6/5/13

Nondepolarizing (competitive) blockers

The first drug that was found to be capable of blocking the skeletal neuromuscular junction was curare, which the native hunters of the Amazon in South America used to paralyze game.

The drug tubocurarine [too-boe-kyoo-AR-een] was ultimately purified and introduced into clinical practice in the early 1940s. Although tubocurarine is considered to be the prototype agent in this class, it has been largely replaced by other agents due to side effects . The neuromuscular blocking agents have significantly increased the safety of anesthesia, because less anesthetic is required to produce muscle relaxation, allowing patients to recover quickly and completely after surgery. Note: Higher doses of anesthesia may produce respiratory paralysis and cardiac depression, increasing recovery time after surgery.]


 1. Mechanism of action:

a. At low doses: Nondepolarizing neuromuscular blocking drugs interact with the nicotinic receptors to prevent the binding of acetylcholine


Figure : Mechanism of action of competitive neuromuscular blocking drugs.


These drugs thus prevent depolarization of the muscle cell membrane and inhibit muscular contraction. Because these agents compete with acetylcholine at the receptor without stimulating the receptor, they are called competitive blockers. Their action can be overcome by increasing the concentration of acetylcholine in the synaptic gap—for example, by administration of cholinesterase inhibitors, such as neostigmine, pyridostigmine, or edrophonium. Anesthesiologists often employ this strategy to shorten the duration of the neuromuscular blockade


b. At high doses: Nondepolarizing blockers can block the ion channels of the end plate. This leads to further weakening of neuromuscular transmission, and it reduces the ability of acetylcholinesterase inhibitors to reverse the actions of nondepolarizing muscle relaxants.


 2. Actions:

Not all muscles are equally sensitive to blockade by competitive blockers. Small, rapidly contracting muscles of the face and eye are most susceptible and are paralyzed first, followed by the fingers. Thereafter, the limbs, neck, and trunk muscles are paralyzed. Then the intercostal muscles are affected, and lastly, the diaphragm muscles are paralyzed. Those agents (for example, tubocurarine, mivacurium, and atracurium), which release histamine, can produce a fall in blood pressure, flushing, and bronchoconstriction.


3. Therapeutic uses:

These blockers are used therapeutically as adjuvant drugs in anesthesia during surgery to relax skeletal muscle. These agents are also used to facilitate intubation as well as during orthopedic surgery.


4. Pharmacokinetics:

All neuromuscular blocking agents are injected intravenously, because their uptake via oral absorption is minimal. These agents possess two or more quaternary amines in their bulky ring structure, making them orally ineffective. They penetrate membranes very poorly and do not enter cells or cross the blood-brain barrier. Many of the drugs are not metabolized; their actions are terminated by redistribution.


Figure: Pharmacokinetics of the neuromuscular blocking drugs. IV = intravenous.


 For example, tubocurarine, pancuronium, mivacurium, metocurine, and doxacurium are excreted in the urine unchanged. Atracurium is degraded spontaneously in the plasma and by ester hydrolysis. [Note: Atracurium has been replaced by its isomer, cisatracurium. Atracurium releases histamine and is metabolized to laudanosine, which can provoke seizures. Cisatracurium, which has the same pharmacokinetic properties as atracurium, is less likely to have these effects.] The aminosteroid drugs (vecuronium and rocuronium) are deacetylated in the liver, and their clearance may be prolonged in patients with hepatic disease. These drugs are also excreted unchanged in the bile. The choice of an agent will depend on how quickly muscle relaxation is needed and on the duration of the muscle relaxation. 




5. Adverse effects:

In general, agents are safe with minimal side effects. The adverse effects of the specific neuromuscular blocking drugs are shown in Figure below .


Figure: Onset and duration of action of neuromuscular blocking drugs (center column), with a summary of therapeutic considerations.


6. Drug interactions:

a. Cholinesterase inhibitors: Drugs such as neostigmine, physostigmine, pyridostigmine, and edrophonium can overcome the action of nondepolarizing neuromuscular blockers, but with increased dosage, cholinesterase inhibitors can cause a depolarizing block as a result of elevated acetylcholine concentrations at the end-plate membrane. If the neuromuscular blocker has entered the ion channel, cholinesterase inhibitors are not as effective in overcoming blockade.

b. Halogenated hydrocarbon anesthetics: Drugs such as halothane act to enhance neuromuscular blockade by exerting a stabilizing action at the neuromuscular junction. These agents sensitize the neuromusclular junction to the effects of neuromuscular blockers.

c. Aminoglycoside antibiotics: Drugs such as gentamicin or tobramycin inhibit acetylcholine release from cholinergic nerves by competing with calcium ions. They synergize with tubocurarine and other competitive blockers, enhancing.



2 comments:

  1. Hello

    I really liked this post, really informative. I am a student of biomedical science and have a pharmacology module. I have a question:
    how does tubocurarine cause histamine release ? Everywhere I looked it comes up as a pure statement that it basically happens and that's it. But how does the drug actually cause histamine release

    ReplyDelete
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