DRUGS ACTING ON THE AUTONOMIC NERVOUS SYSTEM (ANS) and the neuromuscular junctio n 1.

Anatomic characterization of SNA Organization anatomical and pharmacological neurochemistry. • The autonomic nervous system along with the endocrine system coordinates the r egulation and integration of body functions. • Nervous System ------- rapid tran smission of electrical impulses that spread through the nerve fibers that termin ate in effector cells which produce specific effects following the release of ne urotransmitters substances. • Drugs that produce their primary therapeutic effect by imitation or alteration of the functions of SNA are known as autonomous agents, which stimulate the SNA or in some cases block the action of the autonomic nerves ----- S.N.A-visceral, vegetative, or involuntary Includes: nerves, ganglia and plexuses that are distributed in the heart, blood vessels, glands and other viscera and m. smooth fiber with different fabrics. S.N Any nerve that enters or leaves the S.N.C PERIPHERAL CENTRAL (brain and spinal cord) Efferent limb Afferent limb AUTONOMOUS SOMATIC: Features voluntary Parasympathetic NICE S.N.A: • Involuntary, regulates the daily needs and requirements of the body without th e conscious participation of the subject. Consisting of visceral motor neurons l ocated in m. smooth viscera, vasculature and exocrine glands. • Consisting of: • N. efferent: Neurons carry signals from the brain and spinal cord to peripheral tissues (effector organs ------ CNS) by two types of efferent neurons: - Pregaglionar: synaptic connection in the nodes, exits the brainstem. - Postgan glionic: located in the lymph, is usually unmyelinated, ends in effector organs: m.liso of the viscera, m. heart, exocrine glands. • N. Afferent: Whose peripheral neurons transmit information to the central leve l. Reflex regulation of S.N.A p. example, to detect the pressure on the carotid sinus and aortic arch and send signals to the CNS that spreads to the efferent p ortion of the system to respond. • N. Sympathetic "fight or flight" increases FC, mydriasis and blood flow.

- Preganglionic: thoracolumbar synapse in two lymph chains, like strands that ru n along its length - postganglionic: Axons that extend from the ganglia to the g lands and viscera. • N. Parasympathetic: decreases the P.A, F.C, miosis. - Preganglionic: Cranial and sacral. Synapse in ganglia near or attached to the effector organs. - Connections postganglionic • Mixing Phenomena, propulsion and absorption of nutrients in the gastrointestin al tract • sensory afferent neurons and various motor nerves and interneurons • Meissner plexus (secretion and absorption of the GI epithelium, local blood flow and activities neuroinmunitarias) and Auerbach's plexus (contraction and m.liso relaxation GI) • Has sympathetic and parasympathetic elements • Acetylcholine, besides being the transmitter of parasympathetic nerves to SNE, is the primary e xcitatory transmitter acting on nicotinic acetylcholine receptors in the intramu ral ascending pathways. • The blockade of cholinergic neurotransmission by drugs does not negate the excitatory transmission at all, because along with acetylch oline are released cotransmitter Tachykinins as substance P and neurokinin A and contribute to the excitatory responses. * The Enteric Nervous System • At each neuromuscular junction, the termination axoniana loses its myelin shea th and forms a terminal arborization that overcomes a specialized area of the mu scle membrane, called the neuromuscular junction. Chemical neurotransmitters in the SNA • Acetylcholine is the neurotransmitter of all fibers preganglionic autonomic type, all postganglionic parasympathetic and sympathetic postganglionic few. • adrenergic fibers include most postganglionic sympathetic ; • - parasympathetic (cardiac and smooth muscle, glandular cells and nerve endi ngs) • + fibers preganglionic nicotinic acetylcholine release • + fibers postganglion ic muscarinic acetylcholine release • - Simpatico • + fibers preganglionic nicotinic acetylcholine release postganglionic fibers • +-muscarinic acetylcholine release (sweat glands) • alpha and beta, release norepinephrine (cardiac and smooth muscle, glandular c ells, nerve endings) •-of the adrenal medulla, adrenaline and noradrenaline release 2. Autonomic nervous system receptors • cholinergic receptors (colinorreceptores): • colinoceptores are members of the family of G protein-coupled receptors (muscarinic), or the receptor family of i on channels (nicotinic), which is why drugs have been developed, have a high deg ree q selectivity, so q can achieve the desired effect while q is avoided or min imized side effects. • There are two known families of colinorreceptores, called muscarinic and nicotinic. This distinction is based on differential affinity ag ents that mimic the action of acetylcholine (Cholinomimetics). Muscarinic receptors • In addition to joining acetylcholine, these receptors recognize muscarine, an alkaloid found in certain mushrooms. This type of receptor has a weak affinity f

