Cardiac Glycosides

Cardiac Glycosides 化学特性,用途語,生産方法

• 臨床応用

  Although the primary clinical use for digoxin is in the treatment of CHF, this agent also is used in cases of atrial flutter or fibrillation and paroxysmal atrial tachycardia.
  The therapeutic effects of all cardiac glycosides on the heart are qualitatively similar; however, the glycosides largely differ in their pharmacokinetic properties. The latter are greatly influenced by the lipophilic character of each glycoside. In general, cardiac glycosides with more lipophilic character are absorbed faster and exhibit longer duration of action as a result of a slower urinary excretion rate. The lipophilicity of a cardiac glycoside is measured by its partitioning between chloroform and water mixed with methanol: The higher the concentration of the cardiac glycoside in the chloroform phase, the higher its partition coefficient, and the more lipophilic it is. It is evident from a comparison of the coefficients that their lipophilicity is markedly influenced by the number of sugar molecules and the number of hydroxyl groups on the aglycone part of a given glycoside. Lanatoside C, with a partition coefficient of 16.2, is far less lipophilic than that of acetyldigoxin (partition coefficient, 98), which structurally differs only in lacking the terminal glucose molecule. Likewise, a comparison of digitoxin and digoxin structures reveals that they only differ by an extra hydroxyl in digoxin at C-12. This seemingly minor difference in their partition coefficients from 96.5 to 81.5 for digitoxin and digoxin, respectively, results in significant differences in their pharmacokinetic behavior.The glycoside G-strophanthin (ouabain) possesses a very low lipophilic character because of the presence of five free hydroxyl groups on the steroid nucleus of the aglycone ouabagenin.

• 副作用

  The most common and severe side effect of PDE3 inhibitors is ventricular arrhythmias, some of which may be life-threatening. Other side effects included headaches and hypotension, which are not uncommon for drugs that increase cAMP in cardiac and vascular tissues, with other examples being β-agonists.

• 酵素阻害剤

  The mechanism of cardiac contraction involves a G-protein signal transduction pathway, which regulates intracellular calcium concentrations. Activation of the Gs -protein involves the formation of intracellular cAMP, which thereby increases intracellular calcium, stimulating cardiac muscle contraction. Relaxation occurs when the released cAMP is hydrolyzed by cytosolic cAMP-dependent PDE3, one of the phosphodiesterase isofoms. Therefore, inhibition of PDE3 increases intracellular cAMP, promoting cardiac muscle contraction but vasodilation of vascular smooth muscle.
  The overall cardiostimulatory and vasodilatory actions of PDE3 inhibitors make them suitable for the treatment of heart failure, because vascular smooth muscle relaxation reduces ventricular wall stress and the oxygen demands placed on the failing heart. The cardiostimulatory effects of the PDE3 inhibitors increases inotropy, which further enhances stroke volume and ejection fraction. Clinical trials have shown that long-term therapy with PDE3 inhibitors increases mortality in heart failure patients. Therefore, these PDE3 inhibitors are not used for the long-term, chronic therapy of CHF. They are very useful, however, in treating acute, decompensated heart failure or temporary bouts of decompensated chronic failure. They are not used as a monotherapy. Instead, they are used in conjunction with other treatment modalities, such as diuretics, angiotensin-converting enzyme inhibitors, β-blockers, or cardiac glycosides. The PDE3 inhibitors contract cardiac muscle and are used for treating heart failure, whereas the phosphodiesterase 5 (PDE5) inhibitors are vasodilators and are used for treating male erectile dysfunction. Note that the generic names for PDE3 inhibitors end in “ one,” and those for the PDE5 inhibitors end in “fil.”