Wednesday, December 30, 2009

Thanks for returning to the NH blog again! We are witnessing the historical development of some of the drugs used in contemporary pediatric cardiology. Hitherto, we have seen histories of Digoxin, Diuretics, Beta-blockers, ACE inhibitors, Prostaglandins and Sildenafil. Let us witness some history of drugs that set our rhythm right: The Antiarrhythmics!

The first victory on the war against malaria came from natives of Peru. The Cinchona bark, also known as Peruvian bark, Jesuits’ powder, or Devil’s bark was probably the first ever medication to be effective against malaria. This medical remedy from the New World (the American continent) caught the attention of Europe around AD 1650s and very soon ended up being the fancy of medical world. This also started an indiscriminate use there on. It did not take much time for the unscrupulous to realise the potential profit making in the Peruvian bark. To beat the competition, many used fake bitter tasting preparations to mimic the Cinchona bark. Worse were the people who used larger doses imagining faster and more effective recovery. This started the downfall of cinchona bark when cases of dangerous relapses (due to fake medicines) and sudden deaths (due to overdose) appeared.

Soon after the introduction of cinchona bark, the German physician Georg Stahl had recognised its action on the heart and subsequently sporadic attempts were made to exploit this. When the side effects of cinchona bark continued to dominate, further attempts to delineate its effect on heart stopped. Celebrity physician of the time, Thomas Sydenham did an extremely careful study on the Cinchona bark. The prevalent belief of the time was a “Peruvian curse” on the cinchona bark. Sydenham argued vehemently against the “curse hypothesis” and proved that the drug was a safe one, provided the discipline of dosage, timing, and duration of treatment were properly taken care of. Despite the best efforts by Sydenham, the scepticism on Cinchona bark continued.

Around 1820, the purified form of quinine was extracted from Cinchona bark and within the next decade, quinine in its purified form was used all over. This gave the opportunity to few physicians around 1850s to prescribe quinine in supranormal doses for management of heart problems, albeit without any scientific evidence. This practice went on for a few years in a selected group of physicians.

As the Dutch had dominated the Cinchona plantations worldwide, availability of Quinine was the best in Netherlands. Not surprisingly, a patient of atrial fibrillations, who visited the famous Dutch cardiologist Karl Wenckebach in 1912, boasted that he himself can control the fibrillations. The surprised cardiologist asked the patient to prove himself. When the patient returned the next day, to the surprise of Wenckebach, his heart rate was well in control.

On enquiry, the patient revealed the secret. He had simply taken quinine to bring his atrial fibrillation under control! What’s missed was the dose the patient had taken which Wenckebach had forgotten to ask. He presumed the regular dose and tried quinine on about a dozen patients. To his annoyance, only one responded favourably. In 1914, Wenckebach brought out his book on cardiac arrhythmias (please note the year: ECG was yet to be used in clinical practice!!)in which he referred to the matter of Quinine’s anti-arrhythmic action just in passing.

Walter Frey was a busy practicing physician in Berlin, Germany. In 1918, he reported about the use of Quinidine in controlling atrial arrhythmias in a prominent Viennese medical journal. He claimed that quinidine was the most effective of the four principal cinchona alkaloids when it came to anti-arrhythmic action. Although Quinidine was supposed to be the least toxic of all the four components it was still a pretty hazardous drug. That made the medical supervision mandatory.

Quinidine was not a new drug. When the cinchona bark was getting purified, many isomers were isolated. Quinidine was one of these isomers that was isolated in 1833 by Henry and Delondre. When tested as antimalarial, it nowhere matched the effect of quinine. The anit-arrhythmic action gave a new lease of life for the once discarded quinidine. From then on, it has never looked back. It can still be used for treatment of supraventricular and ventricular arrhythmias in many occasions.

Procainamide and Its Analogues

A renowned cardiac surgeon of Cleveland, Ohio, Frederick Mautz was a worried man due to the recurrent per and post operative arrhythmias. He had set out to investigate drugs that could be applied directly to the heart surface prevent these arrhythmias. He was logical in assuming that application of local anaesthetics, like procaine, could act as prophylactic medication against these arrhythmias. Added to this, Procaine had already shown to have similar effect on heart.

With this, the animal experiments started. To the excitement of Mautz, procaine indeed showed highly effective action.
With the success of animal experiments, Mautz proposed the use of intrapericardial instillation of procaine for irregular beats of the heart during surgery. Till then, the only option was the use of quinidine which itself had a temperamental action. Procaine was found to be superior to the effects of quinidine.

