Clonidine

Abstract: Since the first report of clonidine, an α2-adrenoceptor agonist, the indications for this class of drugs have continued to expand. In December 1999, dexmedetomidine was approved as the most recent agent in this group and was introduced into clinical practice as a short-term sedative (<24 hours). α2-Adrenoceptor agonists have several beneficial actions during the perioperative period. They decrease sympathetic tone, with attenuation of the neuroendocrine and hemodynamic responses to anesthesia and surgery; reduce anesthetic and opioid requirements; and cause sedation and analgesia. They allow psychomotoric function to be preserved while letting the patient rest comfortably. With this combination of effects, α2-adrenoceptor agonists may offer benefits in the prophylaxis and adjuvant treatment of perioperative myocardial ischemia. Furthermore, their role in pain management and regional anesthesia is expanding. Side effects consist of mild to moderate cardiovascular depression, with slight decreases in blood pressure and heart rate. The development of new, more selective α2-adrenoceptor agonists with improved side effect profiles may provide a new concept for the administration of perioperative anesthesia and analgesia. This review aims to give background information to improve understanding of the properties and applications of the novel α2-adrenoceptor agonist, dexmedetomidine.

Abstract: NORADRENERGIC neurones of the locus coeruleus (LC; A6 of ref. 1) are inhibited by the systemic or local administration of adrenergic agonists2–5, opiates6,7 and enkephalins8,9. The adrenergic receptors of the LC, which are of the presynaptic or α2 type5, seem to mediate inhibitory responses to recurrent LC collaterals10 and adrenaline inputs from the lower brain stem4,11. In addition to adrenergic receptors, there are opiate receptors located in the LC12,13 which presumably mediate the actions of endogenous opiate-like substances (enkephalins and β-endorphin) located in nerve terminals within the LC14–16. Recently, clonidine, which is the most powerful of the α2 agonists known to inhibit the firing of LC neurones3,5, has been reported to suppress the symptoms of opiate withdrawal in humans17. On this basis, the latter authors suggested that the opiate-withdrawal syndrome may be due in part to increased noradrenergic neuronal activity in areas such as the LC which are regulated by both α2 adrenoceptors and opiate receptors. In this connection, it is interesting that the drug piperoxane, which blocks α2 adrenoceptors and accelerates the firing of LC neurones4,5 produces many of the symptoms (such as anxiety and hypertension) seen in opiate withdrawal18. In the present study, single-cell recording and microiontophoretic techniques were used to establish the development of tolerance of LC cells to the depressant effects of morphine, naloxone-induced withdrawal activations of LC neuronal firing in morphine-dependent animals, and the ability of clonidine to suppress the withdrawal of LC neurones through a non-opiate receptor.

Abstract: Clonidine has proved to be a clinically useful adjunct in clinical anaesthetic practice as well as in chronic pain therapy because it has both anaesthetic and analgesic-sparing activity. The more selective alpha-2 adrenoceptor agonists, dexmedetomidine and mivazerol, may also have a role in providing haemodynamic stability in patients who are at risk of peri-operative ischaemia. The side-effects of hypotension and bradycardia have limited the routine use of alpha-2 adrenoceptor agonists. Investigations into the molecular pharmacology of alpha-2 adrenoceptors have elucidated their role in the control of wakefulness, blood pressure and antinociception. We discuss the pharmacology of alpha-2 adrenoceptors and their therapeutic role in this review. The alpha-2 adrenoceptor agonists are agonists at imidazoline receptors which are involved in central blood pressure control. Selective imidazoline agonists are now available for clinical use as antihypertensive agents and their pharmacology is discussed.