or nicotine. Binding studies applying specific inhibitors is possible to identif y several subclasses of muscarinic receptors are known as M1, M2, M3, M4 and M5. Even when all five subtypes are found in neurons: • M1: are located in parietal cells (secretion of CNS neurons. Formation of IP3 and DAG, increased intracellular calcium • M2: in heart cells and m.liso. Openin g channels presiápticos some sites. Inhibition adenylyl cyclase. Decreases FC to decrease the rate of depolarization. • M3: gl. exocrine and smooth m. (contract ion and secretion). Formation of IP3 and DAG, increased intracellular calcium. • M4, is abundant in the pancreas and lung • M5, is believed to act at the level of the salivary glands and the ciliary muscle MECHANISMS OF SIGNAL TRANSDUCTION OF ACETYLCHOLINE • There are several molecular mechanisms that transmit the signal generated by b inding of acetylcholine to its receptor. • The cholinomimetic may act directly b y binding to and activating receptor, or indirectly by inhibiting the action of acetylcholinesterase (which hydrolyzes to acetylcholine) and thus amplifying the action of acetylcholine. Q It may also be some cholinomimetic act at the same t ime directly and indirectly and by example. neostigmine. • For example: when act ivated M1 or M3 receptors undergo a conformational change and interact with a G protein, which in turn activates phospholipase C. This leads to hydrolysis of ph osphatidylinositol (4,5)-bisphosphate (PIP2), which is obtained by Diacylglycero l (DAG) and IP3 (increase of intracellular Ca.) • Activation of M2 receptors in heart muscle stimulates a G protein that inhibits adenylate cyclase and increase s the permeability K, which the heart reacts with reduced frequency and force of contraction. Muscarinic agonists and antagonists • Pirencepina: tricyclic anticholinergic drug which suppresses a selective musca rinic M1 receptors, for example in the gastric mucosa. It may be useful in the t reatment of gastric and duodenal ulcers Note: to date there are no known clinica lly relevant agents with action on M4 and M5 receptors. • • • • • • In addition to joining acetylcholine, these receptors recognize nicotine, althou gh they show low affinity for muscarine. Nicotine produces first stimulation and then a receptor blockade. They are located in the CNS, adrenal medulla, autonom ic ganglia and neuromuscular junction nicotinic-acting drugs stimulate the corre sponding receptors in those tissues. Nicotinic receptors of autonomic ganglia di ffer from those at the neuromuscular junction. For example, the hexamethonium se lectively blocks the receptors ganglion, while tubocurarine specifically blocks the receptors of the neuromuscular junction NICOTINE ADRENERGIC • adrenergic receptors (adrenoceptors): • In the sympathetic nervous system can distinguish various types of adrenoceptor by pharmacological. At first we identi fied two families of receptors, which were designated "α" nd "β" ccording to t heir response to drenergic gonists epinephrine, norepinephrine nd isoproteren ol. With the use of specific locking drugs nd gene cloning h ve identified sev er l molecul r su types of receptors. These proteins elong to multigene f mil y. Alter tions in the receptor prim ry structure lters its ffinity for v rious

 

 

 

 

 

 

 

 

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isoproterenol

• The lph drenoceptors re su divided into two groups, α1 nd α2, s its ffi nity for gonists nd lph - locking gents. • For ex mple, α1 receptors h ve hi gher ffinity for phenylephrine th t α2 receptors. By contr st, clonidine inds selectively to receptors α2 nd h s less effect on α1.

