Muscle relaxants Flashcards
Why might we need muscle relaxation?
- to offset muscle hypertonicity with ketamine (increases muscle tone as induction agent)- can use BZPs, alpha 2s
- to relieve muscle spams (BZPs)–>pulled muscle
- to facilitate smooth induction of anaesthesia in large animals (GGE)–> centrally acting
- to improve surgical conditions
How do we produce adequate muscle relaxation for surgery
- deep general anaesthesia: induction and maintenance provide muscle relaxation- nb: profound CV depression
Local anaesthesia: can inject LA around motor nerve, muscle will relax i.e. epidural anaesthesia
Centrally acting muscle relaxants: BZPs– provide SOME muscle relaxation- centrally, not locally acting. high doses to get good muscle relaxation (side effect=respiratory depression)
Neuromuscular blocking drugs: prevent transmission at neuromuscular junction
Curare
naturally occuring muscle relaxant
not absorbed GI, don’t work orally (polar molecules)
Mechanism of action of Neuromuscular blocking drugs (NMBs/NMBDs)
target Nicotinic ACh receptor at neuromuscular junction
Signal tranmission: action potential–> calcium release pre-synaptically–>exocytosis of ACh–>activated ACh receptors open ion channels–> NA+ influx into muscle–> EPP–>AP–>contraction
ACh broken down by acetylcholinesterase– terminates action, rapidly brings ACH back into nerve terminal
NMBs: depolarizing or non-depolarizing action at post-synapstic cell. Agonists or antagonists at receptors
NB: ANTIcholinesterases block acetylcholinesterases. Can use anticholinesterase to reverse non-polarizing drugs.
NMBs work by interfering with post-synaptic action of ACh
non-depolarising: tubocurarine, gallamine, pancuronium, vercuronium, atracurium, rocuronium
depolarising: suxamethonium- not widely used in vet med
Non-depolarizing NMBs-Mechanism of action
Competitive antagonist at the nicotinic ACh receptor. Reversible! Block transmission from ACh from binding.
rigid, bulky molecules with quarternary N (polar, charged)- won’t cross cellular membranes, won’t distribute very far in body
Need to block ~80% of receptor sites- muscle tissue have receptor reserve. to block system, need to block a high proportion of receptors
Transmission is “all or nothing”- muscle either contracts or doesn’t. The varying degree of block relates to the proportion of fibres
Some may block ion channels: at higher concentrations
Reversed by anticholinesterases (if you increase the presence of ACh, can overcome block)
Muscles can still respond to K+ or direct electrical stimulation
Non-depolarizing NMBs: effects and side effects
Effects: flaccid motor paralysis- rapidly moving muscles see 1st effects
respiratory muscles last to be effected and first to recover
NB: consciousness and perception of pain are normal- no analgesic propertises. should be used as part of analgesic/anaesthetic protocol
Unwanted effects: fall in BP: ganglion block/histamine release– targeting nicotinic receptors–> N receptors at sympatetic ganglia–>fall in BP
tachycardia: muscarinic receptor block- not totally specific for nicotinic, can bind to muscarinig receptors–> decrease PS–> tachycardia
Pharmacokinetics of NMBS
mostly quaternary ammonium compounds (some steroid base)
Administered IV only- Vd ~ ECF, not highly plasma protein bound
Rate of onset and duration vary
generally metabolized by the liver or can be excreted unchanged by the kidney
Don’t cross BBB (due to physical structure) or placenta (safe to use in c-section)
Two main groups of non-depolarizing NMBs
aminosteroids (suffix “onium”): vecruonium, rocuronium, pancuronium
Benzylisoquinolines: most likely to release histamine (more of a problem in humans)
atracurium, cisatracurium, mivacurium
Vecuronium
aminosteroid non-depolarizing NMB
steroid compound
devoid of CV side-effects: most cardiostable of all muscle relaxants- no drops in CO or BP, choose for cardiac disease
excreted unchanged in bile- prolonged duration of action in severe hepatic disease (avoid if liver disease)
non-cumulative: short acting, topped up as necessary, can give as infusion
Rocuronium
aminosteroid non-depolarizing NMB
fastest onset of any non-depolarizing agent (<2 minute)
occasional tachycardia in dogs
non-cummulative
Atracurium
benzylisoquinolone
can release histamine (uncommon in animals)
Hoffmann elimination: spontaneous degradation at physiological pH and temperature. Not dependent on organ for elimination- choose this if we have patient with hepatic disease. No prolonged duration due to spontaneous breakdown in plasma.
must be stored in fridge.
Relaxants- practical use
relaxants ONLY administered IV
they will induce apnea, so patient must be mechanically ventilated
they are only administered to anaesthetized patients- can’t control ventilation in conscious patient
no anaesthetic or analgesic effects
non-depolarizing NMBs can be “topped up” or given by infusion IV for as long as required.
if you give a clinically sufficient dose, ALL muscles affected (just at different rates). Diaphgram and IC mm are most resistant and last to become affected and first to start working again. Muscles of pharyngeal area highly sensitive, eye becomes centrally fixed.
possible for patient to start breathing again as relaxant effects wears off, but not able to maintain patent airway.
