Experimental and clinical evaluation of neuromuscular blocking agents

Neuromuscular blocking agents can be evaluated in anesthetized cats, dogs, or rhesus monkeys using dose-response relationships to assess the degree of separation between neuromuscular blocking activity and effects on cardiovascular and autonomic systems. Histamine release can be studied in anesthetized dogs by establishing whether any induced hypotension is reduced by pretreatment with H1 and H2 receptor antagonists. In anesthetized cats, the role of the liver in metabolism is investigated after administration of the drug by the hepatic portal vein and determining whether this "first pass" effect through the liver reduces potency. The involvement of the kidneys in the elimination of the drug can be assessed by ascertaining whether or not the potency and duration of action are enhanced after bilateral renal ligation. In anesthetized man, the simultaneous measurement of the tetanic (50 Hz) and single twitch contractions of the adductor pollicis muscle of the hand has proved a valuable technique for the quantitative assessment of skeletal muscle relaxants. Furthermore, the tetanic response overcomes the relative insensitivity of the single twitch, and tetanic fade provides a measure of the effects of these drugs at presynaptic sites. Cumulative effects may be evident as a prolonged recovery after repeated dosage or after an infusion. The effectiveness of neostigmine as an antagonist should be investigated both from partial and complete block, and recovery of respiration should be compared with that of peripheral neuromuscular blockade.