Neurotransmission in the ANS PDF

Welcome To Basic principles of pharmacology YFRM202 MBChB II 1  Welcome To This Lecture Anatomy and Physiology of the Peripheral Nervous System YFRM202 2  Welcome To This Lect...

Welcome To Basic principles of pharmacology YFRM202 MBChB II 1  Welcome To This Lecture Anatomy and Physiology of the Peripheral Nervous System YFRM202 2  Welcome To This Lecture Neurotransmission in the ANS NA, Ach & NANC YFRM202 3  Lecture Overview At the end of this lecture, you should be able to: Describe the basic steps in neurochemical transmission. Describe the biosynthesis, storage, release and termination of action of the main autonomic transmitters – ACh and NA. Describe a non-adrenergic, non-cholinergic (NANC) neurotransmitter. Describe the actions of the following NANC's on the ANS: ATP, Substance P, nitric oxide, dopamine. Describe the sites of drug action as they relate to the basic steps of neurotransmission. 4 Steps in Autonomic Nervous System Transmission 5  Neurotransmission in the autonomic nervous system involves the synthesis, storage, and release of neurotransmitters in response to nerve stimulation. Most neurotransmitters are synthesised in nerve terminals, stored in membrane-bound vesicles, and released into the synapse in response to nerve stimulation. Neurotransmitter action is terminated either by metabolism or neuronal reuptake from the synapse. Drugs exert effects on specific steps in neurotransmission. Brenner & Stevens’ Pharmacology.2023.Chapter 6. Parasympathetic, Neuromuscular Pharmacology, and Cholinergic Agonists Pages 59-73. 6 Rang and Dale’s pharmacology. 2024. Chapter 13. pages 170-181. 7 Steps in Autonomic Nervous System Transmission: Cholinergic Transmission 8  Cholinergic Transmission Choline (precursor for ACh) is transported into the nerve terminal by the choline transporter (CHT). ACh is synthesised in the cytoplasm from acetyl-CoA and choline by the enzyme choline acetyltransferase (ChAT). ACh is transported from the cytoplasm into vesicles by a vesicle-associated transporter (VAT). When an action potential reaches the nerve terminal it causes an influx of Ca²⁺ through voltage-gated Ca²⁺, channels causing exocytosis of the vesicles, releasing ACh into the synapse. Picture source: What-When-How, 2012. Autonomic Nervous System Diagram. [online image] Available at: http://what-when-how.com/wp- content/uploads/2012/04/tmp1467.jpg [Accessed 7 Sep. 2024]. 9 Steps in Autonomic Nervous System Transmission: Adrenergic Transmission 10  Adrenergic Transmission Tyrosine is transported into the presynaptic nerve terminal by a Na⁺ dependent carrier. Tyrosine is converted to Dopa by the enzyme tyrosine hydroxylase. Dopa is converted to Dopamine by the enzyme dopa decarboxylase. Dopamine is transported into the vesicle by the vesicular monoamine transporter (VMAT). Inside the vesicle Dopamine is converted to Noradrenaline (NA) by the enzyme dopamine-β-hydroxylase. Picture source: What-When-How, 2012. Sympathetic and Parasympathetic Pathways. [online image] Available at: http://what-when-how.com/wp- content/uploads/2012/04/tmp1474_thumb1.jpg [Accessed 7 Sep. 2024]. 11  Synthesis of Catecholamines Tyrosine Tyrosine hydroxylase Dopa Dopa decarboxylase Dopamine Dopamine β-hydroxylase Noradrenaline Phenylethanolamine-N- methyltransferase Adrenaline Rang and Dale’s pharmacology. 2024. Chapter 15:Fig. 15.1 Structures of the major catecholamines. Remember: Norepinephrine (NE) = Noradrenaline (NA) Biosynthesis of catecholamines. The rate-limiting step, conversion of tyrosine to dopa, can be inhibited by metyrosine (α-methyltyrosine). 12  Metabolism of Catecholamines Catecholamines are primarily metabolised by 2 enzymes: Catechol-O- methyltransferase (COMT) Monoamine oxidase (MAO) Rang and Dale’s pharmacology. 2024. Chapter 15: Fig. 15.3 The main pathways of noradrenaline metabolism. The oxidative branch (catalysed by aldehyde dehydrogenase [ADH]) predominates, giving vanillylmandelic acid (VMA) as the main urinary metabolite. The reductive branch (catalysed by aldehyde reductase [AR]) produces the less abundant metabolite, 3- methoxy-4-hydroxyphenylglycol (MHPG), which is conjugated to MHPG sulfate before being excreted; MHPG sulfate excretion reflects noradrenaline (NA) release in brain. COMT, catechol- O -methyl transferase; DHMA, 3,4-dihydroxymandelic acid; DHPG, 3,4- dihydroxyphenylglycol; MAO, monoamine oxidase; NM, normetanephrine 13 Non-Adrenergic Non-Cholinergic (NANC) Mediators 14  Non-adrenergic non-cholinergic (NANC) neurotransmitters describe neurotransmitters other than noradrenaline (NA) and acetylcholine (ACh). The major NANC mediators in the ANS are: Nitric oxide and vasoactive intestinal peptide (VIP) in the parasympathetic NS. ATP and neuropeptide Y in the sympathetic NS. Others, such as 5-hydroxytryptamine (serotonin), GABA and dopamine. Rang & Dale’s Pharmacology. 2024 15 Table 13.2 Examples of non-adrenergic non-cholinergic transmitters and co-transmitters in the peripheral nervous system 5-HT, 5-hydroxytryptamine; ATP, adenosine triphosphate; GABA, gamma-aminobutyric acid; NANC, non-adrenergic non-cholinergic; VIP, vasoactive intestinal peptide. Rang & Dale’s Pharmacology.2024. 