Thursday, December 3, 2009

Welcome back to NH blog. We are in witness of “developmental history” of Cardiac medications pertinent to Pediatric Cardiology.

In the last 3 posts, we have seen the historical aspects in the development of Digoxin, Diuretics and Beta-blockers. This post will see another class of drugs, termed as “the most useful class of cardiac drugs” by contemporary Cardiologists: the ACE inhibitors.

The advent of beta-blockers was an epoch making event in the field of cardiology. It inspired a generation of scientists to undertake research in the crucial field of drug development. When the beta-blockers were found to be successful as anyi-hypertensives also, many a minds drifted their attention towards achieving the anti-hypertensive effect with other compounds.

John Vane was one of the researchers working on this issue. In 1960, after witnessing the beta-blocker saga, he shifted his attention towards anti-hypertensives. He was a man of extremely sound fundamentals and true to his nature, he started his research investigating the causes of hypertension. At that period, he was working in the Institute of Basic Medical Sciences at the Royal College of Surgeons of England.

One of his Brazilian post-doctoral students, Sergio Ferreira, brought an extract of the venom of Brazilian arrowhead viper, (Bothrops jararaca), to London. As a matter of interest, they evaluated it. To his surprise, he discovered its capability in blocking the formation of angiotensin II from angiotensin I. This conversion reaction was mediated through an enzyme called Angiotensin Converting Enzyme.

Vane could immediately sense the possible effects of this in the human body. He expressed the findings of his research with some of the leading clinicians. He was disappointed to see the reaction of them. The clinicians were not trained in understanding the developmental research of drugs. They would start with a possible clinical trial, but nothing less than that.

Vane’s initial disappointment could not stop him. His ability to trace something new was impeccable. He had solid belief in his findings and its possible impact on the future of medicine. He decided to approach scientists instead of physicians this time. He made a trip to the famous Squibb Institute for Medical Research in New Jersey and was able to convince the researcher team on the novel concept called “The use of ACE inhibitor in controlling high blood pressure”.

Vane’s honesty, belief and commitment impressed the chief scientist of Squibb, Miguel Ondetti. Ondetti gave the responsibility of fractionating the viper venom to his colleagues. His team did a wonderful job and could elucidate the structure of several peptides from the venom. This confirmed the existence of a very active peptide inhibiting ACE. Vane had already reached this point and had called this compound teprotide. After coinciding with Vane’s observation, Squibb scientists went a step ahead. They could now synthesise the compound and start an animal trial.

Teprotide was administered intravenously in patients with elevated plasma renin levels as a part of first clinical trial. It sure proved to be an effective hypotensive agent. However in the control group with hypertension but normal rennin levels also showed a similar and comparable hypotensive effect. Since it was a peptide, teprotide was obviously inactive orally. So, the next step was an attempt to synthesise an orally active analogue of teprotide.

The Squibb research team started a massive mission for this. They ended up screening about 2000 non-peptides, but all these were in a vain. The team head thought that a new approach would be more worthwhile. At the same time, publication of a scientific paper caught their attention. This paper by Byers and Wolfenden dealt with inhibition of digestive enzyme carboxypeptidase A by benzylsuccinic acid. The authors had found the site called C-terminal phenylalanine residue of of carboxypeptidase A to which substrates were bound. As benzylsuccinic acid had a similar enough structure it could competitively inhibit it.

The Squibb researchers made use of this fact and used numerous techniques for quite some time to finally create a compound which was one-thousand-fold strong in inhibitory activity. This was called captopril which was the first non-peptide ACE inhibitor suitable for oral use and thereby introduction into the clinical use. The scepticism prevailed. To add on to this chaos, an early clinical trial showed captopril with renal damage or granulocytopenia. The Committee on Safety of Medicines of United Kingdom put up the clause of “to be limited for the use only in patients with severe hypertension who had not responded to standard therapy” for captopril when it was marketed.

The scepticism was short lived. An intensive postmarketing surveillance was enough to prove the minor nature of side effects with low incidence for captopril. This led to the extension of licence in 1985 for use in mild to moderate hypertension. Newer modifications of Captopril led to the development of other ACE inhibitors. All these are now firmly established in the treatment of heart failure and in hypertension and are considered as the treatment of choice.

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

On a personal note, with the advent of December, the numbers of people taking leaves are increasing! The foolish rules of “You cannot carry over your leaves to next session” would leave every unfortunate soul who is “not on leave” strangled! Anyway, life goes on and it is time to realise that pain is an integral part of human suffering!

