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NEWER NEUROMUSCULAR BLOCKERS

Is the Practitioner Ready for Muscle Relaxants?

Elizabeth A. Martinez, DVM

Historically, muscle relaxants have not been used routinely in pri­vate practice for several reasons. Because the muscles of respiration are paralyzed, ventilation must be controlled by either a mechanical ventila­tor or an employee assigned to ventilate the animal until muscle strength is restored. Also, when an animal is paralyzed, it is critical that an adequate plane of anesthesia be present. This may be difficult to deter­mine, as the normal indicators to evaluate depth of anesthesia are eliminated. These indicators include purposeful movement in response to a noxious stimulus, palpebral reflex, and jaw tone. For these reasons, the use of neuromuscular blocking agents, or muscle relaxants, in small animals has been limited to teaching hospitals, speciality surgical prac­tices, and research institutions. With improved technology and a higher level of care being offered, this class of drugs may have advantages for the small animal private practitioner as well.

The development of newer muscle relaxants with rapid onset, short duration and recovery times, and minimal cardiovascular side effects as well as easy-to-use peripheral nerve stimulators has made the use of muscle relaxants more attractive for private practitioners in certain cir­cumstances. Muscle relaxants may be administered when rapid control of the airway is needed without concurrent coughing, gagging, or laryn­gospasm. They may also be indicated when muscle relaxation facilitates

From the Department of Small Animal Medicine and Surgery, College of Veterinary Medicine, Texas A&M University, College Station, Texas

VETERINARY CLINICS OF NORTH AMERICA: SMALL ANIMAL PRACTICE

VOLUME 29 • NUMBER 3 • MAY 1999 811

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mechanical ventilation of critically ill patients or fracture/luxation reduc­tions, or to ensure a motionless eye for ophthalmological procedures.

MECHANISM OF ACTION

Muscle relaxants are divided into two classes, nondepolarizing and depolarizing neuromuscular blocking drugs. Both act by interfering with the postsynaptic action of acetylcholine (ACh) at the neuromuscular junction. Nondepolarizing drugs prevent ACh from binding to its recep­tors, preventing depolarization and muscle contraction. Depolarizing drugs bind to the ACh receptor in the same way that ACh does, causing initial muscle fasciculations and persistent depolarization of the muscle fiber.

INDIVIDUAL AGENTS

Discussion of the newer muscle relaxants should begin with a summary of the currently available and commonly used drugs in order to have a basis for comparison. The goal in the development of newer drugs is to eliminate some of the unwanted side effects of the commonly used muscle relaxants such as histamine release or cardiovascular effects. Also, the development of a muscle relaxant with a short onset of action as an alternative to succinylcholine has been the focus of researchers in human medicine in recent years. Available doses of the muscle relaxants discussed in this article are given in Table 1. As is the case with all

Table 1. DOSES OF MUSCLE RELAXANTS IN DOGS AND CATS

Drug

Succinylcholine*

Atracurium* Vecuronium* Pancuronium* Miva_curium Doxacuriumt Rocuronium:j: Cisatracurium

Dose (mg/kg IV)

Dog: 0.22 Cat: 0.11

0.22 0.1 0. 044---0.11 ND 0.008 0.18 ND

IV = intravenously; ND = not determined in dogs or cats. Data from: *Plumb DC: Drug monographs. In Plumb DC (ed): Veterinary Drug Handbook. White Bear Lake,

MN, Pharm Vet Publishing, 1995, pp 61-626. tSavarese JJ, Wastila WB, Basta SJ, et a!: Pharmacology of BW A938U [abstract]. Anesthesiology

59:A274, 1987. :j:Cason B, Baker DG, Hickey RF, et a!: Cardiovascular and neuromuscular effect of three steroidal

neuromuscular blocking drugs in dogs (ORG 9616, ORG 9426, ORG 9991). Anesth Analg 70:382-388, 1990.

NEWER NEUROMUSCULAR BLOCKERS 813

anesthetic agents, the patient's response should be monitored closely, and drug doses should be administered to the desired effect.

Succinylcholine

Succinylcholine is the only depolarizing neuromuscular blocking agent used in veterinary medicine. Succinylcholine has a rapid onset and short duration of action. Termination of its effects is due to rapid hydrolysis by plasma cholinesterase.1 Because of its short duration of action, its use in human patients has been limited to facilitate intubation. Because the larynx of dogs and cats is easily visualized and does not have excessive laryngospasm, the use of succinylcholine in veterinary medicine is not routine.6

The use of succinylcholine is not without significant side effects. A transient increase in serum potassium is seen due to leakage from the interior of cells. This may reach life-threatening levels in the presence of severe burns, trauma, or neuromuscular disease.9 Succinylcholine raises intraocular, intracranial, and intragastric pressure, and its use should be avoided when these effects are undesirable. Other effects include myal­gia and cardiac arrhythmias (e.g., sinus bradycardia, ventricular arrhyth­mias).9

