The document provides information on adverse drug reactions and drug intolerance. It discusses the background and history of pharmacovigilance, the process of monitoring drug safety. It defines key terms like adverse drug reaction and classification of reactions. Investigations for adverse drug reactions include serum tryptase tests and skin testing. Examples of drug intolerances discussed are local anesthetics, beta-lactam antibiotics, NSAIDs, and metronidazole. Management strategies for common drug reactions are also outlined.

1. Seminar -5
DRUG INTOLERANCE
Dr.Payal Dash
PGT
Public Health Dentistry
Seminar 5
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2. CONTENTS
• Introduction
• Background
• Historical milestones
• Terminology
• Classification
• Investigations
• Applied aspects
• Recent Advances
• Summary
• Conclusion
• References
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3. INTRODUCTION
• Adverse drug reactions appear during the clinical use of a drug .
• Important cause of patient morbidity and mortality.
• Around 5% of all hospital admissions are the result of an ADR, and around 10%–
20% of inpatients will have at least one ADR during their hospital stay (Kongkaew
2008; Lundkvist 2004;Pirmohamed 1998)
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4. BACKGROUND
• Pharmacovigilance (PV) is defined by the European Commission (EU) as the
“Process and science of monitoring the safety of medicines and taking action to
reduce the risks and increase the benefts of medicines”
• The etymological roots for the word “pharmacovigilance”are: Pharmakon
(Greek)=medicinal substance, and Vigilia(Latin)=to keep watch.
The activities involved in pharmacovigilance are:
• Postmarketing surveillance and other methods of ADR
• Dissemination of ADR data through ‘drug alerts’, ‘medical letters,’
• Changes in the labelling of medicines
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5. HISTORICAL MILESTONES
Timeline of the historical evolution of Pharmacovigilance. *ASA: acetylsalicylic acid; **WHO: World
Health Orgnaisation; ***EMA: European Medicines Agency
Fornasier, G., Francescon, S., Leone, R. et al. An historical overview over Pharmacovigilance. Int J Clin Pharm 40, 744–747 (2018). https://doi.org/10.1007/s11096-018-0657-1
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6. 6

