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The Pharmacology of the Autonomic Nervous System Oliver Pratt, Carl Gwinnutt* *Correspondence Email: [email protected]

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The Pharmacology of the Autonomic Nervous System Oliver Pratt, Carl Gwinnutt* *Correspondence Email: Carl.Gwinnutt@Srht.Nhs.Uk Update in Anaesthesia Originally published in Anaesthesia Tutorial of the Week (2007) The Pharmacology of the Autonomic Nervous System Oliver Pratt, Carl Gwinnutt* *Correspondence Email: [email protected] INTRODUCTION Summary In our article describing the anatomy and function of A balance exists between the autonomic nervous system (this edition, page 37), sympathetic and parasympathetic outflow. we saw that: Many common pathologies • The autonomic nervous system (ANS) reflexes are and surgical procedures can instrumental in the control of most of the body’s affect this balance, leading organ systems. to disturbances in the function of organ systems. • The afferent limb of these reflexes can be from Drugs can contribute to the ANS or central nervous system (CNS). The autonomic disturbance, Figure 1. The effects of major drug groups on the ‘auto- efferent limb is mediated by the sympathetic but drugs can also be used nomic equilibrium’ to redress the balance. (SNS) or parasympathetic (PNS) divisions, which Those acting on the ANS, are functionally and structurally distinct. The autonomic effects of a drug may be the primary tend to be agonists or intended action – for example the sympathomimetic antagonists at one or more • The observed physiological effect will depend actions of dobutamine, or secondary effects – for of the various receptors, upon which neurotransmitter and types of receptors example the parasympathomimetic action of repeated and this determines their are involved. doses of succinylcholine. clinical effects. Some have slightly different • In the normal, resting situation equilibrium exists In the remainder of this article, we will give an overview modes of action (such as between sympathetic and parasympathetic activity. of the major groups of drugs that act on the autonomic the anticholinesterases Drugs that stimulate or inhibit activity of either nervous system and examine a few “special cases” - drugs or phosphodiesterase the parasympathetic or sympathetic division affect that are commonly used in anaesthetic practice. inhibitors) but still have this balance. marked effects on the ANS. PHARMACOLOGY OF THE SYMPATHETIC TERMINOLOGY NERVOUS SYSTEM Some common terminology is used to describe the In our first article (this edition, page 37), we saw that action of drugs on the autonomic nervous system. most of the effects of the sympathetic nervous system are mediated by catecholamines (most commonly Sympathomimetics are drugs with similar actions to norepinephrine) acting at alpha or beta-adrenoreceptors. the postganglionic fibres of the SNS. They resemble All adrenoreceptors are similar in structure and belong epinephrine (adrenaline) in their actions and are also to the family of G-protein-coupled receptors. referred to as adrenergics or sympathetic agonists. α1-receptors activate phospholipase C and have their Sympatholytics are drugs that oppose the actions of the actions mainly by increasing release of intracellular Oliver Pratt postganglionic fibres of the SNS. They are also referred calcium. Specialist Registrar to as antiadrenergics or sympathetic antagonists. Both α -receptors receptors inhibit adenylate cyclase, Department of Anaesthesia groups are subdivided further depending on their 2 Hope Hospital actions on either alpha or beta- receptors. reducing cAMP formation. Salford M6 8HD β and β -receptors stimulate adenylate cyclase, Parasympathomimetics are agonists at postsynaptic 1 2 UK muscarinic receptors. Their actions resemble increasing cAMP formation. acetylcholine and they are also referred to as Carl Gwinnutt The main actions of these receptors are summarized cholinergics. Consultant in Table 1. Department of Anaesthesia Parasympatholytics are drugs that oppose the actions Drugs with agonist or antagonist effects at both Hope Hospital of the PNS at the muscarinic receptors by blocking types of adrenoreceptor are commonly encountered Salford M6 8HD the actions of acetylcholine. They are also referred to in anaesthetic practice, and the most important are UK as anticholinergics or vagolytics. discussed below. Update in Anaesthesia | www.worldanaesthesia.org page 90 Table 1. Principal actions of sympathetic receptors α1-receptors vasoconstriction, gut smooth muscle relaxation, salivary secretion, glycogenolysis in the liver, contraction of gut sphincters and uterus. α2-receptors vasodilatation (central), vasoconstriction (peripheral), gut smooth muscle relaxation β1-receptors positive inotropy and chronotropy β2-receptors vasodilatation in muscle, gut and kidneys, bronchodilatation, pupillary dilatation, glycogenolysis SYMPATHOMIMETICS • Currently, minimal therapeutic uses but derivatives of amphetamines These drugs can be classified or grouped in a number of different are used as recreational drugs, for example ecstasy. ways, but perhaps the easiest is to classify them according to their α -receptor agonists actions on adrenoreceptors. They either work by directly stimulating 2 α alpha and/or beta-receptors, or indirectly by stimulating the release of 2-receptors are found in the presynaptic membranes of adrenergic norepinephrine (noradrenaline) by acting presynaptically. A further synapses and are widely distributed throughout the body including α class of drugs, the phosphodiesterase inhibitors, have a postsynaptic the CNS. They can be subdivided into three subtypes; 2A (sedation, α α action. analgesia and sympatholysis), 2B (vasoconstriction) and 2C (CNS actions). Despite being agonists, their actions are generally more like α1-receptor agonists sympatholytic drugs, but they are included here on the basis of their receptor activity. Ephedrine • An indirectly acting sympathomimetic, taken up into presynaptic Clonidine nerve terminals displacing norepinephrine and resulting in alpha • A potent α2-agonist acting on the receptors in the spinal mediated vasoconstriction. cord. When given orally or IV results in dose dependent sedation, reduces the dose of induction drug needed, reduces the MAC of • Ephedrine also has a direct β-agonist effect increasing heart rate volatile anaesthetics and provides a degree of analgesia. It increases and cardiac output and blood pressure. haemodynamic stability during surgery, at recovery from • These actions last for 10-15 minutes and repeated doses have a anaesthesia and may reduce cardiac morbidity in high-risk gradually decreasing effect (tachyphylaxis). cases. • Commonly used to treat the hypotension associated with • It reduces shivering and oxygen consumption at recovery. subarachnoid (spinal) block. • When given epidurally, clonidine increases the quality and Phenylephrine duration of block and provides a degree of postoperative analgesia. • A directly acting α1-agonist causing vasoconstriction and This practice has proved particularly popular in caudal epidurals increasing blood pressure, coronary and cerebral perfusion in children. When used with local anaesthetics in spinals, it pressure. increases the duration and quality of block, but may increase the degree of hypotension. The need for a urinary catheter is reduced • Heart rate usually slows due to reflex bradycardia. Cerebral and when compared to the use of intrathecal opioids. coronary blood flow are minimally affected. • Used to treat hypotension associated with spinal and epidural • Clonidine has been used in critical care for sedation, analgesia anaesthesia and topically to provide vasoconstriction in the eye or for invasive procedures and to assist in reducing drug withdrawal nose before surgery. symptoms after prolonged sedation. • Large topical doses have been reported to cause significant CVS Dexmedetomidine side effects including cardiac arrest. • Has an even greater affinity forα 2-receptors than clonidine. Many Metaraminol effects are similar to clonidine but there is less clinical • Predominantly a direct α-agonist causing peripheral experience. vasoconstriction. Also has indirect sympathomimetic actions caused by the release of norepinephrine and epinephrine. β-receptor agonists The main drugs in this group are the naturally occurring catecholamines, • When used in the treatment of acute hypotension, a baroreceptor epinephrine and norepinephrine. mediated bradycardia is frequently seen. Amphetamine Epinephrine • Causes CNS stimulation by releasing and blocking uptake • Predominantly β1 and β2 effects at low dose with increasing of neurotransmitters. Also has peripheral indirect sympathomimetic α effects at higher doses. Useful ‘rescue inotrope’ in resuscitation activity causing acute rises in blood pressure. situations. page 91 Update in Anaesthesia | www.anaesthesiologists.org Norepinephrine • Alternatives include terbutaline, and salmeterol and formoterol • α and β effects at very low dose, butα effects quickly predominate that are longer lasting. as dosage increases. Useful in vasodilatation (sepsis) Ritodrine Dobutamine • β2-agonist used as a uterine relaxant (tocolytic) to prevent premature labour. Given IV initially followed by oral maintenance • Potent β1-agonist. Some β2 mediated vasodilatation is often seen, but occasionally matched by alpha mediated vasoconstriction. therapy. Salbutamol is also used for the same effect. Useful in low cardiac output states. Phosphodiesterase Inhibitors Dopamine • Phosphodiesterase is the enzyme responsible for breakdown of the cAMP produced by β-receptor activation. Inhibition of • β and dopamine-receptor agonism predominates at low dose. 1 phosphodiesterase leads to accumulation of cAMP, which acts to Increasing alpha effects seen
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