Skeletal Muscle Relaxants Dr. Kaukab Azim

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

Presynaptic terminal Sarcolemma Synaptic vesicles Acetylcholine receptors Mitchondrion

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).

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

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.

Muscle Spasticity

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

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

Levels of Muscle Relaxant Intervention Spinal Cord NEUROMUSCULAR Junction Muscle Cells

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

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)

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

Succinylcholine What is phase I neuromuscular blockade? What is the clinical use of succinylcholine? Most often used to facilitate intubation Onset 30-60 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

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:p216-217] 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

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

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).

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.

Pancuronium It is an Aminosteroid compound Onset 3-5 minutes, duration 60-90 minutes Elimination mainly by kidney (85%), liver (15%) Side effects : hypertension, tachycrdia, dysrhythmia,

Vecuronium Analogue of pancuronium Much less vagolytic effect and shorter duration than pancuronium Onset 3-5 minutes duration 20-35 minutes Elimination 40% by kidney, 60% by liver

Rocuronium Analogue of vecuronium Rapid onset 1-2 minutes, duration 20-35 minutes Onset of action similar to that of succinylcholine Intubating dose 0.6 mg/kg Elimination primarily by liver, slightly by kidney

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 25-35 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).

Cisatracurium Isomer of atracurium Metabolized by Hofmann elimination Onset 3-5 minutes, duration 20-35 minutes Minimal cardiovascular side effects Much less laudanosine produced

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.

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)

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

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

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

What do we do about side effects? Muscarinic side effects are minimized by anticholinergic agents Atropine Dose 0.01-0.02 mg/kg Scopolamine glycopyrrolate

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

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

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 300-800 mcg/day

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

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

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)

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

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.

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

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.

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

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

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

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