Hemodynamic effects of muscle relaxants The hemodynamic effects of neuromuscular blocking drugs (muscle relaxants) may be attrib- uted to two basic mechanisms: (1) histamine release; and (2) acetylcholinelike effects that may Anis Baraka, M.D. be central, neuromuscular, or autonomic. Beirut, Lebanon Histamine release In 1939, Alam et al1 demonstrated for the first time that intraarterial injection of ¿/-tubocurarin^ in dogs resulted in release of histamine. Consider- able range of organic bases can directly mobilize histamine from its bound state in the mast cells. All muscle relaxants may stimulate histamine release. The most important relaxant in this con- nection is ¿-tubocurarine.3 This direct histamine- releasing effect can be clinically important in atopic patients. In contrast with this direct effect, the histamine release that follows antigen-antibody re- action is not limited to ¿/-tubocurarine, and has been reported with other relaxants. Acetylcholinelike effects Neuromuscular blocking agents are structurally similar to acetylcholine. They are positively charged quaternary ammonium compounds, which mimic or compete with acetylcholine at the central, neuromuscular, and autonomic cholinoceptive sites. Central sites. Muscle relaxants are ionized hy- 16 Downloaded from www.ccjm.org on October 2, 2021. For personal use only. All other uses require permission. Spring 1981 Hemodynamic effects of muscle relaxants 17 drophylic molecules that do not cross mitter at the neuromuscular junction, readily the blood-brain barrier. How- at the ganglia of both sympathetic and ever, Piess and Manning4 found that parasympathetic systems (nicotinic), moderate doses of curare have a central and at the muscarinic postsynaptic re- action on the mechanism controlling ceptors. In analogy with the different cardiovascular function. Also, Forbes et adrenergic receptors, it appears that nic- al5 showed that pancuronium reduces otinic and muscarinic receptors vary ac- halothane requirements in man. These cording to the target organs. Nicotinic effects can be explained by considering receptors at the neuromuscular junction the blood-brain barrier as a relative and may be different from those present at not an absolute barrier, which can allow the ganglia, and muscarinic receptors of the passage of relaxants. Following in- the heart may be different from musca- travenous injection, the intrathecal con- rinic receptors present elsewhere. centration of rf-tubocurarine is about Muscle relaxants either mimic (ago- 6 1/1000 the plasma concentration. Both nists) or block the effect (antagonists) of nicotinic and muscarinic cholinergic acetylcholine not only at the neuromus- pathways exist in the central nervous cular junction, but also on these auto- system, and may be inhibited by relax- nomic cholinoceptive sites. ants.7"10 Neuromuscular effects. The hemo- Agonists dynamic effects of muscle relaxants may Succinylcholine, consisting of two also be secondary to the neuromuscular acetylcholine molecules linked together, effects. The loss of muscle tone and pe- appears to display all stimulating effects ripheral pooling of blood, together with of the chemical transmitter on both the the initiation of intermittent positive nicotinic and muscarinic cholinergic re- respiration, can greatly impede venous ceptors.3 The net effect is a balance of return and lower cardiac output. That the two actions. After the first dose of is why relaxants that lack histamine succinylcholine, the nicotinic effect usu- release or autonomic side effects, such as ally predominates and results in hyper- metocurine and alcuronium, may lower tension, tachycardia, and arrhythmia. the blood pressure.11 However, after repeated doses and In contrast, the initial muscle fascic- sometimes after the first dose, the mus- ulation associated with depolarizing re- carinic effect predominates and mani- 19 24 laxants such as succinylcholine can aug- fests itself as bradycardia. " Bradycar- ment venous return. Also, the supersen- dia can even be observed in isolated sitivity response of denervated muscles, hearts denoting a direct muscarinic ef- extensive burns, massive trauma, and fect of succinylcholine on the pace- 25 severe sepsis to succinylcholine can in- maker. It can be prevented by prior duce massive hyperkalemia and trigger administration of an anticholinergic serious cardiac arrhythmias.12"18 drug or a pretreatment dose of nonde- Autonomic side effects. Neuromus- polarizing relaxant. cular blocking drugs can be classified according to their effect on autonomic Antagonists transmission. A clear understanding of Nondepolarizing relaxants can have autonomic transmission is the basis of different autonomic effects26: (1) No or such classification. minimal autonomic effects, e.g., dime- Acetylcholine is the chemical trans- methyl tubocurarine (metocurine) and Downloaded from www.ccjm.org on October 2, 2021. For personal use only. All other uses require permission. 