1. Skeletal Muscle Relaxants
Dr. Kaukab Azim

2. Neuromuscular Blockers
Drug List
Neuromuscular Blockers
Spasmolytic Drugs
Non-depolarizing
Blockers
Depolarizing
Central
Peripheral
Tubocurarine
Succinylcholine
Baclofen
Dantrolene
Mivacurium
Tizanidine
Botulinum Toxin
Cisatracurium
Gabapentin
Benzodiazepines
* More drugs are mentioned in other slides

3. Presynaptic terminal
Sarcolemma
Synaptic vesicles
Acetylcholine receptors
Mitchondrion

4. Neuromuscular Junction
Na+
ACh
Neuromuscular
Junction
Na+
Neuromuscular
Blocking Drugs α β δ γ
ACh
Competitive
Tubocurarine
Gallamine
Pancuronium
Vecuronium
Atracurium
Rocuronium
Depolarizing
Suxamethonium
1) Motor neuron depolarization causes action potential to travel down the nerve fiber to the neuromuscular junction.
2) Depolarization of the axon terminal causes an influx of Ca2+
3) Calcium influx triggers fusion of the synaptic vesicles with the membrane of the neuron
4) Release of neurotransmitter (Acetylcholine; ACh)
5) ACh diffuses across the synaptic cleft and binds to post-synaptic nicotinic receptor (NM) located on the muscle fiber at the motor end-plate . Binding of 2 molecules of ACh to the receptor opens the membrane channels causing an influx of Na and outflux of K leading to depolarization of the end plate membrane. This change in voltage is termed the motor end plate potential. If the potential is small, the permeability and the end plate potential return to normal without an impulse being propagated from the end plate region to the rest of the muscle membrane.
6) If the end plate potential is large, the adjacent muscle membrane is depolarized, and an action potential will be propagated along the entire muscle fiber and ultimately causes the release of Ca2+ from the sarcoplasmic reticulum causing CONTRACTION.
7) Unbound ACh in synaptic cleft defuses away or is hydrolyzed (inactivated) by acetylcholinesterase (AChE).

5. Muscle Relaxants What are they used for?
Facilitate intubation of the trachea
Facilitate mechanical ventilation
Optimized surgical working conditions
Treatment of Convulsions / seizures

6. Also used for Muscle spasticity Muscle Spasms
What are spasticity and spasms?
Spasticity can be described as involuntary muscle stiffness and spasms as involuntary muscle contractions. Any muscle can be affected but spasticity and spasms tend to predominantly affect a person's limbs or trunk.

7. Muscle Spasticity

8. Definition of muscle spasm
Increased muscle tone
together with muscle weakness
It is often associated with cerebral palsy, multiple sclerosis, and stroke.

9. Causes of Muscle Spasms
Seen after musculoskeletal injury and inflammation
Involve afferent nociceptive input from damaged area
Excitation of alpha motor outflow
Tonic contraction of affected muscle
Build up of pain-mediating metabolites

10. Levels of Muscle Relaxant Intervention
Spinal Cord
NEUROMUSCULAR Junction
Muscle Cells

11. Muscle Relaxants Definition:
Drugs which relax skeletal muscles by acting at the neuromuscular junction
Depolarizing muscle relaxant
Succinylcholine
Nondepolarizing muscle relaxants
Short acting
Intermediate acting
Long acting

12. They can also be called
Antagonist (nondepolarizing) neuromuscular blocking drugs prevent access of acetylcholine to its NM receptor and prevent depolarization of the motor end plate (d-tubocurarine)
Agonist (depolarizing) neuromuscular blocking drugs produce excessive depolarization of the motor end plate by causing excessive stimulation of the NM receptor (Succinylcholine)

13. Succinylcholine What is the mechanism of action?
Physically resemble Ach
Act as acetylcholine receptor agonist
Not metabolized locally at NMJ
Metabolized by pseudocholinesterase in plasma
Depolarizing action persists > Ach
Continuous end-plate depolarization causes muscle relaxation

