Neuromuscular Blocking Agents - NMBAs
Neuromuscular Blocking Agents - NMBAs
Although most of the currently available anaesthetic agents will provide a degree of muscle relaxation, in general, most of them provide good muscle relaxation only when administrated at high concentration. These high concentrations are associated with severe cardiopulmonary depression, making theses agents unsuitable by themselves for situations where profound muscle relaxation is required during a surgical procedure. Two groups of two groups of drugs are available to increase the degree of muscular relaxation during surgery:
* Centrally acting muscle relaxants: provide muscle relaxation by direct effects within the CNS, e.g. Benzodiazepines: diazepam and midazolam - can not produce as profound degree of relaxation associated with NMBAs
* Neuromuscular blocking agents: acts are the neuromuscular junction (NMJ)
NMBAs: Provide total abolition of muscle tone, allowing complete relaxation of all skeletal muscle groups - including the intercostal muscles (muscles between ribs) and the diaphragm. As these respiratory muscles are blocked, ventilation also stops. Therefore means of support must be available, e.g. a cuffed endotracheal tude and a suitable breathing system. Although muscle relaxants will ultimately cause paralysis of all the skeletal muscles, some groups are more resistant than others; the diaphragm is generally the last muscle to go and is the first to recover function.
They do not cross over the blood-barrier so do not alter consciousness, so has no analgesic or anaesthetic effects, it is possible for the animal to undergo surgery while being completely awake but unable to move. They also remove some of the obvious signs and normal signs of inadequate anaesthesia (movement, ocular position and cranial nerve reflexes) so that monitoring the level of anaesthesia is hard. Because the animal can not respond normally to inadequate anaesthesia, the anaesthetist must ensure the animal is unconscious. However there are signs associated with inadequate anaesthesia that patients under the influence of NMBA still show:
* Increased in pulse rate (unrelated to haemorrhage)
* Increase in arterial blood pressure
* Salivation
* Increased tear production
* Vasovagal syncope (bradycardia, hypotension, pallor)
* Pupillary dilation (but eye will always remain central)
* Slight muscle twitching of the face, tongue or limbs, in response to surgical stimulation
If any of these signs are observed, it should be assumed that anaesthesia is inadequate, and anaesthetic dose should be increased.
There are two classes of NMBAs based on their mechanism of action:
* Depolarising (non-competitive) muscle ...
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* Increased in pulse rate (unrelated to haemorrhage)
* Increase in arterial blood pressure
* Salivation
* Increased tear production
* Vasovagal syncope (bradycardia, hypotension, pallor)
* Pupillary dilation (but eye will always remain central)
* Slight muscle twitching of the face, tongue or limbs, in response to surgical stimulation
If any of these signs are observed, it should be assumed that anaesthesia is inadequate, and anaesthetic dose should be increased.
There are two classes of NMBAs based on their mechanism of action:
* Depolarising (non-competitive) muscle relaxants:
o These agents have a similar chemical structure to acetylcholine (ACh), the neurotransmitter at the neuromuscular junction. Depolarising agents bind to the postjunctional receptor and because or their chemical similarity to ACh, cause the muscle to contract initially, before it relaxes. This is clinically seen as widespread, short-lasting muscle fasciculations throughout the skeletal muscles of the body followed by total flaccidity.
o The fasciculations can cause muscle damage, which may lead to potassium release of the muscle cells and cause post-op pain.
o Usually administrated IV, but can also be given IM.
o Succinylcholine (also called suxamethonium, is the only depolarising agent clinically used) has a rapid onset time (seconds) and is short-acting (3-5 minutes in cat, 20min in dog). It is used to facilitate intubation in humans.
o There are no reversal agents available for depolarising relaxants; duration depends mainly on the dose amount and concentration of circulating pseudocholinesterase.
