Neuromuscular Blocking Agents

Neuromuscular Blocking Agents

Dr. Ahmed Haki Ismael

Neuromuscular Blockers

Competitive Antagonists of the Nicotinic Receptore.g. curare (d-tubocurarine), vecuronium, pancuronium, atracurium, etc…Depolarizing Blockerse.g. succinylcholine, decamethonium

Muscle relaxation does not ensure unconsciousness, amnesia, or analgesia Neuromuscular blocking agents are used to improve conditions for tracheal intubation, to provide immobility during surgery, and to facilitate mechanical ventilation.Depolarizing muscle relaxants act as acetylcholine (ACh) receptor agonists, whereas nondepolarizing muscle relaxants function as competitive antagonists. Depolarizing muscle relaxants are not metabolized by acetylcholinesterase, they diffuse away from the neuromuscular junction and are hydrolyzed in the plasma and liver by another enzyme, pseudocholinesterase (nonspecific cholinesterase, plasma cholinesterase, or butyrylcholinesterase). With the exception of mivacurium, nondepolarizing agents are not significantly metabolized by either acetylcholinesterase or pseudocholinesterase. Reversal of their blockade depends on redistribution, gradual metabolism, and excretion of the relaxant by the body, or administration of specific reversal agents (eg, cholinesterase inhibitors) that inhibit acetylcholinesterase enzyme activity. Compared with patients with low enzyme levels or heterozygous atypical enzyme in whom blockade duration is doubled or tripled, patients with homozygous atypical enzyme will have a very long blockade (eg, 4–6 h) following succinylcholine administration.Succinylcholine is considered contraindicated in the routine management of children and adolescents because of the risk of hyperkalemia, rhabdomyolysis, and cardiac arrest in children with undiagnosed myopathies Key Concepts


Normal muscle releases enough potassium during succinylcholine-induced depolarization to raise serum potassium by 0.5 mEq/L. Although this is usually insignificant in patients with normal baseline potassium levels, a life-threatening potassium elevation is possible in patients with burn injury, massive trauma, neurological disorders, and several other conditions Doxacurium, pancuronium, vecuronium, and pipecuronium are partially excreted by the kidneys, and their action is prolonged in patients with renal failure. Atracurium and cisatracurium undergo degradation in plasma at physiological pH and temperature by organ-independent Hofmann elimination. The resulting metabolites (a monoquaternary acrylate and laudanosine) have no intrinsic neuromuscular blocking effects Hypertension and tachycardia may occur in patients given pancuronium. These cardiovascular effects are caused by the combination of vagal blockade and catecholamine release from adrenergic nerve endings Long-term administration of vecuronium to patients in intensive care units has resulted in prolonged neuromuscular blockade (up to several days), possibly from accumulation of its active 3-hydroxy metabolite, changing drug clearance, or the development of a polyneuropathyRocuronium (0.9–1.2 mg/kg) has an onset of action that approaches succinylcholine (60–90 s), making it a suitable alternative for rapid-sequence inductions, but at the cost of a much longer duration of action.

www.freelivedoctor.com

D-tubocurarine
pancuronium
Vecuronium
Decamethonium
Succinylcholine
Depolarizing Blockers
Competitive Blockers

History of neuromuscular blocking agents

Early 1800’s – curare discovered in use by South American Indians as arrow poison1932 – West employed curare in patients with tetanus and spastic disorders 1942 – curare used for muscular relaxation in general anesthesia1949 – gallamine discovered as a substitute for curare1964 – more potent drug pancuronium synthesized

Curares - Chondrodendron e Strychnos

Strychnos toxifera

West 1932

Milestones of Neuromuscular Blockade in Anesthesia

1942 introduction of dTc in anesthesia 1949 Succinylcholine, gallamine metocurine introduced 1958 Monitoring of NMF with nerve stimulators 1968 Pancuronium 1971 introduction of TOF 1982 Vecuronium,Pipecurium,atracurium 1992 Mivacurium 1994 Rocuronium 1996 Cisatracurium 2000 Rapacurium introduced and removed

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; Depolarizing
1-1.5
6-8
Plasma cholinesterase
D-tubocurarine
Long duration; Competitive
4-6
80-120
Renal and liver
Atracurium
Intermediate duration; Competitive
2-4
30-40
Plasma cholinesterase
Mivacurium
Short duration; Competitive
2-4
12-18
Plasma cholinesterase
Pancuronium
Long duration; Competitive
4-6
4-6
Renal and liver
Rocuronium
Intermediate duration; competitive
1-2
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: decamethonium TC: tubocurarine NEO: neostigmine S: 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 reversed the blockade by 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
Intercostals
Diaphragm
Recovery in Reverse

Other Effects of Neuromuscular Blockers

Action at Autonomic Ganglia e.g. d-tubocurarine blocks, succinylcholine may stimulate newer agents have less ganglionic effects Histamine Release e.g. d-tubocurarine bronchospasm, 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 Dose of 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
www.freelivedoctor.com


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 anesthesiaOrthopedic procedures for alignment of fracturesTo facilitate intubations – use one with a short duration of actionIn electroshock treatment of psychiatric disorders