1. Author: Netherlands Pharmacovigilance Centre Lareb
Version date: 14 Nov 2017
Content: This lecture describes Drug allergy, by R. van Eekeren, PharmD, The Netherlands. This lecture can be used for teaching key aspect 2,3,4: preventing, recognizing, managing ADRs.

2. Drug allergy Pharmacovigilance course 2017
University of Groningen, The Netherlands
Drs R. (Rike) van Eekeren
Pharmacist

3. Hypersensitivity?
Intolerance?
Allergy?
Idiosyncrasy?
Side effect?

4. Learning objectives
Knowing the meaning of terms like allergy, hypersensitivity and intolerance
Explain differences in immunological reaction according to the Gell and Coombs classification and give some examples
Be able to discuss if a drug should be considered as contra- indicated and what consultation with other health care providers is necessary

5. Content ∙ Terminology Various types of hypersensitivity
Some diagnostics
Recordings and actions
Exam question examples

6. Terminology Classification of ADR Mechanism
Side effect / primary and secundary
(type A)
Pharmacological
Hypersensitivity
(type B)
- Allergic
Immunological
- Non-allergic
Pseudo-allergic
Various mechanisms, mimicking allergy
Idiosyncrasy
Genetic susceptibility for side effect or hypersensitivity
Intolerance
(avoid this term)
Sensitivity (poorly defined)
Unusually how treshold for type A reactions
Atypical or unknown reactions

7. Examples Enalapril Mechanism? Cough (dry) Hypotension Rash Angio-edema
(mouth, tongue, throat)
Diarrhoea
Side-effect (collateral Unknown mechanism
Pseudo-allergy Intolerance
Allergy Idiosyncrasy
Hypersensitivity

8. Examples Enalapril Mechanism? Cough (dry) Side-effect / Collateral
Hypotension
Rash
Allergy / hypersensitivity
Angio-edema
(mouth, tongue, throat)
Pseudo-allergy
(true allergy is also possible)
Diarrhoea
Unknown mechanism
Side-effect (collateral) Unknown mechanism
Pseudo-allergy Intolerance
Allergy Idiosyncrasy
Hypersensitivity

9. Content Terminology Various types of hypersensitivity Some diagnostics
Recording and actions
Exam question examples

10. Allergic hypersensitivity
A specific unwanted immune-mediated allergic reaction, resulting in tissue damage
As a rule, previous contact with the allergy inducing substance (allergen) is necessary (sensitization)
Risk of recurrence on repeated exposure with a risk of an increasing severity of the reaction
Cross-reaction based on drug structure may occur

12. Naissbitt et al. Drug Saf 2000; 23 (6):483-507

13. Classification according to Gell & Coombs
Four different type of allergic reactions:
Type I: Immediate hypersensitivity, IgE mediated e.g. urticaria (hives), anaphylactic reaction
Type II: Antibody-dependent cytotoxic hypersensitivity e.g. disorder of production of blood
Type III: Immune complex disease, e.g. serum sickness
Type IV: Delayed T-cell mediated hypersensitivity, e.g. cutaneous reactions

14. Type I allergy
Naisbitt et al. Drug Saf 2000; 23 (6):

15. Urticaria (hives, galbulten)
Wheal flare
Van den Bemt et al. Pharm Weekbl 1998; 133(32):

16. Case report type I Female, 56 years
Hypertension for a couple years, causing abnormalities of the retinal vessels (retinophaty)
Medication
- Betahistine
- Furosemide, Felodipine, Metoprolol
Because of decreased vision, consultation of an ophthalmologist
- Decision to fluorescence angiography
- IV administration fluorescein 100mg / ml;

17. Case report
After administration fluorescein i.v. suddenly unwell - Flushing - Low blood pressure - Treatment with epinephrine, clemastine and dexamethasone,
Died within minutes after administration of fluorescein
A known but very rare side effect fluorescein - Previous exposure to fluorescein - Influence of metoprolol?

