Adverse Drug Reactions: On-target and Off-target aspect


Adverse drug reactions (ADRs) are critical to pharmacology and medical treatment. These unintended consequences, often termed side effects, adverse effects, or toxic effects, are influenced by various factors such as the drug’s mechanism of action, dosage, and the patient’s health status. This article aims to provide an in-depth understanding of these adverse effects’ mechanisms, their impact on drug development, and the various categories of drug toxicities.

The Spectrum of Adverse Effects

Adverse effects can range from common and relatively benign issues to those that pose a serious risk of organ damage or death. Even benign adverse effects can cause significant discomfort and may lead patients to avoid or reduce their medication usage. The type and risk of adverse effects are often determined by the margin of safety between the dose required for efficacy and the dose that causes adverse effects. This margin of safety is not just a function of the drug but also of the patient’s characteristics, such as genetic makeup, comorbidities, or reduced functional reserve in key organs.

Drug Toxicity in Drug Development

Drug toxicity plays a pivotal role in drug development. Regulatory agencies review test data to decide whether the benefits of the drug outweigh its risks. Once a drug is marketed, any unexpected types or frequencies of adverse effects may lead to its reevaluation, restriction to specific patient populations, or complete withdrawal from the market.

Categories of Drug Toxicities

On-Target Adverse Effects

On-target adverse effects occur when the drug binds to its intended receptor but does so inappropriately—either at an incorrect concentration, with suboptimal kinetics or in the wrong tissue. These effects are often shared by every member of the therapeutic class and are known as class effects. For example, antipsychotic agents like haloperidol can lead to an increase in prolactin secretion, causing various on-target effects like amenorrhea and sexual dysfunction.

Off-Target Adverse Effects

Off-target adverse effects happen when a drug interacts with unintended targets. For instance, many compounds interfere with cardiac potassium channels, leading to cardiac arrhythmias and sudden death. Enantiomers of a drug can also cause off-target effects, as seen in the tragic case of thalidomide in the 1960s.

Idiosyncratic Toxicity

Idiosyncratic drug reactions are adverse effects that appear unpredictably in a small fraction of patients for unknown reasons. These effects are not typically manifested in pre-marketing testing and often prompt the withdrawal of the drug from the market.

Mechanisms of Drug Toxicity

Factors Influencing Toxicity

Whether a drug will do more harm than good depends on various factors, including the patient’s age, genetic makeup, preexisting conditions, the dose administered, and other drugs the patient may be taking. Age-dependent differences in pharmacokinetic profiles or drug-metabolizing enzymes can make the very old or very young more susceptible to drug toxicity.

Drug Interactions

Concomitant medications can confound both the efficacy and toxicity of drugs, especially when these medications share or modulate the same metabolic pathways or transporters. Drug interactions with health supplements are also an often under-recognized cause of drug toxicity.


Understanding the mechanisms of both drug action and drug toxicity is crucial for the development of rational therapeutic strategies. While some adverse effects are predictable and manageable, others, especially idiosyncratic reactions, remain a challenge. As science advances, it is hoped that we will gain a better understanding of these mechanisms, leading to safer and more effective drug therapies.

By delving into the complexities of adverse drug reactions, we can better appreciate the intricate balance that healthcare providers must maintain between therapeutic benefit and potential harm. This understanding is not just the responsibility of healthcare professionals but is crucial for patients as well, empowering them to make informed decisions about their treatment options.

Principles of Pharmacology: The Pathophysiologic Basis of Drug Therapy Fourth Edition, 4e. David E. Golan, Ehrin J. Armstrong, April W. Armstrong.

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Disclaimer: This article is for informational purposes only and does not constitute medical advice. Always seek the advice of a healthcare provider with any questions regarding a medical condition.

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