Saturday, November 14, 2009

Welcome back to NH Pediatric Cardiology Blog

I started feeling a kind of vacuum after the History of Pediatric Cardiology was completed. A couple of sessions with Nobel prize winners could do no good to my feelings, as the research involved was neither extensive, nor satisfying. I sought suggestions from my team; and as usual, very few came in! I was suggested to go with some of the musings we came across in the wards and OPD. True life incidents involving parents’ feelings and doctors’ dilemmas were suggested. Incidents which changed our outlooks towards something was another suggestion. Miraculous survivals or an improvement in some of the patients and possible causes of it was another suggestion. All these are no doubt good, but they lack the sustenance value. They may be inserted as snippets, but cannot sustain an entire post. Also, their frequency is less. Nevertheless, I have received all these suggestions with great fervour, and hope to do justice to them sometime in future.

I have known people who are into pharma research. I happened to meet some of them, who have spent years together in developing an elusive drug, just to see nothing at the end of it! But, what a zest they have! I always had the admiration for the creators. It is in this spirit that I will be writing on the history of development of some of the cardiac drugs. They should read like a proper story albeit a true one. It is an ode to the people who have made it for all of us.

It might be prudent to make a beginning with the most famous and equally controversial yet indispensible drug of cardiology. Yes, the mighty DIGOXIN!

Foxglove (Digitalis purpurea Linn) was a folk remedy introduced into medicine in the 18th century. It grew throughout Europe. The term “Fox” was a misnomer as this shrub was originally known as the folksglove due to the shape of its flowers. The shape of the flowers and the colour gave its scientific name, which is derived from what was given to it in AD 1539 by Hieronymus Bock. He explained that
‘digitalis’ was an allusion to the German word fingerhut (finger stall), since the blossoms resembled the fingers of a glove.

Foxglove has a long history of folk use. The Ancient Celtic tribes know about it and made use of its medicinal properties. A family of 13th century Welsh healers applied it to the body by inunctions to relieve headache, abscesses and cancerous growths. It was also listed among herbs used by Edward III of England in the 14th Century.

In 1775, the English physician and botanist William Withering (1741–1799) was asked his opinion of a herbal tea prepared by an old lady on countryside for the relief of dropsy. Her medicinal preparation boasted of phenomenal success to dropsy, for which the then medical world did not have a proper remedy. The cause of dropsy was then unknown, so the possible explanation of the treatment was explained by expulsion of the excess body fluid. Withering, who was a trained botanist, very soon realised that among the 20 or so ingredients in the herbal tea, it was the foxglove that was most likely to be causing the violent vomiting and purging if taken in excess. During the next nine years, Withering treated 158 patients with it, of whom about two-thirds responded favourably. In 1785, he wrote his treatise entitled “An Account of the Foxglove, and Some of its Medical Uses: with Practical Remarks on Dropsy, and Other Diseases”. The write up was not only a list of his observations, but also, a description of how to determine the correct dosage, which was highly relevant since foxglove was a potent poison that was ineffective unless administered at near the toxic dose level. He took care to standardise the doses he used, to a level for determining the correct dosage for each patient. He also discussed different ways of preparing foxglove, preferring the use of powdered leaves.
However, what Withering did not realise was that the stimulant action of Foxglove on the heart which was responsible for its beneficial role in dropsy. It was paradoxical that in the year 1799, the year of his death, Ferriar suggested that the increased urinary output was of secondary importance compared with the power of foxglove to reduce the pulse rate.

Although it was not in great use at that period, some minds could identify the importance of this drug very soon. The need for isolating an active principle from digitalis was recognised and attempts were made in the 1820s for the same. To stimulate research, the Paris Pharmacological Society offered a prize of 500 francs for the isolation of a pure principle from the plant. As per the prevailing financial rule, this sum was to be doubled every five years if no claimant came forward. But, in 1841, the French pharmacists E. Homolle and Theodore Quevenne won the award for their isolation of an impure crystalline material which consisted mainly of impure digitoxin. They called this ‘digitalin’, a name also applied to various products obtained by other workers.

However, the principal cardiotonic glycoside present in the leaves of Digitalis purpurea which was termed Digitoxin, was isolated in 1875 by Schmiedeberg at the University of Strassburg in Germany. He obtained crystals from digitalis leaves.

It was an era when the apparent clinical success would not pave for the regular use of medicines. Because of the lack of a clear understanding of how it was able to affect dropsy, foxglove was rarely used as a cardiac stimulant during the 19th century. German pharmacologist Ludwig Traube revealed the stimulating effect of foxglove on heart muscle in 1850. But it was around 1901 that a clear understanding of the effects of foxglove on heart was revealed by the development of the polygraph by the Scottish physician James Mackenzie and the electrocardiograph by the Dutch physician Willem Einthoven. Subsequent investigations along these lines revealed some of the correct indications for the use of digitalis: atrial fibrillation or in certain forms of heart failure in sinus rhythm.

In 1920, Max Cloetta in Zurich hydrolysed digitoxin under acid conditions and isolated the aglycone, digitoxigenin, which had weak cardiotonic activity. Adolf Windaus finally obtained pure digitoxin in 1925, at the University of Gottingen.

