Skeletal Muscle Relaxants SKELETAL MUSCLE RELAXANTS asthenia

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					SKELETAL MUSCLE RELAXANTS

Neuromuscular Blocking Agents
nondepolarizing blockers:                                     depolarizing blocker:
        Tubocuraine -isoquinoline (long acting)                        Succinylcholine
        Atracurium
        Mivacurium
        Doxcurium – no CV effects
        Metocurine
        Pancuronium – steroid
        Rocuronium --no CV effects
        Rapacuronium – no CV effects
        Pipecuronium – no CV effects
        Vecuronium – no CV effects

Spasmolytic drugs:                                                     Drugs acting directly on skeletal muscles:
benzodiazepines: Diazepam (Valium)                                     Dantrolene (Dantrium)
Baclofen                                                               Botulinum Toxin Type A (Botox)
Tazanidine

Drugs used for acute local muscle spasm: centrally-acting
Cyclobenzapine
Carisoprodol
Chlorphenesin
Orphenaddrine
Methocarbamol

Neuromuscular blocking agents
-drugs used during surgical procedures to cause muscle paralysis by interfering with transmission at the neuromuscular junction
without CNS activity
-2 classes: nondepolarizing (competitive) and depolarizing blocking agent
-curare: -generic term for various South American arrow poisons discovered centuries ago;
         -first used for promoting muscle relaxation with general anesthesia in the 1940s
-tubocurarine: active alkaloid in curare
-numerous drugs can enhance the effects of NM blocking agents:
         -inhalation anesthetics (eg. halothane because they have general CNS depressant effects)
         -antibiotics (esp. aminoglycosides which can decrease ACh release from neuromuscular junction)
         -calcium channel blockers (which decreases calcium influx resulting in decrease presynaptic release of NT)
         -antiarrhythmnic agents (eg. quinidine which blocks sodium channels preventing depolarization of postsynaptic neuron)
         -local anesthetic agents (also blocks sodium channels)


Nondepolarizing (Competitive) Neuromuscular Blocking Drugs
-MOA: -blocks nicotinic receptors competitively resulting in inhibition of sodium channels and excitatory postsynaptic
          potential (EPP)
          -competitively binds with ACh on nicotinic receptor and prevents opening of the sodium channels
          -reversible; surmountable
-anticholinesterase drugs (eg neostigimine, edophonium – which increases ACh in synapse) can antagonize the effects of
tubocurarine and other nondepolarizing neuromuscular blocking agents because the block is surmountable
-can be subdivided into 2 groups: -isoquinoline (tubocurarine – metocurine on above list)
                                     -steroid (pancuronium – vecuronium on above list)
-effects: -causes muscle paralysis
          -sequence of paralysis:    -small, rapidly moving muscles are affected earliest – fingers, toes, jaws, eyes, etc.
                                     -next, the muscles of the limbs, neck, and trunk
                                     -lastly, intercostals muscles and diaphragm = respiratory arrest / death
          -sequence of recovery:     -usually occurs in reverse order: diaphragm > limbs, trunk > fingers, toes, eyes
-other effects:    -CV:     -with the exception of vecuronium, pipecuronium, doxacurium, rocuronium, and rapacuronium, all
                            nondepolarizing muscle relaxants produce some CV effects—especially tubocurarine
                            -tubocurarine can result in pronounced hypotension due largely to histamine release and sympathetic
                            ganglionic blockade – reflex tachycardia
                            -pancuronium can increase heart rate and blood pressure – vagolytic (agent with inhibitory effects on the
                            vagus nerve)
-pharmacokinetics:          -quaternary ammonium compounds which are poorly absorbed from GI tract; IV(preferred) or IM
                            -following IV administration, get rapid redistribution phase followed by slower elimination phase
                            -elimination: undergo varying degrees of liver metabolism; others are excreted in the urine
                                      -atracurium – spontaneously degraded by hydrolysis
                                      -mivacurium and succinylcholine (depolarizing NM blocking agent) – degraded by plasma
                                      cholinesterase sometimes called pseudocholinesterase
-duration of action:        -short acting (10-20min duration): mivacurium, succinycholine (depolarizing NM blocking agent)
                            -intermediate acting: atracurium, rocuronium, vecuronium
                            -the rest are long acting >35 min duration
-clinical uses:    -adjuncts to general anesthetics during surgery
                            -for short surgical procedures, use short acting: atracurium, mivacurium
                            -for endotracheal intubation: rocuronium
                   -for controlled mechanical ventilation – COPD
                   -prevent trauma during convulsions
-adverse effects: -prolonged apnea
                   -antagonized with cholinesterase inhibitors (eg. neostigmine)
-drug interactions can cause:         -respiratory depression
                                      -myasthenia gravis: d/o of NM transmission, marked by fluctuating weakness, esp. oculofacial
                                      muscles and the proximal limb muscles; the weakness characteristically increases with activity
                                      -renal impairment
                                      -liver or CV impairment

Tubocurarine
-weak block on autonomic ganglia
-moderate tendency to cause histamine release
-produces pronounced hypotension due to histamine release and sympathetic ganglionic blockade