Many centres wake up in December and start conducting their mandatory quota of CMEs. Hence, we people are in demand. This adds on to the woes of consulatants who are at the hospital working. On the other hand, most of the CMEs happen on a Sunday and pain of losing a precious Sunday increases with this. We can neither refuse nor whole heartedly accept these invitations. Overall, December ends up being “pain, pain”!

Last year, we reported a case of Truncus with Tricuspid Atresia in the Indian Heart Journal. It is a rare combination indeed. We had another boy aged 14 years with this combination. He had a Tricuspid atresia with the common arterial trunk committed more to RV. The age precluded us from defining his PA anatomy on Echo. On cath, we found a Type 2 Truncus with the origin of LPA stenosed. RPA pressures were systemic. No further management options exist in him. How frequent are such combinations? What is the embryological basis of such lesions? Is a single lung with more than normal pressure tide over such a lesion for such a long time? Are there any other protective issues that we are missing? If so, how to detect them with the available technology? Some questions lead to more questions and minimal answers. Any data, please transfer!

We saw a 6-year-old boy with history of Kawasaki disease. He was treated with Immunoglobulins on day 14 of illness in the past. He is otherwise asymptomatic. On follow up echo, we found an echogenic mass in the dilated LAD along with some aneurysms. His effort tolerance on a treadmill was normal. On the cath study, we found a near complete occlusion of LAD. Some collaterals and retrograde filling of RCA was seen. Since the child was asymptomatic, it was decided to have a close follow up. Is the treadmill a good idea? Can we do it with less invasive methods like Stress thalium instead of TMT? Are there any guidelines for the timing of cath? What are the guidelines for the surgical intervention in such scenarios? AHA has come out with guidelines for Kawasaki disease. Are they pertinent for Developing countries also? Any data with anyone?

What determines the shunt in ASD? Looks like an exam question! It is the RV EDP obviously. We had a 4-year-old girl with ASD R to L, Smallish muscle bound RV, with SO2 of 85%. The desaturation led to cath study. The RV EDP was 12mmHg, which was lesser than LV EDP. Are the EDPs dynamic? Can the RV EDP keep fluctuating? Can it be severe enough to cause cyanosis? Can repairing the ASD a good option? It was decided to go for a BDG with fenestrated ASD closure? Can we follow the same strategy for other instances with high RV EDPs also? Let me know your take on this.

Is there a linear relationship between the AV valve Z score and 2-pump repair? Till what Z scores do we accept the 2-pump repair? We had a 5-year-old with intact IAS, moderate VSD, moderate PS and TV Z score of minus 3. The RV was reasonably sized and reached apex. The RA was not dilated much. It was decided to go for VSD closure, pulmonary valvotomy and PFO open. How would such lesions behave post surgery? The surgical team felt that since the RA was not dilated, the impact of TV narrowing was not much and hence the surgical repair was acceptable. Are there any criteria for 2-pump repair in such instances? Pen your opinions.

We had an interesting coincidence during our cath study. Although it was a shock for the surgeons on the table, their efficiency could tackle the situation. This 4-year-old was operated outside with a right sided BTT shunt 2 years for pulmonary atresia. On echo, the windows were very compromised and we could not see the PA confluence. In the cath study, the arch injection filled both LPA and RPA. We presumed confluence and went ahead. On the table, we found that the PAs were non-confluent. The LPA originated from ascending aorta posteriorly and the RPA filled though the PDA. No doubt that both the PAs filled on the aortic injection simultaneously! We relearned a precious lesson of not presuming without considering the alternatives!! What could have been a surgical disaster was managed by superior surgical skills of our experienced surgical team.

What is the impact of a severe Shone physiology on PDA? We had a 6-year-old girl with severe subvalvar MS, bicuspid aortic valve with severe AS and a large PDA shunting bidirectional. With the aortic pressures being low due to severe MS and AS, and PA pressures being high due to MS, can we decide operability of PDA by the direction of shunt? The child saturated 94% on upper limb and 86% on lower limbs, would it suggest Eisenmengarization? Should we cath the child? The surgical team opined that the child should be cathed for operability. It is again the question of sequential lesions that we had discussed few posts back. We had some surgical success in such lesions in the past, but the patient then was a toddler. The age is against us this time. Is there any way of clinical decision making? Please let me know if you have any experience in this regard.

Pen in your opinions in the comments. You can also send in your opinions and your experiences to my email: I shall post them on your behalf with full credits to the contributor!



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