Choosing a relaxant
NB: not relaxants licensed for animal use
Pre-existing pathology: cardiostability (vecuronium); renal /hepatic disease (atracurium); rapid onset (rocuronium)
Depolarizing NMBs
Mechanism of action: agonist at nicotinic ACh repector, but metabolised slowly. ACh normally rapidly cleared from synapsed. Depolarizing NMB slowly metabolised–>persistence of action–>rapid loss of muscle control–> muscle relaxes.
Flexible structure with free bond rotation- doesn’t block, but interacts with receptor as agonist.
enhanced by anticholinesterases- can’t be reversed in the same way as non-depolarizing NMBs
leads to loss of electrical excitability of muscle cells
no longer respons to K+ or electrical stimulation
Effects: initial fasciculation- twitching/trembling–> individual muscle fibres contracting
subsides as electrical excitability is lost
Phases of depolarizing NMBs
Phase 1: depolarizing, fasciculations, presence of agonist prevents repolarization–> muscle can’t contract
Phase 2: desensitizing- depolarizing shouldn’t be given by bolus or by infusion–> only should be used for short term effects. Ion channels in a prolonged closed state. could be due to channel block or development of unexcitable tissue.
Depolarizing NMBs side effects
non-selective agonist–> can also stimulate muscarinic receptors
bradycardia
potassium release due to prolonged opening of channels–> can cause heart issues
increased intra-ocular pressure due to constriction of muscles surrounding eye
prolonged paralysis: normally 5-20 minutes but can get prolonged (i.e. with use in anticholinesterases) some individuals who lack enzyme to break down these drugs; hepatic impairment can also results in this prolonged paralysis
Malignant hyperthermia
Suxamethonium (succinylcholine)
depolarizing NMBs- v. limited use in vet med
Rapid onset: <1 min
popular in humans for ET tubes
short duration: 3-6 minutes in cats; 15-20 minutes in dogs (not sued in dogs)
Metabolised by plasma and liver cholinesterase- produced by liver- in hepatic disease–> long duration of action.
only used as a single dose
only real indication is feline ET intubtion- when we need to get ET tube in quickly
cat has v. sensitive larynx, can spasm, normally spray LA but that takes a couple minutes.
If we have a cat with a full stomach that needs to be intubated for emergency surgery, a couple minutes is too long–> can use suxamethonium.
Comparison of depolarizing vs. non-depolarizing NMBs
Suxamethonium: initial muscle fasciculation prior to relaxtion, can’t be topped up, can’t be antagonized
Non-depolarizing NMBs: no initial fasciculations, can be topped up as required, can be antagonized.
Indications for use of NMBs
to faciliate ET intubation
to relax skeletal muscle for easier surgical access- i.e. deep dissections of abdomen
to control ventilation during anaesthesia- i.e. during cardiac surgery
ophthalmic surgery: central paralysis of extraocular muscles
Recovery of neuromuscular blockade
will occur spontaneously
as plasma concentration of relaxant declines, drug will move down it’s concentration gradient from NMJ into plasma. Eventually, sufficient relaxant will have left to restore NM transmission.
Can be hastened with NON-depolarizing relaxants only by administering ANTIcholinesterases
Non-depolarizing relaxants are competitive: if ACh concentrations increase to a sufficient level at the NMJ, tranmission will be restored. ACh is broken down by acetylcholinesterases, so if this enzyme is inhibited by anticholinesterase, ACh levels will increase.
Anticholinesterases
neostigmine and edrophonium (common)
pyridostigmine
only effective against NON-depolarizing relaxants
ACh concentrations increase not olny at the NMJ but throughout the body
Action of ACh at muscarinic receptors–> parasympathetic side effects–> bradycardia, salivation, bronchoconstriction, urination and defecation
As a result of these muscarinic effects, usually combined with antimuscarinic/anticholinergic drugs: atropine or glycopyrrolate.
Sugammadex
novel antagonist to rocuronium/vecuronium
cyclodextrin molecule
surrounds relaxant, rendering it inactive
no antimuscarinic needed- no side effects.
expensive
Factors affecting NM blockade
Other drugs: anaesthetics, anticholinesterases, ABX- some aminoglycosides prolong some fx on non-depolarizing NMBs- horses: gentamycin can prolong muscle relaxant effect.
Pathophysiological conditions: hepatic/renal impairment, age (very old, very young get prolonged effect), temperature, acid-base balance, electrolyte disturbance, myasthenia gravis- auto-immune antibodies against ACh receptor. very prolonged side effects fom non-depolarizing agents.
Centrally acting muscle relaxants
BZPs and Guaifenesin
Guaifenesin
=glycerol gualacolate or “Gee gee”, GGE
mechanism of action: blocks impulse transmission at internuncial neurones within spinal cord and brain stem
Effects: relaxes limbs more than respiratory muscles
mild sedation, but no analgesia
uses: smooth induction of anaesthesia in horses and cattle (not licensed in cattle).
Cattle sensitive to hemolysis with GGE solutions, so usually used as a homemade 5% solution in cattle.
Administer via IV catheeter until animal shows signs of ataxia, followed by IV anaesthetic agent
NB: irritnant, therefore need iV catheter.
often: alpha 2, then GGE, then IV induction agent.
