PHARMACOLOGY OF PARASYMPATHETIC NERVOUS SYSTEM Circular and ciliary

PHARMACOLOGY OF PARASYMPATHETIC NERVOUS SYSTEM

Circular and ciliary muscle of eye III VII IX Spinal cord Cervical Salivary and tear glands X heart Toracic lung superior GI tract Lombar Pelvic Ganglia inferior GI tract Sacral Bladder, kidney genital 2

General organisation parasympathetic nervous system Spinal cord Ganglia target tissue Muscarinic Receptors Acetylcholine Nicotinic Receptors 3

General aspects of PNS o cholinergic mediator is acetylcholine (Ach). o Acetylcholine = biogenic amine sintetized in the body from choline and acetylcoenzime A under the action colinacetil-transferase o Ach released from presynaptic endings can bind to: n cholinergic receptors → activate them n acetylcholinesteraze → inactivate Ach 4

o There are two types of cholinergic receptors : n muscarinic receptors (M) n nicotinic receptors (N) 5

Nicotine tobacco Muscarine Amanita muscaria 6

Muscarinic Receptors o specific activated by de muscarine (toxine from Amanita muscaria) o muscarinic receptors subtypes : M 1, M 2, M 3, M 4, M 5 o localised in: n neuroefector parasympathetic synapses in o the smooth muscle o heart muscle o exocrine glands n neuroefector sympathetic synapses o in the sweat glands o and brain 7

Nicotinic Receptors : o specific activated by nicotine o nicotinic receptors subtypes : n NM receptors = muscle R / end plate R; o are located in somatic neuroefector synapses n NN receptors = neuronal R / ganglia R; o are located in interneuronal synapses from all ganglia of the autonomic (parasympathetic, sympathetic) nervous system and o medulosuprarenal 8

Localisation of Nicotinic Receptors Spinal cord ACh (Nicotinic) Skeletal muscle Somatic eferent Simpathetic { ACh (Nicotinic) Ganglia Parasimpathetic { ACh (Nicotinic) Ganglia Noradrenaline Blood vassels Sweat glands ACh (Muscarinic) exocrin glands s. muscles 9

Structure of muscular receptor (NM) Pentameric (2 a, b, d, g/e) a g/e a b Comutator dezvoltare g/e d 2 biding sites of ACh Receptor ~ 250 k. Da ordine agadb (abadg) 2 binding sites for Ch on interference ag (ae) si ad selective cationic channel 10

ACh Acetat + Cholina 11

Clasification o A. Parasympathomimetics (Cholinergics, cholinergic Agonists) 1. With direct mechanism : n a) coline esters : o naturals: Acetylcholine; o synthetics: Carbachol, Betanechol, Metacholine n b) Alkaloids : Pilocarpine 2. With indirect mechanism (anticholinesterases): n a) Reversible: Fizostigmine, Edrofoniu, Neostigmine, Piridostigmine n b) Ireversible: Ecotiopat, Metrifonat, Fluostigmine, Paraoxon, Sarin 12

o B. Parasympatholitics 1. Naturales: q a) Atropine o b) Scopolamine 2. Sinthetics: o a) Pirenzepine, Telenzepine, Propanteline, Oxifenciclimine, Butilscopolamine o b) Homatropine, Tropicamide, Ciclopentolat o c) Trihexifenidil 13

A. Parasympathomimetics o substances that produce similar effects of parasympathetic stimulation and activation of muscarinic and nicotinic neuroeffector cholinergic synapses n direct parasympathomimetics; n indirect parasympathomimetics (anticholinesterases) 14

o 1. DIRECT PARASYMPATHOMIMETICS Mechanism of action: agonist of cholinergic receptors o a) choline esters prototype: Acetylcholine, n chemical mediator of parasimpathetic, n strong agonist of muscarinic and nicotinic R Pharmacodinamic effects: Ach induses 2 type of effects : n muscarinics n nicotinics 15

o 1. DIRECT PARASYMPATHOMIMETICS – mechanism of action colinergic receptors – increase the permeability of cells membrane for some ions o on excitoconductor heart tissue – increase the permeability for K+ şi Cl- - hiperpolarisation of membrane – decrease the heart rate (M) o On autonomic ganglia, smooth muscles (M), skeletal muscles (N) – increase the permeability for Na+ - depolarisation of membrane – increases the muscles tone o On exocrine glands (sweat, salivary (M)) – increases the permeability for Ca+ - gland secretion

