Skeletal Muscle Relaxants Flashcards
What type of transmission process will evoke a skeletal muscle contraction?
Nicotinic cholinergic
What are neuromuscular blocking drugs normally used for?
Adjuncts to general anesthesia, to facilitate intubation and optimize surgical conditions
Which areas of the body do skeletal muscle relaxants NOT have effect on?
Cardiac and smooth muscles
Central nervous system
What are spasmolytic or “centrally-acting’ muscle relaxants used for?
Treat chronic back pain
Painful fibromyalgic conditions
Difference in muscle reaction and central activity between neuromuscular blocking agents vs spasmolytic drugs
Neuromuscular blocking agents: Cause paralysis with NO central effect
Spasmolytic drugs: Reduces spasticity WITH central effects
Which receptors are not normally involved in neuromuscular transmission but proliferate in pathologic conditions like prolonged immobilization in CVS and thermal burns?
Perijunctional/extrajunctional receptors
Stimulation of __________ receptors mobilizes addtional NT towards synaptic membrane to increase Ach at the synapse.
Presynaptic motor axon terminal receptors
Where can you find Nicotinic cholinergic receptors
NMJ
Peripheral autonomic ganglia
In the CNS, nicotinic cholinergic receptors controls _______ release from the ________ sites.
Neurotransmitter; presynaptic
What does binding of Ach to nicotinic cholinergic receptors initiate in muscle? in peripheral ganglia?
End plate potential (EPP); Excitatory postsynaptic potential (EPSP)
Nicotinic cholinergic receptors are composed of how many subunits? And what subunits are these?
5; 2 alpha subunits, 1 beta, 1 gamma, 1 delta
1 gamma is switched to 1 epsilon in adults
In what subunit(s) does Ach bind to in order to cause a conformational change in the nicotinic cholinergic receptor?
Alpha subunits (particularly alpha-beta and alpha-delta
The 2 molecules of Ach must bind ________ in order to cause conformational change in nicotinic cholinergic receptor.
Simultaneously
True or False. A conformational change in the nicotinic cholinergic receptor can be elicited with the binding of 1 molecule of Ach.
False. 2 molecules MUST bind simultaneously in order to elicit a conformational change.
What are the 2 types of muscle relaxants?
Neuromuscular blockers and Spasmolytics
What are the 2 types of neuromuscular blockers?
Nondepolarizing and Depolarizing neuromuscular blockers
What are the 2 subdivisions of nondepolarizing neuromuscular blockers?
Steroidal (“-curonium”) and Isoquinoline derivatives (“-curium”)
What are the steroidal nondepolarizing neuromuscular blockers?
Pancuronium Pipecuronium Rocuronium Papacuronium Vecuronium (PPRRV "-curonium")
What are the isoquinoline derivative nondepolarizing neuromuscular blockers?
Tubocurarine (prototype, first NMB synthesized) Metocurine Doxacurium Atracurium Mivacurium Cistacurium
What is are examples of depolarizing neuromuscular blockers? Which is the only one used clinically?
Succinylcholine (only one used clinically)
Decamethonium
Structural difference between Ach and succinylcholine
Presence of additional 1 or 2 quaternary nitrogens
What ring structure do steroidal derivatives have? Isoquinoline derivatives?
4 ring (steroid nucleus) structure; Basic ring structure
Nondepolarizing neuromuscular blockers are ________ antagonists to the __________ receptors at the __________ of skeletal muscles.
Competitive; Nicotinic cholinergic; NMJ
Nondepolarizing neuromuscular blockers cause the release of _________ to cause bronchospasm, peripheral vasodilation with subsequent hypotension.
Histamine
What route must NMB be given?
Parenteral; they are inactive orally.
NMB exhibit (rapid / slow) initial distribution phase and (rapid / slow) elimination phase
RAPID initial distribution
SLOWER elimination
Steroidal derivatives are mainly metabolized in the __________.
Liver.
What are the metabolites of steroidal derivatives in general? Which is most important and why?
3-hydroxy, 17-hydroxy, 3,17-dihydroxy;
3-hydroxy is 40-80% are potent as the parent drug and therefore produces neuromuscular blockade (accumulation causes prolonged paralysis)
Atracurium and cistacurium produce this metabolite.
Laudanosine
What is “Hoffman elimination”?
Spontaneous deactivation of atracurium (and cisatrucurium) to laudanosine.
What is the half-life of laudanosine? Why is this of importance?
150 minutes. It can therefore accumulate and cause cerebral side effects (high concentrations readily cross BBB) = SEIZURES
Advantage of cisatracurium (potent isomer of atracurium) over atracurium.
Less side effects
Nondepolarizing neuromuscular blockers with liver excretion? Significance?
Rocuronium
Vecuronium
**Shorter 1/2 lives and duration of action
Nondepolarizing neuromuscular blockers with renal elimination? Significance?
