Thread by @AvrahamCooperMD

1/THREAD
Why would adenosine, a purine nucleoside, be able to treat supraventricular tachycardias (SVT)?

And why are its effects so short lived (e.g. <2 seconds)?

The answers will change the way you think about this drug.

#tweetorial #medtwitter

2/
Adenosine is an endogenous purine nucleoside that gets incorporated into RNA, ATP, and cAMP.

It has pleomorphic effects as a signaling molecule via A1, A2A, A2B, and A3 receptors.

pubmed.ncbi.nlm.nih.gov/25687993/

3/
Adenosine was first found to be able to terminate supraventricular tachycardias (SVT) in 1927 in animal experiments.

💡It's mechanism of action was unknown.

pubmed.ncbi.nlm.nih.gov/16994064/

4/
Along with vagal maneuvers and other nodal blockers, adenosine, is now used to treat hemodynamically stable, narrow complex SVT, particularly if involving the AV node w/ reentry loops (eg AVNRT).

pubmed.ncbi.nlm.nih.gov/7800009/

5/
Let's return to our first question. Why would a nucleic acid be able to terminate SVT?

It turns out that adenosine, which is produced endogenously by ATP hydrolysis, acts on the SA and AV nodes via A1 receptors.

pubmed.ncbi.nlm.nih.gov/30972618/

6/
Signaling via A1 adenosine receptors in cardiac tissue leads to ⬇️ cAMP activity and opening of hyperpolarizing membrane potassium channels.

🔑This decreases conduction speed through the AV node (aka negative dromotropy).

pubmed.ncbi.nlm.nih.gov/30562103/

7/
Adenosine signaling through A1 receptors also blocks the opening of L-type membrane calcium channels, which further reduces conduction speed through the AV node.

pubmed.ncbi.nlm.nih.gov/2022011/

8/
By dramatically slowing conduction in the AV node, adenosine can terminate reentrant circuits/loops that involve the AV node (eg AVNRT).

⚡️That's how it treats SVT.

ncbi.nlm.nih.gov/pmc/articles/P…

9/
Let's return to our second question: why is adenosine such an ultra short-acting drug?

💥It turns out that adenosine's half-life in the blood is, incredibly, <1.5 seconds.

pubmed.ncbi.nlm.nih.gov/2539728/

10/
For adenosine inactivation to be so fast, it has to happen in the blood.

And that's exactly what occurs...

11/
Amazingly, adenosine is rapidly taken up by red blood cells (RBCs) and endothelial cells and inactivated intracellularly, in 2 ways:

1. Deamination by adenosine deaminase to inosine
2. Phosphorylation to adenosine monophosphate

pubmed.ncbi.nlm.nih.gov/2022011/

12/
Let's conclude with a cool clinical correlate.

Adenosine also causes vasodilation, via similar membrane hyperpolarizing mechanisms as we saw for negative dronotropy in tweet #6.

pubmed.ncbi.nlm.nih.gov/30972618/

13/
This ability to vasodilate explains why adenosine is used during pharmacologic cardiac stress testing.

Vasodilation of normal arterioles "steals" blood away from stenotic segments, inducing myocardial ischemia.

amboss.com/us/knowledge/C…

14/
Dipyrimadole, another vasodilator used in stress testing, acts as an adenosine re-uptake inhibitor.

This prolongs and enhances the effects of endogenous adenosine on the myocardium, leading to coronary steal from stenotic coronary segments.

pubmed.ncbi.nlm.nih.gov/22129171/

15/
Teleologically, adenosine regulates cardiac energy supply/demand, allowing rapid response to ischemia/tissue injury by coronary vasodilation and ⬇️ conduction speed/heart rate.

This may explain why it has such an ultrashort duration of effect.

pubmed.ncbi.nlm.nih.gov/21094127/

16/SUMMARY
🫀Adenosine terminates SVTs by ⬇️ conduction speed through the AV node (negative dromotropy)
🫀Ultrashort duration of action (<2 sec) = rapid inactivation in endothelial cells + RBCs
🫀This reflects its role in regulating response to cardiac ischemia/injury