Sunday, December 6, 2015

Agonists/Antagonists, Alpha/Beta: How these important terms apply to POTS

Disclaimer: This is a Dummies' attempt to reiterate important scientific concepts. Nothing here should be considered medical device as I am not a doctor; however, if you find anything useful here then it could be a great idea to ask your doctor about it. Coincidentally (and in in very rare form), POTS presents a unique situation where doctors are often the ones learning from their patients.

Another note is that we don't have the full picture about POTS yet, particularly autoimmune cases in which antibodies are involved. I wrote this paper based on the currently available research, which might not give us the whole picture. Take this blog with a grain of salt. 

Background:


As a POTS patient myself, I've had to do a lot of late-night googling of scientific terminology to try and get some kind of grasp on the bizarre illness that lives within me. Normally, obsessing over abstracts and studies to try and pinpoint specific malfunctions in one's on body might be a little bit.. silly. (ie, severe hypochondriasis, tinfoil hat, etc). But in the unique case of POTS, most doctors simply don't have all of the answers. Or conversely, if they DO have all of the answers then the patient might end up even more confused than they were to begin with because you'd have to spend hours obsessing over this information until you finally understood it. Thankfully, that's what I am here for; I have obsessed over it for you! *adjusts helmet made out of Reynolds Wrap*

For now, let's start with a very basic explanation of what agonists and antagonists are. These are important concepts that will pop up again when we discuss current and future POTS medications. Additionally, understanding these terms will lead to better understanding of how antibodies work to cause an autoimmune type of POTS.

Agonist Vs. Antagonist : Definition and meaning:

In Biochemistry, the term Agonist is used to define something that Activates/Stimulates/Causes a Response/Produces an Action from the receptor.


It's opposite, the Antagonist, is something that Deactivates/Disables/Blocks a Response/Produces no Action from the receptor. 


If we are keeping it simple: Agonists turn the light switch on and Antagonists turn the light switch off

"So what exactly do these Agonists or Antagonists turn on or off?" Receptors.

"Receptors? What do they do?" The actions of receptors affect how our body functions and in this case we'll be talking about adrenergic receptors that govern the nervous system. 

"Ok this kind of makes sense... how about an actual example of an Agonist or Antagonist?" 

Here are several examples:
  • The drug Morphine is an Opioid receptor AGONIST. It activates and stimulates the Opioid receptors in our body. If someone is given Morphine, they will feel less pain because of the chemical response that happens when an Opiod Agonist effects Opiod receptors. 
  • Naloxone is the opposite of Moprhine- it is an Opioid receptor ANTAGONIST. It is used to reverse the effects of Morphine or disable these receptors from being activated. (Naloxone can be used to reverse a Morphine overdose)
  • Propanolol is a Beta ANTAGONIST that you might be familiar with. It blocks Beta adrenergic receptors, (hence the term 'Beta Blocker'). The result? Lowered blood pressure and heart rate. 
  • Isoprenaline is a Beta AGONIST. Probably not an ideal drug for most POTS patients as it increases heartrate. I was given this during a Tilt Table Test and it felt like I had been injected with adrenaline. Would not repeat. 

Fun Fact: Agonist has been derived from late Latin word agnista, which means contender. Antagonist has been derived from the Latin antagonista, and from Greek 'antagonistes' which means “competitor, rival or opponent.”

I know it's still a bit confusing. But if you can grasp one point here, it is simply that in layman's terms, Agonist = Activates and Antagonist = Deactivates Got it? Sort of? Ok good, let's move on to Alpha and Beta Adrenergic Receptors.

Beta vs Alpha : Definition and meaning 


Without any further context, Alpha and Beta are simply the first two letters of the Greek alphabet. But in the case of Biochemistry (or in the case of POTS illness) we are using these terms in reference to the Alpha and Beta Adrenergic Receptors that govern major functions in our bodies nervous system.

From wikipedia: "....Many cells possess these receptors, and the binding of a catecholamine to the receptor will generally stimulate the sympathetic nervous system. The sympathetic nervous system is responsible for the fight-or-flight response, which includes widening the pupils of the eye, mobilizing energy, and diverting blood flow from non-essential organs to skeletal muscle."

Alpha and Beta Adrenergic receptors help you dodge an unexpected speeding car as you cross the street (...or help a chicken run faster as it is being chased by a Tiger)

Bottom line: These receptors are the bio-molecular highway for the flight-or-flight system. Now let's take a look at Alpha versus Beta and how they are responsible for different functions.

