ࡱ> y{xM $`bjbj== WW[lppppppp8$8$8$8p$D$|N7x<%<%(d%d%d%d%d%d%6666666$8 :6-pd%d%d%d%d%6)ppd%d%7)))d%Xpd%pd%6)d%6)")"-r)6Tpp6d%0% p(0!8$("}6670N76|;("|;6)ppppAutonomic 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 SNS/PNS. Therefore, to discuss this subject in a more focused manner, today we will discuss this subject from a cell surface receptor-oriented perspective. We will discuss agonists and antagonists of the following receptors:  receptors,  receptors and dopamine receptors (sympathetic receptors), and muscarinic (M) receptors and nicotinic receptors. Again, this subject could become overwhelming, as each organ in the body expresses these receptors. Sometimes, the same receptor can have different responses for different organs. How can this disparity be resolved? Is there a conceptual model to help form a unified picture of what each of these drugs is doing throughout the body? There is. Unifying Model: Bear vs. Couch 1. Sympathetic: How will this organ behave when chased by a bear? 2. Parasympathetic: How will behave while sitting on the couch? Goal of Lecture: To allow you to build a framework of understanding to properly predict the effects and side effects of different drugs simply by knowing what receptor they interact with. I feel this is much more effective than trying to retain lists of seemingly unrelated side effects for all of these drugs. Receptors and Function of the Eye Fig. 1 Ciliary epithelium produces aqueous humor through (1 receptors. This fluid keeps the anterior chamber of the eye at the proper pressure to focus light onto the lens and to the retina. Sympathetic activity stimulates the alpha receptors on the iris to contract longitudinally to pull the iris towards itself, concentrically opening the sphincter. The ciliary muscle and sphincter are stimulated by parasympathetic neurons releasing acetylcholine (Ach), binding muscarinic (M) receptors. These muscles work by: a) ciliary muscle pulls on the trabecular meshwork to open the canal of schlemm and drain the fluid. b) ciliary muscle contracts the entire machinery to accommodate lens by relaxing its pull on the lens. c) The sphincter contracts to constrict the pupil. So under high stress, sympathetics release NE. NE ((, () increases aqueous humor production, and dilates the pupil. Once the stress is gone, the parasympathetics constrict the pupil and drain the anterior chamber. Lungs: Fig. 2 1. Sympathetic activity- (2 receptor stimulation bronchodilates the airways and decreases airway secretions. 2. Parasympathetic activity- Ach stimulates M receptors, bronchoconstrict the airways and also to increase airway secretions. In the lungs there are many other receptors and mediators affecting lung function, but these are not directly involved in the SNS/PNS system. Heart 1. Sympathetic activity- (1 receptor stimulation increases heart rate, contractility, AV nodal conduction and cardiac output. 2. Parasympathetic activity- muscarinic (M) receptor stimulation decreases SA nodal firing, decrease AV node conduction and decrease CO. Blood Vessels The blood vessels express (, (, dopamine (DA), histamine and M receptors. This system is more complex. 1. Sympathetic- NE ((, (1), and epinephrine((1, (2, (1, (2) and dopamine (DA) 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 skeletal vessel beds to increase blood flow to needed muscles. Also lowers vascular resistance overall, and therefore blood pressure. DA- three different mechanisms, concentration-dependent. a.) Low dose DA- dilates renal artery, increasing kidney perfusion. b.) Mid-dose DA- stimulates (2 receptors as well, resulting in dilation of skeletal bed BVs to decrease systemic resistance. c.) High Dose DA- stimulate (1 receptors and blood vessels constrict, resulting in an overall increased blood pressure. (At all three doses, low medium or high, the renal artery is dilated to increase perfusion of the kidney.) low dose DA = D1, , Medium dose DA = (2, High dose DA = (1 The interplay of these drugs with blood vessels and heart rate will be discussed below. GI- Very complex, poorly understood. Parasympathetic activity (M) stimulates GI motility, allows sphincters to open, and increase secretions. sympathetic activity ((, () slows GI motility, increases sphincter tone, and decreases GI secretions. DA receptor activation causes increased GI motility, stimulates secretion, and decreases sphincter tone. opioids- also must be considered in the GI function, as opioids will promptly decrease GI motility, decrease secretions and increase sphincter tone, inducing constipation. Bladder- 1. Sympathetic: The ( receptors prevent bladder contraction by relaxing the bladder, and contracting the internal sphincter. 