Certain diseases such as liver disease, malnutrition, and chronic anemia can cause decreased plasma cholinesterase levels. Also, treatment with organophosphates can inhibit plasma cholinesterase. Succinylcho­line must be used cautiously, if at all, in these patients.1

Atracurium

Atracurium is classified as a nondepolarizing muscle relaxant, with an intermediate duration of action of 20 to 35 minutes. 13 Atracurium is unique in that its metabolism is independent of hepatic or renal function. It is metabolized primarily through Hofmann elimination, with a small percentage undergoing ester hydrolysis.5 Hofmann elimination is pH­and temperature-dependent spontaneous degradation. Acidemia and hypothermia ·may prolong neuromuscular blockade from atracurium administration. Hypotension and tachycardia, resulting from histamine release, can occur following administration of higher doses of atracu­rium. Therefore, atracurium should not be administered to patients with significant cardiovascular disease.14 A metabolite of atracurium, laudanosine, has been reported to cause central nervous system stimula­tion and cardiovascular depression, but these side effects are rarely seen following administration of clinical doses. 10

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Vecuronium

Vecuronium is another intermediate-acting nondepolarizing agent with a duration of action of approximately 25 minutes.B The advantage of vecuronium over atracurium is its lack of cardiovascular or histamine­releasing effects.10 Recovery from vecuronium is dependent on hepatic metabolism. Patients with significant hepatic disease may have pro­longed neuromuscular blockade following vecuronium administration.

Pancuronium

Pancuronium is a long-acting nondepolarizing agent with a dura­tion of action of 30 to 45 minutes. 13 Following administration of pancuro­nium, tachycardia, increased arterial blood pressure, and ventricular arrhythmias can be seen due to its sympathomimetic and vagolytic properties.16 The primary route of elimination of pancuronium is via the kidneys, with the remainder undergoing hepatic metabolism.15

Mivacurium

Mivacurium is a nondepolarizing agent only recently introduced in veterinary medicine. It is unique in that its metabolism is via plasma cholinesterase. Mivacurium has a rapid onset of action and a duration of action of 15 to 20 minutes.U Histamine release can occur following administration of mivacurium. Published data on mivacurium's use in veterinary species are limited, but initial studies in dogs suggest that the optimal dose of mivacurium is less than that required in human patients?

Doxacurium

Doxacurium is the most potent nondepolarizing agent available, with minimal cardiovascular effects and an extremely long onset and duration of action.8 Although its use by the private practitioner may be limited, it may be of advantage for the researcher requiring long-term relaxation without significant cardiovascular effects. Doxacurium is elim­inated via the kidneys and should be avoided in patients with renal disease.4

Rocuronium

Rocuronium was developed as an alternative to succinylcholine for intubation of human patients. It has a rapid onset and intermediate duration of action.3 Rocuronium lacks significant cardiovascular effects

NEWER NEUROMUSCULAR BLOCKERS 815

and does not cause histamine release. Its metabolism is primarily by the liverY As a new neuromuscular blocking agent, its role is yet to be defined. Rocuronium may be advantageous if a rapid onset of action without significant cardiovascular effects is desired.

Cisatracurium

Cisatracurium is a stereoisomer of atracurium. It is approximately 10 times more potent than atracurium, undergoes Hofmann elimination, and does not exhibit histamine release.12 Cisatracurium combines the cardiovascular stability of vecuronium with the nonorgan elimination of atracurium.12 When an equipotent dose is administered, the onset of action and duration and recovery times are similar to those of atracu­rium.

MONITORING NEUROMUSCULAR BLOCKADE

Following administration of a muscle relaxant, the degree of relax­ation should be monitored to allow for proper dosing as well as to determine if and when an antagonist should be given. Residual blockade during the recovery period can lead to muscle weakness and respiratory depression. Monitoring of the neuromuscular junction allows the prac­titioner to detect and treat residual blockade appropriately.

Observation of evoked responses following supramaximal stimula­tion of a peripheral nerve is the method most commonly used to monitor the degree of muscle relaxation. A handheld peripheral nerve stimulator is used to stimulate either the peroneal or ulnar nerve, and the resultant motor response is evaluated and compared with prerelaxant strength.

