Pharmacology of Peripheral nervous system
The autonomic nervous system is the part of the nervous system that is responsible for regulating the functions that are involuntary and maintain homeostasis that is these are the functions that we don’t need to think about for controlling them.
they can include blood pressure control heart rate control respiratory rate control and exocrine gland secretion etc now the reason we need to control these particular functions is to allow the body to perform a range of functions, for example, to enable the body to cope with stress via the sympathetic nervous system and to maintain the state of rest and growth and digestion while the parasympathetic nervous system the control of both sympathetic and parasympathetic nervous system is mainly within the hypothalamus and also within some brainstem control centers.
now when the hypothalamus or the brainstem control centers want to increase or decrease a particular function they will send the signal wire neurons and in caseof the sympathetic nervous system the preganglionic cells will arise from the spinal cord segments t12 l3 while in the case of parasympathetic nervous systemthe preganglionic cells will be presentin the cranial nerve three seven nineand ten and sacral outflow that is s2 s3and s4 now an autonomic fiber is made upof two neurons one of them is preganglionic and the other one is postganglionic and that simply means that one of them will end in a ganglion wherethere will be cell bodies and then there will be another one that will extend from the ganglion to the effector cell the neurotransmitter in the ganglion of thought normal nervous system willalways be acetylnow the sympathetic nervous system willhave a short preganglionic neuron thatusually ends in the sympathetic chainand a post ganglionic neuron that isvery long while the parasympatheticnervous system has a long pre ganglionicneuron and the short post ganglionicneuron which usually ends within the effector cell looking at this diagram we can see the two main divisions of the central nervous system that is the autonomic nervous system and the somaticnervous system the autonomic nervous system is further divided into the parasympathetic nervous system and the sympathetic nervous system now firstly will see the circuit in the parasympathetic nervous system.
now we know that the parasympathetic nervous system has acetylcholine as its chief neurotransmitter as we’ve already described that the ganglions will always shave acetylcholine now that’s understood but in the parasympathetic nervous system,
the postganglionic nerves on the muscarinic receptors will also release acetylcholine coming to the sympathetic nervous system the chief our new transmitter is norepinephrine the postganglionic nerves will release norepinephrine at the alpha and beta-adrenergic receptors on the effector cells now there are two exceptions to this law one is the sympathetic cholinergic pathway that is the sympathetic nerves that innervate.
the sweat glands and the piloerector muscles do not release norepinephrine but their post ganglionicneurons will release acetylcholine justlike the parasympathetic nerves and acton muscarinic receptors on these glands the second exception in the sympathetic nervous system is the adrenal medullainnovation and the release of epinephrinenow the preganglionic neuron will be the same releasing acetylcholine at the adrenal medulla but there is no Post’spost ganglionic neuron actually adrenalmedulla itself is the post ganglionic neuron but it is modified this is known as neuro hormonal transmission that is when the adrenal medulla is stimulatedinstead of releasing norepinephrine at the nerve terminal it will release epinephrine as the major hormone into the blood and not into the nerveterminal now this is an important concept that will come in more detail inthe subsequent lectures but I want you to understand that norepinephrine will always need a nerve terminal for it to perform its function while epinephrine does not need enough terminal and it can act on the receptors that are notnecessarily present on a post synaptic neuron I hope that scare lastly we havethe somatic nervous system and a loweredmotor neuron that is directlyinnervating skeletal muscle and at theneuromuscular Junction we also haveacetylcholine, as the main neurotransmitter and leading to skeletal muscle contraction,
now in order to understand the drugs acting on the autonomic nervous system, we first need to review the types of receptors that are present in the sympathetic nervous system and the parasympathetic nervous system
firstly we will see the parasympathetic receptors which have acetylcholine as the major neurotransmitter and then we’ll look at the sympathetic receptors which have norepinephrine as the chief neurotransmitter but with exceptions,
I already mentioned in the sweat glands where there is acetylcholine and parallel erector muscles and in the adrenal medulla where their epinephrine release dopamine also action sympathetic receptors the parasympathetic nervous system is further divided into nicotinic and muscarinic subtypes the nicotinic receptors are further divided into the nicotinic n-type that is the neuronal type and the nicotinic M type that is the muscle type skeletal muscle type the nicotinic n-type of the receptor is present on the cell bodies in the autonomic ganglia where there is acetylcholine which acts on them and also in the adrenal medulla where when they are stimulated the adrenal medulla releases epinephrine as the chief hormone and some quantities of low norepinephrine,
