The Overlooked Problem of Drug-Receptor Desensitization

Drugs that activate receptors account for almost one-half of all pharmaceuticals. Yet it is ironic that after more than half a century and billions of dollars spent on basic research in the government, academic and pharmaceutical labs, we still don't have a fundamental understanding of how drugs activate their target receptors. One of the most puzzling aspects of understanding how these drugs work is to also understand how they deactivate these same receptors. Often a dose of a drug that activates one person's receptors can deactivate another's. The technical name for this is desensitization, which is also referred to as tachyphylaxis, down-regulation, tolerance or fade.

Desensitization is an overlooked and important side effect of many commonly used drugs and naturally occurring hormones. Desensitization may contribute to a person's inability to tolerate medications including those for the heart, pain or asthma. One reason desensitization has been overlooked is that there exists a common belief that by taking smaller doses one can prevent drug desensitization. Therefore the doctors and pharmaceutical companies suggest the smallest starting doses for many drugs as the appropriate therapy. This isn't always true. Some people are susceptible to small doses and will still experience receptor desensitization. Rightly or wrongly, this practice creates a tightrope between a therapeutic or desensitizing dose that patients and doctors must walk when utilizing medications that desensitize their target receptors. This may affect anywhere from thirty to fifty percent of all pharmaceuticals and be a fertile area for drug development and improvement in the future.

Why haven't the major pharmaceutical companies or the FDA addressed these issues? The answer to this question reflects back to the original statement that we still don't know how drugs activate and deactivate their target receptors. A general model that accurately accounts for receptor activation and desensitization remains to be accepted by the scientific community. Meanwhile, many large pharmaceutical companies face a significant, long-term threat to their current blockbuster drug model. The slowing rate of New Chemical Entity (NCE) introduction clearly demonstrates that a need exists for a better way to find potential drugs. One of the reasons pharmaceutical companies haven't found many NCEs is because they lack a fundamental understanding of how drugs work. They are increasingly bogged down with cumbersome theoretical and molecular models that provide little predictive power for finding new potential drugs.

One way to develop better drugs is to understand and prevent some of their side-effects. Our drugs can be safer, but the FDA and consumer groups have to goad pharmaceutical companies into more open and better scientific studies. The public needs to be better educated about taking drugs - not only their potential for good, but harm as well.

Since many of the drugs that activate receptors also deactivate them depending upon the patient, patients need to know that this can happen. The FDA and the pharmaceutical companies could do more in this regard. Studies that determine the average type and amount of drugs to deliver should also determine when these drugs begin to deactivate these receptors in their target patient population. Currently this isn't done. The FDA could also require these studies to better assess the therapeutic efficacy of NCEs as well as many of the current drugs on the market. The FDA could also require further basic research to provide better drugs with less serious side effects.

Through public education, the bureaucracy can gradually change so that those responsible for safe and effective drugs can produce better pharmaceuticals. Bio Balance is attempting to lead the way toward this future.

Richard Lanzara, Ph.D.
President
Bio Balance, Inc.

Bio Balance ( http://www.bio-balance.com/  ) is an early stage drug development company that has developed the only tested method to prevent drug desensitization at the receptor level. This phenomenon, also known as down-regulation, tolerance or fade, occurs with a large number of very commonly used drugs such as dobutamine for heart failure, isoproterenol for shock or asthma, L-dopa for Parkinson’s Disease, and morphine for pain. Notably, desensitization cannot be remedied by taking larger dosages. With more and more drug, efficacy diminishes and the drug essentially stops working. By using a patented approach, we create new, combination drug candidates that sustain the therapeutic response with a better side-effects profile than the original drugs.