Muscarinic effects receptors

Antagonists of muscarinic acetylcholine receptors had widely been used since 1860 for the treatment of Parkinson s disease, prior to the discovery of l-DOPA. They block receptors that mediate the response to striatal cholinergic interneurons. The antiparkinsonian effects of drugs like benzatropine, trihexyphenidyl and biper-iden are moderate the resting tremor may sometimes respond in a favorable manner. The adverse effects, e.g., constipation, urinary retention, and mental confusion, may be troublesome, especially in the elderly. 

Chapter 1 which showed that since muscarine mimicked some of the actions of ACh (but not all) while nicotine mimicked the other actions of ACh, then ACh probably acted on two distinct types of receptors. The fact that atropine antagonised the muscarinic effects of ACh but not the nicotinic effects, while tubocurarine blocked the nicotinic effects provided firm evidence for this concept. These simple qualitative observations by Langley and others at the beginning of the twentieth century led to the development of more quantitative pharmacological methods that were subsequently used to identify and classify receptors. These methods were based on the use of both (1) agonist and (2) antagonist drugs ... 

Some agonists, such as methacholine, carbachol and bethanecol are structurally very similar to ACh (Fig. 6.6). They are all more resistant to attack by cholinesterase than ACh and so longer acting, especially the non-acetylated carbamyl derivatives carbachol and bethanecol. Carbachol retains both nicotinic and muscarinic effects but the presence of a methyl (CH3) group on the p carbon of choline, as in methacholine and bethanecol, restricts activity to muscarinic receptors. Being charged lipophobic compounds they do not enter the CNS but produce powerful peripheral parasympathetic effects which are occasionally used clinically, i.e. to stimulate the gut or bladder. 

Few drugs, apart from nicotine itself, act specifically on nicotine receptors. One is methylcarbachol, which lacks the muscarinic effects of carbachol and another is dimethylphenylpiperazinium (DMPP), which appears to have some selectivity for the neuronal nicotinic receptor. Neither of them can cross the blood-brain barrier. 

Figure 17.7 Possible mechanism by which atypical neuroleptics with antimuscarinic activity produce few EPSs. Normally the inhibitory effects of DA released from nigrostriatal afferents on to striatal neuron D2 receptors is believed to balance the excitatory effect of ACh from intrinsic neurons acting on muscarinic (M2) receptors (a). Typical neuroleptics block the inhibitory effect of DA which leaves unopposed the excitatory effect of ACh (b) leading to the augmented activity of the striatal neurons and EPSs (see Fig. 15.2). An atypical neuroleptic with intrinsic antimuscarinic activity reduces this possibility by counteracting the excitatory effects of released ACh as well as the inhibitory effects of DA (c). Thus the control of striatal neurons remains balanced...

A G-protein-mediated effect has an absolute requirement for GTP. Reference has already been made to the requirement for GTP in reconstituting hormone-stimulated adenylate cyclase activity. A similar requirement can be demonstrated when the effector is an ion channel, such as the cardiac atrial inward-rectifier K+ channel which is activated following stimulation of the M2 muscarinic acetylcholine receptor. Thus, in the experiment illustrated in Figure 7.8, the channel recorded with a cell-... 

Datta, S., Quattrochi, J. J. Hobson, J. A. (1993). Effect of specific muscarinic M2 receptor antagonist on carbachol induced long-term REM sleep. Sleep 16, 8-14. 

List the side effects of imipramine that result from its blockade of muscarinic acetylcholine receptors. 

Scopolamine A muscarinic cholinergic receptor antagonist that has amnesic side effects. 

The answer is a. (Katzung, p 499.) Of the listed a n tide press ants, only amitriptyline, a tricyclic, causes adverse effects related to blockade of muscarinic acetylcholine receptors. Both trazodone and amitriptyline cause adverse effects related to a-adrenoreceptor blockade... 

Muscarinic and dopaminergic pathways in the CNS interact in control of numerous pathways implicated in diseases, especially those controlling involuntary motor systems. Muscarinic effects on dopamine release are mediated in several ways via different mAChR subtypes. Thus mAChR facilitation of DA release appears to involve M4 receptors on GABA projection neurons to the striatum, while M3 receptors on striatal DA neurons are predicted to inhibit striatal DA release [12],... 

Respiratory Effects. Information on respiratory effects due to exposure to disulfoton is very limited. Exposure to disulfoton causes overstimulation of the muscarinic cholinergic receptors in the respiratory tract (Murphy 1986). This usually results in excessive bronchial secretions, bronchoconstriction, and eventually respiratory failure. Pulmonary edema and hemoptysis were recognized as probable causes of death in a man who ingested an unknown amount of disulfoton (Hattori et al. 1982). Studies regarding inhalation exposure were concerned primarily with lethality or cholinesterase inhibition. However, in intermediate-duration inhalation studies in rats, inflammation... 

---