REFERENCES. Autonomic Nervous System DRUGS CANS) * Basic & clinical pharmacology-katzung * Examination It board

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1 UNIVERSITY OF SULAIMANI COLLEGE OF PHARMACY DEPARTMENT OF PHARMACOLOGY Autonomic Nervous System DRUGS CANS) Dr.Zheen A. Mutabchi.,~ * Basic & clinical pharmacology-katzung * Examination It board review I pharmacology... Katzung, -; REFERENCES * Lippincott illustrated review Pharmacology 2

2 Objectives - Divisions of Nervous System. _.Functions & Importance of the different parts of ANS & SNS. - Neurotransmitters in the ANS (synthesis, storage, release, effects, & deactivation). - Studying cholinergic agonists & antagonists I adrenergic agonists & antagonists I & their clinical applications. 3 4

3 Nervous System I.. Central Nervous System Brain Peripheral Nervous System I..... I.\., ~ Spinal cord Efferent division Afferent division Somatic I They carry signals away from the brain and spinal cord to the peripheral tissues.(output) e.g. motor nerves These neurons bring information from the periphery to the ens.(input) e. g. sensory nerves Sympathetic Parasympathetic 5 AutonomiC NS vs. Somatic NS The ANS differs from the SNS in the following areas: Effectors. -Efferent pathways. Neurotransmitter. 6

4 Effectors The effectors of the SNSare: skeletal muscles. The effectors of the ANS are: Cardiac muscles, smooth muscles, adipocytes, & glands. 7 Motor (Efferent) Pathways Axons in the Somatic NS have A single, myelinated axon extending from the ens to the effector., Axons in the Autonomic NS have two-neuron chain The preganglionic (first) neuron extends to ganglion. The postganglionic (second) neuron extends from ganglion to an effector organ. 8

5 , Neurotransmit,ter Effects All somatic motor neurons release: Acetylcholine (ACh), ANS neurons release:. Norepinephrine (Sympathetic division) Acetylcholine (Sympathetic and.parasympathetic divisions) 9 10

6 Divisions of the ANS. Two divisions Parasympathetic Sympathetic Parasympathetic performs maintenance activities "Housekeeping" or " Rest &. Digest". Sympathetic mobilizes body during extreme situations "fig ht-or-flight". 11 -The two divisions counterbalance each other's activity....most organs receive both sympathetic & parasympathetic innervations. - SOME organ receive only sympathetic innervations like: SWEAT GLAND SPLEEN MOST BLOOD VESSELS

7 Sympathetic. Effects Stimulates heart beat..,. Raises blood pressure. Dilates the pupils. Dilates the trachea and bronchi. Stimulates the conversion of liver glycogen into glucose. 13 Shunts blood away from the skin and viscera to the skeletal muscles, brain, and heart. Inhibits peristalsis in the GIT. Inhibits contraction of the bladder and rectum. 14

8 Parasympathetic.Effects Slowing down of the heart beat, Lowering of blood pressure. Constriction of the pupils. Increased blood flow to the skin and viscera. Peristalsis of the GI tract. 16

9 Sympathetic Preganglionic Fibers arise from thoracolumbar.is. T12 8r. Ll- Ls. Short. preganglionic fibers; long postganglionic,wide Distribution. Ganglia near spinal cord. Extensive preganglionic branching All preganglionicfibers use ACh, MOSTpostganglionic use NE. NE is more stable & diffuses for wider action. Fight or flight. athetic Preganglionic Fibers ernerge from brain and sacral. 1973; Long preganglionic fibers; short postganglionic, Limited to head, neck, 8r. trunk. Ganglia found in visceral.effectors Minimal preganglionic branching All cholinergic fibers use (Ach), rapidly destroyed locally. Rest & digest. 18

10 .E,e ~acri.ij'lii.gllnd.and nas8[muooa. $ubmandlbu1ti' and.lublingual. glands..parotid gland Lung ',. inte_ine Smal.intestine.4drenat.gland andkldne,' Ul'inary'bladdi' R 0: 19

11 21 22

12 synthesis, storage, release, & deactivation of N E Tyrosine DOPA VMWIar s)'stem Dopamine OH... I HO('r... CH-CHcNH-CHa.Adre:t'lllline HOV 23 HO OH i - fh HO (' -NHCH;1. H H Bpi nephrtne CH=O yh f HO 7 '\.. C-C-NHCH~ - I I " H H Metanepnrtne MAO COMT CH=o-'p.. yh n HO V '\ C -- C -- OH - I H 3,4-Dihydmxymandelic acid 3-Methoxy - 4-hydroxymandclicacid (VnniIlylmandeHc acid) MAO HO OH H HO ~,.~--~:-NH2 H H Norepmephrine COMT,... HO'n CH30 HO H '~-~-NH" ~- I I ~ H H NormetancphrilW

