Autonomic Nervous System 1 & 2 PDF

Autonomic Nervous System 1 &2 describe the organisation and effects of autonomic nervous system activation autonomic nervous system contains two neurones; preganglion: neurone with its cell body in C...

Autonomic Nervous System 1 &2 describe the organisation and effects of autonomic nervous system activation autonomic nervous system contains two neurones; preganglion: neurone with its cell body in CNS CNS origin is the basis of initial classfication of sympathetic and parasympathetic divisions postganglionic: neurone with its body in ganglia innervates target tissue describe the synthesis, storage, release, and removal of parasympathetic and sympathetic neurotransmitters sympathetic neurones originate from the thoracic and lumbar region of the spinal cord the preganlionic nerves are short because they attach to the ganglia near the spinal cord the postganglionic nerves are longer because they extend from ganglia to the targeted tissue Autonomic Nervous System 1 &2 1  parasympathetic nerves arrive from medullary and sacral regions of the spinal cord preganglionic are relatively long cause they stretch from the spine to the target tissue (eye, salivary glands) postgnalionic nerves are shorter in parasympathetic system becuase they only go from tissue into the cell predict the effects of parasympathetic and sympathetic agents– Parasympathetic nerves are also called Cholinergic synapse nerve stimulation of heart decreases. which decreases cardiac output (Bradycardia) Autonomic Nervous System 1 &2 2  Lacrimation - the eyes more tears. Acteycholine- a parasympathetic neurotransmitter it is synthesized from choline + Acetyl-Co-enzyme A and catalysed by choline aceytltranferase to become aceytlcholine 💡 Choline + Acetyl-Co-enxzyme A —> choline acetyltranferase = Acetylcholine. after the stmulation at the cholinergic synapse causes the release of ACh, there are several things that can happen to ACh. 1. diffusion 2. metabolised by ACh-Est (found both pre and post junctionally) a. Ach-Est extremely effective at metabolising Ach. if metablised immediately. no change in neurons b. Metabolism of ACh by ACh-Est is the main way in which the function of ACh is terminated in the body 3. ACh activates Pre- junctional M2 Muscuranic receptors. ctivation of M2 reduces further effects of ACh by a negative feedback loop. 4. ACh that crosses synapse actiavtes post-junctional M3 receptors on target tissue causing contraction of smooth muscle. parasympathomimetic agents Autonomic Nervous System 1 &2 3  1. Acetycholine is also a parasympathomimetic agent. this means it mimics the action of a paraympthetic nerve stimulation two acetylcholine receptor subtypes 1. nicotinic acetylcholine receptors 2. muscarinic acetylcholine receptors acetycholine is an agonist ganglionic (nicotinic) and postganglionic (muscarinic) receptors 2. muscarine selective for muscarinic receptors (post ganglionic) resistant to acetylcholinesterase quaternary ammonium compound an alkaloid obtained from Amanita Muscaria (toadstool) 3. nicotine does not resemble either ACh or muscarine selective for nicotinic (ganglionic) receptors predict the effects of muscarinic, nicotinic, a and b receptor stimulation in various organs and tissues anterior chamber of the eye response to increased light Autonomic Nervous System 1 &2 4  accomodation for near vision aqueous humour (fail to drain - gluocoma ) predict the effects of muscarinic agonists, cholinesterase inhibitors and muscarinic antagonists use of muscarinic agonists use to treat open angle gluocoma. Gluocoma occurs due to increased intraocular pressure which causes optic nerve damage dilated pupil impairs aqueous humour drainage and this occurs due to iris tissue folding which blocks drainage angle. muscarinic agonists are used to treat gluocoma due its contraction affects in smooth muscle. this casues the pupils to constrict. it is also used in treating urinary retention and paralyctic ileus. major contraindications for muscarinic agonists Autonomic Nervous System 1 &2 5  cholinesterase inhibitors cholineesterase enzymes catalyse hydrolysis