2. Parasympathetic: Muscarinic receptors in the bladder stimulate bladder contraction and relax the internal sphincter. (Micturition Reflex) Introduction In the last section, we discussed the receptor-oriented behavior of each organ system. We 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. Drugs of the Eye The main disease of the eye (as far as Boards go) and discussed in pharmacology is glaucoma. It is a common disease and can result in blindness. Pathophysiology of glaucoma- Increased pressure in the intraocular space due to increased production and decreased drainage of aqueous humor. Closed angle vs. open angle glaucoma Glaucoma is treated with cholinomimetics, (-blockers, and epinephrine Cholinomimetics- 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 M 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. - Increases local Ach by blocking 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 quite 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. ( Blockers- Timolol is the ( blocker of choice for glaucoma. -blocks (1 and (2 receptors. -Lack of the anesthetic effect of other ( blockers, -Blocks the ( receptors of the ciliary epithelium, decreasing synthesis of aqueous humor w/o anaesthetizing the cornea and causing asensory trauma. -Timolol happens to cross the cornea more effectively than the other ( blockers. Acetazolamide- -diuretic - blocks carbonic anhydrase activity, no HCO3 can be made. - Production of aqueous humor requires the presence of HCO3. - Blocking HCO3 prevents production of aqueous humor. Antimuscarinics- These are not used for glaucoma, as these agents would worsen glaucoma. These agents are used to dilate the eye for eye exams. The prototype is atropine, which blocks muscarinic receptors. Others include homatropine, cyclopentolate and tropicamide. These drugs vary only in their duration of effect. Atropine lasts > 72 h, homatropine 24 h, cyclopentolate 10 h, and tropicamide .5- 4 h. The muscarinic receptor blockade relaxes the ciliary muscle, causing the lens to relax and "thicken", and also relaxes the iris sphincter, resulting in cycloplegia, and mydriasis. Lungs The two main actions of the drugs affecting the lungs occur by: affecting airway diameter, affecting airway secretions. The two receptors involved in this control are (2 and M receptors. 1a. Airway diameter- Bronchodilation--Sympathetic activity (EPI, DA) - Stimulate (2, with: -epinephrine ((1, (2, (1, (2), - medium dose DA, - exogenous (2 agonists (albuterol and other similar drugs), - Causes bronchial smooth muscle dilation and decreased secretions in the lungs. - Withdrawal of these agents or decreased sympathetic activity causes bronchiolar relaxation, and increases bronchiolar secretions. - The antimuscarinic agent ipratropium, a muscarinic receptor antagonist, is very effective in blocking muscarinic bronchoconstriction and increased secretion. - It is a quaternary amine, therefore it crosses membranes poorly and is therefore excellent for inhalation and targeting to the lungs with minimal systemic side effects. - Epinephrine and Dopamine can be used for emergencies where increased ventilation is required, 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. Bronchoconstriction- Muscarinic receptor activity results in decreased airway diameter with increased secretions. Muscarinic drugs are not used for this action, as there is little indication for decreasing the diameter of the airways. Heart- The activity of the heart is controlled through (1 and M receptors. - (1 stimulation of the heart increases heart rate, contractility and cardiac output. Epinephrine, Norepinephrine, dopamine and isoproterenol all increase heart activity. - Muscarinic agonists or cholinesterase antagonists increase Ach, slowing the heart rate, decreasing contractility and decreasing AV nodal conduction velocity through the AV node. - There are