Autonomic Nervous System (ANS) - Drugs & Receptors PDF

AUTONOMIC NERVOUS SYSTEM (ANS) Mafuru Nervous system divisions  THE ANS vs SNS The ANS (or visceral nervous system) is the part of the PNS that acts as a control system functioning largely below the level of consciousness, and controls visceral functions. The S...

AUTONOMIC NERVOUS SYSTEM (ANS) Mafuru Nervous system divisions  THE ANS vs SNS The ANS (or visceral nervous system) is the part of the PNS that acts as a control system functioning largely below the level of consciousness, and controls visceral functions. The SNS functions by controlling activities of voluntary muscles (i.e skeletal muscles)  ANS The ANS affects: — Heart rate, — Digestion, — Respiration rate, — Salivation, — Perspiration, — Diameter of the pupils, — Micturition (urination) & — Sexual arousal  Cont.. It is classically divided into two subsystems: the parasympathetic nervous system (PNS) and sympathetic nervous system (SNS). With regard to function, the ANS is usually divided into sensory (afferent) and motor (efferent) subsystems. Within these systems, however, there are inhibitory and excitatory synapses between neurones. ANS Organ Innervations  Functions ž Sympathetic and parasympathetic divisions typically function in opposition to each other. ž But this opposition is better termed complementary in nature rather than antagonistic. ž For an analogy, one may think of the sympathetic division as the accelerator and the parasympathetic division as the brake.  Cont.. ž The sympathetic division typically functions in actions requiring quick responses. ž The parasympathetic division functions with actions that do not require immediate reaction. ž Consider sympathetic as "fight or flight" and parasympathetic as "rest and digest". ž Some typical actions of the sympathetic and parasympathetic systems are listed below:  Sympathetic nervous system  Promotes a "fight or flight" response, corresponds with arousal and energy generation, and inhibits digestion.  Divertsblood flow away from the gastro-intestinal (GI) tract and skin via vasoconstriction  Cont..  Blood flow to skeletal muscles and the lungs is not only maintained, but enhanced (by as much as 1200% in the case of skeletal muscles).  Dilates bronchioles of the lung, which allows for greater alveolar oxygen exchange.  Increases heart rate and the contractility of cardiac cells (myocytes), thereby providing a mechanism for the enhanced blood flow to skeletal muscles.  Cont..  Dilates pupils and relaxes the lens, allowing more light to enter the eye.  Provides vasodilatation for the coronary vessels of the heart.  Constricts all the intestinal sphincters and the urinary sphincter.  Inhibits peristalysis.  Parasympathetic nervous system — Promotes a "rest and digest" response, promotes calming of the nerves return to regular function, and enhances digestion. — Dilates blood vessels leading to the GI tract, increasing blood flow. This is important following the consumption of food, due to the greater metabolic demands placed on the body by the  Cont.. The parasympathetic nervous system can also constrict the bronchiolar diameter when the need for oxygen has diminished. Dedicated cardiac branches of the Vagus and thoracic Spinal Accessory nerves impart Parasympathetic control of the Heart or Myocardium. During accommodation, the parasympathetic nervous system causes constriction of the pupil and lens. — The parasympathetic nervous system stimulates salivary gland secretion, and accelerates peristalsis. — so, in keeping with the rest and digest functions, appropriate PNS activity mediates digestion of food and indirectly, the absorption of nutrients. — Is also involved in erection of genitals, via the pelvic splanchnic nerves. Receptors of the ANS CHOLINERGIC RECEPTORS — Two families of cholinergic receptors: 1. Muscarinic receptors (M) 2. Nicotinic receptors  1. Muscarinic (M) receptors — Muscarinic receptors belong to the class of G protein–coupled receptors (metabotropic receptors). — These receptors, in addition to binding ACh, also recognize muscarine (Alkaloid from mushrooms) — Subtypes includes: M1, M2, M3, M4 & M5 Locations of muscarinic receptors: — These receptors are found on ganglia of the peripheral nervous system and on the autonomic effector organs, such as the heart, smooth muscle, brain, and exocrine glands. — M1 receptors are also found on gastric parietal cells — M2 receptors on cardiac cells and smooth muscle, & — M3 receptors on the bladder, exocrine glands, and smooth muscle. 