Adverse Drug Reactions in Children: The Double‐Edged Sword of Therapeutics

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According to the World Health Organization (WHO), adverse drug reactions (ADRs) are defined as any noxious and unintended response to a drug that occurs in man at doses normally used for prophylaxis, treatment or diagnosis of disease, or for the modification of physiological function. Although other definitions of ADRs do exist, we have chosen to use this definition due to its practicality and wide use. Despite significant advances in pharmacological and pharmacogenetic knowledge and drug safety research over the past two decades, ADRs continue to constitute a serious public health problem. The minimal rate of ADRs is 5% per course of drug therapy but can be as high as 50% for some drugs such as chemotherapeutic agents. Serious ADRs occur in 6.7% of hospitalized patients with a fatality rate of 0.32% and are one of the four leading causes of death in the developed world.1 It has been estimated that ADRs cause 100,000 and 197,000 deaths annually in the USA and Europe, respectively.1 This translates into one death every 5 min in the USA and roughly equates to 1 in 3,000 to 1 in 4,000 of the general population worldwide. In addition, at over $136 billion annually, the financial cost of ADRs is estimated to exceed the healthcare cost of major chronic diseases, including cardiovascular diseases and diabetes.3 A multitude of factors are at play when determining the rates of ADRs, including the myriad and range of medicines used, local and global population dynamics, variations in ADR definitions, laws governing reporting, and differing healthcare systems. Reporting of ADRs to authorities and regulatory agencies is mostly voluntary and underreporting rates can be as high as 94%.5 These factors among others make accurate estimates of true incidences of ADRs hard to reach.
ADRs may be classified as belonging to a certain type (Table1) according to their reaction profiles: Type A (augmentation of normal drug effects), Type B (bizarre effects), Type C (chronic effects), Type D (delayed effects), and Type E (end of drug use effects). This article will primarily focus on Type A and Type B ADRs.
The majority of ADRs are predictable (Type A, ∼80%), which are related to the drug's pharmacology, tend to be mild, and can resolve with dose reduction (Tables1, 2). Most of Type A ADRs are either excessive therapeutic effects or pharmacologic effects on non‐target tissues (side effects), but may also include drug intolerance, which is an exaggerated response to a drug that may or may not be related to the drug's pharmacology, and hence can be classified as either Type A or Type B ADRs (Figure1, Table2). Excessive therapeutic effects and side effects can result from drug–drug interactions (DDI) or from the patient's condition, including genetics/ethnicity, disease, age, or gender. These patient‐related factors can affect either drug pharmacokinetics (PK) or pharmacodynamics (PD), which can produce an ADR. The unpredictable Type B (∼20%) or idiosyncratic ADRs are generally unpredictable, have no simple dose–response relationship, and can be very severe and life‐threatening.6 There is no clear definition of drug‐induced idiosyncratic reactions, but they are objectively reproducible symptoms that occur at doses tolerated by normal subjects.7 Over 60% of severe ADRs are unpredictable.
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