Cholinesterase inhibitors 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. 

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. 

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. 

The anionic site of ChE does not make such rigid demands on the structure of the cationic head of substrates and inhibitors. For instance, acetyltriethylcholine, which is completely devoid of cholinomimetic activity, is hydrolysed by the cholinesterases at nearly the same rate as ACh. 

---