Mivacurium
-short-acting (degraded by plasma cholinesterase)
-moderate tendency to cause histamine release

Pancuronium
-moderate block on cardiac muscarinic receptors
-vagolytic effects including increase heart rate and blood pressure

Vecuronium
-intermediate-acting

Rocuronium
-intermediate acting
-can be used for endotracheal intubation

Atracurium
-intermediate-acting
-degraded spontaneously via hydrolysis

Succinylcholine -- depolarizing neuromuscular blocking agent
-short acting (degraded by plasma cholinesterase)
-stimulates autonomic ganglia
-stimulates cardiac muscarinic receptors
-slight histamine release


Depolarizing Neuromuscular Blocking Agents
-only one member of this group: succinylcholine (see above, some characteristics discussed with nondepolarizing NM blocking
agents)

-MOA: -block transmission by causing prolonged depolarization of the endplate at the neuromuscular junction
      -phase 1: this is manifested as an initial series of muscle twitches (fasciculations), followed by flaccid paralysis
               -phase 1 blockade is potentiated by anticholinesterases and antagonized by competitive blockers
          -phase 2: if the duration of blockade is prolonged, or if the concentration of the blocker is excessive, then phase 2 blockade
                    occurs in which the pharmacological characteristic is that of a competitive inhibition (resembles nondepolarizing
                    block) and desensitization
                    -phase 2 blockade is antagonized by anticholinesterases and potentiated by competitive blockers
-biochemically, what occurs is:
                    -upon initial use: binds to nicotinic receptor, opens sodium channels, and causes depolarization blockage resulting
                    in muscle twitching, but not prolonged muscle contraction
                    -upon prolonged use: it blocks the opened channel and physically prevents the influx of sodium resulting in
                    desensitization and flaccid paralysis
-duration is brief (5-10 min); effects can be prolonged by repeated injections
-other effects:     -cardiac arrthymias can occur; bradycardia can be prevented by atropine
                    -hyperkalemia – can be life threatening
                              -caused by potassium loss released from muscles
                              -caution in patients with burns, nerve damage, neuromuscular disease, children
                    -slight histamine release
-pharmacokinetics:            -IV; short duration due to rapid inactivation by plasma cholinesterase
                              -unusually prolonged duration: apnea will occur in patients with an abnormal variant of
                              pseudocholinesterase (an autosomal recessive trait in ~1% of Caucasians; rare in Asians and Blacks)
                              -dibucaine number: test for ability to metabolize succinylcholine and can be used to screen
                              aforementioned patients
-clinical uses:     -adjunct to general anesthesia for brief procedures and to facilitate endotracheal intubation
                    -prevent convulsions during electroconvulsive therapy
-adverse reactions:           -apnea; hyperkalemia; increase intraocular pressure
                              -apnea results from relaxation of intercostals muscles; best treated by mechanical ventilation;
                              cholinesterase inhibitors will antagonize only phase 2 and are therefore not effective
                              -emesis, muscle pain (up to 20%)
                              -malignant hyperthemnia:-results from a genetic defect of sarcoplasmic reticulum
                                                           -sudden and prolonged release of calcium with massive muscle contraction and
                                                           increased body temperature
                                                           -highest incidence occurs with succinylcholine and halothane
                                                           -life-threatening
                                                           -treatment: cooling; oxygen administration; dantrolene – IV
-cautions, contraindications:          -genetic disorders of plasma cholinesterase
                                       -hx of malignant hyperthermia
                                       -acute angle-closure glaucoma
                                       -respiratory, liver, cardiovascular, renal d/o’s
                                       -electrolyte imbalance


Nerve Stimulation
-there are three patterns of nerve stimulations which are used clinically to monitor the degree of neuromuscular blockade:
          -train-of-four:    -brief train of four stimuli; the ratio of the amplitude of 4th response (S4) to the amplitude of the 1st
                             response (S1) in the train is a widely used measurement of the degree of neuromuscular blockade
                             -with nondepolarizing blocks, the ratio is 0.4
                             -with depolarizing blocks: -phase 1: the ratio is 1
                                                           -phase 2: the ratio is 0.4
          -double burst      -with nondepolarizing blocks: there is a fade after the first stimulation
                             -with depolarizing blocks: -phase 1: no fade
                                                           -phase 2: fade
          -posttetanic stimulation -with nondepolarizing blocks: -there is potentiation/facilitation and then fade
                                       -with depolarizing blocks:         -phase 1: no potentiation/facilitation or fade
                                                                          -phase 2: potentiation and fade in phase 2
-take home point: non-depolarizing blockade is similar to phase 2 of depolarizing blockade
Spasmolytic drugs
-spasticity: increased skeletal muscle tone of central origin resulting in increase in tonic stretch reflexes and flexor muscle spasms
(and muscle weakness); the hyperactivity results from a loss of spinal and supraspinal descending inhibitory influences on motor
neurons (ie. upper motor neuron lesions)
-spasticity is associated with strokes, CNS injuries, cerebral palsy, and multiple sclerosis
-drugs may ameliorate some of the symptoms of spasticity by modifying the stretch reflex or by interfering directly with the process of
excitation coupling in the muscle

