Download Adverse Drug Reactions in Children

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
[email protected]
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
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
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
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
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
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
factors
– Int J Clin Pharmacol Ther 1988; 36:
530-3
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
confusion
Hypersensitivity Gell & Coombs Type I
Mast Cell
IgE
Vasodilation
Smooth Muscle Contraction
Chemotaxis
Degranulation
Urticaria
Bronchoconstriction
Hypotension - Shock
Inflammation
Hypersensitivity Gell & Coombs Type II
NK Cell
IgG
Cell lysis
Phagocytosis
Phagocyte
Complement
Removed by
Reticuloendothelial
System
Hypersensitivity - Gell &
Blood
Coombs Type III
Vessel
IgG
Complement
Immune
Complexes
Phagocyte
Reactive
Oxygen
Species
Inflammation
Type IV Hypersensitivity
Sensitisation
Antigen
Presenting
Cell
Immunologic
Memory
Target
Cell
Cytotoxic
T Cell
Cytokines
Inflammation
Macrophage
Cell
Destruction
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
allergy
• Patterson, DeSwarte and Greenberger
(1986)
– 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
pharmacology
–
–
–
–
Intolerance
Allergic - Pseudoallergic
Idiosyncratic
Psychogenic
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
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
Commonly Used Drugs
•
•
•
•
•
Penicillins
Opiates
Local Anaesthetics
Acetaminophen
NSAIDs
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
Penicillins
• Most common ADRs are skin rash and
diarrhoea
• Diarrhoea usually self resolving
• Rash may be allergic or may be drugdisease interaction
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
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
Percentage
Time
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
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
causation
• 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
Acetaminophen
•
•
•
•
Commonly used
Very safe in usual therapeutic doses
Only dangerous in overdoses
Can occur in setting of repeated
suproatherapeutic dosing
NSAIDs
• Commonly used and increasingly used
among children and adolescents
• Associated with GI bleeds,
gaastrointestinal discomfort
• Can be associated with
hypersensitivity
NSAIDs
• 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
agents
• 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
adults
– Again, may be more common among
certain staff
Medication Errors in a Paediatric
ER - One Month’s Experience
Type of error
Number
%
Wrong dose
Wrong frequency
Wrong route
Wrong drug
Information
Other
133
117
7
5
7
2
(49.1%)
(43.2%)
(2.6%)
(1.8%)
(2.6%)
(0.7%)
Total
271
(100%)
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
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
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)
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
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
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?
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
Clinical Approach to a Possible
ADR (II)
•
•
•
•
•
Confirmation
Communication
Treatment
Reporting
Coping
– Patient
– Patient-physician relationship
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
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
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