Neuromuscular blocking Agents

1. NEUROMUSCULAR
BLOCKING AGENTS
Dr Shreyas Kate
Dept of Anaesthesiology & Critical Care

2. Contents
• Physiology
• History
• Succinylcholine
• Dibucaine Number
• Classification of Non Depolarizing Neuromuscular Blocking Drugs
• Pharmacokinetics
• Metabolism & Elimination

3. Physiology

6. nACHRs
• Pentameric
• Organizationally it is αεαδβ
• The subunits are organized to form a transmembrane pore, or channel
• has extracellular binding pockets for acetylcholine and other agonists or antagonist
• Are clustered on the crests of the junctional folds
• The receptor density in this area is 10,000 to 30,000/μm2
• Each of the two α subunits has an acetylcholine-binding site. These sites are located in pockets within the
receptor protein, approximately 3.0 nm above the surface membrane at the interfaces of the αH-ε and αL-δ
subunits
• The fetal nAChR contains a γ subunit instead of an adult ε subunit (low-conductance channel)

7. History
• 1942: Griffith and Johnson described d-tubocurarine (dTc) as a safe drug to provide skeletal
muscle relaxation during surgery
• 1952 : Succinylcholine, introduced by Thesleff and Foldes and associates
• 1967, Baird and Reid reported on the clinical administration of the first synthetic
aminosteroid, “Pancuronium”
• 1980s : Vecurominum (aminosteroid) / Atracurium (benzylisoquinolinium) :
• 1990s : Mivacurium (Short acting) / Rocuronium (Intermediate acting)
• By Foldes and colleagues,“…first use of…muscle relaxants…not only revolutionized the
practice of anesthesia but also started the modern era of surgery and made possible the
explosive development of cardiothoracic, neurologic, and organ transplant surgery ”

8. Succinylcholine

9. STRUCTURE-ACTIVITY RELATIONSHIPS
• The depolarizing NMBD, succinylcholine, is composed of two molecules of ach
linked through the acetate methyl groups
• This mechanism results in
• desensitization of the nAChR
• inactivation of voltage-gated Na+ channels at the neuromuscular junction
• increases in K+ permeability in the surrounding membrane
• The end results are failure of action potential generation and neuromuscular
blockade

10. PHARMACOKINETICS
• Rapid onset of effect and an ultrashort duration of action. The ED95 is 0.51 to
0.63 mg/kg
• Administration of 1 mg/kg of succinylcholine results in complete suppression of
response to neuromuscular stimulation in approximately 60 seconds
• Recovery to 90% muscle strength following administration of 1 mg/ kg
succinylcholine requires 9 to 13 min
• T1/2 : 47 seconds
• Metabolism: rapid hydrolysis by butyrylcholinesterase to succinylmonocholine
and choline.
• only 10% of the intravenously administered drug reaches the neuromuscular junction
• The initial metabolite, succinylmonocholine, is a much weaker NMBD than succinylcholine and
is metabolized much more slowly to succinic acid and choline.

11. SIDE EFFECTS
• Cardiovascular Effects:
• stimulates cholinergic autonomic receptors on both sympathetic and parasympathetic ganglia
• Low doses: both negative inotropic and chronotropic response (attenuated by prior
administration of atropine)
• large doses: positive ino & chronotropic
• Arrhythmias:
• Sinus Brady: Stimulation of cardiac muscarinic receptors (predominantly vagal tone, such as in
children who have not received atropine)
• Nodal (Junctional) Rhythms: relatively greater stimulation of muscarinic receptors in the sinus
node, thus suppressing the sinus mechanism and allowing the emergence of the atrioventricular
node as the pacemaker
• Ventricular Dysrhythmias: decreases the threshold of the ventricle to catecholamine-induced
dysrhythmias

12. SIDE EFFECTS
• Hyperkalemia:
• increases the plasma K+ levels by approx 0.5 mEq/dL
• Exaggerated hyperkalemia is seen in
• renal failure
• Uremic neuropathy
• Severe metabolic acidosis
• Hypovolumia
• intraabdominal infections for longer than 1 week
• 1 week after the injury
• Conditions that result in the proliferation of extrajunctional acetylcholine receptors
• upper or lower motor denervation
• Immobilization
• burn injuries
• neuromuscular disease

13. SIDE EFFECTS
• Increased Intraocular Pressure
• Develops within 1 minute of injection
• Peaks at 2 to 4 minutes
• subsides by 6 minutes
• Involve contraction of tonic myofibrils and/or transient dilatation of choroidal blood vessels
• Use of succinylcholine for eye operations is not contraindicated unless the anterior chamber is
open
• Precurarization
• Increased Intragastric Pressure
• more variable
• fasciculations of the abdominal skeletal muscle
• IGP >28 cm H2O is required to overcome the competence of the gastroesophageal junction.
However, when the normal oblique angle of entry of the esophagus into the stomach is altered
(pregnancy, ascites, bowel obstruction, hiatus hernia)the IGP required to cause incompetence
of the gastroesophageal junction is frequently less than 15 cm H2O

