why B2 agonists cause muscle tremor as side effect

[busy08]

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why B2 agonists cause muscle tremor as side effect

 

[Phloston]

why B2 agonists cause muscle tremor as side effect

I've never heard of that before. However, if I had to reason through it, I would start based on knowing that you treat essential tremor with beta-blockers (which is in FA on p. 439). I've never delved into the mechanism, but my assumption would be, for essential tremors, that treatment with beta-blockers causes decreased intracellular cAMP --> decreased PKA --> increased tone of peri-fascicular vascular smooth muscle via phosphorylation of MLCK --> decreased muscle blood flow --> decreased muscle tone --> relief of tremor.

So, therefore, beta-agonists probably do the opposite: increased cAMP --> increased PKA --> increased rate of dephosphorylation of MLCK (likely due to PKA-mediated phosphate transfer to other moieties) --> decreased tone of peri-fascicular vascular smooth muscle --> increased muscle blood flow --> increased muscle tone --> tremor (possibly due to temporal heterogeneity of beta-agonist uptake).

So yeah, that's my guess as to why beta-agonists (non-selective) could cause tremor. As far as why patients with essential tremor self-medicate with EtOH, the GABA potentiation is a separate mechanism that is likely not involved here.

 

[RT2DO]

Beta2 adrenergic receptors like Albuterol are nerve synapses that when stimulated release epinephrine. Adrenergic agonist medications stimulate these particular receptors, which are particularly found in bronchial smooth muscle amongst other places in the body. This action relaxes bronchial smooth muscles during asthma, COPD exacerbations, but increase Alpha activity of the heart. The sympathomimetic are important because some patients experience significant cardiovascular symptoms such as tachycardia, elevated blood pressure, and irregular heart rhythms after taking the medication. Other adverse effects include anxiety, restlessness and tremors. If an adverse reaction is found, the order is usually changed to an anti-cholinergic medication (atrovent) or a large side-chained bronchodilator with minimal cardiac effect (levalbuterol).

 

[Phloston]

Beta2 adrenergic receptors like Albuterol are nerve synapses that when stimulated release epinephrine. Adrenergic agonist medications stimulate these particular receptors, which are particularly found in bronchial smooth muscle amongst other places in the body. This action relaxes bronchial smooth muscles during asthma, COPD exacerbations, but increase Alpha activity of the heart. The sympathomimetic are important because some patients experience significant cardiovascular symptoms such as tachycardia, elevated blood pressure, and irregular heart rhythms after taking the medication. Other adverse effects include anxiety, restlessness and tremors. If an adverse reaction is found, the order is usually changed to an anti-cholinergic medication (atrovent) or a large side-chained bronchodilator with minimal cardiac effect (levalbuterol).

The heart doesn't have alpha-receptors. It has beta-1.

It's also not quite right to say that selective beta-2 agonists induce tachycardia. They induce reflex-tachyardia and a decrease in blood pressure.

 

[RT2DO]

Thank you for pointing out the mistakes 🙂

 

[normtheniner]

The heart doesn't have alpha-receptors. It has beta-1.

It's also not quite right to say that selective beta-2 agonists induce tachycardia. They induce reflex-tachyardia and a decrease in blood pressure.

The heart actually does have alpha-1 receptors, but they play a minor role. Their activation triggers hypertrophy of the the cardiomyocytes if I remember right.

 

[Phloston]

The heart actually does have alpha-1 receptors, but they play a minor role. Their activation triggers hypertrophy of the the cardiomyocytes if I remember right.

The myocardium definitely does not have alpha-receptors, and putting anything alpha-1 + heart on the USMLE would invariably be wrong.

The coronary arteries may have traces of alpha-receptors, as does the majority of the vasculature, but I wouldn't think alpha + heart under any circumstances.

If you can find an article mentioning any significant relationship, that would be awesome (and I'd be happy to learn something new).

 

[Charles_Carmichael]

The myocardium definitely does not have alpha-receptors, and putting anything alpha-1 + heart on the USMLE would invariably be wrong.

