Pharmacology 4th semester

1. NEUROMUSCULAR BLOCKING AGENTS AND SKELETAL MUSCLE RELAXANT (PERIPHERAL)
SATYAJIT GHOSH
B. PHARM 4TH
SEMESTER

2.  Introduction: -
i. Skeletal muscle relaxants are drugs that act peripherally at neuromuscular junction/muscle fibre itself or centrally in the cerebrospinal axis to cause
paralysis or reduce muscle tone.
ii. The neuromuscular blocking agents are used primarily in conjunction with general anaesthetics to provide muscle relaxation for surgery, while centrally
acting muscle relaxants are used mainly for painful muscle spasms and spastic neurological conditions.
 Classification of peripherally acting muscle relaxant: -
Peipherally acting skeletal muscle relaxants
Neuromuscular blocking agents
Nondepolarising Blockers
(Competitive)
Long acting
δ-Tubocurarine
Pancuronium
Doxacurium
Pipecuronium
Intermediate acting
Vecuronium
Atracurium
Cisatracurium
Rocuronium
Rapacuronium
Short acting
Mivacurium
Ultrashort acting
Gantacurium
Depolarising blockers
Succinyl choline
(Suxamethonium)
Decamethonium
Directly acting agents
Dantrolene sodium
Quinine

3.  Neuromuscular blocking agents: -
 Pharmacokinetics: -
All of the neuromuscular blocking drugs are highly polar compounds and inactive orally; they must be administered parenterally.
A- Nondepolarizing Relaxant Drugs (Competitive): -
i. The nondepolarizing neuromuscular blocking drug have rapid initial distribution phase followed by a slower elimination phase.
ii. Neuromuscular blocking drugs are highly ionized, do not readily cross cell membranes, and are not strongly bound in peripheral tissues. Therefore,
their volume of distribution (80–140 mL/kg) is only slightly larger than the blood volume.
iii. The duration of neuromuscular blockade produced by nondepolarizing relaxants is strongly correlated with the elimination half-life.
iv. Drugs that are excreted by the kidney typically have longer half-lives, leading to longer durations of action (>35 minutes). Drugs eliminated by the
liver tend to have shorter half-lives and durations of action.
v. All steroidal muscle relaxants are metabolized to their 3-hydroxy,17-hydroxy, or 3,17-dihydroxy products in the liver. The 3-hydroxy metabolites
are usually 40–80% as potent as the parent drug.
vi. The intermediate-acting steroid muscle relaxants (e.g., vecuronium and rocuronium) tend to be more dependent on biliary excretion or hepatic
metabolism for their elimination. These muscle relaxants are more commonly used clinically than the long-acting steroid-based drugs (e.g.,
pancuronium). The duration of action of these relaxants may be prolonged significantly in patients with impaired liver function.
vii. Atracurium is an intermediate-acting isoquinoline nondepolarizing muscle relaxant that is no longer in widespread clinical use. In addition to
hepatic metabolism, atracurium is inactivated by a form of spontaneous break down known as Hofmann elimination. The main breakdown
products are laudanosine and a related quaternary acid.

4. viii. Laudanosine is slowly metabolized by the liver and has a longer elimination half-life (i.e., 150 minutes). It readily crosses the blood-brain barrier,
and high blood concentrations may cause seizures.
ix. Atracurium has several stereoisomers, and the potent isomer cis-atracurium has become one of the most common muscle relaxants in use today.
Although cis-atracurium resembles atracurium, it has less dependence on hepatic inactivation, produces less laudanosine, and is much less likely to
release histamine.
x. Gantacurium represents a new class of nondepolarizing neuromuscular blockers, called asymmetric mixed-onium chlorofumarates. It is degraded
nonenzymatically by adduction of the amino acid cysteine and ester bond hydrolysis.
xi. Gantacurium is currently in phase 3 clinical trials and not yet available for widespread clinical use. Preclinical and clinical data indicate
gantacurium has a rapid onset of effect and predictable duration of action (very short, similar to succinylcholine).
B- Depolarizing Relaxant Drugs: -
i. The extremely short duration of action of succinylcholine (5–10 minutes) is due to its rapid hydrolysis by butyrylcholinesterase and
pseudocholinesterase in the liver and plasma, respectively.
ii. Plasma cholinesterase metabolism is the predominant pathway for succinylcholine elimination. The primary metabolite of succinylcholine,
succinylmonocholine, is rapidly broken down to succinic acid and choline. Because plasma cholinesterase has an enormous capacity to hydrolyse
succinylcholine, only a small percentage of the original intravenous dose ever reaches the neuromuscular junction.
iii. Neuromuscular blockade produced by succinylcholine can be prolonged in patients with an abnormal genetic variant of plasma cholinesterase.

