Albert Vogl and diuretics drugs

Diuretics are drugs that cause high urine flow. Digitalis, like caffeine, is a diuretic. Tea, coffee, and alcohol are popular household diuretics. Currently in the United States, diuretics are the most prescribed drugs for heart conditions. The National Institutes ofHealth (NIH) has a branch called the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure. Part of the committee’s job is to evaluate hypertension drugs and make recommendations to American consumers. In 1993 and again in 1997, the committee recommended that diuretics and beta-blockers should be the first line of treatment for hypertension. These two classes of drugs are older and less expensive and have proven efficacy and safety.

Serendipity played an important role in the discovery of the first mercurial diuretic, merbaphen (Novasurol). Alfred Vogl credited “a series of fortunate errors and coincidences” for the discovery that completely revolutionized the treatment of congestive heart failure.

On October 7, 1919, Alfred Vogl was a third-year medical student in the First Medical University Clinic (the Wenckebach Clinic) in Vienna. A patient, Johanna, was admitted for congenital syphilis, and Vogl was the clinical clerk in charge of her case. While his Materia Medica (knowledge of drugs) was still immature, Vogl wrote a prescription for a 10% solution of mercury salicylate in water for hypodermic injection. To his embarrassment, the pharmacy informed him that the compound was insoluble in water. At that time, a retired army surgeon was present and happened to have received a new mercurial antisyphilitic, Novasurol. Vogl gratefully took the army surgeon’s suggestion and used Novasurol instead for the injection.

To Vogl’s astonishment, Johanna’s urine output reached 1,200 mL in 24 hours, as compared to her prior average daily urine output of 200 to 500 mL. Similar results were observed for patients with both syphilis and congestive heart failure. By removing fluid, the pressure on the heart was removed. Mercurial diuretics revolutionized the treatment of severe edema from congestive heart failure and were the primary treatment for this disease until the late 1950s and the emergence of thiazide diuretics. Alfred Vogl later immigrated to the United States and taught at the New York University College ofMedicine.

The discovery of chlorothiazide had its share of serendipity as well. Sir James Black, winner of the 1988 Nobel Prize in Physiology or Medicine, once said, “The most fruitful basis for the discovery of a new drug is to start from an old drug.”14 Chlorothiazide was one of many such examples. Because mercurials were notoriously toxic, the sulfanilamides (the sulfa drugs; see chapter 2) quickly replaced them when sulfanilamides were found to have diuretic properties. Diuretics such as furosemide and chlorothiazide resulted from chemical modifications of sulfanilamides.

In 1957, Merck chemist Frederick C. Novello was synthesizing diuretic agents and wanted to make some analogs of an older sulfa drug, dichlorophenamide. Surprisingly, the reaction gave the ring formation product rather than the linear derivatization product. The bicyclic ring formed was a benzothiadiazine derivative. Although disappointed by not getting what he had intended, Novello submitted the compound to the screening program anyway. It proved to be a potent diuretic without elevation of bicarbonate excretion, an undesired side effect. Chlorothiazide was groundbreaking. It was the first nonmercurial orally active diuretic drug whose activity was not dependent on carbonic anhydrase inhibition, such as acetazolamide.

Currently the most frequently prescribed diuretic is hydrochlorothiazide, discovered by Ciba scientists led by George deStevens. Hydrochlorothiazide is a “me-too” drug, a copycat drug that resembles the prototype, based on Merck’s chlorothiazide. In 1957, deStevens became aware of the research of Frederick Novello on the synthesis of disulfonamides in general, chlorothiazide in particular. DeStevens initially changed a six-membered ring on chlorothiazide into five-membered saccharin derivatives, which were inactive. But changing a double bond on chlorothiazide into a single bond gave him a hydrochlorothiazide that was tenfold more potent than the prototype. Hydrochlorothiazide was introduced into medical practice in 1959, and within a short time it became the drug of choice in the treatment of mild hypertension.

Hydrochlorothiazide dominated the market until the emergence of angiotensin-converting enzyme (ACE) inhibitors in the 1990s. Diuretics are still the gold standard for the treatment of hypertension. In addition, diuretics are widely used in certain developing countries as a popular cheap substitute for Viagra - an empty bladder seems to help to achieve penile erection.