2. Nicotinic receptors — These receptors, in addition to binding ACh, also recognize nicotine but show only a weak affinity for muscarine — The nicotinic receptor is composed of 5 subunits, and it functions as a ligand-gated ion channel. — Nicotinic receptors are located in the CNS, the adrenal medulla, autonomic ganglia, and the neuromuscular junction (NMJ) in skeletal muscles. ADRENERGIC RECEPTORS — Two main families of receptors are 1. α receptors & 2. β, receptors — Primarily the receptors binds Norepinephrine (NE) and epinephrine (EN) — Subtype includes: α 1, α 2, β1 & β2 Distribution of receptors: — Adrenergically innervated organs and — tissues usually have a predominant type of receptor. — For example, tissues such as the vasculature of skeletal muscle have both α1and β2 receptors, but the β2 receptors predominate. — Other tissues may have one type of receptor almost exclusively. — Forexample, the heart contains predominantly β1 receptors. Major effects mediated by α- and β-adrenoceptors  Neurotransmitters and pharmacology Acetylcholine is the preganglionic neurotransmitter for both divisions of the ANS, as well as the postganglionic neurotransmitter of parasympathetic neurons. Nerves that release acetylcholine are said to be cholinergic. In the parasympathetic system, ganglionic neurons use Ach as a neurotransmitter, to stimulate muscarinic receptors.  At the effector organs, sympathetic ganglionic neurons release noradrenaline (norepinephrine), to act on adrenergic receptors, with the exception of the sweat glands and the adrenal medulla. At the adrenal cortex, there is no postsynaptic neuron. Instead the presynaptic neuron releases acetylcholine to act on nicotinic  Cont.. — Stimulation of the adrenal medulla releases adrenaline (epinephrine) into the bloodstream which will act on adrenoceptors, producing a widespread increase in sympathetic activity. RECEPTORS & ORGANS- FUNCTIONS 1. THE EYE. — 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  cont.. 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  cont.. Once the stress is gone, the parasympathetics constrict the pupil and drain the anterior chamber. THE LUNGS i. Sympathetic activity- 2 receptor stimulation cause bronchodilatation of the airways and decreases airway secretions.  Cont.. ii. 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.  Cont.. — 3. THE HEART — Sympathetic activity- — 1 receptor stimulation increases heart rate, contractility, AV nodal conduction and cardiac output. — Parasympathetic activity- — muscarinic (M) receptor stimulation decreases SA nodal firing, decrease AV node conduction and decrease CO.  cont — 4. Blood Vessels — The blood vessels express , , dopamine (DA), histamine (H) and muscarinic (M) receptors. — This system is more complex. — i. 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.  Cont.. 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 blood vessel’s to decrease systemic resistance..) High Dose DA- stimulate 1 receptors and  Cont.. — 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. — 5. GASTROINTESTINAL TRACT (GIT) — Very complex, poorly understood.  Cont.. — Parasympathetic activity stimulate muscarinic receptor (M) which stimulates GI motility, allows sphincters to open, and increase secretions — sympathetic activity stimulate &  receptors, slows GI motility, increases sphincter tone, and decreases GI secretions. — DA receptor activation causes increased GI motility, stimulates secretion, and decreases sphincter tone.  Cont.. —opioids- also must be considered in the GI function, as opioids will promptly decrease GI motility, decrease secretions and increase sphincter tone, inducing constipation. — 6.BLADDER. — i. Sympathetic: — The  receptors prevent bladder contraction by relaxing the bladder, and contracting the internal sphincter.  Cont.. — ii. Parasympathetic: — Muscarinic receptors in the bladder stimulate bladder contraction and relax the internal sphincter. (Micturition Reflex)  DRUGS RELATED TO ANS — We have 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. — 1. Drugs of the Eye — The main disease of the eye and discussed in pharmacology is  Cont.. — 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. — Glaucoma is treated with cholinomimetics, -blockers, and epinephrine — — i. 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.  cont… — 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.  Cont.. — b) Physostigmine: - cholinesterase inhibitor - passes easily through the cornea as well as the blood brain barrier. - Increases local Ach by blocking acetyl cholinesterase, increasing ciliary muscle and sphincter muscle contraction.  Cont.. — 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.  Cont.. — ii.  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. — -Timolol happens to cross the cornea more effectively than the other  blockers.  Cont.. — iii: Acetazolamide - is a diuretic drugs - 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.  cont.. — 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.  Cont.. — 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. Drugs that lower IOP 2. Lungs — The two main actions of the drugs affecting the lungs occur by: i) Affecting airway diameter by either bronchodilation or bronchoconstrictions ii) Affecting airway secretions.  Cont.. The two receptors involved in this control are 2 and M receptors. a).Bronchodilation Sympathetic activity (Epinephrine & dopamine)  Cont.. — Stimulate 2, with: -epinephrine (1, 2, 1, 2), medium dose DA, exogenous 2 agonists (albuterol, salbutamol) — 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.  Cont.. —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.  