7. • The main changes in the new legislation were :
• Modification of the definition of adverse drug reactions(ADR);
• Greater involvement of patients and citizens in Pharmacovigilance activities;
• Strengthening of the Eudravigilance database containing reports of suspected
reactions reported by all EU Member States;
• Increasing transparency and timeliness of important information on
Pharmacovigilance problems;
• Obligation of “additional monitoring” for the products contained in the specifc list
kept by the EMA;
• Possibility to impose further safety and/or efcacy studies on the certifcates of
marketing authorization at the time of granting the trust;
• Establishment within the EMA of the Pharmacovigilance Risk Assessment
Committee (PRAC).
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8. TERMINOLOGY
• Adverse Drug Reaction (ADR)
• A response to a drug that is noxious and unintended and occurs at doses normally used in man for the
prophylaxis,diagnosis, or therapy of disease or for modification of physiological function (WHO)
• An appreciably harmful or unpleasant reaction, caused by an intervention related to the use of a
medicinal product,which predicts hazard from future administration and warrants prevention or specific
treatment, or alteration of the dosage regimen, or withdrawal of the product (Edwards)
• Any unexpected, unintended, undesired, or excessive response to a drug that requires discontinuing the
drug(therapeutic or diagnostic), requires changing the drug therapy, requires modifying the dose (except
for minor dosage adjustments), necessitates admission to a hospital, prolongs stay in a health care
facility, necessitates supportive treatment, significantly complicates diagnosis,negatively affects
prognosis, or results in temporary or permanent harm, disability, or death (ASHP)
• Harm directly caused by a drug at normal doses (Edwards)
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9. TERMINOLOGY
• Adverse Drug Event (ADE)
• Any untoward occurrence that may present during treatment with a pharmaceutical product but that
does not necessarily have a causal relation to the treatment (WHO)
• Injuries caused by medical interventions related to a drug.Adverse drug events may result from
medication errors or from ADRs in which there was no error (Bates)
• Unexpected Adverse Reaction
• An adverse reaction, the nature or severity of which is not consistent with domestic labeling or market
authorization,or expected from characteristics of the drug (Cobert)
• Serious Adverse Effect
• Any untoward medical occurrence that at any dose results in death, requires hospital admission or
prolongation of existing hospital stay, results in persistent or significant disability/incapacity, or is life
threatening (Edwards)
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10. TERMINOLOGY
• Signal
• Reported information on a possible causal relation between an adverse event and a drug, the relation
being previously unknown or incompletely documented (Edwards)
• Medication Error
• Any preventable event that may cause or lead to inappropriate medication use or patient harm while
the medication is in the control of the health care professional,patient, or consumer (NCC MERP)
• Errors in the process of ordering or delivering a medication, regardless of whether an injury occurred
or the potential for injury was present (Bates)d
• Inappropriate use of a drug that may or may not result in harm (Nebeker)
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11. CLASSIFICATION
Dose
dependent
predictable
TYPE
A Dose
indepedent
uncommon,
unpredictable
TYPE
B
ADVERSE DRUG REACTION
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12. CLASSIFICATION
• Common,predictable,low mortality
• Related to the pharmacological action of the drug
Type A
Augmented
• Uncommon,unpredictable,high mortality
• Not related to pharmacologic action of drug
Type B
Bizzare
• Uncommon
• Related to the cumulative dose
Type C
Chronic Reaction
Type D
Delayed
Type E
Withdrawal
Type F
Failure of therapy
Uncommon
Usually dose related
Occurs or becomes apparent sometime after use of the drug
Uncommon
Occurs soon after withdrawal of the drug
Common
Dose related
Often caused by drug interactions
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13. CLASSIFICATION
Tolerance
Innate Tolerance Acquired Tolerance
Pharmacokinetic Pharmacodynamic Learned
Acute Tolerance Reverse Tolerance Cross Tolerance
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14. • Innate tolerance
• refers to genetically determined sensitivity (or lack of sensitivity) to a drug that is
observed the first time that the drug is administered.
• Pharmacokinetic tolerance
• dispositional tolerance
• refers to changes in the distribution or metabolism of a drug after repeated
administrations such that a given dose produces a lower blood concentration than the
same dose did on initial exposure
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15. • Pharmacodynamic tolerance
• refers to adaptive changes that have taken place within systems affected by the drug
so that response to a given concentration of the drug is reduced.
• Learned Tolerance
• refers to a reduction in the effects of a drug owing to compensatory mechanisms that
are acquired by past experiences.
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16. • Acute tolerance
• refers to rapid tolerance developing with repeated use on a single occasion,
• Reverse tolerance/sensitization
• Refers to an increase in response with repetition of the same dose of the drug.
• Sensitization results in a shift to the left of the dose–response curve
• Cross-tolerance
• occurs when repeated use of a drug in a given category confers tolerance not only to
that drug but also to other drugs in the same structural and mechanistic category.
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17. • Adverse drug effects may be
categorized as
1.Side effects
2.Secondary effects
3.Toxic effects
4.Intolerance
5.Idiosyncrasy
6.Drug allergy
7.Photosensitivity
8.Drug dependence
9.Drug withdrawal reactions
10.Teratogenecity
It is the appearance of characteristic toxic
effects of a drug in an individual at
therapeutic doses.
It is the converse of tolerance and indicates
a low threshold of the individual to the
action of a drug.
Examples are:
• A single dose of triflupromazine induces
muscular dystonias in some individuals,
specially children.
• Only few doses of carbamazepine may
cause ataxia in some people.
• One tablet of chloroquine may cause
vomiting and abdominal pain in an
occasional patient.
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18. INVESTIGATIONS FOR ADR
• Serum tryptase
• Tryptase is a peptidase made and stored
in mast cells.
• Found in two forms, alpha and beta.
• A significant increase in the
concentration of serum tryptase (> 50
lg.suggests an IgE-mediated
anaphylaxis
• Non-IgE-mediated reactions (such as
complement-mediated reactions) may
generate lower concentrations of 20–50
µ lg.
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19. • Skin testing
• skin prick testing and intradermal testing.
• Skin prick testing involves placing a drop of the drug on the volar surface of the
forearm and pricking the skin through the drop with a lancet. The results are read
after 15–20 min with histamine and saline solutions used as positive and negative
controls.
• Drugs with antihistamine activity should be therefore discontinued several days
before testing, but steroids (oral or inhaled)do not need to be stopped.
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20. • Intradermal tests
• Performed on the forearm or back when skin prick tests are negative.
• They are more difficult to interpret with a higher false-positive rate IgE assays
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21. • Basophil activation test
• As well as mast cell activation, allergens stimulate histamine release and basophil
surface activation of CD63 and CD203.
• The basophil activation test and histaminerelease test are not currently widely
available to clinicians, but may be useful where hypersensitivity is highlysuspected
but not supported by skin testing or IgE assays
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22. APPLIED ASPECTS
• Local anesthetics
• β lactam antibiotics
• Nitroimidazoles
• NSAIDs
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23. APPLIED ASPECTS
1.local anesthetics
Allergic responses- dermatitis ,
bronchospasm, systemic anaphylaxis
hypersensitivity to ester type local
anesthetics more frequent
-Sodium bisulfite allergy
-epinephrine allergy
-latex allergy
-topical anesthetic allergy
-anaphylaxis
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24. • Dental Management in Presence of
Alleged LA allergy
• Elective Dental Care
• emergency dental care
• Dental Management in Presence of
Confirmed LA allergy
• depends on nature of allergy
• administer amide la
• histamine blockers
• general anesthesia
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25. Skin Reactions
• Delayed Skin Reactions
• P-A-B-C-D
• Definitive Care- oral histamine blocker-50mg diphenhydramine /10 mg
chlorpheniramine
• Immediate Skin Reactions-Parenteral histamine blocker-50mg
diphenhydramine(25mg if less than 30kg) /10 mg chlorpheniramine(5mg if less than
30kg)
• Respiratory reactions- Bronchospasm
• P-A-B-C
• oxygen via full face mask
• Epinephrine IM in vastus lateralis muscle (0.3 mg if >30kg)
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26. • Generalised Anaphylaxis
• Administer epinephrine (0.3 ml of
1:1000 for >30kg,0.15ml for <30kg
,0.075 ml for <15kg )
• administer oxygen
• monitor vital signs
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27. APPLIED ASPECTS
2.β lactam antibiotics-penicillins and cephalosporins
• Penicillin G - most nontoxic antibiotics; 20 MU
• Local irritancy and direct toxicity -
• Pain at i.m. injection site, nausea on oral ingestion and thrombophlebitis of injected
vein
• Toxicity - mental confusion, muscular twitchings, convulsions and coma, when very
large doses (> 20 MU) are injected i.v., Bleeding
• Intrathecal injection of PnG not recommended
• Accidental i.v. injection of procaine penicillin produces CNS stimulation,
hallucinations and convulsions
• Being insoluble,it may also cause microembolism.
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28. • Hypersensitivity
• incidence of 1–10% is reported.
• Individuals with an allergic diathesis are more prone to develop penicillin reactions.
• rash, itching, urticaria and fever.
• Anaphylaxis is rare (1 to 4 per 10,000 patients)
• partial cross sensitivity
• Topical application of penicillin is highly sensitizing (contact dermatitis and other
reactions)
• Hyposensitization
• Jarisch-Herxheimer reaction
• syphilitic patient (particularly secondary syphilis)
• shivering, fever, myalgia, exacerbation of lesions
• lasts for 12–72 hours.
• Aspirin and sedation afford relief of symptoms. 28

