Autonomic Pharmacology Lecture Notes PDF

Autonomic Pharmacology Dr. Stan Bardal PCTH 325 ©2020 Dr. Stan Bardal  Disclosure Dr. Stan Bardal – Dept. of Pharmacology – HLTH GB33 – 966-6294 – [email protected]  Disclosure  No conflicts of interest to disclo...

Autonomic Pharmacology Dr. Stan Bardal PCTH 325 ©2020 Dr. Stan Bardal  Disclosure Dr. Stan Bardal – Dept. of Pharmacology – HLTH GB33 – 966-6294 – [email protected]  Disclosure  No conflicts of interest to disclose  Objectives Describe the origin of the sympathetic and parasympathetic system from the central nervous system (e.g. cranio-sacral, or thoraco-lumbar). List the synapses at which acetylcholine (ACh) and norepinephrine (NE) are released. List the neurotransmitters (and their proportion) released from the adrenal medulla, and their clinical significance. List the precursors for the synthesis of ACh, NE and epinephrine. List the main autonomic nervous system receptor subtypes found in the following organs/tissues: heart, blood vessels, kidney, urinary bladder, bronchial smooth muscle, gastrointestinal smooth muscle, salivary glands, sweat glands, liver, uterus, eyes, skeletal muscle, brain. Describe the responses of end organs listed in the previous objective, to activation of each division of the autonomic nervous system and its neurotransmitters. Describe the concept of dominant tone. Describe the pharmacological actions, major side effects and main clinical uses of drugs that mimic, block or modulate the actions of autonomic nervous system neurotransmitters.  Agenda Introduction to the Autonomic nervous system Parasympathetic nervous system (PSNS) Sympathetic nervous system (SNS) Neuromuscular junction Summary/Cases  Agenda Introduction to the Autonomic nervous system – Anatomy/Organization Parasympathetic nervous system (PSNS) Sympathetic nervous system (SNS) Neuromuscular junction Summary/Cases Organization of the nervous system  Nervous system: Divisions The nervous system is divided into two major branches: Central nervous system (CNS) Peripheral nervous system (PNS) The efferent division of the PNS is divided into: – Somatic nervous system Under conscious control – Autonomic nervous system (ANS) Under autonomous control  The ANS Autonomic nervous system governs functions that are not under conscious control Examples: Heart rate/contractility Respiration Digestion The ANS is also subdivided into the sympathetic and parasympathetic nervous system  ANS: Two branches The ANS has two main branches: – Sympathetic nervous system (SNS) ‘fight or flight’ – Parasympathetic nervous system (PSNS) ‘rest and digest’  Autonomic Nervous System Most organs are under the influence of both the sympathetic & parasympathetic nervous systems The sympathetic & parasympathetic divisions have opposing effects: SYMPATHETIC PARASYMPATHETIC Heart Rate Heart Rate Heart Rate Broncho- Bronchial Broncho- dilation Diameter constriction  Dominant tone Although many organs are under the influence of both the SNS and PSNS, one often dominates over the other This might explain why SNS/PSNS targeted drugs are more commonly seen in one organ system Watch for this as we progress through ANS pharmacology and future lectures – In a given organ, are we seeing more PSNS drugs? More SNS drugs?  