Adenosine Injection - Pharmacological Aspects

Overview:

Adenosine is poorly soluble in alcohol, and further solubility can be increased by adjusting the pH. Each injection vial contains a clear solution with three milligrams (mg) of Adenosine and nine mg of Sodium chloride per milliliter, and the solution's pH level is between 4.5 and 7.5. The United States Food and Drug Administration (US FDA) approved Adenosine injection on October 30,1989.

Drug Group:

Class V antiarrhythmic agent.

Available Doses and Dosage Forms:

Adenosine is available in 3 mL (milliliters) and 10 mL single-use ampoules (each mL contains 3 mg (milligrams) of Adenosine).

For Patients:

How Adenosine Works in Myocardial Perfusion Scintigraphy?

Myocardial perfusion scintigraphy is a non-invasive imaging procedure that shows the blood flow pathway through the heart muscle. Adenosine in myocardial perfusion imaging aids in the diagnosis of coronary artery disease (CAD) and the risk assessment in patients unable to exercise. As a stress test, Adenosine works on the A1 and A2 receptors of the heart. Adenosine acts by stimulating the A2A receptor, resulting in vasodilation of blood vessels.

How Effective Is Adenosine?

Adenosine injection is very effective for coronary artery disease (CAD) diagnosis, particularly in those who cannot exercise. In such cases, it can achieve high accuracy and good image quality. It has also proven a strong safety record, with side effects that are usually short-lived. Beta blockers antagonize the effect of Adenosine on blood vessels and make the diagnostic test less effective.

What Are the Things to Inform the Doctor Before Taking Adenosine?

If anyone is being advised or prescribed to take Adenosine, they should let the doctors know if they have heart disease, any lung or breathing issues (like asthma or chronic pulmonary obstructive disease (COPD), or if they are allergic to Adenosine or other medicines, foods, dyes, or even preservatives.

How Is Adenosine Administered?

Adenosine is administered as an IV (intravenous) infusion at a rate of 140 micrograms per kilogram per minute and started six minutes before thallium injection. The procedure has been proven safe in thousands of patients who were evaluated with this method.

What Are the Side Effects of Adenosine?

• Fatal cardiac arrest, irregular heart rhythms, and heart attacks.

• Electrical signal issues in the heart lead to heart block or slowed heart rate.

• Narrowing of airways or trouble breathing.

• Low blood pressure causes symptoms like dizziness or fainting.

• Stroke risk includes both bleeding and blocked blood flow types.

• New or recurring seizures, some requiring immediate medical care.

• Allergic reactions produce symptoms like difficulty breathing, skin redness, or rash.

• Irregular heart rhythm (atrial fibrillation) can occur even in those with no prior history.

• High blood pressure significantly increases and may last for several hours.

Overdose:

Adenosine has a short half-life of less than 10 seconds, so its side effects usually go away quickly once the infusion stops. However, some side effects can be delayed or last longer. Medications like caffeine, Aminophylline, and Theophylline block Adenosine receptors, and Theophylline is sometimes used to treat ongoing side effects of Adenosine. In clinical trials, a slow intravenous dose of theophylline (50 to 125 mg) was used in about two percent of patients to reduce side effects. However, these medications should not be used in patients who experience seizures related to Adenosine.

Storage:

• Store Adenosine at room temperature between 59°F (degrees Fahrenheit) and 86°F (15°C (degrees Celsius) to 30°C).

• Do not refrigerate it, as crystals may form. If crystals appear, gently warm the vial to room temperature to dissolve them.

• The solution should be clear while using it.

• Discard any unused portion.

For Doctors:

Indication:

Adenosine is used alongside a special heart imaging test (called thallium-201 myocardial perfusion scintigraphy imaging) to check blood flow to the heart in people who cannot exercise enough for a stress test.

Dose:

Adenosine is available as a sterile, preservative-free solution in normal saline, provided in two vial sizes:

• 20 mL Single-Dose Vial: Contains 60 mg of Adenosine (three mg per mL). These are packaged individually or in boxes of ten.

• 30 mL Single-Dose Vial: Contains 90 mg of Adenosine (three mg per mL). These are also packaged individually or in boxes of ten.