5. Neuromuscular blocking agent
Agent / Chemical class / Type of action Onset of action (min) Duration of action (min) Mode of elimination
Ultrashort and short duration
Succinylcholine / DCE / depolarising 0.8 – 1.4 6 – 11 Hydrolysis by plasma cholinesterase
Gantacurium / MOCF / competitive 1 – 2 5 – 10 Cysteine adduction, ester hydrolysis
Mivacurium / BIQ / competitive 2 – 3 15 – 21 Hydrolysis by plasma cholinesterase
Intermediate duration
Vecuronium / AS / competitive 2 – 3 25 – 40 Hepatic and renal elimination
Atracurium / BIQ/ competitive 3 45 Hofmann elimination, ester hydrolysis
Rocuronium / AS / competitive 0.5 – 2 36 – 73 Hepatic elimination
Cis-atracurium / BIQ / competitive 2 – 8 45 – 90 Hofmann elimination, renal elimination
Long duration
Pipecuronium / AS / competitive 3 – 6 30 – 90 Renal elimination, Hepatic metabolism
δ- Tubocurarine / CBI / competitive 6 80 Renal and hepatic elimination
Pancuronium / AS / competitive 3 – 4 85 – 100 Renal and hepatic elimination
Doxacurium / BIQ / competitive 4 – 8 120 Renal elimination
Abbreviations:
AS=Amino steroid; BIQ=Benzyl isoquinoline; CBI=Cyclic benzyl isoquinoline; DCE=Dicholine ester;
MOCF=Asymmetric mixed-onium chlorofumarate.
 Pharmacodynamics: -
A- Mechanism of action: -
Nondepolarizing Relaxant Drugs: -
i. The competitive blockers have affinity for the nicotinic (Nm) cholinergic receptors at the muscle end plate, but have no intrinsic activity.
ii. The Nm receptor is a protein with 5 subunits (α2, β, ε or γ, δ) which are arranged like a rosette surrounding the Na+
channel. The two α subunits
carry two ACh binding sites; these have negatively charged groups which combine with the cationic head of ACh. This trigger opening of Na +
channels.
iii. Most of the competitive blockers have two or more quaternary N+
atoms which provide the necessary attraction to the same site, but due to bulky
nature conformational changes are not possible.

6. iv. Competitive blockers generally have thick bulky molecules and were termed Pachycurare by Bovet. Some of the ACh molecules released from
motor nerve endings are not able to combine with the receptors, and magnitude of the end plate potential (EPP) falls & unable to trigger muscle
action potential (MAP) and muscle fails to contract.
v. The antagonism is reversible by increasing the concentration of ACh in vitro and by anticholinesterases in vivo. At very high concentrations,
curare like drugs enter the Na+
channels and directly block them to produce more intense non-competitive neuromuscular block that is only
partly reversed by neostigmine.
vi. The competitive blockers also block prejunctional nicotinic receptors located on motor nerve endings. Since activation of these receptors by ACh
normally facilitates mobilization of additional quanta of ACh from the axon to the motor nerve endings, their blockade contributes to depression
of neuromuscular transmission.
vii. Accordingly, the competitive blockers exhibit the 'fade' phenomenon, i.e. twitch responses during partial block, which are progressively
depressed on repetitive stimulation. Tetanic stimulation during partial nondepolarizing block increases the response to a subsequent single
stimulation (twitch). This is called 'post-tetanic potentiation ', and is probably due to a transient increase in prejunctional ACh mobilization
following tetanic stimulation.
Depolarizing Relaxant Drugs: -
Depolarising blockers have 2 quaternary N+
atoms, but the molecule is long, slender, and flexible, termed Leptocurare by Bovet. The mechanism of
neuromuscular blocked by depolarising relaxant drugs are divided into two phases: -
a- Phase-I block (depolarizing)-
 Succinylcholine is the only clinically useful depolarizing blocking drug. Its neuromuscular effects are like those of acetylcholine except that
succinylcholine produces a longer effect at the myoneural junction.

