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Autonomic Nervous System Pharmacology Therapeutics Semester IV 2002 Lectures 1and 2 John Kefer PH.D. Introduction To discuss the pharmacology of the sympathetic and parasympathetic nervous system can be overwhelming. The number of drugs that influence these systems is immense, and you will be hard pressed to find drugs that do not either directly or indirectly interact with the S S!P S. Therefore, to discuss this sub"ect in a more focused manner, today we will discuss this sub"ect from a cell surface receptor#oriented perspective. $e will discuss agonists and antagonists of the following receptors% & receptors, ' receptors and dopamine receptors (sympathetic receptors), and muscarinic (*) receptors and nicotinic receptors. +gain, this sub"ect could become overwhelming, as each organ in the body e,presses these receptors. Sometimes, the same receptor can have different responses for different organs. How can this disparity be resolved- .s there a conceptual model to help form a unified picture of what each of these drugs is doing throughout the body- There is. Uni ying !odel" /ear vs. 0ouch 1. Sympathetic" How will this organ behave when chased by a bear2. Parasympathetic% How will behave while sitting on the couch#oal o Lecture" To allow you to build a framewor3 of understanding to properly predict the effects and side effects of different drugs simply by 3nowing what receptor they interact with. . feel this is much more effective than trying to retain lists of seemingly unrelated side effects for all of these drugs. 4eceptors and 5unction of the 6ye $ig% 1

1. 0iliary epithelium produces a7ueous humor through 1 receptors. This fluid 3eeps the anterior chamber of the eye at the proper pressure to focus light onto the lens and to the retina. 2. Sympathetic activity stimulates the alpha receptors on the iris to contract longitudinally to pull the iris towards itself, concentrically opening the sphincter. 8. The ciliary muscle and sphincter are stimulated by parasympathetic neurons releasing acetylcholine (+ch), binding muscarinic (*) receptors. These muscles wor3 by% a) ciliary muscle pulls on the trabecular meshwor3 to open the canal of schlemm and drain the fluid. b) ciliary muscle contracts the entire machinery to accommodate lens by rela,ing its pull on the lens. c) The sphincter contracts to constrict the pupil. So under high stress, sympathetics release 6. 6 (, ) increases a7ueous humor production, and dilates the pupil. 9nce the stress is gone, the parasympathetics constrict the pupil and drain the anterior chamber. Lungs" $ig% 2 1. Sympathetic activity& 2 receptor stimulation bronchodilates the airways and decreases airway secretions. 2. Parasympathetic activity& +ch stimulates * receptors, bronchoconstrict the airways and also to increase airway secretions. .n the lungs there are many other receptors and mediators affecting lung function, but these are not directly involved in the S S!P S system. 'eart 1. Sympathetic activity& 1 receptor stimulation increases heart rate, contractility, +: nodal conduction and cardiac output. 2. Parasympathetic activity& muscarinic (*) receptor stimulation decreases S+ nodal firing, decrease +: node conduction and decrease 09. (lood Vessels The blood vessels e,press , , dopamine (D+), histamine and * receptors. This system is more comple,. 1. Sympathetic# 6 (, 1), and epinephrine(1, 2, 1, 2) and dopamine (D+) are released, # 1 vasoconstricts vessels, mainly at the arterioles, to increase pressure! cut off blood flow to unnecessary organs and shunt it to organs that need it. # 2 vasodilates s3eletal vessel beds to increase blood flow to needed muscles. +lso lowers vascular resistance overall, and therefore blood pressure.

)A& three di erent mechanisms* concentration&dependent% a.) Lo+ dose )A& dilates renal artery, increasing 3idney perfusion. b.) !id&dose )A# stimulates 2 receptors as well, resulting in dilation of s3eletal bed /:;s to decrease systemic resistance. c.) 'igh )ose )A& stimulate 1 receptors and blood vessels constrict, resulting in an overall increased ,lood pressure.

(+t all three doses, low medium or high, the renal artery is dilated to increase perfusion of the 3idney.) low dose D+ < D1, , *edium dose D+ < 2, High dose D+ < 1 The interplay of these drugs with blood vessels and heart rate will be discussed below.

#I& :ery comple,, poorly understood. # # # # Parasympathetic activity -!. stimulates =. motility, allows sphincters to open, and increase secretions. sympathetic activity - * . slows =. motility, increases sphincter tone, and decreases =. secretions. )A receptor activation causes increased =. motility, stimulates secretion, and decreases sphincter tone. opioids# also must be considered in the =. function, as opioids will promptly decrease =. motility, decrease secretions and increase sphincter tone, inducing constipation.

