Pharmacotherapeutics I (PTH1) Autonomic Nervous System PDF

Pharmacotherapeutics I (PTH1) Autonomic Nervous System (Cholinergic Transmission – Part I) Dr. Nagwan Shanan Assistant Prof. of Pharmacology Dr. Chris Benham Sep 2020 1 Intende...

Pharmacotherapeutics I (PTH1) Autonomic Nervous System (Cholinergic Transmission – Part I) Dr. Nagwan Shanan Assistant Prof. of Pharmacology Dr. Chris Benham Sep 2020 1 Intended Learning Outcome Discuss the steps of cholinergic transmission including acetylcholine synthesis, storage, release and removal from synapse. Explain the difference between nicotinic and muscarinic receptors. Identify the sites of drugs action and their pharmacological and therapeutic effects. Cholinergic Transmission PS Neuro-effector Junction CNS ACh Nn PNS ACh M Ganglionic transmission Target organ Somatic Efferent Somatic nerve system ACh Nm Neuromuscular Junction (NMJ) Skeletal Muscle Cholinergic Transmission Mediated by acetylcholine (ACh). Involves nicotinic and muscarinic receptors. Includes : Ganglionic transmission Between preganglionic nerve fiber and autonomic ganglia. Parasympathetic neuro-effector junction. Between postganglionic parasympathetic nerve fiber and effector organ. Neuromuscular junction (NMJ) Between somatic nerve & skeletal muscle Cholinergic receptors Cholinergic receptors: activated by acetylcholine I. Autonomic Ganglion (Nn) Nicotinic II. Skeletal muscle (Nm) Receptors III. Effector organs supplied by PNS (Parasympathetic neuroeffctor junction) Muscarinic Receptors Cholinergic Receptors Nicotinic receptors Muscarinic receptors There are several types of both nicotinic and muscarinic receptors Cholinergic Receptors Nicotinic receptors Muscarinic receptors Ligand gated Ion channels G-protein coupled receptors Fast transmission Slower signalling Location: Location: - Autonomic ganglia - Effector organs supplied by PS - NMJ - CNS - CNS Pre and post synaptic Pre and post synaptic. Excitatory & Inhibitory actions Excitatory action (Discussed in the table) Activation of N receptors: On NMJ: Skeletal muscle contraction. On autonomic ganglia: Release of neurotransmitter from post – ganglionic nerve fiber. Muscarinic Receptors GPCRS Excitatory & Inhibitory Effects 8 Muscarinic Receptors M1 (Gq) M2 (Gi/G0) M3 (Gq) M4 M5 “Cardiac” “Glandular & (Gi/G0) (Gq) Smooth muscle” Location Glands Heart (Atria mainly) Glands CNS CNS CNS CNS Smooth muscle: mainly mainly GIT, bladder, eye, bronchi Blood vessels Signalling PLC activated Adenylate cyclase PLC activated As M2 As M1 Pathway ↑IP3 ↓cAMP ↑IP3 & M3 ↑ Ca2+ ↓Ca2+ channels, ↑ K+ ↑ Ca2+ channels EXCITATORY EXCITATORY INHIBITORY (mainly) Functional Glands Cardiac inhibition Glands secretion - - Response secretion Neural inhibition SM contraction CNS excitation ( NT release) Vasodilatation Synthesis of acetylcholine Packaging Choline CAT Synthesis Ca2+ ACh ACh Release Ca2+ Choline carrier Choline ACh Choline + acetate AChE Na Synthesis of acetylcholine 1. Action potential invades CAT: Choline acetyl transferase pre-synaptic terminal. Choline AChE: Acetylcholine esterase CAT 2. Depolarisation Ca2+ ACh opens Ca2+ channels. ACh Ca2+ Choline carrier 3. Ca2+ rise triggers vesicle release Choline 4. Transmitter diffuses across ACh Choline + acetate synaptic cleft to post synaptic receptor AChE 6. Signalling is turned off by transmitter removal 5. Receptor activation Site of drugs action I. Drugs increasing or decreasing ACh level. II. Drugs acting on N receptors III. Drugs acting on M receptors (Agonist or antagonist) 12 I. Drugs decreasing ACh level Site of drugs action choline CAT ACh ACh Choline carrier X X Botulinum toxin Choline ACh Choline + acetate AChE M Na I. Drugs decreasing ACh level Botulinum Toxin M.O.A: Inhibits acetylcholine release from cholinergic nerve terminals (decrease activation of N & M receptors) Food poisoning: - Botulinum toxin (Clostridium botulinum) in preserved food. - Parasympathetic paralysis (Decrease activation of