Pharmacology of the Sympathetic Nervous System 23-4 - Tagged.pdf

Pharmacology of the Sympathetic Nervous System Dr Richard Amison Dept. of Pharmacology & Therapeutics Learning Objectives Name the main subdivisions of the nervous system Describe the functional consequences of stimulating alpha-adrenoreceptors throughout the bod...

Pharmacology of the Sympathetic Nervous System Dr Richard Amison Dept. of Pharmacology & Therapeutics Learning Objectives Name the main subdivisions of the nervous system Describe the functional consequences of stimulating alpha-adrenoreceptors throughout the body Describe the functional consequences of stimulating beta-adrenoreceptors throughout the body Describe the sequence of events that occurs during Noradrenergic synaptic transmission Describe the key points at which drugs might interfere with the process of chemical synaptic transmission in the sympathetic nervous system Describe the clinical applications of adrenoreceptor agonists and their sides effects Describe the clinical uses of adrenoreceptor antagonists and their side effects The Nervous System Nervous System Peripheral Nervous Central Nervous System System Somatic NS Autonomic Enteric NS NS Parasympathetic NS Sympathetic NS  The Peripheral Nervous System (PNS) What is the Peripheral Nervous System? - Made up of the somatic nervous system and the autonomic nervous system Consists of neuronal tissue outside the brain and spinal cord The Autonomic Nervous System Made up of the Sympathetic Nervous System (Adrenergic) and Parasympathetic Nervous System (Cholinergic) Main processes regulated by the Autonomic Nervous Conveys output of the CNS to the rest of the body System except for motor innervation of the skeletal muscle (this is controlled by the somatic nervous system - Contraction and Relaxation of Smooth Muscle - Exocrine and some endocrine secretions - Heartbeat (Force and Rate of Contraction) - Energy metabolism Sympathetic branch of the Autonomic NS Sympathetic Nervous System – Controls the ‘fight or flight’ response. Main functions Increased Heart Rate (Cardiac muscle contraction) Bronchodilation (Relaxation of airway smooth muscle) Gluconeogenesis Pupil Dilation (Smooth muscle contraction) Decreased GI function – decreased peristalsis Vasoconstriction Primary Neurotransmitter: Noradrenaline Sites for Potential Drug Intervention Electrochemical Signalling at a Noradrenergic Synapse Synthesis and storage of noradrenaline in Vesicles Depolarisation of Presynaptic Terminal Activation of Voltage-Gated Ca2+ channels Vesicle fusion with nerve terminal membrane and exocytosis Diffusion of noradrenaline across synaptic cleft Activation of post-synaptic adrenergic receptors Generation of post-synaptic signal Activation of Second messenger cascades (neuroeffector junction) Signal termination Noradrenaline Signalling in the Sympathetic Nervous System: Areas for Drug Targeting?  Noradrenaline Signalling in the Sympathetic Nervous System: Noradrenaline Synthesis α-methyl-tyrosine α-methyl-tyrosine is a tyrosine analogue which inhibits tyrosine hydroxylase thus blocking the formation of DOPA from tyrosine Uses: Reduces Blood Pressure Side Effects: Sedation, Parkinsonism, Diarrhoea  Noradrenaline Signalling in the Sympathetic Nervous System: Noradrenaline Storage Unprotected Monoamines are broken down by MAO into inactive metabolites NA is protected from MAO by being loaded into Vesicles via VMAT Pharmacological targeting of VMAT can be used to prevent storage and depletion of function neurotransmitter eg Reserpine Within 24 hours of treatment, the nerve is depleted of NA. Side Effects: Profound CNS depression = Uptake 1 = Vesicular monoamine transporter (VMAT)  Noradrenaline Signalling in the Sympathetic Nervous System: Neurotransmitter Release Neurotransmitter release is regulated by negative feedback mechanisms facilitated by autoreceptors Presynaptic expressed α2 adrenoreceptors Activation of autoreceptors (typically Gi/o) coupled inhibit exocytosis Stimulation of these receptors (eg Clonidine) can be used to inhibit neurotransmitter release Autoreceptors can be found on neurones mediated by other neurotransmitters to inhibit exocytosis  Noradrenaline Signalling in the Sympathetic Nervous System: Post-Synaptic adrenergic receptors All neurotransmitters are agonists at their respective receptors – Receptor Activation is critical for signal transduction Governed by affinity, the ability of a For example: drug to bind to a receptor 1) Ion channel opening 2) Second Messenger signalling cascade activation Governed by efficacy, the ability of an agonist to activate the receptor once bound  Adrenergic Receptors: GPCRs G Protein Coupled receptor – 7 Transmembrane spanning alpha-helical domains Agonist activation induces a conformational change causing GTP/GDP exchange and dissociation of the alpha subunits from the beta/gamma subunits Mediate slower synaptic transmission – coupled to 2nd messenger cascades Three main types of G Proteins to Consider 1) Gq – Stimulatory α-adrenergic receptors: Coupled to PLC Α1 - coupled to Gq Α2 - coupled to Gi 2) Gs – Stimulatory Coupled to Adenylyl Cyclase β-adrenergic receptors: β1, β2, - coupled to Gs 3) Gi –Inhibitory Coupled to Adenylyl Cyclase  α1 adrenergic receptor signalling pathways Structure GPCR, Gq coupled Gq – stimulatory effects on PLC Main Locations Post Synaptic smooth muscle