as well now the chief function of nicotinic n-type is neurotransmission the nicotinic M ormuscle type is present on the skeletal muscle in the neuro muscular Junction andupon release of acetylcholine and when it acts on these receptors it causesskeletal muscle contraction now boththese nicotinic receptors are ligandgated ion channels that means that whenacetylcholine binds to them it causesthe influx of positive charged ions andleads to the depolarization coming tothe muscarinic subtypes we have M onereceptor M 2 and 3 and 4 and M 5 the M 1type is chiefly present in the CNS and in the gastric glands in the CNS upon stimulationit causes CNS excitation while in thegastro plants when stimulated cause sincreased acid secretion the M 2receptor is mainly present in the heartonly present in the heart and specifically in the SA node where itwill decrease the heart rate there is negative Crona tropic effect in the AVnode decreasing AV nodal conduction thuscausing negative drama tropic effect aswell but it is not present on theventricular muscle and Purkinje fibersthat is why it has no ionotropic effectthe ventricular muscle and Purkinjefibers are mainly under sympatheticcontrol coming to the M 3 receptors theyare present on the smooth muscles thoseof the bronchioles which when stimulatedwill cause pronto spasm the sphincterpupil eye muscle of the iris causingmeiosis the ciliary muscle of the eyecausing cyclope pragya that isaccomodation for near vision and blurredvisionJ tract causing diarrhea contraction ofdetrusor muscle of the bladder areleading to urinary urination and urinaryincontinence and three receptors arealso present on the sphincters which ingeneral will relax except the lower esophageal sphincter which will contractnow to think of it it is actuallylogical because under parasympathetic control we digest food right so if weare digesting and the stomach is contracting we need the lower esophageals phincter to contract so that the stomach contents do not go back into theesophagus and cost reflux and three receptors are also present in theexocrine glandsnow the exocrine glands in the main bronchioles will increase the secretionand trigger an asthmatic attack in asusceptible individual this doesn’thappen actually but in cases where wegive and three agonists the sweat andlacrimal glands also celebrity glandswill also increase their secretion and remember the sweat glands are under sympathetic control lastly n3 receptorsare also present on the blood vessel endothelium where and remember they’renot on the smooth muscle,
they’re on the endothelial cells so upon acting upon the endothelial and three receptors they will lead to the release of nitric oxide that is a vasodilator and thus there will be vasodilation which is contradictory to the general action of n3 on smooth muscles which is contraction the same thing occurs in the sphincter switch relaxed upon m3stimulation one thing to remember is that we don’t really release acetylcholine into the blood it is mainly a neurotransmitter but this effect of m3 on the endothelial cells leading to relaxation occurs when we exogenously add Mr. acetylcholine or anyother quaternary ammonium compound that resembles estelle Kalinin is functionthe m4 and m5 are present in the CNS mainly and leading to excitation now the muscarinic receptors unlike the nicotinic receptors are deepercoupled receptors which involves secon dmessengers as well the m1 isspecifically GQ coupled which uses theIP 3 dag pathway which leads tointracellular increased calciumconcentration the m2 receptor is GIcoupled which leads to diminished cyclicAMP II in the cell the m3 receptor justlike m1 is GQ coupled coming to thesympathetic receptors the first receptorthat is alpha is further classified intoalpha 1 and alpha 2 alpha 1 receptor ismainly present in the radial muscle ofthe eye where it contracts and causesmid rises it is also present in thearterioles of skin and viscera whichcauses contraction upon stimulation and thus causes the pale-faced and decreasedsupply to the viscera upon sympatheticstimulation in the wings it also causescontraction trigonal sphincter is alsocontracted by alpha 1 receptor leadingto urinary retention they are alsopresent in the prostatic urethra andspecifically the alpha 1 a type and wewill see this when we are discussing thebenign prostatic hyperplasia they arealso present in the male sex organs inthe liver where they increaseglycogenolysis and in the kidney wherethey decrease renin release the alpha 2receptor is an auto receptor mainly andis present on the presynaptic neuronterminals and there it mediates negativefeedback upon norepinephrine thérèse anddecreases its release when it isstimulated it is also present in theplatelets where it causes plateletaggregation and the pancreas itdecreases insulin release and in thecelery body it decreases across humorproduction and thus decreasingintraocular pressure the sympatheticreceptors are all g-protein coupled andin volt second messengers,
the alpha 1 isGQ coupled while alpha 2 is GI coupled the beta receptors are further classified into B1 beta 2 and beta 3 receptors the beta 1and beta 2 RGS coupled coming to the beta 1 it is mainly present in the heart in the SA node where it will increase the heart rate leading to a positive chrono tropic effect in the AV node where it will increase the conduction velocity leading to a positive drama topic effect and in the ventricular muscle and the Purkinje fibers where itwill increase the contractility and thushave a positive inotropic effect thebeta 1 receptors are also present in thekidney where they increased reninrelease at low doses of epinephrine nowremember in general beta receptors aremore sensitive than alpha receptors sobeta receptors at low doses of the new transmitter norepinephrine or the hormone epinephrine beta receptors will be stimulated first at low doses while at higher doses,