16 Effects of Drugs on Neurotransmission 17 Drugs can interfere with neurotransmission at the following steps: Synthesis of NT Storage of NT in vesicles Release of NT into the synapse Interaction of the NT with post-synaptic receptors Termination of NT action Rang & Dale’s Pharmacology.2024. NT = neurotransmitter 18  Drug Effects on Cholinergic Neurotransmission Synthesis of NT Hemicholinium blocks the choline transporter from transporting the precursor for ACh, choline, into the nerve terminal. This prevents ACh synthesis from taking place. Storage of NT in vesicles Vesamicol blocks the vesicle-associated transporter (VAT) from transporting ACh from the cytoplasm into the vesicle. Rang and Dale’s pharmacology. 2024. Chapter 14: Fig. 14.2. Events and sites of drug action at a nicotinic cholinergic synapse. Acetylcholine (ACh) is shown acting postsynaptically on a nicotinic receptor controlling a cation channel (e.g. at the neuromuscular or ganglionic synapse), and also on a presynaptic nicotinic receptor that acts to facilitate ACh release during sustained synaptic activity. The nerve terminal also contains acetylcholinesterase (not shown); when this is inhibited, the amount of free ACh, and the rate of leakage of ACh via the choline carrier, is increased. Under normal conditions, this leakage of ACh is insignificant. At muscarinic cholinergic junctions (e.g. heart, smooth muscle and exocrine glands), both postsynaptic and presynaptic (inhibitory) receptors are of the muscarinic type. AcCoA, acetyl coenzyme A; AChE, acetylcholinesterase; CAT, choline acetyltransferase; CoA, coenzyme A. 19  Drug Effects on Cholinergic Neurotransmission Release of NT into the synapse Botulinum toxin blocks exocytosis of vesicles, inhibiting ACh release into the synapse Interaction of the NT with post-synaptic receptors Drugs can act as agonists, e.g. pilocarpine (used in the eye as eye drops) Drugs can act as antagonists, e.g. atropine Termination of NT action Acetylcholinesterase inhibitors (e.g. pyridostigmine (Neostigmine)) inhibit ACh breakdown by AChE Rang and Dale’s pharmacology. 2024. Chapter 14: Fig. 14.2 Events and sites of drug action at a nicotinic cholinergic synapse. Acetylcholine (ACh) is shown acting postsynaptically on a nicotinic receptor controlling a cation channel (e.g. at the neuromuscular or ganglionic synapse), and also on a presynaptic nicotinic receptor that acts to facilitate ACh release during sustained synaptic activity. The nerve terminal also contains acetylcholinesterase (not shown); when this is inhibited, the amount of free ACh, and the rate of leakage of ACh via the choline carrier, is increased. Under normal conditions, this leakage of ACh is insignificant. At muscarinic cholinergic junctions (e.g. heart, smooth muscle and exocrine glands), both postsynaptic and presynaptic (inhibitory) receptors are of the muscarinic type. AcCoA, acetyl coenzyme A; AChE, acetylcholinesterase; CAT, choline acetyltransferase; CoA, coenzyme A. 20 Drug Effects on Adrenergic Neurotransmission Synthesis of NT Metyrosine inhibits conversion of tyrosine to dopa (precursors in the NA synthesis pathway) Storage of NT in vesicles Reserpine blocks the vesicular monoamine transporter (VMAT) from transporting dopamine from the cytoplasm into the vesicle (drug used for treating HPT in the past) Release of NT into the synapse Release of NA via exocytosis into the synapse is inhibited by bretylium (used for emergency prevention & treatment of Ventricular arrythmias) and guanethidine (old HPT treatment) Rang and Dale’s pharmacology. 2024. Chapter 15: Fig. 15.8 Generalised diagram of a noradrenergic nerve terminal, showing sites of drug action. EMT, extraneuronal monoamine transporter; MAO, monoamine oxidase; MeNA, methylnoradrenaline; NA, noradrenaline; NET, neuronal noradrenaline transporter. Rang and Dale’s pharmacology. 2024. 21  Drug Effects on Adrenergic Neurotransmission Interaction of the NT with post-synaptic receptors Drugs can act as agonists at specific receptor subtypes, e.g. salbutamol (β₂ stimulant) Drugs can act as antagonists at specific receptor subtypes, e.g. propranolol (β blocker) Termination of NT action Breakdown of NA can be inhibited by the use of COMT-inhibitors (e.g. entacapone) or MAO inhibitors (e.g. selegeline) Tricyclic antidepressants and cocaine can inhibit the re-uptake of NA back into the presynaptic neuron Brenner & Stevens’ Pharmacology. 2023. Page 62 – Figure 6.3 Remember: Norepinephrine (NE) = Noradrenaline (NA) 22  Checklist Can you...  Describe the basic steps in neurochemical transmission?  Describe the biosynthesis, storage, release and termination of action of the main autonomic transmitters – ACh and NA?  Describe a non-adrenergic, non-cholinergic (NANC) neurotransmitter?  Describe the actions of the following NANC's on the ANS: ATP, Substance P, nitric oxide, dopamine?  Describe the sites of drug action as they relate to the basic steps of neurotransmission? 23  References Brenner and Steven’s pharmacology. 2023.Chapter 6. Parasympathetic, Neuromuscular Pharmacology, and Cholinergic Agonists. Pages 59-73 Rang and Dale’s Pharmacology 9h edition. 2024.Chapter 13. Chemical mediators and the autonomic nervous system. Pages 170-181 & Chapter 14. Cholinergic transmission. Pages 182-204. Chapter 15. Noradrenergic transmission. Pages 205-224. 24 25 26