Cont.. — 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.  Cont.. — 3. 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.  Cont.. ž Muscarinic agonists or cholinesterase antagonists increase Ach, slowing the heart rate, decreasing contractility and decreasing AV nodal conduction velocity through the AV node. ž There are few agents used in cardiology to stimulate M receptors. ž  blockers are employed to slow heart rate instead. ž  blockers will be covered in the cardiac lecture. ž however, know that atenolol, metoprolol, are both 1 specific, and therefore the best  blocker for use in asthmatics. ž Also, labetolol and carvedilol has both  and 1 activity, carvedilol is used for CHF treatment because it decreases afterload.  Cont.. ž Non-selective  blockers can exacerbate an asthma attack. ž 4. drugs affecting the blood vessels. ž Before moving on to the drugs affecting the blood vessels, we must first engage in a review of the baroreceptor reflex. ž Baroreceptor Reflex:  Cont.. ž Anything that changes arterial pressure, such as an alpha agonist or high dose dopamine, causes an automatic decrease in heart rate by stimulating the brainstem nucleus tractus solitarius (NTS) to decrease basal sympathetic stimulation of the heart. ž The change in sympathetic activity changes norepinephrine (NE) release at the SA node, and heart rate and contractility are altered accordingly.  cont.. — 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 arterial pressure increases, the sympathetic activity is inhibited, and heart rate and contractility decrease  cont.. — Blood Vessels/ Baroreceptor Reflex — i. Epinephrine stimulates 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  Cont.. ž 1- increase heart rate ž 2 – dilates skeletal vessel beds ž Overall, you see increased HR, increased BP. ž ii. Norepinephrine stimulates 1, 1 ž 1- constricts arterioles and large arteries ž 1- increase heart rate, contractility ž Although 1 increases arterial pressure, baroreceptor reflex results in a subsequent decreased HR and 1 vs vagus = vagus wins.  Cont.. — Overall see increased pressure, decreased heart rate. — iii. Isoproterenol stimulates 1, 2 receptors — stimulates heart through 1 directly. — 2 stimulates vasodilation, leading to decrease in BP, stimulating the baroreceptor reflex and further stimulating heart rate.  Cont.. — iv. Dopamine stimulates 1, 1, 2, D1 receptors. — All effects are dose-dependent — if give a low dose, only D1 receptors is activated 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 receptor  Cont.. ž v. -1 agonists: Phenylephrine, methoxyamine are specific 1 agonists, which increase arterial pressure, stimulating the baroreceptor reflex and decreasing heart rate. ž vi. Non-selective  antagonists ž To fully understand how these drugs operate we must remember that 2 receptors mainly affect the central nervous system.  Cont.. — 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.  Cont.. — Vii. Prazosin — is an 1 specific antagonist which can be used as a second line agent for control of hypertension, and to treat urinary retention. — Because phenoxybenzamine and phentolamine block 1 and 2 receptors, tachycardia is exacerbated with these drugs and can be problematic.  Cont.. ž However, these drugs are used to temporarily control the more dangerous malignant hypertension associated with pheochromocytoma until surgery can be performed. ž These drugs are preferred over prazosin because they block 1 more effectively. However, the exacerbation of tachycardia makes the use of these drugs temporary.  Cont.. — Viii. 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.  Cont.. ž 5.GI Pharmacology ž The GI system expresses /, DA receptors, M receptors, opioid receptors, and serotonin (5HT) receptors. ž Sympathomimetic drugs- Drugs acting on //DA receptors down regulate GI activity. ž These drugs decrease motility, decrease secretory activity, and increase sphincter tone.  Cont.. — Antidopaminergic drugs such as the cisapride and metoclopramide are used extensively in hospital setting as antinausea and antimotility agents. — Muscarinics- increase blood flow to the gut, increase motility, increase secretions of the GI tract.  Cont.. — 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  Cont.. — 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.  Cont.. — 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.  Cont.. — 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. ž Ondansetron is used for serious nausea and vomiting, such as post-operative nausea & vomitting that is resistant to the more common DA blockers such as cisapride and metoclopramide. ž Ondansetron is also used for the intractable nausea and vomiting associated with chemotherapy.  Cont.. ž 6. Bladder ž There are 2 main receptors for the bladder,  and M receptors. ž The muscarinic agonist bethanechol is used to stimulate bladder function in non- obstructive disease, such as diabetic nephropathy. ž The muscarinic antagonist propantheline is used to stimulate urinary retention in incontinence.  Cont.. — 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.