Nomenclature Different terms are used to indicate the PSNS: – Cholinergic (acetylcholine) – Muscarinic (muscarinic receptors) In the SNS: – Adrenergic (adrenaline)  Anatomy PSNS nerves: Craniosacral Originate from the top (“cranio”) and bottom (sacral) regions of the spinal cord SNS nerves: Thoracolumbar Middle (thoracic and lumbar) regions of the spinal cord  ANS Anatomy Both the SNS and PSNS have ganglia, M a ‘relay N station’ Most drugs work at postganglionic The NT released receptors on onto receptors at target organs the ganglia is ACh α acetylcholine N β The receptors at the ganglia are nicotinic N receptors N  Neurotransmitters (NT) Acetylcholine is synthesized Acetyl from Acetyl CoA and Choline CoA The Ach is then stored in Choline synaptic vesicles… ACh And released… ANS Anatomy M N α N β N The adrenal medulla is an important source of NT, releases: Epi: 80% NE: 20%  Neurotransmitters (NT): Synthesis Key NT like dopamine, NE, and Epi are all synthesized TYROSINE from tyrosine DOPA As a group, these are called catecholamines DOPAMINE NOREPINEPHRINE EPINEPHRINE  Receptor distribution: Cholinergic There are two types of cholinergic receptor: -Nicotinic and Muscarinic Nicotinic Muscarinic NM NN M1 M3 M2 M4 M5 Found in: Found in: Muscle Ganglia Adrenal CNS Immune Five subdivisions of muscarinic receptors  Receptor distribution: Adrenergic Adrenergic receptors are divided into alpha (α) and beta (β) α1 α2 α1A α1B α1D α2A α2B α2C β1 β2 β3  Agenda Introduction to the Autonomic nervous system Parasympathetic nervous system (PSNS) – Receptor distribution – Ligands Sympathetic nervous system (SNS) Neuromuscular junction Summary/Cases PSNS M N α N β N  Receptor distribution: Cholinergic There are two types of cholinergic receptor: -Nicotinic and Muscarinic Nicotinic Muscarinic NM NN M1 M3 M2 M4 M5 Found in: Found in: Muscle Ganglia Adrenal CNS Immune Five subdivisions of muscarinic receptors  PSNS-Receptors Receptors in the PSNS are referred to as Muscarinic (M) Several subtypes have been identified (M1-M5) – Most drugs targeting M receptors are not classified by subtype There are fewer drugs that target muscarinic receptors compared to adrenergic receptors – However these receptors tend to be important for drug side effects  M1, M3, M5 receptors G-protein coupled (Gq) R G-protein (Gq) Phospholipase C (PLC) Smooth muscle Contraction Diacylglycerol IP3 Ca2+ (bladder) (DAG)  M2, M4 receptors G-protein coupled (Gi) R G-protein (Gi) Adenylate cyclase (AC) Ca2+ channels Heart rate cAMP (L-Type, Cardiac)  PSNS-Receptors The effects of a muscarinic agonist oppose those of an adrenergic agonist: ? Recall the fight of flight response. In contrast, what would a parasympathetic response look like? Heart? Lungs? Sphincters? (GI, bladder) Walls?  PSNS-Receptors The effects of a muscarinic agonist oppose those of an adrenergic agonist: Heart (M2): Decreased rate, contraction Lungs: Bronchoconstriction Sphincters (GI and bladder) Relaxation Walls (Bladder, GI tract) Contraction  To pee or not to pee… Example of coordinated action: bladder and urination Wall In the PSNS… ? Bladder What would a PSNS response look like in the bladder? Would this result in urination or not? Sphincter  To pee or not to pee… Example of coordinated action: bladder and urination Wall PSNS: M3 in bladder wall: contracts Bladder M3 in sphincter: relaxes Yes, would result in urination – Similar effect (coordinated action) in the GI tract Sphincter  PSNS-Receptors Secretion: Increased secretion: – Salivary, respiratory, tears Eye: – More on this later  PSNS-Receptors Secretion: Increased secretion: – Salivary, respiratory, tears Eye: – More on this later Also keep in mind that M receptors tend to play an important role in the CNS – Role in cognitive function Ligands for muscarinic receptors There are different ways to stimulate M receptors Direct: – using an agonist Indirect: – acetylcholinesterase inhibitors increase the concentration of acetylcholine Reversible Acetylcholine Irreversible Acetylcholinesterase Acetate + Choline  Indirect-acting Cholinergic Drugs There are three types of chemical reaction that can occur when cholinesterase is bound: Acetylation: – Rapid recovery – Physiological Carbamylation: – Slower recovery – Reversible drugs (eg. neostigmine) Phosphorylation: – No recovery – Irreversible drugs (eg. ‘nerve gases’) Indirect-acting Cholinergic Drugs Irreversible cholinesterase inhibitors have been used as poisonous gases in warfare What would an excessive cholinergic response look like?  