29. • Semi Synthetic Penicillins
• Classification
• 1. Acid-resistant alternative to penicillin G
• Phenoxymethyl penicillin (Penicillin V).
• 2. Penicillinase-resistant penicillins
• Methicillin, Cloxacillin, Dicloxacillin.
• 3. Extended spectrum penicillins
• (a) Aminopenicillins: Ampicillin,Bacampicillin, Amoxicillin.
• (b) Carboxypenicillins: Carbenicillin.
• (c) Ureidopenicillins: Piperacillin,Mezlocillin.
• β-lactamase inhibitors- Clavulanic acid Sulbactam, Tazobactam
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30. • Ampicillin
• Diarrhoea is frequent after oral administration.
• It produces a high incidence (up to 10%) of rashes, especially in patients with AIDS,
EB virus infections or lymphatic leukaemia.
• Avoid in immediate type of hypersensitivity to PnG patients
• Amoxicillin
• It is a close congener of ampicillin (but not a prodrug); similar to it inall respects
except:
• Oral absorption is better; food does not interfere with absorption; higher and more
• sustained blood levels are produced.
• Incidence of diarrhoea is lower.
• It is less active against Shigella and H.influenzae.
• It is more active against penicillin resistantStrep. pneumoniae.
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31. • Clavulonic acid
• are the same as for amoxicillin alone; but g.i. tolerance is poorer—especially in
children.
• Candida stomatitis/vaginitis and rashes. hepatic injury
• Cephalosporins
• Pain after i.m. injection
• Diarrhoea
• Hypersensitivity reactions
• Nephrotoxicity
• Bleeding
• Neutropenia and thrombocytopenia
• A disulfiram-like interaction with alcohol
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32. • Metronidazole
• Less frequent side effects are—headache glossitis, dryness of mouth and dizziness.
• Urticaria, flushing, heat, itching, rashes
• Prolonged administration may cause peripheral neuropathy and CNS effects.
Seizures , Leucopenia ,Thrombophlebitis
• Interactions
• disulfiram-like intolerance to alcohol occurs
• Enzyme inducers (phenobarbitone, rifampin) may reduce its therapeutic effect.
32

