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Adenosine
Physiology
- endogenous compound found in virtually all cell types
- nucleoside: adenine + D-ribose
- formed from AMP or S-adenosylhomocysteine. Can be formed either
intracellularly or extracellularly. Degradation requires uptake by cells as it
involves intracellular enzymes. Transport system is inhibited by dipyridamole
Receptors
- 3 types of receptors. A1 and A2 receptors are subtypes of P1 class of
receptors
- A1 or A2 agonist-receptor complex is responsible for inhibition or stimulation
of adenylate cyclase and a decrease or increase in intracellular cAMP
respectively.
- adenosine also has actions which are not mediated via cAMP
- both cAMP mediated effects and other actions appear to be mediated by G
proteins
- A1 and A2 receptors blocked by methylxanthines such as theophylline
- A3 receptor has recently been characterized. It is resistant to blockade by
methylxanthines but may be stimulated by both A1 and A2 agonists
Cardiac electrophysiological effects
- mostly mediated by A1 receptor
- depression of sinus node automaticity and AVN conduction. Associated with an
increase in PR and AV intervals but not in HV interval, suggesting a site of
action proximal to bundle of His. Mediated by:
- activation of a specific outward K current which is independent of
adenylate cyclase. Results in shortening of the atrial action potential,
hyperpolarisation of the SAN cells and depression of the amplitude, duration
and rate of rise of action potential in AVN cells.
- attenuation of effects of catecholamines by inhibiting adenylate cyclase
stimulation of the inward calcium current in atrial and ventricular myocytes.
Greater inhibition of this current occurs after previous stimulation by beta
agonists
- stimulation of presynaptic adrenergic receptors on adrenergic nerves which
decreases the amount of norepinephrine released for any given level of
sympathetic stimulation
Haemodynamic effects
- result of interplay between direct effects and indirect effects mediated
through alterations in autonomic nervous system tone
- potent vasodilator with dose-related decrease in peripheral vascular
resistance. Affects almost all vascular beds. May be a direct result of A2
receptor activation or may involve release of endothelium-derived relaxing
factor or prostaglandin. Has little effect on CVP, suggesting that it has little
effect on capacitance vessels
- decrease in peripheral vascular resistance results in increased cardiac
output. Non-hypotensive doses can cause a rise in cardiac index of 50% and an
improvement in early ventricular filling dynamics. Increase in cardiac output
may cause a rise in systolic and mean PAP despite a decrease in pulmonary
vascular resistance
- adenosine-induced decreases in BP may cause an increase in heart rate through
activation of baroreflexes. Response is less than that seen with other
vasodilators, partly as a result of direct negative chronotropic effects
- directly stimulates afferent nerves, including chemoreceptors to increase
sympathetic tone
- negative chronotropic effects in combination with potent vasodilatation may
cause profound hypotension during anaesthesia or in patients with intravascular
volume depletion
- coronary vasodilator (via A2 receptor). May play a role in coronary
autoregulation with increased adenosine concentrations resulting from increased
ATP utilization. Predominantly affects small coronary arterioles. Exogenously
administered adenosine may result in coronary steal
- in renal circulation produces A2 receptor mediated vasodilatation of
postglomerular efferent arterioles and A1 receptor-mediated constriction of
afferent arterioles. Latter results in a decrease in GFR, RBF, filtration
fraction and urine flow
- in pulmonary circulation causes vasodilatation. Can result in inhibition of
hypoxic pulmonary vasoconstriction and increased pulmonary shunt
Myocardial protection
- appears to be an endogenous protective agent during ischaemia and
reperfusion injury
- has direct actions to attenuate ischaemia, reduce infarction, and enhance
recovery of reperfused myocardium although when administered exogenously may
cause myocardial ischaemia. Difference in effect relates to site of delivery of
adenosine. In patients with a steal-prone anatomy adenosine will be delivered
predominantly to collaterals while in patients with endogenously produced
adenosine secondary to ischaemia the adenosine concentration will be highest in
the ischaemic region
Drug interactions
- dipyridamole potentiates action by inhibiting uptake
- methylxanthines are competitive antagonists and may necessitate larger doses
- can be safely administered to patients taking digoxin, quinidine, beta
blockers, calcium blockers, ACE inhibitors
Adverse effects
- occur in approx 20% but are brief (<1 min)
- include:
- facial flushing
- SOB
- chest tightness
- asystole
Contraindications
- not recommended in patients with sick sinus syndrome due to possibility of
prolonged heart block
- bronchospasm
© Charles Gomersall December 1999
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