few agents used in cardiology to stimulate M receptors. ( blockers are employed to slow heart rate instead. - ( blockers are covered in the cardiac chapter, and are beyond the scope of this lecture; (however, know that atenolol, metoprolol, are both (1 specific, and therefore the best ( blocker for use in asthmatics (good board question). Also, labetolol and carvedilol has both ( and (1 activity, carvedilol is used for CHF treatment because decreases afterload (boards). Non-selective ( blockers can exacerbate an asthma attack. ) Baroreceptor Reflex: Before moving on to the drugs affecting the blood vessels, we must first engage in a review of the baroreceptor reflex. Fig 3 Anything that changes arterial pressure, such as an alpha agonist or high dose dopamine, causes an automatic decrease in HR by stimulating the brainstem .nucleus tractus solitarius to decrease basal sympathetic stimulation of the heart. The change in sympathetic activity changes NE release at the SA node, and heart rate and contractility are altered accordingly. - When arterial pressure decreases, the blood vessels signal the NTS to increase sympathetic tone, and heart rate goes up to compensate and maintain organ perfusion. - When arterialpressure increases, the sympathetic activity is inhibited, and heart rate and contractility decrease. Blood Vessels/ Baroreceptor Reflex Epinephrine- ((1, (2, (1, (2)We have discussed the baroreceptor reflex. How do drugs with multiple receptor actions affect the blood pressure and heart rate? Which receptor action wins? (1- constricts arterioles and large arteries (2- blocks central nervous system release of norepinephrine (1- increase heart rate (2 dilates skeletal vessel beds Overall, you see increased HR, increased BP. Norepinephrine- ((1, (1) (1- constricts arterioles and large arteries (1- increase heart rate, contractility Although (1 increases arterial pressure, baroreceptor reflex results in a subsequent decreased HR and (1 vs vagus = vagus wins. Overall see increased pressure, decreased heart rate. Isoproterenol- ((1, (2) - stimulates heart through (1 directly. - (2 stimulates vasodilation, leading to decrease in BP, stimulating the baroreceptor reflex and further stimulating heart rate. Fig. 4. Know these figures for boards! Dopamine- ((1, (1, (2, D1) All effects are dose-dependent- -if give a low dose, only see D1 activity in renal artery. - medium dose results in skeletal vessel dilation and increased heart rate through (1 and the baroreceptor reflex. - High dose results in increased arterial pressure via (1. (-1 agonists- Phenylephrine, methoxyamine are specific (1 agonists, which increase arterial pressure, stimulating the baroreceptor reflex 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 CNS and are normally stimulated by NE which has (1 and (2 activities. The (2 receptor inhibits release of norepinephrine from the CNS. Phenoxybenzamine and Phentolamine are non-selective (-blockers, used to control hypertension and tachycardia associated with pheochromocytoma. Prazosin- 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). Because phenoxybenzamine and phentolamine block (1 and (2 receptors, tachycardia is exacerbated 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 prazosin because they block (1 more effectively. However, the exacerbation of tachycardia makes the use of these drugs temporary. Phenoxybenzamine binds (1 irreversibly. Phentolamine binds (1 reversibly. Effectiveness and Orthostatic Hypotension? Muscarinic Agonists- Stimulation of muscarinic receptors on blood vessels results in vasodilation through the production of nitric oxide. Thus, one side effect of muscarinic agonists or cholinesterase inhibitors is vasodilation, potentially leading to orthostatic hypotension. GI Pharmacology The GI system expresses (/(, DA receptors, M receptors, opioid receptors, and 5HT receptors. Sympathomimetic drugs- Drugs acting on (/(/DA receptors down regulate GI activity. These drugs decrease motility, decrease secretory activity, increase motility, and increase sphincter tone. (Antidopaminergic drugs such as the cisapride and metoclopramide are used extensively in hospital setting as antinauseate and promotility agents.) Muscarinics- increase blood flow to the gut, increase motility, increase secretions of