M receptors) & motor paralysis (Decrease activation of Nm receptors on skeletal muscles). - Respiratory paralysis (Paralysis of respiratory skeletal muscles) - High mortality I. Drugs decreasing ACh level Botulinum Toxin Therapeutic uses: Given in case of: - Muscle spasms (increased muscle tone) Botulinum toxin leads to skeletal muscle relaxation as it decrease the activation of Nm receptors. - Overactive bladder (Frequent urination) Botulinum toxin leads to relaxation of the detrusor muscle of urinary bladder as it decrease the activation of M receptors. - Hyperhidrosis (excessive sweating) Botulinium toxin decrease the activation of M receptors on sweat glands - Cosmetics: To reduce wrinkles (Given intradermal). Botulinum toxin leads to skeletal muscle relaxation as it decrease the activation of Nm receptors. I. Drugs decreasing ACh level Botulinum Toxin Therapeutic uses: Given in case of: - Migraine The treatments are approved for patients aged 18 and older who experience 15 or more migraine days per month. I. Drugs increasing ACh levels Site of drugs action choline CAT ACh ACh Choline carrier X Choline ACh Choline + acetate AChE X Anticholinesterases Na M I. Drugs increasing ACh levels Acetylcholine esterase inhibitors: Inhibits acetylcholine esterase in cholinergic synapses, thus increasing the acetylcholine level. Short Acting Intermediate Acting Long Acting Edrophonium Neostigmine Organophosphates Therapeutic Use: Therapeutic Use: (Irreversible blockade Diagnosis of 1.Treatment of of acetylcholine esterase Myasthenia Gravis Myasthenia Gravis excessive increase (Oral). of ACh 2. Reverse the effects a) Insecticides (Parathion) of neuromuscular causes human poisoning blockers after surgery b) Nerve gas (i.v) Physostigmine Therapeutic use: Eye drops for Glaucoma ( IOP) I. Drugs increasing Ach levels Myasthenia Gravis Autoimmune disease affecting skeletal muscle at NMJ. Antibodies are secreted against Nicotinic Rs. Symptoms: Muscle weakness Anticholinesterase: Increase acetylcholine level in synapse (Prolonged and enhanced post-synaptic response) improving the muscle contraction. 19  I. Drugs increasing Ach levels Neuromuscular Blocker Acetylcholine esterase inhibitor Acetylcholine Nm 20 I. Drugs increasing Ach levels Glaucoma Patients with glaucoma can experience elevated intraocular pressure which can affect the optic nerve. Level of aqueous humor controls the intraocular pressure (IOP) 21 How does Novichok act? Novichok: Group of nerve agents used as chemical weapons. Note: Check muscarinic actions of Ach and then review. II. Drugs acting on N receptors Site of drugs action choline CAT Pre-synaptic ACh Nicotinic ACh R Curare X ACh Choline carrier + X Choline ACh Choline + acetate AChE Curare X Post-synaptic Nicotinic ACh R Na Skeletal muscle II. Drugs acting on N receptors Curare M.O.A: Blocks nicotinic receptors at NMJ (neuromuscular blocker) & autonomic ganglia. It is mixture of naturally occurring alkaloids. Causes skeletal muscle relaxation (Not used therapeutically). Chondrodendron tomentosum Charles Waterton II. Drugs acting on N receptors Modern muscle relaxants (curare derivatives) are currently used in surgery to cause muscle paralysis during anaesthesia. ▪ Depolarizing neuromuscular blockers Succinylcholine causes depolarizing blockade of nicotinic receptors at NMJ (i.e causes initial stimulation of nicotinic receptors and muscle depolarization followed by receptor blockade and muscle paralysis). ▪ Non-Depolarizing neuromuscular blockers e.g. Rocuronium. Competitive acetylcholine (ACh) antagonists that bind directly to nicotinic receptors on the postsynaptic membrane, thus blocking the binding of ACh so the motor endplate cannot depolarize. This leads to muscle paralysis. Choice based on onset of action, duration, elimination, metabolism, side effects and complications. References Rang & Dale’s Pharmacology (2019). 9th Ed. Elsevier. Section 2:14 (Chemical mediators: Cholinergic transmission) 26