PresenterDr C. HandiquePGT,Dept of pharmacology

“ When the solution becomes the problem”

Hypersensitivity refers to undesirable reactions produced

by the normal immune system, including allergies

and autoimmunity.

These reactions may be damaging, uncomfortable, or

occasionally fatal.

Hypersensitivity reactions require a pre-sensitized

(immune) state of the host.

Adverse Drug Reactions

A

Augmented effects

B

Bizarre effects

C

Chronic effects

D

Delayed effects

E

End of treatment effects

It is an immunologically mediated reaction producing

symptoms unrelated to the pharmacodynamic profile of the

drug, generally occuring with much smaller doses and have

a different time course of onset and duration.

Drug hypersensitivity reactions account for about 1/6th of all

adverse drug reactions.

Drug hypersensitivity reactions can become manifest in a

great variety of clinical symptoms and diseases, some of

which are quite severe and even fatal.

The most common allergic reactions occur in the skin and

are observed in 2-3% of hospitalized patients.

Antibiotics and antiepileptics are the drugs most frequently

causing them.

The risk of sensitization and the severity of clinical

symptoms depend on the state of immune activation of the

individual, the dose and duration of treatment, sex and the

immunogenetic predisposition.

Type Mechanism Example

I IgE mediated hypersensitivty Anaphylaxis, urticaria, asthma

II Cytotoxic, antibody dependent Hemolytic anaemia, thrombocytopenia, interstitial nephritis

III Immune complex damage Serum sickness, arthusreaction, PSGN, SLE

IV Delayed or cellular hypersensitivity

Contact dermatitis transplant rejections

Type I IgE Mediated Reactions

The IgE system is geared to react to small amounts of

antigens.

Very small amounts of a drug are apparently sufficient to

interact and stimulate these receptor-bound IgE molecules.

The drug causes formation of tissue sensitizing IgE

antibodies that are fixed to mast cells or leucocytes.

The subsequent exposure to drug, degranulates mast cells or

activates leucocytes with release of chemical mediators of

allergy.

IgE-mediated reactions to drugs are usually thought to

depend on the prior development of an immune response to a

hapten/carrier complex.

This sensitization phase is asymptomatic and may have

occurred during an earlier drug treatment.

These reactions include anaphylaxis, atopy and asthma.

Clinical features

IgE-mediated reactions can cause mild to severe, even lethal,

diseases.

Symptoms may start with palmar, plantar, genital, and axillar

itch, and facial and thoracal redness

They often herald a severe, anaphylactic reaction, developing

rapidly within minutes.

Anaphylactic shock occurs often within 10 to 15 minutes, and

asphyxia due to laryngeal edema often occurs between 15 and

60 minutes.

It rely on the formation of complement-fixing IgG

antibodies.

The mediator of type II reactions is IgG/ IgM, complement

or membrane attack complex.

It results when drug binds to RBC and is recognized by IgG

antibody.

The antigen antibody reaction then triggers the lysis of RBC

either by activating the complement system or by the action

of cytotoxic T cells or by phagocytosis by macrophages.

It is rare and best documented for high-dose penicillin and

cephalosporin.

Quinine-induced immune thrombocytopenia

It is caused by a remarkable class of IgG and/or IgM

immunoglobulins.

They react with selected epitopes on platelet membrane

glycoproteins, only when the drug is present in its soluble form.

Hemolytic anemia attributed to penicillin and its derivatives,

cephalosporins, levodopa, methyldopa, quinidine and some

antiinflammatory drugs is also a type II reaction to these drugs

Soluble antigen antibody forms soluble complexes which

are deposited on vascular endothelium and activate

complement

This occurs within 1-2 weeks of drug administration

It is characterized by allergic inflammatory reactions in

tissues, glomerular nephritis and serum sickness.

Formation of immune complexes is a common event in the

frame of a normal immune response and does not normally

cause symptoms.

Immune complexes may be formed during drug treatment :

either if the drug forms a hapten-carrier complex and thus

gives rise to an immune reaction,

or if the drug is a (partly) foreign protein, which elicits an

immune reaction itself (e.g. a chimeric antibody).

