Neuromuscular Blocking Drugs

General Information

Neuromuscular blocking drugs (NMBDs) interfere with the action of acetylcholine at the neuromuscular junction and cause paralysis of the affected skeletal muscle.  They are used clinically as an adjunct to anesthesia to paralyze reflex muscle movements. They are also used in the ICU to facilitate mechanical ventilation and to manage patients with head trauma or tetanus.  Neuromuscular blocking drugs, by themselves, have no effect at all on consciousness or pain sensation. 

 These drugs fall into two categories: non-depolarizing blocking agents and depolarizing blocking agents. Non-depolarizing agents act by competitively blocking the binding of acetylcholine to its receptors. Depolarizing blocking agents mimic the effect of acetylcholine at the neuromuscular junction by depolarizing the plasma membrane of the muscle fiber.  This initially causes muscle contraction followed by paralysis.  

There is only one depolarizing blocking drug currently in use – succinylcholine. Of the non-depolarizing blocking agents, there are two types of drugs:  the benzylisoquiolinium drugs and the aminosteroidal drugs. Research on non- depolarizing NMBDs has been directed towards the development of drugs with rapid onset, brief duration of action and few adverse side effects.

Depolarizing Blocking Drugs

·       Succinylcholine

Succinylcholine (Suxamethonium) is the only depolarizing drug currently in use. It has a rapid onset (less than 60 seconds) and very brief duration of action which makes it useful for emergency intubation. Some serious side effects, including cardiac arrest, prolonged apnea, hyperkalemia and malignant hyperthermia have been reported.

Chemical structure: C14H30Cl2N2O4

Molecular Weight: 361.31

Dosage:  Succinylcholine is typically given as a bolus injection of 1mg/kg which is more than 3 times the ED95. Recent data suggests that reducing the dose to 0.45 mg/kg (1.5 x ED95) provides acceptable intubating conditions while minimizing some of the succinylcholine-induced side effects and complications.  Reducing the dose also allows a more rapid return of spontaneous respiration and airway reflexes.

0.45mg/kg: Onset time: 65+/-2.5 sec; duration of action: 5+/-0.1 min (n = 26)

0.60mg/kg: Onset time: 55+/-2.5 sec; duration of action: 6.4+/-0.8 min (n = 27)

1.0mg/kg: Onset time: 44.9+/=2.5 sec; duration of action: 12.5 +/-1.3 min (n = 35)

 

PMID: 21772925. Ezzat A, Fathi E, Zarour A, Singh R, Abusaeda MO, Hussien MM. The optimal succinylcholine dose for intubating emergency patients: retrospective comparative study. Libyan J Med 6: 7041 – 7047, 2011.

 

PMID: 1456536. Naquib M, Samarkandi A, Riad W, Alharby SW. Optimal dose of succinylcholine revisited. Anesthesiology 99: 1045 – 1049, 2003.

 

Pharmacokinetics:

Dosage: 1 mg/kg (n = 8; age: 44+/-7; Weight: 58+/-6 kg)

Volume of distribution: 16.4+/-14.7 ml/kg

Clearance: 40.5 +/-38.3 L/min

Half life: 16.6+/-4.8 seconds

 

PMID: 8122251. Hoshi K, Hashimoto Y, Matsukawa S. Pharmacokinetics of succinylcholine in man. Tohoku J Exp Med 170: 245 – 250, 1993.

 

Pharmacological Effects:

Most of the contraindications to use of succinylcholine relate to the potential to induce hyperkalemia. This occurs as a result of an upregulation of muscle nicotinic acetylcholine receptors (AChR) in advanced neuromuscular disorders, including spinal cord injury and muscular dystrophy. When these receptors are depolarized by succinylcholine, there is an efflux of potassium into the plasma, leading to acute hyperkalemia and subsequent cardiac arrest. Conditions which cause an increase in AChRs have the potential to cause a hyperkalemic response to succinylcholine.

 

PMID: 16394702   Martyn JA, Richtsfeld M. Succinylcholine-induced hyperkalemia in acquired pathologic states: etiologic factors and molecular mechanisms. Anesthesiology 104: 158 – 169, 2006.   

 

PMID: 15155326. Miller R. Will succinylcholine ever disappear? Anesth Analg 98: 1674 – 1675, 2004.