Cholinergic response Excess cholinergic response: Secretions? – Increased (drooling, tearing, clogged airways) Lungs? – Bronchoconstriction (difficulty breathing) Heart? – Reduced heart rate (decreased endurance) GI motility? – Increased (nausea, vomiting, diarrhea) Urinary tract? – Contraction of bladder, relaxation of sphincters (urination)  Parasympatholytics Analogous to sympatholytics, parasympatholytics block PSNS responses More commonly referred to as anticholinergics or anti-muscarinics Accomplished by antagonism of M receptors (eg. Atropine)  Anticholinergics Atropine is the prototypical anticholinergic What for ? What would atropine be some side effects and uses would why? you expect to see from using atropine? Mouth? Heart? Gut? Bladder?  Anticholinergics Atropine is the prototypical anticholinergic What would be some uses for atropine? Intubation? – Clear airways by drying up secretions Ophthalmology? – Dilate pupils to facilitate eye exams Asthma? – Dilate bronchioles As an antidote? – Counteract poisoning by cholinesterase inhibitors  Anticholinergics Atropine is the prototypical anticholinergic ? What side effects would you expect to see from using atropine? Mouth? Heart? Gut? Bladder?  Anticholinergics Atropine is the prototypical anticholinergic What would be some side effects of atropine? Adverse effects: Mouth? – Dry mouth Heart? – Tachycardia Gut? – Constipation Bladder? – Difficulty urinating  Agenda Introduction to the Autonomic nervous system Parasympathetic nervous system (PSNS) Sympathetic nervous system (SNS) – Receptor distribution – Ligands Neuromuscular junction Summary/Cases  Receptor distribution: Adrenergic Adrenergic receptors are divided into alpha (α) and beta (β) α1 α2 α1A α1B α1D α2A α2B α2C β1 β2 β3 Sympathetic nervous system (SNS) Alpha-1 (α-1) Function: constriction of smooth muscles Location: – Sphincters: bladder, GI tract – Blood vessels: vasoconstriction Blood vessel  Receptor types 2. G-protein coupled R G-protein 2nd messengers Cell signaling  Alpha-1 adrenergic receptors 2. G-protein coupled R G-protein IP3 Increased Ca2+ Contraction Sympathetic nervous system (SNS) Alpha-2 (α-2) Function: inhibition of presynaptic norepinephrine (NE) release  Alpha-2 agonists Binding of agonist to presynaptic α2 receptors inhibits release of NE NE α2 Sympathetic nervous system (SNS) Beta-1 (β-1) Function: stimulates the heart Location: – Heart: increased heart rate, atrioventricular conduction, and contractility  Beta-1 adrenergic receptors 2. G-protein coupled R G-protein Adenylate cyclase (AC) Heart rate Ca2+ channels cAMP Contractility (L-Type, Cardiac)  Beta-1 adrenergic receptors The liver, kidney and uterus are only innervated by the SNS: Kidney: – Beta-1 receptors stimulate renin release – Renin causes an increase in blood pressure  Beta-2 adrenergic receptors Beta-2 (β-2) Function: relaxation of smooth muscles Location: – Lungs: bronchodilation – Blood vessels in skeletal muscle: vasodilation – GI tract, bladder, uterus: relaxation of walls Bladder  Beta-2 adrenergic receptors 2. G-protein coupled R G-protein Adenylate cyclase (AC) Bronchodilation cAMP  To pee or not to pee… Example of coordinated action: Wall bladder and urination SNS: Bladder β-2 in bladder wall: relaxes α-1 in sphincter: contracts Sphincter  Beta-2 adrenergic receptors Other functions of beta-2 receptors: The liver, kidney and uterus are only innervated by the SNS Liver: – Beta-2 receptors mediate glucose release by: Gluconeogenesis – Formation of new glucose Glycogenolysis – Breakdown of glycogen to glucose  Agenda Introduction to the Autonomic nervous system Parasympathetic nervous system (PSNS) Sympathetic nervous system (SNS) – Receptor distribution – Ligands Neuromuscular junction Summary/Cases  Ligands for adrenergic receptors Sympathomimetics are drugs that mimic stimulation of the sympathetic nervous system: – By directly activating adrenergic receptors (e.g., norepinephrine, adrenaline) – By increasing the amount of sympathetic neurotransmitter in the synapse  Sympathomimetics How to increase the amount of NT in the synapse? 