Adverse Drug Reactions in Dentistry (ADRs): Burden of

Disease and Special Considerations

Michael J. RiederSection of Paediatric Clinical Pharmacology

Children’s Hospital of Western OntarioDivision of Clinical PharmacologyFaculty of Medicine & DentistryUniversity of Western Ontario

London, Ontariomrieder@uwo.ca

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

QuickTime™ and aPhoto - JPEG decompressor

are needed to see this picture.

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 98,000 people in the USA die each year as a result of medical errorseach 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 CellDegranulation

Inflammation

VasodilationSmooth Muscle Contraction

Chemotaxis

UrticariaBronchoconstrictionHypotension - Shock

IgE

Hypersensitivity - Gell & Coombs Type II

NK Cell

Phagocyte

IgG

Complement

Cell lysisPhagocytosis

Removed byReticuloendothelial

System

Hypersensitivity - Gell & Coombs Type III

Phagocyte

IgGComplement

ImmuneComplexes

ReactiveOxygenSpecies

Inflammation

BloodVessel

Type IV Hypersensitivity

CytotoxicT Cell

AntigenPresenting

Cell

Macrophage

TargetCell

CellDestruction

Cytokines

Inflammation

ImmunologicMemory

Sensitisation

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

drug-disease 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

Time

Percentage

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

ExperienceType of error Number %Wrong dose 133 (49.1%)Wrong f requency 117 (43.2%)Wrong route 7 (2.6%)Wrong drug 5 (1.8%)I nf ormation 7 (2.6%)Other 2 (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 childrentreated, 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

QuickTime™ and aPhoto - JPEG decompressor

are needed to see this picture.

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