Consider Perioperative Clonidine Administration—it Has Anxiolytic, Antiemetic, and Analgesic Properties
Bryan J. Fritz MD
Shashank Saxena MD
Clonidine, originally introduced clinically as a nasal decongestant and subsequently used as a centrally acting antihypertensive, has become increasingly utilized for its anesthetic properties. The sedative effects of α2-agonists have been known since their introduction. In fact, a volunteer once slept for an entire day following a dose of intranasal clonidine. Human and animal studies performed in the late 1960s demonstrated a profound reduction in minimum alveolar concentration (MAC) when inhalation agents were administered concurrently with α2-receptor agonists such as clonidine. α-Receptor agonists have been utilized in veterinary medicine for many years as a regional anesthetic, but only relatively recently have they been employed in human patients. Tamsen and Gordh injected a parenteral preparation of clonidine epidurally into two patients in 1984, after they first established its safety in animals. Since that time a large body of research has explored both the safety and the clinical benefits of clonidine as an analgesic; however, it is only approved by the U.S. Food and Drug Administration (FDA) to treat hypertension and in the treatment of cancer pain. Though it is more popular in Europe, clonidine is used off-label in the United States for many other benefits.
CHEMICAL PROPERTIES/PHARMACOLOGY
Clonidine, an imidazoline, is a partial α2-aerometric receptor agonist that acts primarily presynaptically and inhibits norepinephrine release in the nucleus tractus solitarii of the medulla oblongata. It is not highly selective at α-receptors, as it has a selectivity ratio of approximately 200:1 for α2– to α1-receptors, respectively. Furthermore, clonidine is able to interact with nonadrenergic imidazoline receptors found in the brain, kidney, and pancreas. α2-Adrenergic receptors function through G-protein mechanisms. Four subtypes exist, and all activate well-defined intracellular cascades. Clonidine was first thought to exhibit its effects primarily through presynaptic receptors in the medulla, though it is now known to act both directly in spinal preganglionic sympathetic neurons as well as in the dorsal horn by pre- and postsynaptic mechanisms.
PHYSIOLOGIC EFFECTS
The primary affect of clonidine is sympatholytic, but—possibly because it binds with many different receptors—the drug has various actions beyond antihypertensive properties, such as sedation, anxiolysis, analgesia, and as an adjunct with other anesthetics. Clonidine causes a decrease in central sympathetic outflow, thereby lowering arterial pressure. At low doses, clonidine has an anxiolytic effect on the central nervous system (CNS), though at higher doses it can be anxiogenic and cause hypertension, most likely as a result of α1-activity. Little effect is exerted on the respiratory system, save a small reduction in minute ventilation. α2-Receptors of β-cells in the pancreas are stimulated and cause a temporary inhibition of insulin release. This has not been proven to be problematic in a clinical setting. Clonidine has the added benefit for anesthesia of an antisialagogue effect.
DOSING/DURATION OF ACTION
The high lipid solubility of clonidine allows rapid and complete absorption after oral administration. Less than 50% is metabolized hepatically to inactive metabolites, with the remaining drug excreted unchanged by the kidneys. Orally, the peak plasma level is reached in 1 to 1.5 hours. It readily crosses the blood-brain barrier with an elimination half-life of 30 minutes after epidural injection of 150 mcg. In general, hemodynamic effects peak at around 1 to 2 hours and last approximately 6 to 8 hours. Sedation occurs in a dose-dependent fashion within 20 minutes regardless of the route of administration. These effects can last 4 to 6 hours. Dosing information on clonidine is shown in Table 51.1.
ANTIHYPERTENSIVE EFFECTS
Hypertensive patients usually respond to clonidine with a more profound drop in blood pressure than do normotensive patients. Though clonidine reduces heart rate, it seems to have little effect on the baroreceptor reflex, thus accompanying orthostatic hypotension and profound bradycardia are produced less frequently than with other antihypertensive drugs. Researchers have shown an attenuation of the stress response to direct laryngoscopy when a minimum dose of 4 mcg/kg clonidine is administered intravenously (IV) preoperatively. Further studies have shown a possible benefit in reducing perioperative cardiac ischemia, though conflicting reports exist. Rapid discontinuation of clonidine can precipitate a hypertensive crisis, so clonidine should be continued throughout the perioperative period.
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