Muscarinic effects o colinergici R from the postsynaptic membrane of the effectors cells; on small doses. o This effects are antagonised by Atropine. a) cardiovascular system : depression heart depression: o decreses atrial contraction force (negativ inotrop effect) o bradicardia by depression of sinusal node (negativ cronotrop) o decreasing of atrio-ventricular driving by depression of A-V node and Hiss fasciculum (negativ dromotrop) n vessels: o vasodilation (decrease BP) by releasing of NO (nitric oxid) from endothelial cells n 17

Muscarinic effects b) respiratory system : n bronchoconstriction n bronchial gland hypersecretion n crisis of dyspnea expiratory (in asthmatics) 18

c) digestiv sysytem: n stimulation of g-i smooth muscle n increses of digestive glands secretion; gastric acid hypersecretion n sphincters relaxation n stimulating bile and gall bladder d) renal excretory system: n bladder contracts, the sphincter relaxes e) Eye n active miosis (contraction of circular smooth muscle of the iris) n lowers intraocular pressure (local instilation) f) CNS stimulation g) exocrine glands (salivary, sweat, tears): n stimulation → hypersecretion 19

1. DIRECT PARASYMPATHOMIMETICS – mechanism of action o nicotinic receptors - coupled to Na+/K+channels - moderately increases of the number of Na open channels Binding of a large number of molecules of Ach at nicotinic receptor blocking sodium channels in open position (membrane stabilization), respectively - off the nervous impulse. 20

2. Nicotinic effects o nicotinic R – n autonomic ganglia n and motor end plates; n high doses (experimentaly conditions) 21

Matural esters of choline - ACETYLCHOLINE Therapeutic Uses: - local ophthalmology - Miochol (acet. Ylcholine), eye drops 1% - Systemic administration - TPSV - Intracoronary - heart surgery Contraindications - Asthma - Thyrotoxicosis - Peptic Ulcers 22

Synthetic esters of choline representatives : n Carbachol n Metacholine n Betanechol Farmacokinetics: cholinei esters are hydrolysed: very rapid: Acetylcholine (not use as medicine) more slow: Metacholine not hydrolised in the body (Carbachol, Betanechol) → persistent effect Mechanism of action: Ach-like. 23

Carbachol Pharmacodinamic action: muscarinic and nicotinic effects predominant action: digestive tract, bladder and eye (and is more persistent than Ach) Therapeutic Uses (limited) - as miotics - in glaucoma (local) - stimulating s. muscle - postoperative bowel and bladder inertia (systemic) Side effects: - strong gastric hypersecretion Ex: ISOPTO CARBACHOL, sol. ophthalmic 3%. 24

Methacholine - is hydrolysed more slowly Pharmacodynamic Action: - predominant cardiovascular action. Therapeutic Uses: n paroxysmal tachycardia n arteritis n Raynaud's syndrome 25

Betanechol Pharmacodinamic action: n Only muscarinic effecte – predominantly on digestiv and urinal system. n Relativly long action (resistant to cholinesterase) Therapeutic use: n intestinal and vezical atonia (oral or s. c) Side effects: relatively frequent n abdominal colic n weating n dyspnea n h. TA Contraindications: (intramuscular and i. v) n mechanic obstruction of the digestive tract or urinary tract 26 n Prezentation: URECHOLINE, f. , cpr.

