Antagonists symptoms and conditions

I am a male 55. Started taking Altace 15 years ago. BP kept creeping up. I work outside for a living. Sometimes work is very hard, climbing mountains, carrying land surveying equipment ect. Dr started me on lisinopril 40 mg, dropped altace which I had been taking with HCT 25mg. Started getting numbness in left hand and charley horse in elbow after playing mandolin for 10 minutes. I thought this strange. Now I have muscle cramps in legs and I am wiped out when I get home. (thought must be getting old) Then other joints, shoulders, and knees stared hurting and lower back. Started thinking what has happen to me?! I am completely falling apart! That's how I found this web site. Now I wonder, snake venom sounds about right. I had started thinking I had been poisoned. Guess I'll make a DR appointment or move to an "old folks home". At least I won't have a stroke.......right?

I was reading some research from the 90's where one researcher called montelukast an inverse agonist. So then, I looked for any thing more current on that subject. It would seem that genetic variation is again involved.

1: J Pharmacol Exp Ther. 2004 Apr;309(1):102-8. Epub 2004 Jan 12. Links
Inverse agonist activity of selected ligands of the cysteinyl-leukotriene receptor 1.Dupré DJ, Le Gouill C, Gingras D, Rola-Pleszczynski M, Stanková J.
Immunology Division, Department of Pediatrics, Faculty of Medicine, Université de Sherbrooke, Sherbrooke, Québec, J1H 5N4 Canada.

Cysteinyl leukotrienes (CysLTs) are associated with several inflammatory processes, including asthma. Due to this association, considerable effort has been invested in the development of antagonists to the CysLT receptors (CysLT(1)R). Many of these molecules have been shown to specifically interact with CysLT(1)R, but little is known about their impact on the conformation of the receptor and its activity. We were especially interested in possible inverse agonist activity of the antagonists. Using a constitutively active mutant (N106A) of the human CysLT(1)R and the wild-type (WT) receptor coexpressed with the G(alphaq) subunit of the trimeric G protein, we were able to address this issue with ligands commonly used in therapy. We demonstrated that some of these molecules are inverse agonists, whereas others act as partial agonists. In cells expressing the CysLT(1)R mutant N106A exposed to Montelukast, Zafirlukast, or 3- phenyl]-(2-dimethylcarbamoylethylsulfanyl)methylsulfanyl] propionic acid (MK571), the basal inositol phosphate production was reduced by 53 +/- 6, 44 +/- 3, and 54 +/- 4%, respectively. On the other hand, 6(R)-(4-carboxyphenylthio)-5(S)-hydroxy-7(E),9(E),11(Z),14(Z)-eicosatetraenoic acid (BayU9773) and 1- -phenyl ethanone] (LY171883) acted as partial agonists and alpha-pentyl-3- benzyl alcohol (REV 5901) as a neutral antagonist. However, in cells expressing CysLT(1)R and G(alphaq), all antagonists used had inverse agonist activity. The decrease in basal inositol phosphate production by ligands with inverse agonist activity could be inhibited by a more neutral antagonist, confirming the specificity of the reaction. We demonstrate here that Montelukast, MK571, and Zafirlukast can act as inverse agonists on the human CysLT(1) receptor.

PMID: 14718577

When I saw that researchers acknowledged the number of potential gene variants that are involved in determining the efficacy of montelukast and then I am reading the reports of the side effects, I am wondering why montelukast was ever approved for seasonal allergies. Asthma is potentially life threatening. But why take Singulair -montelukast for annoying allergies that won't kill you.

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" However, logically one might predict that it will be the combination of the polymorphisms in these different key regulatory enzymes and receptors that may ultimately determine treatment response. There have been some attempts to tease out the possible contribution of different genes important in this pathway for treatment response to a Cys leukotriene receptor 1 antagonist.18 However, because of the number of potential gene variants that may contribute to efficacy, large studies will be needed to fully evaluate the potential contribution of pharmacogenetic variability in this pathway to treatment response to Cys leukotriene receptor 1 antagonists. Work in the cardiovascular field has demonstrated the potential importance of genetic variants in this pathway to disease risk and also to treatment response,19 suggesting the potential for important effects to be defined in asthma."

(Chest. 2006;130:1873-1878.)
© 2006 American College of Chest Physicians

Pharmacogenetics of Asthma
Ian P. Hall, DM
* From the Division of Therapeutics and Molecular Medicine, University Hospital of Nottingham, Nottingham, UK.
Correspondence to: Ian P. Hall, DM, Division of Therapeutics and Molecular Medicine, University Hospital of Nottingham, Nottingham NG7 2UH, UK; e-mail: Ian.Hall@nottingham.ac.uk

http://www.chestjournal.org/cgi/content/full/130/6/1873

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Some of you who are following this site may remember that I posted that when I was following the pathways of the leukeotriene receptor antagonist Singulair that I got to a point where I concluded that there has to be a genetic component (meaning that there are different gene groups of people) and that the efficacy of Singulair (and possibly safety) can vary depending upon what gene group people are in. So I took a little time to see if anybody else was already studying that issue. And YES, they are -- including Merck.

quote:

" However, logically one might predict that it will be the combination of the polymorphisms in these different key regulatory enzymes and receptors that may ultimately determine treatment response. There have been some attempts to tease out the possible contribution of different genes important in this pathway for treatment response to a Cys leukotriene receptor 1 antagonist.18 However, because of the number of potential gene variants that may contribute to efficacy, large studies will be needed to fully evaluate the potential contribution of pharmacogenetic variability in this pathway to treatment response to Cys leukotriene receptor 1 antagonists. Work in the cardiovascular field has demonstrated the potential importance of genetic variants in this pathway to disease risk and also to treatment response,19 suggesting the potential for important effects to be defined in asthma."

