ALPHA₂-AGONISTS, SEDATIVES OR ANALGESICS?

Riku Aantaa, MD, PhD

Department of Anesthesiology and Intensive Care, University of Turku, Finland

Until recently, clonidine has been the sole alpha₂-agonist available for human use. Even though clonidine has regulatory approval only for treatment of hypertension, anaesthesiologists have used it as an anaesthetic adjunct to facilitate the management of their patients. Clonidine has been employed to provide increased perioperative cardiovascular and sympathoadrenal stability as well as sedation and analgesia (1). In 1999, dexmedetomidine, a novel selective and specific alpha₂-agonist, was granted marketing authorisation in the USA for postoperative sedation of intensive care patients (2, 3).

SEDATION

The molecular pharmacology underlying the mechanism of action of alpha₂-agonists is very well established (4). The sedative action of the alpha₂-agonists has been pinpointed to locus coeruleus (5), the predominant noradrenergic nucleus in the brain stem. More specifically, the mechanism of the sedative action of alpha₂-agonists has been attributed to changes in transmembrane ion conductance and hyperpolarization of excitable neural cells (4). This distinct mechanism of action from general anaesthetics or e.g. benzodiazepines may prove particularly useful in the clinical setting. Indeed, the feasibility of dexmedetomidine in the treatment of postoperative patients requiring mechanical ventilation in the ICU has recently been assessed (3). These patients were successfully sedated and calm but still remained rousable while being connected to the ventilator. In addition, the patients did not experience respiratory depression and when weaned from the ventilator, the dosing of dexmedetomidine used for sedation did not need to be altered (3). Increased sympathoadrenal stability adds to the attractivity of alpha₂-agonists as it contributes to decreased oxygen consumption and increased hemodynamic stability (6). The alpha₂-agonists have also a significant hypnotic interaction e.g. with volatile anaesthetics (7).

ANALGESIA

Whereas the mechanism and site of action of the sedative effect of the alpha₂-agonists can be pinpointed to hyperpolarization of excitable cells in the locus coeruleus, the mechanism of action of the analgesic effect of these compounds is a more complex issue (8). The alpha₂-agonists can obviously induce analgesia by acting at three different sites: in brain and brain stem, spinal cord and in peripheral tissues. Alpha₂-adrenergic and opioidergic systems have common effector mechanisms in the locus coeruleus, probably through a common transduction mechanism, representing a supraspinal site of action. In the spinal cord, the analgesic action of alpha₂-agonists is likely related to activation of the descending medullospinal noradrenergic pathways or to the reduction of spinal sympathetic outflow at presynaptic ganglionic sites. There is also significant interaction between opioids and alpha₂-agonists at the spinal cord level (9).

Both currently available alpha2-agonists clonidine and dexmedetomidine induce significant sedation when administered intramuscularly, intravenously or perorally and the clinical analgesic effectiveness of these compounds in the treatment of pain via these routes of administration is modest (1, 9). Whether more selective or water soluble compounds will provide increased analgesic efficacy with lesser adverse effects (sedation, hypotension, bradycardia) remains to be seen (10).

Epidural administration of clonidine has been widely investigated and, indeed, epidural clonidine has been granted marketing authorization in the USA for treatment of intractable cancer pain in opioid tolerant patients as an “orphan drug” status (11). Alternative routes of administration such as intrathecal administration are presently being investigated for utilization of old and new alpha₂-agonists in analgesia (10, 12).

CONCLUSION

The pharmacological profile of alpha₂-agonists shows many beneficial facets that can be exploited by the anesthesiologists. These include both sedation and analgesia. Whether the introduction of dexmedetomidine will prove feasible in sedation of ICU patients will soon be seen. Pharmaceutical development of epidurally and intrathecally administered old or new alpha₂-agonists may result in better analgesic efficacy with less adverse effects in treatment of various modes of pain.

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