Parasympathomimetic activity

Pilocarpine is classified as a tertiary amine that has parasympathomimetic activity. When administered as eye drops, it causes pupillary constriction or miosis and is therefore indicated in the treatment of glaucoma. In glaucoma, multiple-drug therapy may be necessary to achieve the desired intraocular control. Pilocarpine may be used in combination with topical beta-blockers such as timolol. 

Although the pharmacological properties of pilocarpine have been studied extensively (106), little is known of the structural requirements for its parasympathomimetic activity. In 1982 Aboul-Enein and Al-Badr published an extensive review on the structure-activity relationship of compounds that are structurally related to pilocarpine (102) this review also gives a prognosis of receptor sites. A general conclusion is that any slight structural modification of the pilocarpine molecule causes a drastic reduction in or complete loss of its biological activity. 

Signal Transduction Model The pharmacological effects of drugs may be mediated by a time-dependent signal transduction process, which involves multiple steps. Sun and Jusko proposed a signal transduction model to account for the delayed effect of pharmacodynamic responses. This model has been used to characterize the parasympathomimetic activity of scopolamine and atropine in rats. ... 

Perlstein, I. Stepensky, D. Krzyzanski, W. Hoffman, A. A signal transduction pharmacodynamic model of the kinetics of the parasympathomimetic activity of low-dose scopolar-mine and atropine in rats. J. Pharm. Sci. 2002, 91 (12), 2500-2510. 

Giolinergic drugs mimic the activity of the parasympathetic nervous system (PNS). They also are called parasympathomimetic drugs. An understanding of the PNS is useful in understanding the cholinergic dni. ... 

Some 2-amino derivatives (36) have been reported to show local anaesthetic, parasympathomimetic, long-lasting myorelaxant, brief hypotensive and mild antiarrhythmic activities [83]. Analogous cyclic amidines (37) with a 3-phenyl group were examined for potential hypoglycaemic agents [7]. Ten of 16 compounds showed weak to moderate activity in the rat. The most active compound was (37, R1 = OMe R2 = R3 = H, R4 = cyclopropyl), although it was less active than tolbutamide [84]. 

The choline ester, carbachol, activates M-cholinoceptors, but is not hydrolyzed by AChE. Carbachol can thus be effectively employed for local application to the eye (glaucoma) and systemic administration (bowel atonia, bladder ato-nia). The alkaloids, pilocarpine (from Pilocarpus jaborandi) and arecoline (from Areca catechu betel nut) also act as direct parasympathomimetics. As tertiary amines, they moreover exert central effects. The central effect of muscarinelike substances consists of an enlivening, mild stimulation that is probably the effect desired in betel chewing, a widespread habit in South Asia. Of this group, only pilocarpine enjoys therapeutic use, which is limited to local application to the eye in glaucoma... 

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. This conclusion is true but incomplete, and we now know that muscarinic receptors have a broader distribution and many functional roles. To understand the actions of cholinomimetic drugs it is essential to recognize that muscarinic receptors (1) mediate the activation of effectors by ACh released from parasympathetic nerve... 

Muscarine Muscarine, molecular formula C9H2qN02, first isolated from fly agaric Amanita muscaria, occurs in certain mushrooms, especially in the species of the genera Inocybe and Clitocybe. It is a parasympathomimetic substance. It causes profound activation of the peripheral parasympathetic nervous system, which may result in convulsions and death. Muscarine mimics the action of the neurotransmitter acetylcholine at the muscarinic acetylcholine receptors. 

Bethanechol Muscarinic agonist t negligible effect at nicotinic receptors Activates Mi through M3 receptors in all peripheral tissues causes increased secretion, smooth muscle contraction (except vascular smooth muscle relaxes), and changes in heart rate Postoperative and neurogenic ileus and urinary retention Oral and parenteral, duration 30 min does not enter central nervous system (CNS) Toxicity Excessive parasympathomimetic effects, especially bronchospasm in asthmatics Interactions Additive with other parasympathomimetics... 

Edrophonium Alcohol, binds briefly to active site of acetylcholinesterase (AChE) and prevents access of acetylcholine (ACh) Amplifies all actions of ACh increases parasympathetic activity and somatic neuromuscular transmission Diagnosis and acute treatment of myasthenia gravis Parenteral quaternary amine does not enter CNS Toxicity Parasympathomimetic excess Interactions Additive with parasympathomimetics... 

Pathophysiology can influence muscarinic activity in other ways as well. Circulating autoantibodies against the second extracellular loop of cardiac M2 muscarinic receptors have been detected in some patients with idiopathic dilated cardiomyopathy and those afflicted with Chagas1 disease caused by the protozoan Trypanosoma cruzi. These antibodies exert parasympathomimetic actions on the heart that are prevented by atropine. In animals immunized with a peptide from the second extracellular loop of the M2 receptor, the antibody is an allosteric modulator of the receptor. Although their role in the pathology of heart failure is unknown, these antibodies should provide clues to the molecular basis of receptor activation because their site of action differs from the orthosteric site where acetylcholine binds (see Chapter 2). 

Whether a toxin is naturally reactive to biological macromolecules or receptors, or requires metabolic activation to produce such a species, e.g. the enzyme-mediated transformation of tremorine (9) to the active parasympathomimetic agent oxotremorine (10), it will usually be subject to chemical or enzymic inactivation in vivo. Interruption of the latter process via appropriate substitution may thus lead to an increase in biological activity or toxicity over that of the parent compound. Perhaps the most striking example of this is provided by the extreme metabolic stability and toxicity of TCDD and the nontoxicity of its de- chloro analogue dibenzodioxin (Table 3). 

Bymaster FP, Carter PA, Yamada M, Gomeza J, Wess J, Hamilton SE, Nathanson NM, McKinzie DL, Felder CC (2003a) Role of specific muscarinic receptor subtypes in cholinergic parasympathomimetic responses, in vivo phosphoinositide hydrolysis, and pilocarpine-induced seizure activity. The Eur J Neurosci 17 1403-10... 

From the influence of the autonomic nervous system it follows that all sympatholytic or sympathomimetic and parasympatholytic or parasympathomimetic drugs can produce corresponding effects on cardiac performance. These possibilities are exploited therapeutically for instance, p-blockers for suppressing excessive sympathetic drive (p. 96) ipratropium for treating sinus bradycardia (p. 108). An unwanted activation of the sympathetic system can result from anxiety, pain, and other emotional stress. In these cases, the heart can be protected from harmful stimulation by psychopharmaceuticals such as benzodiazepines (diazepam and others important in myocardial infarction). 

SAFETY PROFILE Poison by ingestion, subcutaneous, intramuscular, intraperitoneal, and intravenous routes. Experimental reproductive effects. Human systemic effects by intramuscular and intravenous routes wakefulness, euphoria, hallucinations or distorted perceptions, tremors, convulsions, excitement, motor activity changes, muscle weakness, analgesia, withdrawal, parasympathomimetic effects, nausea or vomiting, and dermititis. Can cause drug dependency and other central nervous system effects. An analgesic. When heated to decomposition it emits toxic fumes of NOx. See also ALLYL COMPOUNDS. 

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