14. Succinylcholine What is phase I neuromuscular blockade?
What is the clinical use of succinylcholine?
Most often used to facilitate intubation
Onset seconds, duration 5-10 minutes
Succinylcholine
What is phase I neuromuscular blockade?
What is phase II neuromuscular blockade?
Resemble blockade produced by nondepolarizing muscle relaxant
Succinylcholine infusion or dose > 3-5 mg/kg

15. Succinylcholine What is phase I neuromuscular blockade?
Repetitive firing and release of neurotransmitter. Acetylcholine receptors remain open. Preceded by fasciculations.
What is phase II neuromuscular blockade?
Postjunctional membrane does not respond to ACh even when resting membrane potential is restored i.e. Desensitisation blockade or Phase II block.
Neuromuscular blockade
[CEACCP 2004 Vol 4(1) "Pharmacology of neuromuscular blocking drugs"; SH4:p ]
Neuromuscular junction
NMJ contains 3 types of nicotinic acetylcholine receptors (nAChR) * Junctional (post-synaptic) * Extrajunctional (post-synaptic) * Presynaptic
Phase I block (depolarising blockade)
aka accommodation block
Often preceded by muscle fasciculation
[CEACCP article] Suxamethonium stimulates prejunctional ACh receptors --> Repetitive firing and release of neurotransmitter --> Fasciculation
[SH4:p217] Skeletal muscle fasciculation reflects the generalised depolarisation of postjunctional membranes produced by suxamethonium
Mechanism of phase I block
Also see previous section
Basically, due to suxamethonium's longer action (than ACh) --> Junctional nAhRs stay open --> Membrane potential cannot be restored --> Inactivated voltage-sensitive Na+ channels cannot revert back to resting state --> Action potential cannot be generated
Characteristics of phase I block
Decreased contraction in response to single twitch stimulation
Decreased amplitude but sustained response to continous stimulation
TOF ratio of >0
Absence of post-tetanic facilitation
Augmentation of neuromuscular blockade after anticholinesterase drug * i.e. block increases, rather than decrease, as with non-depolarising NMBDs
Onset of phase I block is accompanied by skeletal muscle fasciculations
Recovery from Phase I block
Recovery from phase I block occurs when
Suxamethonium diffuse away from the neuromuscular junction (down the concentration gradient)
Plasma concentration decreases when suxamethonium is metabolised by plasma cholinesterase (pseudocholinesterase)
Phase II block (desensitisation blockade)
Prolonged exposure to suxamethonium or large doses of suxamethonium (>2mg/kg IV) --> Postjunctional membrane does not respond to ACh even when resting membrane potential is restored * i.e. Desensitisation blockade or Phase II block. * May be a safety mechanism to prevent overexcitation of the NMJ
According to CEACCP article, desensitisation block and phase II block are two different things.
According to [SH4:p217], these two are the same thing.
Transition from phase I to phase II block is fairly abrupt * Initial manifestation as tachyphylaxis
At any one time there could be varying degrees of phase I and phase II blockade present at the same time
Mechanism of phase II block
Exactly mechanism is UNKNOWN.
Possible mechanisms include:
Presynaptic block --> Reduction in synthesis and mobilisation of ACh
Postjunctional receptor desensitisation
Initial depolarisation activates the Na-K ATPase pump --> Repolarisation
Characteristics of phase II block
Resembles that of nondepolarising NMBDs * But mechanism is likely to be different
Fade of the train-of-four twitch response
Tetanic fade
Post-tetanic potentiation
Anticholinesterase drugs will antagonise effects of a phase II blockade
Characteristics of nondepolarising neuromuscular blockade
[SH4:p222]
Decreased twitch response to a single stimulus
Unsustained response (fade) during continuous stimulation
TOF ratio of <0.7
Posttetanic potentiation
Potentiation of other nondepolarising NMBDs
Antagonism by anticholinesterase
NOT accompanied by fasciculations
NB.
Twitch response is decreased because some fibres are contracting normally and others are blocked
Fade in response to continuous electrical stimulation - some fibres are more susceptible to being blocked by NMBDs and need greater sustained release of ACh to trigger their response

