17.2: Drug Toxicity: Risk factors

Adverse Drug Reactions (ADRs) are potential complications that arise during pharmacotherapy, influenced by multiple risk factors. Age plays a significant role; both neonates and the elderly are at heightened risk due to their respective immature and diminished metabolic and elimination processes. Gender also impacts ADRs, with females experiencing a 1.5 to 1.7-fold greater risk than males, which may be linked to pharmacokinetic, pharmacodynamic, and hormonal differences. Notably, neonates, the elderly, and females are critically underrepresented in clinical trials.

The use of concurrent medications is another critical factor. Polypharmacy increases the complexity of drug regimens, elevating the risk of drug-drug interactions, which can lead to ADRs. Also, the longer the duration of therapy, particularly in patients with pre-existing organ dysfunction, the greater the likelihood of an ADR occurring.

Comorbid conditions, such as congestive heart failure, malnutrition, and diabetes, alter drug pharmacokinetics and pharmacodynamics, potentially leading to drug accumulation and toxicity. Drugs with a narrow therapeutic index, like anticoagulants and antiepileptics, are particularly associated with ADRs because of the fine line between therapeutic and toxic concentrations.

Finally, ethnicity and genetics significantly influence individual responses to medication, a field known as pharmacogenetics. Genetic differences can affect drug metabolism, concentration, and toxicity. For instance, 5–10% of the population has variations in the CYP2D6 enzyme, impacting antidepressant metabolism and leading to increased toxicity risks. Additionally, 59% of drugs in ADR studies are metabolized by at least one enzyme that shows genetic variability, which can result in unexpected ADRs or variable efficacy. For example, this may include hemolytic anemia associated with glucose-6-phosphate dehydrogenase deficiency or altered cardiac responses due to variations in genes encoding cardiac ion channels.

Adverse drug reactions, or ADRs, depend on various factors. These include age, gender, drug regimen, therapy duration, comorbidities, genetic makeup, therapeutic index, and ethnicity.

Neonates and the elderly are the most vulnerable due to their immature or diminished liver and kidney function.

Females are at a higher risk of toxicity due to variations in pharmacokinetics, immune responses, and hormones.

Additionally, taking multiple prescriptions, over-the-counter drugs, or natural products increases drug-drug interactions and toxicity risk.

Congestive heart failure, hepatitis, or obesity can alter how a patient metabolizes drugs, leading to increased drug accumulation and toxicity.

Drugs with a narrow therapeutic index require consistent dose monitoring to prevent ADRs

Genetic variations in drug-metabolizing enzymes, transporters, and drug targets can cause minimal to severe ADRs.

For example, if given antiarrhythmics, 1–2% people with mutations for genes encoding cardiac ion channels may experience long-QT syndrome, leading to cardiac arrest.