Drug toxicity refers to the level of damage that a compound can cause to an organism. The toxic effects of a drug are dose-dependent and can affect an entire system as in the CNS or a specific organ such as the liver.

Drug toxicity can be a major factor limiting the usefulness of widely used agents. The incidence of adverse drug reactions in patients who have HIV infection varies with the type of drug and dosages used, the interactions between drugs and the stage of HIV infection.⁵

HIV-related idiosyncratic factors, organ dysfunction in late-stage disease and multiple drug therapy are the primary reasons for the increased risk of drug toxicities in HIV patients.

The issue of drug interactions has become particularly critical in the era of protease inhibitors. However, although the number of potential drug interactions is substantial, few require dosage modifications. Among these, clinicians should be vigilant when using concomitant prophylaxis and treatment of mycobacterial diseases with rifamycin, macrolides and HIV protease inhibitors.

Drug toxicity and withdrawal commonly cause anxiety. Table 1 lists a number of drugs that may cause anxiety. Urine toxicology may reveal the presence of anxiogenic stimulants, such as cocaine and amphetamines. Patients with underlying anxiety disorders may be particularly sensitive to the activating effects of caffeine use, and caffeine abstinence in chronic users may produce anxiety. Alcohol withdrawal may present with anxiety, tremulousness, and insomnia. When accompanied by autonomic arousal, alcohol withdrawal may progress to delirium and require intensive medical management. Serotonin reuptake inhibitors, traditional neuroleptics, and other dopamine blockers frequently induce akathisia that may be described by the patient as anxiety or restlessness. If dose reduction or switching to another agent are not possible, low-dose beta-blockers, anticholinergics, and benzodiazepines may be effective in reducing the symptoms.

Drug toxicity is a major issue in development. Beyond toxicity attributable to relative overdosing from variable metabolism, genetically related adverse events can arise from drug target (or related pathway) polymorphisms, immunologic predisposition (e.g., abacavir hypersensitivity), genetically based disease variability, and genetically based organ vulnerabilities (White et al., 2006). Sorting out the mechanistic bases of drug adverse events will be straightforward in some cases and highly complicated in others. The size of most drug development programs will only allow elucidation of the most clear-cut genetic association. Regulatory issues do not complicate such investigations, except in the rare instance where the drug is not safe enough to be approved absent the test. In these cases, sponsors should discuss with FDA the amount of evidence needed to demonstrate that use of the test confers an adequate level of safety.

Thanks and Regards,

Robert Her.