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The Autonomic Nervous System BY: Dr: Waheeba Mustafa Ali BSc Pharmacy MSc Clinical pharmacy  The autonomic nervous system is the major involuntary portion of the NS is responsible for automatic ,unconscious body function such control HR and GIT. comprises three...

The Autonomic Nervous System BY: Dr: Waheeba Mustafa Ali BSc Pharmacy MSc Clinical pharmacy  The autonomic nervous system is the major involuntary portion of the NS is responsible for automatic ,unconscious body function such control HR and GIT. comprises three divisions: sympathetic, parasympathetic and Enteric. The autonomic system controls smooth muscle (visceral and vascular), exocrine (and some endocrine) secretions, rate and force of the heart, and certain metabolic processes (e.g. glucose utilization).  Acetylcholine receptors Three main types of mAChR occur: – M1 receptors (‘neural’) producing slow excitation of ganglia. – M2 receptors (‘cardiac’) causing decrease in cardiac rate and force of contraction (mainly of atria). – M3 receptors (‘glandular’) causing secretion, contraction of visceral smooth muscle, vascular relaxation.  Drugs acting on muscarinic receptors Muscarinic agonists Important compounds include acetylcholine, carbachol , methacholine. Main effects are bradycardia and vasodilatation (endothelium- dependent), leading to fall in blood pressure; contraction of visceral smooth muscle (gut, bladder, bronchi, etc.); exocrine secretions, pupillary constriction and ciliary muscle contraction, leading to decrease of intraocular pressure. Main use is in treatment of glaucoma (especially pilocarpine).  Muscarinic antagonists Most important compounds are atropine, hyoscine, ipratropium and pirenzepine. Main effects are inhibition of secretions; tachycardia, pupillary dilatation and paralysis of accommodation; relaxation of smooth muscle (gut, bronchi, biliary tract, bladder); inhibitionof gastric acid secretion (especially pirenzepine); central nervous system effects (mainly excitatory with atropine; depressant, including amnesia, with hyoscine), including antiemetic effect and antiparkinsonian effect.  Clinical uses of muscarinic antagonists Cardiovascular Treatment of sinus bradycardia (e.g. after myocardial infarction for example atropine. Ophthalmic To dilate the pupil: for example cyclopentolate eye drops. Neurological Prevention of motion sickness: for example hyoscine (orally or transdermally). Parkinsonism, especially to counteract movement disorders caused by antipsychotic drugs for example benzhexol, benztropine  Respiratory Asthma and chronic obstructive pulmonary disease: ipratropium or tiotropium by inhalation. Gastrointestinal To facilitate endoscopy and gastrointestinal radiology by relaxing gastrointestinal smooth muscle (antispasmodic action): for example hyoscine. To treat peptic ulcer disease by suppressing gastric acid secretion for example pirenzepine (M1-selective antagonist).  Cholinesterase and anticholinesterase drugs Effects of anticholinesterase drugs are due mainly to enhancement of cholinergic transmission at cholinergic autonomic synapses and at the neuromuscular junction. Anticholinesterases that cross the blood–brain barrier (e.g.physostigmine, organophosphates) also have marked central nervous system effects. Autonomic effects include bradycardia, hypotension, excessive secretions, bronchoconstriction, gastrointestinal hypermotility and decrease of intraocular pressure. Neuromuscular action causes muscle fasciculation and increased twitch tension, and can produce depolarization block. Anticholinesterase poisoning may occur from exposure to insecticides or nerve gases.  Clinical uses of anticholinesterase drugs To reverse the action of non-depolarising neuromuscular-blocking drugs at the end of an operation (neostigmine). Atropine must be given to limit parasympathomimetic effects. To treat myasthenia gravis (neostigmine or pyridostigmine). Alzheimer’s disease e.g. donepezil. Glaucoma.  Classification of adrenoceptors Main pharmacological classification into α and β. Subtypes Adrenoceptor subtypes: – two main α-adrenoceptor subtypes, α1 and α2 – three β-adrenoceptor subtypes (β1, β2, β3) – all belong to the superfamily of G-protein-coupled receptors  The main effects of receptor activation are as follows: – α1 receptors: vasoconstriction, relaxation of gastrointestinal smooth muscle, salivary secretion and hepatic glycogenolysis. – α2 receptors: inhibition of transmitter release (including noradrenaline and acetylcholine release from autonomic nerves), platelet aggregation, contraction of vascular smooth muscle, inhibition of insulin release. β1 receptors: increased cardiac rate and force, delayed cardiac hypertrophy. – β2 receptors: bronchodilatation, vasodilatation, relaxation of visceral smooth muscle hepatic glycogenolysis and muscle tremor. – β3 receptors: lipolysis. Adrenoceptor agonists: Noradrenaline and adrenaline show relatively little receptor selectivity. Selective α1 agonists include phenylephrine and oxymetazoline. Selective á2 agonists include clonidine and á-methylnoradrenaline. They cause a fall in blood pressure, partly by inhibition of noradrenaline release and partly by a central action. Selective B1 agonists include dobutamine. Increased cardiac contractility may be useful clinically, but all B1 agonists can cause cardiac dysrhythmias. Selectiveβ2 agonists include salbutamol, terbutaline and salmeterol, used mainly for their bronchodilator action in asthma. Selective β3 agonists may be developed for the treatment of obesity  Clinical uses of adrenoceptor agonists: Cardiovascular system: – cardiac arrest: adrenaline – cardiogenic shock: dobutamine (B1 agonist). _ Anaphylaxis (acute hypersensitivity): adrenaline. Respiratory system: – asthma :selective â2-receptor agonists (salbutamol, terbutaline, salmeterol, formoterol) – nasal decongestion: drops containing xylometazoline or ephedrine for short-term use. Others _premature labour (salbutamol). á-Adrenoceptor antagonists: Drugs that block α1- and α2 adrenoceptors (e.g. phenoxybenzamine and phentolamine) were once used to produce vasodilatation in the treatment of peripheral vascular disease, but this use is now largely obsolete. Selective α1 antagonists (e.g. prazosin, doxazosin, terazosin) are used in treating hypertension. Postural hypotension and impotence are unwanted effects. Tamsulosin is α1A selective and acts mainly on the urogenital tract. Clinical uses of á-adrenoceptor antagonists Severe hypertension :α1-selective antagonists (e.g. doxazosin) in combination with other drugs. Benign prostatic hypertrophy (e.g. tamsulosin, a selective α1A-receptor antagonist). Phaeochromocytoma: phenoxybenzamine (irreversible antagonist) in preparation for surgery.  β-Adrenoceptor antagonists: Non-selective between β1- and β2-adrenoceptors: propranolol. β1 selective: atenolol, nebivolol. Alprenolol and oxprenolol have partial agonist activity. Many clinical uses Important :are bronchoconstriction, and bradycardia and cardiac failure (possibly less with partial agonists). Side effects include cold extremities, insomnia, depression, fatigue. Some show rapid first-pass metabolism, hence poor bioavailability. Some drugs (e.g. labetalol, carvedilol) block both α and β-adrenoceptors. Clinical uses of β-adrenoceptor antagonists Cardiovascular. – angina pectoris – myocardial infarction – dysrhythmias – heart failure – hypertension (no longer first choice). Other uses: – glaucoma (e.g. Timolol eye drops) – thyrotoxicosis (as adjunct to definitive treatment (e.g. preoperatively). – anxiety ,to control somatic symptoms (e.g. palpitations, tremor) – migraine prophylaxis. – benign essential tremor. Thanks