Patient-Related Factors
Age, disease states, genetics, gender, nutrition, multidrug therapy use, and herbal therapies use are patient-related factors that influence the likelihood of adverse drug reactions.
Age-geriatrics
Age-related alterations in pharmacokinetics and pharmacodynamics may affect the response of elderly patients to certain medications, and may increase the susceptibility for ADRs among elderly patients (13- 15) (Table 1). The risk of ADRs among elderly patients is probably not due to age alone. ADRs may be related more to the degree of frailty and medical conditions of the patient (15). On average, older persons have five or more coexisting diseases that may increase the risk of adverse events. Polypharmacy seems to be more of a common problem among the elderly. The average elderly patient takes 4.5 chronic medications and fills 13 prescriptions yearly (15). Elderly patients appear to have a decline in homeostatic mechanisms. The imbalance of homeostatic mechanisms and the decline in function reserves may put a patient at greater risk for ADEs due to decreased tolerance of medications and the ability to handle stressful situations (16).
Age-pediat rics
The two factors responsible for increasing risks of ADRs in children are pharmacokinetic changes and dose delivery issues. Age-related differences in pharmacokinetics in children are documented (17). However, the data on both efficacy and safety are often limited or not studied at all in this population. Thus, it is unclear whether an increased risk for ADRs exists in this group.
However, there is a potential risk for increased ADRs if appropriate considerations are not taken into account in view of pharmacokinetic changes (18). It is important to note that only one-fourth of the drugs approved by the FDA have indications specific for use in a pediatric population (17). Medications used in adults are often given to children without FDA safety and efficacy data. Compatibility and stability issues with dosage forms intended for adults that have been altered (e.g., dilution or reformulation) can increase risks for ADRs. Information on pediatric age-related difference in neonates, children, and adolescents may aid in prevention of pediatric ADRs (18) (Table 2). Further studies of drug use in pediatrics are needed in order to prevent ADRs.
Concurrent diseases
Diseases such as hepatic or renal diseases can influence the incidence of ADRs by altering the pharmacokinetics of drugs, such as absorption, distribution, metabolism, or excretion (6).
Hepatic disease
Patients with liver disease have an increased susceptibility to certain drugs due to decreased hepatic clearance for drugs metabolized by the liver or due to enhanced sensitivity (6). For example, impaired hepatic metabolism can precipitate central nervous system (CNS) toxicity in patients on theophylline, phenytoin, or lidocaine; or ergot poisoning on ergotamine (19). Increased sensitivity to drugs is also encountered in liver disease( 19). The use of anticoagulants increases the risk of bleeding due to the reduced absorption of vitamin K or decreased production of vitamin K-dependent clotting
factors. There is an enhanced risk for respiratory depression and hepatic encephalopathy due to morphine Vigorous use of diuretics can precipitate hepatic coma due to potassium loss in liver disease. There is an increased risk of hypoglycemia with sulphonylurea antidiabetic drugs due to decreased glycogenesis in liver disease. Liver disease can also cause hypoalbuminemia due to decreased liver synthesis of albumin. For drugs that are extensively bound to albumin, such as phenytoin, an enhanced risk of drug toxicity could occur because of the increase in free drug concentration.
There are no useful methods to quantify the degree of liver disease that can assist in dosage adjustment. A practical approach involves checking patients for elevated
prothrombin time, rising bilirubin levels, and/or falling albumin levels. In such instances, drugs that have an altered response in liver disease or cause hepatotoxicity need to be avoided. Renal disease Impaired renal function increases the incidence of ADRs for drugs that depend on the kidney for their elimination. Unlike liver disease, use of pharmacokinetic dosing principles can minimize the risk for adverse effects.
Mechanisms responsible for enhanced ADRs in renal disease include delayed drug excretion, decreased protein binding due to hypoalbuminemia, and increased drug sensitivity (6). Delayed renal excretion is responsible for enhanced toxicity with drugs such as aminoglycosides, digoxin, vancomycin, chlorpropamide, H2-antagonists, allopurinol, lithium, insulin, and methotrexate (20). For some drugs, the accumulation of a toxic metabolite during renal failure is responsible for ADRs. This is the case with meperidine, where a toxic metabolite, normeperidine, accumulates in renal failure (20). Patients with accumulation of uremic toxins have increased sensitivity to certain drugs. There may be anenhanced response to CNS depressants (such as barbiturates and benzodiazepines), hemorrhagic effects from aspirin or warfarin, and other bleeding effects from antibiotics that inhibit platelet aggregation, such as carbenicillin, ticarcillin, and piperacillin.
Other diseases
On theoretical grounds, other diseases associated with hypoalbuminemia could predispose patients to adverse reactions and to altered responses to drugs that are highly protein bound (21) (Table 3).
The presence of other diseases can influence the risk for ADRs. Many of these adverse effects are related to an extension of the pharmacologic effects of the drug in the presence of certain pathophysiology. Numerous examples are given in Table 4 (6). Patients who have had a previous reaction to drugs are also more likely to experience an ADR (22). Patients with history of allergic diseases also have an increased risk due to a genetically related ability to form immunoglobulin E.
