Muscle relaxants

Dr. Kamashi Kumar

St. George’s University
School of Veterinary Medicine
Anatomy, Physiology & Pharmacology Department
Lecture Level outcomes

1. Explain the importance of muscle relaxants use in Veterinary medicine.

2. Compare the pharmacokinetics and pharmacodynamics of various muscle

relaxants (centrally acting, depolarizing and non-depolarizing muscle
relaxants)

3. Determine the appropriate muscle relaxant drug suitable for the various
species.

4. Explain the side-effects and contraindications of muscle relaxant drugs.

5. Discuss the drug-drug interactions with muscle relaxants

 Muscle relaxants

Centrally-acting muscle relaxants

• Guaifenesin, methocarbamol

• Benzodiazapines

Peripheral skeletal muscle relaxants

• Neuromuscular blockers
 Centrally-acting muscle relaxants
Sedation
Muscle relaxation
Guaifenesin in the CNS "TRIPPLE DIP "
- xylazine
• used in humans as expectorant
- ketamine
• Mechanism of action
• Skeletal muscle relaxant (centrally) - selectively depresses impulse neurotransmission at the
internuncial neurons in the spinal cord, brainstem and subcortical areas of the brain → produces
sedation and muscle relaxation
• No significant analgesic effects
• does not cause paralysis of the respiratory muscles at therapeutic doses
• Clinical use in veterinary medicine
• Induction and maintenance of anesthesia in horses
• “Triple drip” - combination of guaifenesin, xylazine and ketamine
 Centrally-acting muscle relaxants

Guaifenesin
• Muscle relaxation lasts for 15-30 mins.

• Hepatic metabolism to a glucuronide, excreted in urine

• Storage: crystallized under 22°c; kept warmed (> 22°c) for

improved solubility (place bag in a warmer to dissolve the crystals)

- Use 5% solutions → higher concentration is irritating

- never use in awake horses

- Accidental overdose – ataxia & poor recovery

 Centrally-acting muscle relaxants

Methocarbamol (Robaxin®)

• short-term musculoskeletal pain, acts centrally – but the MOA is not clear

• Common clinical use - management of spasms associated with Intervertebral disk

Disease (IVDD)

• administered orally or IV
 Centrally-acting muscle relaxants
Benzodiazepines
Classified as “sedative-hypnotics” or “minor tranquilizers”
• Midazolam, diazepam, alprazolam, clonazepam, zolazepam
Clinical uses Diazepam is mainly used to treat anxiety, insomnia, panic attacks and symptoms of acute
alcohol withdrawal. It is also used as a premedication for inducing sedation, anxiolysis, or
amnesia before certain medical procedures. Long acting
1. Anticonvulsants
2. Anesthesia adjunct – induction, sometimes maintenance
3. Muscle relaxation
4. Anti-anxiety
5. Appetite stimulant (Diazepam)
• wide therapeutic index (margin of safety)
• hepatic metabolism – use cautiously in animals with poor liver function
 Benzodiazepines
Mechanism of action
Peripherally acting muscle relaxants

Neuromuscular blockers: AcH Inhibitors

• Acts by interfering with the action of endogenous neurotransmitter acetylcholine

(ACh) on the nicotinic cholinergic receptor at the neuromuscular junction

modulating transmembrane ion movements

Skeletal muscular paralysis and muscular relaxation

 Neuromuscular blockers

Indications:

• As an adjunct to general anaesthesia (muscle relaxation)

• Used concurrently with sedative/hypnotic agents (for mechanical ventilation

process)

• Aids in the endotracheal tube intubation procedure

• For balanced anaesthetic technique (↓ the amount of anesthetic drug required)

 Curare:
History of development a bitter resinous substance obtained
from the bark and stems of some South
American plants. It paralyses the motor
Source: nerves and is traditionally used by some
Indian peoples to poison their arrows
and blowpipe darts.
• Isolated from curare, a plant material used as a poison by South American Indians.

• Important constituent isolated from curare → d-tubocurarine

• This inhibited muscle contraction acting at nerve-muscle junction.

