INDEX adverse effects

Monoamine oxidase inhibitors have a low therapeutic index. Adverse effects include orthostatic hypotension, impotence and insomnia. Overdoses become manifest by symptoms of agitation, hyper-reflexia followed by convulsions. Rare but serious cases of hepatotoxicity have been associated with the use of isocarboxazid and of phenelzine. 

To assess tlie overall potential for noncarcinogenic effects posed by more dian one chemical, a liazard index (HI) approach has been developed based on EPA s Guidelines for Healdi Risk Assessment of Chemical Mixtures. This approach assumes that simultaneous subtlu eshold exposures to several chemicals could result in an adverse healtli effect. It also assumes tliat tlie magnitude of the adverse effect will be proportional to tlie sum of the ratios of the subtlireshold exposures to acceptable exposures. The non cancer hazard index is equal to tlie sum of the hazard quotients, as described below, where E and tlie RfD represent the same exposure period (e.g., subclironic, clironic, or shorter-term). 

The quantitative measurement of toxicity level is expressed by parameters like NOEL (no observed effect level), NOAEL (no observed adverse effect level), and ADI (acceptable daily intake). The NOEL values are divided by 100 to obtain ADI values. The 100 safety factor derives from 10 x 10, where the 10s represent the animal-to-human conversion rate and the human variability factor. Currently, the most useful index of safety is the ADI, expressed as milligrams of test substance per kilogram of body weight (ppm), with the recommendation not to eat more than the ADI per day. The FDA, EU, and WHO agree on the ADI principle. 

TSCATS is an online index to unpublished, nonconfidential studies covering chemical testing results and adverse effects of chemicals on health and ecological systems. The studies are submitted by US industry to EPA under several sections of the Toxic Substance Control Act (TSCA). There are four types of documents in the database Section 4 chemical testing results, Section 8(d) health and safety studies, Section 8(e) substantial risk of injury to health or the environment notices, and voluntary documents submitted to EPA known as a For Your Information (FYI) notice. 

Atrial fibrillation (AF) is the most common arrhythmia encountered in clinical practice. It is important for clinicians to understand AF, because it is associated with substantial morbidity and mortality and because many strategies for drug therapy are available. Drugs used to treat AF often have a narrow therapeutic index and a broad adverse effect profile. 

Theophylline is a non-specific phosphodiesterase inhibitor that increases intracellular cAMP within airway smooth muscle resulting in bronchodilation. It has a modest bronchodila-tor effect in patients with COPD, and its use is limited due to a narrow therapeutic index, multiple drug interactions, and adverse effects. Theophylline should be reserved for patients who cannot use inhaled medications or who remain symptomatic despite appropriate use of inhaled bronchodilators. 

Minimum reportable concentration. The lower concentration limit for a method is usually measured by determining the detection limit. This is basically an instrument signal to noise ratio, and it does not include calibration effects. At low concentrations the calibration process often has a major adverse effect on precision. Detection limits are useful for comparing the inherent sensitivity of methods, but they are not realistic indexes of measurable concentrations in routine analysis. 

Only two short-term prospective studies on the effect of soy on the breast have been performed to date. The first reported the effects of two weeks of soy supplementation on the breast of women who were due to have surgery for either benign or malignant breast disease (Hargreaves, 1999). Soy had no adverse effects on any histological index of proliferation. However, a rise of pS2 protein and lowering of apolipoprotein D was observed in the nipple aspirate of women taking soy compared with controls. (A similar effect has... 

GPT = glutamic pyruvic transaminase GSH = glutathione Hemato = hematological hr = hour(s) LCso= lethal concentration. 50% kill LOAEL = lowest-observed-adverse-effect level LI = labeling index M = male min = mlnute(s) mo = moth(s) musc/skel = musculoskeletal NOAEL = no-observed-adverse-effect level NS = not specified Resp = respiratory ... 