16. Succinylcholine Does it have side effects? Cardiovascular
Fasciculation
Muscle pain
Increase intraocular pressure
Increase intragastric pressure
Increase intracranial pressure
Hyperkalemia
Malignant hyperthermia

17. Nondepolarizing Muscle Relaxants
Long acting
Pancuronium
Intermediate acting
Atracurium
Vecuronium
Rocuronium
Cisatracurium
Short acting
Mivacurium
Mechanism of Action
All bind nicotinic Ach receptors and competitively block Acetylcholine, thereby preventing muscle contraction
i.e.
They are competitive antagonists
Mechanism of Action: In small clinical doses they act the predominantly at the nicotinic receptor site to block ACh.
At higher does they can block prejunctional Na channels thereby decreasing ACh release.
Because of the competitive nature of the postsynaptic blockade, transient relief of the block can be achieved by increasing ACh levels at the synaptic cleft (i.e. use cholinesterase inhibitors).

18. Tubocurarine This was the first muscle relaxant used clinically
Therapeutic Use: Adjuvant drugs in surgical anesthesia
Pharmacology: Must be given by injection because they are poorly absorbed orally. Do not cross the BBB.
Elimination: Generally excreted unchanged (i.e. not metabolized).
Adverse Effects: Tubocurarine causes release of histamine from mast cells – decrease in blood pressure, bronchospasms, skin wheals.
Drug interaction: Competes with succinylcholine for it’s the end plate depolarizing effect.

19. Pancuronium It is an Aminosteroid compound
Onset 3-5 minutes, duration minutes
Elimination mainly by kidney (85%), liver (15%)
Side effects : hypertension, tachycrdia, dysrhythmia,

20. Vecuronium Analogue of pancuronium
Much less vagolytic effect and shorter duration than pancuronium
Onset 3-5 minutes duration minutes
Elimination 40% by kidney, 60% by liver

21. Rocuronium Analogue of vecuronium
Rapid onset 1-2 minutes, duration minutes
Onset of action similar to that of succinylcholine
Intubating dose 0.6 mg/kg
Elimination primarily by liver, slightly by kidney

22. Atracurium Metabolized by Onset 3-5 minutes, duration 25-35 minutes
Ester hydrolysis
Hofmann elimination (spontaneous degradation in plasma and tissue at normal body pH and temperature)
Onset 3-5 minutes, duration minutes
Side effects:
histamine release causing hypotension, tachycardia, bronchospasm
Laudanosine toxicity
(Laudanosine is a metabolite of atracurium and cisatracurium. It decreases seizure threshold and this it can induce seizures, however, such concentrations are unlikely to be produced at therapeutic doses)
Atracurium, a nondepolarizing muscle relaxant, is eliminated through several pathways, including Hofmann elimination (spontaneous degradation in plasma and tissue at normal body pH and temperature) and ester hydrolysis (catalysis by nonspecific esterases).

23. Cisatracurium Isomer of atracurium Metabolized by Hofmann elimination
Onset 3-5 minutes, duration minutes
Minimal cardiovascular side effects
Much less laudanosine produced

24. Mivacurium
Has the shortest duration of action of all nondepolarizing muscle relaxants
Onset of action is significantly slower
Use of a larger dose to speed the onset can be associated with profound histamine release leading to hypotension, flushing, and bronchospasm.
Clearance of mivacurium by plasma cholinesterase is rapid and independent of the liver or kidney.
Mivacurium is no longer in widespread clinical use. It is an investigational ultra-short-acting
Mivacurium is another isoquinoline compound, has the shortest duration of action of all nondepolarizing muscle relaxants (Table 27–1). However, its onset of action is significantly slower than that of succinylcholine. In addition, the use of a larger dose to speed the onset can be associated with profound histamine release leading to hypotension, flushing, and bronchospasm. Clearance of mivacurium by plasma cholinesterase is rapid and independent of the liver or kidney (Table 27–1). However, because patients with renal failure often have decreased levels of plasma cholinesterase, the short duration of action of mivacurium may be prolonged in patients with impaired renal function. Although mivacurium is no longer in widespread clinical use, an investigational ultra-short-acting isoquinoline nondepolarizing muscle relaxant, gantacurium, is currently in phase III clinical testing. This novel compound has a very rapid onset and short duration of action.

