Directly and Indirectly Acting Cholinomimetics

These are example of  cholinomimetics drugs:-
1.Acetylcholine
2.Ambenonium
3.Bethanechol
4.Carbachol
5.Demecarium
6.Donepezil
7.Echothiophate
8.Edrophonium
9.Galanthamine
10.Isofluorophate
11.Methacholine
12.Neostigmine
13.Physostigmine
14.Pilocarpine
15.Pralidoxime
16.Pyridostigmine
17.Rivastigmine
18.Tacrine


       Cholinomimetic drugs can elicit some or all of the effects that acetylcholine (ACh) produces. This class of drugs includes agents that act directly as agonists at cholinoreceptors and agents that act indirectly by inhibiting the enzymatic destruction of endogenous ACh (i.e.,cholinesterase inhibitors).
   
       The directly acting cholinomimetics can be subdivided into agents that exert their effects primarily through stimulation of muscarinic receptors at parasympathetic neuroeffector junctions (parasympathomimetic drugs) and agents that stimulate nicotinic receptors in autonomic ganglia and at the neuromuscular junction. This chapter focuses on the parasympathomimetic drugs and cholinesterase inhibitors.

Muscarinic Receptors and Signal Transduction:-

      Classical studies by Sir Henry Dale demonstrated that the receptors activated by muscarine, an alkaloid isolated from the mushroom Amanita muscaria, are the same receptors activated by ACh released from parasympathetic nerve endings,from which the general notion that muscarinic agonists have parasympathomimetic properties was born.

  

       All muscarinic receptors are members of the seven transmembrane domain, G protein–coupled receptors, and they are structurally and functionally unrelated to nicotinic ACh receptors. Activation of muscarinic receptors by an agonist triggers the release of an intracellular G-protein complex that can specifically activate one or more signal transduction pathways. Fortunately, the cellular responses elicited by odd- versus evennumbered receptor subtypes can be conveniently distinguished.

       Activation of M1, M3, and M5 receptors produces an inosine triphosphate (IP3) mediated release of intracellular calcium, the release of diacylglycerol (which can activate protein kinase C),and stimulation of adenylyl cyclase. 

        These receptors are primarily responsible for activating calcium-dependent responses, such as secretion by glands and the contraction of smooth muscle.

Activation of M2 and M4 receptors inhibits adenylyl cyclase,and activation of M2 receptors opens potassium channels. The opening of potassium channels hyperpolarizes the membrane potential and decreases the excitability of cells in the sinoatrial (SA) and atrioventricular (A-V) nodes in the heart. The inhibition of adenylyl cyclase decreases cellular cyclic adenosine monophosphate (cAMP) levels,which can override the opposing stimulation of adenylyl cyclase by β-adrenoceptor agonists.