Pipecuronium (60%)
Doxicurium, Pancuronium (80% - long 1/2 life)
Tubocurarine (40%)
Metocurarine (40%)
**Longer 1/2 lives and duration of action
Nondepolarizing neuromuscular blockers with plasma elimination? Significance?
Atracurium
Cisatracurium
Mivacurium
**Can be given to patients with liver and kidney dysfunction
Which of the nondepolarizing neuromuscular blockers have the fastest time of onset?
Rocuronium (60-120 seconds)
Nondepolarizing neuromuscular blockers with short duration (10-20 minutes)?
Mivacurium
Nondepolarizing neuromuscular blockers with intermediate duration (20-35 minutes)?
Atracurium
Vecuronium
Rocuronium
Nondepolarizing neuromuscular blockers with long duration (>35 mins)?
Pancuronium Tubocurarine Gallamine Doxacurium Metocurine Pipercurium
Mechanism of action of nondepolarizing neuromuscular blockers in low dose?
Low: compete for binding to postsynaptic nicotinic receptor sites in NMJ of skeletal muscle, Interfere with presynaptic release of Ach
Mechanism of action of nondepolarizing neuromuscular blockers in high doses?
More intense motor blockade by blocking the pore of the nicotinic receptor channel complex
Which muscles are affected first in neuromuscular blockade?
Small muscles (face, had, foot) –> large muscles (abdominals, trunk, paraspinous, diaphragm) last
Which muscle is paralyzed last by NMBs? Which recovers first?
Diaphragm; Diaphragm =D
Recovery of the muscles in NMB is in what order?
Reverse. Last ones affected are first to recover, etc…
Nondepolarizing neuromuscular blockers have a ______ volume of distribution?
Limited (will only be slightly above blood volume (80-140 ml/kg)
Nondepolarizing neuromuscular blockers with mininmal effects on the CVS?
Vecuronium
Pipecuronium
Doxacurium
Rocuronium
Nondepolarizing neuromuscular blockers that cause hypotension 2/2 histamine release causing vasodilation (in order of most to least)
Tubocurarine»_space; Metocurine > Atracurium > Mivacurium > (Cisatracurium)
Nondepolarizing neuromuscular blockers that cause ganglionic blockade in large doses
Tubocurarine
Metocurarine
Nondepolarizing neuromuscular blockers that increase HR, CO with increased systemic vascular resistance?
Pancuronium
Characteristics of selected nondepolarizing neuromuscular blockers: Rapacuronium
Shortest onset and duration
Alternative to succinylcholine
High incidence of severe bronchospasm
OUT OF CLINICAL USE (Hello!?!?! picka different one to teach us then!!!)
Characteristics of selected nondepolarizing neuromuscular blockers: Mivacurium
High doses cause histamine release
Caution: Pt with hx of allergies, asthma
Characteristics of selected nondepolarizing neuromuscular blockers: Atracurium
Primary inactivation is by Hoffman Elimination (metabolite: laudanosine)
Cause seizures at high concentration of laudanosine metabolite
Mechanism of action of depolarizing neuromuscular blockers (Succinylcholine)
Nicotinic AGONIST causing twitching and fasciculations initially
What enzyme(s) degrade succinylcholine?
Butyrylcholinesterase (liver enzyme)
Pseudocholinesterase (plasma enzyme)
Difference between succinylcholine and acetylcholine
Slower hydrolysis therefore stays at receptor site longer and repeated opening and closing of receptor channel
Why is succinylcholine given in continuous infusion?
Only small doses reach the NMJ d/t hydrolysis in the plasma by pseudocholinesterase
What is the onset of action of succinylcholine? duration of action?
60-90 seconds; 5-10 minutes
What conditions prolong succinylcholine blockade?
Decreased pseudocholinersterase levels Atypical pseudocholinesterases (abnormal gene variant)
What kind of patients will have decreased pseudocholinesterase levels?
Liver disease Pregnant Burn Patients on oral contraceptives Patients on MAOI, echothiopate, cytotoxic drugs, neoplastic disease, anticholinesterases, tetrahydroamacrine, hexafluorenium
What is the dibucaine number and how does it predict paralysis time?
Dibucaine # is the % enzyme that is inhibited by dibucaine. It predicts the ability of the patient to metabolize succinylcholine; The lower the dibucaine number, the longer the paralysis time
What is the normal dibucaine number (homozygous typical)
70-80
Dibucaine number for heterozygous ATYPICAL? How much longer is the neuromuscular blockade in response to mevacurium/Sch?
50-60; increased by 50-100%
Dibucaine number for homozygous ATYPICAL? How much longer is the neuromuscular blockade mevacurium/Sch?
20-30; increased by 4-8 hours
What are the 2 phases in depolarizing neuromuscular blockade?
Phase I or Depolarizing block
Phase II or Desensitizing block
Describe the Phase I block
Sch binding to 2 alpha subunits cause opening of the channel with subsequent repetitive depolarization
Repetitive firing causes fasciculations until action potential cannot occur (depolarizing block = no end plate repolarization)
No excitation-contraction coupling causing flaccid paralysis
True or False. Cholinesterase inhibitors augment phase I block.
