Thursday, January 7, 2010

Hearty welcome to NH blog again. We are in the process of learning something about the developmental history of cardiac drugs. This time, we shall see the development of Calcium Channel blockers.

The 1,4-dihydropyridines have an important role in the human biochemistry. Despite the role it played and the ease with which it can be evaluated, very surprisingly, minimal research had taken place involving this vital compound. The research scientists group of Bayer laboratories learnt this and started working on it. True to their research reputation, they did not leave any stone unturned. Once they had a lead, they tested for its organ efficiency and found a reasonable change in the cardiac output. They focused their energies on the molecular variant and ended up developing and testing more than 2000 analogues! The result was a patent application for a new drug called Nifedipine in the year 1967 by two scientists named Friedrich Bossert and Wulf Vater. They registered the drug for its supposed activity as coronary vasodilator.

With that started the hunt for the actual action of Nifedipine. Over a couple of years, they found that nifedipine acted by blocking calcium channels in the cardiac conduction tissue and in the smooch muscles of blood vessels. Thereby, Nifedipine led to the relaxation of the myocardial tissue and blood vessels. The resultant action was coronary vasodilatation and drop in both systemic and pulmonary vascular resistance. As an obvious result, this should have reduced the afterload and oxygen consumption. Thus, it was a drug with potential benefit in angina with hypertension. With this background, Nifedipine had a grand entry into the markets in 1975.

The major hitch of Nifedipine was its short duration of action. As the popularity of the drug picked up, this issue was to be sorted out. The research groups started the action in two sides.

The first was to develop analogues of nifedipine for longer duration of action. This would have the advantage of a sustained action on blood pressure. The result was the development of felodipine and amlodipine. In the same bargain, some more drugs were developed, which showed a higher specificity for Calcium channels of other organ systems. Nimodipine was one such development with effect on cerebral blood vessels. The advantage was its specificity, in which it did not affect the systemic blood pressure. However, all this new developments would take high levels of research and finances, not to mention the time.

The second approach was more logical and much simpler: creation of a sustained release preparation of Nifedipine. This happened quite fast and was marketed easily. With the popularity Nifedipine enjoyed, it was not difficult to make the presence for the sustained release preparation. However, the research team was aware of the short life of this strategy and had realised the effacement of molecule once the new preparations took over. But the gamble had paid off. The SR preparation effectively bridged the gap and made the constant market for the drug till the newer generation ones took over. Even today, the dihydropyridine analogues enjoy a great market presence in the field.

Compared to the systematic research of Nifedipine, the other calcium channel blocker, Verapamil was more of serendipitous in its invention. It was supposedly a takeoff from the atropine in the field of antispasmodics. In this group came mebeverine, which enjoyed some success. However, the other molecule called verapamil did not have such luck. It was synthesised by the famous Knoll pharma. Its chief of research, Ferdinand Dengel has been credited for its creation and discovery of possible uses. Once the initial trials were over, Dengel realised that the drug was nowhere near the antispasmodic action. What caught his attention was its potential action as coronary dilator. He led the research to take over towards the use in angina. The success of the trials led to the introduction of the drug in the market in 1968. Soon it was realised that the drug can cause depression of conduction activity. This action prompted Albrecht Fleckenstein at the University of Freiburg to evaluate the molecule on those lines. That explained why the drug failed as an agent for smooth muscle relaxation; it was more specific for cardiac muscles! The much more interesting finding of the research was the reversibility of its action by calcium. This led Fleckenstein to assume that the drug was indeed a calcium blocker. Further research showed that the assumption was correct and Verapamil blocked the movement of calcium ions into cardiac cells. It was credited as the first calcium antagonists. As better understanding of the cardiac physiology and the role of calcium channels became apparent, the anti-arrhythmic action of Verapamil was acknowledged in 1970s. Its action as the relaxation agent also became useful in controlling the hypertension, albeit the use is minimal for this purpose at present.

The other calcium channel blocker, Diltiazem has much more serendipitous history! It was supposed to be sought as a psychotropic drug by the Japanese. The Tanabe Seiyaku Company of Japan was working in this regard. After huge number of possible variations in the combination of the medicational research, what they ended up with was Diltiazem! The initial drug was a racemic mixture of many isomers of the drug. The research team ended up segregating each isomer and started testing them. As a part of serendipity, the dextro isomer showed great vasodilator effect. The team decided to conduct the trial for this molecule. It was finally shown to have vasodilatory action simulating papaverine on coronary circulation. Logically, they tested it against calcium ion movement across cardiac muscle membrane. It was found to be a positive blocker! Thus was born the first coronary vasodilator which was actually a calcium antagonist. Later, as a comparison with the other drugs of the group, it was tested for its action on cardiac rhythm. It was positive for that action also! Theoretically, it stood between the Nifedipine and Verapamil, with good qualities of both in the same drug. Its spectrum makes it a desired preparation even today for selective indications.

Next issue may be the last one for the history of drug development. If anyone has any ideas for future posts, please let me know.