* Non-depolarising (competitive) muscle relaxants:
o Compete with ACh for postjunctional binding sites and cause blockage of the motor endpate without the initial stimulation seen with depolarising agents.
o Theses agents are much more used as they are reversible and "topped-up" as required.
o Only administered IV
o Many types of non-depolarising agents have been used in veterinary practice a lot are not used anymore:
* D-Tubocurarine: seldom used these days because injection causes histamine release in dogs, resulting in vasodilation, hypotension, tachycardia and bronchial spasm.
* Gallamine: unpopular because of tachycardia and hypotension after injection.
* Alcuronium: long acting relaxant, only occasionally used now
* Pancuronium: has a intermediate onset and long duration of action (more than 30 min), causes modest tachycardia after injection, but remains a useful agent
* Vecuronium: a popular drug, derived from pancuronium, has an intermediate duration of action (20-30 min). It has minimal increasing effects after repeated doses and little if any cardiovascular effects.
* Atracurium: another popular relaxant because of its intermediate duration of action and rapid onset time. It is spontaneously degraded and so the agent is favoured in animals with disease elimination pathways (liver and kidney).
Non-depolarising neuromuscular blockers can be antagonised using a combination of anticholinesterase (edrophonium or neostrigmine; inhibits the enzyme, acetylcholinesterase, which is responsible for the breakdown of acetylcholine, causing an increase of ACh at the neuromuscular juntions, displacing the non-polarising agents that is bound to the receptors. This can result in unwanted sideffects: bradycardia, salivation, bronchospasm and diarrhoea) and anticholinergic/antimuscarinic (atropine or glycopyrrolate; which is given to offset the side effects) drugs.
Indications for NMBAs - include ocular, abdominal and thoracic surgery
* To relax skeletal muscles for easier surgical access: Particularly for dissection deep within the abdomen (e.g. when working around the kidneys or adrenal glands) and also routine abdominal procedures, such as ovariohysterectomy
* Immobility for delicate surgery: intraocular-, micro-, neurological surgery
* To reduce anaesthetic requirements: When the body is relaxed, the CNS is less stimulated and less anaesthetic agent is required to stimulate the CNS
* To facilitate control of respiration during intrathoracic surgery - allows for positive-pressure ventilation to be imposed without the animal fighting the ventilator: For thoracic surgery and repair of diaphragmatic hernias, positive pressure ventilation is required. NMBAs allow smooth takeover of the patients breathing, prior to opening the chest. Normally fairly easy to take over in small dogs and cat by simply hyperventilation, but large dogs may particular resist and NMBAs helps take control.
* To assist reduction of dislocated joints
* To facilitate endotracheal intubation in cats: the only practical indication for the use of depolarising agents is to aid endotracheal intubation in cats. The cat has an exquisitely sensitive larynx that may spasm when stimulated. Local anaesthetic spray can also be used, but take some time to work. NMBAs are good when do not have the time to wait, administered IV after the animal has first been masked down.
* To reduce the amount of GA agent required: deceased muscle tone lead to decreased CNS stimulation and less anaesthetic is then required.
* To assist ophthalmic procedures: commonly administered to animals undergoing cataract surgery to paralyse extra-ocular muscles and allow central positioning of the eye.
* Oesophageal foreign body removal: Oesophageal foreign body removal is dogs. A relaxed oesophageal musculature allows retrieval of relatively large objects without the need for thoracotomy.
* Laparotomies: Reduces the amount of traction required to produce exposure, causing less tissue trauma on the wound margins with less post-op inflammation and pain.
Peripheral nerve stimulation: It is hard to determine the degree of neuromuscular blockage present in a patient, most commonly a nerve stimulator is used to help quantify the intensity of relaxation. The most common form of stimulation is train-of-four (TOF) where four electrical pulses are applied to the nerve over a 2-second period. In the non-paralysed animal, four distinct muscle twitches, each of identical strength, will occur. If a non-depolarising relaxant is then administered, the fourth twitch in the TOF will become weaker and eventually disappear, followed by the third twitch and the second and eventually the first, if sufficient relaxant is given.
