Neuromuscular Blockers

• Competitive Antagonists of the Nicotinic Receptor

e.g. curare (d-tubocurarine), vecuronium, pancuronium, atracurium, etc…

• Depolarizing Blockers

e.g. succinylcholine, decamethonium

D-tubocurarine pancuronium

Vecuronium

Decamethonium

SuccinylcholineDepolarizing

Blockers

CompetitiveBlockers

Neuromuscular blockers differ from each other in:

• Mechanism of action

• Duration of action

• Speed of onset and offset of action

• Selectivity of action and safety margin

• Adverse effects

Agent Pharmacological

Properties

Onset time (min)

Duration

(min)

Elimination

Succinylcholine Ultrashort acting;

Depolarizing1-1.5 6-8

Plasma cholinesterase

D-tubocurarine Long duration;

Competitive4-6 80-120

Renal and liver

Atracurium Intermediate duration;

Competitive2-4 30-40

Plasma cholinesterase

Mivacurium Short duration;

Competitive2-4 12-18

Plasma cholinesterase

Pancuronium Long duration;

Competitive4-6 4-6

Renal and liver

Rocuronium Intermediate duration;

competitive1-2 1-2

Renal and liver

Classification of Blockers

Muscle AP

Nerve AP

Left Leg Muscle Stimulation

Right Leg Nerve Stimulation

Right Leg Muscle Stimulation

Site of Action of d-Tubocurarine

G: gallamine; TC: tubocurarine; NEO: neostigmine; S: succinylcholine.

Non-depolarizing Block

Depolarizing Block

C10: decamethoniumTC: tubocurarineNEO: neostigmineS: succinylcholine

Competitive Depolarizing

Effect of previous d-tubocurarine

Additive Antagonistic

Effect of previous decamethonium

None/antagonistic May be additive

Efect of cholinesterase inhibitors

Reverse No antagonism

Effect on motor end plate

Elevated threshold to Ach; no depolarization

Partial, persisting depolarization

Initial excitatory effect None Transient fasciculations

Effect of KCl or tetatnus on block

Transient reversal

No antagonism

Comparison of Competitive and Depolarizing Blocking Agents

Dual Block by Depolarizing Agents

C10: decamethonium; NEO: neostigmine; TC: tubocurarine

NEO reversedthe blockadeby C10.

Depolarizing Blocker

Competitive Blockade

Competitive Blocker

Noncompetitive Blockade

(desensitization)(electrogenic Na pump)

(direct channel block)

Changing Nature of Neuromuscular Blockade

Sequence of Paralysis

Fingers, orbit (small muscles)

limbs Trunk neck

IntercostalsDiaphragm

Recovery in Reverse

Other Effects of Neuromuscular Blockers

• Action at Autonomic Ganglia e.g. d-tubocurarine blocks, succinylcholine may stimulatenewer agents have less ganglionic effects

• Histamine Release e.g. d-tubocurarinebronchospasm, bronchial and salivary secretions

Adverse Effects/Toxicity• Hypotension• Decreased tone and motility in GI tract• Depolarizing agents can cause increased K

efflux in patients with burns, trauma, or denervation and lead to hyperkalemia

• Prolonged apnea (many reasons, check for pseudochlinesterase genetic polymorphism)

• Malignant hyperthermia (succinylcholine + halothane especially)

• Sinus bradycardia/junctional rhythm (with succinylcholine)

Systolic BP Systolic BP

% Change in Systolic BP with d-Tubocurarine as a Function of Dose and Depth of Anesthesia

Increasing Doseof d-tubocurarine

Increasing Depth(% Halothane)

0.25%

0.5%

0.75%

6 mg/m2

12 mg/m2

18 mg/m2

Influence of Type of Anesthetic on Enhancement of Neuromuscular Blockade By d-Tubocurarine

HR CO

SVR MAP

Hemodynamic Effects of d-Tubocurarine and Pancuronium

Drug Interactions

• Cholinesterase Inhibitors (antagonize competitive and enhance depolarizing)

• Inhalational Anesthetics (synergistic)

• Aminoglycoside Antibiotics (synergistic)

• Calcium Channel Blockers (synergistic)

Therapeutic Uses

• Adjuvant in surgical anesthesia

• Orthopedic procedures for alignment of fractures

• To facilitate intubations – use one with a short duration of action

• In electroshock treatment of psychiatric disorders