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AUTONOMIC NERVOUS SYSTEM: The nervous system is concerned with the initiation, control and coordination of various body functions The nervous system is divided into 2systems: 1. Central nervous system 2. Peripheral nervous system Peripheral nervous system is divided into: somatic nervous system autonomic nervous system Autonomic nervous system is again subdivided into sympathetic nervous system para -sympathetic nervous system The autonomic nervous system (ANS or visceral nervous system) is the part of the peripheral nervous system that acts as a control system functioning largely below the level of consciousness, and controls visceral functions.[1] The ANS affects heart rate, digestion, respiration rate, salivation, perspiration, diameter of the pupils, micturition (urination), and sexual arousal. Whereas most of its actions are involuntary, some, such as breathing, work in tandem with the conscious mind. It is classically divided into two subsystems: the parasympathetic nervous system and sympathetic nervous system. With regard to function, the ANS is usually divided into sensory (afferent) and motor (efferent) subsystems. The enteric nervous system is sometimes considered part of the autonomic nervous system, and sometimes considered an independent system. The sympathetic nervous system has ganglia away from organs where as in para sympathetic system the ganglia is nearer to the organs and away from CNS. The different actions shown by both the systems are given below: SYMPATHETIC NERVOUS SYSTEM: They originate from thoraco-lumbar region also known as adrenergic neuron. It is always active at a basal level (called sympathetic tone) and becomes more active during times of stress. Its actions during the stress response comprise the fight-or-flight response. At synapses within the sympathetic ganglia, preganglionic sympathetic neurons release acetylcholine, a chemical messenger that binds and activates nicotinic acetylcholine receptors on postganglionic neurons. In response to this stimulus, postganglionic neurons principally release noradrenaline (norepinephrine). Prolonged activation can elicit the release of adrenaline from the adrenal medulla. Once released, norepinephrine and epinephrine bind adrenergic receptors on peripheral tissues. Binding to adrenergic receptors causes the effects seen during the fight-or-flight response. These include pupil dilation, increased heart rate, occasional vomiting, and increased blood pressure. Increased sweating is also seen due to binding of cholinergic receptors of the sweat glands. Dopamine is the predominant neurotransmitter in the brain. Adrenaline, noradrenaline and dopamine are Catecholamines. BIOSYNTHESIS OF NEURO-TRANSMITTER: tyrosine ,the precursor is an esse4ntial aminoacid present in food,blood fluids and synthesized in the body from related aminoacid phenylalanine tyrosine is takrn up from the circulation by the adrenergic neuron and in the presence of tyrosine hydroxylase which catalyses conversion of tyrosine to dihydroxy phenyl alanine(DOPA) DOPA in the presence of decarboxylase is converted into dopamine Dopamine is now actively taken up by synaptic vescicle &in the presence of dopamine b-hydroxylase is converted to Nor-adrenaline Adrenal medulla contains an enzyme N-methyl transferase which converts Noradrenaline to adrenaline TERMINATION OF CATECHOLAMINES: Nor-adrenaline and adrenaline serves the function of neurotransmitter as well as they are hormones in the body After they are releaed from synaptic cleft .they have the following fate: 1. uptake of nor-adrenaline: 75-90% released neurotransmitter is taken up by adrenergic neuron or extraneuronal site uptake 2. metabolic degradation of catecholamines: these catecholamines are metabolized by 2 enzymes: endogenously by MONOAMINO OXIDASE(MAO) exogenously by CATECHOL-O-METHYL