1) Increase neurotransmitter release  Sympathomimetics How to increase the amount of NT in the synapse? 1) Increase neurotransmitter release 2) Inhibit reuptake of neurotransmitter  Fate of neurotransmitters Reuptake pumps Reuptake pumps sit presynaptically, and remove neurotransmitter from the synapse  Sympathomimetics Inhibit reuptake of neurotransmitter Inhibiting NT reuptake increases the amount of NT in the synapse  Sympathomimetics How to increase the amount of NT in the synapse? 1) Increase neurotransmitter release 2) Inhibit reuptake of neurotransmitter 3) Inhibit metabolism of neurotransmitter MAO D A Neurotransmitters and MAO Monoamine oxidase (MAO) is an enzyme that breaks down catecholamines like: Norepinephrine NE MAO D A Serotonin 5HT Dopamine DA  Sympathomimetics Inhibit metabolism of neurotransmitter MAO inhibitors will thus inhibit breakdown of these NT, increasing their concentration in the synapse. MAO D A  Ligands for adrenergic receptors Sympathomimetics are drugs that mimic stimulation of the sympathetic nervous system: – By directly activating adrenergic receptors (e.g., norepinephrine, adrenaline) – By increasing the amount of sympathetic neurotransmitter in the synapse By increasing release of neurotransmitter into the synapse By decreasing the re-uptake or the metabolism of neurotransmitter  Sympatholytics Sympatholytics are drugs that block or reduce sympathetic activity: – By directly blocking adrenergic receptors (e.g., propranolol) – By decreasing the amount of sympathetic neurotransmitter released into the synapse (e.g., clonidine) β-1  Sympatholytics Sympatholytics are drugs that block or reduce sympathetic activity: – By directly blocking adrenergic receptors (e.g., propranolol) – By decreasing the amount of sympathetic neurotransmitter released into the synapse (e.g., clonidine) Alpha-2 agonists  ANS Pharmacology and the Eye Eye: – Two different sets of muscles in the eye: – Iris muscle Two iris muscles control the size of the pupil: – Circular muscle – Radial muscle See next slide for more detail – Ciliary muscle  Eye: 2 different sets of iris muscle: Circular(sphincter): Radial(longitudinal): M3,M2 receptors alpha-1 receptors contraction constricts pupil contraction dilates pupil  ANS Pharmacology and the Eye Eye: – Two different sets of muscles in the eye: – Iris muscle Two iris muscles control the size of the pupil: – Circular muscle – Radial muscle – Ciliary muscle Controls shape of lens and focuses image on retina Controls production of aqueous humor – The most common indication treated by ophthalmic drugs is glaucoma  Glaucoma Glaucoma is a common condition in elderly Caused by an Increase in intraocular pressure (IOP) Why?  Glaucoma and IOP Increased IOP is due to a buildup of aqueous humor (AH) due to: – Decreased drainage – Increased production  Glaucoma and IOP Increased IOP is due to a buildup of aqueous humor (AH) due to: – Decreased drainage – Increased production – Therefore most common ways to treat glaucoma: Increase drainage of AH Decrease production of AH  Glaucoma and PSNS PSNS: M2,M3 receptor stimulation: Contracts ciliary muscle, opens trabecular meshwork and canal of Schlemm Source: Wikimedia commons  Glaucoma and SNS SNS: Beta-2 receptors: – Mediate vasodilation, which increases blood flow and AH secretion Thus Beta-2 antagonists used in