of acetycholine actetylcholineesterase is found at nerve junction acetylcholinesterase terminates action of acetylcholine at nerve terminals pseudocholinesterase is found in non nerve tissues cholinesterase inhibitors inihibit the catalytic activity of cholinesterase enzymes this leads to the accumulation of acetylcholine and increases neurotransmission in the nerve. there are three classes of cholinesterase inhibitors 1. short acting Edrophonium. combines reversibly with acetylcholinesterase and is effective for a few minutes can be used to diagnose myasthenia gravis (skeletal muscle disease) it is an autoimmune disease affecting the neuromuscular junction Autonomic Nervous System 1 &2 6  its antibodies attack the nicotinic receptors preventing acetylcholine from binding and facilitating muscle contractions. these leads to muscle weakness cholinesterase inhibit the metabolism of acetylcholine increasing the amount pressent in the tissue. to stimulate any available nicotinic receptors. effect of cold on enzyme activity? the cold decreases the enzyme activity. for example, droopy eyelid. putting ice on it reduces antibodies and increases acetylcholine 2. longer acting cholinesterase inhibitors physostigimine (Calabria bean) and neostigmine form carbamylated intermediates that take minutes to hours to hydrolyse. this means the actelycholine has more time to accumulate in the body and exert its therapeutic effects. used to treat myasthenia gravis. physostigmine and neostigmine are eventually destroyed in the reaction Lecture 2 therapeutic uses of cholinesterase inhibitors eye it decreases intraocular pressure in open angle glaucoma constriction of the pupil in cyclopegia (paralysis of ciliary muscle) ciliary muscle contracts, lens thickens, pupil constricts and allows eye to accomodate for near vision skeletal neuromuscular junction cholinesterase inhibitors are used in reversal of paralysis caused by curare-like drugs Autonomic Nervous System 1 &2 7  it is used in the diagnosis and treatment of myasthenia gravis the cell communication is mediated by nicotinic acetylcholine receptors Gastrointestinal system used when there is a lack of normal smooth muscle tone or stretch used if there is lower oesophageal and gastric contraction used to manage paralytic ileus treatment of atropine(muscle relaxant) poisoning cholinesterase inhibitors are used in cases of acute toxicity caused by atropine Long acting, irreversible cholinesterase inhibitors organophosphates when they become phosphorylated with acetylcholinesterase it forms a very stable intermediate that takes very long to release the enzyme acetylcholinesterase If Pralidoxime is administered quickly after the intermediate is formed it reactivates acetlycholineesterase to be able to metabolise acetylcholine again. organophosphate risks. Insecticides; it is very poisonous so its used to kill parathion agriculture, horticulture and urban gardening. causes accidental deaths due to poisoning Nerve gases sarin (nerve gas developed in Germany WW2) assasination and terrorist attacks deadly at low concentrations due its irreversible and long acting nature toxicity due to increased ACh at cholinergic synapses persistent stimulation will lead to neurotransmisson pralysis Autonomic Nervous System 1 &2 8  acute poisoning with cholinesterase inhibitors signs and symptoms due to activation of muscarinic and nicotinic receptors there is alot of acetylcholine in the nuerosmuscular junction. which means in the case of cholinesterase inhibitor poisoning, there will be a blockade in the neuromuscular junction of respiratory skeletal muscles. This will cause respiratory failure and may result in DEATH other signs and symptoms include; bronchoconstriction, accumulation of respiratory secretions, weakened/paralysed respiratory muscles, central respiratory paralysis bradycardia sweating,salivation, lacrimation constriction of the pupils increases gastrointestinal activity Cholinesterase inhibitors poisonig : Treatment Stop exposure to cholinesterase inhibitor to prevent further absorption Assist respiration Administer cholinergic antagonist