Pilocarpine alkaloid from din leaf of Pilocarpus jaborandi Pharmacodinamic action: Muscarinic effects - predominantly: o miosis n iris circular muscle contraction - decrease in intracellular pressure n ciliary muscle contraction - to foster close Miosis and ciliary muscle contraction favors increasing aqueous humor drainage through Schlemm canal → lowers intraocular pressure. o hypersecretion of exocrine glands (salivary and sweat mostly) 27

Pilocarpine Therapeutics use: glaucoma (local conjunctival sac) takes effect 4 -6 hours irites, irido-cyclites Atropine poisoning (in administration iv) only antagonizes the peripheral effects. (limited to systemic adm) sialogog in salivary gland stones Side effects: pain in the eyebrows (at the beginning of treatment in glaucoma) may develop tolerance to the effects of eye Prezentation: DROPIL eye drops. 2%; ISOPTO CARPINE eye drops. 1%, 2%; PILOGEL gel oft. , ointment with nitric pilocarpin, oint. oft. OCUSERT PILO-20, OCUSERT PILO-40 oftalmic insert (tank-type therapeutic system with controlled local release, the effect lasts seven days). 28

2. INDIRECT PARASYMPATHOMIMETICS – (Anticholinesterases) Clasification o Depending on the reversibility of action: n reversible: o Fisostigmine o Edrofoniu o Neostigmine o Piridostigmine o Ambenonium Cloride n ireversible: organo- fosfate derivatives o Ecotiophate o Metriphonate o Fluostigmine o Paraoxon o Sarin 29

2. INDIRECT PARASYMPATHOMIMETICS – (Anticholinesterases) Mechanism of action: o Anticholinesterases are substances that make a complex with acetylcholinesterase - block (inhibit) the hydrolyse activity on Ach. And therefore accumulates Ach - Ach effects occur stronger and more prolonged 30

Reversible indirect parasimpathomimetics Neostigmine - is a quaternary ammonium compound Farmacokinetics: difficult to cross biological membranes intestinal absorption is low and variable oral dose is much higher than the injection (x 15) effect during 30 min Mechanism of action: moderate reversible block colinesterazele Pharmacodinamic action: Ach-like muscarinic effect: n stimulate digestive tract motility and urinary bladder nicotinic effect : n selective contracting striated muscle (small doses) 31

Neostigmine Therapeutic use: o inertia intestinal and urinary retention (postoperative) o myasthenia gravis (diagnosis and treatment) o antidote for poisoning with Nondepolarizing skeletal (type d-tubocurarine) o glaucoma (rare) Side effects (overdose): n n nausea vomiting salivation bronchial hypersecretion, welders, abdominal colic Contraindications: n asthma, Parkinson's disease n mechanical obstruction of the digestive - urinary tract; n be avoided in pregnant women. Dosage forme: MIOSTIN tb. 15 mg, amp, 0, 5‰. 32

Fizostigmine (Eserine) Mechanism of action: moderate reversible block cholinesterase Pharmacodinamics action: Ach-like, predominantly: miosis - reduces intraocular pressure, the effect is maintained 24 -48 h Somatic stimulant nicotine effects → somatic striated muscle contraction. Therapeutic use: n Glaucoma - topically applied n corneal ulcer - topically applied n antidote properties on overdose anticholinergic drugs (atropine, phenothiazines, tricyclic antidepressants ) Side effects: local iritation after long period of administration Dosage forme: eye drops 0, 5% şi 1% (4 - 6 x 1 drop/day). 33

Piridostigmine o has Fisostigmine- like actions, o more intense and prolonged Therapeutic use: n postoperative bowel inertia n myasthenia gravis Edrophonium o Acts predominantly on striated muscles o Action is short (150 sec) Therapeutics use: n diagnostics of myastenia gravis n anticurarizant antidote (type d-tubocurarine) 34

Indirectly ireversible parasimpathomimetic (organofosfate derivatives) Depending on the compound they has the muscarinic and nicotinic action in diferent territories Mechanism of action: o ireversibly bind to (covalentely bonds) the esterasic site of colinesterase (phosphorilase the hidroxyl of serine) – block the enzime activity Enzyme reactivators (cholinesterase reactivators): - Obidoxima 35

Pharmacotoxicology: o When the free colinesterazelor falls below 30% of normal - marker for poisoning by excess accumulation of Ach in the CNS o Cholinergic crisis manifests itself: n muscarinic Symptoms omiosis o. Salivary, bronchial hypersecretion onausea, vomiting, diarrhea obronchospasm with respiratory disorders → asphyxia, bradycardia ohypertension then hypotension n Nicotinic Symptoms o fascicular skeletal muscle contractions, convulsions o High doses cause death by respiratory depression 36