33. Vardakas, K. Z., Kalimeris, G. D., Triarides, N. A., & Falagas, M. E. (2018). An update on adverse drug reactions related to β-
lactam antibiotics. Expert Opinion on Drug Safety, 17(5), 499–508. doi:10.1080/14740338.2018.1462334
33

34. Ibuprofen
- safest traditional NSAID
-Side effects are milder and their incidence is lower.
-Gastric discomfort, nausea and vomiting, though less than aspirin or indomethacin, are
still the most common side effects.
-Gastric erosion and occult blood loss are rare.
-CNS side effects include headache, dizziness,blurring of vision, tinnitus and
depression.
-Rashes, itching and other hypersensitivity phenomena
are infrequent.
-Fluid retention is less marked.
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35. Laidlaw TM, Cahill KN. Current knowledge and management of hypersensitivity to aspirin and NSAIDs. J Allergy Clin Immunol Pract. 2017;5(3):537-
545
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36. • ASPIRIN-EXACERBATED RESPIRATORY DISEASE
• Widal syndrome, Samter triad, aspirin-sensitive asthma, and aspirin-induced asthma,
• distinct inflammatory syndrome affecting both the upper and lower airways.
• characterized by the triad of asthma, recurrent eosinophilic,nasal polyps, and
respiratory reactions induced by aspirin and all cyclooxygenase 1 (COX-1) inhibitors
36

37. Kowalski ML, Agache I, Bavbek S, et al. Diagnosis and management of NSAID-exacerbated respiratory disease (NERD): a EAACI position paper. Allergy.
2019:74(1)28-39.
37

