Neuromuscular Blockers

Introduction

Muscle relaxation is part of a balanced anaesthetic technique. Most anaesthetic agents produce a mild-moderate amount of muscle relaxation and often this is not sufficient. Increased muscle relaxation can be produced by increasing anaesthetic depth, the use of local anaesthetic techniques, or the use of centrally or peripherally acting muscle relaxants. However, it is important to realise that muscle relaxants have no anaesthetic or analgesic effect themselves and so should never be used alone.

Neuromuscular blocking agents(NMBA) are peripherally acting muscle relaxants. They can be classified as depolarising or non-depolarising depending on whether they are competitive or not.

Neuromuscular Transmission

To understand tranmission of an action potential at the neuromuscular junction it is important to understand the anatomy of the junction. At the nerve terminal, there are a huge number of vesicles containing acetylcholine (ACh), a neurotransmitter. On the muscle membrane there are a number of nicotinic ACh recpetors. As an action potential reaches the nerve terminal, the ACh contain vesicles fuse with the prejunctional membrane releasing it into the junctional cleft. They diffuse across the cleft and bind to the post-junctional receptors. After binding of two ACh molecules to the two binding sites on the repector the activation of ion channel opening leading to an end-plate potential. If enough channels open, the muscle membrane depolarises and an action potential is generated. This causes release of calcuim ions from the sarcoplasmic reticulum leading to muscle contraction. Binding of ACh is extremely short before it is released and hydrolysed, causing the end of the action potential and muscle contraction. If only one of the two sites is occupied, then ion channel opening does not occur and no action potential is produced.

Monitoring after NMBA Administration

NMBAs act on all skeletal muscles, which includes respiratory muscles. This means that it is essential to have facilities to provide controlled ventilation. Muscles have different sensitivities for NMBAs, with the diaphragm being particularly resistant making it the last to be paralysed and the first to recover. However, laryngeal tissues appear to be relatively sensitive, meaning it may take longer for these tissues to recover after administation. This makes patients at risk of upper airway obstruction after the endotracheal tube has been removed.

Peripheral nerve stimulators are commonly used to assess the muscle relaxation. These devices supply a small electrical current through electrodes, which have been attached to the skin above a peripheral nerve. If the muscle is still under blockade then there is no response to the current, whereas if the blockade is no longer present a muscle twitch is produced. The electrodes can be placed directly onto the skin or via subcutaneous needles. Commonly used sites include the ulnar, peroneal or facial nerve. The most common stimulation pattern used is the train-of-four. This technique involves the delivery of 4 pulses over a 2 second period. If there is non blockade then 4 twitches are observed of equal strength. If a non-depolarising agent has been administered, the twitches become gradually weaker until they disappear. If a depolarising agents has been administered, then the twitches are absent.

The administration of muscle relaxants also makes monitoring anaesthesia difficult as many of the parameters used are affected by the muscle relaxant. For example, eye position often remains central in patients that have received NMBAs. Similarly the palpebral reflex is commonly used to assess anaesthetic depth but in patients that have received NMBAs this reflex is absent. Therefore the following can still be used to asses anaesthetic depth -

• Pulse rate
• Blood pressure
• Salivation and lacrimation
• End-tidal carbon dioxide
• Muscle twitching

Indications for Use

• Deep dissection during surgery.
• Thoracic Surgery
• Replacement of dislocations and fractures.
• Intraocular procedures.

Depolarising Neuromuscular Blockers

Depolarising agents are non-competive neuromuscular blocking agents. Suxamethonium is currently the only depolarising agent in clinical use. It is ultra short acting wih rapid onset of action.

Mechanism of Action

Suxamethonium (succinylcholine) comprises of 2 acetylcholine (ACh) molecules bound together. Binding to post synaptic receptors, suxamethonium generating an action potential. However, it is not broken down by acetylcholinesterases and so remains bound to the receptor. It is this binding that prevents normal transmission at the site. Therefore, it produces an initial muscle contraction followed by a prolonged period of muscle relaxation. It relies on a fall in concentration of the agent in the blood before it unbinds to travel down the concentration gradient back into the circulation. It is here that is broken down by pseudocholinesterase enzyme.

Pharmacological Considerations

Suxmethonium is adminstered intravenously with muscle relaxation seen 30-60s after administration. Duration of action is variable between species, lasting approximately 5 minutes in cats but 20-30 minutes in dogs. This is thought to be due to the amount of pseudocholinesterase enzyme present.

Contraindications and Side Effects

• Prolonged duration of actions may be seen in patients with liver disease, renal disease or malnutrition due to reduced levels of pseudocholinesterase.
• Cardiovascular effects such as variations in heart rate and blood pressure may be seen due to the structural similarity of suxamethaonium to ACh.
• Potassium levels may increase, which is normally insignificant in a healthy patient. However, patients with denervation this efflux may cause potentially fatal arrhythmias.
• Should not be used in patients with penetrating eye injuries due to the increases in intraocular pressure seen.
• Malignant hyperthermia trigger.
• Muscle soreness and myoglobinuria.

Clinical Uses

Suxamethaonium is used to aid endotracheal intubation of cats.

Non-Depolarising Neuromuscular Blockers

Non-depolarising agents are competitive neuromuscular blocking agents. Unlike depolarising agents there are a number of different drugs available for use. They should not be used on concious patients.

Mechanism of Action

Non-depolarising agents act by binding to the post synaptic acetylcholine (ACh) receptors, but unlike the depolarising agents, do not cause ion channel opening and therefore there is no action potential. However, by binding to the receptors they prevent binding by ACh thereby blocking normal transmission. This means that there is no stimulation before relaxation is seen upon administration. It also only requires binding at one of the two sites on the receptor to have its blocking effect.

Pharmacological Considerations

Non-depolarising agents can be administered intravenously. Onset and duration of action varies between 2-5 minutes depening on the drug used (see below). Electrolyte imbalances can potentiate the action of these agents.

Contraindications and Side Effects

• Response to these drugs may be altered by underlying neurological conditions that are present in patients e.g. myasthenia gravis patients have a reduced number of ACh receptors and so are more sensitive where as patients with denervating diseases are less sensitive as there are increased numbers of ACh receptors.
• Patients with hepatic or renal disease may have prolonged recovery time after the administration of vecuronium or pancuronium due to hepatic metabolism and renal excretion impairment.
• Increases in heart rate and blood pressure may be seen.
• Atracurium has been associated with histamine release reactions - This is reduced with the use of cis-atracurium.

Clinical Uses

Non-depolarising agents can be used during surgery to improve muscle relaxation and also allow for mechanical ventilation.

Drugs in this Class

Atracurium

Onset of action is approximately 3-5 minutes.

Duration of action is approximately 20-35 minutes.

Metabolised by non-specific esterases, and so independent of hepatic or renal function.

Potential histamine release reactions.

Cis-atracurium

Isomer of atracurium - More potent.

Not associated with histamine release.

Vecuronium

Onset of action is approximately 2-3 minutes.

Duration of action is approximately 30-45 minutes.

Minor hepatic metabolism but depends on biliary excretion to terminate its effect.

Pancuronium

Onset of action is approximately 2 minutes.

Duration of action is approximately 25 minutes.

Ocassionally see tachycardia and hypertension.