Adverse Drug Reactions in Dentistry (ADRs): Burden of Disease and Special Considerations

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Adverse Drug Reactions in Dentistry (ADRs)
Burden of Disease and Special Considerations

• Michael J. Rieder
• Section of Paediatric Clinical Pharmacology
• Childrens Hospital of Western Ontario
• Division of Clinical Pharmacology
• Faculty of Medicine Dentistry
• University of Western Ontario
• London, Ontario
• mrieder_at_uwo.ca

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Maria

• 6 year old child who had a dental abscess treated
  in the clinic
• Penicillin started 1 week ago
• Over the past two days, she has developed fever,
  malaise and a rash

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Objectives

• Appreciate rate of ADRs
• Understand patterns of ADRs to drugs common to
  dental practice
• Appreciate an approach to an ADR associated with
  dental therapy

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Perspective on Therapy

• God and His Majesty forbid, the fire of the enemy
  is not half so dangerous as a single drug
• M. Platov, 1812

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Selective Therapy

• Era of selective therapy began in two labs in
  Europe
• Cambridge in 1928 - Sir Alexander Fleming
  -discovery of penicillin
• Germany in 1935 - Gerhard Domagk - discovery of
  sulfanilamide
• Demonstration of antimicrobial activity
• Serenpedity at work - neither investigator was
  trying to find an antibiotic

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Changes in the Paradigm

• Demonstration of antimicrobial activity of major
  importance
• Illustration - therapy of Strep. meningitis
  consisted of rabbit serum, supportive therapy and
  prayer
• Infectious deaths common
• Medical paradigm - care, not cure

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Changes in Care - Consequences

• Sulfanilamide activity described in 1935
• Widespread clinical use by 1937
• Major change in clinical care paradigms
• In first 10 years of use, 10,000 lives saved in
  UK among children who would have died of Strep.
  Infections
• Care becomes Cure (Lewis Thomas, Reflections of a
  Biology Watcher)

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Elixir of Sulfanilamide Tragedy

• Sulfanilamide dissolved in ethylene glycol to
  improve palatability
• Ethylene glycol - a potent nephrotoxin
• No pre-marketiug toxicity studies done
• Approximately 170 deaths from renal failure,
  mostly among children
• Responsible chemist committed suicide
• Major issue in Congress - led to changes that led
  to current drug regulatory system

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Introduction

• Adverse Drug Reactions are a common and important
  clinical problem
• Seen in 5 of patients treated
• Responsible for 5 of all hospital admissions
• JAMA 1998 279 1200-5

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98,000 people in the USA die each year as a
result of medical errors
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ADRs in Dentistry

• Relatively little data with respect to ADRs in
  Dental practice compared to Medical practice
• What data is present suggests that overall rates
  may be similar
• No a priori reason to assume different rates

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ADR Rates

• Overall, rate of ADRs in dental patients appears
  to be similar to adults
• Risk appears to relate to known risk factors
• Int J Clin Pharmacol Ther 1988 36 530-3

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Risk Factors for ADRs

• History of a previous ADR
• Polypharmacy
• Impairment of the organs of excretion (hepatic or
  renal dysfunction)
• Extremes of age
• Female gender

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History of ADRs

• Elixir of Sulfanilamide Tragedy, 1937
• Chloramphenicol Grey Baby Syndrome, 1950s
• Thallidomide Teratogenicity, 1960s
• Drug substitution errors 1980s
• Ten-fold errors 1990s
• Molecular Misadventures

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ADR Classification

• ADRs often called drug allergy
• Immune involvement is common, but true drug
  allergy is relatively rare
• Mislabelling leads to therapeutic confusion

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Hypersensitivity - Gell Coombs Type I
Vasodilation Smooth Muscle Contraction Chemotaxis
Mast Cell
Degranulation
Urticaria Bronchoconstriction Hypotension - Shock
Inflammation
IgE
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Hypersensitivity - Gell Coombs Type II
Cell lysis Phagocytosis
IgG
NK Cell
Phagocyte
Complement
Removed by Reticuloendothelial System
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Hypersensitivity - Gell Coombs Type III
Blood Vessel
IgG
Complement
Immune Complexes
Phagocyte
Reactive Oxygen Species
Inflammation
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Type IV Hypersensitivity
Immunologic Memory
Sensitisation
Target Cell
Antigen Presenting Cell
Cytotoxic T Cell
Cytokines
Inflammation
Cell Destruction
Macrophage
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Gell and Coombs

• Elegant, erudite classification system
• Mechanistic
• Sadly, does not address the vast majority of ADRs

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ADR Classifications

• A number of schemes have been proposed
• Unfortunate and common use of the term allergy
• Patterson, DeSwarte and Greenberger (1986)
• Predictable
• Unpredictable
• New England Review of Allergy Proceedings, 1986,
  7 325-42

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Predictable ADRs

• Predicated on and predictable from the drugs
  pharmacology
• Side Effects
• Secondary Effects
• Interactions
• Toxicity

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Unpredictable ADRs

• Not known to be related to the drugs
  pharmacology
• Intolerance
• Allergic - Pseudoallergic
• Idiosyncratic
• Psychogenic

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Predictable ADRs

• Side Effects
• Fine tremor associated with inhaled salbutamol
  (albuterol)
• Secondary Effects
• Pseudomembranous colitis after lincomycin therapy
• Interactions
• Bleeding when coumadin and cimetadine are given
  concurrently
• Toxicity
• Metabolic acidosis in salicylate overdose

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Unpredictable ADRs

• Intolerance
• Intractable vomiting associated with erythromycin
  therapy
• Allergic - Pseudoallergic
• Anaphylaxis or urticaria associated with
  pencillin therapy
• Idiosyncratic
• Stevens-Johnson Syndrome associated with
  sulphonamides
• Psychogenic
• Environmental Hypersensitivity