19. Anaphylaxis (2)

20. Anaphylactic reaction and - shock
Anaphylactic reaction - At least two “organ systems” involved - Symptoms can vary considerably
Anaphylactic shock - Anaphylactic reaction in combination with very low blood pressure - Immediate treatment is required - High risk of death
Anaphylactic reaction may precede an anaphylactic shock

21. Type II allergy
Naisbitt et al. Drug Saf 2000; 23 (6):

22. Type II reactions Blood dyscrasias Involved drugs Hemolytic anaemia
Penicillins, cephalosporins, NSAIDs, kinidine, …
Thrombocytopenia
Sulfonamides, beta-lactam antibiotics, NSAIDs, carbamazepine, heparin, …
Neutropenia
Propylthyuracil, flecainide, …
Timing : > 5-8 days to weeks after exposure (sometimes asymptomatic at first)

23. Type III allergy
Naisbitt et al. Drug Saf 2000; 23 (6):

24. Case report type III Male, 35 years
Bupropion 150 mg for smoking cessation
One week after starting bupropion complaints - Fever, Fatigue - Rash on forearms - Lymph node swelling - Upper abdominal pain - Arthralgia
Increased markers for inflammation, decrease in renal and liver function
Referred to an internist; diagnosis “serum sickness like reaction”

25. Serum sickness like Reaction
Type III reaction - Formation of immune complexes between antibodies and drug - Precipitation of antibodies in various organs
Inflammation - Usually within 2-3 weeks after starting - Upon re-exposure occur within a week
Rare, serious side effect, which should be recongnized in time and treated.
Drugs: antibiotics, bupropion

26. Type IV allergy
Naisbitt et al. Drug Saf 2000; 23 (6):

27. Example of contact dermatitis after ingestion of a herbal drug
Van den Bemt et al. Pharm Weekbl 1998; 133(32):

28. Case report type IV
Female 88 years, amputation of lower leg in the past
Medication - Carbamazepine - Oxazepam - Lactulose - Nitrofurantion
Eczema of - Hands and feet - Head

29. Case Eczema Carbamazepine is replaced by oxcarbazepine
Complaints are gradually worse
After discontinuation only gradual improvement
Treatment with tropical steriods
Note: cross hypersensitivity
Carbamazepine
Oxcarbazepine

30. Clinical presentations type IV
Contact dermatitis
Maculopapular eruptions
Drug fever
Acute generalized exanthematous pustolosis (AGEP)
Stevens-Johnsom syndrome and toxic epidermal necrolysis (SJS / TEN)
Drug-induced hypersensitivity syndrome (DRESS)
Interstitial pneumonitis
Granulomatous hepatitis

32. Non-allergic hypersensitivity
Pseudo-allergy - Signs and symptoms that mimic immunologic drug allergies - No immunological mechanism
Idiosyncrasy - Unknown mechanism - Genetic predisposition

33. Pseudo-allergy
Direct mastcell stimulation - Opiates  pruritus, urticaria - Vancomycin  flushing during infusion (red man synd) - Ciprofloxacin  urticaria
Alteration in immunological mediators - Aspirin, NSAIDs  exacerbation asthma, rhinitis  urticaria, angioedema - ACE inhibitors  angioedema
Direct complement activation - Radio contrast media  anaphylaxis, shock

34. Idiosyncrasy (example)
Hemolytic anaemia caused by nitrofurantion, sulfasalzine, hydroxychloroquine, glibenclamide, ..., in patients with G6PD deficiency

35. Idiosyncrasy / Risk factors

36. Content Terminology Various types of hypersensitivity Some diagnostics
Recording and actions
Exam question examples

37. Diagnosis
Correct anamnese - Symptoms - Time relationship - Changes in the use of drugs - Prior exposure to drugs
Physical examination - Additional diagnostics (lab, skin testing) - Specific IgE to penicillin allergy (RAST) - Skin prick - Proofs (oral challenge; patch in type IV) - Specific parameters histamine and tryptase in type I, complement in type III eosinophils in type IV

39. Afbeelding: website LUMC

40. Content Terminology Various types of hypersensitivity Some diagnostics
Recording and actions
Exam question examples

41. Which information should be recorded?

42. Which information should be recorded?

43. To avoid, or?
Should a drug that has caused a true immunologic reaction always be avoided in future?
Should a drug that has caused a pseudo allergic reaction always be avoided in future?

44. Learning objectives
Knowing the meaning of terms like allergy, hypersensitivity and intolerance
Explain differences in immunological reaction according to the Gell and Coombs classification and give some excamples
Be able to discuss if a drug should be considered as contra- indicated and what consultation with other health care providers is necessary

45. Exam question (1) a. Type I, immediate type
Urticaria (hives) is a sign of a specific type of allergic reaction. Do you know which one?
a. Type I, immediate type
b. Type II, cytotoxic reaction
c. Type III, immune complex reaction
d. Type IV, delayed type

46. Exam question (2) a. Postural hypotension b. Dry cough c. Angioedema
Give an example of a non-allergic hypersensitivity reaction of enalapril (ACE-inhibitor)
a. Postural hypotension
b. Dry cough
c. Angioedema
d. Rash