reducing AH secretion and treating glaucoma Alpha-2 receptors – Reduce NE release: Facilitates drainage and reduces production of AH Therefore Alpha-2 agonists are used  Other ANS effects on EYE PSNS: Stimulation of M receptors causes contraction of ciliary muscle – Causes the lens of the eye to bulge, improving near vision and blurring far vision Source: Wikimedia commons  Agenda Introduction to the Autonomic nervous system Parasympathetic nervous system (PSNS) Sympathetic nervous system (SNS) Neuromuscular junction (NMJ) – Neuromuscular blockers – NMJ agonists – Other Summary/Cases  Cases You are working in a pharmacology laboratory that is trying to identify a new compound. The compound you are currently testing causes dilation of the pupil, increased heart rate as well as reduced gastrointestinal motility. Which type of receptor agonist or antagonist do you think the compound is?  Cases: Answers You are working in a pharmacology laboratory that is trying to identify a new compound. The compound you are currently testing causes dilation of the pupil, increased heart rate as well as reduced gastrointestinal motility. Which type of receptor agonist or antagonist do you think the compound is? What can cause dilation of the pupil?  Eye: 2 different sets of iris muscle: Circular(sphincter): Radial(longitudinal): M3,M2 receptors alpha-1 receptors contraction constricts pupil contraction dilates pupil  Cases: Answers You are working in a pharmacology laboratory that is trying to identify a new compound. The compound you are currently testing causes dilation of the pupil, increased heart rate as well as reduced gastrointestinal motility. Which type of receptor agonist or antagonist do you think the compound is? What can cause dilation of the pupil? Muscarinic antagonist or alpha-1 agonist  Cases: Answers You are working in a pharmacology laboratory that is trying to identify a new compound. The compound you are currently testing causes dilation of the pupil, increased heart rate as well as reduced gastrointestinal motility. Which type of receptor agonist or antagonist do you think the compound is? What can cause dilation of the pupil? Muscarinic antagonist or alpha-1 agonist What can cause increased heart rate?  Cases: Answers ANS effects in the Heart (Summary/Review) SNS: PSNS: Beta-1 (β1) receptors mediate: M2 receptors: Increased heart rate Decreased heart rate Increased AV conduction Decreased AV conduction Increased contractility  Cases: Answers You are working in a pharmacology laboratory that is trying to identify a new compound. The compound you are currently testing causes dilation of the pupil, increased heart rate as well as reduced gastrointestinal motility. Which type of receptor agonist or antagonist do you think the compound is? What can cause dilation of the pupil? Muscarinic antagonist or alpha-1 agonist What can cause increased heart rate? Muscarinic antagonist or Beta-1 agonist What can cause reduced GI motility?  Cases: Answers ANS effects in the gut (Summary/Review) SNS: PSNS: β2 receptors mediate: M receptors: Relax walls Contract walls (peristalsis) α1 receptors: Relax sphincters Contract sphincters Increased gastric acid Source: Wikimedia commons  Cases: Answers You are working in a pharmacology laboratory that is trying to identify a new compound. The compound you are currently testing causes dilation of the pupil, increased heart rate as well as reduced gastrointestinal motility. Which type of receptor agonist or antagonist do you think the compound is? What can cause dilation of the pupil? – Muscarinic antagonist or alpha-1 agonist What can cause increased heart rate? – Muscarinic antagonist or Beta-1 agonist What can cause reduced GI motility? – Muscarinic antagonist or Beta-2 agonists (minimal)  Case #2 You are working in a pharmacology laboratory that is trying to identify a new compound. The compound you are currently testing causes skeletal muscle blood vessels to relax, bladder wall relaxation and bronchodilation. Which type of receptor agonist or antagonist do you think the compound is?  