Author: Admin (---.vnnyca.adelphia.net)
Date: 11-28-02 13:31
Angiotensin Receptor Blockers (ARBs) are a class of extremely selective drugs, targeting just one thing, the receptor through which Angiotensin II reacts with other molecules. The ARBs job is to bind at the receptors for Angiotensin II, thus blocking the ability of Angiotensin II to bind there. The ARB is inert. There is no reaction. If the Angiotensin II had mated to the receptor it would have produced a cascade of inflammatory cytokines. Below is a 3-D view (from UCR) of the Secosteroid 1,25-D receptor
It's not the same as Angiotensin II, but I wanted to give you some idea of the complexity of these molecules, and of the ways they interact (besides which, it looks neat)
On the right you have the (blue) 1,25-D molecule entering the VDR and binding with it to start the chemical reactions.
The first thing you can see is that these molecules are very complex. Trying to design a drug such as an ARB, is made even harder by the fact that these molecules vibrate, or change their relative shape, due to molecular forces.
So it should really come as no surprise when I tell you that not all of the ARBs are equally effective at locking out Angiotensin II from releasing its inflammatory cytokines. Some work better than others.
ARBs have been incorrectly developed and marketed as "Blood Pressure" drugs --> which they are not
It was really a surprise to their developers that ARBs did not attack hypertension as effectively as the scientists had hoped. Older drugs, like the ACE Inhibitors and Calcium Channel Blockers, do a much better job at reducing blood pressure. ARBs are only recommended for MILD cases of hypertension, and usually used in conjunction with a more effective BP drug.
But Angiotensin II is a key element in the inflammatory process. and ARBs are proving effective at reducing Diabetic Retinopathy and Nephropathy, in addition to reducing Heart Disease and Strokes. These conditions are both caused by a vascular inflammation very similar to that in Sarcodiosis. Unfortunately, your Doc may not have found out about this yet
So what have ARBs to do with Sarcoidosis?
Firstly, the obvious connection is that any drug which can reduce the amount of retinopathy and nephropathy is most certainly of interest. But there is more than that. We (Liz and I) have described how Angiotensin II plays a key role in the inflammatory granuloma, and found that if you block Angiotensin II from binding at the site of the inflammation you also reduce the level of 1,25-D being generated. Thus the symptoms of Hypervitaminosis D are reduced. We also suspect, but cannot yet prove, that the long term damage done by the granuloma to the tissue in which they reside will be reduced. But at this point you can hang your hat on the ARBs reducing your fatigue and other symptoms, and that is probably good enough
But Sarcoidosis is such severe inflammation that you have to block every single receptor
Here is a graph of the dosage of Benicar, the most effective of the ARBs, against blood pressure change. You can see that almost all the reduction in blood pressure is achieved at a relatively low dose (around 40mg/day). But you can also see that the blood pressure continues to reduce (by incrementally smaller amounts) as you increase the dosage. This is because as the dosage gets higher there are more ARB molecules available to bind at every one of those pesky receptors.
Doc will be familiar with dosing the ARB for all his hypertension patients, at the 40mg once-a-day level, which can be catastrophic for Sarc patients. We documented side effects from Psychedelic Dreams to Neuropathy as a result of inappropriate ARB dosage. Read this paper if you want to know more background. Our most complex manuscript, "New treatments emerge as Sarcoidosis yields up its secrets" goes into the inflammatory chemistry in more detail.
We found that it is critical to dose the ARBs frequently. For Benicar (olmesartan medoxomil) there is safety data that supports twice daily dosing at 40mg every 12 hours. I suggest you ask Doc to sign off on trying that, and then change to the more effective 40mg every 8 hours after he (and you) are comfortable with using the ARBs as an anti-inflammatory.
Diovan (Valsartan) also works fairly well, use it only if Benicar is not available in your country. 80 mg every 8 hours was what we found best (you are going to need a cooperative doctor to prescribe Diovan at these dosages). Diovan tends to leave you with Sinus congestion, and I found that it gave me ringing in the ears. But it is much better than nothing.
Finally there is Avapro (Irbesartan). Use it only if Diovan and Benicar are not available where you live. I found 150 mg every 8 hours worked fairly well, but I had problems with the Avapro not absorbing from my stomach once I started to get a little "hyper D". 'Your mileage may vary'.
There are other ARBs, including Atacand and Cozaar. I tried Atacand (Candesartan) but couldn't get it to work. Don't let Doc talk you off the proven 3. Do your best to get the Benicar.
Migraines and Headaches
A new study has been released which proved that ARBs are very effective against headaches, even in the general population. Print it out for Doc and maybe that will be a factor in persuading him/her to prescribe ARBs for you. This study was paid for by the makers of candesartan, and so that is the ARB they used. Make sure that Doc actually prescribes one of the top three, and that the dose is split into 8 hour traunches so that it is effective for you, the sarcoidosis patient, who has special needs due to the large number of extra Angiotensin II receptors that are present in your inflamed tissue.
All the ARBs are some of the safest drugs in the formulary. They are very targeted, do just one job, and do it well. The predominant 'side-effect' from taking an ARB is that your blood pressure will drop. You will have to manage this. You can see that Benicar is supposed to get a maximum blood pressure reduction of about 15 mm Hg. In my case, because it and the Minocin controlled the underlying sarcoidosis, a huge drop in my blood pressure from 150/95 to an average of 115/65 was actually what I experienced. However, people that start off with blood pressures closer to 'normal' (120/60) will not experience such a big reduction in their BP. Nevertheless, I suggest you buy a cuff and measure yours, at least until you 'get the feel of it'.
Those patients that are mildly hypertensive can have Benicar precribed for that hypertension. If you take Benicar, at least 40mg every 12 hours, you will find it will reduce your fatigue and other 1,25-D symptoms.
If you are not hypertensive your Doctor will need to prescribe the drug "off-label". Some doctors will not do that.
You may require increased dosage if you need to spend time out of doors. Use of an ARB will not allow you to spend all of your time out-of-doors. But it will increase your threshold to the point where a little sunshine exposure can be easily tolerated. You still gotta wear eye protection
..Trevor.. (C) Copyright 2002, SarcInfo.com