TRANSFERASE(COMT) a) MONOAMINO OXIDASE: This enzyme is abundantly present in almost all of the outer membrane of mitochondria It is present in the adrenergic nerve terminal ,CN,platelets,liver,kidney &intestine. They belong to protein family of flavin-containing amine oxidoreductases. In humans there are two types of MAO: MAO-A and MAO-B. b) Both are found in neurons and astroglia. c) Outside the central nervous system: MAO-A is also found in the liver, gastrointestinal tract, and placenta. MAO-B is mostly found in blood platelets. Serotonin, norepinephrine (noradrenaline), and epinephrine (adrenaline) are mainly broken down by MAO-A. Both forms break down dopamine equally. Specific reactions catalyzed by MAO include: epinephrine or norepinephrine to 3,4-Dihydroxymandelic acid metanephrine or normetanephrine to vanillylmandelic acid dopamine to dihydroxyphenylacetic acid b)CATECHOL-O-METHYL TRANSFERASE: It is widely distributed in the body both at Neuronal &Non-Neuronal tissues. Catechol-O-methyl transferase is involved in the inactivation of the catecholamine neurotransmitters (dopamine, epinephrine, and norepinephrine). The enzyme introduces a methyl group to the catecholamine, which is donated by S-adenosyl methionine (SAM). Specific reactions catalyzed by COMT include: Norepinephrine -> Normetanephrine Epinephrine -> Metanephrine Dihydroxyphenylethylene glycol (DOPEG) -> Methoxyhydroxyphenylglycol (MOPEG) 3,4-Dihydroxymandelic acid (DOMA) -> Vanillylmandelic acid (VMA) ADRENOCEPTOR: The adrenergic receptors (or adrenoceptors) are a class of G proteincoupled receptors that are targets of the catecholamines, especially noradrenaline (norepinephrine) and adrenaline (epinephrine). Although dopamine is a catecholamine, its receptors are in a different category. Dopamine has been used as a neurotransmitter since the beginning of nerve system evolution. There are two main groups of adrenergic receptors, α and β, with several subtypes. α receptors have the subtypes α1 (a Gq coupled receptor) and α2 (a Gi coupled receptor). Phenylephrine is a selective agonist of the α receptor. β receptors have the subtypes β1, β2 and β3. All three are linked to Gs proteins, which in turn are linked to adenylate cyclase. Agonist binding thus causes a rise in the intracellular concentration of the second messenger cAMP (cyclic adenosine monophosphate). Downstream effectors of cAMP include cAMP-dependent protein kinase (PKA), which mediates some of the intracellular events following hormone binding. Isoprenaline is a selective agonist. Receptor Agonist α1: Noradrenaline Phenylephrine Methoxamine Cirazoline Xylometazoline α2: Dexmedetomidine Medetomidine Romifidine Clonidine Detomidine Lofexidine Xylazine Tizanidine Guanfacine Amitraz β1 Noradrenaline Isoprenaline Dobutamine Antagonist Alfuzosin Doxazosin Phenoxybenzamine Phentolamine Prazosin Tamsulosin Terazos Yohimbine Idazoxan Atipamezole Metoprolol Atenolol β2 Salbutamol (Albuterol in USA) Bitolterol mesylate Formoterol Isoprenaline Levalbuterol Metaproterenol Salmeterol Terbutaline Ritodrine Butoxamine Propranolol β3 Amibegron Solabegron Dopamine L-DOPA SR 59230A Chlorpromazine Trichlorperazine Dopamine Haloperidol Risperidone Domperidone D1 D2 PARA-SYMPATHETIC NERVOUS SYSTEM: They origate from craniosacral outflow also known as Cholinergic Neuron The preganglionic fibre is long &the post ganglionic fibre is shorter The neurotransmitter at the effector end organ is acetyl choline(Ach) Ach is an ester of choliune &acetic acid BIOSYNTHESIS OF ACETYL CHOLINE: Choline is a member of Vit B complex & essential nconstituent of the food is taken up by active transport from the circulation by cholinergic neurons Acetyl coenzyme-A derived from pyruvate donates acetyl group to choline to form acetyl choline with the help of the enzyme choline acetyl transferase Acetyl choline is stored in synaptic vesicle TERMINATION OF CTION OF ACH:: After