• • • Α2 RECEPTOR • • • • They are located mainly in presynaptic nerve terminals or in other cells such as pancreatic beta adrenégico neuromediators control and excretion of insu lin, respectively. When a nerve is stimulated sympathetic adrenergic, norepineph rine is released across the synaptic cleft and interacts with the receptor alpha 1. fraction of norepinephrine released is "recycled" and alpha 2 receptor act ivates the neuronal membrane. The alpha 2 receptor stimulation produces an inhib itory feedback of the release of noradrenaline in adrenergic stimulated neuron. The inhibitory action decreases the continued secretion of the mediator and serv es as a local modulator mechanism to reduce the excretion of sympathetic neurotr ansmitters while there is a strong sympathetic activity. Inhibition of adenylate cyclase and decreased levels of intracellular MP C mediate the effects resultin g from binding to alpha 2. Nerve endings and adrenergic inhibition of presynapti c adenylyl cyclase, c MP decreased platelets, lipocytes, smooth muscle • Inhibition of the release of norepinephrine, inhibition of insulin release. • • Β RECEPTORS • beta receptors show several different answers to the alpha receptor. These rea ctions are recognized by a high activity by isoproterenol stimulation and lower sensitivity to adrenaline and noradrenaline. In the case of beta receptors, the power rating is as follows: • Isoproterenol -------- --- adrenaline noradrenalin e • The beta-adrenoceptors can be subdivided into groups β1, β2, β3 h ve een id entified sed on their ffinity for drenergic gonists nd nt gonists • et 1 receptors h ve lmost identic l ffinity for dren line nd nor dren li ne. Postsyn ptic effector cells denylyl cycl se stimul tion nd especi lly the he rt, lipocytes nd incre sed cAMP. As r in, nerve endings presyn ptic drener gic nd cholinergic. • T chyc rdi , incre sed lipolysis, incre sed myoc rdi l contr ctility.

 

RECEPTOR α1 • • These receptors re found in the postsyn ptic mem r ne of effector org ns c n medi te m ny ch r cteristic effects, which were design ted s the initi l form α1 drenergic, including smooth muscle contr ction. Effector cell post-form tio n of DAG nd IP3, nd in p rticul r syn ptic incre se in intr cellul r C + smoo th muscle. V soconstriction, incre sed peripher l resist nce, elev ted lood pre ssure, dil ted pupils, incre sed closure of the intern l sphincter of the urin r y l dder. The α1 receptor ctiv tion initi tes series of re ctions medi ted y G protein ctiv tion of phospholip se C, which le ds to the form tion of IP3 f rom phosph tidylinositol, su st nce c p le of rele sing C into the endopl sm ic reticulum into the cytosol.

 

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• 1.-RECEPTOR α1 nd α2 • The lph drenoceptor synthetic gonist isoproterenol stimul tes, ut timul tion y n tur l c techol mines dren line potenti l level is descri ed s follows: • Adren line -------- ----------- norepinephrine

induce we k re ction when the its ctivity is intense, with s nd nor dren line. For the lph

 

 

 

 

 

 

 

 

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• et 2 receptors h ve higher ffinity for dren line th n nor dren line. Tissu es in which these receptors predomin te s the skelet l muscle v scul ture re p rticul rly re ctive to the effects of circul ting dren line rele sed the dren l medull . Postsyn ptic effector cells denylyl cycl se stimul tion nd p rticu l rly smooth muscle nd incre sing cAMP • V sodil t tion, slight decre se in peripher l resist nce, ronchodil tion, inc re se in muscle nd liver glycogenolysis, incre sed gluc gon rele se, rel x tion of smooth muscle of the uterus.

THANK YOU • BIBLIOGRAPHY - Rich rd H rvey, P. Ch mpe Ph rm cology. Editori l Mc Gr w Hill. 2nd edition 20 05 pp.31-71 - B sic Ph rm cology Ther peutics Goodm n nd Gilm n 's. 11th Editio n

 

• Bet 3 postsyn ptic effector cells Stimul tion of denylyl cycl se nd especi l ly lipocytes. nd incre sed cAMP. • Binding of neurotr nsmitter to receptor et 1 or et 2 ctiv tes denyl te cycl se nd, consequently, incre ses the concent r tion of cAMP in the cell.

 

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