Saturday, November 21, 2009

Welcome back to NH Pediatric Cardiology blog.

In the previous post, we saw the History of Digoxin. In the present post, we shall see the development of another important life saving class of drugs: The Diuretics.

Mercury can be considered as one of the oldest of all drug prototypes. The majority of drug prototypes come from the animal and vegetable sources; mercury belongs to a minority that was derived from the minerals. An ancient Hindu work by Nagarjuna, named “Rasa Rathnakara” had masterly description of using the mercury and related compounds to strengthen the weak hearts. Mercury had also been employed by Paracelsus in the treatment of dropsy.

The first diuretics were organomercurials; toxic, but effective. Their introduction into clinical medicine was in the late 1880s. Mercury benzoate, was the initially chosen one because it was slightly soluble in water. The fusion with of inorganic mercury with an organic compound was aimed at reducing the irritancy and toxicity of inorganic mercurials and to obtain a slow, sustained release of mercuric ions from the organic complex. This was followed by the marketing of a number of injectable organomercurials. One such compound was introduced in 1912 by F. Bayer & Company for the treatment of syphilis. This was called merbaphen, a double salt of sodium mercurichlorophenyloxyacetate with barbitone.

Serendipitous use struck gold seven years after the introduction of merbaphen when Arthur Vogl, a third year medical student at the Wenckebach Clinic in Vienna’s First Medical University, had ordered a 10% solution of mercury salicylate to be prepared by the hospital pharmacy. When he did not get the preparation, he went to the pharmacy and was told that a solution in that concentration could only be prepared as an oily injection. A colleague suggested Vogl to use merbaphen injection instead and was done. As a routine, the meticulous nursing staff maintained the chart of the urine output of the patient. Vogl was surprised to see that, the patient who was struggling to pass 500 ml of urine in 24 hours had passed 1200 ml in 24 hours after the very first dose of merbaphen. After the third daily injection, this had increased to 2 litres in 24 hours; a feat which no other known medication of that time could achieve! Interested in creating a cause-effect relationship, Vogl withheld the medication for a few days and dramatically, the urine outflow decreased. On resumption of the injections, urine output improved again. Vogl decided to extend this use in other patients. He chose to administer merbaphen to another syphilitic patient with advanced congestive heart failure. Conventional diuretics of those times had no effect on this man. Vogl was not surprised this time to see his patient passing massive amount of almost colourless urine with the first dose of merbaphen. The flow continued throughout the day and the night and by the next morning the patient had passed about 10 litres with thorough exhaustion and elation at the same time! Vogl found that profound diuresis was produced in any patient injected with merbaphen. But other antisyphilitic mercurials could not produce any effect close to this. After confirming this in multiple subjects, Paul Saxl decided to conduct a thorough clinical evaluation. This transformed the treatment of the severe oedema of congestive heart failure, allowing it to recover to normal function. No other medication used hitherto had any activity comparable to this.

The joy was short lived. It was soon recognised that merbaphen injections posed a risk of severe renal damage or fatal colitis. But the effect was not ignorable. So, improvisation process began and soon, merbaphen was replaced by another antisyphilitic agent, mersalyl, which was administered on an intermittent schedule to minimise toxicity.

Around the late nineteenth century that mercury and mercurous chloride were introduced as oral diuretics. Tablets combining finely dispersed metallic mercury with digitalis remained on the market until rendered obsolete by the introduction of the thiazide diuretics in the 1950s.

The demand for a non-toxic, potent diuretic was critical and the challenge was accepted by a team of researchers from Sharp & Dohme, under the direction of Karl Beyer in the early 1950s. The then recent developments in renal physiology had convinced him that the moment had come to design a safe, effective diuretic. The renal physiology had proved the role of renal tubules in the reabsorption of water from the glomerular filtrate. It was understood that the efflux of sodium ions across the tubule wall was the responsible factor. It was believed that mercurial diuretics interfered with movement of ions by inhibiting dehydrogenase enzymes inside the tubular cells. This prompted the Sharp & Dohme scientists to try designing mercury-free inhibitors of dehydrogenases in order to avoid the toxic effects of mersalyl.