Clinical features

The clinical symptoms of a type III reaction may be

hypersensitivity, small vessel vasculitis and/or serum

sickness

Serum sickness was first described with the use of

heterologous or foreign serum for passive immunizations

Hypersensitivity vasculitis reportedly has an incidence of 10–

30 cases per million people per year.

Most reports concern cefaclor, followed by trimethoprim-

sulfamethoxazole, cephalexin, amoxicillin, NSAIDs and

diuretics.

These reactions are mediated by T cells and monocytes/

macrophages rather than by antibodies.

The activation of sensitized T cells results in the release of

cytokines which activate macrophages, granulocytes and

natural killer cells

The term delayed is used to differentiate a secondary cellular

response, which appears 48-72 hours after antigen exposure,

from an immediate hypersensitivity response.

Often mentioned disorders are contact dermatitis, chronic

transplant rejections and hypersensitivity pneumonitis

They are a pathogenetically poorly defined problem

Most of these reactions resemble the clinical features of

milder forms of immediate, IgE-mediated reactions, but

some reactions cause anaphylaxis and can be lethal.

Detection of specific immune mechanism is negative.

NSAID induced pseudoallergic reactions seem to arise less

rapidly often >15 minutes after intake than true IgE-

mediated allergies

They may require higher drug doses than true IgE-mediated

reactions

Neither IgE nor Tcell reactions are evident.

The reactions are recurrent, but provocation tests often

remain negative.

The most common form of such reactions is related to

NSAIDs.

Drug reactions commonly manifest

with dermatologic symptoms

The most common dermatologic

manifestation of drug reaction are

morbilliform rashes.

Urticaria is typically a

manifestation of a truly allergic,

Type I reaction, but it may appear

with Type III or pseudoallergic

reactions as well.

Severe nonallergic, hypersensitivity cutaneous reactions

include erythema multiforme, Stevens-Johnson syndrome,

and toxic epidermal necrolysis.

Eczematous rashes are most commonly associated with

topical medications and usually represent contact dermatitis,

which is classified as Type IV reaction to a drug exposure.

Anaphylaxis is a serious allergic reaction that is rapid in

onset and may cause death.

Anaphylaxis typically presents many different symptoms over

minutes or hours with an average onset of 5 to 30 minutes if

exposure is intravenous and 2 hours for foods.

The most common areas affected include

skin, respiratory, gastrointestinal, heart and vasculature and

central nervous system with usually two or more being

involved.

Treatment for anaphylaxis

Immediate treatment with adrenaline is imperative.

Adrenaline 0.5 mg im is given. It is to be repeated every 5-10 min in case patient doesn’t improve.

H1 antihistaminic chlorpeniramine 20 mg im/slow iv acts as an adjuvant.

Intravenous hydrocortisone sodium succinate 200 mg should be added in severe/recurrent cases.

It may be followed by oral prednisolone for 3 days.

Anaphylactoid reactions refer to clinically similar events as

anaphylaxis but are not mediated by IgE.

It is also known as pseudoanaphylaxis.

They are a type of anaphylaxis that does not involve an

allergic reaction but are due to direct mast

cell degranulation.

Multivalency Haptenization

Conversion to active metabolites

Multivalency

Generally, an antigen must be presented to the immune

system in a multivalent form to elicit a specific immune

response.

Valency refers to the number of binding sites available to

bind antibody.

Multivalency is necessary to ensure cross-linking of

receptors on the surface of cells, which then causes

transduction of the signal within the cell and the initiation of

an immune response.

Drugs alone are poor stimulators of immune responses due

to their simple structure and low molecular weight.

Drugs can fulfill the requirement for multivalency and elicit

an immune response in two ways:

(1) Form hapten-carrier complexes and

(2) Be converted into reactive intermediates.

Haptenization

A hapten would be a particular drug, which would be

immunogenic in protein-conjugated but not free form.

