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

PHARMD GURU Page 1 ADVERSE DRUG REACTIONS - CLASSIFICATION, MECHANISM, PREDISPOSING FACTORS, CAUSALITY ASSESSMENT [DIFFERENT SCALES USED] 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. PHARMACOVIGILANCE

PHARMD GURU Page 3 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 capacity of gastrointestinal mucosa. Any alteration in the rate or extent of drug absorption may result in either therapeutic failure or toxicity. DISTRIBUTION:  Several factors determine the extent of distribution of a drug, including regional blood flow, membrane permeability and protein/tissue binding. Changes in drug distribution may predispose to ADRs, although the clinical significance of such mechanisms is yet to be proved. METABOLISM :  In an individual who has a reduced metabolic rate, accumulation of the drug in the body may be higher leading to increased risk of ADRs (especially type A reactions), while therapeutic failure may occur in an individual who has an enhanced metabolic rate. These changes are due to interindividual variations in drug metabolising capacity, which in turn is greatly influenced by genetic, environmental and other factors.  For example, the oxidising enzyme, CYP3A4, responsible for the metabolism of a great variety of medicines (like nifedipine, erythromycin and cyclosporine) shows a genetically determined ten-fold difference in activity between individuals. This enzyme is irreversibly inhibited by grapefruit juice. Drinking a glass of grapefruit juice will dramatically increase the bioavailability of medicines metabolised by CYP3A4.
PHARMD GURU Page 4 ELIMINATION: The main routes of excretion for many drugs are the kidneys (excretion through urine) and liver (yields metabolites which are then excreted by the kidneys). One of the most important causes of type A ADRs is a change in the drug elimination rate. Drug accumulation due to reduced elimination may predispose to ADRs as a result of increased drug concentration in plasma and tissue. Conversely, reduced concentration of the drug in plasma and tissue due to enhanced drug elimination may lead to therapeutic failure. PHARMACODYNAMIC CAUSES: Increased sensitivity of target tissues or organs may predispose a person to ADRs. DRUG RECEPTORS: Most drugs elicit their response by combining with receptors. These receptors are either protein molecules or enzymes. The amount and sensitivity of receptors of one individual may differ from those of another individual. Some individuals may have fewer specific drug receptors while others may have a higher number of less active receptors. This inter variability between different individuals can greatly affect the drug effect when the drug acts through these specific receptors. HOMEOSTATIC MECHANISMS:  Many physiological factors may determine the extent of a drug’s effect in an individual as drug effects occur within the environment of the body’s physiological mechanisms.  For example, intravenous atropine produces a variable increase in heart rate and some individuals develop tachycardia of 160 beats per minute at a dose which is almost ineffective in others. The magnitude of the observed effect is dependent on the balance between parasympathetic and sympathetic cardiac tone, which appears to be under genetic control.