Christopher Matthias on blood pressure problems
All right, to start with a discussion of a condition called orthostatic hypotension. Now, if that terms sounds rather unfamiliar then its effects probably will be familiar to you. This idea of if you stand up rather quickly you get that rather light headed or faint feeling. Now, somebody who's particularly interested in that is Christopher Matthias and he's a professor of neural vascular medicine within the Faculty of Medicine on the St Mary's campus here. You can probably put orthostatic hypotension a bit more scientifically than I just have done.
Gareth Mitchell: This podcast is brought to you by the numbers five and four. Five because Imperial College is now fifth in the global university rankings and four because that's how many places we've gone up since this time last year. Oh, and this is our official monthly podcast, by the way. And welcome to the December edition. Hello, I'm Gareth Mitchell a lecturer in our Science Communication Group and also presenter of the BBC technology programme Digital Planet. And we have some technology for you on this very podcast this month in the emergency room where it's more VR than ER these days brining in medical stimulation to train student doctors
Christopher Mathias: Gareth, thank you, yes. It is commoner than people think. It's been an under-recognised problem. And in essence it is when we stand up we are subjected to a number of gravitational Newtonian forces. The key, of course, with our circulation is to ensure that we get adequate blood, which contains nutrients and contains of course oxygen in particular, to organs which are functioning. That's all organs of course in the body but particularly those organs which are right at the top and above the heart and that is of course the brain. And this is where the autonomic nervous system comes in. Because it's a fairly fantastic system which tends to adapt so quickly. So it tends to ensure that we maintain our levels of blood pressure. Maintain adequate amounts of blood and therefore nutrients and oxygen to all organs but particularly those above the heart. And this is why we tend to not just adapt but regulate so rapidly. So this is the reason why in fact you just have it very transiently for a few moments, a few seconds usually, and then of course you're perfectly okay. If it continues for a period, and this is a very short period in a way, say, for more than a few seconds and certainly for minutes, that's when major problems can arise because then you're not getting the blood to the areas that you need to and you suffer from the problems of what we call organ hypoperfusion.
GM: And when you say hypoperfusion then, this is the lack of blood being where it needs to be and in this case within the brain?
CM: Absolutely right, yes. It's because the actual pressure head is low.
GM: And what kind of people suffer from this particular difficulty?
CM: Just to give you some examples. In Parkinson's disease we now know that about 50 per cent or 60 per cent do have this problem. Another disease closer to home and which is very common is of course diabetes mellitus. A disease which is, as you well know, increasing steadily thanks to our putting on weight, as it were, amongst other causes. Now, here even though there's a proportion only who have a neurothopy even the small numbers of a very common disease mean an enormous number of patients. So there are quite a lot of patients in different groups who've got this problem.
GM: Just how serious or how debilitating is it for these people?
CM: This is a very interesting and a very important question, which, again, is part of the reason why this may have been missed for some time. Some faint. So they lose consciousness. They collapse and then it becomes very obvious. However, there are situations where this may not be as severe as that. So they may, for instance, not be able to focus properly with their vision. So there are a whole variety of visual disturbances. They may just feel dizzy but nothing more than that, which is distressing in itself. Some can get pain in their neck muscles because of course they're not having enough blood to the muscles going to the neck. Or some may not be passing urine adequately during the day when the blood pressure is low. So there's a whole range of these symptoms. And there are some, especially in the elderly, who are more prone to this problem, who may collapse without a clear cause and may not be able to remember why they have fallen.
GM: And as for mitigating it then you're particularly interested in this compound within the brain called noradrenaline. So how does that come into things?
CM: Yes. Now, noradrenaline is the key chemical, the neurotransmitter, which is released by various neurons within the brain and, importantly for blood pressure control, in the periphery also. So there are the nerves known as the sympathetic nerves. They release noradrenaline when needed and this acts upon the blood vessels to constrict and keep the blood pressure up. Of course the reverse can occur. If you want to lower the blood pressure where there's less of discharge, less noradrenaline, the blood vessels dilate. In the context of orthostatic hypotension we are particularly interested in the replacement of noradrenaline in the periphery. Now, this is actually quite a tall order for a variety of reasons because it in essence means that you're trying to reconstruct the sympathetic nerves, which is not easy.
GM: How do you get round that?
CM: Well, it's been a big stumbling block for many years, many decades. Over the recent past we've had a few breakthroughs. This is a drug which chemically looks identical to noradrenaline accept for what is a carboxyl group at one end of the drug. With this carboxyl group it can be given by mouth. So unlike noradrenaline, which if it's given by mouth is effectively chewed up in the gut and therefore is ineffective, this drug can be given my mouth. It's taken into the circulation and then it's acted upon by an enzy me called dopa decarboxylase. It takes away the carboxyl group and therefore conv er ts it directly into noradrenaline. So, presto, you've got your endogenous neurotransmitter noradrenaline in the periphery.
GM: And this case you're talking about, this is part of a big clinical trial that you are effectively part of?
CM: It was a pan-European trail with a number of centres. And Imperial were very fortunate that we led. And I was fortunate to be the principle investigator leading these trials. Because we've conducted two trials so far.
GM: And just give us an outline of the results of those trials.
CM: Yes, I can tell you in the first trail we used two groups of patients. Patients with what's called pure autonomic failure and patients with multiple system atrophy who also have parkinsonian and cerebellar features. In this trial in a very large number of these patients there was benefit particularly with the higher doses of the drug. There were very few side effects. And very importantly there wasn't the reverse of hypotension. There wasn't what we call supine hypertension. And in the second trial we used a larger number of patients with MSA, that's with autonomic failure and the parkinsonian and cerebellar features and also typical Parkinson's disease who also had orthostatic hypotension. And here we used different doses of the drug and we also used a matching placebo. And this was done in a randomised double-blind trial. So neither the patient nor we knew exactly what either the dosage was or whether it was an active drug or placebo.
GM: I know you found a therapeutic effect from the drug and a measurable one. So away from the figures then just if you can speak anecdotally. You started with patients who presumably were in terrible difficulty. They were fainting a lot. They were really suffering. What kind of a difference did this drug make to them?
CM: It's made a tremendous amount of difference. In the two trials, these were short lived trials because it's still in the early stages of this drug, and it certainly made a tremendous amount of difference in terms of some of the symptoms which they had. Especially in the first study which was the dose escalating study so we could reach the optimum dose since we were aware of what we were using. What is of interest is going back to the rare disorder, the brother and sister. Now, these people had great difficulty in walking around in their daily life and managing their jobs and so on. And the drug completely transformed them so they were able to get about their business. They could work. They didn't faint. It really completely transformed their lives. They still remain on it and they're still extremely grateful for the fact that they're on the drug.
GM: Professor Christopher Matthias there. Well, in a moment high tech in high stress emergency situations with the latest in ultra real training exercises for student medics
http://www3.imperial.ac.uk/media/podcasts/magazinepodcasts2007/decembertranscript
