Central α₂ Adrenergic and Benzodiazepine Agonists and Their Antagonists

Alpha₂ adrenergic and benzodiazepine agonists are among the agents used to improve the quality of chemical immobilization with opioids and cyclohexylamines. Both classes of drugs have prominent sedating and muscle relaxing properties. Alpha₂ agonists, in addition, are analgesic and markedly reduce anesthetic requirements, whereas the benzodiazepine agonists have anxiolytic, amnesic, and anticonvulsant activity. The two classes of drugs depress the central nervous system through different mechanisms. Alpha₂ agonists decrease central nervous system activity by α₂ receptor-mediated hyperpolarization of neurons in the locus coeruleus and frontal cortex, and presynaptic inhibition of norepinephrine release throughout the brain and spinal cord. Benzodiazepine agonists work indirectly by enhancing the effects of γ-aminobutyric acid (GABA) on chloride ion flux. GABA is the major inhibitory mediator in the brain. Benzodiazepines also bind to receptors in glycine-mediated inhibitory pathways in the brain and spinal cord. Cardiovascular effects of α₂ agonists include peripheral vasoconstriction and centrally mediated inhibition of catecholamine release. A transient increase in blood pressure is followed by decreases in myocardial contractility, cardiac output, heart rate, and blood pressure. Benzodiazepines cause vasodilation and a modest decrease in cardiac contractility, but sympathetic nervous system reflexes remain intact. After benzodiazepine administration, catecholamine release tends to restore cardiac output and blood pressure toward normal, whereas α₂ agonist-induced cardiovascular depression is long lasting. Specific receptor antagonists to α₂ and benzodiazepine agonists are under development. These agents can be used to provide more rapid recovery from sedation and immobilization or to treat animals receiving an overdose of the agonists. The benzodiazepine antagonist, flumazenil, is virtually without pharmacologic effect when given alone, while yohimbine and the other α₂ antagonists have intrinsic central nervous and cardiovascular activity and must be used judiciously.