Although, in theory, they had proved the requirement, practically, it was a daunting task that took many years of intensive research. After series of failures, they decided to reaffirm their hypothesis. They went back to understand the correct action of mercurials. This turned out to be the turning point. It was the realised that both merbaphen and mersalyl possessed a phenoxyacetic acid moiety. When an unsaturated ketone was attached to the 4-position of the benzene ring, potent hydrogenase inhibitor was obtained. When they sought the influence of additional substituents, it was shown that chlorine or methyl groups attached to the benzene ring further enhanced potency. Ultimately, ethacrynic acid emerged as a safe, orally active diuretic in 1962, five years after a separate group of Sharp & Dohme chemists had announced their discovery of the thiazide diuretics with similar properties.

Thaddeus Mann and David Keilin were the researchers working at the University of Cambridge in 1940. They had had isolated in an enzyme in pure state a year before which was known to play an important role in the output of carbon dioxide by the lungs. The enzyme was called carbonic anhydrase. They observed the fall in carbon dioxide binding power of the blood caused by some of the recently discovered antibacterial sulphonamides. They carried out an experiment to determine whether this could be accounted for by inhibition of carbonic anhydrase. The experiment confirmed their suspicions. Sulfanilamide was the prototype.

At the Harvard Medical School, researcher Horace Davenport discovered large amounts of carbonic anhydrase in the kidneys. Earlier, Rudolf Hober had observed alkaline diuresis in patients who had been given massive doses of sulphanilamide. Now it could be accounted for by increased excretion of sodium bicarbonate caused by carbonic anhydrase inhibition. The resorption of water from the tubules of the kidney depended principally on the absorption of sodium ions from the lumen. When the enzyme was inhibited, sodium ions were excreted in the urine because the process responsible for their reabsorption was blocked.

Davenport informed the data to Richard Roblin at the Lederle Division of the American Cyanamid Company and sought a more potent inhibitor of carbonic anhydrase from them. Thiophen-2-sulfonamide was provided in the belief that it would be more acidic than conventional sulfonamides and that this would enhance its ability to compete with carbon dioxide for the active site on the enzyme. It was about 40 times more potent than sulphanilamide in inhibiting carbonic anhydrase.

Boston physician William Schwartz in 1949 experimented with oral sulfanilamide to obtain diuretic effect. But he had to abandon this due to toxic side effects. But, this observation prompted Roblin’s interest in carbonic anhydrase inhibitors again. He and James Clapp restarted their experimentation and within a year, acetazolamide was synthesised. It was about 330 times more potent than sulfanilamide as an inhibitor of the enzyme.

Acetazolamide was available as orally active diuretic in 1952. Soon, it was noticed to have a variety of complications. The only way to use acetazolamide was on an intermittent schedule. Serendipitously, the inhibition of carbonic anhydrase in other parts of the body was turned to advantage, as in the treatment of glaucoma. Acetazolamide remains in use for this purpose even today.

Karl Beyer could not be left behind for long. Leading a new project for Merck, Sharp and Dohme, he analysed the problem with sulphanilamide. He found that that it inhibited carbonic anhydrase at the distal end of the renal tubules, rather than solely at the proximal end. This could be accounted for the increased excretion of bicarbonate. He sought a carbonic anhydrase inhibitor that acted in the proximal portion. Such a drug would have the advantage of being useful antihypertensive agent. It was the time when low salt diets were believed to be an effective means of controlling high blood pressure. The first carbonic anhydrase inhibitor that Beyer came out with the name of carzenide. But, in humans it was poorly absorbed from the gut and had weak diuretic activity. It still inspired James Sprague and Frederick Novello to research further. This led to the introduction of clofenamide which was a potent carbonic anhydrase inhibitor. Further medication of this was dichlorphenamide which produced an increase in chloride secretion in humans.

Dichlorphenamide served as a baseline drug for the future research. Further research was aimed at achieving better dieresis with no further reduction in chloride ion excretion.

Novello and colleagues made the N-formyl analogue with formic acid. This resulted in an unplanned ring closure to form a benzothiadiazide. As a matter of routine, this novel compound was entered in the screening programme. It was a matter of surprise and delight to the team when it was found to be a potent diuretic which did not increase bicarbonate excretion. Clinical tests confirmed the safety of this orally active diuretic with marked saluretic activity.

With the first reports in 1957 it was termed ‘chlorothiazide’. It had duration of action of 6–12 hours. Literally overnight, singlehandedly, it rendered mercurial diuretics obsolete for the treatment of cardiac oedema associated with congestive heart failure. Chlorothiazide still remains in use because of its low price.

On the other side, Ciba scientists led by George De Stevens replaced the formic acid used to produce chlorothiazide with formaldehyde and thereby obtained hydrochlorothiazide, which was ten times as potent as chlorothiazide. Since then, many other thiazides have been developed.