Theophylline is a drug v/ith a narrov/ therapeutic index, plasma concentrations of v/hich must be maintained at 10-20 mg/L. Plasma concentrations above 20 mg/L increase the severity and frequency of adverse effects. 

Lithium ions. Lithium salts (e.g., acetate, carbonate) are effective in controlling the manic phase. The effect becomes evident approx. 10 d after the start of therapy. The small therapeutic index necessitates frequent monitoring of Li+ serum levels. Therapeutic levels should be kept between 0.8-1.0 mM in fasting morning blood samples. At higher values there is a risk of adverse effects. 

As phenytoin has a narrow therapeutic index therapeutic drug monitoring to establish therapeutic levels is mandatory. Dose and concentration dependent adverse effects are nausea, vomiting, tremor, confusion, headache and dizziness, nystagmus and ataxia. 

Geriatric Considerations - Summary Increased risk of side effects in patients with CVD and hepatic dysfunction. Theophylline has a narrow therapeutic index and is associated with numerous drug interactions. Target serum concentrations are 5-20 mg/L, with adverse effects increasing between 15-20 mg/L. Hepatic metabolism and renal excretion declines with age and the half-life of theophylline increases by 3 to 9 hours in older adults. Smoking induces theophylline metabolism therefore, if a pa-tienf sfops smoking, empiric dosage reduction may be indicated and follow serum concenfrafions closely. 

Reboxetine is generally well tolerated. Compared to placebo, most frequently reported adverse effects in the reboxetine group are dry mouth and insomnia (Versi-ani et ah, 2000). There are also reports of tremor, hypertension, and somnolence in association with reboxetine use. Reboxetine has a wide therapeutic index and does not appear to increase the QTc or alter cardiac conduction. 

Anxiolytics and Sedative-Hypnotics. Because of their large therapeutic index, measurement of anxiolytic or sedative-hypnotic serum concentrations is not usually necessary in clinical practice, unless abuse, overdose, or inadvertent toxicity are suspected. Some data indicate that plasma alprazolam levels of 40 ng/mL may be required to manage panic disorder ( 51) (see the sections Adverse Effects of Anxiolytics and Adverse Effects of Sedative-Hypnotics in Chapter 12). 

Given the wide therapeutic index of the SSRIs, the safety issues that make TDM a standard of care with the TCAs are not applicable to this class. Although the risk and severity of their typical adverse effects (e.g., nausea) increase with dose escalation, there is almost no chance of life-threatening toxicity. Hence, physicians can adjust the dose of these drugs upward without this concern. The issue of TDM with the SSRIs, therefore, involves increasing the percentage of patients who will experience an optimal antidepressant response. 

Venlafaxine is converted by CYP 2D6 to ODV, which is subsequently cleared by CYP 3A3/4 ( 501). ODV has virtually the same in vitro pharmacology as venlafaxine. Thus, the total of venlafaxine plus ODV is believed to be the relevant concentration determining clinical effect ( 137). Theoretically, venlafaxine should be relatively impervious to even substantial CYP 2D6 inhibition because ODV levels would decrease proportionate to the increase in venlafaxine levels such that the total level would remain the same. In contrast, the inhibition of CYP 3A3/4 would be potentially more clinically relevant because it should decrease ODV clearance and thus increase total levels. Nevertheless, such an interaction would not be expected to do more than increase the usual dose-dependent adverse effects of venlafaxine because of its wide therapeutic index. 

In summary, although lithium has revolutionized the treatment of bipolar disorder, its narrow therapeutic index, numerous adverse effects, and relative ineffectiveness in a large proportion of bipolar patients has led to an expanding number of alternative approaches, including the following ... 

As mentioned earlier, the clinical trials with TCAs in children and adolescents with MDD have generally been disappointing ( 120, 122,123). In addition, these medications have a less favorable adverse effect profile and thus higher patient attrition rates during the acute treatment phase compared with newer antidepressants. They also have a lower therapeutic index (i.e., difference between therapeutic and toxic dose see Chapter 7). 

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