• Active research

curare-like compounds as new NMB (neuromuscular blocker) agents

• NMB possess structural groups that can interact with nACh receptor

• Competitive nondepolarizing agents or as depolarizing agents

Impulse transmission at the somatic neuromuscular junction

nACh receptor
↓
ACh release Depolarization
from ↓
cholinergic
neuron into muscle
Axonal action synapse contraction
potential
Nicotinic cholinergic receptor – signal transduction

• It requires the activation of a large number of nACh to excite a single muscle

fiber → muscle contraction

• Single action potential – 40-300 synaptic vesicles fusion

• ACh binds to postsynaptic membrane nAChR

• At synapse → rapid action of AChE cleaves ACh

free ACh within the synapse is rapidly reduced after single action potential
 Structure of Nicotinic cholinergic receptor
• nAChR – pentameric molecule that spans the postsynaptic membrane – α2βγδ
• The subunits have an extracellular and an intracellular domain are arranged circumferentially to form a
rosette around a central lumen
• Ion influx – depolarization
• Agonist and antagonist binding sites are on the α-subunit

• Receptors contain anionic (- ve charge) sites

• electrostatic attraction for cationic nitrogen (+ charge) moiety of ACh and exogenous agonists
(neuromuscular blockers)
Competitive nondepolarizing agents ach is blocked. cant bind, no transmission

• Occupies the nACh receptor → stabilizes the receptor → ACh cannot

access its binding site

• Resulting in muscle paralysis for the duration of their effect

• Large, rigid molecules

• Ex. d-tubocurarine, vecuronium, atracurium, pancuronium

 Depolarizing agents

• Causes membrane depolarization → characterized by muscle fasciculation, followed

by neuromuscular blockade → muscle paralysis

• Acts like ACh

initial channel activation and ion flow → persistent interruption in ion flow.

• Long, slender, flexible molecules that allow free bond rotation

• Ex. Succinyl choline

 Pharmacological considerations

Various drugs, toxins, electrolytes and other agents – alter the synthesis, storage, release,
receptor interactions and catabolism of ACh.
• ACh synthesis is decreased by lack of choline – essential nutrient in the B-vitamin complex
• Local anaesthetics – inactivates Na+ channels and K+ Channels
• Puffer fish poison (tetrodotoxin) and shellfish poison (saxitoxin) – decrease the permeability of excitable
membrane to Na+ → axonal action potential are not generated → paralysis
• acts non-competitively; more potent
• Botulinum toxin – inhibits exocytosis (hydrolyses SNARE protein complex)
• Mg++ ions interfere with the release of ACh by competing for the transport mechanisms responsible for
mobilization of Ca++; also acts on postsynaptic receptors (↓ ACh effects)
• Aminoglycoside antibiotics – inhibit release of ACh from presynaptic neuron (also postsynaptic effects of
ACh is ↓)
• Cholinesterase inhibitors – overdosage results in muscle weakness
Competitive Nondepolarizing agents

• These agents compete with ACh for nACh receptors

• Binds with same affinity as ACh → no receptor activation→ paralysis of muscles

• Prototype – d-tubocurarine
• monoquaternary alkaloid derived from the bark of

South American plant, Chondrodendron tomentosum

• d-tubocurarine derived drugs – atracurium, cisatracurium, pancuronium,

vecuronium, rocuronium, mivacurium, doxacurium and gantacurium
 Competitive Non-depolarizing agents

• Categorized as pachycurares (bulky molecules) having their amine functions

incorporated into rigid ring structures

• Two groups of pachycurares:

• Aminosteroid agents - pancuronium, vecuronium, rocuronium

• Benzyl-isoquinolinium compounds - atracurium, cisatracurium,

mivacurium, doxacurium
 competes with Ach for binding sites
Atracurium endotracheal intubation

• Intermediate with a dose-dependent onset of action (5 mins.)

• Duration of action – approx. 30-40 mins. in dogs

• Repeated doses are not cumulative

• Longer term maintenance is achieved by constant rate of infusion

• Elimination is by ester hydrolysis & Hoffman elimination (high pH and temperature)

favor breakdown.

• appropriate for hepatic or renal insufficiency patients

Atracurium

• By IV infusion – decomposes to laudanosine

▪ Laudanosine (CNS stimulant) – seizures, hypotension and tachycardia

▪ Requires hepatic metabolism

▪ Usually the toxicity is not significant – when proper dose is used

• used in dogs, cats, horses (a preferred choice)

• Histamine release → bolus IV injection (hypotension, tachycardia)

• Aminoglycoside antibiotics (gentamicin)

• augment neuromuscular blockade

Cisatracurium

• 1R cis- 1’R cis isomer of atracurium

• Onset of action – 5 mins.

• Duration of action – 30-40 mins.

