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

PHARMD GURU Page 3 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. 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.
PHARMD GURU Page 4 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. DISEASE: The pharmacological effects of a drug which are not apparent in a healthy individual may be unmasked by inter current diseases. An example is an asthmatic patient who develops bronchoconstriction while taking nonselective beta blockers such as propranolol. MECHANISMS OF TYPE-B ADR’S: The causes of type B reactions may be pharmaceutical or pharmacokinetic, or may be determined by target tissue or organ response. PHARMACEUTICAL CAUSES:  The main sources for the pharmaceutical causes of type B reactions include decomposition of the active ingredient, effects of the nondrug excipients (additives, preservatives, colouring and solubilising agents) and synthetic by- products of active constituents.  In most cases, the use of decomposed drug products may result in therapeutic failure.