Autonomic Pharmacology Overview

Autonomic Pharmacology

• Drugs target the entire autonomic nervous system, affecting both sympathetic and parasympathetic systems
• Nicotinic ACh receptors are found at synapses between pre- and postganglionic neurons in both systems, as well as skeletal muscles
• Skeletal muscle AChRs are pentameric, using α subunits, while autonomic AChRs use 2-7 subunits
• Hexamethonium is a non-competitive antagonist of autonomic nicotinic ACh receptors, blocking both sympathetic and parasympathetic effects without affecting skeletal muscles
• It's no longer used due to numerous side effects
• Postganglionic parasympathetic neurons use muscarinic ACh receptors to target effectors

Drugs Targeting the Parasympathetic Nervous System

• Muscarinic ACh receptors are G-protein coupled receptors with 7 transmembrane domains
• Five types exist, with M1, M2, and M3 being significant
• M1 receptors are in the stomach and salivary glands, activating phospholipase C (PLC)
• M2 receptors are in cardiac muscle, inhibiting adenylyl cyclase to reduce cAMP levels
• M3 receptors are in smooth muscle, bronchi, and exocrine glands, activating PLC

Muscarinic Agonists/Parasympathomimetic Drugs

• These drugs activate muscarinic ACh receptors, mimicking parasympathetic stimulation
• Effects include decreased heart rate, vasodilation, smooth muscle contraction (gut, respiratory tract), salivation, and lacrimation

Muscarinic Antagonists

• Used to treat asthma, bradycardia, constricted pupils, urinary incontinence, and motion sickness
• Ipratropium/tiotropium relax bronchial smooth muscle, atropine increases heart rate, tropicamide relaxes iris sphincter muscle, oxybutynin/tolterodine relaxes bladder smooth muscle, and hyoscine treats motion sickness
• Muscarinic agonists can counteract effects of ACh esterase inhibitors
• ACh esterase inhibitors are used post-surgery to prevent paralysis, but can cause unwanted ACh effects, so atropine counteracts these side-effects. AChE inhibitors are also administered in myasthenia gravis.

Drugs Targeting the Sympathetic Nervous System

• Sympathetic postganglionic neurons use noradrenaline (NA) as a neurotransmitter
• Adrenoceptors are G-protein coupled receptors, with 5 types (α1, α2, β1, β2, β3)
• α1 receptors cause smooth muscle contraction (vasoconstriction), often coupled with local anaesthetics to prevent spread
• α2 receptors are involved in CNS control of hypertension and facial erythema
• β1 receptors increase heart rate and contractility
• β2 receptors cause smooth muscle relaxation (bronchi, blood vessels, bladder) and stimulate lipolysis
• β3 receptors cause smooth muscle relaxation and stimulate lipolysis

Adrenoceptor Agonists and Antagonists

• Drugs can be agonists (mimicking) or antagonists (blocking) for these receptors
• Agonists and antagonists have various clinical uses, including hypertension treatment, nasal decongestion, and shock treatment

Drugs Targeting the SyNS via Catecholamine Regulation

• Noradrenaline (NA) is synthesized from tyrosine, stored in vesicles, and released into synapses
• NA's action is ended by reuptake via the Noradrenaline Transporter (NAT)
• Enzymes like Monoamine oxidase (MAO) break down NA within neurons
• Drugs can inhibit NAT or MAO to regulate NA levels
• Examples of NAT inhibitors include desipramine and cocaine, including side effects like tachycardia and dysrhythmia

Sympathetic Amines

• Amphetamine-like drugs are structurally similar to NA, transported into neurons by NAT, and into vesicles by VMAT
• These lead to NA leakage, causing effects like bronchodilation, vasoconstriction, and increased blood pressure, being common drugs in substance abuse.
• Examples of sympathetic amines include amphetamine, ephedrine, and tyramine.