Medical Pharmacology Topics
Nicotinic cholinergic receptors are ligand-gated ion channels that respond to a rapid pulse of acetylcholine in response to a nerve impulse. When acetylcholine binds to the receptor, a pore opens and allows passage of ions (mostly Na and K) to depolarize the muscle end plate. Such depolarization causes opening of fast voltage-gated Na channels that trigger the action potential to cause contration of the muscle.
The fast Na channels only open briefly and cannot be opened again until the membrane is repolarized. Because acetylcholine is so rapidly degraded by cholinesterase, depolarization of the end plate and and "resetting of the fast Na channels occurs in the very brief time between the pulses of acetylcholine released by repeated firing of cholinergic nerve. Repetitive firing of the motor nerves leads to re[eated muscle action potential and thus sustained muscular contraction.
Neuromuscular blockers are used to paralyze skeletal muscle and thus prevent movement in patients under general anesthesia for surgical procedures. Their use allows for ligther anesthesia use, although the neuromuscular blockers have no analgesic properties.
These agents are either antagonists or persisent agonists at the nicotinic receptor of the neuromuscular junction. The antagonists block transmission of he action potential from the nerve to the muscle. Persistent agonists continuously stimulate acethylcholine receptors, not allowing repolarization of the muscle cell to receive the next action potential.
Non-depolarizing neoromuscular blockers act as competitive antagonists at the nicotinic receptors of the neuromuscular junction. Recovery from paralysis with non-depolarizing reuromuscular blockers can be acelerated by administration of a cholinesterase inhibitor. These agents cause muscle paralysis in a predicted sequence (and recovery in the opposite sequence):
The prototype agent, d-turbocuraine, is the active agent in the South American arrow poison curare. All the drugs in this class contain at least one quaternary nitrogen, which dominates their pharmacokinetics. Agents in this class fall into one of two categories based on their chemical structure: benzylisoquinolines or ammoniosteroids.
Benzylisoquinolines have complex ring structures similar to d-turbocurarine, and share the same side effect profile: ganglionic blockade, and histamine release. The occurrence of ganglionic blockade has been almost eliminated in newer agents, while histamine release has also been greatelly educed. Agents in this class include d-turbocurarine, atracuronium and mivacuronium.
The ammoniosteroids have structures containing the same steroid nucleus as steroid hormones. Hepatic metabolisms often plays a significant role in action termination. The amoniosteroids include pancuronium, vecuroniumand rocuronium. Rocuronium is a high potency agent with a rapid onset of action (1-2 min vs 2-6 min for others).
Problems associated with non-depolrizing blockade include ganglionic blockade, muscarinic blokade and histamine release. The ganglionic blockade will decrease blood pressure and is seen more with d-turbocurarine, less with pancuronium, and even less with atracuronium or vecuronium. Histamine release will decrease blood pressure, increase bronchospasm and secretion, and is seen more with d-turbocurarine, less with atracuronium. Muscarinic receptor blockade by pancuronium will lead to tachycardia.
|Ganglionic Blockade||d-turbocurarione > pancuronium > atracuronium/vecuronium|
|Histamine Release||d-turbocurarione > atracuronium > ammoniosteroids|
Quaternary amines are excreted primarily by the kidneys except for rocuronium and vecuronium (hepatic), atracuronium (spontaneous and plasma esterases) and mivacuronium (plasma esterases).
Duration of action depends on their metabolism. Those eliminated renaly have a longer half-time (pancuronium ~ 107 min, d-turbocurarine ~ 173 min). The dration of action will be further increased for renaly excreted neuromuscular blocker when used in elderly patients or those with otherwise impaired renal function. Vecuronium and atracuronium have an intermediate duration of action (~ 90 and 40 min respectively), and mivacuronium has the shortest duration of action (~ 15-20 min).
Drugs that enhance curare-type neyromuscular blockade include aminoglycoside antibiotics, cacium blockers and certain inhaled anesthetics (halothane, isoflurane, enflurane).
Depolarizing neuromuscular blockers act as persistent agonists at nicotine receptors, thus stimulate the rexceptor to depolarize the muscle endplate just as acetylcholine. But unlike acetylcholine, their relatively slower dergadation rate results in paralysis, probably by two mechanisms: Phase I block and Phase II block.
During phase I block, the agonist ocupies the nicotinic receptor at the muscle endplate and produce depolarization. This initial stimulation is often manifested as a wave of muscle fasciculation (twitching) immediately after drug administration. Since the drug is relatively resistant to degradation, it will remain on the receptor and the endplate remains in the depolarized state. Cholinesterase inhibitors will worsen phase I block.
Phase II block occurs after a few minutes of depolarization, when the muscle endplate is thought to gradually repolarize, although paralisis continues. This is thought to represent a change in the nicotinic receptor, in response to the peripheral occupation by the drug, to the "desensitized state". Thus as more receptors shift to the "desensitized" state, the endplate repolarizes but transmision remains blocked. As the drug is eventually cleared and receptors become unoccupied, they revert to the original active state. Cholinesterase inhibitors will sometimes partially reverse phase II block.
Succinylcholine is the only depolarizing neuromuscular blocker, and its structure is simply two acetylcholine molecules attached to each other. Althoug relatively resistant to degradation by the acetylcholinesterase associated with cholinergic nerve terminals, it is cleared relatively rapidly by plasma esterases, and is therefore prefewrred over most of the non-depolarizing blockers when a brief duration of action is desied (5-10 min).
Problems associated with depolarizing neuromuscular blockade include myalgia (muscle soreness), hyperkalemia and atypical interactions in some individuals. Depolarization will induce the release of potassium from skeletal muscle, which may lead to cardiac arrythmias, especially in patients with extensive burns or soft tissue damage, and in paraplegics. Some patients may have atypical pseudocholinesterases which will lead to prolonged paralysis. Malignant hyperthermia is rare but letal, and is due to an uncontrolled release of calcium from the sarcoplasmic reticulum. Hypertermia is most ofter seen when halothane is administered in combination with succinylcholine, and may be treated with dantrolene.
Continue to "General Anesthesia" or take a quiz: [Q1] [Q2].
Need more practice? Answer the review questions below.
Questions (a bit incomplete):
1- What is the main use of neuromuscular blockers?
2- List the sequence of paralysis after administration of a neuromuscular blocker.
3- What is the difference between non-depolarizing and depolarizing neuromuscular blockers?
4- What are the differences between benzylisoquinolines and ammoniosteroids?
5- What are the problems associated with non-depolarizing neuromuscular blockers?
6- What characteristic dominates the pharmacokinetics of non-depolarizing neuromuscular blockers and how?
7- List the three prototypes of neuromuscular blockers.