The structure of digitoxigenin was determined by Walter Jacobs and his colleagues at the Rockefeller Institute in New York, but it was not until 1962 that chemists at Sandoz in Basle elucidated the structure of the sugar residue and hence that of the entire molecule of digitoxin.

In the late 1920s, it was discovered that the powdered leaves of Digitalis lanata, once popularly known as ‘woolly foxglove’, had greater physiological activity than those of Digitalis purpurea. This led Sydney Smith of Burroughs Wellcome in London to isolate digoxin. This is now used more than either powdered digitalis leaves or digitoxin since it does not bind as strongly to proteins in the tissues and plasma, resulting in less delay before a therapeutic concentration of unbound drug can build up. Clearance from the body is also faster as only unbound drug is filtered by the kidneys; consequently digoxin is less cumulative and thus safer to use. It has become the standard digitalis preparation in current usage.

Thanks to the painstaking efforts of Withering, experimental medicine was now able to exploit the single greatest breakthrough in the history of drug discovery. Progress from prehistoric times until then had been pitiful because two essential factors were missing: access to chemical compounds with consistent potency and effective methods of clinical investigation. Access to these during the past two hundred years has made it possible to identify and exploit beneficial drugs, free from the dogmatic teachings that were the legacy of the past and a major obstacle in the path of drug discovery. The discovery of Digoxin paved a new revolution in the field of drug discovery and its scientific analysis. The nature hides millions of such drugs, waiting for the mankind to explore with open mind. We need more “Witherings” to do it!

If we can name one more class of drugs used to a great extent in the clinical cardiology, it must be diuretics. The journey till the point of high ceiling diuretics has been equally fascinating. It all started with experimental medicine with keen eyes and mind with meticulous observations. We shall see the development of Diuretics in the next post.

On a personal note, we were wondering how much challenges this small filed of pediatric cardiology can pose! Someone had once told me, “You have 4 valves and 4 chambers. How much is there to learn in Pediatric Cardiology?” With every new challenge, I remember that person!

We saw an 11-year-old boy in our OPD with NYHA class 2 symptoms. On examination, he had RV apex, RV forces, wide fixed split, PSM at RLSB. Also had an ESM at RUSB. Except for the ESM, everything was fitting into the diagnosis of ASD. What we saw in echo was surprising. The IAS was intact. RV was hypertensive and dysfunctional. There was a severe TR. Further, the IVS was intact. MPA continues as RPA with absent LPA. RPA had a gradient of around 50mmHg. The fixed split and PSM were thus explained. Also, the ESM could find a place. But, what started first? Was it the RPA stenosis (which is underestimated now) the primary event? What might have caused RV dysfunction? We have no previous records. In such cases how to explain the chronology of events?

We saw a 17-year-old boy with Tetralogy of Fallot. Though echo windows were compromised, we could see a dilated origin of Left coronary artery. We subjected him for cath study, which showed a large Left coronary to PA collateral. This was second such instance we had seen such an anatomy with TOF. However, in this boy, the PAs were small. McGoon ratio was 1.2 How to go about? This boy had SO2 of 86%. BTT shunt is unlikely to improve his saturation or PA sizes. He had no angina pain and no indication of coronary steal. Dr Sunita suggested Treadmill test for inducible ischemia. TMT was terminated due to effort intolerance, but no angina. TMT did not show any ST-T changes. This boy had achieved 6.5 METS. The surgical team is keen on ligation of coronary to PA collateral and creation of BTT shunt. But the question remains same: Has the patient earned his surgery? Can we wait? Is it advantageous or not to wait? Please let me know your takes on this situation.

The enigma of sequential lesions never ends amusing us. We have a 4-year-old boy with VSD and a tight coarctation of aorta. Cath data is obviously has its limitations and usually not accepted well by surgeons. In this case, the cath data showed PVRI of 14 Wood units with oxygen. We suggested balloon dilatation of CoA and reassessment of VSD. However, the surgical team was in favour of doing both of them together. Is there any concrete data in determining operability in such sequential compound lesions? I would like to know the opinion from experienced. Also, please quote some references if anyone has.

What baseline saturation in OPD is the cut-off for Eisenmengarization? At OPD, we get both baseline SO2 at rest and with exercise whenever deemed necessary. Sometimes, the data does not match with the cath data. Is there a reasonable cut-off for the OPD saturation below which the cath is not necessary? If anyone knows any number for this, please let me know the reference.

Perloff defines the Anamolous Pulmonary Venous connection and Anamolous Pulmonary venous drainage separately. We happened to see an infant with all 4 pulmonary veins draining independently into the right atrium. The LA was fed by an ASD. There was no common confluence. Is it an abnormal connection or drainage? We have seen such a pattern earlier also, but never pondered on the embryological basis for such an anomaly. If anyone knows any case reports, please let me know.

Thanks to Dr Amit Misri for the comments. I have posted them on the comments section on the previous post.

I shall also welcome our new follower, Dr Sanjay Panda. Can you please introduce yourself for the others, Sir? The team would love to hear more about you.

Please send your inputs. Feel free to send it to my email drkiranvs@gmail.com I shall post it on your behalf.

Regards

Kiran

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