Special drug adverse effect: QT Lengthening

I won't have time to cover in any detail the topic of "adverse effects of drugs". I had suggested that you should read through the ppt file to get some ideas...

There is one type of adverse effects that has been observed with drugs with a great variety of functionally and chemically diverse features - and this made it difficult in the early days of its discovery to understand what is going on. But now we seem to know: I can only recommend that you do some self-studying, trying to comprehend this adverse effect that has been responsible for several drug withdrawals because of reports of death as the ultimate outcome (viz terfenadine, cisapride...others).

This adverse effect is referred to as QT-Lengthening or Long QT Syndrome. The initial phase is a lengthening of the QT interval on the EKG, and thus a bradycardia. This in itself may not be a serious problem but this condition may precipitate a tachycardia in form of ventricular arrhythmia referred to as Torsades de Pointes, and this indeed can be fatal.

Here are some points you should remember in connection with this topic:

• Many drugs can cause the phenomenon.
• It is now recognized that it is due to an effect (usually not predictable unless the drugs are known to affect excitable cells), involving mutated or genetically defective ion channels (one of the K-channels in particular). These ion channel defects - about 12 possibilities usually are listed (Na and K channels) although most cases involve only three of these - are referred to as "channelopathies".
• Repolarization of the cardiac action potential is thus delayed by the drug that interacts somehow with these channels, causing a bradycardia.
• During this extended, lengthened QT period, the likelihood of a spontaneous pacemaker cells kicking in is increased now leading to triggered tachyarrhythmia: the Torsades des Pointes.
• Without coordinated and productiue ventricular contractions a perfusion deficit develops leading to weakness, temporary awareness or performance problems, and if this persists for more than a certain time (1 min or so?) it can be fatal.
• Drugs can cause this effect on their own, but sometimes the problem is due to metabolism and drug interaction issues whereby a prodrug is not quickly metabolized to its active form, so that the prodrug plasma concentration remains too high and then can cause QT lengthening (case in point: terfenadine,  an old and now withdrawn H1-antihistamine). Such delays in metabolism can be due to co-administered drugs like erythromycin or ketoconazole which inhibit CYP enzymes.
• Some individuals have a genetic condition (Long QT Syndrome) predisposing them to this adverse drug effect.
• Nowadays, new drug applications require EKG data showing that they do not cause QT Lengthening.

Nice story? Now you know, in a nutshell, how it works!