The Pharmacokinetic Properties, Physiological Effects and Clinical Applications of Adenosine triphosphate

Adenosine triphosphate is a purine nucleotide found in every cell of the human body. In addition to its well established role in cellular metabolism,extracellular Adenosine triphosphate and its breakdown product adenosine, exert pronounced effects in a variety of biological processes including neurotransmission, muscle contraction, cardiac function, platelet function, vasodilatation and liver glycogen metabolism. These effects are mediated by both P1 and P2 receptors. A cascade of ectonucleotidases plays a role in the effective regulation of these processes and may also have a protective function by keeping extracellular Adenosine triphosphate and adenosine levels within physiological limits. [1]

Figure1: Structure of Adenosine triphosphate

Introduction

Adenosine triphosphate is a naturally occurring nucleotide which is present in every cell. It consists of a purine base (adenine), ribose and 3 phosphate groups. Nucleotides were first recognised as important substrate molecules in metabolic interconversions, and later as the building blocks of DNA and RNA. More recently, it was found that nucleotides are also present in the extracellular fluid under physiologic circumstances. Extracellular Adenosine triphosphate is broken down by a cascade of ectoenzymes and xanthine oxidase to form uric acid, which is excreted in urine. Extracellular Adenosine triphosphate appears to be involved in the regulation of a variety of biological processes including neurotransmission, muscle contraction, cardiac function, platelet function, vasodilatation and liver glycogen metabolism. Adenosine triphosphate can be released from the cytoplasm of several cell types and interacts with specific purinergic receptors on the surface of many cells.[2]

Pharmacokinetic Properties

The average physiological level of Adenosine triphosphate within mammalian cells is 3152 ± 1698 (SD) μmol/L. The Adenosine triphosphate content in tissue cells is somewhat higher than in blood cells.In human erythrocytes Adenosine triphosphate levels of 1500 to 1900 μmol/L are detected. Research has found that after intravenous injection of Adenosine triphosphate, red blood cells rapidly uptake Adenosine triphosphate. In a study involving cancer patients, infusion of Adenosine triphosphate at a rate of 50 μg/kg/min increased whole blood Adenosine triphosphate levels by 63%; while infusion at a higher rate of 75 μg/kg/min only slightly increased whole blood Adenosine triphosphate levels (by 67%). After intraperitoneal bolus injection of adenine nucleotides in mice, an increase in erythrocyte Adenosine triphosphate levels (from 600 to 1700 μmol/L) was preceded by an increase in liver Adenosine triphosphate (from 3000 to 700 0 μmol/L). The IP mode of administration of adenine nucleotides seems to favour uptake by the liver, presumably because they enter the portal circulation. [3]

Physiological Effects

Adenosine triphosphate acts as a neurotransmitter in both the central and peripheral nervous system and can also modulate the release of other neurotransmitters. There is evidence that Adenosine triphosphate plays a role as sensory neurotransmitter and adenosine as neuromodulator when both are released from non-nociceptive, large diameter, primary afferent neurons and capsaicin-sensitive, small diameter, primary afferent nerve terminals in the dorsal horn, and that adenosine in particular inhibits pain transmission. It also seems likely that the effects of Adenosine triphosphate on pain are dependent on Adenosine triphosphate being broken down to adenosine.

Clinical Applications

Adenosine triphosphate and particularly adenosine at low doses may modulate pain. Intravenous Adenosine triphosphate in mice was found to have a dose-dependent analgesic activity on hot plate and phenylquinone-induced stretching assays. In dogs, when adenosine was used in combination with halothane, halothane requirement was reduced by 49%. Adenosine triphosphate and adenosine (150 to 300 μg/kg/min intravenously) have been used successfully during surgery for phaeochromocytoma to reduce systemic blood pressure. Adenosine triphosphate has been used to antagonise the vasoconstrictive activities of noradrenaline (norepinephrine) and/or sympathetic nerve stimulation. Low dose adenosine intravenous infusion (30 to 50 μg/kg/min) in patients undergoing bypass surgery evoked coronary vasodilatation with only minor effects on the systemic circulation, and, therefore, may possibly be useful in the prevention of early occlusion of coronary artery bypass grafts. [4]

References

[1] Hendrik, J, Agteresch, et al.Adenosine Triphosphate[J].Drugs, 1999. 58 (2): 211-232.

[2] Forrester T, Identification of adenosine triphosphate in human plasma and the concentration in the venous effluent of forearm muscles before, during and after sustained contractions. J Physiol (Lond) 1969; 204 (2): 347-64.

[3] Traut TW. Physiological concentrations of purines and pyrimidines. Mol Cell Biochem 1994; 140 (1): 1-22.

[4] Sawynok J, Sweeney MI. The role of purines in nociception. Neuroscience 1989; 32 (3): 557-569

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