18 Cleveland Clinic Quarterly Vol. 48, No. 1 diallylnortoxiferine (alcuronium). (2) manent quaternary nitrogen, whereas Nicotinic blockers, e.g., rf-tubocurarine. the other nitrogen is a tertiary amine (3) Muscarinic blockers, e.g., gallamine, with a pKa 8.1. ¿/-Tubocurarine can pancuronium. Org NC45, a homologue release histamine and block ganglionic of pancuronium was found to have nicotinic transmission of both the vagus fewer autonomic effects than that of and sympathetic pathways within the pancuronium.27 neuromuscular-blocking dose range. The dose-ratio of autonomic to neu- Both the ganglion-blocking and the his- romuscular block has been termed the tamine-releasing properties of the drug "autonomic margin of safety,"28"30 and may be attributed to the presence of a is equal to: tertiary amine. Muscarinic blockers, e.g., pancuronium ED 50 for vagal and sympathetic and gallamine. The two drugs do not inhibition release histamine or block ganglionic ED 95 for neuromuscular blockade transmission. However, both block the Neuromuscular blocking drugs can be vagal muscarinic receptors in the dose classified according to their "autonomic range required for neuromuscular block. margin of safety" into two categories: The vagolytic properties of gallamine overlie the neuromuscular blocking ac- 1. High autonomic margin of safety tion,26 and is dose-related32; that of pan- The drug will show a wide separation curonium is only significant at the up- of neuromuscular block from its auto- per end of the neuromuscular dose-re- 26 nomic side effects, e.g., dimethyl tubo- sponse curve. The potent vagolytic ef- curarine and diallylnortoxiferine. fect of pancuronium and gallamine may Dimethyl tubocurarine (metocurine) be related to their structure. Pancuron- is a bis-quaternary ammonium molecule ium is the nondepolarizing relaxant having no ganglionic blocking or hista- most closely related structurally to ace- mine-releasing properties. Thus, it has tylcholine, whereas the vagolytic prop- a high autonomic safety margin. The erty of gallamine is due to the presence drug is produced as a result of methyl- of three positively charged nitrogen at- 30 ation of the parent relaxant </-tubocu- oms. rarine at the tertiary amine and at the The antivagal effects of both galla- hydroxyl groups. mine and pancuronium are limited to Diallylnortoxiferine (alcuronium) is the cardiac muscarinic receptors. Such also a bis-quaternary ammonium com- selective vagolytic effect on the heart pound, which does not block ganglionic denotes that the muscarinic receptors of transmission or release histamine. Its the heart, in analogy with the cardiac neuromuscular block is only associated beta-adrenergic receptors, may be dif- with mild vagal blockade. ferent from muscarinic receptors present elsewhere.33 2. Low autonomic margin of safety In addition to the classic receptors The drug will have autonomic side that mediate the autonomic responses, effects in doses required to achieve neu- specific receptors are present presynap- romuscular block. tically that regulate the release of the Nicotinic blockers, e.g., d-tubocurarine. transmitter. At the autonomic ganglia, 31 Everett et al reported that the ¿/-tubo- transmission is modulated by a cholin- curarine molecule contains only one per- ergic muscarinic monosynaptic excit- Downloaded from www.ccjm.org on October 2, 2021. For personal use only. All other uses require permission. Spring 1981 Hemodynamic effects of muscle relaxants 19 atory pathway and a multisynaptic in- muscarinic blockers such as gallamine hibitory pathway. The latter contains and pancuronium will increase myocar- an interneuron possessing a muscarinic dial contractility and arteriovenous con- receptor, which upon stimulation causes duction,42 and induce tachycardia and a release of inhibitory neurohumor, pos- hypertension. sibly dopamine.34 At the sympathetic The hemodynamic effect of muscle nerve terminals, presynaptic alpha ad- relaxants, and the interaction with the renergic receptors (alpha 2) mediate a anesthetic used, drug therapy, and the negative feedback mechanism that condition of the patient, are factors that leads to inhibition of catecholamine determine the choice of the relaxant. release probably by restricting the cal- For example, neuromuscular blocking cium available for the excitation-secre- drugs having a nicotinic blocking effect, tion coupling. In contrast, presynaptic such as rf-tubocurarine, may be the re- beta-adrenoreceptors (B3) mediate a laxants of choice in hypertensive pa- positive feed-back mechanism leading tients or