• Elimination - Hoffman
Mivacurium

• Short acting NMB

• Onset of action – 5 mins.; duration of action –15- 20 mins.

• Metabolized by plasma ChE

Doxacurium

• Slow acting NMB

• Slow onset of action – 40 mins.; long duration of action –100- 120 mins.

• Increased propensity of histamine release and cardiovascular side effects

Pancuronium

• Dose-dependent onset of action (5 mins.) and long duration of effect (30-60 mins.)

• Shows cumulative effect (constant rate infusions are avoided)

• Excreted by kidney and remaining metabolized in liver

• Possess vagolytic activity → increase heart rate

• Causes PGI2 release → vasodilation

• Stable at room temperature for 6 months

Vecuronium

• Removal of methyl group of pancuronium

vecuronium
• Devoid of CVS effects

• Molecular instable → available as lyophilized powder and reconstituted prior to

administration

• Dose-dependent onset of action (5 mins.) and intermediate duration of effect (30-40 mins.)

• metabolized in liver and renal elimination

• Horses – long duration of action (120 minutes)

Rocuronium
• Lacks the acetyl ester in the steroid nucleus
of pancuronium & vecuronium

• rapid onset of action (1-2 mins.) and

intermediate duration of effect (20-30 mins.)

• Devoid of CVS side effects and histamine

release

• metabolized in liver and renal elimination

• stable at room temperature

Gantacurium

• New class asymmetric mixed-onium chlorofumarates

• rapid onset of action (1-2 mins.) and ultrashort duration of action (5 mins.)

• Degraded in plasma by pH sensitive chemical hydrolysis; inactivation by cysteine

adduction

• Devoid of CVS side effects

• metabolized in liver and renal elimination

• Reversal by ChE inhibitor and Cysteine substitution

• available as lyophilized powder and reconstituted only prior to administration

 Depolarizing agents

Succinylcholine chloride
• only used agent

• mostly the use is limited because of side-effects

• Composed of 2 molecules of ACh linked back-to-back through acetate methyl groups

• Acts as similar as ACh

• stimulates cholinergic receptors at neuromuscular junction, at nicotinic ganglionic and muscarinic
autonomic sites

• Produces a prolonged depolarization of the neuromuscular end plate → not allow the
postsynaptic membrane to completely repolarize → Nm junction unresponsive to ACh
Succiny choline – NM block action
• Phase I block

• Depolarization of Nm motor end plate → persistent permeability of ions, Na+ (influx) &
K+ ions (efflux)

• Membrane potential should reset – channel reactivation

• Causes persistent depolarization

• not hydrolyzed by synaptic AChE

• metabolized by plasma cholinesterases

Succinylcholine – NM block action

• Phase II block

• Occurs after prolonged exposure or large doses of a depolarizing agent

desensitization of nACh receptor

• It resembles as that of blockade of nondepolarizing Nm blockade

• Initial depolarization subsides

end plate transiently sensitive to depolarizing agents → gradually progressed to competitive

NMB like blockade

• could be reversed by cholinesterase inhibitors

Succinylcholine – NM bock action

• Rapid onset of action and an ultrashort duration of action (6-10 mins.)

• Rapid hydrolysis of plasma butyrylcholinestaerse

• ↓ in ChE activity → prolong recovery

Succinylcholine - side-effects:

• Generalized autonomic stimulation, cardiac dysrhythmias, hyperkalemia, increase in

intraocular pressure, hyperthermia, muscle pain
Neuromuscular blockers

• At least 75% of postsynaptic nicotinic receptors must be blocked to get some relaxation

• 90% receptors blocked → for complete cessation of transmission (total paralysis)

• Mechanical ventilation should be given → Paralysis of diaphragm

• Reversible Cholinesterase inhibitors were effective in antagonizing the effects of the

nondepolarizing NMB

• More ACh in synapse → for interaction with cholinergic receptors to reverse the effects

Clinical use of reversible cholinesterase inhibitors – reverse the neuromuscular

blockade of non-depolarizing agents.
Pharmacological effects of neuromuscular blocking agents

• Given only for anaesthetized patients

• Relaxation of skeletal muscles
• Narrow therapeutic index

Skeletal muscle:
• Nondepolarizing NMB
• flaccid paralysis (acts at synapse level)
• Reversed by AChE inhibitors

• Succinylcholine
• transient muscle fasciculation - NM paralysis
• short duration of action – rapid biotransformation
• synergistic effects with AChE inhibitors (ACh + succinylcholine are available)
• Horses & pigs – less responsive to succinylcholine (difference in activity of plasma ChE)
Pharmacological effects of neuromuscular blocking agents

