Beta Blockers and Asthma

[DreamMachine]

.

---

Members don't see this ad.

 

[meddog1]

Esmolol is suppose to be pretty darn cardioselective, whereas Labetolol is not and is (theoretically) more prone to get you into trouble.

I used Esmolol in a PT with a hx/o asthma once with no problems. I was not cavalier though, let me tell ya.

 

[DrRobert]

All of the pulmonologists I've spoken with about this topic seem to think that the evidence for bronchospasm is weak at best. Therefore, I've never seen one hesitate to give their patients beta blockers.

 

[Mike MacKinnon]

Where i currently work I give metoprolol on a regular basis to cardiac patients. Ive been doing it for a number of years. Ive read the research on bronchospasm with hx asthma, its isnt particularily impressive but im always looking for it.

Seems that the only real contraindication is Status asthmaticus.

 

[militarymd]

I give lopressor ALL the time...in 13 years...had one patient who MAY have had worsening bronchospasm....but there were many other things going on....really hard to put it to the lopressor alone.

 

[The_Sensei]

I give lopressor ALL the time...in 13 years...had one patient who MAY have had worsening bronchospasm....but there were many other things going on....really hard to put it to the lopressor alone.

Same here.....no 13 year track record yet, but I essentially give lopressor with impunity to patients with asthma. Yet another example of the dogmatic teachings being disseminated to residents.....

 

[TIVA]

Even labetolol is not a bad drug to give for treating hypertension in asthmatics. It is both a selective alpha one blocker and a non selective beta blocker. However, it's alpha effects outweigh it's beta effects by 7 to 1. Thus, you have an ideal drug for CAD patients: reduce afterload, decrease myocardial work, decrease myocardial oxygen demands.

 

[meddog1]

Even labetolol is not a bad drug to give for treating hypertension in asthmatics. It is both a selective alpha one blocker and a non selective beta blocker. However, it's alpha effects outweigh it's beta effects by 7 to 1. Thus, you have an ideal drug for CAD patients: reduce afterload, decrease myocardial work, decrease myocardial oxygen demands.

I agree. It's a great drug. Anyone on here ever give it to an asthmatic?
I'd be curious to hear if there were any side-effects.

 

[Noyac]

I agree. It's a great drug. Anyone on here ever give it to an asthmatic?
I'd be curious to hear if there were any side-effects.

Yes

SE's - none, ever.

 

[bubalus]

Even labetolol is not a bad drug to give for treating hypertension in asthmatics. It is both a selective alpha one blocker and a non selective beta blocker. However, it's alpha effects outweigh it's beta effects by 7 to 1. Thus, you have an ideal drug for CAD patients: reduce afterload, decrease myocardial work, decrease myocardial oxygen demands.

Correct me if I'm wrong, but I thought the beta effects outweighed the alpha effects by 7:1, i.e., primarily a beta-blocker with some weaker alpha-1 blocking action.

 

[seattledoc]

Correct me if I'm wrong, but I thought the beta effects outweighed the alpha effects by 7:1, i.e., primarily a beta-blocker with some weaker alpha-1 blocking action.

I'll second that, it's mostly a beta blocker with a little alpha effect. So it lowers blood pressure without making the HR go too low.

 

[AJM]

As a pulmonary fellow, I get very annoyed when I hear that a physician withholds a beta blocker simply because of a history of asthma. The concern of beta blockers in asthma is mostly theoretical -- there is no data to show that beta blocker therapy in stable asthmatics increases bronchospasm, morbidity, or mortality. The only time I would be concerned about giving an asthmatic a beta blocker is when they are actively wheezing. For some reason this myth of beta blockers causing bronchospasm in asthmatics has been perpetuated despite the lack of data.....

 

[TIVA]

Correct me if I'm wrong, but I thought the beta effects outweighed the alpha effects by 7:1, i.e., primarily a beta-blocker with some weaker alpha-1 blocking action.

Hmmm ... maybe I am wrong. One book states just what you're saying, which is an alpha to beta blockade ratio of 1:7.

However the other book says that labetolol has a primary reduction in SVR and a smaller reduction in HR/contractility. So, if alpha one mediates SVR whereas beta (one primarily) mediates the heart, then you would think it's alpha to beta ratio would be in favor of alpha.

And a third book goes on to say that at labetolol has intrinsic B2 agonist activity.

So, at the end of the day, all I know is that labetolol is a great drug. It'll bring down the BP smoothly and predictably (if titrated in 5-10 mg aliquots) without causing bradycardia and no bronchospasm per say.