it’s release from synaptic vesicle , acetyl choline combines with receptors remain bound for less than millisecond & is quickl;y hydrolysed by an enzyme called Acetyl cholinesterase It is terminated by hydrolysis of ester linkage of the molecule There are 2 types of choline esterase enzyme acetylcholinesterases (AChEs)(True ache) the butyryl or pseudocholinesterases (BuChE) (pseudo cholinesterase) True cholinesterase is present in cholinergic neuron,synapse &neuro muscular junction Pseudo cholinesterase `is present in blood ,liver, intestine &other organs CHOLINERGIC RECEPTORS: They are classified into MUSCARINIC RECEPTORS NICOTINIC RECEPTORS MUSCARINIC RECEPTORS AGONISTS:Acetyl choline ,pilocarpine , muscarinie MUSCARINIC RECEPTOR ANTAGONIST:atropine ,pirenzepine LOCATION: M1=ganglia &stomach M2=heart M3=smooth muscles , secretary glands CLASSIFICATION: 1)ETERS OF CHOLINE:acetyl choline, methacholine, carbachol, bethachol 2)CHOLINOMIMETIC ALKALOIDS: pilocarpine , muscarine, arecholine 3)CHOLINESTERASE INHIBITORS: These are also known as anti-cholinesterases Physostigmine, neostigmine,pyridostigmine, edrophonium, ambenonium, demecarium 4)IRREVERSIBLE ANTICHOLINESTERASE: These are also known as organo phosphorous compounds Malthion, parathion, DDT, diisopropyl fluro phosphate(DFP), octa methyl pyro phosphate tetramide(DMPA) ACETYLCHOLINE: ACH is an ester of choline with acetic acid Chemically acetylcholine is quarternary amino compound &acetyl choline is extremely hygroscopic Given orally itb is rapidly destroyedc in the GIT When given by IV route it fails to produce its actions even at large doses This is becoz ach is destroyed in the plasma by the enzyme pseudocholinesterase The only important action after IV administration of Ach is transient fall in B.P PHARMACOLOGY OF METHACHOLINE: Source: synthetic Category: cholinergic agonist Class:esters of choline Mechanism of action: it occupies muscarinic receptors & stimulate it Route of administration is by oral route PHARMACOKINETICS: well absorbed orally Totally resistant to pseudocholinesterae& has longer derivation of action It is metabolized in liver, &excreted through urine ADVERSE EFFECTS:nausea, vomiting, diarrhea CONTRAINDICATIONS:it is contraindicated in hyperthyroidism, bronchial asthama, peptic ulcers CARBACHOL:both true & pseudocholinesterase It is better absorbed from GIT than the cholinesterase ROA: oral, topical & parenteral Paralytic ileus & retention of urine More potent than methacholine &bethacholine PILOCARPINE: Source: : Pilocarpine, alkaloid of vegetable origin, with primarily muscarinic properties from the leaves of pilocarpus microphyllus & other species pilocarpus jaborandi elicits sweat and salivary hypersecretion. pilocarpine is especially used in the form of ophthalmic solutions for treatment of glaucoma where, by reducing iris diameter, it facilitates the flow of aqueous humor by trabeculum and canal of Schlemm . It is also used by general route in the treatment of hyposialy. It is present in several proprietary formulations. ADVERSE EFFECTS:nausea, vomiting &pulmonary edema MUSCARINE: It is an alkaloid obtained from poisonous mushroom Amantia muscarina It has only muscarinic action It is not uised therapeutically ARECHOLINE: It is found in betel nut Areca catechu It has muscarinic as well as nicotinic actions Use in vomiting practice Doesn’t have therapeutic applications in humans B.NICOTINIC Autonomic ganglia: Both sympathetic & para sympathetic ganglia are stimulated Thios effect is manifested at higher doses High dose of Ach after atropine causes tachycardia &raise in B.P due to timulation of sympathetic ganglia and releae of catecholamines SKELETAL MUSCLES: It induce the contraction of skeletal muscles Intraarterial high dose cause twitching &fasciculation CNS: Ach injected IV , doen’t penetrate BBB & no central effects are seen Cholinesterase are rarely usede.