7.  Succinylcholine reacts with the nicotinic receptor to open the channel and cause depolarization of the motor end plate, and this in turn
spreads to the adjacent membranes, causing transient contractions of muscle motor units.
 Because succinylcholine is not metabolized effectively at the synapse, the depolarized membranes remain depolarized and unresponsive to
subsequent impulses (i.e., a state of depolarizing blockade).
 Furthermore, because excitation-contraction coupling requires end plate repolarization and repetitive firing to maintain muscle tension, a
flaccid paralysis result.
b- Phase II block (desensitizing)—
 With prolonged exposure to succinylcholine, the initial end plate depolarization decreases and the membrane becomes repolarized. Despite
this repolarization, the membrane cannot easily be depolarized again because it is desensitized.
 Later in phase II, the characteristics of the blockade are nearly identical to those of a nondepolarizing block (i.e., a non-sustained twitch
response to a tetanic stimulus), with possible reversal by acetylcholinesterase inhibitors.
B- Pharmacological actions: -
a- Skeletal muscles: -
 Intravenous injection of nondepolarizing blockers rapidly produces muscle weakness followed by flaccid paralysis.
 Small fast response muscles (fingers, extraocular) are affected first; paralysis spreads to hands, feet- arm, leg, neck, face-trunk- intercostal
muscles-finally diaphragm: respiration stops.
 The rate of attainment of peak effect and the duration for which it is maintained depends on the drug, its dose, anaesthetic used,
haemodynamic, renal and hepatic status of the patient and several other factors.

8.  Though the sequence in which muscles are involved is somewhat different from the competitive blockers, the action of SCh develops with
such rapidity that this is difficult to perceive. Apnoea generally occurs within 45- 90 sec, but lasts only 2- 5 min; recovery is rapid.
b- Histamine release: -
 d-TC releases histamine from mast cells. This is due to the bulky cationic nature of the molecule. Histamine release contributes to the
hypotension.
 Flushing, bronchospasm and increased respiratory secretions are the other effects. Atracurium and mivacurium have significant histamine
releasing potential.
c- Cardiovascular system: -
 δ-Tubocurarine produces significant fall in BP. This is due to-
 ganglionic blockade
 histamine release and
 reduced venous return- a result of paralysis of limb and respiratory muscles.
 Heart rate may increase due to vagal ganglionic blockade. Pancuronium tends to cause tachycardia and rise in BP, while atracurium may
cause hypotension.
 All newer nondepolarizing drugs viz. vecuronium, rocuronium and cis-atracurium have negligible effects on BP and HR.
 Cardiovascular effects of SCh are variable. Generally, bradycardia occurs initially due to activation of vagal ganglia followed by tachycardia
and rise in BP due to stimulation of sympathetic ganglia.

9. d- C.N.S.: -
 All neuromuscular blockers are quaternary compound - do not cross blood-brain barrier. Thus, on i.v. administration no central effects
follow. However, d-TC applied to brain cortex or injected in the cerebral ventricles produces strychnine like effects.
C- Interactions with Other Drugs: -
 Anaesthetics: -
 Inhaled (volatile) anaesthetics potentiate the neuromuscular blockade produced by nondepolarizing muscle relaxants in a dose dependent
fashion.
 Of the general anaesthetics that have been studied, inhaled anaesthetics augment the effects of muscle relaxants in the following order:
isoflurane (most); sevoflurane, desflurane, halothane; and nitrous oxide (least).
 The most important factors involved in this interaction are the following:
 Nervous system depression at sites proximal to the neuromuscular junction (i.e., CNS);
 Increased muscle blood flow (i.e., due to peripheral vasodilation produced by volatile anaesthetics), which allows a larger fraction of the
injected muscle relaxant to reach the neuromuscular junction; and
 Decreased sensitivity of the postjunctional membrane to depolarization.
 Antibiotics: -
 Neuromuscular blockade enhanced by antibiotics (e.g., aminoglycosides). Many antibiotics cause a depression of evoked release of
acetylcholine.
 The mechanism of this prejunctional effect appears to be blockade of specific P-type calcium channels in the motor nerve terminal.

