Saturday, November 28, 2009

Welcome back to the NH Pediatric Cardiology blog.

We saw the historical development of Digoxin and Diuretics in the last 2 posts. In this post, we shall see the development of another important class of cardiac drugs: the Beta Blockers.

The huge laboratory of Eli Lilly in Indianapolis is a place for innovation. The recordings of events are so meticulous that serendipities are not unusual. In this lab, Irwin Slater was working on the analogues of isoprenaline to create long-acting bronchodilators. The agents were screened for their ability to relax tracheal strips contracted by pilocarpine to simulate the asthmatic bronchoconstriction. Adrenaline was used on these strips to ensure their responsiveness between the tests. Some strips were by chance got exposed to dichloroisoprenaline. Surprisingly, these strips did not relax when the adrenaline was added. For the first time, an antagonism to adrenaline was noted. In 1957, at a scientific meeting, Slater reported the phenomenon of dichloroisoprenaline antagonism.

This finding got the keen attention of Neil Moran, at Emory University in Atlanta. He requested Eli Lilly to provide samples of the new drug to investigate its effects on the heart. He was surprised to find that dichloroisoprenaline not only antagonised the changes in heart rate and muscle tension produced by adrenaline, it also mimicked the activity of the adrenaline to a certain extent. He reported his findings in a prominent journal.

It was the time when ICI Pharmaceuticals Division (now incorporated in AstraZeneca) had decided to make it big in the market. For this, they had caught a big man – James Black (Knighted in future, after winning the Nobel) Moran’s report caught the attention of James Black. The equipped Lab of ICI at Alderley Park in Cheshire was seeking a major breakthrough and had funded Black with a grant to further diversify his investigations into coronary artery disease.

Black had a phenomenal sense of first principles. He had for long believed that there exists an alternative way of treating angina. It would simply be to find a drug to reduce the oxygen demand of the heart. Black did not believe in merely increasing blood supply by vasodilators such as the nitrates. He sensed that treating a patient just symptomatically would not solve the issue. Black was in pursuit of a medication with longer, better and sustained effect that could increase the life span of the patient.

Black, by then, had realised the relationship between the heart rate and the oxygen demand. The influence of catecholamines on heart rate was well established. He was logical enough to correlate the effects of suppressing adrenaline and noradrenaline on heart rate and thereby the oxygen demand. But, his experiments along these lines till then had no gain.

On reading Moran’s paper a new wave of thought occurred to Black. He immediately realised the potential of this paper. His team had done extensive work on receptors which Raymond Ahlquist had described as beta-adrenoceptors. It should be possible to find an analogue of dichloroisoprenaline devoid of intrinsic action. This molecule can bind to the beta receptors in the heart.

Black entrusted his colleague John Stephenson to synthesise the drug of his ideas. The first effective beta-adrenoceptor blocker was synthesised in February 1960, by replacing the bulky chlorine atoms of dichloroisoprenaline with a second benzene ring to form pronethalol. The drug was orally active but short-acting. A small clinical trial on 30 patients confirmed the anticipated actions pronethalol in angina. The side effects noted were mild. It also gave pleasant surprises to the research team when its action went beyond the angina. Black had anticipated prevention of atrial fibrillation and atrial or ventricular tachycardias through diminution of the response to emotional or exercise-induced
sympathomimetic activity. This was confirmed in the trail. The drug also showed a marked hypotensive effect when taken for several months. This was totally unexpected but well desired. This led to the development of another trail in hypertensive patients. Pronethalol proved its value in reducing blood pressure also. Finally, the research team thought, the wonder drug was born!

But their happiness was short lived. Long-term toxicity testing in mice was received within few month of the trail of the drug and showed the association of pronethalol with cancer of the thymus gland. But such a big breakthrough could not be left alone. ICI decided to launch the drug late in 1963. Its use was limited to patients whose lives were seriously at risk. Today, the drug has become only a historical reference, but it started a new era in cardiac management.

No sooner the thymus carcinoma report arrived, the ICI research team started to improvise the drug. As a result, within a short time of the launch of pronethalol, the new drug propranolol was launched by ICI in 1964. It was found to be non-carcinogenic and ten times as potent as pronethalol. This marked the arrival of beta blockers in the therapeutic world and stood as the yardstick against which any improved version would be compared. All the other beta-blockers developed since then, retained the anti-anginal, anti-arrhythmic and antihypertensive properties of pronethalol.

The success of propranolol can be gauged by its existence in market even today.

Few hundred miles from ICI lab, one more team was evaluating the same compound – dichloroisoprenaline. But this centre called AB Hassle at Goteborg, Swedan was interested in potential anti-arrhythmic action. Short time after the launch of Propranolol, this centre developed and launched Alprenolol which very soon was acclaimed as an effective anti-arrhythmic with useful activity as anti-hypertensive medication. The success of this drug instigated other firms to take up active research in this group of drugs.