Treatment of intoxication with organophosphate compounds Antidots: Atropine i. v. 2 → 4 amp Cholinesterase reactivators: TOXOGONINE (obidoxima) i. v. – in first 6 hours 37

Indirectly ireversible parasimpathomimetic (organofosfate derivatives) Therapeutic use: purely local in glaucoma due to increased toxicity Ecotiophate - pressure-lowering effect of intense and lasting eye lasting 1 -2 weeks Sides effects: n specific cataract after prolonged treatment with high doses. Dosage form: eye drops 0, 03 - 0, 25% de 1 -2 x/d. Fluostigmine – effects like ecotiophate n Duration of eye pressure lowering effect - 1 week Dosage form: ointment, eye drops 38

Parasympatholitics Clasification Natural compounds n Atropine n Scopolamine Semisynthetic and synthetic compounds o Quaternary amines indicated for the treatment of gastrointestinal and genitourinary tract disorders n Anisotropine n Isopropamide n Clidinium n Glicopirolate n Metanteline n Propanteline n Metscopolamine n Butilscopolamine 39

Parasympatholitics Clasification Semisynthetic and synthetic compounds o tertiary amines indicated for the treatment of gastrointestinal and genitourinary tract disorders n Pirenzepine n Oxifenciclimine n Oxibutinine n Tridihexetil n Tolterodine n Propiverine o quaternary amine indicated in the treatment of asthma n Ipratropium o tertiary amine indicated in the treatment of Parkinson's disease / pseudoparkinsonism n Benztropine 40

Parasympatholitics Clasification Semisynthetic and synthetic compounds o indicated in the treatment of central anticholinergic drug pseudoparkinsonismului n Biperiden n Orfenadrine n Prociclidine n Trihexifenidil o central anticholinergic indicated localized in skeletal muscle spasm n Carisoprodol n Ciclobenzaprine n Clorzoxazone n Metaxolon n Metocarbamol n Orfenadrine, Clorfenesine 41

Parasympatholitics Clasification Semisynthetic and synthetic compounds o antimuscarinic used in ophthalmology to produce mydriasis for diagnostic n Homatropine n Ciclopentolate n Tropicamide 42

Parasympatholitics Parasimpaticoliticele are substances that oppose the effects of Ach and muscarinic excitation of parasympathetic effects 1. Natural parasympatholitics a) Atropine - It is an alkaloid extracted from the leaves and roots of Atropa Belladona and other Solanaceae. Pharmacokinetics: o o is absorbed rapidly after oral administration or injection; Diffuses well in all organs and tissues; → inactive metabolites hepatic metabolism; Urinary elimination (60% Unchanged) Mechanism of action: o Atropine in an competitiv antagonist of the Ach. Muscarinic effects o It is bind on muscarinic cholinergic receptors, it blocks and prevents the formation of complex R-Ach → it oppose characteristic effects of such substances with parasimpaticomimetic 43

Pharmacodynamic action: a) Cardiovascular system Low doses and normal vagal tone → bradicardia şi h. TA (poor); Usual dose→ tachicardia; b) Digestiv system Decrese the salivary secretion (the most intense action) hiposecreţie weak stomach; relaxes gastrointestinal smooth muscle →antispasmodic action; Biliare device at moderate antispasmodic 44

Pharmacodynamic action: c) Renal/excretory system o diminish the tone and amplitude of ureteral contractions and bladder smooth fibers → moderate antispasmodic effect. d) Respiratory system o reduces bronchial secretions; o bronchodilator effect (relaxes bronchial muscles); o antibronhoconstrictor effect (by inhibition of vagal component of bronchospasm); o stimulates breathing by stimulating the bulbar respiratory center. 45

c) Eye - Atropine applied topically in the conjunctival sac and produces strong effects: o passive mydriasis by circular fibers of the iris paralysis; o cycloplegic = paralysis of accommodation for near vision, the ciliary body muscle relaxation o increased intraocular pressure o decreased tear secretion 46

f) CNS Depending on the dose: o high doses, stimulates the CNS (agitation, hallucinations, delirium, bulbar paralysis and death) o usual doses of atropine in cholinergic receptor blockade of nigro-striatal system can restore a balance between dopamine and Ach (favorable effect in Parkinson's disease) 47

