PHARMACOLOGY OF PARASYMPATHETIC NERVOUS SYSTEM

1. PHARMACOLOGY OF PARASYMPATHETIC NERVOUS SYSTEM

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

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

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

5. There are two types of cholinergic receptors : • muscarinic receptors (M) • nicotinic receptors (N)

6. Nicotine Muscarine tobacco Amanita muscaria

7. Muscarinic Receptors • specific activated by de muscarine (toxine from Amanita muscaria) • muscarinic receptors subtypes : M1, M2, M3, M4, M5 • localised in: • neuroefector parasympathetic synapses in • the smooth muscle • heart muscle • exocrine glands • neuroefector sympathetic synapses • in the sweat glands • and brain

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

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

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

11. ACh ACh Acetat + Cholina

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

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

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

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

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

17. Muscariniceffects • colinergici R from the postsynaptic membrane of the effectorscells; on small doses. • This effects are antagonised by Atropine. a) cardiovascular system : depression • heartdepression: • decreses atrial contraction force (negativinotropeffect) • bradicardia by depression of sinusal node(negativcronotrop) • decreasing of atrio-ventriculardriving by depression of A-V node and Hissfasciculum(negativdromotrop) • vessels: • vasodilation(decrease BP) by releasing of NO (nitricoxid) fromendothelialcells

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

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

20. 1. DIRECT PARASYMPATHOMIMETICS–mechanism of action 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

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

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

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

24. 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 hypersecretionEx: ISOPTO CARBACHOL, sol. ophthalmic 3%.

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

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

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

28. Pilocarpine Therapeutics use: • glaucoma (local conjunctival sac) takes effect4-6 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 oftalmicinsert (tank-type therapeutic system with controlled local release, the effect lasts seven days).

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

30. 2. INDIRECT PARASYMPATHOMIMETICS–(Anticholinesterases) Mechanism of action: • Anticholinesterases are substances thatmake a complexwithacetylcholinesterase- block (inhibit) the hydrolyse activity on Ach. And therefore accumulates Ach - Ach effects occur stronger and more prolonged

31. Reversible indirectparasimpathomimetics 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: • stimulate digestive tract motility and urinary bladder • nicotinic effect : • selective contracting striated muscle (small doses)

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

33. 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: • Glaucoma - topically applied • corneal ulcer - topically applied • 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).

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

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

36. Pharmacotoxicology: • When the free colinesterazelor falls below 30% of normal - marker for poisoning by excess accumulation of Ach in the CNS • Cholinergic crisis manifests itself: • muscarinic Symptoms • miosis • Salivary, bronchial hypersecretion • nausea, vomiting, diarrhea • bronchospasm with respiratory disorders → asphyxia, bradycardia • hypertension then hypotension • Nicotinic Symptoms • fascicularskeletal muscle contractions, convulsions • High dosescause death by respiratory depression

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

38. 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: • specific cataract after prolonged treatment with high doses. Dosage form: eye drops0,03 - 0,25% de 1-2x/d. Fluostigmine – effects like ecotiophate • Duration of eye pressure lowering effect - 1 week Dosage form: ointment, eye drops

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

40. Parasympatholitics Clasification Semisyntheticandsyntheticcompounds • tertiary amines indicated for the treatment of gastrointestinal and genitourinarytractdisorders • Pirenzepine • Oxifenciclimine • Oxibutinine • Tridihexetil • Tolterodine • Propiverine • quaternary amine indicated in the treatment of asthma • Ipratropium • tertiary amine indicated in the treatment of Parkinson's disease / pseudoparkinsonism • Benztropine

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

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

43. 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: • 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: • Atropinein an competitivantagonist of the Ach. Muscarinic effects • 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

44. Pharmacodynamic action: a) Cardiovascular system Low doses and normal vagal tone → bradicardia şi hTA (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

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

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

47. f) CNS Depending on the dose: • high doses, stimulates the CNS (agitation, hallucinations, delirium, bulbar paralysis and death) • 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)

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

49. Acute poisoning with atropine (symptoms): mydriasis, photophobia Tachycardia, dysphagia, constipation urinaryretention (peripheraleffect); agitation, hallucinations, convulsions, coma (central effect)hyperthermia Treatment of poisoning: Specifically: physostigminei.v.; Symptomatic: benzodiazepines (diazepam) duringtheexcitation. Dosageform: ATROPINESULFAT amp. 1‰ şi 0,25‰ (s.c., i.m., i.v. slowly); Eye drops included in standard preparations 49

50. b) Scopolamine - It is an alkaloid extracted from Daturastramonium. Pharmacodynamiceffect: • parasimpaticoliticeatropine-like effects, but two times more intense and of shorter duration, • predominant action on exocrine glands and eyes; • central effects: inhibits CNS depressant psychomotor → low doses. Therapeuticuse: • the preanesthesia (in combination with hydromorphone, morphine); • the motion sickness; • in Parkinson (Atropine increased as the tremor). • Dosageform: SCOPOLAMINE BROMHIDRATEamp.; SCOPODERM TTSpatchappliedretroauricular, maintain max. 3 days, the motion sickness.