Adverse Drug Reactions in Children - PowerPoint

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					Adverse Drug Reactions in Dentistry
  (ADRs): Burden of Disease and
      Special Considerations
                 Michael J. Rieder
    Section of Paediatric Clinical Pharmacology
     Children’s Hospital of Western Ontario
         Division of Clinical Pharmacology
         Faculty of Medicine & Dentistry
          University of Western Ontario
                  London, Ontario
• 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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• Appreciate rate of ADRs
• Understand patterns of ADRs to
  drugs common to dental practice
• Appreciate an approach to an ADR
  associated with dental therapy
 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
          Selective Therapy
• Era of selective therapy began in two labs in
   – 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
    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
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)
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

• Adverse Drug Reactions are a common
  and important clinical problem
• Seen in 5% of patients treated
• Responsible for 5% of all hospital
  – JAMA 1998; 279: 1200-5
    98,000 people in the USA die
each year as a result of medical errors
        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
              ADR Rates
• Overall, rate of ADRs in dental patients
  appears to be similar to adults
• Risk appears to relate to known risk
   – Int J Clin Pharmacol Ther 1988; 36:
     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
         History of ADRs

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

• ADRs often called “drug allergy”
• Immune involvement is common, but
  true drug allergy is relatively rare
• Mislabelling leads to therapeutic
       Hypersensitivity -
      Gell & Coombs Type I
                       Smooth Muscle Contraction
  Mast Cell                   Chemotaxis

              Inflammation    Urticaria
IgE                      Bronchoconstriction
                         Hypotension - Shock
          Hypersensitivity -
        Gell & Coombs Type II

                 IgG       Cell lysis
  NK Cell                Phagocytosis


    Complement            Removed by
     Hypersensitivity - Gell &
        Coombs Type III        Blood


       Type IV Hypersensitivity
 Sensitisation    Immunologic
 Antigen                        Target
Presenting                       Cell
                    T Cell  Cytokines

         Gell and Coombs

• Elegant, erudite classification system
• Mechanistic
• Sadly, does not address the vast
  majority of ADRs
        ADR Classifications
• A number of schemes have been proposed
• Unfortunate and common use of the term
• Patterson, DeSwarte and Greenberger
   – Predictable
   – Unpredictable
     • New England Review of Allergy Proceedings,
       1986, 7: 325-42
          Predictable ADRs

• Predicated on and predictable from
  the drug’s pharmacology
  –   Side Effects
  –   Secondary Effects
  –   Interactions
  –   Toxicity
         Unpredictable ADRs

• Not known to be related to the drug’s
  –   Intolerance
  –   Allergic - Pseudoallergic
  –   Idiosyncratic
  –   Psychogenic
          Predictable ADRs
•  Side Effects
   – Fine tremor associated with inhaled salbutamol
• Secondary Effects
   – Pseudomembranous colitis after lincomycin
• Interactions
   – Bleeding when coumadin and cimetadine are
     given concurrently
• Toxicity
   – Metabolic acidosis in salicylate overdose
        Unpredictable ADRs
• Intolerance
   – Intractable vomiting associated with
     erythromycin therapy
• Allergic - Pseudoallergic
   – Anaphylaxis or urticaria associated with
     pencillin therapy
• Idiosyncratic
   – Stevens-Johnson Syndrome associated with
• Psychogenic
   – Environmental Hypersensitivity
       Commonly Used Drugs

•   Penicillins
•   Opiates
•   Local Anaesthetics
•   Acetaminophen
•   NSAIDs

• Can cause all four types of Gell &
  Coombs reactions
• Commonest is Type I
• Said to occur in as many as 10% of

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

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

• 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


• 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
       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
           Skin Testing

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

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

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

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

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

• Macrolides - can be associated with
  vomiting and GI upset
• Most common with erythromycin, less
  common (but not unknown) with newer
• Clindamycin - diarrhoea more common
  than with other agents
           Special Cases
• Drug Substitution
• 10 fold errors
  – Unique problem in Paediatrics
  – More common among certain staff
• Drug Errors
  – Probably more common in children than
  – Again, may be more common among
    certain staff
 Medication Errors in a Paediatric
  ER - One Month’s Experience
Type of error     Number     %
Wrong dose         133     (49.1%)
Wrong frequency    117     (43.2%)
Wrong route         7       (2.6%)
Wrong drug          5       (1.8%)
Information         7       (2.6%)
Other               2       (0.7%)
Total              271     (100%)
        Medication Errors

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

• Pre-clinical use often includes juvenile
• 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)
   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
  – Common events not reported
  – Rare events over-stated

• 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
   Approach to an Undesired
• Careful Clinical Approach
• Evaluation of therapeutic goals
  – Have we achieved the goal?
  – If not, how are we going to achieve the
  – Do we need to revise our goals or do we
    need to revise our strategy?
Clinical Approach to a Possible
            ADR (I)

• History and Physical Examination
    – Drug, dose, timing, rationale, other
•   Analysis of Drug Exposure
•   Differential Diagnosis
•   Obtaining Information
•   Coming to a Clinical Opinion
Clinical Approach to a Possible
           ADR (II)
•   Confirmation
•   Communication
•   Treatment
•   Reporting
•   Coping
    – Patient
    – Patient-physician relationship
• 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
          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
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• Therapy - supportive,
  monitoring for complications,
  possible use of pulse
        Take Home Message

•   Know the drugs that you are using
•   Be vigilant
•   When in doubt, ask
•   When faced with a dilemma, seek
    expert opinion
• Canadian Institutes of Health Research -
• 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