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1. Sympathetic" The receptors prevent bladder contraction by rela,ing the bladder, and contracting the internal sphincter. 2. Parasympathetic" *uscarinic receptors in the bladder stimulate bladder contraction and rela, the internal sphincter. (*icturition 4efle,)

Introduction .n the last section, we discussed the receptor#oriented behavior of each organ system. $e will now discuss the drugs of the sympathetic!parasympathetic nervous system affecting each of these organ systems, and the resulting side effects of each of these drugs. )rugs o the /ye The main disease of the eye (as far as /oards go) and discussed in pharmacology is glaucoma. .t is a common disease and can result in blindness. 1. Pathophysiology of glaucoma# .ncreased pressure in the intraocular space due to increased production and decreased drainage of a7ueous humor. 2% 0losed angle vs% open angle glaucoma =laucoma is treated with cholinomimetics, #bloc3ers, and epinephrine 0holinomimetics# The use of these agents is based on their chemistry. Tertiary amines such as pilocarpine and physostigmine are uncharged molecules and therefore pass easily through membranes. These two drugs have the same effect on the eye but through two distinct mechanisms. a) Pilocarpine" # direct muscarinic agonist # passes easily through the cornea # Stimulates * receptors on the ciliary muscle and the sphincter muscle of the iris. This helps open the canal of Schlemm, and helps fluid reach it. b) Physostigmine" & cholinesterase inhibitor # passes easily through the cornea as well as the blood brain barrier. # .ncreases local +ch by bloc3ing acetylcholinesterase, increasing ciliary muscle and sphincter muscle contraction. Pilocarpine vs% Physostigmine" Pilocarpine, based on its own individual charge, does not cross the blood#brain#barrier 7uite as easily as physostigmine, so less central nervous system effects with pilocarpine. Therefore, pilocarpine is the drug of choice for glaucoma, and if a patient does not respond well, physostigmine can also be tried. (loc1ers# Timolol is the bloc3er of choice for glaucoma. #bloc3s 1 and 2 receptors. #>ac3 of the anesthetic effect of other bloc3ers, #/loc3s the receptors of the ciliary epithelium, decreasing synthesis of a7ueous humor w!o anaestheti?ing the cornea and causing @asensoryA trauma.

&Timolol happens to cross the cornea more effectively than the other bloc3ers. Aceta2olamide# #diuretic # bloc3s carbonic anhydrase activity, no H098 can be made. # Production of a7ueous humor re7uires the presence of H098. # /loc3ing H098 prevents production of a7ueous humor. Antimuscarinics# These are not used for glaucoma, as these agents would +orsen glaucoma. These agents are used to dilate the eye for eye e,ams. The prototype is atropine, which bloc3s muscarinic receptors. 9thers include homatropine, cyclopentolate and tropicamide. These drugs vary only in their duration of effect. +tropine lasts C D2 h, homatropine 2B h, cyclopentolate 1E h, and tropicamide .F# B h. The muscarinic receptor bloc3ade rela,es the ciliary muscle, causing the lens to rela, and Gthic3enG, and also rela,es the iris sphincter, resulting in cycloplegia, and mydriasis. >ungs The two main actions of the drugs affecting the lungs occur by% 1) affecting airway diameter, 2) affecting airway secretions. The two receptors involved in this control are 2 and * receptors. 1a. +irway diameter# /ronchodilation##Sympathetic activity -/PI* )A. # Stimulate 2, with% #epinephrine (1, 2, 1, 2), # medium dose D+, # e,ogenous 2 agonists (albuterol and other similar drugs), # 0auses bronchial smooth muscle dilation and decreased secretions in the lungs. # $ithdrawal of these agents or decreased sympathetic activity causes bronchiolar rela,ation, and increases bronchiolar secretions. # The antimuscarinic agent ipratropium, a muscarinic receptor antagonist, is very effective in bloc3ing muscarinic bronchoconstriction and increased secretion. # .t is a 7uaternary amine, therefore it crosses membranes poorly and is therefore e,cellent for inhalation and targeting to the lungs with minimal systemic side effects. # /pinephrine and )opamine can be used for emergencies where increased ventilation is re7uired, but due to their systemic side effects, are not used for long term therapy. # Norepinephrine has little effect on the lungs because it is specific for 1. b. /ronchoconstriction# *uscarinic receptor activity results in decreased airway diameter with increased secretions. *uscarinic drugs are not