Binding of agonist to receptor causes conformational Cellular Response Activation of PLC/IP3/DAG signalling change Key effects Constriction, Secretion GDP exchanged for GTP bound to G Protein NA Hydrolysis of GTP provides energy for dissociation of α- subunit, from β/ɣ subunits α- subunit activates PLC which results in the formation of IP3 and DAG IP3 mobilises Ca2+ from intracellular stores and DAG stimulates PKC Ca2+ dependent responses ↑ intracellular Ca2+ activates Ca2+ dependent Smooth Muscle contraction responss PLC phospholipase C; IP3 inositol 1,4,5 triphosphate; DAG diacylglycerol PKC phosphorylates downstream target proteins  α2 adrenergic receptor signalling pathways Structure GPCR, Gi coupled Main Locations Pre Synpatic nerve terminals (autoreceptor) Gi – Inhibitory effects on Adenylyl Cyclase Cellular Response Inhibition of adenylyl cyclase Key effects Inhibition of NA release Binding of agonist to receptor causes conformational change GDP exchanged for GTP bound to G Protein Hydrolysis of GTP provides energy for dissociation of α- subunit, from β/ɣ subunits α- subunit inhibits Adenylyl Cyclase which prevents the formation of cAMP Therefore no Protein Kinase A activation cAMP ; cyclic adenosine monophosphate  β1 and β2 adrenergic receptor signalling pathways β1 adrenergic receptors β2 adrenergic receptors Structure GPCR, Gs coupled GPCR, Gs coupled Main Locations Mostly Cardiac Muscle Bronchial smooth muscle and skeletal muscle Cellular Response Stimulation of adenylyl cyclase Stimulation of adenylyl cyclase Key effects Increased force and rate of contraction Smooth Muscle relaxation Gs – Stimulatory effects on Adenylyl Cyclase Binding of agonist to receptor causes conformational change GDP exchanged for GTP bound to G Protein Hydrolysis of GTP provides energy for dissociation of α- subunit, from β/ɣ subunits α- subunit activates Adenylyl Cyclase which results in the formation of cAMP cAMP activates Protein Kinase A which phosphorylates downstream target proteins TISSUE LOCALISATION CAN RESULT IN DIFFERENT FUNCTIONAL OUTCOMES FROM THE SAME G PROTEIN α-adrenergic receptor antagonists (α-blockers) α-blockers block sympathetic vasoconstrictor tone to decrease blood pressure a) Non-selective blockers (block both a1 and a2) Phenoxybenzamine (Irreversible competitive antagonist) – No longer used clinically Phentolamine (Reversible competitive antagonist) – No longer used clinically They have few direct effects on cardiac tissue but can cause severe reflex tachycardia b) Selective blockers (Only a1-selective are of clinical interest)  Doxazosin – 1mg orally, once daily  Tamsulosin – 0.4mg orally, once daily Decreased risk of reflex tachycardia when compared with non-selective a-blockers. Doxazosin and Tamsulosin used as antihypertensive agents as well as used for benign prostatic hyperplasia Side Effects: Postural hypotension, nasal congestion, impotence, priapism, diarrhoea β-Adrenergic antagonists (β-blockers) a) Non-selective (block both a1 and β receptors) Labetolol – 100mg orally, twice daily β-blockers are commonly used prescription drugs. Reduce arterial blood pressure by with fewer side effects than a- Directly block sympathetic nervous input into blockers the heart Use: Stable congestive heart failure – Decreased force of contraction b) β-selective (block β1 and β2 receptors) – Decreased frequency of  Propanolol – 10-40mg orally, 3 times daily contraction – Decreased vascular tone (mechanism unknown) Use: Treatment of disturbances in cardiac rhythm, myocardial infarction, – Leads to decreased cardiac output and decreased blood pressure angina c) β1-subtype selective (cardioselective) Formerly used extensively as  Atenolol – 25-50mg orally, once daily antihypertensive agents, no longer recommended by NICE (National Institute for Clinical Excellence) as first line treatment Use: Treatment of disturbances in cardiac rhythm, myocardial infarction, angina  Chemical Neurotransmitters of the Nervous System: Neurotransmitter Termination Noradrenergic signalling is terminated when the neurotransmitter is removed from the synapse. This can be done by 3 main mechanisms 1) Simple Diffusion away from the synapse 2) Uptake of neurotransmitter into the presynaptic terminal or by other cells e.g. Uptake of NA through the norepinephrine transporter (NET)/Uptake 1 3) Enzymatic degradation e.g. MAOA  MAO inhibitors  Phenylzine - 15mg orally, 3 times daily Tyrosine and the ‘Cheese effect’ (irreversible non-selective inhibitor, inhibits both isoforms  Moclobemide - 300mg orally, daily in divided Tyrosine is found in cheese, wine and yogurt and is doses normally degraded by MAO. However, in patients taking MAO inhibitors, tyrosine is not metabolised (short acting MAOA selective inhibitor and can lead to hypertensive crisis's.  Selegiline – 5mg orally, once daily (irreversible MAOB selective inhibitor – selective for dopamine and used in Parkinson’s Disease Chemical Synaptic Transmission: Areas for Drug Targeting?  Take Home Comments By identifying drugs with greater Selectivity of action, usually through targeting of specific receptor subtypes, the chances of producing good therapeutic agents with reduced side effects are markedly increased Salbutamol (β2 agonist; asthma; premature labour) Atenolol (β1 antagonist; hypertension, angina) Doxasosin (a1 antagonist; hypertension) Labetalol (a1/β antagonist; hypertension)