14. SIDE EFFECTS
• Myalgia:
• The incidence of muscle pain varies widely, from 0.2% to 89%
• damage produced in muscle by the unsynchronized contractions of adjacent muscle fibers just
before the onset of paralysis
• Masseter Muscle Rigidity:
• increase in masseter muscle tone of up to 500 g lasting 1 to 2 min is a normal finding in adults
• Anaphylaxis
• The incidence of anaphylactic reactions may be close to 0.06%
• When the muscle relaxant cross-links with IgE, degranulation and release of histamine,
neutrophil chemotactic factor, and platelet-activating factor occur
• The release of these mediators can induce cardiovascular collapse, bronchospasm, and skin
reaction

15. CLINICAL USES
• Rapid-sequence induction
• 1mg/kg of succinylcholine is recommended to facilitate endotracheal intubation at 60 seconds
• Prior administration of succinylcholine enhances the depth of blockade caused by
a subsequent dose of nondepolarizing NMBD
• INTERACTIONS WITH ANTICHOLINESTERASES
• The effect of succinylcholine (1 mg/kg) was prolonged from 11 to 35 minutes when it was given
5 minutes after administration of neostigmine (5 mg).

16. Dibucaine Number
• Succinylcholine-induced neuromuscular blockade can be significantly prolonged if
a patient has an abnormal genetic variant of butyrylcholinesterase
• Dibucaine inhibits normal butyrylcholinesterase to a far greater extent than the
abnormal enzyme. This observation led to the establishment of the dibucaine
number
• Although the dibucaine number indicates the genetic makeup of an individual with
respect to butyrylcholinesterase

17. NON DEPOLARIZING MUSCLE RELAXANTS

19. BENZYLISOQUINOLINE
• d-Tubocurarine
• Atracurium/Cisatracurium
• Mivacurium
• Doxacurium

20. STERIODAL
• Pancuronium
• Vecuronium
• Rocuronium
• Rapacuronium
• Pipecuronium

22. POTENCY OF NONDEPOLARIZING
NEUROMUSCULAR BLOCKING DRUGS
• Drug potency is commonly expressed by the dose-response relationship. The dose
of an NMBD required to produce an effect (e.g., 50%, 90%, or 95% depression of
baseline twitch height, commonly expressed as ED50, ED90, and ED95) defines its
potency
• Onset:
• potent NMBDs have slower onset times than less potent drugs
• Buffered diffusion causes repetitive binding and unbinding to receptors, thus keeping potent
drugs in the neighborhood of the effector sites and potentially lengthening the duration of
effect
• onset time will be dependent on blood flow to muscle

23. POTENCY OF NONDEPOLARIZING
NEUROMUSCULAR BLOCKING DRUGS
• DURATION OF ACTION:
• muscle blood flow
• Redistribution
• The terminal half-life of atracurium is around 20 minutes, whereas the elimination half-lives of both
vecuronium and rocuronium are between 60 and 120 minutes
• duration of action and recovery IS SIMILAR

25. METABOLISM AND ELIMINATION
• Steroidal Compounds
• Pancurnium: deacetylated (Liver) Renal excretion
• Vec: deacetylated (Liver) Renal excretion
• The principal metabolite of vecuronium, 3-desacetylvecuronium, is a potent NMBD (≈80% of the
potency of vecuronium)
• Roc: eliminated primarily by the liver, with a small fraction (≈10%) eliminated in the urine

26. METABOLISM AND ELIMINATION
• Benzylisoquinolinium Compounds:

27. ADVERSE EFFECTS OF NEUROMUSCULAR
BLOCKING DRUGS
• Autonomic Effects

28. ADVERSE EFFECTS OF NEUROMUSCULAR
BLOCKING DRUGS
• Histamine Release

29. ADVERSE EFFECTS OF NEUROMUSCULAR
BLOCKING DRUGS
• Hypotension
• Tachycardia
• Dysrhythmias
• Bradycardia (opioid coadministration)
• Respiratory Effects :
• M2 receptors are located presynaptically,Blockade causes bronchoconstriction.
• M3 receptors, which are located postsynaptically, Blockade causes bronchodilation.
• The affinity of the compound rapacuronium to block M2 receptors is 15 times higher than its
affinity to block M3 receptors. This explains the high incidence (>9%) of severe bronchospasm
• Allergic Reactions: 1 in 6500 administrations of NMBDs