Adenosine

Adenosine

1. Adenosine Endothelium independent vasodilator

2. Coronary hyperaemia: The life thread Coronary blood flow can increase up to 5 times the basal flow to meet increased demand Increase in blood flow is referred to as a hyperemia Observed in response to ischemia and exercise Quantifying the hyperemic response is a critical step in understanding the coronary circulation and is applied in most physiological assessments of myocardial blood flow

3. Coronary vasodilators Adenosine Papaverine Sodium nitroprusside ATP Dobutamine Nikorandil Nitro-glycerine Regadenoson

4. 3 Receptors

5. Stood the test of time Coronary vasodilator for microcirculation hyperaemia FFR is really only used for intermediate stenosis (40% to 70%) Popular SVT Rx

6. 5 actions Negative Chronotropic Negative Dromotropic Negative Inotropic Antithrombotic Bronchospasm

7. 2 Uses Diagnostic -FFR Therapeutic-SVT/Coronary vasodilator

8. 2 Ways to increase extracellular level Inhibiting adenosine kinase during ischemia because ATP depletion Inhibiting adenosine deaminase by dipyradamole

9. Within, across and out In the intracellular space, adenosine can be synthesized de novo during purine biosynthesis or accumulate as a result of ATP breakdown . Intracellular adenosine concentrations increase when there is a mismatch between ATP synthesis and use as in ischemia or hypoxia Not freely pass across the cell membrane and requires the use of nucleoside transporters to facilitate the process . Extracellular adenosine arises from active transport of intracellular stores or from breakdown of adenine nucleotides outside the cell

10. Cell surface G-receptors A1 A2 A3 A B Gi protein–bound A1 receptors reduces adenyl cyclase activity and decreases intracellular cAMP Adenosine Highest affinity for the A1 and A2a receptors Mostly neural transmittor regulation in heart and other Gs protein–bound increases adenyl cyclase activity and cAMP levels Vasodilation of most vascular beds including the coronary circulation Produces vasoconstriction in renal afferent arterioles and hepatic veins Activation of the Gi protein–bound A3 receptors reduces adenyl cyclase activity and decreases intracellular cAMP

11. Difference A1 Receptor A2-A and -B A3 Generally have an inhibitory function Negative inotropic Negative Chronotropic Negative Dromotropic Inhibition of atrioventricular (AV) node conduction and prolongation of the refractory period via inhibition of cAMP -mediated calcium influx and enhances potassium conduction A2 A Coronary a rtery vasodilator Anti-inflammatory effects A major target of caffeine A2 B receptors Mast cells and are thought to produce mast cell degranulation and b ronchial constriction A3 Peripherally located but are thought to play a role in mediating pre-conditioning

12. 2 Concerns Hypotension Heart block

13. 3-compartment model R1 R2 R3 The large epicardial vessels (0.5- to 5.0-mm diameter) make up the first compartment Small coronary arteries/pre-arterioles (100- to 500-mm diameter) Arterioles (<100-mm diameter) branch into intramyocardial capillaries to create the third compartment

14. Dynamic ceilling 60 % of resistance is provided at the arteriolar level, 25% at the capillary level 15 % in the venular compartment During hyperaemia, total resistance decreases across the coronary circulation by 70 % In the arteriolar and venular compartments, resistance decreases by 86% and 98%, respectively, resulting in minimal alteration of capillary hydrostatic pressure such that the capillaries offer the most resistance to coronary blood flow at hyperaemia Capillaries provide the ceiling for the hyperaemic response

15. Different vasodilator Adenosine Nitroglycerine Adenosine exerts its predominant vasodilatory effect on coronary microvessels <150 mm in diameter . Whether this is an endothelium-dependent process is unclear. An intact endothelium is not necessary for an adenosine response in vitro . However, work performed in humans in vivo has demonstrated that the vasodilator effect of adenosine in the forearm can be inhibited by a nitric oxide synthase inhibitor . Endothelium dependent

16. 2 Methods of Administration Intravenous Intra coronary Femoral/brachial Sustained Dose is 140-mg/kg/min infusion Greater efficacy for achieving maximal hyperemia compared with the conventional IC dosing Added advantage that FFR pullback and more complex physiological assessments can be made Its peak effect occurs <10 s Duration of effect is 20 sec Current recommendations for IC adenosine dosing are 40 mg in the right coronary artery and 60 mg in the left coronary artery, increasing the doses incrementally by 30 mg to a maximum of 150 mg . We suggest a higher bolus dose of IC adenosine (100–150 mg) to ensure an adequate hyperemic response 4. No reflow phenomenon

17. 2 studies in PPCI AMISTAD I AMISTAD II Reduced infarct size, but did not reduce the primary clinical endpoint, with in-hospital and 6-month clinical outcome being similar to those in the placebo group

18. 2 Guidelines support European Society of Cardiology American Heart Association Treatment of no-reflow using IC adenosine is recommended

19. 2 Conditionings Pre-conditioning Post-conditioning A1 and A3 receptors 10-min IV adenosine infusion (dose of 2 mg/min) administered before the PCI pre-conditioned the myocardium improve outcomes in elective PCI and CABG A2a and A3 receptor a protocol :consisted of 4 cycles of 1 min of balloon inflation followed by 1 min of balloon deflation within 1 min of reflow after coronary stent deployment Reduces CPK/CPK-MB

20. Novel Agents for Achieving Hyperaemia Cyclosporine Regadenoson The most promising pharmacological post-conditioning mimetic drug InhibitS formation of the mitochondrial permeability transition pore, a key component of lethal reperfusion injury . The mitochondrial permeability transition pore appears to form in the early stages of reperfusion in response to the calcium overload and reactive oxygen species generation that develops with reperfusion Selective adenosine a2a receptor agonist And in theory should produce hyperemic effects similar to those of adenosine without the additional side effects often seen with A1, a2b, and A3 receptor activation IV bolus FFR study

21. Arrhythmia IV adenosine in a bolus dose of 6 to 12 mg (or higher) slows AV nodal conduction and by this mechanism interrupts re-entrant pathways involving the AV node and restores sinus rhythm in most patients with SVT Typical AV nodal re-entrant tachycardia AV reciprocating tachycardia with a concealed bypass tract, and AV reciprocating tachycardia in Wolff-Parkinson-White syndrome Unmask atrial flutter/atrial fibrillation Correct diagnosis of broad complex tachycardia Terminate VT of triggered activity

22. Side effects Ubiquitous action IV>IC Flushing -36.5% Dyspnoea-35.2% Chest pain-34.6% Gastrointestinal discomfort -14% Headache-11% AV block - 7.6% Arrhythmia -0.36% Bronchospasm - 0.1%

23. Tomorrow ,You are my treating physician