On a personal note, we had our departmental “publication meet” recently. As usual, many a write ups are in the long process of preparation. Our mercurial boss got impatient about the delay of her lethargic team. I was advised to give up blogging and to get serious with research. I think it is a good advice for now, as the number of people reading my blog does not make any justice to my effort. I can as well concentrate on writing papers and getting credit for publication! If you find the frequency of the blog posts getting reduced in the future, you know whom to blame!!

How does a restrictive VSD in Tricuspid atresia type II behave? If anyone says as IIb, they are obviously wrong; it becomes subaortic obstruction! It is clearly unlike that of type I. But a beginner needs to understand the finesse of anatomy and should not give feel that a restrictive VSD in Tricuspid atresia II is type b. We had earlier seen a report from outside in which the baby clinically had PAH, but the echo report said Tricuspid atresia IIb. The present baby we saw had a frank narrowed pulmonary valve with sever PS. We recalled the opportunity we had of learning from others mistake! We understood the importance of measuring the size of VSD in such cases and comparing it with aortic annulus. On cath study, this boy had a mean PA pressure of 16mmHg, which was not very much OK for BD Glenn. How about creating a Glenn and doing a PA band at the same time? What is the future of such a manoeuvre? Is there any experience of doing this combo procedure? We could also recall a baby with Tricuspid atresia IC, who had undergone a PA band at age of 4 months and at the age of 2 years, had a PVWP of 17mmHg. Do the post PA bands behave any different from type B physiology in Tricuspid atresia? Does the initial period of high flow change the pressure dynamics in post Glenn any way? Any role of creating a Glenn with PA band tightening here? Please send me your takes on these.

What are the indicators of RV failure in cTGA, VSD, PS physiology? Can the progressively increasing TR be an indicator? We had a 3-year-old baby with cTGA, VSD and PS with more than mild TR. Since the age of the baby is less than the institute acceptance for RV to PA homograft and the baby was symptomatic, it was the choice between BTT shunt Vs an early Senning + Rastelli. How would each of them go about? The chance of getting an optimal sized homograft and the possibilities of repeat procedure were the caveats for Senning + Rastelli. Compared to this, the BTT shunt would increase the RV volume load in a cTGA. Is it OK to load the fragile RV for another year or so? What would be the impact on eventual RV function? Would a failed RV permit us to proceed with any procedure in future? Is there any way of making a vis-to-vis comparison? Any data on this? Please let me know.

Can cTGA have the great arteries crossing each other? We had a 2-year-old with situs ambiguous, common atrium with ill-defined pulmonary venous connection with interrupted IVC. Now that the atrial morphology could not be defined, the upper floor anatomy was unclear. However, on the echo, the ventricles appeared to have d loop with the VA concordance. One of our team members pointed towards the dilemma of labelling ventricular cavities in AVCD. Hence, if the loop was presumed to be L, then it would be AV concordance with VA discordance! Now, can a discordant VA connection have crossing great arteries? Although I maintained that it is not possible, I was not very sure of my answer, more so in a situation with situs ambiguous! If you have any data on this, please post it.

What is the definition of cardiac TAPVC? The most common answer would be the pulmonary venous confluence draining into coronary sinus or rarely, to directly at SVC – RA junction. We had an infant who presented with features of TAPVC. On echo, we found the pulmonary veins forming a common confluence and going up via the left ascending vertical vein, which entered the persistent Left SVC. There was no bridging innominate vein in this boy. The LSVC came back to heart and opened into the RA via coronary sinus! Technically, it is common confluence opening into CS. Is the variant cardiac or supracardiac? The question is more etymological, as the surgical team had no reservations on surgery, whatever name we called it! But, as a matter of interest, we debated the name. I felt that the cardiac variant should always be in physical link with the surface of heart throughout its entire course and any deviation from it would not be a cardiac variety, more so if it comes with a vertical vein. One of our team members tried to improve my words by saying that the cardiac variant should always be intrapericardial. We would like to get an opinion from the readership. Does the definition involve only the destination or the journey too? Please write your take on it.

Coming back to TAPVC, we often come across mixed TAPVC. Less common but seen variants are the dual drainage, which involves the different pulmonary vein combinations entering RA via separate entry sites. Technically, dual drainage is different from mixed TAPVC. The question is, should they be considered as a separate entity? The traditional Darling’s classification of TAPVC does not mention dual drainage at all. What is the opinion from the surgical clan? Should the naming follow only when the management differs or should it be adherent to the embryological basis? Definitely, the embryological basis of dual drainage is different from that of other variants. What is your take on it? Pen your opinions.

Let me know your opinions on the issues raised or any issues you want to rise! The whole objective of the Blog is to encourage the exchange of opinions on the issues that may not have a straight forward answer. The opinions from your side would be very valuable to lot many for ages. Don’t hesitate to post questions if any genuine problem is bothering you. Let the enlightened readership be your guide to a “Yet to be opened door”. You can either use the comments section or use my email for posting your views and questions. Best of luck.



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