Physical Address
304 North Cardinal St.
Dorchester Center, MA 02124
Adenosine and adenosine triphosphate (ATP)
General information
Adenosine and adenosine triphosphate (ATP), its phosphorylated derivative, have been used to treat acute paroxysmal supraventricular tachycardias and adenosine has also been used in the diagnosis of narrow-and broad-complex tachycardias [ ].
Several reviews of the clinical pharmacology, actions, therapeutic uses, and adverse reactions and interactions of adenosine and ATP have appeared [ ]. After intravenous administration adenosine enters cells, disappearing from the blood with a half-life of less than 10 seconds; intracellularly it is phosphorylated to cyclic AMP. Its mechanism of action as an antidysrhythmic drug is not known, but it may act by an effect at adenosine receptors on the cell membrane. Its electrophysiological effects are to prolong AV nodal conduction time by prolonging the AH interval, without an effect on the HV interval. The pharmacological and adverse effects of adenosine triphosphate are similar to those of adenosine.
Although adenosine and ATP very commonly cause adverse effects, they are generally mild and usually transient, because adenosine is rapidly eliminated from the blood (with a half-life of less than 10 seconds). Adverse effects have been reported in 81% of patients given adenosine and 94% of patients given ATP [ ]. Exercise reduces the non-cardiac adverse effects and the incidence of major dysrhythmias [ ]. Reducing the duration of adenosine infusion from 6 to 4 minutes reduced the incidence of chest discomfort and ischemic ST segment changes, but had no impact on non-cardiac effects [ ].
Several studies have reported the efficacy and safety of adenosine and ATP in the treatment of tachycardias in children [ ].
In 18 children with aortic valve disease or Kawasaki disease, adenosine stress myocardial perfusion imaging was associated with the usual adverse effects, most commonly flushing and dyspnea [ ].
Exercise reduces both non-cardiac adverse effects and dysrhythmias in patients who are given adenosine for diagnostic purposes in myocardial perfusion imaging [ ]. This has been confirmed in two studies. In the first of these, 793 patients were given an intravenous infusion of adenosine 140 micrograms/kg/minute while exercising for 6 minutes or for a similar time without exercise [ ]. The rate of hypotension and dysrhythmias was significantly less in those who exercised (14 of 507) than in those who did not exercise (16 of 286). Overall reactions were more common in women than in men (5.7% versus 1.8%). All the adverse effects were transient and no specific therapy was required. The authors attributed the difference to the increase in sympathetic tone during exercise, which would have partly counteracted the hypotension and the negative chronotropic and negative dromotropic effects of adenosine. However, there was a major difference between the two groups, in that those who did not take exercise were considered unfit for exercise, which may have been associated with an increased risk of adverse effects. Nevertheless, the authors discarded that possibility, because the frequency of adverse reactions in those who did not take exercise was similar to frequencies that have previously been reported.
In the second study 19 patients received an intravenous infusion of adenosine 140 micrograms/kg/minute for 4 minutes during exercise or for 6 minutes without exercise; the patients undertook both protocols [ ]. Again, there were fewer adverse effects in those who took exercise, but only hypotension, chest pain, and headache were significantly different; there was a reduction in the frequency of flushing, which was almost significant. In addition, adverse effects were experienced for longer and the severity was greater in those who did not take exercise.
Drug studies
Observational studies
In 44 patients with paroxysmal supraventricular tachycardia, adenosine terminated the tachycardia in 16 and revealed the type of tachycardia in 21; in three of six patients it contributed to the diagnosis of broad-complex tachycardia; latent ventricular pre-excitation was induced in two of 12 patients [ ]. Subjective complaints after adenosine were common (at least one symptom in 50 of 62 patients), but all were transient.
Studies of the use of intravenous adenosine with 201 Tl in myocardial scintigraphy continue to be published, showing adverse effects that have been previously reported. In a phase II study in 44 patients given adenosine 120 or 140 micrograms/kg/minute for 6 minutes there was chest pain or discomfort in 23 and flushing or a feeling of warmth in 12 [ ]. Adenosine reversibly lowered blood pressure and increased heart rate slightly; the fall in systolic blood pressure was more than 20 mmHg from baseline in 26% of patients who received 120 micrograms/kg/minute and in 52% of those who received 140 micrograms/kg/minute. The same authors reported similar adverse effects in a phase III study in 207 patients given 120 micrograms/kg/minute [ ] and in a clinical trial in 31 patients [ ].
