Drug Allergy(Adverse Reactions to Drugs)

Drug allergy is often a common term used to depict any unexpected and unwanted event or affect that occurs when an individual is taking a specific drug or therapeutic agent. A better, overall term to describe these circumstances would be an adverse reaction to a drug.

Overview of Adverse Drug Reactions

  • Most reactions do not involve the immune system
  • A skin rash is the most common type of drug reaction,
  • Most drug reaction occurs in adult females and those individuals who are frequently exposed to multiple medications
  • Most allergic drug reactions occur to beta-lactam (e.g. penicillin) antibiotics than to other antibiotics.
  • Reactions to radio contrast media (RCM) and aspirin/nonsteroidal anti-inflammatory agents are frequent causes of allergic-like or nonimmunologic reactions

Classification of Adverse drug reactions

Predictable risks

  • Toxic: overdose or side effects, delayed expression (e.g. teratogenicity, malignancy)
  • Allergy-like side effects
  • Superinfection
  • Drug interactions

Disease-associated risk

  • Impaired degradation, excretion of drugs, or both due to organ system failure (increased toxicity)
  • Conditions mimicking allergic reactions
  • Ampicillin reactions with infectious mononucleosis and other viral illnesses

Coincidental risks

  • Exanthematous infectious disease
  • Controversial: Stevens-Johnson Syndrome
  • Psychogenic

Risk of susceptible population

  • Intolerance
  • Idiosyncrasy
  • Allergy

Definition of Terms used to Describe Adverse Reactions to Drugs:

  • Intolerance: That condition in which a drug produces its expected toxic side effects at an unusually low dose. About 90% of adverse reactions to drugs fall into the intolerance group.
  • Drug overdose: toxic reaction owing to excess drug dose or impaired excretion.
  • Drug interaction: actions of two or more drugs on the toxicity or effects of each individual agent.
  • Idiosyncrasy: That condition in which the adverse reaction is strange and pharmacologically unexpected (i.e., different from the usual toxic reactions). Reactions of intolerance and idiosyncrasy may be related to the presence of enzyme defects in some patients.
  • Allergy: An acquired potential for developing an adverse reaction that is immunologically mediated. Allergy and hypersensitivity are often used interchangeably. In practise, of course, many reactions that are generally considered to be allergic could in fact be idiosyncratic, since no immune mechanism has been identified.
  • Anaphylactoid: An adverse reaction that mimics an allergic reaction but is produced by toxic rather than immune release of potent vasoactive and smooth muscle reactive mediators.
  • Carrier: A substance with immunogenic potential that, when coupled with a low molecular- weight drug or metabolite, renders that chemical (the hapten) immunogenic.
  • Cross-reaction: The reaction of an antibody or antigen-specific lymphocyte with an antigen other than the one that induced its formation. For example penicillin cross-reacts with cephalosporin antibiotics.
  • Hapten: A substance that can react with a specific antibody but is of a molecular weight too low for it to be immunogenic by itself. Penicillin is an example of a hapten.

DRUG ALLERGY

Immunologically-mediated (true allergy) to drugs account for 6-10% of all adverse drug effects. There are a number of specific characteristics that are generally helpful in distinguishing drug allergy from other adverse drug reactions, such as:

  • Previous treatment without adverse event
  • Occurs in only a small fraction of patients
  • Symptoms can be reproduced by a very small dose of drugs
  • Onset is usually after several days but within several months of initial administration of the drug
  • Subsides within several days to weeks following discontinuation of the drug.
  • Differs from any known pharmacologic manifestation
  • Can mimic other known allergic reaction including anaphylaxis and serum sickness

Immunologic Drug Reactions

  • Type I — IgE-antibody-mediated (e.g., Penicillin, insulin urticaria or anaphylaxis)
  • Type II — anti-tissue cytotoxic antibodies (e.g., drug-induced haemolytic anaemia or thrombocytopenia [reduced platelets])
  • Type III — antigen-antibody immune complex involving complement reactions (e.g., serum sickness-like drug reactions)
  • Type IV — cell-mediated or delayed hypersensitivity (e.g., neomycin contact dermatitis)

Risk Factors for Allergic Reactivity

  • Allergic drug reaction more common in adults than children
  • Genetic factors that control drug metabolism may influence the risk of drug hypersensitivity
  • Atopy is not a risk factor, but being atopic predisposes to a more severe reaction
  • Immunosuppression may enhance the sensitising potential of some drugs. An immunosupressed patient may become deficient in those suppressor T cells that regulate IgE antibody synthesis.