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Commonly Used Drugs

• Penicillins
• Opiates
• Local Anaesthetics
• Acetaminophen
• NSAIDs

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Penicillins

• Can cause all four types of Gell Coombs
  reactions
• Commonest is Type I (hypersensitivity)
• Said to occur in as many as 10 of patients

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Penicillins

• Most common ADRs are skin rash and diarrhoea
• Diarrhoea usually self resolving
• Rash may be allergic or may be drug-disease
  interaction

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Penicillins

• Stated incidence of allergy 10
• Actual incidence probably much lower
• ADRs described probably represent viral-drug
  interactions
• Can be verified or refuted with skin testing

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Penicillins

• Penicillin skin testing available at selected
  centres
• Testing requires use of both minor and major
  determinants
• Accurate in even small infants
• Often deferred until several years after an event

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Percentage
Time
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Opiates

• Commonly used for severe pain
• Dose-related respiratory depression in high doses
• About 5 of the population develops urticaria on
  usual doses
• NOT an allergy - reflects sensitivity
• Crosses the class

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Local Anaesthetics

• Commonly and widely used
• Two common problems - inadvertent intravenous
  injection and allergy
• Allergy tends to be unique to class (amide or
  ester)
• Can be tested for

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Skin Testing

• Commonly used
• Role is to determine safety, not causation
• Hence, usually uses agents of the other class

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Local Anaesthetic Sensitivity

• Ocassionally involves both classes
• A considerable problem for the practicing dentist
• Benadryl may be used instead - modestly effective

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Acetaminophen

• Commonly used
• Very safe in usual therapeutic doses
• Only dangerous in overdoses
• Can occur in setting of repeated
  suproatherapeutic dosing

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NSAIDs

• Commonly used and increasingly used among
  children and adolescents
• Associated with GI bleeds, gaastrointestinal
  discomfort
• Can be associated with hypersensitivity

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NSAIDs

• Can be cross-class
• In this case, may need to use therapeutic
  alternatives

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Other Agents

• Macrolides - can be associated with vomiting and
  GI upset
• Most common with erythromycin, less common (but
  not unknown) with newer agents
• Clindamycin - diarrhoea more common than with
  other agents

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Special Cases

• Drug Substitution
• 10 fold errors
• Unique problem in Paediatrics
• More common among certain staff
• Drug Errors
• Probably more common in children than adults
• Again, may be more common among certain staff

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Medication Errors in a Paediatric ER - One
Months Experience
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Medication Errors

• Paediatric doses need to be individualized
• Knowledge of paediatric doses often much less
  than optimal
• Certain staff - trainees, those unused to working
  with children, mathematically inept - at higher
  risk

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Unique Cases

• Special cases arise in which ADR patterns are not
  the same in children as in adults

Cefaclor-associated serum sickness - seen in 1
of children treated, but probably 0.1 to 0.01 of
adults -Can J Clin Pharmacol 1999 6 197-201
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Pre-Marketing Research

• Pre-clinical use often includes juvenile animals
• Classically, Phase I - III trials include 300 to
  5000 patients
• Hence, will NOT detect rare but potentially
  serious events (e.g. most drug-induced
  hypersensitivities)

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Limitations of Usual Data

• Use of usual data sources for ADR assessment
  (e.g. CPS) significant
• However, usual data sources (e.g. CPS) are poor
  sources of ADR information
• Common events not reported
• Rare events over-stated

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Implications

• Novel or serious ADR patterns to new drugs may
  not be appreciated based on the pre-marketing
  data available
• The CPS may not help you much
• Vigilance is important, especially for novel
  agents

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Approach to an Undesired Event

• Careful Clinical Approach
• Evaluation of therapeutic goals
• Have we achieved the goal?
• If not, how are we going to achieve the goal?
• Do we need to revise our goals or do we need to
  revise our strategy?

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Clinical Approach to a Possible ADR (I)

• History and Physical Examination
• Drug, dose, timing, rationale, other events
• Analysis of Drug Exposure
• Differential Diagnosis
• Obtaining Information
• Coming to a Clinical Opinion

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Clinical Approach to a Possible ADR (II)

• Confirmation
• Communication
• Treatment
• Reporting
• Coping
• Patient
• Patient-physician relationship

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References

• Patterson R, DeSwartre RD, Greenberger PA et al.
  Drug allergy and protocols for management of
  drug allergies. New England Review of Allergy
  Proceedings 1896 7 325-42
• Rieder MJ In vitro and in vivo testing for
  adverse drug reactions. Pediatric Clinics of
  North America 1997 44 93-111
• Gupta A, Waldhauser L Adverse drug reactions
  from birth to early childhood. Pediatric Clinics
  of North America 1997 44 79-92

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What About Maria?

• Stevens-Johnson Syndrome
• Pathogenesis related to bioactivation of drug to
  a reactive intermediate and then (probably)
  immune propagation
• Issues - multi-organ involvement, risk of
  infection
• Therapy - supportive, monitoring for
  complications, possible use of pulse
  corticosteroids

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Take Home Message

• Know the drugs that you are using
• Be vigilant
• When in doubt, ask
• When faced with a dilemma, seek expert opinion

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Acknowledgments

• Canadian Institutes of Health Research - MRC
• Kidney Foundation of Canada
• Hospital for Sick Children Foundation
• Drs. Gideon Koren, Doreen Matsui, Shinya Ito,
  Greg Kearns, Bruce Carleton,
• Drs. Sanford Cohen, Neil Shear, Ralph Kauffman,
  Stuart MacLeod