used for this action, as there is little indication for decreasing the diameter of the airways. 'eart& The activity of the heart is controlled through 1 and * receptors. # 1 stimulation of the heart increases heart rate, contractility and cardiac output. 6pinephrine, orepinephrine, dopamine and isoproterenol all increase heart activity. # !uscarinic agonists or cholinesterase antagonists increase +ch, slowing the heart rate, decreasing contractility and decreasing +: nodal conduction velocity through the +: node. # There are few agents used in cardiology to stimulate * receptors. bloc3ers are employed to slow heart rate instead. # bloc3ers are covered in the cardiac chapter, and are beyond the scope of this lectureH (however, 3now that atenolol* metoprolol, are both 1 specific, and therefore the best bloc3er for use in asthmatics (good board 7uestion). +lso, la,etolol and carvedilol has both and 1 activity, carvedilol is used for 0H5 treatment because decreases afterload (boards). on#selective bloc3ers can e,acerbate an asthma attac3. ) (aroreceptor 3e le4" /efore moving on to the drugs affecting the blood vessels, we must first engage in a review of the baroreceptor refle,. $ig 5

+nything that changes arterial pressure, such as an alpha agonist or high dose dopamine, causes an automatic decrease in H4 by stimulating the brainstem .nucleus tractus solitarius to decrease basal sympathetic stimulation of the heart. The change in sympathetic activity changes 6 release at the S+ node, and heart rate and contractility are altered accordingly. # $hen arterial pressure decreases, the blood vessels signal the TS to increase sympathetic tone, and heart rate goes up to compensate and maintain organ perfusion. # $hen arterialpressure increases, the sympathetic activity is inhibited, and heart rate and contractility decrease. /lood :essels! /aroreceptor 4efle, 6pinephrine# (1, 2, 1, 2)J$e have discussed the baroreceptor refle,. How do drugs with multiple receptor actions affect the blood pressure and heart rate- $hich receptor action wins1# constricts arterioles and large arteries 2# bloc3s central nervous system release of norepinephrine 1# increase heart rate 2 K dilates s3eletal vessel beds 9verall, you see increased H4, increased /P.

orepinephrine# (1, 1) 1# constricts arterioles and large arteries 1# increase heart rate, contractility +lthough 1 increases arterial pressure, baroreceptor refle, results in a subse7uent decreased H4 and 1 vs vagus < vagus wins. 9verall see increased pressure, decreased heart rate. .soproterenol# (1, 2) # stimulates heart through 1 directly. # 2 stimulates vasodilation, leading to decrease in /P, stimulating the baroreceptor refle, and further stimulating heart rate. $ig% 6. 7no+ these igures or ,oards8

Dopamine# (1, 1, 2, D1) +ll effects are dose#dependent# #if give a low dose, only see D1 activity in renal artery. # medium dose results in s3eletal vessel dilation and increased heart rate through 1 and the baroreceptor refle,. # High dose results in increased arterial pressure via 1. #1 agonists# Phenylephrine* metho4yamine are specific 1 agonists, which increase arterial pressure, stimulating the baroreceptor refle, and decreasing heart rate. Non&selective antagonists& To fully understand how these drugs operate we must remember that 2 receptors mainly affect the central nervous system. This receptor is on the presynaptic sympathetic vessels in the 0 S and are normally stimulated by 6 which has 1 and 2 activities. The 2 receptor inhibits release of norepinephrine from the 0 S. Pheno4y,en2amine and Phentolamine are non#selective #bloc3ers, used to control hypertension and tachycardia associated with pheochromocytoma. Pra2osin& is an 1 specific antagonist which can be used as a second line agent for control of hypertension, and to treat urinary retention (see below). /ecause pheno4y,en2amine and phentolamine bloc3 1 and 2 receptors, tachycardia is e,acerbated with these drugs and can be problematic. However, these drugs are used to temporarily control the more dangerous malignant hypertension associated with pheochromocytoma until surgery can be performed. These drugs are preferred over pra2osin because they bloc3 1 more effectively. However, the e,acerbation of tachycardia ma3es the use of these drugs temporary. Pheno,yben?amine binds 1 irreversibly. Phentolamine binds 1 reversibly. 6ffectiveness and 9rthostatic Hypotension*uscarinic +gonists# Stimulation of muscarinic receptors on blood vessels results in vasodilation through the production of nitric o,ide. Thus, one side effect of muscarinic agonists or cholinesterase inhibitors is vasodilation, potentially leading to orthostatic hypotension. =. Pharmacology K The =. system e,presses !, D+ receptors, * receptors, opioid receptors, and FHT receptors. Sympathomimetic drugs# Drugs acting on !!D+ receptors down regulate =. activity. These drugs decrease motility, decrease secretory activity, increase motility, and increase sphincter tone.

