Cholinesterase Cholinomimetics

Cholinesterase inhibitors are a very important class of compounds related to cholinomimetics. Besides their therapeutic importance, a few of them are used as pesticides in agriculture, and the most toxic are used as chemical poisoning agents. Use of these substances is based on changes that take place after inactivation of cholinesterase or pseudocholinesterase (a less specific enzyme), i.e. effects observed as a result of acetylcholine buildup in neuro-effector compounds. Cholinesterase inhibitors are classified both by their chemical structure as well as by the type of their chemical reaction with the enzyme, which determines their temporary action. 

Drugs that may be affected by tacrine include anticholinergics, cholinomimetics, cholinesterase inhibitors, and theophylline. 

Drugs that may interfere with rivastigmine include anticholinergics and cholinomimetics and other cholinesterase inhibitors. 

Gl Cholinesterase inhibitors may be expected to increase gastric acid secretion because of increased cholinergic activity. Monitor patients closely for symptoms of active or occult Gl bleeding, especially those at increased risk for developing ulcers. GU Cholinomimetics may cause bladder outflow obstruction. 

Pilocarpine is a naturally occurring cholinomimetic alkaloid that is structurally distinct from the choline esters. It is a tertiary amine that crosses membranes relatively easily. Therefore, it is rapidly absorbed by the cornea of the eye, and it can cross the blood-brain barrier. Pilocarpine is a pure muscarinic receptor agonist, and it is unaffected by cholinesterases. Muscarine is an alkaloid with no therapeutic use, but it can produce dangerous cholinomimetic stimulation following ingestion of some types of mushrooms (e.g., Inocybes). 

Landauer, W. 1977. Cholinomimetic teratogens. V. The effect of oximes and related cholinesterase reactivators. Teratology 15 33-42. 

The beneficial effect of precursors (e.g., lecithin), cholinesterase inhibitors (e.g., physostigmine, donepezil), or drugs with cholinomimetic effects (e.g., bethanechol) for actue mania was discovered in part from the work of Janowsky et al. ( 29), leading to their cholinergic—noradrenergic balance hypothesis. Interestingly, lithium is also able to raise RBC choline concentrations and CNS cholinergic activity ( 274). 

Some cholinesterase inhibitors also inhibit butyrylcholinesterase (pseudocholinesterase). Flowever, inhibition of butyrylcholinesterase plays little role in the action of indirect-acting cholinomimetic drugs because this enzyme is not important in the physiologic termination of synaptic acetylcholine action. Some quaternary cholinesterase inhibitors also have a modest direct action as well, eg, neostigmine, which activates neuromuscular nicotinic cholinoceptors directly in addition to blocking cholinesterase. 

The most prominent pharmacologic effects of cholinesterase inhibitors are on the cardiovascular and gastrointestinal systems, the eye, and the skeletal muscle neuromuscular junction (as described in the Case Study). Because the primary action is to amplify the actions of endogenous acetylcholine, the effects are similar (but not always identical) to the effects of the direct-acting cholinomimetic agonists. 

The effects of the cholinesterase inhibitors on these organ systems, all of which are well innervated by the parasympathetic nervous system, are qualitatively quite similar to the effects of the direct-acting cholinomimetics (Table... 

The major therapeutic uses of the cholinomimetics are for diseases of the eye (glaucoma, accommodative esotropia), the gastrointestinal and urinary tracts (postoperative atony, neurogenic bladder), the neuromuscular junction (myasthenia gravis, curare-induced neuromuscular paralysis), and very rarely, the heart (certain atrial arrhythmias). Cholinesterase inhibitors are occasionally used in the treatment of atropine overdosage. Several newer cholinesterase inhibitors are being used to treat patients with Alzheimer s disease. 

The cholinesterase inhibitors cause significant adverse effects, including nausea and vomiting, and other peripheral cholinomimetic effects. These drugs should be used with caution in patients receiving other drugs that inhibit cytochrome P450 enzymes (eg, ketoconazole, quinidine see Chapter 4). Preparations available are listed in Chapter 7. 

Muscarinic cholinomimetics mediate contraction of the circular pupillary constrictor muscle and of the ciliary muscle. Contraction of the pupillary constrictor muscle causes miosis, a reduction in pupil size. Miosis is usually present in patients exposed to large systemic or small topical doses of cholinomimetics, especially organophosphate cholinesterase inhibitors. Ciliary muscle contraction causes accommodation of focus for near vision. Marked contraction of the ciliary muscle, which often occurs with cholinesterase inhibitor intoxication, is called cyclospasm. Ciliary muscle contraction also puts tension on the trabecular meshwork, opening its pores and facilitating outflow of the aqueous humor into the canal of Schlemm. Increased outflow reduces intraocular pressure, a very useful result in patients with glaucoma. All of these effects are prevented or reversed by muscarinic blocking drugs such as atropine. 

Cholinesterase inhibitors have less marked effects on vascular smooth muscle and on blood pressure than direct-acting muscarinic agonists. This is because indirect-acting drugs can modify the tone of only those vessels that are innervated by cholinergic nerves and because the net effects on vascular tone may reflect activation of both the parasympathetic and sympathetic nervous systems. The cholinomimetic effect at the smooth muscle effector tissue is minimal since few vascular beds receive cholinergic innervation. Activation of sympathetic ganglia may increase vascular resistance. 

Betel nut chewing is a common practice in some Asian and Pacific cultures. In subjects with schizophrenia the chewing of betel nut has been preliminarily associated with fewer positive and negative symptoms (Sullivan et al., 2000). Constituents of betel nut have cholinomimetic properties as well as possibly also inhibitory effects on cholinesterase (Gilani et al., 2004). Arecoline, a major component of betel nut, is a known muscarinic and nicotinic agonist (Tripathi, 1983). 

Table 2 lists some of the effects of antl-Ch s and cholinomimetic drugs on brain function (79-84). Doses of OP compounds that are toxic, but too small to threaten life, produce a variety of clinical manifestations, including miosis, muscular fasclculatlon, and apprehension (85,86). The acute behavioral alterations are usually accompanied by marked desynchronization of the EEG (87). Larger doses of OF compounds—which may induce convulsions, muscular paralysis, and death—cause slowing of the EEG pattern followed by the appearance of spike waves that herald the onset of seizures. Symptomatic recovery Is normally complete within 2-9 wk, at which time the erythrocyte cholinesterase content usually has returned to normal (88,89). 

The cholinomimetics act on the neuromuscular junction (muscarinic), either by directly stimulating the acetylcholine receptors on the smooth muscle ceUs or by increasing the levels of acetylcholine in the neuromuscular junction by blocking cholinesterase activity. Some cholinomimetics, such as bethanechol, can act both at the level of the myenteric plexus (nicotinic) and directly on the intestinal smooth cells. 

Acetylcholine-like drugs (cholinomimetics) are subdivided in two ways on the basis of their mode of action (ie, whether they act directly at the acetylcholine receptor or indirectly through inhibition of cholinesterase) and for those that act directly, on the basis of their spectrum of action (ie, whether they act on muscarinic or nicotinic cholinoceptors Figure 7-1). Acetylcholine may be considered the prototype that acts directly at both muscarinic and nicotinic receptors. Neostigmine is a prototype for the indirect-acting cholinesterase inhibitors. 

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