Diseases, ADRs

Once an adverse event is associated with a drug, comparisons between patients with ADRs and those who have taken the drug but have not suffered an adverse reaction can be made. Possible differences include dosing, duration of treatment, other diseases present (comorbidity), other drugs... 

All drugs may cause adverse drug reactions (ADRs). These adverse effects are either unpredictable (hyper-sensitivity) or dose-depending. The risk of ADR is increased for several reasons in the elderly. The physiological alterations, the high number of medications and concomitant diseases increase the risk of ADR. This is further... 

The argument is that the disease or a symptom or sign of the disease and the drug ADR may interact as follows ... 

Compliance. Early improvement may cause the patient to stop the drug and the improvement of the ADR may be inappropriately assigned to tachyphylaxis of the ADR failure of the disease to improve may persuade the patient to add a rescue drug or increase the dose of the study drug or even stop the drug impaired mental or cognitive function due to the disease may affect compliance. 

Observational bias by halo effects. Perception of an ADR may be swamped by the symptoms of the disease, thus as the disease symptoms resolve the ADR becomes apparent. 

Unblinding. If the patient or physician are unblinded due to rapid improvement of the disease or an ADR they may be led to expect ADRs with the active treatment. 

Pharmacological clinical activity bias. An AE that is already present due to the disease may be increased if it is also an ADR of the drug or vice versa. For example, the diarrhea of gastroenteritis may be alleviated by codein-containing preparations given to relieve pain while the inertia of a severely depressed patient may be sufficiently resolved by an antidepressant to enable the patient to commit suicide. 

Singularity of the Drug. The principle involved in the singularity method of linking a drug with an ADR is based on two assumptions Only one drug was administered, and there was no basic disease or co-morbid state that could be related to the ADR marker being used in the assessment. 

Incomplete Information. Incomplete information is not unique to ADR evaluation but is common to all areas of medical practice. The lack of sufficiently detailed, time-related data on drug administration and disease markers may make it impossible to render a reasoned judgment on many ADR cases, leaving them in their original and unsatisfactory anecdotal status. 

ADRs frequently mimic spontaneously occurring diseases, hence the same diagnosis or symptom could appear as an AE or disease. 

In the identification of new ADRs, it is important not to separate a possible side effect from a disease. 

In the early 1960s, drug companies began to lobby for government indemnity for the vaccines they developed, tested, and produced. Because so many people are vaccinated at one time, particularly school-age children, ADRs from a vaccine can carry considerable liability. As more diseases have become vaccine-preventable, more ADRs have been reported. In 1974, impetus for indemnity increased when the courts upheld a jury verdict of 200,000 for a child who developed polio from the Sabin live-polio vaccine. ... 

What is, perhaps, most disturbing is the assertion by Coulter and Fisher in 1985 that the ADRs from DPT should not have happened. They document that Japan switched to an acellular form of the DPT virus in 1981, which was just as effective in preventing the diseases but had fewer ADRs. Shoemaker reports that In Japan, the Ministry of Health, instead of trying to cover up problems with the vaccines, chose to find a solution." According to Shoemaker, it took almost 20 years for the United States to stop using the whole-cell version of the vaccine, and manufacturers are still distributing the whole-cell version in third-world countries "undoubtedly because it is cheaper to make." ... 

Severe, life-threatening diseases, such as cancer require a different drug discovery approach. Safety requirements in most oncology targets tolerate more side effects, which otherwise would severely limit the use of a medicine in other indications. For example, in addition to hair loss, a common side effect of cancer treatment, compounds which affect cell cycle, cell proliferation and apoptosis pathways also cause other serious side effects and make the patient endure severe adverse drug reactions (ADRs). 

Adverse drug reactions constitute a major morbidity, causing deaths in some cases. About 6% of all hospital admissions are related to ADRs and about half of these are avoidable. There is also a substantial diagnostic problem since there is a limited way in which the body may respond patho-physiologically. This means that ADRs often masquerade as other diseases. Commonly reported ADRs are given in Table 1. 

Special studies on drugs or diseases may yield signals that were unexpected. On the other hand such studies may not be any larger than the premarketing studies and thus have little power to find less common ADR signals. Moreover, they are usually narrowly focussed, involve only a few drugs and are limited in time. 

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