In recent years, immunosuppression associated with HIV infections has become a major risk factor for adverse drug reactions. Over half of the patients with AIDS develop adverse reactions when treated with trimethoprim-sulfamethoxazole. The incidence of reactions to Ampicillin is inversely proportional to CD4+ cell counts. Several other drugs have been found to have a higher than expected tendency to produce adverse reactions in HIV-infected patients. Most are mild-to-moderate skin eruptions, but the risk of anaphylaxis and even toxic epidermal necrolysis may also be enhanced in HIV infection

Topical medication to the skin (apparently not to the mucous membrane) is the most likely to sensitise and oral administration the least likely. Intravenous administration of a drug is less likely to sensitise than other parenteral routes.

The chemical nature of the drug also determines its allergenicity. Whether it is able to form stable conjugates with carrier proteins either directly or via a reactive metabolite.

Psuedoallergic Reactions

Allergic-like side effects can be produced directly by certain drugs in the absence of any evidence of hypersensitivity. In contrast to true allergic reactions, these occurs promptly the first time the drug is taken, if the dose is sufficiently high, appear only when the dose is increased. There are drugs that directly release histamine from mast cells. These histamine releasers produce reactions that are similar to anaphylaxis. Since they are not immunologically mediated they are referred to as anaphylactoid reactions. Examples of histamine releasing drugs:

  • Opiates
  • Vancomycin
  • Polymyxins
  • Radiograph contrast Media

Clinical Features of an Allergic Reaction

Only a small percentage of patients exposed to a drug will develop a true allergic reaction. In part, this depends on the chemical nature of the drug. Drugs that commonly induce allergic reactions include:

  • Penicillin
  • Sulpha antibiotics
  • Allopurinol (prescribed for gout)
  • Anti-seizure drugs
  • Anti-arrhythmia (heart medication)

When a true allergy develops, the signs and symptoms depend on the part of the immune system that is reacting. The potentially most severe reaction occurs when an allergic person’s immune system produces the allergic antibody IgE in response to a drug. When the person’s body encounters the drug again, IgE allergic antibodies bound to the mast cells result in release of histamine and other chemicals. This triggers symptoms of an allergic reaction, which may range from scattered hives to anaphylaxis.

The chances of developing an allergic reaction may be increased if the drug is given frequently, in large doses, or by injection rather than by a pill. The most important factor may be an inherited genetic tendency of the immune system to develop allergies. Contrary to popular myth, however a family history of allergy to a specific drug does not mean that a patient has an increased chance of reacting to the same drug.

  • The most common allergic reaction to a drug is a measles-like rash (without hives), which typically occurs after several days to two weeks of treatment. This is most likely caused by specific immune cells in the skin, which react to the drug. In most cases, only the skin is affected and the rash usually clears once the drug is discontinued. If there is itching an antihistamine may be helpful.
  • Urticaria (hives) and Drug Reactions:
    • Severe urticaria may be a manifestation of mild anaphylaxis or anaphylactoid reactions
    • Urticaria is suggestive, but not diagnostic of an allergic aetiology
    • Urticaria may be affected by other factors, such as viral infections.
    • A drug-induced rash that does not include urticaria does not rule out immunologic involvement.
  • Rarely, blisters develop in association with a drug rash. This is a sign of a serious complication, called erythema multiforme major (Stevens-Johnson syndrome), and should be treated as an emergency.
  • Anaphylaxis is the most severe allergic reaction. Symptoms suggestive of anaphylaxis include:
    • Sense of warmth, flushing, hives
    • Swelling of the throat
    • Asthma or wheezing
    • Nausea or vomiting
    • Light headedness from low blood pressure or shock
    • Abdominal cramping

These symptoms require emergency attention including an immediate injection of adrenaline. Rarely, if the reaction is not immediately treated with adrenaline, anaphylaxis can result in death.

All patients with drug anaphylaxis should be given a Medic-Alert bracelet, naming the drug that caused the reaction.