Both come in flip-top glass vials designed for single use.

What Are the Pharmacological Aspects of Adenosine?

Pharmacodynamics:

Adenosine affects the heart and blood vessels in several ways:

• It slows the heart rate, electrical signals, and the strength of heart contractions, likely by activating A1 receptors.

• It causes vasodilation in the body, probably as a result of A2 receptors.

Overall, Adenosine typically causes a mild to moderate drop in blood pressure (systolic, diastolic, and mean arterial pressure), often leading to a reflex increase in heart rate. In rare instances, it can cause low blood pressure (hypotension) or a fast heart rate (tachycardia).

Mechanism of Action:

It facilitates opening up the blood vessels of the heart, thereby enhancing blood flow to the heart. Such an action is achieved by activating specific A1 and A2 Adenosine receptors on cell surfaces. Even though the mechanism is not clear, there is a presumption that the walls of blood vessels relax through:

• Inhibition of calcium influx into smooth muscle cells.

• Activates a chemical known as adenylate cyclase, which promotes muscle relaxation.

• Diminishing the activity of nerve signals that constrict blood vessels.

Inside the cells, Adenosine is readily metabolized to non-active forms (AMP (adenosine monophosphate) or inosine) that do not have an effect on blood vessel tone. For the diagnostic imaging of the heart, Adenosine enhances blood flow in healthy heart arteries but has less effect on narrowed (stenotic) arteries. This disparity leads to lower thallium-201 uptake in areas that are generally serviced by narrowed arteries compared to healthy arteries. This would make it easier to observe blocked or narrowed arteries.

Pharmacokinetics:

• Distribution: If Adenosine is administered intravenously, it quickly gets taken up by erythrocytes and endothelial cells lining blood vessels. This is due to a particular system of transport that makes Adenosine permeable in both directions, i.e., inward and outward, to cross cells freely.

• Metabolism: In the cells, Adenosine undergoes metabolism primarily through two pathways:

  • Adenosine enzyme can convert itself into Adenosine monophosphate (AMP).

  • Alternatively, it can be deaminated by Adenosine deaminase into inosine. The latter occurs, especially if the first pathway becomes saturated. Inosine can leave the cell as is or be further broken down into other substances like uric acid. AMP becomes part of the cell’s energy storage system.

• Elimination: Adenosine is cleared from the blood primarily by cellular uptake; its half-life is extremely short, less than 10 seconds. When the concentration of Adenosine surpasses normal ranges, it can be metabolized extracellularly through an ecto-enzyme called ecto-adenosine deaminase.

• Effect of Kidney or Liver Disease: Since Adenosine does not depend on kidney or liver function to act or metabolize, kidney or liver disease has no effect on its safety or efficacy.

Toxicity:

No animal studies have been conducted to check if Adenosine could cause cancer or affect fertility. In lab tests, Adenosine did not show any harmful genetic effects in standard tests (like the Ames Test and mammalian microsome assay). However, at very high concentrations over extended periods in cell cultures, Adenosine, like other similar compounds, has been shown to cause changes in chromosomes.

Clinical Studies:

In two studies involving 319 participants (including 106 healthy individuals and 213 patients with suspected or known heart disease), Adenosine and exercise stress tests were compared for heart imaging. Independent reviewers found that the images matched in 85.5 percent of cases overall and up to 93 percent when analyzing specific blood vessel areas.

Among the participants, 193 patients had recent coronary angiograms for further comparison. Adenosine and exercise testing both identified significant heart artery blockages (50 percent or more narrowing) with 64 percent sensitivity. Adenosine's specificity (correctly identifying no blockages) was 54 percent, compared to 65 percent for exercise testing. Confidence intervals for Adenosine showed sensitivity between 56 to 78 percent and specificity between 37 to 71 percent.

Additional studies using specialized heart flow measurements showed that Adenosine at a dose of 0.14 mg per kg per minute significantly increased blood flow in the heart in about 95 percent of cases within two to three minutes. Blood flow returned to normal within one to two minutes after stopping the Adenosine infusion.

What Are the Contraindications of Adenosine?

Adenosine should not be used in people who have:

• Second or third-degree heart block unless they have a working pacemaker.