Dichlorphenamide was still the baseline drug for the research. Some modifications in the acidic side of it and replacement with a carboxyl group gave a new molecule. This led Hoechst to introduce frusemide (also known as ‘furosemide’) in 1962. It had a quicker onset of activity, more intense and of shorter duration than any other diuretic. Frusemide had a different site of action within the kidney tubule and became known as a loop diuretic because it acted in the region known as the loop of Henle. Loop diuretics were valuable in patients with pulmonary oedema arising from left ventricular failure. Despite thiazides being indicated for most patients requiring a diuretic, frusemide is widely prescribed.

Bumetanide is a more potent loop diuretic introduced by Leo researchers ten years after frusemide. Hoechst introduced its analogue known as piretanide when their patent on frusemide expired.

In the next post, we shall see the fascinating history of one more class of drugs.

On a personal note, the work at NH is getting heavier with all the addition of Tamil Nadu government insurance schemes. We ended up doing echoes for patients with eye burning, skin infections and healed fractures! The screening does not happen at any place for such patients. Most of them would like to take the advantage of the free services and would insist on getting all the investigations done free of cost. The ensuing load on doctors and the compromise in the quality of investigations done are nobody’s concern. We insisted on putting up a higher limit to the numbers everyday for the scheme patients. But, eventually, we would end up seeing loads of children who would probably not require echocardiography otherwise. I don’t know how much of quality compromise has happened due to extension of echo and OPD timings by at least 2 hours every day!

Is it possible to a Fontan repair in a case of interrupted IVC? The usual protocol is to do a Kawashima repair, which does not involve incorporation of hepatic veins into the venous circuit. The chances of AV fistulae are higher possibly due to the lack of hepatic factors. But, if by any chance we can incorporate the hepatic veins into the venous circuit, would this be called Fontan repair? In case of one such boy, our surgeons evaluated the cath images and were of the opinion that a Fontan repair can be done. Any inputs?

How often do we find a diverticulum in the RV? We had one such patient with DORV of single ventricle physiology. His RV angiogram showed an outpouch of contractile nature. The close DD would be an aneurysm which would be devoid of any contractile elements. Atrial diverticulae and LV diverculae are known. But this is first RV diverticulum we have come across in recent times.

In cases of older children with Tetralogy, if PA sizes are small and eventual McGoon ratio is low, should we consider Brock’s procedure? It is said that, as the age progresses, the PA sizes cannot improve with BTT shunt. Is the improved antegrade flow the best way of improving PA sizes? If so, can Brock’s be the way? It is true that the patient would through for bypass for this. But, if it has the potential to prepare the patient for the future complete correction, is it not worth it? Are there any repots of using Brock’s procedure for such a purpose? It is a “third world” problem and developed countries may not have seen such an eventuality. If anyone’s got any data or experience on this, please let me know.

Is there an oral inotrope that is as effective as IV? Can levosimendan qualify? In cases of chronic ventricular failures, the patients cannot be on IV inotropes for long. They can have some solace if they can be treated at home with some oral inotropes. The traditional drugs with inotropic action may not suffice all the times. If anyone had any personal experiences with their patients, please let me know.

In the last post, I had put up the case of sequential lesions. Our patient had a VSD and severe coarctation. The query was the operability assessment of VSD in the presence of severe Coarctation. We decided to balloon the coarctation and check for VSD operability. After successful balloon coarctoplasty, we found that the VSD had a PVRI of 18 wood units. Is there a way of assessing the same thing prior to coarctation intervention? Any experiences? Please let me know.

How many times do we come across cyanosis in ASD in children? It is a typical exam question and most of us know about 5 to 6 causes. But, we happened to see one child with ASD and cyanosis. The subcostal windows were suboptimal. All the causes we knew were verified, but with no gain. At last, we decided to do a contrast study and found to our surprise that the RSVC was entering directly into LA! There was no LSVC or PAPVC or TAPVC. How common is such a situation? I came across such a lesion for the first time.

We happened to see one 18-year-old boy with unobstructed TAPVC and dTGA with ASD and intact IVS. Is there any advantage of doing any surgical procedures now? Is it ethical leaving him as he is? Again, these are the “third world” dilemmas! What is the natural history of an untreated dTGA? Does the co-existing TAPVC has changed the course? Any inputs?

I would be happy to see your inputs. In case of any difficulty in posting a response, please send it to my email drkiranvs@gmail.com I shall post your response on your behalf.

2 comments:

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