Adenosine
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Transcript of Adenosine
AdenosineEndothelium independent vasodilator
Coronary hyperaemia: The life thread1. Coronary blood flow can increase up to 5 times the basal flow to
meet increased demand2. Increase in blood flow is referred to as a hyperemia3. Observed in response to ischemia and exercise4. Quantifying the hyperemic response is a critical step in
understanding the coronary circulation and is applied in most physiological assessments of myocardial blood flow
Coronary vasodilators
1. Adenosine2. Papaverine3. Sodium nitroprusside4. ATP5. Dobutamine6. Nikorandil7. Nitro-glycerine8. Regadenoson
3 Receptors
Stood the test of time
1. Coronary vasodilator for microcirculation hyperaemia FFR is really only used for intermediate stenosis (40% to 70%)
2. Popular SVT Rx
5 actions
1. Negative Chronotropic 2. Negative Dromotropic3. Negative Inotropic4. Antithrombotic5. Bronchospasm
2 Uses
1. Diagnostic -FFR2. Therapeutic-SVT/Coronary vasodilator
2 Ways to increase extracellular level 1. Inhibiting adenosine kinase during ischemia because ATP depletion2. Inhibiting adenosine deaminase by dipyradamole
Within, across and out
1. 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
2. Not freely pass across the cell membrane and requires the use of nucleoside transporters to facilitate the process.
3. Extracellular adenosine arises from active transport of intracellular stores or from breakdown of adenine nucleotides outside the cell
Cell surface G-receptors
A1 A2 A3A 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
Difference
A1 Receptor A2-A and -B A3
1. Generally have an inhibitory function
2. Negative inotropic 3. Negative Chronotropic4. Negative Dromotropic 5. Inhibition of atrioventricular
(AV) node conduction and prolongation of the refractory period via inhibition of cAMP-mediated calcium influx and enhances potassium conduction
A2A1. Coronary artery
vasodilator2. Anti-inflammatory effects3. A major target of caffeine
A2B receptors4. Mast cells and are thought
to produce mast cell degranulation and bronchial constriction
A31. Peripherally located but
are thought to play a role in mediating pre-conditioning
2 Concerns
1. Hypotension2. Heart block
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
Dynamic ceilling
1. 60% of resistance is provided at the arteriolar level,2. 25% at the capillary level3. 15% in the venular compartment4. During hyperaemia, total resistance decreases across the coronary
circulation by 70%5. 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
6. Capillaries provide the ceiling for the hyperaemic response
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
2 Methods of Administration
Intravenous Intra coronary
1. Femoral/brachial 2. Sustained 3. Dose is 140-mg/kg/min infusion 4. Greater efficacy for achieving maximal hyperemia
compared with the conventional IC dosing
5. Added advantage that FFR pullback and more complex physiological assessments can be made
1. Its peak effect occurs <10 s 2. Duration of effect is 20 sec 3. Current recommendations for ICadenosine 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
2 studies in PPCI
1. AMISTAD I 2. AMISTAD II 3. 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
2 Guidelines support
1. European Society of Cardiology 2. American Heart Association3. Treatment of no-reflow using IC adenosine is recommended
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
Novel Agents for Achieving HyperaemiaCyclosporine 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 agonistAnd 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
Arrhythmia
1. 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
2. Typical AV nodal re-entrant tachycardia3. AV reciprocating tachycardia with a concealed bypass tract, and AV
reciprocating tachycardia in Wolff-Parkinson-White syndrome4. Unmask atrial flutter/atrial fibrillation 5. Correct diagnosis of broad complex tachycardia 6. Terminate VT of triggered activity
Side effects
1. Ubiquitous action2. IV>IC3. Flushing -36.5%4. Dyspnoea-35.2%5. Chest pain-34.6%6. Gastrointestinal discomfort -14%7. Headache-11%8. AV block - 7.6%9. Arrhythmia -0.36%10. Bronchospasm - 0.1%
Tomorrow ,You are my treating physician