Comparative studies
The perioperative antinociceptive and analgesic effects of intraoperative adenosine 50–500 micrograms/kg/minute have been compared with those of remifentanil 0.05–0.5 micrograms/kg/minute in 62 patients undergoing major surgical procedures in a randomized, double-blind study [ ]. Intraoperative inhibition of the cardiovascular responses to surgical stimulation was similar after by adenosine and remifentanil, and both maintained excellent hemodynamic stability. However, there were striking postoperative differences:
- 1.
initial pain score was significantly reduced by 60% by adenosine compared with remifentanil and it remained lower throughout the 48-hour recovery period;
- 2.
postoperative morphine requirements during the first 0.25, 2, and 48 hours were consistently lower after adenosine than after remifentanil;
- 3.
patients who received adenosine were significantly less sedated;
- 4.
postoperative end-tidal and arterial carbon dioxide pressures were significantly higher after remifentanil.
In a comparison of intracoronary adenosine 24–288 micrograms with and without nitroprusside in 53 patients with no reflow despite coronary artery reperfusion, one patient had advanced atrioventricular block, which responded to atropine, and another had bradycardia, which resolved spontaneously [ ].
In 50 patients in whom intravenous adenosine 140 micrograms/kg/minute was compared with intracoronary adenosine 60–150 micrograms, intravenous adenosine caused angina (26%), dyspnea (16%), and nausea (2%), while intracoronary adenosine caused dose-related atrioventricular block [ ].
The effects of abciximab or intracoronary adenosine distal to the occlusion on immediate angiographic results and 6-month left ventricular remodelling have been studied in 90 patients undergoing primary angioplasty with coronary stenting [ ]. Abciximab enhanced myocardial reperfusion, with a reduced incidence of 6-month left ventricular remodelling. In contrast, adenosine improved angiographic results but did not prevent left ventricular remodelling. Adverse events were not reported.
Placebo-controlled studies
In 608 patients with ST-elevation acute myocardial infarction randomized to receive infusions of saline or adenosine 10 micrograms/kg/minute for 6 hours after the start of thrombolysis, there was a trend to reduced cardiovascular mortality with adenosine after 12 months, 9% versus 12% with placebo among all patients (OR = 0.71, 95% CI = 0.4, 1.2) and 8% versus 15% among patients with anterior myocardial infarction (OR = 0.53, 95% CI = 0.23, 1.24) [ ]. There were no adverse effects of adenosine. A much larger trial would be needed to confirm the trend to a beneficial effect on mortality after myocardial infarction.
Organs and systems
Cardiovascular
The most common cardiac effects of adenosine are atrioventricular block, sinus bradycardia, and ventricular extra beats. Occasionally serious dysrhythmias occur [ ], including ventricular fibrillation [ ]. ATP can cause transient atrial fibrillation [ ]. Chest pain occurs in 30–50% of patients and dyspnea and chest discomfort in 35–55%. Chest pain can occur in patients with and without coronary artery disease, and the symptoms are not always typical of cardiac pain.
Myocardial ischemia
Adenosine can cause cardiac ischemia by activating adenosine A1 receptors in the heart. However, in a double-blind, placebo-controlled, crossover study in eight healthy volunteers, adenosine 100 μg/kg/minute did not alter ischemic pain in an exercising arm [ ]. Otherwise, the usual adverse effects were noted, including facial flushing and mild chest tightness.
ST segment depression can occur during adenosine myocardial perfusion imaging and is an independent predictor of subsequent cardiac events and worse outcome, particularly in association with ischemic defects. In a retrospective analysis of 3231 patients undergoing adenosine myocardial perfusion imaging, 228 (7%) had ischemic electrocardiographic changes during adenosine infusion [ ]. Of these, 66 (29%, 2% of all patients) had normal imaging. An age- and sex-matched group of 200 patients with normal imaging without electrocardiographic changes served as controls. During a mean follow-up of 29 months, those who had had electrocardiographic changes during imaging had significantly more adverse cardiac events than those in the control group (non-fatal myocardial infarction, 7.6% versus 0.5%; subsequent revascularization, 14% versus 2.5%). Although cardiac death alone did not differ between the two groups (3.0% versus 1.0%), cumulative survival free from cardiac death and non-fatal myocardial infarction was worse in patients with ST segment depression during adenosine infusion and normal imaging (11% versus 1.5%). The authors concluded that patients with normal myocardial perfusion images in whom ST segment depression occurs during adenosine administration are at higher risk of future cardiac events than similar patients without electrocardiographic evidence of ischemia.
In 75 patients with aortic stenosis, intravenous adenosine caused the usual adverse effects (flushing, chest pain, dyspnea, dizziness, headache, and nausea) in 8–41% of patients, second-degree heart block in seven, and third-degree heart block in two; there was transient ST segment depression greater than 1 mm in six patients [ ].
Despite this, acute myocardial infarction after adenosine is rare, but has been reported in a 71-year-old man who was given an intravenous infusion of adenosine 140 micrograms/kg/minute for 3 minutes [ ]. The authors suggested that coronary vasodilatation had led to reduced perfusion pressure in collaterals, with a further contribution from reduced flow secondary to aortic stenosis.
You're Reading a Preview
Become a Clinical Tree membership for Full access and enjoy Unlimited articles
If you are a member. Log in here