Therapeutics cardiac toxicity

Cardiac Glycosides Therapeutic and Toxic Plasma Digoxin Levels... 

A new cuithracycllne, aclacinomycin A (Fig. 9) which we discovered in 1976 (28), has been proved by clinical study to be indispensable in the treatment of leukemia. It exhibits a therapeutic effect against leukemia and lymphoma, even against cases resistant to treatment with daunonycin and adriamycin. Dantchev et al. (8) proved that aclacinonycin A has markedly a lower cardiac toxicity in hamsters than does adriamycin. This low cardiac toxicity has also been confirmed by clinical study. 

The cardiac toxicity of quinidine includes A-V and intraventricular block, ventricular tachyarrhythmias, and depression of myocardial contractility. Ventricular arrhythmia induced by quinidine leading to a loss of consciousness has been referred to as quinidine syncope. This devastating side effect is more common in women than in men and may occur at therapeutic or subtherapeutic plasma concentrations. 

Thus, the upper limit to the therapeutic range is a function of toxicity rather than reduced efficacy in contrast to the other TCAs. Perry et al. ( 326) proposed a minimal threshold for this tertiary amine TCA of 265 ng/mL (imipramine plus desimipramine) with a remission rate of 42% above this threshold versus 15% below it. Of note, this threshold for optimal antidepressant response is closer to the threshold for CNS and cardiac toxicity than for any other TCA. Preskorn and colleagues ( 327) found a lower optimal threshold for imipramine plus desimipramine (125 ng/mL) when it was used to treat clinical depression in children and adolescents than when used in adults. 

The cardiac toxicity of tricyclic antidepressants in overdose has been a source of continued concern. Undesirable cardiovascular effects, besides representing a major therapeutic limitation for this category of drugs, delineate an area in which tricyclic compounds with novel structures, as well as second-generation antidepressants, may have significant advantages. The cardiovascular effects of tricyclic antidepressants and the new generation of antidepressants have been reviewed (SEDA-18,16) (16). 

Therapeutic chronic use of sertraline has reportedly caused visual defects, cardiac toxicity, gastrointestinal irritation, renal pathology, and loss of appetite. 

A. PPA, phenylephrine, and ephedrine have low toxic therapeutic ratios. Toxicity often occurs after Ingestion of just 2-3 times the therapeutic dose. Strokes and cardiac toxicity have been reported after therapeutic doses of ephedra and PPA. 

This chapter describes research by an interdisciplinary and international team focused on the preparation and evaluation of some dispersions of nanomatetials having potential application for injection into overdosed humans and to reverse cardiac toxicity by absorbing or binding the toxin. Specifically, the commonly overdosed therapeutics amiodarone, amitriptyline, and bupivacaine, and the illicit drug cocaine, are the deleterious chemicals under consideration for rapid reduction in concentration in blood. 

Common side effects of theophylline therapy include headache, dyspepsia, and nausea. More serious side effects such as lethal seizures or cardiac arrythmias can occur if blood levels are too high. Many derivatives of theophylline have been prepared in an effort to discover an analogue without these limitations (60,61). However, the most universal solution has resulted from the development of reHable sustained release formulations. This technology limits the peaks and valleys in semm blood levels that occur with frequent dosing of immediate release formulations. ControUed release addresses the problems inherent in a dmg which is rapidly metabolized but which is toxic at levels ( >20 7g/mL) that are only slightly higher than the therapeutically efficacious ones (10—20 p.g/mL). Furthermore, such once-a-day formulations taken just before bedtime have proven especially beneficial in the control of nocturnal asthma (27,50,62). 

Cardiac glycosides have a small ratio of toxic to therapeutic concentration. Possible adverse effects are nausea, vomiting, abdominal pain, diarrhoea, fatigue, headache, drowsiness, colour vision disturbances, sinus bradycardia, premature ventricular complexes, AV-block, bigeminy, atrial tachycardia with AV-Block, ventricular fibrillation. There are several mechanisms relevant for their toxic action (Table 2). 

---