An example would be penicillins and other betalactams that

bind covalently to proteins.

Conversion into reactive intermediates

This may occur via drug metabolism in the liver or

elsewhere.

This is the case with sulfonamides, which are acetylated

and oxidated to yield the predominant N4-sulfonamidoyl

hapten.

Chronic diseases that require continuous or frequent courses of

therapy with the same or cross-reactive drugs

Some allergic reactions are more likely to occur with certain

infections

Aminopenicillins with EBV infection,

Sulfonamides with AIDS patients

Atopy, a genetically determined state of hypersensitivity,

manifested as asthma, hay fever, and atopic dermatitis

History of other drug allergy

The diagnosis of drug hypersensitivity is usually based on

clinical judgment, because definitive, confirmatory drug-

specific testing is often difficult.

General criteria for drug hypersensitivity

The patient’s symptomatology is consistent with an

immunologic reaction.

The patient was administered a drug known to cause such

symptoms.

The temporal sequence of drug administration and

appearance of symptoms is consistent with drug reaction.

Laboratory data are supportive of an immunologic

mechanism to explain the drug reaction.

Lab tests for IgE mediated

reactions

Skin testing

RAST testing

Serum Tryptase

Lab tests done for type II cytolytic reactions

Lab tests for type III immune complex reactions include

ESR

CRP

ANA

AHA

Complement studies

Tissue immunofluroscence studies

Lab tests for type IV

hypersensitivity reaction

Patch test

Lymphocyte proliferation assay

The most important and effective measure is the

discontinuation of the offending medication.

Alternative medications with unrelated chemical structures

should be substituted when available.

In the majority of patients, symptoms will resolve within two

weeks if the diagnosis of drug hypersensitivity is correct

Additional therapy for drug hypersensitivity reactions is

supportive and symptomatic.

Systemic corticosteroids may speed recovery in severe cases.

Topical corticosteroids and oral antihistamines may improve

dermatologic symptoms.

The severe drug reactions of Stevens-Johnson syndrome and

toxic epidermal necrolysis require additional intensive

therapy.

Desensitization is a method to reduce or eliminate an

organism's negative reaction to a substance or stimulus.

It is the loss of responsiveness to the continuing or

increasing dose of a drug

Desensitization is a reversible process that is dependent on

the continued presence of the drug.

It is also drug-dose dependent in that a substantial dose

increase may result in breakthrough allergic symptoms.

The starting dose for the drug can be determined by

performing intradermal skin tests with the native drug at a

dose that does not cause a non-specific irritant reaction.

For example, if a 0.02 ml intradermal injection of a drug at

1 mg/ml concentration does not cause a local or systemic

reaction, oral desensitization may be started at the dose

injected

Parenteral desensitization should be using 1/10 or 1/100 of

the dose that was administered intradermally.

pencillin cephalosporins

Sulfa drugs NSAIDs

All forms of natural and semisynthetic penicillins can causeallergy, but it is more commonly seen after parenteral than oraladministration.

The reported history of penicillin allergy ranges from 1% to10%.

Anaphylaxis is rare i.e 1 to 4 per 10,000 patients but may befatal.

It has been estimated that up to 60% of penicillin-allergicpatients will experience another allergic event if given the drugagain

There are two clinical pictures of penicillin allergy, acute

and sub-acute reactions mediated by IgE and IgG antibodies

respectively.

The acute allergic reaction arises immediately or rapidly

within minutes to an hour or two and includes sudden

anaphylaxis.

Sub acute picture may occur 7 to 10 days after penicillin

treatment starts or 1–2 days after repeat therapy. In this

setting the picture is sub-acute and can include urticaria,

fever and arthralgias or arthritis.

Major and Minor Determinants

The betalactam ring is unstable and readily acylates lysine

residues in proteins.

The penicilloyl epitope is produced, which is called the

“major determinant”

Penicilloyl IgE responses are associated with urticarial

reactions.

Beta lactams also haptenize covalently through carboxyl

and thiol groups, which results in a variety of “minor”

determinants.