True.
Describe the Phase II block
Higher doses = prolonged closed state
There is gradual repolarization but NM transmission remains blocked d/t desensitized membrane (channel block)
Phase II block is (sensitive / not sensitive) to cholinesterase inhibitors?
Sensitive
Effects of Sch on CVS
- Cardiac arrythmias with halothane (sinus bradycardia, ventricular arrythmias)
- Stimulation of ALL cholinoreceptors ((-) ionotropic & chronotropic effects)
- Direct myocardial effects (increased muscarinic and ganglionic stimulation)
How to prevent effects of Sch on CVS
Thiopental
Atropine
Ganglionic blocking drugs
Nondeoplarizing NMB
Adverse effects of Depolarizing NMBs
Hyperkalemia Cardiac arrest especially in children with subclinical Duchenne's muscular dystrophy Malignant hyperthermia Increased IOP Increased intragastric pressure Muscle pains (myalgia) 2/2 fasciculations Masseter spasm Increased(?) ICP
Effect of tubocurarine (0.1-0.4 mg) infusion
Initially motor weakness flaccidity and inexcitable to motor stimulation
Effect of Sch (1-2 mg/kg) infusion
Transient muscle fasciculations (chest, abdomen, arm, neck, legs) and then paralysis of respiratory muscles
When do you monitor effects of NMB?
1) Before intubation
2) Intraoperatively
3) During recovery - spontaneous and after reversla of cholinesterase inhibitor
How do you assess neuromuscular transmission?
By nerve stimulation (transdermal electrical stimulation of peripheral nerve of the hand and recording the pattern of contractions/twitches
What is the TOF (train of four) ratio?
After application of four stimuli of 2Hz, TOF ratio is the ratio of the strength of the 4th contraction to the 1st contraction.
In late phase II, the blockade characteristics are identical to those of _________ block. Describe. How is this reversed?
NONdepolarizing block; Nonsustained twitch response to a tetanic stimulus; Reversal by acetylcholinesterase inhibitors.
What does the single twitch pattern of electrical stimulation determine?
Determines peak effect
What does the TOF pattern of electrical stimulation determine?
Differentiates nondepolarizing vs depolarizing block
What does the double burst pattern of electrical stimulation determine?
It detects residual of neuromuscular block
A TOF ratio of 0.15-0.25 is indicative of?
Adequate surgical relaxation
A TOF ratio of ______ is needed for safe extubation adn recovery after surgery?
> 0.9
Pancuronium is contraindicated in tachycardic patients because?
it is a sympathetic stimulator
Drug interactions that augment or enhance neuromuscular block
Anesthetics
Antibiotics: aminoglycosides
Local anesthetics (high doses block neuromuscular transmission)
Drug interactions that increase duration of Sch
Sch given after administration of neostigmine
Drug interactions that prevent fasciculations from Sch
Nondeoplarizers given before Sch increase dose requirement of Sch
Effect of Myasthenia gravis (Sch infusion)
Enhanced neuromuscular blockade
Effect of age (elderly >70 YO) (Sch infusion)
Prolonged duration d/t decreased clearnce
decreased dose needed
Effect of UMN disease, burns
DO NOT USE in burns
Resistance to nondepolarizing blocker
Dose increase needed
How do you reverse the blockade of nondepolarizing blockers
Competitive antagonism Provide cholinesterase inhibitors (increase Ach) - neostigmine, pyridostigmine, edrophonium Anticholinergic added (atropine) to counter cholinergic effects
What is Suggamedex?
Novel cyclodextrine drug, rapidly inactive steroidal NMB drug, it is a selective relaxant binding agent
How do spasmolytics relieve muscle spasms?
Modify the stretch reflex arc or by interfering directly with the skeletal muscle
Which spasmolytic does not act on the CNS?
Dantrolene
Examples of centrally-acting spasmolytics
Diazepam Baclofen Cyclobenzaprine Carisoprodol Methocarbamol Chlorophenasin carbamate Chlorozoxasone Orphenadrine citrate Menphanasin
Examples of peripherally-acting spasmolytics
Dantrolene
Episirone HCl
Pheniramidone
Mechanism of action of diazepam
Binds with components of GABA(A) to facilitate GABA mediated presynaptic inhibition
Mechanism of action of baclofen
Agonist of GABA(B) receptor resulting to hyperpolarization
Reduces pain by inhibition of substance P
Mechanism of action of Tizanidine
Significant alpha2 adenoreceptor agonist with fewer CVS effects
Mechanism of action of Dantrolene
Interferes with the release of calcium from SR by binding to the ryanodine receptors (prevents channel opening)
Prevents excitation-contraction coupling
What is the drug of choice for malignant hyperthermia?
Dantrolene
Malignant hyperthermia is a result of?
Massive release of calcium from SR leading to uncontrolled contraction and stimulation of metabolism in skeletal muscles