• Heart rhythm problems like sick sinus syndrome or very slow heartbeats unless they have a working pacemaker.

• Lung conditions that cause airway narrowing or spasms, such as asthma.

• A known allergy to Adenosine.

Warnings and Precautions:

• Severe Heart Risks: Adenosine can cause potentially fatal heart conditions, such as cardiac arrest, arrhythmias, and a heart attack. It is contraindicated for patients in whom signs of acute myocardial infarction are present or unstable cardiovascular conditions exist. Emergency resuscitation equipment should always be on hand.

• Heart Block and Slow Heart Rate: Adenosine can slow down the heart's electrical signals, potentially causing different levels of heart block or a very slow heart rate. About six percent of patients in clinical trials experienced some form of heart block. Its use is cautioned only for patients with mild pre-existing heart block, and it should be avoided in severe blockages without a pacemaker. It is contraindicated if the heart block becomes severe or persistent.

• Breathing Problems: Adenosine can cause breathing difficulty or airway constriction in dyspnea or bronchospasm. It must be administered with caution in patients suffering from diseases of the lung, like emphysema and chronic bronchitis, but not in patients with asthma or any other disease that results in airway spasms. Discontinue use if severe breathing problems arise, and one should be well-equipped in case of emergencies.

• Low Blood Pressure: Adenosine may cause blood pressure to fall, especially in patients with certain conditions such as dehydration, heart valve problems, or narrowed arteries. Discontinue the medication if low blood pressure signs and symptoms do not go away or worsen.

• Stroke Risk: Strokes, either from bleeding or blocked blood flow, have been associated with the use of Adenosine. Its actions on blood pressure may play a role.

• Seizures: Seizures, including those that are prolonged and require hospitalization, have occurred with Adenosine therapy. Certain drugs, such as Aminophylline, enhance this effect. Patients with a history of seizure disorders should avoid taking Adenosine.

• Allergic Reactions: Symptoms may include difficulty breathing, throat tightness, skin redness, rash, or chest discomfort. Emergency treatment and resuscitation may be required if the reaction worsens.

• Irregular Heartbeat (Atrial Fibrillation): Adenosine can cause a disturbance in the heart, known as atrial fibrillation, even in those individuals with no prior history. It usually occurs shortly after the infusion and resolves spontaneously within minutes to hours.

• Hypertension: In a small percentage of patients, Adenosine may cause substantial hypertension. If not responding promptly with reversibility within minutes, hypertension can be sustained for hours.

What Are the Drug Interactions of Adenosine?

• Effects of Other Drugs on Adenosine: Medications like caffeine, Aminophylline, and Theophylline (Adenosine receptor blockers) can reduce the effects of Adenosine. The safety and effectiveness of Adenosine when used with these drugs have not been fully studied. Medications like Dipyridamole (nucleoside transport inhibitors) can increase Adenosine’s effects. The safety and effectiveness of combining these drugs also have not been fully studied. If possible, stop medications that might reduce or enhance Adenosine’s effects for at least five drug half-lives before using Adenosine.

• Effects of Adenosine on Other Drugs: Adenosine has been used with heart medications like beta-blockers, cardiac glycosides, and calcium channel blockers without clear harmful interactions. However, its effectiveness with these drugs has not been fully studied. Adenosine should be used cautiously with these heart medications because it may add to their effects on slowing heart electrical signals (SA and AV nodes).

Specific Considerations:

1. Pregnancy: Adenosine falls under category C in pregnancy. There are not enough studies done on pregnant women or animals to declare its safety. It should be prescribed during pregnancy only when it is needed and the benefits far outweigh the risks.

2. Nursing Mothers: It is not known whether Adenosine passes into breast milk. Since many drugs are excreted into breast milk and may affect nursing infants adversely, there is a potential risk for mothers. Therefore, these mothers should decide if they should either discontinue nursing or discontinue the drug according to the relative severity of either the mother's illness or the nursing infant's condition.

3. Children: The safety and efficacy of Adenosine have not been established for patients under 18 years of age.

4. Older Adults: The studies involved too few patients older than 65 years, so no conclusion could be drawn about whether they respond differently compared with other age groups. Other experiences, though, have not indicated significant differences in how older adults respond to the drug.