13 NANC Transmission Neurotransmitters rather than Ach,NE, and Dopamine may be.stored in nerve vesicles with the previously mentioned ones or alone like: ATP, Substance P,. Enkiphalines, Neurotensin. They are acting as a modulator of neurotransmitter release... 25

14 Question..? Complex organ control: the EYEas an example. See: Examination & board review by Katzung: chapter 6, page 52, 9th edition. 28

15 Cholinergic Drugs - Cholinoceptor activating - Cholinesterase inhibitors 29 Sites of Ach release 1. Ganglia. All Sympathetic & Parasympathetic ganglia. 2. Post ganglionic parasympathetic nerve endings. 3. Sweat Gland. 4. Somatic nerve endings supplying Skeletal Muscles. 5. Adrenal medulla. 6. ens. 30

16 CHOLINERGIC AGONIST DRUGS I Direct~cting Indirect lacting I 1 I. Muscarinic Nicotinic : : : 1 Edrophonium ~ ~ Alkaloids Choline ester Carbamate ~ Pilocarpine Ach,Methacholine, : MlISCCIine carbachol, ' organophospha~es Arecoline bethanicol 31.Presynaptic V~L<:~EiiIS, contaniing aeel:ybcj'toiine AGetyk;hgfine~ DiliGd;..aciin'Q ctuj~~nergicdrus 32

17 MUSCARINIC NICOTINIC 33

18 UNIVERSITY OF SULAIMANI COLLEGE OF PHARMACY DEPARTMENT OF PHARMACOLOGY& TOXICOLOGY Drugs affecting Autonomic Nervous..System CANS) Dr.ZheenA. Mutabchi 1 REFERENCES... * Basic & dinical pharmacology Katzung * Examination &. board review pharmacology --Katzung * Lippincott illustrated review Pharmacology 2

19 Cholinergic Drugs - Cholinoceptor activating - Cholinesterase inhibitors 3 Sites of Ach release 1. Ganglia. All Sympathetic & Parasympathetic ganglia. 2. Post ganglionic parasympathetic, nerve endings. 3. Sweat Gland. 4. Somatic nerve endings supplying Skeletal Muscles. 5. Adrenal medulla. 6. ens. 4

20 .t J t. D Ifec ac Ing I I Muscarinic 1 I Alkaloiij Pilocarpine Muscarine Arecoline Lobeline CHOLINERGIC AGONIST DRUGS I I Nicotinic Choline ester.ach, Methacholine,. carbachol, bethanicol Indirect lacting I... : : Edrophonium ~ ~ T :..Carbamate t Organophosphates 5 ~ Presynaptic ve(~.dcles. mntaining aosi;yk;holine AG8tYfd1glin&~ Oire:cl-aclil.ng cholinergic dn.js 6

21 MUSCARINIC NICOTINIC 7

22 Subtypes Locations M Ml ;, _.. G"'PCR M3 ms N.. Ligand lon-., channel 9 M Ml M3 N ms, 10

23 11 12

24 DIRECT ACTING DRUGS ACETYLCHOLINE Quaternary ammonium compound. Has both muscarinic & nicotinic activity. Has NO therapeutic application rapid inactivation lack of specificity H31 o n, H3C-.c -0 ~;CH2-cH2-~ -'CH3 Ace Ichollne. CH:l;I 13 Tissue & Organ effects Heart... vagal stimulation Blood vessels... parasympathetic innervations..??! G.1. T. R.T.S. Eyes. 14

25 I Raba'" AV oonduotion t r-'----- REJlStiessne_ frrimbilmty Hall!Uclrnatlons Antfpftridnsonfan effect Antietnetfe, effect: Bronchllal secretion Brol"lchocol"IstrJction + Ilmcreased b400d,' flcpa" for incr_s~ng heet dfss4patlon IBronchllal sec:.-etion decreased Brol"lchodillatfon c, * Bethanechol * similar to Ach. quaternary ammonium. compound... * Not hydrolyzed by AChE. * Has STRONG MUSCARINIC but no nicotinic activity. Mainly acts on smooth muscle of bladder &GIT. '* Therapeutic value in Post partum & postoperative atonic bladder. * S/E. 16