e.g., atropine Administer pralidoxime in the case of organophosphate poisoning Administer anticonvulsant if required (excess acetylcholine can cause convulsions in the brain Monitor for potential cardiac irregularities Administer diazepam to treat agitation and provide sedation Muscarinic antagonists - Atropine Typical competitive muscarinic antagonist Highly soluble belladonna alkaloid from Atropa belladonna (deadly nightshade) Autonomic Nervous System 1 &2 9  Muscarinic antagonists compete with acetylcholine at the muscarinic receptor Atropine acts as antagonist and inhibits acetylcholine effects Major Pharmacological Effects of Muscarinic Antagonists (Atropine) decrease sweating, salivation, lacrimation decrease gastrointestinal motility decrease gastric acid secretion decrease production of bronchial mucus Bronchodilatation increased heart rate Side effects – dry mouth & skin, urinary retention, cycloplegia, glaucoma, depression, hallucinations,increased body temperature Treatment of atropine poisoning. gastric lavage; Wash out of body cavity. to prevent furthur absorption cholinesterase inhibitor : increase ACh at cholinergic synapse Body temperature is lowered. this counters rise in temperature effectively lowers sweating anticonvulsant e.g diazepam to counter CNS effects Autonomic Nervous System 1 &2 10  describe the classification of adrenoceptors: a- and breceptor subtypes including their respective agonists and antagonists Noradrenergic Neurotransmission: Noradreline primary neurotransmitter released from sympathetic autonomic neurones it is sympathomimetic and catecholamine synthesised and stored in sympathetic nerves released upon electrical excitation of the nerve varicosities Adrenal medulla: adrenaline Adrenal Medulla: Adrenaline Inner portion of adrenal gland – adrenal gland sits above each kidney Synthesises and stores adrenaline similar in structure and function to noradrenaline Modified sympathetic ganglion – innervated chromaffin cells contain adrenaline Adrenaline is synthesised from noradrenaline by phenylethanolamine N- methyltransferase very fast. Adrenaline is stored in vesicles and released upon electrical stimulation of preganglionic nerves innervating the adrenal gland Autonomic Nervous System 1 &2 11  Structures of catecholamines structural modification of noradreline by increasing its bulk with other substituents on the N-atom will increase its resistance to monoamine oxidase (MAO) allowed to remain longer in the body. modification of catechol -OH groups will increase noradrenaline resistance to catechol-o-methyl trenferase (COMT) Autonomic Nervous System 1 &2 12  Adrenoceptors: Location and Function Alpha1-receptors (post-synaptic) bloodvessels: vasoconstriction lung: decrease secretion GI tract: decrease smooth muscle motility and tone eye: radial muscle contraction (mydriasis, dilation) Beta-receptors heart: increase rate and force of contraction bloodvessels: vasodilatation GI tract: decrease smooth muscle motility and tone lung: bronchodilatation,increase secretion eye: ciliary muscle relaxation (distant vision) predict the effects of various drugs affecting sympathetic neurotransmission: direct, indirect and mixed acting sympathomimetics; inhibitors of the noradrenaline transporter (NET), extraneuronal transporter (ENT), and monoamine oxidase (MAO) Adrenergic drugs Adrenoreceptor agonits direct acting sympathomimetics inderict acting mixed-acting Adrenoreceptor antagonists ⍺ and β- adrenoreceptor antagonists monoamine oxidase inhibitors breaks down/ metabolises noradrenaline and adrenaline. adrenoreceptor subtypes adrenoreceptors are classified into 𝛼 or β subtypes based on molecular cloning of distinct protein moeities Autonomic Nervous System 1 &2 13  functional characteristics potencies of various stimulatory catecholamines 𝛼: noradrenaline → adrenaline → Isoprenaline β: Isoprenaline → adrenaline → noradrenaline some drugs selectively inhibit some, but not all, of the actions of noradrenaline drugs inhibit the actiond of noradrenaline at 𝛼 - but not at β- receptors and vice versa 𝛼 - adrenoreceptors can be sub-classified into 𝛼1 and 𝛼2 