Mechanism of competitive block
Drugs in this class act at the level of peripheral neuromuscular synapses. Unlike agents affecting the central nervous system (e.g., benzodiazepines), they work directly at the skeletal muscle motor end-plate.
Their molecules typically contain two positively charged centers (nitrogen atoms). Due to this, they bind to nicotinic acetylcholine receptors on the postsynaptic membrane. The block is strictly competitive: the relaxant molecule and the endogenous neurotransmitter acetylcholine "compete" to occupy the receptor.
Upon binding to N-receptors, the relaxant prevents acetylcholine from inducing membrane depolarization. As a result, the muscle fiber loses its ability to contract, and a neuromuscular block develops.
Historical background and structural features
The first known substance with this effect was tubocurarine, an alkaloid isolated from plant extracts of Strychnos and Chondodendron. These were the exact plants used by South American Indians to prepare the famous curare arrow poison.
Interestingly, the meat of animals killed with such weapons was completely safe for consumption. This is explained by the physicochemical properties of curare-like substances: they are quaternary ammonium compounds. Their molecules are large and highly hydrophilic, which means they are practically unabsorbed from the gastrointestinal tract.
Chemical classification and duration of effect
Based on their chemical structure, nondepolarizing relaxants are divided into two main classes:
- Benzylisoquinolines: contain isoquinoline rings (tubocurarine, atracurium, cisatracurium, mivacurium).
- Aminosteroids: have a steroid nucleus as their base (pancuronium, pipecuronium, vecuronium, rocuronium).
The duration of induced muscle relaxation depends on how the drug is eliminated from the body or degraded:
- Long-acting (30–60 minutes and longer). Eliminated primarily by the kidneys. The record holder here is pipecuronium, whose effect can last for about 2 hours.
- Intermediate-acting (20–40 minutes). Excreted via bile (vecuronium, rocuronium). Of note is atracurium, which undergoes Hofmann elimination — spontaneous non-enzymatic degradation directly in the blood plasma. This makes it the drug of choice for patients with hepatic or renal failure.
- Short-acting (10–15 minutes). Rapidly broken down by plasma cholinesterase (mivacurium).
Clinical use and side effects
The main indication for curare-like agents is surgery (for total muscle relaxation during operations). They are also used to manage severe tonic convulsions in tetanus or strychnine poisoning.
The onset of muscle relaxation follows a strict "top-to-bottom" pattern:
- Muscles of the face, neck, and larynx.
- Muscles of the trunk and limbs.
- Respiratory muscles.
It is critically important to understand that paralysis of the respiratory muscles leads to respiratory arrest, requiring immediate transition of the patient to mechanical ventilation.
Side effects are closely related to the chemical class:
- Benzylisoquinolines tend to provoke histamine release. This can lead to anaphylactoid reactions: a drop in blood pressure, skin flushing, and bronchospasm. Tubocurarine has the strongest histaminergic effect and additionally blocks autonomic ganglia, which is why it is rarely used today.
- Aminosteroids do not release histamine, but they are capable of moderately blocking cardiac M-cholinergic receptors, causing tachycardia.
Decurarization: How to Reverse Neuromuscular Blockade
The restoration of neuromuscular conduction at the end of surgery is called decurarization. In modern practice, two fundamentally different approaches are used.
Traditional pharmacological method Based on the administration of anticholinesterase agents. These drugs inhibit the enzyme acetylcholinesterase, preventing it from breaking down acetylcholine. The concentration of the neurotransmitter in the synapse increases sharply, displacing the muscle relaxant from the receptors. To avoid dangerous side effects (bradycardia, excessive salivation), atropine must be administered 10 minutes prior to the procedure.
Selective reversal (innovative method) Used exclusively for aminosteroids (vecuronium and rocuronium). The patient is intravenously administered sugammadex—a modified gamma-cyclodextrin consisting of 8 glucose molecules. It works on the principle of encapsulation: it traps the relaxant molecule inside its ring, forming a stable inactive complex. A huge advantage of this method is the complete absence of any effect on M-cholinergic receptors, meaning there is no need to use atropine.
Briefly: answers to topical questions
Which nondepolarizing muscle relaxants undergo Hofmann elimination?
Atracurium undergoes Hofmann elimination. This process is a spontaneous non-enzymatic hydrolysis of the drug in blood plasma. Due to this elimination pathway, the duration of action of atracurium does not depend on liver and kidney function, making it the drug of choice in renal or hepatic impairment.
Which specific anticholinesterase drugs are used for traditional decurarization?
The following anticholinesterase agents are used for traditional pharmacological decurarization (restoration of neuromuscular conduction):
- Neostigmine bromide — inhibits acetylcholinesterase, which leads to the accumulation of acetylcholine and the displacement of the muscle relaxant from its bond with receptors.
- Galantamine — administered intravenously and used as an antagonist of curare-like nondepolarizing muscle relaxants.
What are the contraindications to the use of nondepolarizing muscle relaxants?
A contraindication to the use of peripheral muscle relaxants is severe myasthenia gravis. If muscle relaxation is required in patients with myasthenia gravis, short-acting nondepolarizing muscle relaxants may be used with caution: in patients older than 1 month, rocuronium bromide. Depolarizing muscle relaxants should be avoided in myasthenia gravis.
What is the difference in the mechanism of action between depolarizing and nondepolarizing muscle relaxants?
The mechanism of action of these groups differs in their effect on the postsynaptic membrane.
| Characteristic | Nondepolarizing muscle relaxants | Depolarizing muscle relaxants |
|---|---|---|
| Mechanism of blockade | Blockade of end-plate nicotinic receptors (competitive antagonism) | Stimulation of nicotinic receptors |
| Effect on the membrane | Prevention of depolarization | Sustained (prolonged) depolarization of the postsynaptic membrane |
| Clinical presentation | Muscle relaxation phase occurs immediately | Initial phase of muscle fasciculations, followed by muscle relaxation |
The order of muscle relaxation upon administration of muscle relaxants proceeds from "top to bottom": first the face and neck, then the trunk and limbs, and finally the respiratory muscles (diaphragm).
Class and exam questions
Why is the meat of animals killed with curare arrow poison safe to eat?
The active components of the venom are hydrophilic quaternary ammonium compounds. Due to their large molecular size and hydrophilicity, they are completely unabsorbed from the gastrointestinal tract into the blood.
Which muscle relaxant is safest to use in renal or hepatic impairment?
The drug of choice would be atracurium. It does not require renal or hepatic function for elimination, as it undergoes Hofmann elimination—spontaneously breaking down in the blood plasma.
Why is atropine administered to the patient before traditional decurarization?
Anticholinesterase agents increase acetylcholine levels throughout the body, leading to the stimulation of M-cholinergic receptors (causing bradycardia, hypersalivation). Atropine preemptively blocks these receptors, protecting the heart and glands from excessive excitation.
Which nondepolarizing agent has the fastest onset of action?
They usually act slower than depolarizing agents, with rocuronium being the exception. Its muscle-paralyzing effect develops very rapidly—within 60–90 seconds after administration.
What else to study on this topic
- Depolarizing muscle relaxants: mechanism of action and differences
- Features of Hofmann elimination in pharmacokinetics
- Symptoms and treatment of strychnine poisoning
- Pharmacology of anticholinesterase agents
- Chemical structure of cyclodextrins and their medical applications
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