Cholinesterase inhibitors and their use in myasthenia gravis

CHAPTER 15


Cholinesterase inhibitors and their use in myasthenia gravis


Cholinesterase inhibitors are drugs that prevent the degradation of acetylcholine (ACh) by acetylcholinesterase (also known simply as cholinesterase [ChE]). By preventing the inactivation of ACh, cholinesterase inhibitors enhance the actions of ACh released from cholinergic neurons. Hence, the cholinesterase inhibitors can be viewed as indirect-acting cholinergic agonists. Since cholinesterase inhibitors can intensify transmission at all cholinergic junctions (muscarinic, ganglionic, and neuromuscular), these drugs can elicit a broad spectrum of responses. Because they lack selectivity, cholinesterase inhibitors have limited therapeutic applications. Cholinesterase inhibitors are also known as anticholinesterase agents.


There are two basic categories of cholinesterase inhibitors: (1) reversible inhibitors and (2) “irreversible” inhibitors. The reversible inhibitors produce effects of moderate duration, and the irreversible inhibitors produce effects of long duration.




Reversible cholinesterase inhibitors


Neostigmine


Neostigmine [Prostigmin] typifies the reversible cholinesterase inhibitors and will serve as our prototype for the group. The drug’s principal indication is myasthenia gravis.



Chemistry

As indicated in Figure 15–1, neostigmine contains a quaternary nitrogen atom, and hence always carries a positive charge. Because of this charge, neostigmine cannot readily cross membranes, including those of the GI tract, blood-brain barrier, and placenta. Consequently, neostigmine is absorbed poorly following oral administration and has minimal effects on the brain and fetus.


image
Figure 15–1  Structural formulas of reversible cholinesterase inhibitors.
Note that neostigmine and edrophonium are quaternary ammonium compounds, but physostigmine is not. What does this difference imply about the relative abilities of these drugs to cross membranes, including the blood-brain barrier?


Mechanism of action

Neostigmine and the other reversible cholinesterase inhibitors can be envisioned as poor substrates for ChE. As indicated in Figure 15–2, the normal function of ChE is to break down acetylcholine into choline and acetic acid. This process is termed a hydrolysis reaction because of the water molecule involved. As depicted in Figure 15–3A, hydrolysis of ACh takes place in two steps: (1) binding of ACh to the active center of ChE, followed by (2) splitting of ACh, which regenerates free ChE. The overall reaction between ACh and ChE is extremely fast. As a result, one molecule of ChE can break down a huge amount of ACh in a very short time.


image
Figure 15–2  Hydrolysis of acetylcholine by cholinesterase.

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Figure 15–3  Inhibition of cholinesterase by reversible and “irreversible” inhibitors. (See text for details.)

As depicted in Figure 15–3B, the reaction between neostigmine and ChE is much like the reaction between ACh and ChE. The only difference is that ChE splits neostigmine more slowly than it splits ACh. Hence, once neostigmine becomes bound to the active center of ChE, the drug remains in place for a relatively long time, thereby preventing ChE from catalyzing the breakdown of ACh. ChE remains inhibited until it finally succeeds in splitting neostigmine off.



Pharmacologic effects

By preventing inactivation of ACh, neostigmine and the other cholinesterase inhibitors can intensify transmission at virtually all junctions where ACh is the transmitter. In sufficient doses, cholinesterase inhibitors can produce skeletal muscle stimulation, ganglionic stimulation, activation of peripheral muscarinic receptors, and activation of cholinergic receptors in the central nervous system (CNS). However, when used therapeutically, cholinesterase inhibitors usually affect only muscarinic receptors on organs and nicotinic receptors of the neuromuscular junction (NMJ). Ganglionic transmission and CNS function are usually unaltered.







Therapeutic uses



Reversal of competitive (nondepolarizing) neuromuscular blockade.

By causing accumulation of ACh at the NMJ, cholinesterase inhibitors can reverse the effects of competitive neuromuscular blocking agents (eg, pancuronium). This ability has two clinical applications: (1) reversal of neuromuscular blockade in postoperative patients and (2) treatment of overdose with a competitive neuromuscular blocker. When neostigmine is used to treat neuromuscular blocker overdose, artificial respiration must be maintained until muscle function has fully recovered. At the doses employed to reverse neuromuscular blockade, neostigmine is likely to elicit substantial muscarinic responses. If necessary, these can be reduced with atropine. It is important to note that cholinesterase inhibitors cannot be employed to counteract the effects of succinylcholine, a depolarizing neuromuscular blocker.





Drug interactions





Acute toxicity



Treatment.

Intravenous atropine can alleviate the muscarinic effects of cholinesterase inhibition. Respiratory depression from cholinesterase inhibitors cannot be managed with drugs. Rather, treatment consists of mechanical ventilation with oxygen. Suctioning may be necessary if atropine fails to suppress bronchial secretions.






Other reversible cholinesterase inhibitors



Physostigmine

The basic pharmacology of physostigmine is identical to that of neostigmine—except that physostigmine readily crosses membranes whereas neostigmine does not. Why? Because, in contrast to neostigmine, physostigmine is not a quaternary ammonium compound and hence does not carry a charge. Because physostigmine is uncharged, the drug crosses membranes with ease.


Physostigmine is the drug of choice for treating poisoning by atropine and other drugs that cause muscarinic blockade, including antihistamines and phenothiazine antipsychotics—but not tricyclic antidepressants, owing to a risk of causing seizures and cardiotoxicity. Physostigmine counteracts antimuscarinic poisoning by causing ACh to build up at muscarinic junctions. The accumulated ACh competes with the muscarinic blocker for receptor binding, and thereby reverses receptor blockade. Physostigmine is preferred to neostigmine because, lacking a charge, physostigmine is able to cross the blood-brain barrier to reverse muscarinic blockade in the CNS. The usual dose to treat antimuscarinic poisoning is 2 mg given by IM or slow IV injection.







Ambenonium, edrophonium, and pyridostigmine


Ambenonium [Mytelase], edrophonium [Enlon, Reversol], and pyridostigmine [Mestinon] have pharmacologic effects much like those of neostigmine. One of these drugs—edrophonium—is noteworthy for its very brief duration of action. All three drugs are used for myasthenia gravis. Routes of administration and indications are summarized in Table 15–1.

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Jul 24, 2016 | Posted by in NURSING | Comments Off on Cholinesterase inhibitors and their use in myasthenia gravis

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