The coronary arteries may have traces of alpha-receptors, as does the majority of the vasculature, but I wouldn't think alpha + heart under any circumstances.

If you can find an article mentioning any significant relationship, that would be awesome (and I'd be happy to learn something new).

While I definitely agree with you that this is extremely unlikely to pop up on Step 1, it looks like the myocardium does have alpha-1 receptors:

http://circheartfailure.ahajournals.org/content/2/6/654.long

A quick PubMed search yielded that on the first page. I have not read it though, so if I misunderstood the abstract, my bad.

Edit: Additional review article, if you're bored: http://www.ncbi.nlm.nih.gov/pubmed/18032391

 

[Phloston]

Thanks for posting that.

 

[busy08]

Thanks for explanations

 

[normtheniner]

Thanks for explanations

Just to follow up on this. We talked about this today in pharmacology. Apparently there are Beta receptors on muscle which enhance the activity of the nicotinic receptors found on muscles. Therefore, when you give a Beta agonist it will enhance the Nm receptor leading to more sensitivity to stimulation by the muscle (via somatic ACh). This leads to tremors and twitching that are seen when given Beta2 agonists.

 

[Phloston]

Just to follow up on this. We talked about this today in pharmacology. Apparently there are Beta receptors on muscle which enhance the activity of the nicotinic receptors found on muscles. Therefore, when you give a Beta agonist it will enhance the Nm receptor leading to more sensitivity to stimulation by the muscle (via somatic ACh). This leads to tremors and twitching that are seen when given Beta2 agonists.

Did your professor actually make that conclusion in the last sentence, or are you making that conclusion?

 

[normtheniner]

Did your professor actually make that conclusion in the last sentence, or are you making that conclusion?

He actually made that conclusion. I actually re-watched that segment before I posted to make sure. Its a moot point regardless. Not sure step 1 would ask that kind of question. Whats more important is knowing that they cause those symptoms.

 

[AZ7]

Also, correct me if im wrong -
Beta agonists shift Potassium into the cells causing hypokalemia which is responsible for the muscle spasms/tremors?
Or is the Nm receptor sensitization more appropriate?
@Phloston Any input will be appreciated

 

[wyang517]

Also, correct me if im wrong -
Beta agonists shift Potassium into the cells causing hypokalemia which is responsible for the muscle spasms/tremors?
Or is the Nm receptor sensitization more appropriate?
@Phloston Any input will be appreciated

My pharmacology professor explained today that both mechanisms can cause the tremor.

However, my question is, how does increasing intracellular K+ cause tremor?
I thought increasing K+ in the cell would hyperpolarize the cell (moving the membrane potential lower from 0), thus, making the cell harder to become excited... hence the tremor...

 

[alex yang]

My pharmacology professor explained today that both mechanisms can cause the tremor.

However, my question is, how does increasing intracellular K+ cause tremor?
I thought increasing K+ in the cell would hyperpolarize the cell (moving the membrane potential lower from 0), thus, making the cell harder to become excited... hence the tremor...

shouldn't it be depolarized? Since more cations rush into the cell and make the intracellular charge not that negative.

 

[Kendragon]

Well if we look at it from the opposite direction first:
Decreased intracellular K+ - although it increases the RMP, thereby decreasing the threshold, it actually causes the cell to become more refractory, rather then excitable. This is because when you increase RMP slightly, some sodium channels will become inactivated. It will also makes it more difficult for inactivated channels to return to their resting state after an action potential. This is known as neural accommodation and is why an increased RMP (eg hyperkalemia or decreased intracellular k+) can cause muscle weakness.

Therefor, I'm assuming that an increased in intracellular K+ would cause the opposite effect. Although it would cause a slight increase in RMP, it would speed up the reactivation of inactivated sodium channels, decreasing the refractory period of the cells and making them more rapidly able to depolarize again. The increase in RMP wouldn't actually make it harder to become excited, since the influx of Na during an action potential will have no problem in overcoming the slight increased RMP to trigger a depolarization.

Let me know if my explanation makes sense haha!