10.  Local Anesthetics and Antiarrhythmic Drugs: -
 In small doses, local anaesthetics can depress post tetanic potentiation via a prejunctional neural effect. In large doses, local anaesthetics can
block neuromuscular transmission.
 With these higher doses, local anaesthetics block acetylcholine-induced muscle contractions as a result of blockade of the nicotinic receptor
ion channels.
 Other Neuromuscular Blocking Drugs: -
 The end plate-depolarizing effect of succinylcholine can be antagonized by administering a small dose of a nondepolarizing blocker.
 To prevent the fasciculations associated with succinylcholine administration, a small non-paralyzing dose of a nondepolarizing drug can be
given before succinylcholine (e.g., d-tubocurarine, 2 mg IV, or pancuronium, 0.5 mg IV).
 Adverse Effects: -
 Malignant Hyperthermia: -
i. Malignant hyperthermia is a potentially life-threatening event triggered by the administration of certain anesthetics and neuromuscular blocking
agents.
ii. The clinical features include contracture, rigidity, and heat production from skeletal muscle, resulting in severe hyperthermia (increases of up to
1°C/5 min), accelerated muscle metabolism, metabolic acidosis, and tachycardia.
iii. Uncontrolled release of Ca2+
from the sarcoplasmic reticulum of skeletal muscle is the initiating event. Most of the incidents arise from the
combination of depolarizing blocking agent and anesthetic.
iv. Treatment entails intravenous administration of dantrolene, which blocks Ca2+
release from the sarcoplasmic reticulum of skeletal muscle. Rapid
cooling, inhalation of 100% O2, and control of acidosis should be considered adjunct therapy in malignant hyperthermia.
 Respiratory Paralysis: -

11. i. It is the complete or severe weakness of the respiratory muscle. This condition may be associated with: motor neuron diseases, peripheral nerve
diseases, neuromuscular nerve diseases.
ii. Treatment of respiratory paralysis arising from an adverse reaction or overdose of a neuromuscular blocking agent can be done by positive-pressure
artificial respiration with O2 and maintenance of a patent airway until recovery of normal respiration is ensured.
iii. With the competitive blocking agents, this may be hastened by the administration of neostigmine methylsulfate (0.5–2 mg IV) or edrophonium (10
mg IV, repeated as required up to a total of 40 mg).
 Histamine release from mast cells: -
i. Some clinical responses to neuromuscular blocking agents (e.g., bronchospasm, hypotension, excessive bronchial and salivary secretion) appear to
be caused by the release of histamine.
ii. Succinylcholine, mivacurium, and atracurium cause histamine release, but to a lesser extent than tubocurarine unless administered rapidly.
iii. The amino steroids pancuronium, vecuronium, pipecuronium, and rocuronium have even less tendency to release histamine after intradermal or
systemic injection.
iv. Histamine release typically is a direct action of the muscle relaxant on the mast cell rather than anaphylaxis mediated by immunoglobulin E.
 Uses of Neuromuscular Blocking Drugs: -
 Surgical Relaxation: -
One of the most important applications of the neuromuscular blockers is in facilitating intracavitary surgery, especially in intra-abdominal and
intrathoracic procedures.
 Endotracheal Intubation: -
By relaxing the pharyngeal and laryngeal muscles, neuromuscular blocking drugs facilitate laryngoscopy and placement of an endotracheal tube.
Endotracheal tube placement ensures an adequate airway and minimizes the risk of pulmonary aspiration during general anesthesia.