Autonomic effects
• Ganglionic nicotinic receptors are blocked (but less sensitive)
• curare like drugs → ganglionic transmission is functional
• Succinylcholine – transient ganglionic transmission → hypertension

Histamine release
• d-tubocurarine – causes histamine release
• depends on species, dosage, route of administration
• Bronchospasm, increase in respiratory tract secretions, hypotension
• Succinylcholine - weak histamine releasing agents

CNS
• Not permeable in BBB – highly charged quaternary ammonium compound
 Pharmacological effects of neuromuscular blocking agents

CVS

• d-tubocurarine → hypotension

• Pancuronium – slight increase in heart rate and blood pressure in dogs & cats

• Succinylcholine

• Increases arrhythmogenicity of epinephrine during halothane anesthesia in dogs

• Catecholamines should be cautiously used with depolarizing NMB agents

• Contraindicated in digitalized patients

• Horses – hypertension, initial bradycardia followed by tachycardia, AV conduction

abnormalities, myocardial damage
Pharmacological effects of neuromuscular blocking agents

Ocular effects
• Succinylcholine causes contracture of ocular muscles

• contraindicated in glaucoma

Serum potassium
• Depolarizing agents – release of K+ ions from skeletal muscle.

• Not preferred for patients with hyperkalemia and muscular disorders (Golden Retriever
muscular dystrophy)
 NMB agents interact and • Depolarization of end plate by succinylcholine –
modulate activities with other stabilized by d-tubocurarine
NMB agents. • Succinylcholine – antagonizes the curare effects

ChE inhibitors – increase the

intensity of depolarizing agents

Drug interactions
Organophosphates (insecticides
+ anthelmintic), carbamates, ChE
inhibitors → similar effects

Aminoglycoside antibiotics
(neomycin, kanamycin, • interact synergistically at Nm junction with NMB
gentamicin, streptomycin) –
decrease ACh release → Nm agents, anaesthetics
blockade

Liver disease – ↓ hepatic

synthesis of AChE – duration of
succinylcholine prolonged
Clinical use of NMB

• Muscle paralysis – extraocular muscles, facial muscles, head & neck, limb muscles,
laryngeal muscles, abdominal muscles, intercostal muscles ad diaphragm

• facilitate tracheal intubation

• Sedation/tranquilization is advisable to manage the fear reactions associated with the

paralysis effect

• Muscle relaxation for surgery

• Used with anaesthetic agents

• Paralyze respiratory muscles (mechanical ventilation)

Margin of safety of neuromuscular transmission

• monitor the muscle relaxation – safely terminate the NMB effects

• During recovery – spontaneous respiration starts

• Small fraction of post synaptic receptors are available for interaction with ACh –
during this phase, if patient exposed to other drug which would cause neuromuscular
blockade → serious complications
gentamicin, Amikacin (IV)
• Never administer aminoglycosides antibiotics → severe apnea → fatal

• Carefully considered in a multiple drug regimen → depressing myoneural function

• Positive pressure ventilation
• Withdraw the use of NMB agent
• Other drugs synergistic with NMB should be
avoided
• Reversal of nondepolarizing NM blockade –
Clinical
AChE inhibitors, sugammadex
• AChE inhibitors (edrophonium, neostigmine,
reversal of NM
pyridostigmine) – increase ACh level – paralysis
competitive
• Succinylcholine (only for phase II block)
• Usually succinylcholine gets bio-transformed
by plasma ChE
AChE inhibitors
• For severe muscarinic effects - bradycardia, hypotension, bronchoconstriction,
increase in GI activity

• Edrophonium is most preferred – rapid onset, mild muscarinic effects

• Antidote: Atropine or glycopyrrolate

• Respiratory acidemia (hypoventilation) & calcium channel blockers – reduce the

reversal of NM blockers
 Sugammadex
• Reverse the effects of nondepolarizing agents

• First drug known as selective relaxant binding agent (SRBA)

• Modified γ-cyclodextrin tightly encapsulates aminosteroid based nondepolarizing

NMB → elimination

• Most effective for reversal of rocuronium, vecuronium, pancuronium

• Devoid of muscarinic side effects

 ▪ NMB – significance for muscle relaxation

▪ Drug interactions of NMB

Summary ▪ Narrow therapeutic index → careful
monitoring is required