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


su st nces.
• 1.-RECEPTOR α1 nd α2 • The lph drenoceptor
induce we k re ction when the
synthetic
gonist isoproterenol stimul tes, ut its ctivity is intense, with s
timul tion y n tur l c techol

mines dren line nd nor dren line. For the lph
potenti l level is descri ed s follows:
• Adren line -------- ----------- norepinephrine 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.
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.
• •
•
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
rineis 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.


• 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.
• 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.
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