 

Non-Depolarizing Blocking Drugs

 

Aminosteroidal Drugs

·       Pancuronium (introduced in1972)

            Chemical structure: C35H60Br2N2O4

            Molecular Weight: 732.68

            Largely replaced by pipecuronium

            It has a slow onset of action and recovery rate and also produces vagal block tachycardia.

 

·       Vecuronium (introduced in 1984)

            C35H57BrN2O4

            Molecular Weight: 637.74

            Dosage: IV bolus of 0.08 – 0.1 mg/kg

 

·       Pipecuronium (introduced in 1991) developed from modifications in the pancuronium molecule leading to increased potency and decreased vagolytic activity.

            Chemical structure: C35H62Br2N4O4

            Molecular Weight: 762.71

            Dosage: IV Bolus of 0.05 – 0.1 mg/kg

            Pharmacokinetics

            Dose: 0.07mg/kg IV by bolus injection.  N = 10; Age: 49+/-7 years; Weight: 81.5+/-10kg

            Volume of distribution at steady state: 314+/-66 mL/kg

            Clearance: 2.5+/-0.7ml/kg/min

            Elimination half-life: 154+/-61 minutes.

 

            PMID: 131685. Ornstein E, Matteo RS, Schwartz AE, Jamdar SC, Diaz J. Pharmacokinetics and         pharmacodynamics of pipecuronium bromide (Arduan) in elderly surgical patients.

            Anesth  Analg 74: 841– 844, 1992.

 

            Dose: 0.1mg/kg IV bolus injection.  N = 8; Age: 56+/- 12 years; Weight: 64 +/- 8 kg.

            Volume of distribution at steady state: 350+/-81 mL/kg.

            Clearance: 2.96+/-1.05ml/kg/min.

            Elimination half-life: 111+/-46 minutes.

 

            PMID: 8250313. D’Honneur G, Khalil M, Dominique C, Haberer JP, Kleef UW, Duvaldestin P.         Pharmacokinetics and pharmacodynamics of pipecuronium in patients with cirrhosis.

            Anesth Analg 77: 1203 – 1206, 1993.

 

            Pipecuronium Pharmacological Effects

            No significant cardiovascular changes or histamine release have been reported with     pipecuronium.

 

·       Rocuronium (introduced in 1994)

            Chemical structure: C32H53N2O4

            Molecular Weight: 529.78

            Dosage: IV bolus 0.3mg/kg (ED95) – 0.6 mg/kg

            Onset of action: 1.5 -2 minutes. Higher doses (2 x ED95) have a faster onset of action but at the        expense of a longer duration of action.

            No clinically significant cardiovascular effects were observed after doses up to 1.2 mg/kg.

            The liver is the major site of elimination with 33% of a single dose of 1.0 mg/kg recovered from        urine within 24 hours.

           

            Pharmacokinetics:

            Dose: IV bolus 1mg/kg; N = 10; Age: 51.4 (range 30 -60 years; 3 men, 7 women); Weight: 68.8          kg (56- 75Kg).

            Volume of distribution at steady state: 0.267 L/kg

            Clearance: 3.97 ml/kg/min

            Half life: 162 +/-32 minutes

 

            PMID: 21034625. Yang L, Wang HL, Zhang LP, Bi SS, Lu W, Yang BX, Guo XY. Population           pharmacolinetics of rocuronium delivered by target-controlled infusion in adult patients. Chin        Med J (Engl). 123: 2543 – 2547, 2010.

            PMID: 1829656. Wierda JM, Kleef UW, Lambalk LM, Kloppenburg WD, Agoston S. The     pharmacodynamics and pharmacokinetics of Org 9426, a new non-depolarizing neuromuscular    blocking agent, in patients anaesthetized with nitrous oxide, halothane and fentanyl.

            Can J Anaesth 38: 430 – 435, 1991.

 

Bezylisoquinolinium  Drugs

·       D-Tubocurarine (Introduced in 1942).

            Chemical Structure: C37H42Cl2N2O6

            Molecular Weight: 681.66

            Initial dosage: 0.1 – 0.2mg/Kg

            ED95 Dose: 0.51 mg/kg

            Duration of blockade: 80 minutes.

            This was the first non-depolarizing NMBA to gain acceptance and usage in the ICU. It is now             rarely used because it induces both histamine release and autonomic ganglionic blockade.     Metabolism and elimination are affected by both renal and hepatic dysfunction.