12.  Control of Ventilation: -
In critically ill patients who have ventilatory failure from various causes (e.g., severe bronchospasm, pneumonia, chronic obstructive airway disease), it
may be necessary to control ventilation to provide adequate gas exchange and to prevent atelectasis.
 Treatment of Convulsions: -
Neuromuscular blocking drugs (i.e., succinylcholine) are occasionally used to attenuate the peripheral (motor) manifestations of convulsions
associated with status epilepticus, local anesthetic toxicity, or electroconvulsive therapy.
 Individual agents: -
Neuromuscular (Nm) blocking agent
Drug Therapeutic Uses Clinical Pharmacology and Tips Preparations
Succinylcholine
(Nm agonist),
Depolarising
Induction of neuromuscular
blockade in surgery and during
intubation
 Induces rapid depolarization of motor end plate,
inducing phase I block
 Resistant to and augments AChE inhibition; induces
fasciculations, then flaccid paralysis
 Influenced by anesthetic agent, type of muscle, and
rate of administration
 Leads to phase II block after prolonged use
 Metabolized by butyryl cholinesterase; not safe for
infants and children
 Contraindications: history of malignant hyperthermia,
muscular dystrophy
MIDARINE, SCOLINE,
MYORELEX, ENTUBATE = 50
mg/ml inj, 2ml amp
δ-Tubocurarine
 Induction of neuromuscular
blockade in surgery and during
intubation
 All neuromuscular blocking
agents are administered
parenterally
 Produces partial blockade of ganglionic ACh
transmission that can produce hypertension and
reflex tachycardia
 Can induce histamine release
Mivacurium
 Short acting due to rapid hydrolysis by plasma
cholinesterase
 Use with caution in patients with renal or hepatic
insufficiency

13. Pancuronium
 Shows antimuscarinic receptor activity
 Renal and hepatic elimination
 Vagolytic activity may cause tachycardia,
hypertension, and increased cardiac output
PAVULON, PANURON,
NEOCURON = 2mg/ml in 2ml
amp
Rocuronium
 Amino steroid
 Stable in solution
 More rapid onset than vecuronium and cis-atracurium
 Hepatic elimination
ROCUNIUM, CUROMID =
10mg/ml in vials
Vecuronium
 Amino steroid
 Not stable in solution
 Hepatic and renal elimination
NORCURON = 4mg amp.,
dissolved in 1ml solvent
NEOVEC = 4mg amp., 10mg vials
Metocurine
 Three times more potent than tubocurarine
 Less histamine release
Atracurium
Preferred agent for patients with
renal failure
 Susceptible to Hofmann elimination and ester
hydrolysis
 Same dosage for infants > 1 month, children, and
adults
TRACRIUM = 10mg/ml inj. In
2ml vials
Cis-atracurium
 More potent than atracurium, Hofmann elimination,
no histamine release
NIMBEX = 2mg/ml inj.
Doxacurium  Renal elimination
Pipecuronium  Hepatic metabolism; renal elimination ARDUAN = 4mg/2ml inj.
Gantacurium
 New compound class; in clinical trial stage
 Fastest onset and shortest acting
 Metabolism: rapid cysteine adduction, slow ester
hydrolysis
 Directly acting muscle relaxants: -
 Dantrolene: -
i. Its effects resemble those of centrally acting muscle relaxants. Neuromuscular transmission or MAP are not affected, but muscle contraction is
uncoupled from depolarisation of the membrane.

14. ii. Dantrolene acts on the Ryanodine Receptor (RyR1), which are located in the sarcoplasmic reticulum membrane and are responsible for the release of
Ca2+
from intracellular stores during excitation-contraction coupling in both cardiac and skeletal muscle, and prevents Ca2+
release through these
channels.
iii. Since Ca2+
channels in the sarcoplasmic reticulum of cardiac and smooth muscles are of a different subtype (RyR2), these muscles are affected little by
dantrolene.
iv. Dantrolene is slowly and incompletely absorbed from the G.I.T. It penetrates brain and produces some sedation. but has no selective effect on
polysynaptic reflexes responsible for spasticity.
v. It is metabolized in the liver and excreted by kidney with a t½ of 8- 12 hours. Used orally dantrolene (25- 100 mg QID) reduces spasticity in upper
motor neurone disorders, hemiplegia, paraplegia, cerebral palsy and multiple sclerosis.
vi. Used i.v. (1mg/kg repeated as required), as the choice for malignant hyperthermia which is due to persistent release of Ca2+
from sarcoplasmic
reticulum (induced by fluorinated anaesthetics and SCh in genetically susceptible individuals with abnormal RyR1).
Adverse effects: -
Muscular weakness is the dose limiting side effect. Sedation, malaise, light headedness and other central effects occur.
Troublesome diarrhoea is another problem.
Long term use causes dose dependent serious liver toxicity in 0.1-0.5 % patients.
 Quinine: -
It increases refractory period and decreases excitability of motor end plates. Thus, responses to repetitive nerve stimulation arc reduced. It decreases
muscle tone in myotonia congenita. Taken at bed time (200-300mg) it may abolish nocturnal leg cramps m some patients.