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In an effort to improve the efficacy of their existing pharmaceuticals, drug developers have increasingly turned to the concept of prodrugs in order to achieve this goal. Prodrugs are inactive forms of therapeutic drugs that are activated by either a chemical or a biological reaction inside a patient’s body. This necessity for activation can confer on prodrugs certain advantages over the base compounds or other formulations that they are similar to.

Understand the Nature of Prodrugs

Prodrugs can confer several different types of benefits on patients for whom they are prescribed. They start with the formulation of an active drug that, for various reasons, may have therapeutic limitations. Some active drugs, for example, are unstable at ambient temperatures or insoluble when passing through the body’s major metabolic pathways. In these cases, conversion to a prodrug can increase stability and reduce insolubility, ensuring that the active drug enters the body effectively.

Conversion to prodrugs can offer different benefits in other circumstances as well. For example, the conversion can improve the specificity of an active drug’s therapeutic effects. When properly designed, prodrugs can reach particular targeted organs or tissues before they are biotransformed through the patient’s natural metabolic processes, thereby releasing their active drugs at the precise sites at which they are required. For some prodrugs, the biotransformation can take place at a consistent pace over a period time rather than occurring too rapidly, leading to “on/off” effects. Prodrugs can also improve patients’ acceptance of active drugs that have unpleasant tastes, odors, or other undesirable characteristics.

Prodrugs Have an Impact on ADHD

A variety of pharmacological interventions are available for attention-deficit/hyperactivity disorder (ADHD), but substantial between-patient variability exists in drug absorption, sometimes resulting in broad ranges of times to maximum concentration. The prodrug concept has recently found application in a new treatment for ADHD. Approved by the FDA in February 2007, lisdexamfetamine dimesylate is the first—and so far the only—prodrug stimulant approved for treating ADHD. The agent, a prodrug formulation of the stimulant d-amphetamine, is one of several drugs with efficacy in the treatment of ADHD. Its novel prodrug formulation provides reliable and consistent symptom reduction throughout the day (up to 6:00 pm) after oral administration, an achievable accomplishment because the agent—which is pharmacologically inactive—is transformed into d-amphetamine only after it is administered. This is in contrast to several long-acting medications prescribed to treat ADHD that are taken orally; other agents use delivery systems that release the active drugs in two or more “pulses” each day. By understanding the nature and activity of this prodrug, psychiatrists, pediatricians, and other clinicians may better determine the conditions under which they might prescribe lisdexamfetamine dimesylate for patients with ADHD.

Other Prodrugs Benefit Different Conditions

In addition to lisdexamfetamine dimesylate for patients with ADHD, several other prodrugs in current clinical use are illustrating the various advantages of the approach. They include: valacyclovir for viral infections; fosphenytoin for seizures in patients with epilepsy; enalapril for hypertension; and levodopa for Parkinson’s disease. Each of these agents works by different mechanisms of action, but represent significant advances in medicine. Much like the development of lisdexamfetamine dimesylate for ADHD, there is hope that new prodrugs will add to our current armamentarium of treatments for other chronic conditions.

Robert L. Findling, MD has indicated to Physician’s Weekly that he has the following financial disclosures: Abbott, AstraZeneca, Bristol-Myers Squibb, Celltech-Medeva, Cypress Biosciences, Forest, GlaxoSmithKline, Johnson & Johnson, Eli Lilly, Neuropharm, New River, Novartis, Organon, Otsuka, Pfizer, Sanofi-Aventis, Sepracore, Shire, Solvay, Supernus Pharmaceuticals, and Wyeth.