Therapeutic use: o preanesthesia (reduces bronchial hypersecretion induced by some general anesthetics) o antidote in poisoning with anticholinesterase (pilocarpine and organophosphorus) o sinus bradycardia, AV block (pacemaker); o in ophthalmology: mydriatic fundus exam and treatmentciclitelor irido Side effects: dry mouth constipation cycloplegic mydriasis, Photophobia urinary retention Contraindication: o closed-angle glaucoma o prostate adenoma o pyloric stenosis o o 48

Acute poisoning with atropine (symptoms): o o o mydriasis, photophobia Tachycardia, dysphagia, constipation urinary retention (peripheral effect); agitation, hallucinations, convulsions, coma (central effect) hyperthermia Treatment of poisoning: o Specifically: physostigmine i. v. ; o Symptomatic: benzodiazepines (diazepam) during the excitation. Dosage form: ATROPINE SULFAT amp. 1‰ şi 0, 25‰ (s. c. , i. m. , i. v. slowly); Eye drops o included in standard preparations 49

b) Scopolamine - It is an alkaloid extracted from Datura stramonium. Pharmacodynamic effect: o parasimpaticolitice atropine-like effects, but two times more intense and of shorter duration, o predominant action on exocrine glands and eyes; o central effects: inhibits CNS depressant psychomotor → low doses. Therapeutic use: o the preanesthesia (in combination with hydromorphone, morphine); o the motion sickness; o in Parkinson (Atropine increased as the tremor). o Dosage form: SCOPOLAMINE BROMHIDRATE amp. ; SCOPODERM TTSpatch applied retroauricular, maintain max. 3 days, the 50 motion sickness.

2. Synthetic Parasimpatholitics - parasimpaticolitice are drugs with selective actions a) Gastric Anti-secretives parasimpatholitics - use in ulcer treatment aims to reduce excitosecretorii vagal influences Propanteline- is associated with antimuscarinic action and ganglioplegic (at the intramural plexus) → inhibitory effects of gastric and intestinal motility are more selective. Therapeutic use: o hyperacidity gastritis; o gastric ulcer. Side effects: atropinic-like, but lower. Dosage form: PROPANTELINA, dg. 51

Pirenzepine o Does gastric antisecretory action intense. Selectivity for gastric acid secretion is probably due to muscarinic M 1 receptor blockade. Therapeutic efficacy of cimetidine ulcer is close. Therapeutic use: o peptic ulcer, reflux esophagitis, Zollinger-Ellison syndrome (high dose). o Atropinic unwanted effects are more rare than other anticholinergics. Dosage forme: GASTROZEPIN, tb. (de 2 x /zi). Telenzepine o Parasympathcolitic potent gastric anti-secretoary 4 -10 times Pirenzepine. Oxifenciclimine o Atropinic like antisecretory action lasting effect (6 -8 hours), relatively well tolerated. 52

Ipratropium o early asthma. o in bronchial asthma with long-term trend, producing an increase in viscosity of bronchial secretions with bronchial collapse. Oxibutinine o improving bladder spasms after surgery o It is also indicated in children with meningomyelocele or other neurological disorders urinary incontinence. o Oxybutynine is administered orally or as instilaţii bladder catheter (bladder continence increases, reduce the risk of infection and renal damage). 53

b) Anticholinergic mydriatic - are predominantly acting anticholinergic mydriatic substances. Pharmacodynamic action: o produce mydriasis and cycloplegic effect shorter than atropine. Therapeutic use: in ophthalmology for retinal examination and preoperative for cataract. Homatropine, eye drops 1% o Mydriasis and cycloplegia are fast and durază 1 -3 days. Ciclopentolate, eye drops 1% o Mydriasis and cycloplegia durază 24 h. Tropicamide o Mydriasis and cycloplegia maintained ~ 6 hours. o Dosage forme: MYDRIUM, eye drops 54

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