Case #2 You are working in a pharmacology laboratory that is trying to identify a new compound. The compound you are currently testing causes skeletal muscle blood vessels to relax, bladder wall relaxation and bronchodilation. Which type of receptor agonist or antagonist do you think the compound is? What causes relaxation of skeletal muscle vessels?  Cases: Answers ANS effects in the circulation (Summary/Review) SNS: PSNS: β2 receptors (skeletal muscle): Minimal contribution Vasodilation Stimulation of M3 receptors α1 receptors: results in nitric oxide release, Vasoconstriction which causes vasodilation  Case #2 You are working in a pharmacology laboratory that is trying to identify a new compound. The compound you are currently testing causes skeletal muscle blood vessels to relax, bladder wall relaxation and bronchodilation. Which type of receptor agonist or antagonist do you think the compound is? What causes relaxation of skeletal muscle vessels? – Beta-2 agonist What causes relaxation of bladder wall?  Cases: Answers ANS effects in the bladder (Summary/Review) Wall SNS: PSNS: β2 receptors (bladder wall): M3 in bladder wall: Relaxation Bladder Contraction α1 receptors (sphincter): M3 in sphincter: Contraction Relaxation Net: Do not pee Net: Pee Sphincter  Case #2 You are working in a pharmacology laboratory that is trying to identify a new compound. The compound you are currently testing causes skeletal muscle blood vessels to relax, bladder wall relaxation and bronchodilation. Which type of receptor agonist or antagonist do you think the compound is? What causes relaxation of skeletal muscle vessels? – Beta-2 agonist What causes relaxation of bladder wall? – Beta-2 agonist or Muscarinic antagonist What causes bronchodilation?  Cases: Answers ANS effects in the lungs (Summary/Review) SNS: PSNS: β2 receptors: M2,M3 receptors: Bronchodilation Bronchoconstriction Increased secretions  Case #2 You are working in a pharmacology laboratory that is trying to identify a new compound. The compound you are currently testing causes skeletal muscle blood vessels to relax, bladder wall relaxation and bronchodilation. Which type of receptor agonist or antagonist do you think the compound is? What causes relaxation of skeletal muscle vessels? – Beta-2 agonist What causes relaxation of bladder wall? – Beta-2 agonist or Muscarinic antagonist What causes bronchodilation? – Beta-2 agonist or Muscarinic antagonist  Copyright Sourcing Permission: Courtesy of course author Dr. Stanley Bardal, Department of Pharmacology, University of Saskatchewan. Slide 8a: Source: https://commons.wikimedia.org/wiki/File:Complete_GI_tract.png https://commons.wikimedia.org/wiki/File:Complete_GI_tract.png Permission: Public Domain. Courtesy of Mikael Häggström. Slide 8b: Source: https://commons.wikimedia.org/wiki/File:Lungs_(animated).gif https://commons.wikimedia.org/wiki/File:Lungs_(animated).gif Permission: Public Domain. Courtesy of Mikael Häggström. Slide 8c: Source: https://pixabay.com/en/heart-valve-circulatory-human-2222964/ https://pixabay.com/en/heart-valve-circulatory-human-2222964/ Permission: CC0 1.0 ( http://creativecommons.org/publicdomain/zero/1.0/) Public Domain. Courtesy of burlesonmatthew. Slide 14a: Source: https://commons.wikimedia.org/wiki/File:Lungs_(animated).gif Permission: Public Domain. Courtesy of Mikael Häggström. Slide 14b: Source: https://commons.wikimedia.org/wiki/File:Lungs_(animated).gif Permission: Public Domain. Courtesy of Mikael Häggström. 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