Although several patterns of stimulation may be employed, the train-of-four pattern is most commonly used. This pattern consists of four supramaximal impulses delivered at a frequency of two twitches per second. The degree of muscle relaxation is evaluated by comparing the response to the last twitch to that of the first twitch. Prior to muscle relaxation, the ratio of last twitch-to-first twitch strength is approxi­mately 1.0. The twitch ratio decreases as the degree of muscle relaxation deepens. During recovery from neuromuscular blockade, a ratio of 0.7 or greater correlates with clinical signs of adequate recovery.2

ANTAGONISM OF MUSCLE RELAXANTS

Residual muscle relaxation following administration of nondepolar­izing neuromuscular blocking agents may be antagonized with the use of anticholinesterase drugs. This class of drugs includes neostigmine, pyridostigmine, and edrophonium. They act by inhibiting the enzyme, acetylcholinesterase, that is responsible for the hydrolysis of ACh. Fol-

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lowing administration of one of these drugs, ACh accumulates at the neuromuscular junction. Because muscle relaxants compete with ACh for the same receptor binding site, the increase in the number of ACh molecules relative to the number of relaxant molecules at the neuromus­cular junction restores neuromuscular transmission. Prior treatment with atropine or glycopyrrolate prevents the bradycardia that may be seen following administration of an anticholinesterase drug.

Even if the effects of a muscle relaxant were antagonized, ventilatory depression can occur if the antagonist's effects wear off before the muscle relaxant is completely eliminated. Therefore, support and monitoring of ventilation must continue into the recovery period to ensure that no residual blockade exists.

SUMMARY

Current research on the development of new neuromuscular blocking agents is directed towards producing agents that have a rapid onset of action and predictable duration of action and recovery times, with minimal hemodynamic effects. For the veterinary practitioner, these newer agents should be considered when muscle relaxation is required for certain surgical procedures. Care must be taken to monitor paralyzed patients appropriately to ensure adequate ventilation and anesthetic depth. Vigilant monitoring should exist during the recovery period for the development of muscle weakness from residual blockade and the ability to reverse the effects of neuromuscular blockade. The use of neuromuscular blocking agents in veterinary patients should continue to increase as newer drugs and better monitoring techniques are developed.

References

1. Benson GJ, Thurmon JC: Clinical pharmacology of succinylcholine. JAVMA 176:646-647, 1980

2. Brand JB, Cullen DJ, Wilson NF, et al: Spontaneous recovery from nondepolarizing neuromuscular blockade: Correlation between clinical and evoked response. Anesth Analg 56:55-58, 1977

3. Cason B, Baker DG, Hickey RF, et al: Cardiovascular and neuromuscular effect of three steroidal neuromuscular blocking drugs in dogs (ORG 9616, ORG 9426, ORG 9991). Anesth Analg 70:382-388, 1990

4. Cook RD, Freeman JA, Lai AA, et al: Pharmacokinetics and pharmacodynamics of doxacurium in normal patients and those with hepatic or renal failure. Anesth Analg 72:145-150, 1991

5. Fisher DM, Canfell PC, Fahey MR, et al: Elimination of atracurium in humans: Contri­bution of Hofmann elimination and ester hydrolysis versus organ-based elimination. Anesthesiology 65:6-12, 1986

6. Hubbell JAE: Disadvantages of neuromuscular blocking agents. Vet Clin North Am Small Anim Pract 22:351-352, 1992

7. Lucasik VM: Neuromuscular blocking drugs and the critical care patient. J Vet Emerg Crit Care 5:99-113, 1996

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8. Martinez EA, Wooldrige AA, Hartsfield SM, et al: Neuromuscular effects of doxacu­rium chloride in isoflurane-anesthetized dogs. Vet Surg 27:279-283, 1998

9. Miller RD, Savarese JJ: Pharmacology of muscle relaxants and their antagonists. In Miller RD (ed): Anesthesia, ed 2. New York, Churchill Livingstone, 1986, pp 889-944

10. Miller RD, Rupp SM, Fisher DM, et al: Clinical pharmacology of vecuronium and atracurium. Anesthesiology 61:444-453, 1984

11. Mirakhur RK: Newer neuromuscular blocking drugs: An overview of their clinical pharmacology and therapeutic use. Drugs 44:182-199, 1992

12. Nimbex (Cisatracurium Besylate) Injection Prescribing Information. Research Triangle Park, NC, Glaxo Wellcome, 1996

13. Plumb DC: Drug monographs. In Plumb DC (ed): Veterinary Drug Handbook. White Bear Lake, MN, Pharma Vet Publishing, 1995, pp 61-626

14. Scott RPF, Savarese JJ, Basta SJ, et al: Atracurium: Clinical strategies for preventing histamine release and attenuating the hemodynamic response. Br J Anaesth 57:550-553, 1985

15. Silverman DG, Mirakhur RK: Nondepolarizing relaxants of long duration. In Silverman DG (ed): Neuromuscular Block in Perioperative and Intensive Care. Philadelphia, JB Lippincott, 1994, pp 171-183

16. Stoelting RK: The hemodynamic effects of pancuronium with D-tubocurarine in anes­thetized patients. Anesthesiology 36:612-615, 1972

Address reprint requests to

Elizabeth A. Martinez, DVM Department of Small Animal Medicine and Surgery

College of Veterinary Medicine Texas A&M University

College Station, TX 77843-4474

e-mail: emartinez@cvm.tamu.edu