25. Drug Interactions
Cholinesterase Inhibitors decrease the effectiveness of nondepolarizing agents
Aminoglycoside antibiotics increase action of nondepolarizing drugs
Calcium channel blockers increase the actions of nondepolarizing drugs
Inhalational anesthetics enhance neuromuscular blockade by nondepolarizing drugs
Cholinesterase Inhibitors decrease the effectiveness of nondepolarizing agents
Aminoglycoside antibiotics (e.g. streptomycin) decrease ACh release by competing with Ca2+ – increase action of nondepolarizing drugs
Calcium channel blockers increase the actions of nondepolarizing drugs by decreasing the amount of ACh released (i.e. increase action of nondepolarizing drugs)
Halogenated carbon anesthetics (e.g. Isoflurane) enhance neuromuscular blockade by 1) decreasing excitability of motoneurons, 2) increasing muscle blood flow, and 3) decreased kinetics of AChRs (increase action of nondepolarizing drugs)

26. Reversal of Neuromuscular Blockade
Why do we need to reverse the effect of neuromuscular blockers?
Because they paralyze the muscles. Once the surgery is over, the muscles need to work again.
Goal: re-establishment of spontaneous respiration and the ability to protect airway from aspiration

27. Reversal of Neuromuscular Blockade by Anticholinesterases
Effectiveness of anticholinesterases depends on the degree of recovery present when they are administered
Anticholinesterases
Neostigmine
Onset 3-5 minutes, elimination halflife 77 minutes
Pyridostigmine
Edrophonium

28. What is the mechanism of action?
Inhibiting activity of acetylcholineesterase
More Ach available at NMJ, compete for sites on nicotinic cholinergic receptors
Action at muscarinic cholinergic receptor
Bradycardia
Hypersecretion
Increased intestinal tone

29. What do we do about side effects?
Muscarinic side effects are minimized by anticholinergic agents
Atropine
Dose mg/kg
Scopolamine
glycopyrrolate

30. Neuromuscular Blockers
Drug List
Neuromuscular Blockers
Spasmolytic Drugs
Non-depolarizing
Blockers
Depolarizing
Central
Peripheral
Tubocurarine
Succinylcholine
Baclofen
Dantrolene
Mivacurium
Tizanidine
Botulinum Toxin
Cisatracurium
Gabapentin
Benzodiazepines
* More drugs are mentioned in other slides

31. Centrally acting spasmolytic drugs
Mechanism
Baclophen
GABAB receptors causing hyperpolarization by increasing potassium conductance
Averse effects: drowsiness and increased seizure activity
Tizanidine
α2 adrenoreceptor agonist
Gabapentin
Unknown but may enhance GABA synthesis
Diazepam
GABAA receptor

32. Baclofen Mechanism of action: GABAB agonist
Clinical effects: decreased hyperreflexia; reduced painful spasms; reduced anxiety
Dose: orally 5 mg three times daily, gradually increase to 20 mg four times daily or higher; intrathecally initially 50 mcg/day increase to mcg/day

33. Baclofen
Adverse effects: weakness, sedation, hypotonia, ataxia, confusion, fatigue, nausea, liver toxicity
Chronic effects: rapid withdrawal may cause seizures, confusion, increased spasticity
Route of administration: oral, intrathecal
Pediatric doses: oral doses not well established; intrathecal doses 25 mcg/day initially increase to 274 mcg/day as tolerated

34. Tizanidine and Clonidine
Mechanism of action: alpha-2 receptor agonist
Clinical effects: reduced tone, spasm frequency, and hyperreflexia

35. Tizanidine and Clonidine
Adverse effects: drowsiness, dizziness, dry mouth, orthostatic hypotension
Chronic effects: rebound hypertension with rapid withdrawal
Route of administration: oral, transdermal patch (Clonidine)

