Screening Methods for Antiarrhythmic Drugs

Screening Methods for Antiarrhythmic Drugs

1. Definition, scope and the distinctive problem of antiarrhythmic screening

• Antiarrhythmic screening is the ordered set of in vitro, isolated-organ and in vivo assays used to detect, quantify and classify a test compound's ability to prevent or terminate a disorder of cardiac rhythm, and to expose its converse liability — proarrhythmia (SK Gupta Ch.18, pp.292–304; Vogel 4e V1 Part I, pp.237–286).
• Arrhythmias remain among the most challenging human disorders to diagnose and to treat, and their complex pathophysiology has proved difficult to model — this is the framing statement of the whole screening field (SK Gupta Ch.18, p.292).
• Direct correlations between the traditional arrhythmia mechanisms — abnormal excitability, abnormal conduction, abnormal repolarization — and the underlying molecular or cellular biology are poorly defined, because the primary aetiologies of many human arrhythmias remain unknown (SK Gupta Ch.18, p.292).
• The consequence for screening design is a surrogate strategy: because the human disease cannot be copied, the experimenter induces an arrhythmia of known mechanism by a defined stimulus and asks whether the test compound raises the threshold for it, delays its onset, shortens it, or prevents death (SK Gupta Ch.18, p.292; Vogel 4e V1 Part I, p.239).
• No animal model can accurately resemble the human disease condition, and species differences also exist; the practical answer is not to abandon models but to select an appropriate model and species so that close similarities with humans suffering from — or threatened by — arrhythmias can be developed (SK Gupta Ch.18, p.292).
• Although an animal is not the same as a human patient, arrhythmogenic mechanisms derived from animal experiments have tremendously helped in diagnosing arrhythmias and adapting therapeutic strategies (SK Gupta Ch.18, p.292).
• Because several arrhythmic syndromes now have identified genetic causes, genetic models reproducing those mechanisms have become feasible; initial murine modelling revealed that in many cases the pathophysiology of the respective human disease is more complex than had been suspected (SK Gupta Ch.18, p.292).
• Insights from human genetic studies and animal models strongly suggest the primary molecular defect may contribute at many stages in the causal chain leading to arrhythmia — so a comprehensive analysis needs knowledge of (i) membrane effects of the primary defect, (ii) downstream intracellular signals, (iii) the developmental results of these perturbations, and (iv) the integration of compensatory responses and environmental factors (SK Gupta Ch.18, p.292).
• Precise modelling will therefore require not only mutation of specific residues in known disease genes but also the systematic study of each of the many steps in arrhythmogenesis; ultimately such models will enable unbiased screening for disease mechanisms and novel therapies (SK Gupta Ch.18, p.292).
• Winslow (1984) reviewed the methods for detection and assessment of antiarrhythmic activity, and Szekeres (1979) proposed a rational screening programme for the selection of effective antiarrhythmic drugs — these are the canonical methodological reviews cited by the compendium (Vogel 4e V1 Part I, p.239).
• Winbury (1956) framed the rationale for a screening programme in terms of the relation between atrial and ventricular antiarrhythmic assay methods — i.e. the recognition that a compound active on one chamber may not be active on the other (Vogel 4e V1 Part I, p.240).
• Arrhythmia models in the rat specifically were reviewed by Cheung, Pugsley and Walker (1993) (Vogel 4e V1 Part I, p.239).
• Scope boundary for this topic: these methods answer "does this molecule have antiarrhythmic activity, of which class, at what dose, with what proarrhythmic risk?" — they are not the clinical pharmacology of the marketed antiarrhythmics; KDT Ch.39 is used here only for the mechanistic and classificatory vocabulary the assays must resolve (KDT 8e Ch.39, pp.570–583).