38. • Management
• Avoidance of NSAIDs and use of alternative drugs
• Aspirin desensitization and high-dose aspirin therapy
• Leukotriene-modifying drugs
• Biologics (omalizumab, mepolizumab, and dupilumab)
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39. • MULTIPLE NSAID-EXACERBATED URTICARIA/ANGIOEDEMA IN
PATIENTS WITH UNDERLYING CUTANEOUS DISEASE
• NSAID-exacerbated urticaria/angioedema or NSAID-exacerbated cutaneous disease,
• defined as an increase in the frequency or severity of chronic urticaria and/or
angioedema with the use of any COX-1 inhibitor
• Management
• (1) management of the underlying chronic urticaria,
• (2) avoidance of all COX-1 inhibitors, and
• (3)use of selective COX-2 inhibitors for pain as needed
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40. • MULTIPLE NSAID-INDUCED URTICARIA/ANGIOEDEMA IN OTHERWISE
ASYMPTOMATIC PATIENTS
• defined as the development of urticaria and/or angioedema
• following exposure to any COX-1 inhibitor in patients who haveno history of chronic
urticaria or angioedema
• Management
• As with multiple NSAID-exacerbated urticaria/angioedema,
• NSAID avoidance or selective COX-2 inhibitor use is recommended. Successful
desensitization to aspirin (9 of 11 patients)
• using a rapid oral protocol has been reported with durable
• tolerance of aspirin for up to 2 years.
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41. • SINGLE NSAID-INDUCED ANAPHYLACTIC REACTIONS
• Anaphylaxis, urticaria, or angioedema can be induced by a single NSAID agent
• Management
• Avoidance of the culprit agent
• 1/100th the target dose of aspirin (eg, 1-3 mg) or lower is recommended
• DELAYED REACTIONS TO NSAIDs
• includes reactions that can involve any organ system ranging from cutaneous to
systemic reactions occurring after 24 hours or more of exposure
• Management
• Selection of a suitable alternative
• NSAID will need to be determined
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42. 42

43. 43

44. RECENT ADVANCES
• Unraveling urticaria
• Omalizumab, an anti-IgE antibody, is
recommended for the therapy of
chronic spontaneous urticaria (CSU)
refractory to antihistamines used even
at 4-fold doses
• complete response in 85 and 60% of
patients started on 300 and 150 mg,
respectively, and a high safety profile
• The Diagnostic ABC for Angioedema
• AE without wheals has long been
classified as either hereditary or
acquired.
Int Arch Allergy Immunol 2018;177:324–333 327
DOI: 10.1159/000494931
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45. CONCLUSION
• Adverse drug reactions, can be severe and life-threatening.
• They impact on patient stay, healthcare costs, morbidity and mortality, and
potentially affect future anaesthesia or drug exposure.
• Recognition of an ADR and identification of the causative agent can be challenging.
• As peri-operative specialists, anaesthetists must remain up to date with all aspects of
ADRs, including possible clinical presentations, common causative agents,
appropriate management and subsequent reporting
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46. SUMMARY
• Adverse drug reaction important cause of mortality and morbidity
• Various classification of adverse drug reactions
• Type A are dose dependent whereas type B are dose independent or
hypersensitivity reactions which is of four types
• Investigations of ADR can be done by Skin prick test, intradermal test
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47. REFERENCES
• Essentials of Medical Pharmacology Seventh Edition, K.D.Tripathy.Jaypee ,Page-374-465
• Goodman & Gilman’s The PharmacologicalBasis of THERAPEUTICS,eleventh edition,Page -
156,170
• Laidlaw, T. M., & Cahill, K. N. (2017). Current Knowledge and Management of Hypersensitivity to
Aspirin and NSAIDs. The Journal of Allergy and Clinical Immunology: In Practice, 5(3), 537–545.
doi:10.1016/j.jaip.2016.10.021
• Kowalski, M. L., Asero, R., Bavbek, S., Blanca, M., Blanca-Lopez, N., Bochenek, G., … Makowska,
J. (2013). Classification and practical approach to the diagnosis and management of hypersensitivity to
nonsteroidal anti-inflammatory drugs. Allergy, 68(10), 1219–1232. doi:10.1111/all.12260
• Vardakas, K. Z., Kalimeris, G. D., Triarides, N. A., & Falagas, M. E. (2018). An update on adverse
drug reactions related to β-lactam antibiotics. Expert Opinion on Drug Safety, 17(5), 499–508.
doi:10.1080/14740338.2018.1462334
• Patton, K., & Borshoff, D. C. (2018). Adverse drug reactions. Anaesthesia, 73, 76–84.
doi:10.1111/anae.14143
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