The problem with procaine was its short duration of action. Added to this, if used repeatedly, the cumulative effect was dangerous to central nervous system. To overcome this, procaine was researched extensively to improve the duration of action, reduce CNS side effects and to improve the cardio-specificity. The result was Procainamide, which is useful till today to treat ventricular arrhythmias on acute basis. When efforts were made to use the drug for long-term, the risk of inducing systemic lupuserythematosus appeared. Hence, it is not for long term therapy.

Efforts were made to improvise the molecule for long term use. In this bargain, the team of French scientists headed by Laville and Justin-Besanc of Laboratoires Delagrange tested 2-chloroprocainamide. Although it had negligible anti-arrhythmic action, it was found to be a very effective antiemetic on oral administration. This was further improved to create metoclopramide.

In the next post, we shall see the development of another group of drugs. Just before that, let me tell you that I am about to finish this series on the “developmental history” of drugs used in Pediatric Cardiology. I need some ideas for the new series. If anyone can give me some ideas for the new series, it would be very helpful. Please note that the responsibility of the research on your ideas would be entirely mine! I would not disturb you for any further help, unless you wish to provide me some. However, the credit for the idea will be fully acknowledged in the blog with the full name of the contributor!!

On a personal note, the New Year is fast approaching. Our team is depleted as of now! Consumption of remaining leaves or the wretched climate of Bangalore causing respiratory problems has taken the toll on the rest!! With half the team doing more than full work, the time available for decent academics and discussions get progressively shorter. Hope, we shall get back to full strength soon.

What if the cath tracing of PA mimic that of RV? We had a 4-year-old who had undergone ICR for TOF with transannular patching a couple of years back. He came back with an aneurysmally dilated RVOT. On cath, PA tracing was as described above. Unless we see the location of catheter on screen, we cannot make out the PA entry on tracing. Traditionally, homograft repair is considered as the surgical option. However, our surgical team felt that a reduction plasty of RVOT can be done. Is the impingement of this dilated RVOT on LPA very common? If any data with anyone, please let me know.

What should be the ideal device for a bizarre PDA? We used a regular PDA device in a bizarre PDA in a 34-year-old. The larger side of device sat nicely in the ampulla and before the release, it slipped into the duct and found its home at one of the constrictions of the duct. Before we could make any other change, the device seemed to settle well there. We decided to leave the device as it is. What might be the possible complications? Is the muscular duct as good as the ampulla for accommodating the device? Any experiences in this regard? Please comment your ideas on it.

The DILV with NRGA would be a Holmes’ heart; the same with malposed GA would be a Joubert’s heart. How about a DILV with side-by-side great arteries? We happened to see one like this. This baby had a classical DILV, but with PA from LV and Aorta from OC. On short axis, they had a side-by- side relationship. Is there a name for such a combo? How common are these entities? If you have seen one, please tell me.

Is the TV anatomy in Ebsteins with AV concordance any different from Ebsteins with AV-VA discordance? We know that physiologically, they connect to different great arteries and different pressures. But, anatomically, is the displacement or histology any different? Does it translate to any difference in surgical approach and outcome? What does the surgical team opine about this? We had one of our senior surgeons mentioning the practical difficulties of treating a CTGA with Ebsteins. If there are issues, can we take any measures to ensure better outcome in the post-surgical period? If any research has been made on this which you have come across, please send it to us.

We often come across infants with Single Ventricle physiology with a moderate PS. Many times these babies saturate around 75-80% on baseline. What can be done for them? The PS would not be sufficient to enable BD Glenn. The saturations do not allow PA tightening. BT shunt would be negative for future Glenn. How should we be going about? Please drop in your suggestions.

We saw a 2-year-old with Transitional AVCD with common atrium and uncertain pulmonary venous drainage. The pulmonary veins were draining into the roof of common atrium all around. The IVC was interrupted and there was bilateral SVC. There was an inevitable mixing at the atrial level, as for any other common atrium. However, this baby had mild cyanosis and clubbing with the saturation of 80%. Such picture does not occur in regular cases of common atria. How does the streaming affect the situation? We are planning to establish the correct anatomy of pulmonary veins in this baby with a cardiac CT. Can the interrupted IVC explain this picture? If you have come across such a picture, please tell me about your observations.

Pen in your comments. Use my email if you find any problem posting your comments.

Happy, prosperous and eventful 2010 to all of you



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