Most anaphylactic reaction occurs within one hour after the patient takes the drug. In 5-20% of cases, a recurrence of the anaphylactic reaction may occur up to several hours later. This is more common in patients who had a severe initial reaction. In patients at risk of anaphylaxis, the culprit, IgE antibody, was produced by the immune system in response to a prior exposure to the drug. As initial IgE production is gradual, many patients show no symptoms; others may develop itchy hives while taking the drug.

Clinical Manifestations of Penicillin Allergy

  • Immediate Type I – <1hour: Anaphylactic shock, urticaria (hives), angioedema (swelling of lips, tongue etc.)
  • Accelerated – 1-72 hours: Mainly urticaria
  • Skin: Measles-like rash, pruritus, Erythema Multiforme, Bullous Erythema, Erythroderma (generalised redness of the whole body)
  • Serum Sickness (Type III Reaction): Skin rash, joint pains, fever
  • Blood Disorders (Type II Reaction): Low white blood cell count, low platelets, anaemia
  • Renal: Nephritis
  • Late [Type IV Reaction] – >72 hours): Measles-like rash, Contact Dermatitis

Diagnosis of Drug Allergy

Any reaction to a drug, even over the counter medication should be reported to your doctor. It is important to know that you could develop an allergy to a drug that you have previously taken without ill effects.

Skin Prick Test

Currently, only limited tests are available to diagnose specific medication allergy. Allergy skin testing to determine the presence of IgE antibody is available for penicillin and insulin. Skin testing is sometimes done for other medication.

General anaphylaxis is unlikely because of the small amount of allergen (drug) introduced, but a physician should always be available for such occurrences.

Intradermal Test

This is more sensitive than the skin prick test for drug allergy.

0.05 — 0.1ml of the drug is injected intradermally in the upper arm and read at 30 minutes, 24 hours and 48 hours.

A positive reaction at 30 min is suggestive of immediate type (type 1) allergy and positive reaction at 48 h indicates delayed-type hypersensitivity (type 1V), for example allergic contact allergy (same information as patch gives).

The risk of general anaphylaxis is higher than in prick test because of the larger amount of allergen injected.

Patch Test

This test can be useful in patients who have a delayed reaction to drugs. Drugs that can be tested by patch test include:

  • Ampicillin
  • Clindamycin
  • Acyclovir (Zovirax)
  • Terbenafine
  • NSAIDs
  • Paracetamol
  • Macrolide Antibiotics
  • Hydrocortisone
  • Neomycin

Oral Challenge

Skin Tests and Patch Tests are only useful in a minority of patients with drug allergy, for the majority of patients if the diagnosis needs to be confirmed, it has to be done by oral challenges in a clinical or hospital setting

One study done, investigating children with suspected Antibiotics Allergy by Oral challenges, showed that the majority of suspected drug reactions were actually due to infectious disease or interaction of an infectious agent and the antibiotics.

Can drug Allergy be "outgrown"?

Yes, 70% of patients with penicillin allergy will lose their allergy over 5 to 10 years. Skin tests or RAST can be done to see if you are still allergic. There is no test to predict the chance of developing recurrent rashes. In the case of rashes caused by the antibiotic ampicillin, many patients can tolerate re-administration if the drug is necessary, but this might have to be done under supervision.

If you have had a blistering rash related to a drug, you should never be prescribed that drug again.

Remember to inform the doctor of all your drug reactions every time you are prescribed any medicine.

Treatment of Drug Allergy

  • Avoidance & use of Alternative drug is best option

    All patients should be given a Medic-Alert bracelet

  • Desensitisation

    Drug desensitisation can be a useful procedure in some carefully selected patients who have had an allergic or an allergic-like reaction to an agent but require the drug because their illness is serious and no substitute is available. Most information exists on desensitisation procedures involving immunological IgE reactions, especially those involving penicillin and insulin. Desensitisation has also proved helpful in the cases of some non-immunological anaphylactoid reactions, such as aspirin and sulphonamide-containing antibiotics. Drug desensitisation has been proved unsuccessful and dangerous when attempted for reactions of the febrile mucocutaneous type (e.g. Stevens-Johnson syndrome)

Drugs for which desensitisation has been used successfully include:

  • Aspirin
  • Trimethoprim/sulfamethoxazole
  • Penicillin
  • Allopurinol
  • Insulin
  • Vancomycin

Useful link – JCAAI : Drug Hypersensitivity
http://www.jcaai.org/Param/Drug.htm

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