36. Benzodiazepines Diazepam Lorazepam (Ativan) Clonazepam Clorazepate
Ketazolam
Tetrazepam
Diazepam (Valium)
Lorazepam (Ativan)
Clonazepam (Klonopin)
Clorazepate (Tranxene)
Ketazolam (Solatran)
Tetrazepam (Myolastan)

37. Diazepam (Valium)
Mechanism of action: enhance GABAA activity (chloride channels)
Clinical effects: decreased resistance to passive joint range of motion (ROM); decreased hyperreflexia; reduced painful spasms; sedation; reduced anxiety
Diazepam is a benzodiazepine that binds to a specific subunit on the GABAA receptor at a site that is distinct from the binding site of the endogenous GABA molecule. The GABAA receptor is an inhibitory channel which, when activated, decreases neuronal activity. Benzodiazepines do not supplement for the neurotransmitter GABA, rather benzodiazepines such as diazepam bind to a different location on the GABAA receptor with the result that the effects of GABA are enhanced. Benzodiazepines cause an increased opening of the chloride ion channel when GABA binds to its site on the GABAA receptor leading to more chloride ions entering the neuron which in turn leads to enhanced central nervous system depressant effects. Diazepam binds non-selectively to alpha1, alpha2, alpha3 and alpha5 subunit containing GABAA receptors.
Because of the role of diazepam as a positive allosteric modulator of GABA, when it binds to benzodiazepine receptors it causes inhibitory effects. This arises from the hyperpolarization of the post-synaptic membrane, owing to the control exerted over negative chloride ions by GABAA receptors.
Diazepam appears to act on areas of the limbic system, thalamus, and hypothalamus, inducing anxiolytic effects. Its actions are due to the enhancement of GABA activity. Benzodiazepine drugs including diazepam increase the inhibitory processes in the cerebral cortex.]
The anticonvulsant properties of diazepam and other benzodiazepines may be in part or entirely due to binding to voltage-dependent sodium channels rather than benzodiazepine receptors. Sustained repetitive firing seems to be limited by benzodiazepines' effect of slowing recovery of sodium channels from inactivation.
The muscle relaxant properties of Diazepam are produced via inhibition of polysynaptic pathways in the spinal cord.

38. Diazepam (Valium)
Adverse effects: sedation, weakness, hypotension, memory impairment, ataxia, confusion, depression
Chronic effects: dependency, withdrawal, and tolerance possible
Routes of administration: oral, intravenous, rectal

39. Peripheraly acting spasmolytic drugs Dantrolene
Mechanism of action:
Dantrolene reduces skeletal muscle strength by interfering with excitation-contraction coupling in the muscle fibers
Normal contraction involves release of calcium from its stores in the sarcoplasmic reticulum through a calcium channel
Dantrolene interferes with the release of calcium through this sarcoplasmic reticulum calcium channel.
Cardiac muscle and smooth muscle are depressed only slightly, perhaps because the release of calcium from their sarcoplasmic reticulum involves a different process.

40. Dantrolene:
Indications: 1- Muscle spasticity 2- Malignant hyperthermia:
Indications:
1- Muscle spasticity
2- Malignant hyperthermia:
Patients at risk for this condition have a hereditary impairment in the ability of the sarcoplasmic reticulum to sequester calcium.
Following administration of one of the triggering agents (general anesthetics or succinylcholine) there is a sudden and prolonged release of calcium, with massive muscle contraction, lactic acid production, and increased body temperature.
Treatment of malignant hyperthermia:
control acidosis and body temperature
Reduce calcium release with intravenous dantrolene

41. Botulinum Toxin (Botox)
Enters the pre-synaptic terminal and binds to acetylcholine
Inhibits acetlycholine from entering the synaptic cleft
Toxin serves as a block at the neuromuscular unction
Can be administered to a specific muscle or group via local injection

42. Botox
Used in treatment of patients with focal dystonia as found in stroke and spinal cord lesions
Used to restore volitional motor control thus increasing use of extremities and improving function, mobility and opportunities to participate in meaningful occupations
Prevention of joint contraction and fixation

43. Thank you