the GI tract. - Bethanechol has been used to stimulate the GI tract and increase secretions for digestion in diabetic nephropathies, or after surgeries that decrease vagal function, two conditions that lead to GI paralysis. Anti-muscarinics- Propantheline, a competitive muscarinic receptor antagonist is used to relax the smooth muscle of the GI tract, increases sphincter tone and decreases secretions. - This drug is used to decrease nervous stomach/irritable bowel syndrome. Opioid Agonists- constipation is a common side effect of opioids. Opioid receptors exist in high density in the GI 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. Ondansetron- ondansetron is a 5HT antagonist. Serotonin plays a role in the nausea and vomiting reflex. Ondansetron blocks GI serotonin receptors, and therefore prevents nausea and vomiting. Ondansetron is used for serious nausea and vomiting, such as post-op N/V that is resistant to the more common DA blockers such as cisapride and metoclopramide. Ondansetron is also used for the intractable nausea and vomiting associated with chemotherapy. Bladder There are 2 main receptors for the bladder, ( and M receptors. The muscarinic agonist bethanechol 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 prazosin and terazosin (longer half-life) can increase micturition by relaxing the smooth muscle of the internal sphincter, as well as the smooth muscle of an enlarged and therefore obstructive prostate. Note: The lack of lists of side effects in this lecture is for a purpose. Every side effect of all of these drugs has been discussed. By knowing how each class of drug interacts with its receptors in each organ system, you can then correctly predict the side effects of each drug. This level of understanding is of greater depth than the book chapters provided to you. With an understanding of how these drugs will affect other organ systems (rather than memorizing a list of side effects) you will be well served on boards and on the floors next year. Questions: What is the effect of pilocarpine and other direct muscarinic agonists on the eye? Lungs? Heart? Blood vessels? Glands? Bladder? GI tract? Answer: (miosis and accommodation/bronchoconstriction and increased bronchial secretions/bradycardia and decreased contractility/ vasodilation and decreased blood pressure/ increased secretions/ increased urination/ increased GI motility) What is the effect of physostigmine and other cholinesterase inhibitors on the eye? Lungs? Heart? Blood vessels? Glands? Bladder? GI tract? Skeletal muscles? What is the effect of timolol and other ( blockers on the eye? Lungs? Heart? Blood vessels? Glands? Bladder? GI tract? What is the effect of atropine and other antimuscarinics on the eye? Lungs? Heart? Blood vessels? Glands? Bladder? GI tract? (remember the mnemonic: Red as a beet (no sweating, so hyperthermia can occur), dry as a bone, mad as a hatter (due to abnormal nerve conduction in the CNS), blind as a stone (mydriasis and poor near-sightedness). What is the effect of albuterol and other (2 agonists on the eye? Lungs? Heart? Blood vessels? Glands? Bladder? GI tract? (Usually, 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). What is the effect of EPI, NE and DA on the eye? Lungs? Heart? Blood vessels? Glands? Bladder? GI tract? Kidney? What is the effect of methoxamine, phenylephrine and other ( agonists on the eye? Lungs? Heart? Blood vessels? Glands? Bladder? GI tract? Baroreceptor reflex? What is the effect of non-specific ( agonists on the eye? Lungs? Heart? Blood vessels? Glands? Bladder? GI tract? Baroreceptor reflex? What role does orthostatic hypotension play with these drugs? Name the other drugs discussed in this lecture which may cause orthostatic hypotension? What is the effect of ( agonists on the eye? Lungs? Heart? Blood vessels? Glands? Bladder? GI tract? Baroreceptor reflex? Orthostatic hypotension? What is the effect of cisapride and metoclopramide on the blood vessels? GI tract? What is the effect of bethanechol and other muscarinic agonists on the eye? Lungs? Heart? Blood vessels? Glands? Bladder? GI tract? What is the effect of propantheline and other muscarinic antagonists on the eye? Lungs? Heart? Blood vessels? Glands? Bladder? GI tract? 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