Drugs effective doses

Sulfasalazine is often associated with either dose-related or idiosyncratic adverse drug effects. Dose-related side effects usually include GI disturbances such as nausea, vomiting, diarrhea, or anorexia, but may also include headache and arthralgia. 

Often, drug effects do not parallel changes in plasma concentration. This can result from distri-... 

Not all associations represent a cause-effect relationship. Because most epidemiologic studies of drug effects do not employ random allocation, it is important to determine if a legitimate cause-effect relationship exists. A central methodologic concern in observational studies is confounding—i.e., the possibility that the apparent effect of an exposure or intervention is due wholly or partly to other factors associated with it that have their own impact on the outcome of interest. Criteria have been proposed to help determine if an association is causal. The fewer criteria that are met, the less likely it is that an association is causal. Table 9-3 is adapted from the work of Hill and Stolly. Practitioners should ask the series of questions listed in the table to interpret findings from studies to determine if an association is likely to be causal. 

Temporal Relationships of Adverse Events. The temporal relationship between duration of product exposure and development of an adverse event is important in assessing causality. But how can data on temporal relationships be systematically summarized in a database containing thousands or even hundreds of thousands of subjects Temporal relationships cannot be clearly elicited if only frequencies of adverse events between treatment and control groups are compared. There can be many disparities in the subjects time of exposure or time at risk. Toxic manifestations of drugs may not occur until several months or even years after the initial exposure to the drug. How do we systematically assess delayed toxicity of a previously prescribed drug from the effect of a newly prescribed drug Such a scenario occurred with reported cases of pancreatitis associated with valproic acid therapy, in which some cases appeared several years after therapy [2]. 

Certain xenobiotics are very toxic even at low levels (eg, cyanide). On the other hand, there are few xenobiotics, including drugs, that do not exert some toxic effects if sufficient amounts are administered. The toxic effects of xenobiotics cover a wide spectrum, but the major effects can be considered under three general headings (Figure 53-1). 

Psychoses, when they occur, appear to be due to drug effect interacting with a vulnerable personality organization (Luisada 1978). Our experience has been that some adolescents with borderline personality disorders, as well as adolescents at risk of schizophrenic decompensation, may have this vulnerability. Although we do not have hard data to support the hypothesis that patients with PCP psychoses that are most resistant to treatment have the poorest long-term prognosis (Erard et al. 1980), our observations have been that persistence of symptoms of psychosis after the first 2 to 3 weeks of treatment often correlates with extended periods of impai rment. 

But do the clinical-trial data submitted to the FDA even establish proof of principle Recall that the rather small differences found between drug and placebo in the trials submitted to the FDA could have been due to the breaking of blind on the basis of perceived side effects. It may simply be evidence of an enhanced placebo effect, rather than a true drug effect. As I noted in Chapter i, once side effects are taken into account, the difference between SSRI and placebo is not even statistically significant.30... 

I suppose that some ingenious minds will be able to find a way of accommodating the chemical-balance hypothesis to these data, but I suspect that the accommodation will require convoluted circumventions, like those used by the Flat Earth Society in their efforts to maintain their defunct theory in the face of photographic evidence from space. If depression can be equally affected by drugs that increase serotonin, drugs that decrease it and drugs that do not affect it at all, then the benefits of these drugs cannot be due to their specific chemical activity. And if the therapeutic benefits of antidepressants are not due to their chemical composition, then the widely proffered chemical-imbalance theory of depression is without foundation. It is an accident of history produced serendipitously by the placebo effect. 

It has been suggested that MDMA and cannabis are soft drugs without many adverse effects. Do you agree (Note this question also applies to Chapter 7.)... 

The answer is a. (Hardman, p 436J The most common side effects associated with tricyclic antidepressants are their anti muscarinic effects, which may be evident in over 50% of patients. Clinically, the anti muscarinic effects may manifest as dry mouth, blurred vision, constipation, tachycardia, dizziness, and urinary retention. At therapeutic plasma concentrations, these drugs usually do not cause changes in the EKG Direct cardiac effects of the tricyclic antidepressants are important in over dosage. 

Finally, attitudes about the power of certain drugs (drug myths and positive expectancies) can cause problems for some people. Usually these myths are completely false and not supported by research. Other myths may have some kernel of truth to them, but usually those beliefs do not tell the whole story about drug effects. Often, beliefs in these myths create misperceptions about the power of drug use that are difficult for professionals to intervene upon. Usually these myths proclaim the drug s ability to make a person more likeable and sociable, more physically powerful, more intellectually capable, more energetic, and more sexually potent and attractive. 

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