The issue of clarithromycin and increased cardiac deaths #2 - Pharmacology

Clarithromycin is a macrolide bacteriostatic antimicrobial that came onto the market in 1991. It enjoyed considerable success as an orally administrable macrolide, being relatively lipophilic and having a slightly longer elimination half-life. Came off patent about 10 years ago.

It acts by inhibiting bacterial protein synthesis by blocking the ribosomal RNA. Resistance develops as bacteria acquire various resistance genes, such as the plasmid erm (A) gene that confers an ability to methylate the adenine in the binding site.

Clarithromycin can be administered orally with a bioavailability of about 50%. Its permeability across biological membranes is only due in part to its lipophilicity. A significant part of the process depends on a complex interplay between influx and efflux transporters expressed on various membranes. Consequently intra-cellular, and tissue concentrations do not correlate with circulating unbound drug concentrations. Interestingly, tissue interstitial fluid concentrations are lower than free drug concentrations in plasma, but intra-cellular concentrations are to a variably extent much higher than plasma free concentrations.

The protein binding of clarithromycin is about 60-70%. The Volume of Distribution is about 10 L/kg, which is consistent with significant permeability into tissues. Again this increased permeability results not only from lipophilicity but from the complex interplay of influx and efflux transporters, in this case clearly favouring influx.

Clarithromycin is eliminated by both hepatic metabolism and renal elimination. It is extensively metabolized by CYP3A4 (which it also inhibits), to a principal metabolite 14-(R) hydroxyclarithromycin, which is also pharmacologically (less) active. The pharmacokinetics is not linear, and the elimination half-life increases from 3-5 hours at lower doses, to 5-7 hours at higher doses. Tissue concentrations persist for much longer.

Clarithromycin produces a range of adverse reactions, but the one that concerns us for this discussion is with respect to cardiac death. Like many of the macrolides, clarithromycin has an effect on the myocardial delayed potassium rectifier current, leading a prolongation of the QT interval of the ECG. This prolongation of the QT interval is associated with risk of torsades de pointe and a fatal ventricular arrhythmia.

The usual adult dosage is 250-500 mg 12 hourly for 7-14 days.

Clarithromycin is a drug with very interesting pharmacological properties. Give a thought as to how these properties contribute to variability in the clinical response and the risk-benefit ratio particularly with respect to the problem of cardiac death.

(To be continued)

Ibn Sina and clinical pharmacology

It is probably an auspicious occasion to recognize that the preceding discussions on efficacy are not anything new, and that their very foundations were laid a thousand years ago by an amazing Persian Shia physician called Abū ‘Alī al-Ḥusayn ibn ‘Abd Allāh ibn Sīnā, or just "ibn Sina" or Avicenna.

In the second volume of his famous treatise "The Canon of Medicine", he identified 7 important principles which are still valid today, and establish the foundations of modern clinical pharmacology. He writes:

“Experimentation will bring us complete understanding of the strength of drugs; however,only if the conditions below are followed.”:

"The drug must be free from any extraneous accidental quality."

"It must be used on a simple, not a composite, disease."

"The drug must be tested with two contrary types of diseases, because sometimes a drug cures one disease by Its essential qualities and another by its accidental ones."

"The quality of the drug must correspond to the strength of the disease. For example, there are some drugs whose heat is less than the coldness of certain diseases, so that they would have no effect on them."

"The time of action must be observed, so that essence and accident are not confused."

"The effect of the drug must be seen to occur constantly or in many cases, for if this did not happen, it was an accidental effect."

"The experimentation must be done with the human body, for testing a drug on a lion or a horse might not prove anything about its effect on man."

31st Pharmacological and Therapeutic Society of Thailand Meeting

I just spent 3 wonderful days in Khon Kaen, Thailand at the 31st Pharmacological and Therapeutic Society of Thailand Meeting. I was there as the honoured guest of the Society to deliver the 'Chiravat Sadavongvivad Memorial Lecture was on " The ABC Transporters: Their role in determining drug resistance and drug response'. The proceedings are published in the Thai Journal of Pharmacology. For Khon Kaen University, see here.

Apart from enjoying the characteristically warm and wonderful hospitality of the hosts, it was a great time to catch up with old friendships and also on an academic front, to try and understand a bit more about Thai ideas of ethnicity issues.