Minor determinant IgE responses are associated with

anaphylaxis

Penicillin skin sensitivity testing

A positive skin test indicates the presence of IgE antibodies

to penicillin and immediately excludes the use of it and

related ß-lactam antibiotics

A BPO-polylysine conjugate and penicillin G in a

concentration of 1000U/ml are available for skin testing

It is performed by prick technique-a drop of a dilute

allergenic extract is placed on the skin, which is then pricked

or punctured through the extract, usually by “tenting” up

the skin with the tip of a stylet.

Hypersensitivity reactions are the most important adverse

effects of cephalosporins.

Rashes are the most frequent manifestation.

Anaphylactic reactions to cephalosporins are much less

common than anaphylaxis associated with penicillin

About 10% patients allergic to penicillin show cross

reactivity with cephalosporins.

Skin testing

Currently there are no reliable cephalosporin allergens

available for skin testing.

A positive Coomb’s test occurs in many patients, but

hemolysis is rare

Allergic reactions to cephalosporins do not appear to

correlate with positive penicillin test reactions.

Co-trimoxazole is used extensively in the HIV population for

prophylaxis against Pneumocystis carinii pneumonia.

The overall prevalence of sulfa hypersensitivity in the general

population is approximately 3.3%, while in the HIV population

it is in the range of 17-20%

The incidence of adverse events to cotrimazole is greater than

50% in patients receiving the medication for treatment for

active PCP

Sulfa drugs are metabolized in the liver by two pathways:

--oxidative metabolism by the cytochrome p450 system

- acetylation by N-acetyltransferase.

Sulfamethoxazole is predominantly cleared by acetylation

and excreted by active tubular excretion.

The alternative pathway yields a reactive metabolite,

sulfamethoxazole hydroxylamine, which can generate an

immune response

Mechanism

The mechanism of hypersensitivity to cotrimoxazole is poorly

understood.

Several hypotheses have been put forward to explain the

predominance of reactions in HIV patients:

◦ slow acetylation in HIV patients

◦ polypharmacy with drugs such as INH and rifampin that

compete for metabolism in the liver

◦ reduced availability of cellular glutathione

Hypersensitivity diseases caused by NSAIDs are relatively

common in the population

The prevalence of these reactions in the population varies

between 0.1% and 0.3%

Immunologic reactions to NSAIDs can be subdivided into

immediate and delayed.

Immediate Reactions

Urticaria and Angioedema - acetaminophen, and aspirin

Allergic Anaphylaxis - ibuprofen, ketorolac, indomethacin,

acetaminophen, aspirin, diclofenac and celecoxib.

Delayed Reactions

Fixed-drug Eruptions.

Toxic Epidermal Necrolysis

Stevens-Johnson Syndrome

Acute Generalized Exanthyematous Pustulosis

Nonallergic Hypersensitivity

It includes Aspirin-induced asthma which is characterized by

asthma, rhinosinusitis, nasal polyposis, and aspirin

hypersensitivity.

Asthmatic reactions induced by NSAIDs occur in 5% to 20%

of adult asthmatic patients.

The pathogenesis seems to involve the combined effects of

chronic inflammation and a pharmacogenetic abnormality

of arachidonic acid metabolism in response to NSAIDs.

This reaction typically occurs 7 to 10 days after exposure and

causes fever, arthralgias, and rash.

Mechanism involves drug-antibody complexes and complement

activation.

Some patients have frank arthritis, edema, or GI symptoms.

Symptoms are self-limited, lasting 1 to 2 wk.

β-lactam and sulfonamide antibiotics, iron dextran and

carbamazepine are mostly implicated.

Serum Sickness

This disorder may develop when a drug alters the RBC

membrane, uncovering an antigen that induces autoantibody

production.

Antibodies then develop against the red blood cells. The

antibodies attach to red blood cells and cause them to break

down too early.