Another giant of a firm, Ciba, was successful in developing another beta-blocker called Oxprenolol, which retained partial agonist activity with beta1 and beta2-adrenoceptors. The advantage was immediately palpable. This agent did not produce as much bradycardia as the other beta-blockers, as this drug was capable of stimulating beta1-adrenoceptors in the heart. This property was termed as “instrinsic sympathomimetic activity” (ISA). This feature was useful in patients with peripheral vascular problems. Because of the ISA, oxprenolol did not cause feeling of coldness in extremities in patients with peripheral vascular disease, which was an undesirable feature of other beta-blockers. However, the stimulation of beta2-adrenoceptors in the lungs was suboptimal and oxprenolol was not proved sufficiently safe for use in asthmatic patients.

This led to the development of timolol, which which was initially used as antihypertensive. Some researchers found the utility of direct application of Timolol to the eye for the reduction of intraocular pressure in chronic simple glaucoma.

Few researchers kept Propranolol as the baseline drug and started improvising on it. The dihydro analogue of propranolol was the most promising and the compound was taken up by the Squibb Institute for Medical Research in Princeton. The ensuing compound led to nadolol. The dihydro component rendered it water soluble and less lipophilic. This property prevented it from entering the central nervous system, thereby reducing CNS side-effects such as sleep disturbance and nightmares associated with other beta-blockers. Also, low lipophilicity reduced the entry of the drug into liver cells. This reduced the rate of metabolism and ensured a longer duration of action.

The Mead Johnson lab could sense the potential market for beta-blokers by 1960. Their chief scientist, Larsen was a renowned name in the field of Sulfonamides. Logically, he used a sulphonamide side chain to isoprenaline in the place of phenolic group. This led to the development of Sotalol. Pharmacological evaluation showed all the components of beta-blockade. Also, as an added bonus, it also relaxed tracheal, uterine and intestinal muscles. Due to its hydrophilic nature, sotalol did not enter the CNS and had longer duration of action as nadolol.

The development of sotalol reached the ICI chemists. This led them to devise a series of its further analogues. Practolol was developed like this. Evaluation testing of Practolol had all the desired action on the heart but failed to antagonise the peripheral vasodilation caused by isoprenaline in anaesthetised dogs. For the first time a beta-blocker was selective for heart receptors. This literally caused a wave of elation in the medical community. This drug could avoid bronchospasm in patients with asthma or obstructive airways disease, which was actually a major clinical problem with beta-blockers. Practolol was marketed in 1970 for use in asthmatic patients with co-existing heart problems with much jubilation. But the excitement was short lived. Practolol on long term oral therapy could cause a serious oculomucocutaneous reaction, leading to blindness. This led to a seriously fast pursuit of alternative and better drugs and soon, practolol was abandoned. The new drug was Atenolol. As Practolol, it was relatively selective with regard to its action on beta2-adrenoceptors in the lung and on beta1-adrenoceptors in the heart. For a long time Atenolol was the most frequently prescribed beta-blocker and the third-best-selling drug in the world (after ranitidine and cimetidine). Its low lipophilicity prevented its entry into the CNS.

Atenolol, due to its phenomenal success, now stands as the baseline against which the new class of beta-blockers are developed. May & Baker developed acebutolol which could not replace Atenolol effectively. Acebutolol did not have much selectivity for cardiac receptors but it retained partial agonist activity.

Chemie Linz introduced a new developed beta-blocker compound called celiprolol. It was the first cardioselective beta-blocker with partial agonist activity. Labetalol was soon introduced by Allen & Hanbury, which had the added advantage of blocking the action of sympathomimetic amines both at beta-adrenoceptors and also at alpha1-adrenoceptors. Thus it was more effective anti-hypertensive at a lower level of adrenoceptor blockade.

Lateral thinking is a part of drug development industry! The scientists should analyse every bit of information to be better equipped to face challenges. Many drugs end up with severe side-effects, making the drug useless for the purpose. However sometimes the side-effects turn the table around – it becomes the main effect and form a therapeutic entity. Many such examples exist in the history of drug development. Beta-blockers have also contributed to this list. The side-effect associated with propranolol and other lipophilic beta-blockers was the vivid dreams or even hallucinations. The ICI scientists capitulated on this. When others in the world tried to reduce the lipophilicity to avoid CNS entry, brains at ICI prepared analogues of propranolol to increase lipophilicity further. This resulted in psychoactive drugs. In 1969 ICI patented viloxazine as an antidepressant drug. It was a relatively non-sedating antidepressant which inhibited both noradrenaline and 5-HT reuptake in the brain. The main use of this drug was in patients experiencing anticholinergic and cardiac side effects of antidepressant drugs such as imipramine and amitriptyline.

In the next post we shall see the “Developmental History” of one more class of cardiac drugs!

On a personal note, we are experiencing the “side-effects” of expansion! Incorporation of peripheral institute for high-end services is a part of growth of corporate hospitals. But the peripheral centres would not accept newly recruited specialists. They want the same specialists in the original corporate institute to attend their clientage. When the number of specialists is scarce, such demands would put extra stress on the existing specialists. This is a “no-win” situation for everyone, but is a part of the problem faced by expanding corporates also. The management which should handle such situations are usually clueless on such issues and would conveniently transfer their responsibilities to the head of the concerned speciality team. “How to...” is the major issue. If find a solution, I shall let you know!

