Drug Related Factors
Drug Related Factors
Dose
ADRs may be the result of ingestion of increased amounts of a drug. Dosing issues are especially likely with narrow therapeutic index drugs. Examples of these types of drugs include digoxin, anticoagulants, anticonvulsants, antiarrhythmics, antineoplastic agents, bronchodilators, sedatives, and hypnotics (1 1).
Dosage form and delivery system
Many of the ADRs related to the dosage form and delivery system are the result of local irritation or hypersensitivity reactions (1 2). Local irritation to the gastrointestinal (GI) tract can occur with oral dosages. For example, toxicity resulting in mouth ulcerations is associated with antineoplastic drugs. In addition, the use of certain formulations, such as sustained release preparations, can increase esophageal injury if esophageal transit is delayed. For example, a controlled release wax matrix of potassium chloride has been associated with significant esophageal erosions. Factors identified to predispose to esophageal injury include large film-coated tablets, capsules, large sustainedrelease preparations, rapidly dissolving formulations, and ingestion of solid oral dosage forms before bed rest with very little water intake (12). Localized tissue irritation can be seen from the intramuscular (IM) route. This is especially an issue when the formulation pH differs from the pH of the surrounding tissue or when precipitation of poorly soluble drugs occurs (12). Incorrect administration of IM injections is probably the most important factor that causes local adverse effects. Local skin irritation can also be seen with transdermal delivery systems due to the alcohols, nonionic surfactants, and adhesives.
Hypersensitivity reactions can occur due to the presence of contaminants or excipients in pharmaceutical dosage forms (e.g., outbreaks of eosinophilia-myalgia syndrome associated with oral tryptophan contaminants in various drugs) (12). Another example is the anaphylactoid reactions to the surfactant Cremaophor EL, which is used in paclitaxel (Taxol).
Direct toxicity effects related to use of preservatives also has been documented. For example, severe metabolic acidosis and death in infants was attributed to the presence of benzyl alcohol. a preservative used in bacterostatic normal saline that was used to flush catheters (12).
The use of specific intravenous (IV) delivery devices also can cause ADRs. For instance, use of plastic infusion sets for IV administration of nitroglycerin has resulted in subtherapeutic effects due to diffusion of the drug into the plastic tubes (12).
Formulation effects, such as bioavailability differences, can cause ADRs when patients are switched to generic products. For example, significant adverse effects have occurred with anticonvulsants and thyroid preparations (12).
Interactions between drugs
It has been estimated that 6.9% of ADRs are due to drugdrug interactions (6). The most likely reason for an adverse drug interaction is the pharmacokinetic changes that result in altered metabolism or excretion of drugs, or the pharmacodynamic changes that result in synergistic or additive effects of drugs.
Dose
ADRs may be the result of ingestion of increased amounts of a drug. Dosing issues are especially likely with narrow therapeutic index drugs. Examples of these types of drugs include digoxin, anticoagulants, anticonvulsants, antiarrhythmics, antineoplastic agents, bronchodilators, sedatives, and hypnotics (1 1).
Dosage form and delivery system
Many of the ADRs related to the dosage form and delivery system are the result of local irritation or hypersensitivity reactions (1 2). Local irritation to the gastrointestinal (GI) tract can occur with oral dosages. For example, toxicity resulting in mouth ulcerations is associated with antineoplastic drugs. In addition, the use of certain formulations, such as sustained release preparations, can increase esophageal injury if esophageal transit is delayed. For example, a controlled release wax matrix of potassium chloride has been associated with significant esophageal erosions. Factors identified to predispose to esophageal injury include large film-coated tablets, capsules, large sustainedrelease preparations, rapidly dissolving formulations, and ingestion of solid oral dosage forms before bed rest with very little water intake (12). Localized tissue irritation can be seen from the intramuscular (IM) route. This is especially an issue when the formulation pH differs from the pH of the surrounding tissue or when precipitation of poorly soluble drugs occurs (12). Incorrect administration of IM injections is probably the most important factor that causes local adverse effects. Local skin irritation can also be seen with transdermal delivery systems due to the alcohols, nonionic surfactants, and adhesives.
Hypersensitivity reactions can occur due to the presence of contaminants or excipients in pharmaceutical dosage forms (e.g., outbreaks of eosinophilia-myalgia syndrome associated with oral tryptophan contaminants in various drugs) (12). Another example is the anaphylactoid reactions to the surfactant Cremaophor EL, which is used in paclitaxel (Taxol).
Direct toxicity effects related to use of preservatives also has been documented. For example, severe metabolic acidosis and death in infants was attributed to the presence of benzyl alcohol. a preservative used in bacterostatic normal saline that was used to flush catheters (12).
The use of specific intravenous (IV) delivery devices also can cause ADRs. For instance, use of plastic infusion sets for IV administration of nitroglycerin has resulted in subtherapeutic effects due to diffusion of the drug into the plastic tubes (12).
Formulation effects, such as bioavailability differences, can cause ADRs when patients are switched to generic products. For example, significant adverse effects have occurred with anticonvulsants and thyroid preparations (12).
Interactions between drugs
It has been estimated that 6.9% of ADRs are due to drugdrug interactions (6). The most likely reason for an adverse drug interaction is the pharmacokinetic changes that result in altered metabolism or excretion of drugs, or the pharmacodynamic changes that result in synergistic or additive effects of drugs.
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