Digitalis

Digitalis - In the second half of 18th century, William Withering, an English physician, heard that the local population was able to cure dropsy using a complex plant decoction. After having tested the various herbs on dropsy, digitalis leaf remained the most active and probably contained a substance increasing the ability of the weakened heart to improve pumping blood ( Figure 1.9 ). In 1775, Withering published a pamphlet in which he reported his discovery, meticulously describing how the extract of the digitalis should be prepared, and giving precise instructions on dosage, including warnings about side effects and overdose from the experience learnt from 163 patients.

Digitalis purpurea Candy Mountain

Fleur Digitale abeille digitaline champs

The only but not least problem was a dreadful continuous vomiting and diarrhea during the treatment that was caused by the fact that the boundary between the therapeutic dose and poisoning was exceedingly narrow. It was therefore evident and absolutely necessary to purify the active substance in order to fi x the effective and non-toxic dosage.

After decades of works, Augustin Eugène Homolle and Théodore Quevenne, two Parisian pharmacists obtained from foxglove leaves an amorphous substance they called “ digitaline, ” keeping the “ ine ” terminology, as they were sure that it was an alkaloid.In fact it was a complex substance containing a specific sugar. It is not until 1867 that another French pharmacist,

Claude Adolphe Nativelle was able to purify foxglove leaves and to produce the effective substance in the form of white crystals 49 that he called “ crystallized digitalin. ” Just a few years, later the German, Oswald Schmiedeberg, managed to produce digitoxin (1875). 50 Shortly thereafter reports began to come in about other medicinal herbs which had the same effect on the heart as the foxglove products. Ethnopharmacy gave birth to ouabain, extracted by Albert Arnaud from Acocanthera roots and bark, and strophantin, extracted from Strophantus . Both of these drugs had previously been used by arrow hunters in Equatorial Africa. One hundred years later, explanation for the cardiotonic properties of digitalis, ouabain and strophantin were given through molecular pharmacology experiments. The story began when Jens Christian Skou (Aarhus, Denmark) ( Figure 1.54 ) studied in the early 1950s the action of local anesthetics.

He thought that membrane protein might be affected by local anesthetics. He therefore had the idea of looking at an enzyme which was embedded in the membrane: ATPase, discovering that it was most active when exposed to the right combination of sodium, potassium and magnesium ions. 51 Only then did he realize that this enzyme might have something to do with the active transport of sodium and potassium across the plasma membrane. Skou left out the term “ sodium-potassium pump” from the title of his publication, continuing his studies on local anesthetics. In 1958, Skou met Robert L. Post (Nashville, USA), who had been studying the pumping of sodium and potassium in red blood cells 52 recently discovered that three sodium ions were pumped out of the cell for every two potassium ions pumped in, 53 his research being made by the use of a substance called ouabain which had recently been shown to inhibit the pump.

Conversations between Post and Skou about ATPase drove Skou to verify if ouabain inhibited the pump. Indeed, it did inhibit the enzyme, thus establishing a link between the enzyme and the sodium–potassium pump. Skou received a Nobel Prize in Chemistry (1997). Julius C. Allen and Arnold Schwartz (Houston, USA) then studied digitalis effect on cardiac contractility (the positive inotropic effect), caused by the drug’s highly specifi c interaction with Na /K -ATPase. It has been established that partial inhibition of the ion pumping function of cardiacNa /K -ATPase by digitalis glycosides led to a modest increase in intracellular Na , which in turn, affected the cardiac sarcolemmal Na /Ca 2 exchanger, causing a signifi cant increase in intracellular Ca 2 and in the force contraction.