 

            PMID: 11902255. Murray MJ, Cowen J, DeBlock H, Erstad B, Gray AW Jr., Tescher AN,      McGee WT, Prielipp RC, Susla G, Jacobi J, Nasraway SA Jr., Lumb PD. Clinical practice      guidelines for sustained neuromuscular blockade in the adult critically ill patient. Crit Care Med           30: 142 – 156, 2002.

 

·       Atracurium (introduced in 1983)

            Chemical Structure: C65H82N2O18S2

            Molecular Weight: 1243.50

            Initial dosage: 0.4 – 0.5 mg/kg

            ED95 Dose (effective dose for 95% patients): 0.25mg/kg

            Duration of blockade: 25 – 35 minutes.

            Intermediate –acting NMBA with minimal cardiovascular adverse effects. It is associated with            histamine release at higher dosages. It is inactivated in plasma by ester hydrolysis and Hofmann      elimination so that renal or hepatic dysfunction does not affect the duration of blockade. One of       the metabolites is laudanosine which can have a CNS stimulant effect.

            Atracurium has been associated with persistent neuromuscular weakness.

 

            PMID: 6285767. Katz RL, Stirt J, Murray AL, Lee C. Neuromuscular effects of atracurium in            man. Anesth Analg 61: 730 – 734, 1982.

            PMID: 7113256. Neill EA, Chapple DJ. Metabolic studies in the cat with atracurium: a           neuromuscular blocking agent designed for non-enzymatic inactivation at physiological pH.         Xenobiotica 12: 203 – 210, 1982.

 

·       Doxacurium(introduced in 1991). Not currently widely used due to its long duration of action. Largely been replaced by mivacurium.

Chemical structure: C56H78Cl2N2O16

Molecular weight: 1106.13

 

·       Mivacurium(introduced in 1992)

            One of the shortest acting NMBAs available. It consists of a mixture of three steroisomers (trans-     trans 57%; cis-trans 36% and cis-cis 6%). Rapid hydrolysis by plasma cholinesterases explains the brief duration of action.

            Chemical Structure: C58H80N2O14

            Molecular Weight: 1029.26

            Pharmacokinetics: N = 8; Age: 18 – 40 years

            Dosage: 0.15 mg/kg  (2 x ED95)

            Clearance: 45.7ml/kg/min

            Half life: 2 minutes

            Volume of distribution at steady state: 0.054L/kg

 

            PMID: 9054251. Lacroix M, Donati F, Varin F. Pharmacokinetics of mivacurium isomers and           their metabolites in healthy volunteers after intravenous bolus injection.

            Anesthesiology 86: 322 -330, 1997.   

 

·       Cisatracurium (introduced in 1995) it is an isomer of atracurium

Chemical Structure: C53H72N2O12

Molecular Weight: 929.15

Dosage: 0.1 – 0.4 mg/kg

Onset of maximum neuromuscular block:

5.2+/-0.3 minutes with a dose of 0.1mg/kg (2 x ED95)

2.7 +/- 0.1 minutes with a dose of 0.2 mg/kg (4 x ED95)

1.9 +/- 0.1 minutes with a dose of 0.4 mg/kg (8 x ED95)

Clearance: (2 x ED95) 4.7 – 5.3 ml/kg/min

Volume of distribution at steady state: Ranges from 141 +/- 34 to 190 +/- 47 ml/kg

Half- Life: 22 – 35 minutes

Laudanosine is also a metabolite of cisatracurium , but levels are 5 to 10 times lower than after atracurium use.

           

 

Reviews

PMID: 10223167. Atherton DP, Hunter JM. Clinical pharmacokinetics of the newer neuromuscular blocking drugs. Clin Pharmacokinetics 36: 169 – 189, 1999.

PMID: 16402115. Bowman WC. Neuromuscular block. Br J Pharmacol 147 Suppl 1: S277 – S286, 2006.

PMID:  11434449. Sparr HJ, Beaufort TM, Fuchs-Buder T. Newer neuromuscular blocking agents: how do they compare with established agents? Drugs 61: 919 – 942, 2001.

PMID: 11902255. Murray MJ, Cowen J, DeBlock H, Erstad B, Gray AW Jr., Tescher AN, McGee WT, Prielipp RC, Susla G, Jacobi J, Nasraway SA Jr., Lumb PD. Clinical practice guidelines for sustained neuromuscular blockade in the adult critically ill patient. Crit Care Med 30: 142 – 156, 2002.

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