subtypes based on their sensitivies to particular agonists and antagonists alpha 1 and alpha 2 receptora are physically separated alpha 1 is found primarily at postjunctional sites its found on smooth muscle cells where it causes contraction alpha 2 is found prejunctionally on sympathetic nerve endings it activation inhibits noradrenaline release though a negative feedback loop β - Adrenoreceptor subtypes β-Adrenoceptors have been sub-classified into β1, β2 and β3 subtypes β1-Adrenoceptors in abundance in heart increase in heart rate and force β2-Adrenoceptors in abundance in respiratory tract, blood vessels and liver relaxation of airway and vascular smooth muscle, glycogenolysis/gluconeogenesis in the liver (regulate glucose levels) β3-Adrenoceptors in adipose tissue, bladder, brain, potential treatment for diabetes; overactive bladder; anxiety and depression Adrenoreceptor agonists Direct effects of an adrenoceptor agonist on an effector cell depends on Autonomic Nervous System 1 &2 14  receptor selectivity of the drug a versus b receptors a/b receptor subtypes adrenoceptor profile of the cell which receptors does the cell contain? cellular response to receptor activation b2 receptors in airway smooth muscle Clinical Uses of Catecholamines: Adrenaline Anaphylactic reactions (b-adrenoceptors) first-line treatment for acute anaphylactic reaction caused by bee stings and drugs (e.g., penicillin) administered in conjunction with antihistamines and glucocorticoids Cardiac arrest (b1-adrenoceptors) helps to restore cardiac rhythm In local anaesthetic solutions (a1-adrenoceptors) (bolus dose) vasoconstrictor effect – increases duration of action decreases risk of systemic toxicity Autonomic Nervous System 1 &2 15  Indirect-Acting Sympathomimetics No direct agonist activity at a- or b-receptors release noradrenaline from nerves block noradrenaline uptake Inhibit noradrenaline metabolism noradrenaline activates a- and/or b-receptors The pharmacology of these compounds is that of noradrenaline at the receptor level example of indirect-acting drug = Amphetamine - MAO x, COMT x Mixed-Acting Sympathomimetics: Ephedrine Derived from the plant Ephedra Exert action by a combination direct actions on adrenergic receptors releases noradrenaline from sympathetic nerves First orally active sympathomimetic Not a substrate for COMT or MAO so prolonged duration of action Used clinically to relieve nasal congestion vasoconstrictor pseudoephedrine is the stereoisomer /-ephedrine Adrenoceptor Antagonists Prevent endogenous adrenoceptor agonists from binding to and stimulating adrenoceptors Adrenoceptor antagonism may be clinically useful a1-adrenoceptor antagonism treatment of hypertension b1-adrenoceptor antagonism Autonomic Nervous System 1 &2 16  treatment of angina, arrhythmia, hypertension, post-myocardial infarction etc. Antagonism of a2- and/or b2-adrenoceptors is generally not clinically useful and is often associated with adverse effects because a2 regulates release of noradrenaline and b2 regulate airway smooth muscle (can make it diificult to breathe) b-Adrenoceptor Antagonists Prevent endogenous adrenoceptor agonists from binding to and activating b-adrenoceptors Used to treat cardiovascular diseases hypertension, angina, cardiac remodelling, myocardial infarction, heart failure, arrhythmia – e.g., metoprolol Some b-adrenoceptor antagonists may be more effective in some patients and clinical situations and in reducing adverse reactions – different spectrum of properties Non-Selective b-Adrenoceptor Antagonists: Adverse Effects Most adverse reactions are due to excessive b- adrenoceptor blockade and the greatest danger occurs when the drug is first given –may precipitate congestive heart failure in untreated patients where maintenance of cardiac output depends on sympathetic drive (b1-blockade) – may induce bronchoconstriction in asthmatics (b2-blockade) – may potentiate hypoglycaemia in diabetics by inhibiting catecholamine- induced mobilisation of glycogen stores (b2-blockade) and masking symptoms of hypoglycaemia such as tachycardia (b1-blockade) Autonomic Nervous System 1 &2 17