We are witnessing a surge of patients from a neighbouring state due to a newly launched insurance scheme by state Government. This is letting us see adolescent age group with a newly diagnosed complex CHD. We saw TAPVC in second decade, Truncus at 8 years, many cases of TOF in late second decade, Eisenmengered DORV and so on. All these children would never have had a diagnosis also, let alone treatment if not for the support from Government. After the phenomenal success of Yeshaswini health insurance scheme ( of Karnataka state, many states have tried to emulate it. A large amount of credit for the success of Yeshaswini should be shared by Narayana Hrudayalaya also. Dr Devi Shetty was instrumental in devising and executing the scheme, which was adopted by the Government of Karnataka in a big and “never before in the country” way. One can get the entire story from multiple sources including Harvard journals, London school of Economics website, Wall Street Journal website and so on. Those who interested in the success story of Yeshaswini can Google for it with Dr Devi Shetty’s name.

How fast can a subaortic membrane recur? We have a 3.5-year-old who underwent SAM excision 2 years back with minimal obstruction post-operatively. The toddler has come back with severe LVOT obstruction with recurrence of SAM now. What might be the cause of such a fast recurrence? To begin with, what was the cause of such severe SAM at 1.5-year-old? Are these dynamics different from SAM in older age group? When SAM excision has not worked for 2 years also, how long it would work now? Is the pathophysiology of such subgroups different? Is there an additional problem with LVOT? Do such subgroups require different lines of surgical management? Should a Konno be performed in them? Is only Konno enough or a Ross-Konno is required? Should such an extensive surgery be done at the inception or on Re-do if required? Are cases of re-do for SAM in such young age described? Any inputs on these issues? If anyone has any data, please let me know. If references are also provided (if any), it would be much appreciated.

We had a 5-year-old with Tricuspid atresia IIB. The cath data was in favour of surgical intervention. However, this baby had veno-venous collateral. It was deemed that the collateral can decompress the PA pressure and the actual PA pressure would be much more than the measured PA pressure in the cath (12mmHg). Is there any way of putting a correction factor for such situations? Can we just presume something and change our plans? What would be more logical in such cases? Please put in your thoughts.

When we look for reversibility of PVRI in the cath studies, we use oxygen or NO or both. If the post-oxygen data turns out be good by drop in the PVRI, we operate. However, such patients don’t live with higher concentration of oxygen after the surgery. So, what is the logic behind the using these agents to check the reversibility? This question was popped up in one of our sessions and a satisfactory answer could not be obtained by the house. Any references on this?
Has anyone done any research in this? What was the original explanation be the researchers who devised these techniques? Please let me know.

How does a combination of obstructive lesion and a shunt lesion behave? I had put this question for last two posts in the case of a VSD and Coarctation. Is the logic different for PDA with coarctation? We had a toddler with large PDA and severe coarctation. Cath data showed a Qp/Qs of <1 and a PVRI of 16 Wood units.However, he was deemed operable and taken up, despite the cath data. Same data in an adolescent with VSD and coarctaion was termed inoperable. Is it because of age or the dynamics are different? This question is getting more interesting and tougher at the same time. Please put in your comments on it.

We saw a 9-year-old with TAPVC with Truncus! I had never come across such a combination before. The age was surprising. More surprising was the fact that the child was not cyanosed! Two cyanotic lesions with high Qp have failed to produce cyanosis till this age either by mixing or by high PVRI. Few people have a strong combo of luck and ill-luck running parallel!

We saw an infant who was stable with no features of increased Qp. He had a single S2 with a click and a continuous murmur. It was a perplexing clinical scenario. On echo, we found a type 2 truncus with mid segment narrowing of both PAs! This is the first time I came across a type 2 truncus with bilateral PA narrowing. Good for the kid!

What is the worldwide mortality pattern of PA bands? Is this practiced extensively in the west? Our surgeons continue to have a tough time with these surgeries. One of our senior surgeons was in favour of abandoning these surgeries for some time! Aren’t the indications for these surgeries getting modified in the current era?How are the centres across Europe and American continents doing? If you know about it, please enlighten us!

Some news from the department to share: The stork visited the Alvas! Dr Rashmi and Dr Prem Alva are the proud parents of a lovely daughter now. Best wishes for the new parents. Let the Almighty bless the newborn with all His might!

Applications are invited for the Fellowship in Pediatric Cardiology affiliated to Rajiv Gandhi University of Health Sciences, Bangalore. The fellowship would be of 18to 24 months duration. The training would happen entirely at Narayana Hrudayalaya. Doctors with post-graduate qualification in Pediatrics (MD or DNB) or Cardiology (DM) would be eligible to take the entrance exam and interview. For further details please visit the NH website:

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