drug in order to diagnose drug hypersensitivity reactions.

• DPT is widely considered to be the “gold standard” to establish or exclude the diagnosis of hypersensitivity to a certain drug

• DPTs are performed under medical surveillance.

• Commercial preparation of the drug is administered preferably by oral route at a starting dose which depends on the type of drug, severity of drug hypersensitivity reactions under investigation.

• Dosage is increased at regular intervals until the full therapeutic dose is given or any severe adverse reaction occurs

• DPT should never be performed on patients who have experienced severe, life-threatening immunocytotoxic reactions, vasculitic syndromes, exfoliative dermatitis, erythema multiforme major/Stevens-Johnson syndrome, drug induced hypersensitivity reactions (with eosinophilia)/DRESS and toxic epidermal necrolysis

TREATMENT OF DRUG ERUPTIONS• Approach to the treatment of drug eruptions

depends on the severity of the reactions:

1. Mild conditions:( morbilliform rash, FDE, AGEP)• Withdrawal of suspected drug• Symptomatic treatment with emollients, mild-

moderately potent topical corticosteroids & systemic antihistamines

• If the patient is receiving multiple medications, withdraw all medications, except the essential ones & consider alternative , non cross reacting drugs

Management of severe drug reactions

1. Promptly discontinue any and all possible offending drugs 2. Admit the patient in an ICU or burns ward under aseptic conditions3. Assess the condition of the patient to determine the prognosis

based on the SCORTEN score in cases of SJS/TEN

Correct the fluid & electrolyte imbalance:• Fluid loss and electrolyte imbalance should be

closely monitored and corrected• The fluid requirement is calculated based on the

parklands formula & 3/4ths of this total amount is given to a pt with TEN

Parkland’s formula = 4 ml/kg body wt × % BSA involved according to the rule of nine

Nutritional support:• Patient should be allowed to eat a soft, easily

chewable diet if oral feeding is feasible• If oral feeding is not possible, then nasogastric

tube feeding or parenteral feeding can be given • Early and continuous feeding decreases the risk

of stress ulcers, reduces bacterial dislocation, enterogenic infection

Temperature control: • Should be maintained at 30-32° c to avoid heat

loss

Wound care :

• Detached or detachable epidermis should be left in position as a biological dressing & only the denuded skin be covered with a dressing

• Condy’s compresses or petrolatum impregnated gauzes can be used

• An air fluid bed / water bed may be used to make the patient comfortable

Ophthalmic care : • 2 hourly instillation of eye drops ( saline or

antibiotic drops )• Developing synechiae are disrupted by a blunt

instrument

ANTIBIOTICS:• Are indicated if there is widespread epidermal

detachment

SPECIFIC TREATMENTS:

1. CORTICOSTEROIDS:

• Oral prednisolone (1-2 mg/kg/day) or parenteral steroids ( dexamethasone 8-16 mg daily or hydrocortisone) can be started within the first 72 hours in a patient with limited skin surface involvement to prevent wide spread diffusion, and continue for 3-5 days followed by rapid tapering

• Role of corticosteroids is controversial• Systemic corticosteroids may delay wound healing,

increase the risk of infection, mask early signs of sepsis, and may precipitate gastrointestinal bleeding

2. CYCLOSPORINE:

• It acts by inhibiting the activated T lymphocytes, macrophages & also interferes with the metabolism of TNF-α and possesses anti apoptotic properties

• Cyclosporine interrupts the disease progression & decreases the time taken for complete reepithelization

• Dose is 3-5 mg/kg/day oral or IV upto 2 weeks followed by weaning over another 2 weeks

• Watch out septic complications and severe leukopenia

3. INTRAVENOUS IMMUNOGLOBULINS:

• Can be considered if pt is seen within 48-72 hrs of bulla onset & in cases with active progressing lesions even after 72 hrs

• Total dose is 2 gr/kg , which is given as 0.4 g/kg/day for 5 consecutive days

• Adverse effects are risk of thromboembolism, hemolysis, vasomotor symptoms & anaphylactic reactions

• But the major limiting factor is its high cost

PREVENTION OF DRUG ERUPTIONS• Avoid drugs implicated in a previous reaction• Where it is essential to readminister one of a group of

the drugs to a patient with previous history of a drug eruption to related medication, then if possible preliminary skin testing should be carried out to enable identification of safe alternative therapy (under the cover of oral corticosteroids and antihistamines to prevent anaphylactic reaction)

• If no acceptable alternative for an essential drug is available, then consider rapid desensitization therapy

DESENSITIZATION THERAPY• Defn: The induction of a state of unresponsiveness to a

compound responsible for a hypersensitivity reaction( immediate IgE mediated reaction)

• It is a high risk procedure used only in patients in whom alternatives are less effective or not available

• It is performed by administering increasing doses of the medication over a short period of time ( from several hours to a few days ) until the total cumulative therapeutic dose is achieved & tolerated

• The starting doses range from 1/10000 to 1/100 of full therapeutic dose( it is also determined by taking into account the severity of previous reaction

managament of drug reactions

Health & Medicine

drug withdrawal

drug history

drug patch tests

type of drug

drug onset

diagnosis drug reactions

drug elimination skin

severe adverse drug