Drugs that can cause this type of hemolytic anemia include:

Cephalosporins, Dapsone, Levodopa, Levofloxacin,

Methyldopa, Nitrofurantoin , Quinidine

Hemolytic Anaemia

This reaction, can start up to 12 wk after initiation of drug

treatment and can occur after a dose increase.

Symptoms may persist or recur for several weeks after stopping

drug treatment.

Patients have prominent eosinophilia and often develop

hepatitis, exanthema, facial swelling, generalized edema, and

lymphadenopathy.

Carbamazepine, phenytoin, allopurinol and lamotrigine are

frequently implicated

DRESS

Hydralazine, propylthiouracil and procainamide

can cause an SLE-like syndrome.

It may be mild with arthralgias, fever, and rash or fairly

dramatic with serositis, high fevers, and malaise

The antinuclear antibody test is positive.

Penicillamine can cause SLE and other autoimmune

disorders like myasthenia gravis.

Some drugs can cause perinuclear antineutrophil

cytoplasmic autoantibodies (p-ANCA)–associated vasculitis. .

Other Autoimmune Diseases

Here a patient without previous pulmonary disease develops

respiratory symptoms, chest x-ray changes, deterioration of

pulmonary function, histologic changes, or several of these

findings in association with drug therapy.

Depending on the drug, it can cause interstitial fibrosis,

organizing pneumonia, asthma, noncardiogenic pulmonary

edema, pleural effusions, pulmonary eosinophilia,

pulmonary hemorrhage, or veno-occlusive disease

Pumonary Effects

Condition Agent

Asthma Asprin, timolol, methylphenidate,sulfasalazine

Hypersensitivitypneumonitis

Azathioprine, mercaptopurine, busulfan,fluoxetine

Interstitialpneumonia

Amphotericin B, bleomycin, busulfan,carbamazepine

Pleural effusion Amiodarone, bleomycin, bromocriptine,busulfan

Tubulointerstitial nephritis is the most common allergic

renal reaction

It is primary injury to renal tubules and interstitium

resulting in decreased renal function.

The acute form is most often due to allergic drug reactions

or to infections

The symptoms include fever, rash and enlarged kidneys

About 23% of patients have eosinophilia. There may be

hematuria, sterile pyuria or proteinuria

The drugs commonly implicated are antibiotics like

methicillin, anticonvulsants, diuretics and NSAIDS.

Corticosteroids are not useful in this setting.

Therapy consists of adequate fluid intake, which can require

several liters of extra fluid.

Stevens Johnson Syndrome

It is a form of a life-threatening skin condition, in which cell

death causes the epidermis to separate from the dermis.

The syndrome is thought to be a hypersensitivity complex that

affects the skin and the mucous membranes

This immune reaction can be triggered by drugs or infections.

Genetic factors are associated with a predisposition to SJS.

Slow acetylators, patients who are immunocompromised, and

patients with brain tumors undergoing radiotherapy with

concomitant antiepileptics are among those at most risk.

Sulfonamides

Penicillin

Barbiturates

Lamotrigine

Phenytoin

trimethoprim

Herpes simplex virus

AIDS

Coxsackievirus

Influenza

Hepatitis

Mumps

A life-threatening skin condition that is usually caused by a

reaction to drugs.

The disease causes the epidermis to detach the dermis, all

over the body.

Microscopically, TEN causes cell death throughout the

epidermis.

Often, the diagnosis is made clinically.

If the clinical history is consistent with Stevens–Johnson

syndrome, and the skin lesion covers greater than 30% of the

body surface area, the diagnosis of TEN is appropriate

Sulfonamide

NSAIDS

Allopurinol

Methotrexate

Antiretroviral drugs

Corticosteroids

Phenobarbitone

Phenytoin

Carbamazepine

Valproic acid

To conclude..

Drug Hypersensitivity Syndrome is potentially life-

threatening with significant morbidity.

Prompt diagnosis is vital, along with identification and early

withdrawal of suspect medicines.

However many of these drug reactions are pharmacological

reactions rather than hypersensitivity reactions.

So in assessing drug reactions, a detailed clinical history and

careful documentation of reactions are most important.