alpha receptors will be stimulated so to understand this at low doses of of epinephrine say beta receptors are stimulated and they increase renin release thus increasing blood pressure that happens in a normal sympathetic activation but we saw in the alpha 1 stimulation that it caused the kidney to decrease renin release and thus decrease the blood pressure now in general if we think this is unlike sympathetic response because sympathetic response generally increases the blood pressure alpha 1 is actually let’s say safety valve for decreasing the blood pressure,
in cases where there is too much stimulation by catecholamines for example in pheochromocytoma where there is too much of the epinephrine so the beta 1 receptors will get desensitized and the major major response will be while the alpha 1 receptors which will decrease renin release and thus there will not be that much hypertension andthis will act as a safety wolf I hopethat’s clear beta 1 receptors are alsopresent in the ciliary body of the eyewhere it will increase equus humorproduction in contrast to the alpha 2where it decreased at cosa humanproductioncoming to the beta 2 receptors rememberabout beta 2 receptors that they aregenerally not innervated and that meansthat the neurotransmitter that only actsin the nerve terminal the epochnorepinephrine will never reach the beta2 receptors while the epinephrine which is the hormone will reach the beta 2receptors and cause the functions that are caused by beta 2 the beta 2receptors are present on the blood vessels where it relaxes the bloodvessels smooth muscles the bronchial smooth muscles which also it relaxes in the liver,
it causes increasedglycogenolysis increased gluconeogenesisand also increased lipolysis all thesethree functions will increase theglucose level of the blood now onefunction of beta 2 that might seem a bitodd to you but I’ll explain it is on thepancreas where it increases insulinrelease to a little extent now that isbecause during sympathetic stimulationwhere we increase the blood glucoselevel for the skeletal muscles to workbetter we need some amount of insulinfor the skeletal muscles to up to touptake the and glucose and thus performits function because you know the glutereceptors are insulin dependent most ofthem the beta 3 receptors are mainlypresent in the fat cells which uponstimulation will cause slap policieslastly we have dopamine and the onewhich is released peripherally not inthe central nervous system dopamine atlow doses relaxes the visceral westvillage ER that is the renal bloodvessels the mesenteric blood vessels andthe coronary blood vessels the renalblood vessels when dilated will reallywill result in increased renal bloodflow and increased GFI at moderate dosesas we know that dopamine is theprecursor of norepinephrine andepinephrine and this is similar instructure it can at moderate doses itwill firststimulate the beta receptors because Isaid that the beta receptors are moresensitive so when it stimulates the beta1 receptors at the heart it willincrease the contractility and increasethe Kartikput as well and also the beta-2receptors which will cause blood vesselrelaxation now at high doses dopaminewill stimulate the alpha receptorsparticularly the alpha one which willincrease the blood pressure wirevasoconstriction and thus dopamine is anexcellent drug to use in shock now that we know where
these receptors are located and what their functions are we now know that we can use them to our advantage in certain disease condition show that is by stimulating them with agonists or blocking them with antagonists to get our desired action but to remember in the autonomic nervous system almost every organ has dual supply that is by both sympathetic and parasympathetic nervous system,
as we saw previously so this gives us an advantage and in order to get a specific effect in the body, we can do two things because we have dual innovation and two switches one will increase it.
the particular function and the other is decreasing so we can do two things to achieve one specific effect one is by stimulating and a receptor that we need to work by an agonist or block the other receptor that acts against that receptor by an antagonist now although we have this two choices blocking the antagonist is always a good choice.
the reason is that agonist efficacy that means the agonist can produce response at a receptor and if we administer an agonist for one particular function to be stimulated it will find the receptor everywhere in the body and cause a response at those receptors as well and cause a wide range of side-effects while contrasting the antagonist has zero efficacy,
that means it can not stimulate receptors it only blocks them so by administering an antagonist we won’t have those side effects an example of this effect is if we want to use a drug to treat hypertension or high blood pressure we have two choices we can give em three agonists which will versatile eight
the m3 receptors on the endothelium which will release nitric oxide and caused by the dilation and we can also give alpha one blockers which will alpha one usually contracts the vessels so alpha one blockers will relax now the problem with m3 agonists will be that the n3 agonist will find the m3receptor everywhere that is we have discussed that it is present in the smooth muscles causing diarrhea urinary incontinence stool incontinence in the uterus
it will cause abortion and premature deliveryfrança spasm in the glands it will cause increased length gland Urals secretion meiosis Cyclopaedia and all those side effects but in alpha-blockers, it will not cause effects at any other receptor and no side effects that’s why a blocker is always a good choice.
