Tiêu đề 25. ADVERSE DRUG REACTIONS - CLASSIFICATION, MECHANISM, PREDISPOSING FACTORS, CAUSALITY ASSESSMENT.pdf ✅

PHARMD GURU Page 1 DEFINITION: The WHO defines an adverse drug reaction (ADR) as ‘any response to a drug which is noxious and unintended, and which occurs at doses normally used in man for prophylaxis, diagnosis or therapy of disease, or for the modification of physiological function’. Thus, this definition excludes overdose (accidental or intentional), drug abuse, treatment failure and drug administration errors. Often, the terms ‘adverse drug reaction’ and ‘adverse drug event’ are used synonymously, although they are not. An adverse drug event (ADE) is a broader term and includes ‘any untoward medical occurrence presenting during the administration of a drug’. Thus, an ADR can also be considered as an ADE, but not all ADEs are ADRs. CLASSIFICATION:  Traditionally, ADRs are classified into two categories: type A and type B reactions.  Type A (augmented) reactions are usually the exacerbation of the pharmacological effects of a drug and are thus dose-dependent. An example is insulin-induced hypoglycemia.  These reactions are usually predictable due to the known pharmacology of a drug and are thus preventable.  Although the incidence of type A reactions is high, they are generally associated with less morbidity and mortality. Because of their high incidence, the public health impact is large.  In contrast, type B (bizarre) reactions are hypersensitivity reactions and are not dose-dependent. An example is a penicillin induced hypersensitivity reaction.  These reactions are often not predictable and preventable in the individual case (unless the patient has a known history of this type of reaction).  This type is associated with high morbidity and mortality but its occurrence in the clinical setting is low. ADVERSE DRUG REACTIONS - CLASSIFICATION, MECHANISM, PREDISPOSING FACTORS, CAUSALITY ASSESSMENT
PHARMD GURU Page 2  Recently, newer classifications have been proposed. One of these includes, in addition to type A (augmented) and type B (bizarre), a type C (continuous) and a type D (delayed effects).  Type C reactions are diseases that occur at a higher frequency among exposed patients than those unexposed, although the exact mechanism is unknown. One example is the higher frequency of cardiovascular events among patients exposed to the COX- 2 inhibitor rofecoxib compared with an unexposed control group. MECHANISM OF ADVERSE DRUG REACTION: MECHANISMS OF TYPE-A ADR’S: A drug suspected to have caused an ADR in one patient may not necessarily cause a similar adverse reaction in another patient. This is due to inter-individual variability, which may predispose an individual to an ADR. Any type-A reaction, which occurs in an individual, may be attributed to any one or more of the following mechanisms: PHARMACEUTICAL CAUSES:  Changes in the drug quantity present in a particular product and changes in its drug release properties.  A classic example concerns two brands of the poorly soluble antifungal agent griseofulvin having widely different particle size in the final dosage form. By switching patients stabilized on the brand with bigger particle sizes to the brand with the smaller size, the peak concentration of griseofulvin increased dramatically, leading to toxicity. PHARMACOKINETIC CAUSES: Changes in the absorption, distribution, metabolism and elimination of drugs may alter drug effects by changing the concentration of drug present at the site of action. ABSORPTION:  Alterations in the rate and extent of drug absorption may result in adverse drug effects.  Following oral administration, many factors may influence the extent of drug absorption including drug formulation, gastrointestinal motility, first pass metabolism, concomitant administration of other drugs and the absorptive