(Chest. 2006;130:1873-1878.)
© 2006 American College of Chest Physicians

Pharmacogenetics of Asthma
Ian P. Hall, DM
* From the Division of Therapeutics and Molecular Medicine, University Hospital of Nottingham, Nottingham, UK.
Correspondence to: Ian P. Hall, DM, Division of Therapeutics and Molecular Medicine, University Hospital of Nottingham, Nottingham NG7 2UH, UK; e-mail: Ian.Hall@nottingham.ac.uk

http://www.chestjournal.org/cgi/content/full/130/6/1873

And Merck sponsored a study on this which is now completed.

http://clinicaltrials.gov/ct2/show/NCT00116324?intr=%22Montelukast%22&rank=79

Of course, it was sponsored by Merck and paid for by Merck.

I don't know if the study discovered anything but I believe this is an indication that Merck acknowledges genetic differences in populations that may predict the success of montelukast.

I am not any where close to being an expert in this field. I have another background but I believe that there are experts who can tell you exactly why you had side effects from Singulair.

I was a 2:42 marathoner. I used a synthetic varnish containing isocyanates, pentanedione, organic solvents, in one 7-hour session; the company-recommended respirator did not in fact prevent transmission: Severe chemically- induced asthma, plus neuropathy, plus, plus.

I've used Advair 500/50 for six years. There have been many diverse effects from the chemical exposure; I'd not questioned any being Advair side effects. But the raised blood pressure was not initial, and certainly not a priori. Diminished hearing, diminished eyesight, anxiety. Again, not to lump in, but these questions are new for me. But the point I'd like to bring before this group is this: In August I was diagnosed with ehlichiosis , and was prescribed 28 days on doxycycline. They recommend eliminating many possible antagonists to the doxycycline. My respiratory capacity had been continually diminishing. My ongoing physician said this was to be expected and recommended only the next more powerful steroid. Not a good solution. Before all this I was strong; repaired myself. In the absence of constructive answers, wondering if the Advair was weakening me, making me dependent, I quit the Advair as well on beginning the doxycycline. Today is eleven days post-doxycycline. Eight days ago there began with increasing severity, a terrible wracking deep cough producing dark yellow mucus. Painful. No fever. Grevious throat from the wracking, but I question whether this is a cold or infection. It's just in my lungs. Maybe it's as though I've thrown off an epithelial coating. These past two days the quantity of deep yellow mucus is not as ready, but the wracking and coughing is more severe. And my lung capacity, my respiratory capacity, is frighteningly diminished. Until these past two days I'd considered this an infection, especially post-doxy. But it doesn't feel like an infection. And I'm scared. Is this because I quit the Advair abruptly after long regular use? Have any of you had a similar experience. Can you discuss the effects of abruptly discontinuing Advair. Have you stayed off it. What's happened to your respiratory capacity. Have you any professional studies, trials or experience to recommend. Thanks.

I was prescribed Lisinopril three days ago. The day after my first dose, I was having losse bowel movements, but thought nothing of it because some medications just take time for your body to adjust to.

The day after my second dose, I was still having the loose bowel movements and began to feel bloated and a little crampy while at work. My stomach began to swell a little. As the day went on, the bloating and pain became noticeably worse to where other people began to comment on how swollen my stomach was getting. I was also feeling an occasional on and off tightening low in my throat.

I called my doctor and left a phone consult (where they have 72 hours to get back to you). By the time I left work, my stomach size had gotten even larger to where I appeared to be about 4-5 months pregnant!

I went home and laid down for an hour and woke up in a lot of pain and called the nurse call center where they advised me to go to the emergency room to be checked out.
I suspected the Lisinopril since that was the only new thing I had done in the past couple of days, but the ER said they never heard of such a reaction and that Lisinopril was a very mild medication.

They took X-rays of my stomach and told me my intestines appeared to be full and that I was constipated. I asked how that is possible when you have had loose stools for two days, but they said I was and gave me a massive laxitive and sent me home. What a mistake! The laxitive did what a laxitive should do, but made nothing better, it only increased the cramping and pain.

The next day I went into work and had to leave early. The doctor called me back for my consult and said it sounded like it was possibly a rare side effect (intestinal swelling) of Lisinopril. A little searching on the net found that it can happen with any ACE inhibitor though. I was told to immediately discontinue use, go on a liquid diet for a couple of days to rest my stomach and DO NOT take any more of the laxitives the ER gave me because that would only aggravate the problem.

I should be feeling better in a couple of days and the doctor said I could attempt to try the Lisinopril again to be sure if it was that causing the reaction, but he didn't blame me when I said I'd rather not.

After the holiday I need to get in contact with my doctor to see what else they can prescribe for my blood pressure. Does anyone have any suggestions I can research and bring with me to that appointment of other medications that aren't ACE inhibitors or water pills (allergic to Sulfa and cannot take) that have worked well on their BP without so many scary side effects?