 

[sdn1977]

I just got back from vacation & saw another one of your interesting drug threads! As a pharmacist, I think beta blockers are great drugs which have an interesting history & as a drug class has some characteristics which have been carried forward & sometimes been misinterpreted as "myth". However, some of the "myths" have some basis in fact, albeit not current fact.

In short....James Black, who was a physician, won the Nobel Prize in 1988 for the discovery of propranolol. His Nobel Lecture in 1988 was on the principles of syntopic antagonism which was the basis for his research on beta blockers & later, histamine antagonists. In searching for a practical beta blocker (his intent was to find a drug which might relieve angina by decreasing myocardial oxygen demand) his lab started with the prototype which was a pure isopropyl derivative of noradrenaline then modified the chemical in an attempt to make a more selective agonist & by perhaps substituting a different, larger group....they might produce a more selective antagonist.

Concurrently, the Lilly labs (Eli Lilly Inc - the drug company) make a long acting variant which displayed particular brochoconstrictor activity in their attempt to find a beta blocker.

Both labs worked the chemical variations to produce the myocardial & vascular results they were looking for, but in the process of researching, actually studied compounds in humans which produces bronchospasm. These compounds were not the ones which actually were brought to market, but nonetheless, all the effects were reported in the research studies - bronchial in additon to cardiovascular. (An interesting aside...some early compounds made some subjects have a feeling of "impending doom" which is sometimes reported occasionally even now). That is why you'll see side effects, such as bronchospasm, sleep disturbances, depression, etc..listed as possible side effects.

Much more than you ever wanted to know about the history of beta blockers, I'm sure....but that is how this concern probably started. The research started on these drugs in 1958 & this is one of the early productive efforts of rational drug design - which is why it is of interest to me.

Bronchospasm is not a significant issue in this class - deliberately due to the efforts to design this out of the class. However, due to the concept of syntopic antagonism (a pharmacologic term which relates the interaction & overlap of different binding ligands), it can occassinally exacerbate an already present clinical situation. It occurs more frequently with the nonspecific blockers - propranolol & labetalol than with the B-1 selective blockers (metaproterenol, atenolol & esmolol). It also has a lot to do with receptor sensitivity, lipophilicity, intrinsic sympathomimetic activity of the compound, etc...in determining which drugs might or might not cause a reaction & what patients might be vulnurable.

I'll have to come back later with the actual ratios of alpha to beta blockade if you're really that interested, but its probably not clinically significant. This is probably far more than you ever wanted to know...........so I'll leave it at that!

 

[militarymd]

cool

 

[AJM]

I just got back from vacation & saw another one of your interesting drug threads! As a pharmacist, I think beta blockers are great drugs which have an interesting history & as a drug class has some characteristics which have been carried forward & sometimes been misinterpreted as "myth". However, some of the "myths" have some basis in fact, albeit not current fact.

In short....James Black, who was a physician, won the Nobel Prize in 1988 for the discovery of propranolol. His Nobel Lecture in 1988 was on the principles of syntopic antagonism which was the basis for his research on beta blockers & later, histamine antagonists. In searching for a practical beta blocker (his intent was to find a drug which might relieve angina by decreasing myocardial oxygen demand) his lab started with the prototype which was a pure isopropyl derivative of noradrenaline then modified the chemical in an attempt to make a more selective agonist & by perhaps substituting a different, larger group....they might produce a more selective antagonist.

Concurrently, the Lilly labs (Eli Lilly Inc - the drug company) make a long acting variant which displayed particular brochoconstrictor activity in their attempt to find a beta blocker.

Both labs worked the chemical variations to produce the myocardial & vascular results they were looking for, but in the process of researching, actually studied compounds in humans which produces bronchospasm. These compounds were not the ones which actually were brought to market, but nonetheless, all the effects were reported in the research studies - bronchial in additon to cardiovascular. (An interesting aside...some early compounds made some subjects have a feeling of "impending doom" which is sometimes reported occasionally even now). That is why you'll see side effects, such as bronchospasm, sleep disturbances, depression, etc..listed as possible side effects.

Much more than you ever wanted to know about the history of beta blockers, I'm sure....but that is how this concern probably started. The research started on these drugs in 1958 & this is one of the early productive efforts of rational drug design - which is why it is of interest to me.

Bronchospasm is not a significant issue in this class - deliberately due to the efforts to design this out of the class. However, due to the concept of syntopic antagonism (a pharmacologic term which relates the interaction & overlap of different binding ligands), it can occassinally exacerbate an already present clinical situation. It occurs more frequently with the nonspecific blockers - propranolol & labetalol than with the B-1 selective blockers (metaproterenol, atenolol & esmolol). It also has a lot to do with receptor sensitivity, lipophilicity, intrinsic sympathomimetic activity of the compound, etc...in determining which drugs might or might not cause a reaction & what patients might be vulnurable.

