Drug and the hypersensitivity reactions

hypersensitivity its pathomechanism, adverse drug reactions and their clinical syndromes

1. Drug and the hypersensitivity reactions Presenter Dr C. Handique PGT,Dept of pharmacology

2. “ When the solution becomes the problem”

3. 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. Hypersensitivity

4. Adverse Drug Reactions

5. Types

6. 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. Drug Hypersensitivity

7. 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.

8. 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, arthus reaction, PSGN, SLE IV Delayed or cellular hypersensitivity Contact dermatitis transplant rejections Types of Hypersensitivity Reactions

9. Type I IgE Mediated Reactions

10. 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.

11. 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.

12. Pathogenesis

13. 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.

14. Type II Hypersensitivvity Reaction

15. 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.

16. 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

17. Type III : Immune Complex Deposition

18. 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.

19. 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).

20. 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 .

21. Type IV Hypersensitivity Reactions

22. 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

23. Pseudoallergy

24. 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

25. 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 .

26. Clinical Symptoms of Drug Hypersensitivity

27. 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.

28. 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.

29. Anaphylaxis

30. 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.

31. 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.

32. 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 . Anaphylactoid Reactions

33. Pathomechanisms of Drug Hypersensitivity

34. Pathomechanisms of Drug Hypersensitivity

35. 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.

36. 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.

37. 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.

38. 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 .

39. 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 Factors Increasing Risk of Allergic Reactions

40. Diagnosis

41. 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.

42. 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.

43. Lab tests for IgE mediated reactions Skin testing RAST testing Serum Tryptase

44. Lab tests done for type II cytolytic reactions

45. Lab tests for type III immune complex reactions include ESR CRP ANA AHA Complement studies Tissue immunofluroscence studies

46. Lab tests for type IV hypersensitivity reaction Patch test Lymphocyte proliferation assay

47. 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 Therapy and Management

48. 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.

49. 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. Drug Desensitization

50. 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 .

51. All forms of natural and semisynthetic penicillins can cause allergy, but it is more commonly seen after parenteral than oral administration. The reported history of penicillin allergy ranges from 1% to 10%. Anaphylaxis is rare i.e 1 to 4 per 10,000 patients but may be fatal. It has been estimated that up to 60% of penicillin-allergic patients will experience another allergic event if given the drug again Penicillins

52. 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.

53. 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

54. 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 .

55. 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 . Cephalosporins

56. 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.

57. 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

58. 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

59. 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

60. 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 NSAIDS

61. 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

62. 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.

63. Clinical syndromes

64.  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

65. 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

66. 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 l amotrigine are frequently implicated DRESS

67. 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

68. 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

69. Condition Agent Asthma Asprin , timolol , methylphenidate, sulfasalazine Hypersensitivity pneumonitis Azathioprine , mercaptopurine , busulfan , fluoxetine Interstitial pneumonia Amphotericin B, bleomycin , busulfan , carbamazepine Pleural effusion Amiodarone , bleomycin , bromocriptine , busulfan

70. Tubulointerstitial Nephritis

71. 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 T he symptoms include fever,   rash and enlarged kidneys About 23% of patients have  eosinophilia . There may be hematuria , sterile pyuria or proteinuria

72. The drugs commonly implicated are antibiotics like methicillin , anticonvulsants, diuretics and NSAIDS. Corticosteroids   are not useful in this setting. T herapy consists of adequate fluid intake, which can require several liters of extra fluid.

73. Stevens Johnson S yndrome

74. 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.

75. Sulfonamides Penicillin Barbiturates Lamotrigine Phenytoin trimethoprim Herpes simplex virus AIDS   Coxsackievirus  Influenza Hepatitis Mumps

76. Toxic Epidermal Necrolysis

77. 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

78. Sulfonamide NSAIDS Allopurinol Methotrexate Antiretroviral drugs Corticosteroids Phenobarbitone   Phenytoin Carbamazepine Valproic acid

79. 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.