Neuromuscular Blocking Agents

Depolarizing Agent

Succinylcholine

0.5-1.5 mg/kg intubation dose. Affinity to nicotinic ACH receptors/ligand-gated Na channels, working as receptor agonist. It causes depolarization, ie, muscle fasciculations (cause of myalgia postop), usually not seen in young children and elderly patients. Diffuse away from NMJ, hydrolyzed in plasma and liver by pseudocholinesterase. Affect cholinergic receptors in addition to those at the NMJ (may see increase/decrease in BP and HR; see below)

Phase 1 Block

The end plate cannot depolarize as long as the depolarizing muscle relaxant binds to the ACH receptor.  A phase 1 block can progress into a phase 2 block due to ionic and conformational changes in the ACH receptor, which resembles a non-depolarizing muscle relaxant. Abnormal pseudocholinesterase enzyme results in prolonged block by Succinylcholine - up to 4-8 hrs. Pts need to have a Dibucaine test before hospital discharge. (Dibucaine inhibits normal pseudocholinesterase by 80% but inhibits atypical enzyme only by 20%, which is why there is a more prolonged blockade).

Upregulation of receptors causes an exaggerated response to depolarizing muscle relaxants (more receptors being depolarized)

Downregulation of receptors (myasthenia gravis) causes a resistance to depolarizing agents (less receptors available)

TOF

• Ulnar: adductor pollicis muscle
• Medial malleolus: posterior tibia nerve
• Facial nerve stimulation: orbicularis oculi

Disappearance of 4th twitch = 75% block, 3rd twitch = 80% block, 2nd twitch 90% block

Uniform twitches, no fade with double burst stimulation (DBS) or tetany (sustained stimuli 50-100 Hz lasting 5 sec)

Side Effects

Cardiovascular

Low dose

• Negative chronotropic and inotropic effects - the bradycardia most pronounced in children (prevented with .02 mg/kg atropine IV)
• Seen in adults with a second dose of succinylcholine (0.4 mg atropine IV prophylactically)

Higher dose

• Usually increases HR and contractility and elevates circulating catecholamine levels

Fasciculations

Prevent fasciculations by pretreatment with a small dose of a nondepolarizing agent

• Since this usually antagonizes a depolarizing block, a higher dose is needed.

May cause myalgia

Hyperkalemia

Raises serum K⁺ by 0.5 mEq/L - life-threatening with preexisting hyperkalemia, burn injury, massive trauma, and neurological disorders (Duchene's muscle dystrophy) due to upregulation of receptors following injury

Elevated Intragastric Pressure

Abdominal wall fasciculations increase the intragastric pressure, which is offset by the increased tone in the lower esophageal sphincter, so there is no increased risk of aspiration

Elevated Intraocular Pressure

The transient increase may compromise an injured eye

No good preventive treatment

Masseter Muscle Rigidity

A transient increase in muscle tone is evidenced by difficulty opening the mouth for DL

This may be an early sign of malignant hyperthermia

Malignant Hyperthermia

Succinylcholine is a potent trigger agent. Massive calcium release, most likely from mutated ryanodine receptors in the sarcoplasmic reticulum

Treat with 100% oxygen, dantrolene 2.5 mg/kg/IV (binds channel and inhibits Ca release), fluids, cooling, and symptomatically

Nondepolarizing Agents

Two Chemical Groups

Steroidal Compounds (rocuronium, vecuronium, pancuronium)

Vecuronium 0.05-0.1 mg/kg intubation dose. ACH receptor competitive antagonist

Rocuronium 0.6-1.2 mg/kg intubation dose. Longer onset. It can be used to prevent fasciculations by giving 10-15% of the intubation dose 5 min before succinylcholine (note the need for a higher dose of succinylcholine if used)

Pancuronium 0.08-0.12 mg/kg intubation dose. Causes HTN and tachycardia due to vagal blockade and sympathetic stimulation (ganglionic stimulation and decreased catecholamine reuptake). Caution in pts with CAD. It may cause arrhythmias due to increased AV conduction and increased catecholamine release

Benzylisoquinolines

Hoffman's elimination eliminates these drugs

Atracurium 0.3-0.5 mg/kg/IV intubation

• Releases Histamine (increases HR, decreases BP due to vasodilatation, and may cause bronchospasm)
• Avoid in asthma patients

Cisatracurium 0.1-0.15 mg/kg/IV intubation

• No histamine
• Four times more potent than atracurium

Reversal of Blockade

Dependent on redistribution, gradual metabolism by the liver (vecuronium/pancuronium) and kidney (vecuronium/pancuronium = prolonged effect in kidney failure patients) or administration of reversal agents (cholinesterase inhibitors), which increase the amount of available Ach at the NMJ.

The primary goal is to maximize nicotinic (autonomic ganglia and skeletal muscle receptors) transmission and minimize muscarinic side effects (end-organ effector cells in bronchial smooth muscle, salivary glands, and SA node)

Upregulation of receptors causes resistance to nondepolarizing relaxants

• More receptors must be blocked

Downregulation of receptors causes increased sensitivity to nondepolarizing relaxants

Maintenance relaxation is used to facilitate surgery, and it is adjusted by the use of a peripheral nerve stimulator as well as clinical signs

• Breathing, movement

Potentiated by inhalational agents

TOF

• Ulnar: adductor pollicis muscle
• Medial malleolus: posterior tibia nerve
• Facial nerve stimulation: orbicularis oculi

Disappearance of 4th twitch = 75% block, 3rd twitch = 80% block, 2nd twitch 90% block

Uniform twitches, no fade with double burst stimulation (DBS) or tetany (sustained stimuli 50-100 Hz lasting 5 sec)

TOF with non-depolarizing drugs is similar to TOF with depolarizing drugs

The difference from depolarizing drugs is a fade (indicative of a non-depolarizing block)

• Fade is more evident during sustained tetanic stimulation or double burst stimulation (DBS), which is why these are preferred to determine the adequacy of recovery
• Posttetanic potentiation is the ability of tetanic stimulation during a partial nondepolarizing block to increase the evoked response to a subsequent twitch
  • Maybe due to a transient increase in Ach mobilization

Pharmacologic Characteristics

Temperature

Hypothermia prolongs blockade due to decreased metabolism

Acid-Base balance

Respiratory acidosis potentiates the blockade and antagonizes its reversal

Electrolyte abnormalities

Hypokalemia and hypocalcemia potentiate the block

Age

Neonates have increased sensitivity to nondepolarizing agents due to the immaturity of NMJ. May need a larger dose due to higher extracellular volume and, therefore, a higher volume of distribution

Muscle groups and the onset of action

The diaphragm, jaw, larynx, and facial muscles respond to and recover from muscle relaxation sooner than the thumb if you are using the adductor pollicis as a measurement for the PNS

Laudanosine

Both atracurium and cisatracurium produce laudanosine as a breakdown product of the Hoffman elimination. Laudanosine has been associated with CNS excitation and possible precipitation of seizures

It is crucial in hepatic failure patients, as laudanosine is metabolized by the liver and excreted in urine and bile