I'll have to come back later with the actual ratios of alpha to beta blockade if you're really that interested, but its probably not clinically significant. This is probably far more than you ever wanted to know...........so I'll leave it at that!

What a great history! I'll have to remember that.

I wonder if part of the reason we don't really see significant bronchoconstriction any more is not only because of the more prevalent cardioselective beta blockers but also because we tend to start with lower doses of beta blockers and then titrate them up. The standard teaching is that if you start right away with a high-dose beta blocker, it can precipitate acute heart failure (in pts with pre-existing heart failure), and make patients feel significantly tired. Instead, by starting low and ramping up the dose, you can get to the same higher dose with a lower risk of these side effects. I wonder if this also the case with bronchoconstriction. Correct me if I'm wrong, but I believe that the early clinical experience with beta blockers was that they started at a high initial dose and saw many side effects - hence the early clinical mantra that you never give a beta blocker to a patient with a h/o heart failure. This idea was later debunked by a very gutsy study where they gave lower dose beta blockers to CHF patients and found decreased mortality with beta blockade. No similarly designed study has been done for asthma and beta blockers, so many people tend to cling to the original beta blocker experience with asthmatics, even if that research may be no longer clinically relevent today.

 

[sdn1977]

What a great history! I'll have to remember that.

I wonder if part of the reason we don't really see significant bronchoconstriction any more is not only because of the more prevalent cardioselective beta blockers but also because we tend to start with lower doses of beta blockers and then titrate them up. The standard teaching is that if you start right away with a high-dose beta blocker, it can precipitate acute heart failure (in pts with pre-existing heart failure), and make patients feel significantly tired. Instead, by starting low and ramping up the dose, you can get to the same higher dose with a lower risk of these side effects. I wonder if this also the case with bronchoconstriction. Correct me if I'm wrong, but I believe that the early clinical experience with beta blockers was that they started at a high initial dose and saw many side effects - hence the early clinical mantra that you never give a beta blocker to a patient with a h/o heart failure. This idea was later debunked by a very gutsy study where they gave lower dose beta blockers to CHF patients and found decreased mortality with beta blockade. No similarly designed study has been done for asthma and beta blockers, so many people tend to cling to the original beta blocker experience with asthmatics, even if that research may be no longer clinically relevent today.

I agree - the dosing of b blockers has changed over time & actually required some getting used to particularly in congestive heart failure. For a long time, it seemed counterintuitive to use something in these pts which might precipitate or worsen a condition. However, the large trials which were reported in 2003 - 2 or 3 studies I think, showed carvedilol, bisoprolol, metoprolol & others available only in Europe actualy reduced mortality in pts with stable congestive heart failure, regardless of severity.

For metoprolol & bisoprolol the doses used are exactly as you describe - low & increase slowly. The effects in the begininning are neutral & sometimes adverse then benefits accumulate over weeks or months.

Interestingly....the third generation - carvedilol has effects which are seen within days & shorten hositalization in these pts. The effects of this drug are also seen with bronchospasm & diabetes which was the point you brought up.

So....from a pharmacologic standpoint, the investigation now has become....is it necessary to block only the b1 receptor - because positive effects are seen with the nonselective agents as well so are there other binding ligand sites we don't know about? Also....there are still some pts who are unable to tolerate any of them & current studies are underway to determine a way to identify these pts before actually giving them the drug.

Again....a very interesting class of drug & a great example of using drug design to obtain the effects you specifically want in an identified class of pts.

 

[meddog1]

This is why we Anesthesiologists love you Pharmachologists so much. Very good discussion!

 

[sdn1977]

This is why we Anesthesiologists love you Pharmachologists so much. Very good discussion!

I do thank you, but I'm a pharmacist - not a pharmacologist. The pharmacologist does the research - usually a PhD, but sometimes a PharmD/PhD, but I'm just a PharmD - pharmacist. I help get the research info to the right people - providers & pts - so the drugs can be used optimally in a clinical setting.

Your comment was flattering, but I don't want to misrepresent myself (just j/king!!!)

 

[Qtip96]

I agree - the dosing of b blockers has changed over time & actually required some getting used to particularly in congestive heart failure. For a long time, it seemed counterintuitive to use something in these pts which might precipitate or worsen a condition. However, the large trials which were reported in 2003 - 2 or 3 studies I think, showed carvedilol, bisoprolol, metoprolol & others available only in Europe actualy reduced mortality in pts with stable congestive heart failure, regardless of severity.