Age, disease states, genetics, gender, nutrition, multidrug therapy use, and herbal therapies use are patient-related factors that influence the likelihood of adverse drug reactions.
Age-geriatrics
Age-related alterations in pharmacokinetics and pharmacodynamics may affect the response of elderly patients to certain medications, and may increase the susceptibility for ADRs among elderly patients (13- 15) (Table 1). The risk of ADRs among elderly patients is probably not due to age alone. ADRs may be related more to the degree of frailty and medical conditions of the patient (15). On average, older persons have five or more coexisting diseases that may increase the risk of adverse events. Polypharmacy seems to be more of a common problem among the elderly. The average elderly patient takes 4.5 chronic medications and fills 13 prescriptions yearly (15). Elderly patients appear to have a decline in homeostatic mechanisms. The imbalance of homeostatic mechanisms and the decline in function reserves may put a patient at greater risk for ADEs due to decreased tolerance of medications and the ability to handle stressful situations (16).
Age-pediat rics
The two factors responsible for increasing risks of ADRs in children are pharmacokinetic changes and dose delivery issues. Age-related differences in pharmacokinetics in children are documented (17). However, the data on both efficacy and safety are often limited or not studied at all in this population. Thus, it is unclear whether an increased risk for ADRs exists in this group.
However, there is a potential risk for increased ADRs if appropriate considerations are not taken into account in view of pharmacokinetic changes (18). It is important to note that only one-fourth of the drugs approved by the FDA have indications specific for use in a pediatric population (17). Medications used in adults are often given to children without FDA safety and efficacy data. Compatibility and stability issues with dosage forms intended for adults that have been altered (e.g., dilution or reformulation) can increase risks for ADRs. Information on pediatric age-related difference in neonates, children, and adolescents may aid in prevention of pediatric ADRs (18) (Table 2). Further studies of drug use in pediatrics are needed in order to prevent ADRs.
Concurrent diseases
Diseases such as hepatic or renal diseases can influence the incidence of ADRs by altering the pharmacokinetics of drugs, such as absorption, distribution, metabolism, or excretion (6).
Hepatic disease
Patients with liver disease have an increased susceptibility to certain drugs due to decreased hepatic clearance for drugs metabolized by the liver or due to enhanced sensitivity (6). For example, impaired hepatic metabolism can precipitate central nervous system (CNS) toxicity in patients on theophylline, phenytoin, or lidocaine; or ergot poisoning on ergotamine (19). Increased sensitivity to drugs is also encountered in liver disease( 19). The use of anticoagulants increases the risk of bleeding due to the reduced absorption of vitamin K or decreased production of vitamin K-dependent clotting
factors. There is an enhanced risk for respiratory depression and hepatic encephalopathy due to morphine Vigorous use of diuretics can precipitate hepatic coma due to potassium loss in liver disease. There is an increased risk of hypoglycemia with sulphonylurea antidiabetic drugs due to decreased glycogenesis in liver disease. Liver disease can also cause hypoalbuminemia due to decreased liver synthesis of albumin. For drugs that are extensively bound to albumin, such as phenytoin, an enhanced risk of drug toxicity could occur because of the increase in free drug concentration.
There are no useful methods to quantify the degree of liver disease that can assist in dosage adjustment. A practical approach involves checking patients for elevated
prothrombin time, rising bilirubin levels, and/or falling albumin levels. In such instances, drugs that have an altered response in liver disease or cause hepatotoxicity need to be avoided. Renal disease Impaired renal function increases the incidence of ADRs for drugs that depend on the kidney for their elimination. Unlike liver disease, use of pharmacokinetic dosing principles can minimize the risk for adverse effects.
Mechanisms responsible for enhanced ADRs in renal disease include delayed drug excretion, decreased protein binding due to hypoalbuminemia, and increased drug sensitivity (6). Delayed renal excretion is responsible for enhanced toxicity with drugs such as aminoglycosides, digoxin, vancomycin, chlorpropamide, H2-antagonists, allopurinol, lithium, insulin, and methotrexate (20). For some drugs, the accumulation of a toxic metabolite during renal failure is responsible for ADRs. This is the case with meperidine, where a toxic metabolite, normeperidine, accumulates in renal failure (20). Patients with accumulation of uremic toxins have increased sensitivity to certain drugs. There may be anenhanced response to CNS depressants (such as barbiturates and benzodiazepines), hemorrhagic effects from aspirin or warfarin, and other bleeding effects from antibiotics that inhibit platelet aggregation, such as carbenicillin, ticarcillin, and piperacillin.
Other diseases
On theoretical grounds, other diseases associated with hypoalbuminemia could predispose patients to adverse reactions and to altered responses to drugs that are highly protein bound (21) (Table 3).
The presence of other diseases can influence the risk for ADRs. Many of these adverse effects are related to an extension of the pharmacologic effects of the drug in the presence of certain pathophysiology. Numerous examples are given in Table 4 (6). Patients who have had a previous reaction to drugs are also more likely to experience an ADR (22). Patients with history of allergic diseases also have an increased risk due to a genetically related ability to form immunoglobulin E.