Benzodiazepines: Diazepam (Valium)
-MOA: enhances GABA-mediated presynaptic inhibition
-clinical uses:  -spastic states and spasm due to local muscle trauma
                 -limited sedation with greatest benefit seen in patients with MS and spinal cord injury
-psychological and physical dependence can occur (Schedule IV drugs)

Baclofen
-MOA: GABA agonist; causes hyperpolarization and presynaptic inhibition
          -inhibits release of excitatory transmitters (eg. glutamic acid, aspartic acid) involved in spinal reflex pathways
-effects: -very effective in relieving involuntary flexor spasms and resistance to passive movements
          -less sedating than Diazepam
-pharmacokinetics:            -well absorbed orally; intrathecal via an implantable infusion pump
                              -widely distributed, excreted primarily by the kidney unchanged
                              -plasma half-life is 3-4 hours
-adverse reactions:           -drowsiness, lassitude, dizziness
                              -ataxia, confusion, hallucinations, seizures
                              -intrathecal: coma, respiratory depression, seizures
-cautions:          -avoid abrupt withdrawal: hallucinations, psychosis, seizures have been reported upon withdrawal
                    -impaired renal function
                    -epilepsy
                    -CNS depressants
-clinical use:      -spasticity in patients with MS and spinal cord injury
                    -trigeminal neuralgia


Tizanidine
-structurally related to clonidine
-MOA: -alpha-2 agonist; increases presynaptic inhibition of motor neurons
          -also inhibits nociceptive transmission in the spinal cord
-side effects:      -asthenia (weakness – 41%);
                    -drowsiness, hypotension, dry mouth

Drugs that act directly on skeletal muscle

Dantrolene
-a hydantoin derivative
-MOA: -may bind to the ryanodine receptors on the calcium channel of the sarcoplasmic reticulum
          -decrease calcium release and excitation-contraction coupling in skeletal muscles
-effects: usually diminishes spasticity but tends to cause generalized muscle weakness
-pharmocokinetics:           -oral absorption is slow and incomplete; IV for malignant hyperthermia
                             -slowly metabolized in the liver (hydroxylated); half-life is about 8 hrs
-adverse reactions:          -muscle weakness, drowsiness
                             -severe liver toxicity, potentially fatal hepatitis
-caution, contraindications:           -liver disease
                                       -ambulatory patients
                                       -perform liver function test periodically
                                       -patients over age 35, esp. females
-clinical use:     -spasticity of cerebral origin (oral)
                   -malignant hyperthermia (IV, DOC)
Botulinum toxin type A (Botox)
-obtained from clostridium botulinum; given IM
-MOA: -decrease ACh release and decrease neuromuscular conduction resulting in muscle paralysis and reduced wrinkles
          -muscle function returns gradually over 3-6 months
-clinical use:     -strabismus (lack of parallelism of the eyes) ; blepharospasm (involuntary muscle contraction of the eyelids)
                   -cervical dystonia (spasmodic torticollis); writer’s cramp; spasms due to MS or cerebral palsy
                   -reduces wrinkles or frown lines
-adverse reactions:         -dysphagia (difficulty swallowing - 20%); dyspnea (shortness of breath), aspiration, pneumonia
                            -muscle weakness, dyspepsia (impaired gastric function), pain at injection site
                            -severe headache; temporary ptosis; drooling and asymmetrical smile


Drugs used for acute local muscle spasm
-centrally acting skeletal muscle relaxants
-most muscle strains and minor injuries are self-limiting and respond rapidly to rest and physical therapy – immobilization, cold
compresses, whirlpool baths, etc.
-these drugs may provide some symptomatic relief in localized muscle spasm; all are CNS depressants and act as sedatives

Cyclobenzapine
-related structurally and pharmacologically to tricyclic antidepressants
-has some adjunctive muscle relaxant capabilities at a dose of 30mg
-effects: -strong antimuscarinic effects
-adverse reactions:         -sedation, dry mouth, dizziness
                            -tachycardia, blurred vision, confusion, visual hallucination, urinary retention
-cautions:         -urinary retention
                   -glaucoma


Clinical Case Scenario
A patient underwent a surgical procedure lasting 2 hrs. Anesthesia was provided by isoflurane, supplemented by intravenous
midazolam (sedative hypnotic) and a nondepolarizing muscle relaxant. At the end of the procedure, glycopyrrolate
(antimuscarinic agent) was administered followed by pyridostigmine (anticholinesterase inhibitor).

The main reason for glycopyrrolate administration is to prevent activation of cardiac muscarinic receptors
       -when administering a cholinesterase inhibitor  can inc ACh  inc vagal effect to heart  causes bradycardia and heart
       block  need to give atropine-like compound to block effect on heart.

Glycopyrrolate would be LEAST likely to be needed during reversal of the effects of a nondepolarizing relaxant if the agent
used was: Pancuronium
       -Pancuronium itself has antimuscarinic effects

				
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Description: Skeletal Muscle Relaxants SKELETAL MUSCLE RELAXANTS asthenia