(Antidopaminergic drugs such as the cisapride and metoclopramide are used e,tensively in hospital setting as antinauseate and promotility agents.) *uscarinics# increase blood flow to the gut, increase motility, increase secretions of the =. tract. # (ethanechol has been used to stimulate the =. tract and increase secretions for digestion in diabetic nephropathies, or after surgeries that decrease vagal function, two conditions that lead to =. paralysis. +nti#muscarinics# Propantheline, a competitive muscarinic receptor antagonist is used to rela, the smooth muscle of the =. tract, increases sphincter tone and decreases secretions. # This drug is used to decrease nervous stomach!irritable bowel syndrome. 9pioid Agonists& constipation is a common side effect of opioids. 9pioid receptors e,ist in high density in the =. tract, and directly mediate decreased motility, decreased secretion, and increased sphincter tone through the enteric nervous system and the central nervous system. These actions delay passage of the fecal mass and increased absorption of water. 9ndansetron& ondansetron is a FHT antagonist. Serotonin plays a role in the nausea and vomiting refle,. 9ndansetron bloc3s =. serotonin receptors, and therefore prevents nausea and vomiting. 9ndansetron is used for serious nausea and vomiting, such as post#op !: that is resistant to the more common D+ bloc3ers such as cisapride and metoclopramide. 9ndansetron is also used for the intractable nausea and vomiting associated with chemotherapy. /ladder There are 2 main receptors for the bladder, and * receptors. The muscarinic agonist ,ethanechol is used to stimulate bladder function in non# obstructive disease, such as diabetic neuropathy. The muscarinic antagonist propantheline is used to stimulate urinary retention in incontinence. The # antagonist pra2osin and tera2osin (longer half#life) can increase micturition by rela,ing the smooth muscle of the internal sphincter, as well as the smooth muscle of an enlarged and therefore obstructive prostate. Note" The lac1 o lists o side e ects in this lecture is or a purpose% /very side e ect o all o these drugs has ,een discussed% (y 1no+ing ho+ each class o drug interacts +ith its receptors in each organ system* you can then correctly predict the side e ects o each drug%

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This level o understanding is o greater depth than the ,oo1 chapters provided to you% :ith an understanding o ho+ these drugs +ill a ect other organ systems -rather than memori2ing a list o side e ects. you +ill ,e +ell served on ,oards and on the loors ne4t year% Nuestions% $hat is the effect of pilocarpine and other direct muscarinic agonists on the eye- >ungs- Heart/lood vessels- =lands- /ladder- =. tract+nswer% (miosis and accommodation!bronchoconstriction and increased bronchial secretions!bradycardia and decreased contractility! vasodilation and decreased blood pressure! increased secretions! increased urination! increased =. motility) $hat is the effect of physostigmine and other cholinesterase inhibitors on the eye- >ungsHeart- /lood vessels- =lands- /ladder- =. tract- S3eletal muscles$hat is the effect of timolol and other bloc3ers on the eye- >ungs- Heart- /lood vessels=lands- /ladder- =. tract$hat is the effect of atropine and other antimuscarinics on the eye- >ungs- Heart- /lood vessels- =lands- /ladder- =. tract- (remember the mnemonic% 4ed as a beet (no sweating, so hyperthermia can occur), dry as a bone, mad as a hatter (due to abnormal nerve conduction in the 0 S), blind as a stone (mydriasis and poor near#sightedness). $hat is the effect of albuterol and other 2 agonists on the eye- >ungs- Heart- /lood vessels=lands- /ladder- =. tract- (Osually, only blood pressure and heart effects are discussed## remember, agonists are selective, but not perfectly selective and you can get some interaction between receptor subtypes). $hat is the effect of 6P., 6 and D+ on the eye- >ungs- Heart- /lood vessels- =lands/ladder- =. tract- Kidney$hat is the effect of metho,amine, phenylephrine and other agonists on the eye- >ungsHeart- /lood vessels- =lands- /ladder- =. tract- /aroreceptor refle,$hat is the effect of non#specific agonists on the eye- >ungs- Heart- /lood vessels- =lands/ladder- =. tract- /aroreceptor refle,- $hat role does orthostatic hypotension play with these drugs- ame the other drugs discussed in this lecture which may cause orthostatic hypotension$hat is the effect of agonists on the eye- >ungs- Heart- /lood vessels- =lands- /ladder=. tract- /aroreceptor refle,- 9rthostatic hypotension$hat is the effect of cisapride and metoclopramide on the blood vessels- =. tract-

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$hat is the effect of bethanechol and other muscarinic agonists on the eye- >ungs- Heart/lood vessels- =lands- /ladder- =. tract$hat is the effect of propantheline and other muscarinic antagonists on the eye- >ungs- Heart/lood vessels- =lands- /ladder- =. tract-