26 CARBACHOL Similar to Ach in its affinity to M,N Receptors. Similar to bethanicol in its resistance to AchE. DOA is tonq 1 hr. Glaucoma. 17 Natural alkaloid., Tertiary amine structure. Stable to hydrolysis by AChE. Contraction of the ciliary muscles & MIOSIS. Glaucoma. Pilocarpine Pll~1f1W1lJW IPu~1wlda 18

27 Adverse. reactions.. ftlxldtl Iellflm itllbttl~lnlmil_mdn'\v1lil _m _,Dl;_~f ~!_titio~i_~ alipi.sntdt Il1Id acnyil1, J, >', u,i '. 'maet)" IfiQ ' 'Hallen. :accul1.jol-. I.. '""'".. V,..",,>'...~ I~. '.J ' ill ~ ~.. 1Il,~;]inl~ou~131~,~bl 19 II,'.ml'"m~'~~'~~t!~~~!~~... ~~ ejj~~i_m'awj,'~i'd~m~~m&lili' I,.~~i ra; 111~~fJhltll (illlm " fl~j~ni~~, ~.r~~m~~i. :.;g]]l~,, 20

28 INDIRECT ACTING CHOLINERGIC AGONISTS CLASSIFICATION CHEMICAL STRUCTURE: -- Esters of carbamic acid: carbamates neostigmine -- Esters of phosphoric acid: phosphates organophosphates -- R-OH:. Edrophonium 21 CLASSIFICATION DURATION OF ACTION -- Very short acting edrophonium -- intermediate -long acting carbamates( carbaryl, propoxure, aldicarb) -- very long- acting organophosphates( malathion, parathion, sumithion, sarin, & tabun), 22

29 CLASSIFICATION REVERSIBILITY. --Reversible: Physostigmine, neostigmine,pyridostigmine, rivastigmine, donepezil, edrophonium, ambinonium. -- Irreversible: organophosphates (parathion, malathion, echothiophate, nerve gases [tabun, sarin, soman]; diazinon, dyflos). ' 23, Presynaptic \fesiclehs mntaining aosl lcholine. Acstylcoolinesterass Acafylcht)lina" ~; ldire,d..,acting cholinergic drug 24

30 PreSYnipticvesi~,~ oonmining acetylchol'ine IndnGt"ading cholnergic drug bound to acetylchounmtems~ (S9; nut box) There are two major types of cholinesterases.acetylcholinesterase (AChE) also known as true, specific I and are found mai.nlyat (cholinergic neuroeffector junction) pseudocholinesterase (pseudo-che) (liver, skin, plasma) 26

31 There are two main forms of cholinesterase both enzymes belong to the family of serine hydrolases: -acetylcholinesterase (AChE), which is mainly membrane bound, relatively specific for ACh and responsible for rapid ACh hydrolysis at cholinergic..synapses. - butyrylcholinesterase (BuChE) or pseudocholinesterase, which is relatlvelv non-selective and occurs in plasma and many tissues. 27

32 Clinical applications of indirect acting cholinomimetics 29 REVERSIBLE ANTICHOLINESTERASES Physostigmine,.~ Ph'J4':R.''; DiI'Je o 1.1 -C-O-H 30

33 Uses -GLUCOMA -OVERDOSES of ATROPINE,TCA. -Intestinal & bowel atony. -ACCOMMODATIVE ESOTROPIA ADVERSE EFFECTS U 1 s 31 REVERSIBLE ANTICHOLINESTERASES NEOSTIGMINE HaG 32

34 USES...Myasthenia Gravis direct stimulation Nm indirect effect on AchE Urinary Retention & paralytic ileus Antidote for Tubocurarine 33. EDROPHONIUM USES I.V. in diagnosis of Myasthenia Gravis 34

35 PYRIDOSTIGMINE AMBENONIUM, - Chronic management of Myasthenia Gravis - DOA: 3-6 hrs 4-8 hrs 36

36 DONEPEZIL is used to treat mild to moderate Alzheimer's disease. In long term studies, donepezh delayed the progression of the disease for up to 55 weeks. Donepezil increases acetylcholine in the brain by inhibiting its metabolism. 37 The drug is well absorbed after oral administration and absorption is unaffected by food. It is highly bound (96%) to plasma proteins. It is metabolized in the liver to several metabolites, some of which are pharmacologically active; metabolites and - some unchanged drug are excreted mainly in urlne, Adverse effects include nausea, vomiting, diarrhea, bradycardia, and possible aggravation of asthma, peptic ulcer disease, and chronic obstructive pulmonary disease. Jaw tremor 38

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