For metoprolol & bisoprolol the doses used are exactly as you describe - low & increase slowly. The effects in the begininning are neutral & sometimes adverse then benefits accumulate over weeks or months.

wow! great stuff sdn1977. just thought i'd add a few points of clarification. the major relevant studies were CIBIS II (bisoprolol), US Carvedilol HF Study and COPERNICUS (carvedilol), and MERIT HF (Toprol XL). it is worth clarifying that the standard of care for metoprolol formulation used for heart failure is the sustained release succinate (Toprol XL). the short-acting tartrate formulation was used in the MDC trial, which did not demonstrate the profound mortality benefit demonstrated with the SR/XL in MERIT HF. key thing for practitioners to remember is that the target dose for beta-blockers in heart failure is pretty high if you want to obtain the mortality benefits documented in the studies (i.e. Toprol XL 200mg/day, carvedilol 25-50mg/day).

again, sdn, thanks for all of your valuable input!

 

[sdn1977]

wow! great stuff sdn1977. just thought i'd add a few points of clarification. the major relevant studies were CIBIS II (bisoprolol), US Carvedilol HF Study and COPERNICUS (carvedilol), and MERIT HF (Toprol XL). it is worth clarifying that the standard of care for metoprolol formulation used for heart failure is the sustained release succinate (Toprol XL). the short-acting tartrate formulation was used in the MDC trial, which did not demonstrate the profound mortality benefit demonstrated with the SR/XL in MERIT HF. key thing for practitioners to remember is that the target dose for beta-blockers in heart failure is pretty high if you want to obtain the mortality benefits documented in the studies (i.e. Toprol XL 200mg/day, carvedilol 25-50mg/day).

again, sdn, thanks for all of your valuable input!

Qtip - I agree - the standard of care is the sustained release Toprol in these pts. However, many insurance companies do not allow coverage for toprol unless the pt cannot tolerate multiple day dosing. I have actually attempted to obtain treatment authorization requests utilizing the study data & I know our cardiologists try. However, the only way we have been able to get authorization when not on formulary is to document "physical" problems with multiple day dosing....pt takes >10 medications/day, pt has a physical issue with swallowing & can't do it often, etc...Carvediolol is usually never on the formulary & we often have to document treatment failure with atenolol & metaproterenol before carvediolol is approved (its still too new & expensive).

My own county's Medicaid formulary does not allow Toprol & I've never been able to get authorization. This is a situation where current recommenddations are sometimes not followed in the practical situation due to money (Toprol is expensive!) so you do the best you can.

Thanks for pointing that difference out though! As an aside...I've never seen a report of any bronchospasm with the sustained release form & the pts rarely are fatigued with it as they are when starting metaproterenol or atenolol - do you see a difference?

 

[Qtip96]

Qtip - I agree - the standard of care is the sustained release Toprol in these pts. However, many insurance companies do not allow coverage for toprol unless the pt cannot tolerate multiple day dosing. I have actually attempted to obtain treatment authorization requests utilizing the study data & I know our cardiologists try. However, the only way we have been able to get authorization when not on formulary is to document "physical" problems with multiple day dosing....pt takes >10 medications/day, pt has a physical issue with swallowing & can't do it often, etc...Carvediolol is usually never on the formulary & we often have to document treatment failure with atenolol & metaproterenol before carvediolol is approved (its still too new & expensive).

My own county's Medicaid formulary does not allow Toprol & I've never been able to get authorization. This is a situation where current recommenddations are sometimes not followed in the practical situation due to money (Toprol is expensive!) so you do the best you can.

Thanks for pointing that difference out though! As an aside...I've never seen a report of any bronchospasm with the sustained release form & the pts rarely are fatigued with it as they are when starting metaproterenol or atenolol - do you see a difference?

it really sucks that access to important lifesaving drugs are so restricted in your country. the US medical system has got it's problems, but in many cases of documented mortality benefit within reasonable limits, it's accessible. Toprol XL and Coreg are on most prescriptions plans (including many variants of Medicare) and is usually tier 2 or "intermediate" copay. one of my colleagues told me that there have been successful lawsuits in more than 1 state where the plaintiff sued his/her cardiologist for prescribing metoprolol tartrate for CHF when compelling mortality benefit data for Toprol XL and Coreg was published (i bet this case would not have gone far in most other countries).

never personally seen bronchospasm with Toprol XL. i do see fatigue with Toprol as with atenolol, but they are two different patient populations and treatment for different indications (CHF vs. CAD, HTN, afib, SVT, etc.). i cannot ascertain whether this is a central effect or temporary negative inotropic effect (which the CHFers may be more sensitive to). further, for the latter indications, my practice has been to start at a higher dose and titrate more aggressively.