Alpha Receptors: Responsible For Vasoconstriction of Veins

(From Wikipedia) α receptors have several functions in common, but also individual effects. Common (or still unspecified) effects include:

Beta Receptors: Increase cardiac output when activated. 

(From Wikipedia) Actions of the β1 receptor include:

Actions of the β2 receptor include:
  • Heart muscle contraction

The important thing to understand is that Beta Adrenergic receptors are responsible for increasing heartrate/cardiac output while Alpha Adrenergic Receptors are responsible for vasoconstriction. 

Important Note: Beta Receptors and Alpha Receptors do many, many things in our body. It would be overwhelming (and quite frankly unnecessary) to talk about every single action that these receptors are responsible for. (i.e. smooth muscle contraction of the urethral sphincter- let's leave that out for now)  

As there are subtypes of alpha and beta (Beta1, Beta2, Alpha1, Alpha2...etc) there are also 'subtypes' of each subtype (ie. Alpha2A, Alpha2B, Alpha2C..). I will try to tackle this in a future post, but if you really want to geek out now then simply view The wikipedia page for Adrenergic Receptors.

Now that we have a basic understanding of Alpha vs Beta and Agonist vs Antagonist, we can better discuss the concept of Autoimmune POTS. 

POTS Antibodies: How these terms relate to an Autoimmune Postural Orthostatic Tachycardia Syndrome


Firstly, let's go ahead and separate fact from fiction with respects to POTS being Autoimmune.

-Do we have strong evidence that many cases of POTS have Autoimmune involvement? Yes. Thanks to organizations like Dysautonomia International, brilliant POTS experts like David Kem and Satish Raj and teams of scientists at Oklahoma University and Vanderbilt University- We have that evidence. ( http://jaha.ahajournals.org/content/3/1/e000755.full

-Are all cases of POTS Autoimmune? There is no evidence to suggest that all cases of POTS are Autoimmune. The answer is probably just 'no'.  I don't think it would be ridiculous to assume that 'most' or 'over half' of all POTS cases have Autoimmune involvement. Either way, this area is the main focal point of current research.

As a side note, if an individual more or less 'woke up' with POTS- (in other words they had a rather sudden onset of POTS after being sick) then I would take a wager that his or her POTS is very likely of autoimmune origin. (of course this is where science stops and mystery begins as there are many factors that may contribute to the actual birth of an autoimmune disease such as stress, genetics, coexisting conditions, diet,  etc etc.... way above my pay-grade as a looney blogger)



So in what way do POTS antibodies function? What do they DO? How can antibodies cause POTS? Well, looking at the paper published in Feburary of 2014 called "Autoimmune Basis for Postural Orthostatic Tachycardia Syndrome" it is proposed that POTS antibodies primarily act as Beta Agonists and/or Alpha Antagonists

So stop for a second and imagine what that might look like based on the crash course definitions earlier in this blog. Firstly, if POTS antibodies are Beta Agonists, that means they are activators of the Beta Adrenergic receptors The result of this is increased heartrate and increased cardiac output. Secondly, the antibodies are also Alpha Antagonists- which means that these antibodies actually disable Vasoconstriction. Disabling vasoconstriction isn't really a big deal... until you need to do things like, oh I don't know, stand up for a while!

The image below (taken from this study)  illustrates the disastrous chain reaction that happens when someone who has these antibodies tries to stand up.

B1AR-AAb= Beta 1 adrenergic recetpor autoantibody
a1AR-AAb=Alpha 1 adrenergic receptor autoantibody


Note: This is definitely a time where I need to point out that I can only pretend to understand this information. My goal here is simply to help make this semi-relatable to POTS patients in hopes that it may lead to better understanding or treatment of their illness. With respects to beta antibodies mentioned in this paper, these antibodies may have both agonist and antagonist capabilities simultaneously-- but again, I want to keep this somewhat simple. The bottom line is that an autoimmune form of POTS is seen where cardiac output is deliberately increased and veins are dilated by antibodies.

I have removed a large section here about medications. Please feel free to join 'POTS discussion for patients pretending to be doctors' if you like to pretend to understand this medical jargon and are a POTS patient and want to explore patients experiences with different medications. There are many many weapons and tools available to live a normal life. At the time of writing this I am most interested in NOS altering drugs but this is a very subjective personal experience that might not apply to everyone.