PHARMACOLOGY OF PARASYMPATHETIC NERVOUS SYSTEM

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Spinal cord

Cervical

Toracic

Lombar

Sacral

X

III

VII

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PelvicGanglia

Circular and ciliary muscleof eye

Salivary and tear glands

heart

lung

superior GI tract

inferior GI tract

Bladder, kidneygenital

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Acetylcholine

Acetylcholine

Nicotinic Receptors

Muscarinic Receptors

Spinal cord Ganglia target tissue

General organisation parasympathetic nervous system

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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

Ach released from presynaptic endings can bind to: cholinergic receptors → activate them acetylcholinesteraze → inactivate Ach

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

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Amanita muscariaMuscarine

N

N

CH3

Nicotinetobacco

CH3

OH

N

CH3CH3

CH3

+CH3

OH

N

CH3CH3

CH3

+

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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

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Nicotinic Receptors : specific activated by nicotine nicotinic receptors subtypes :

NM receptors = muscle R / end plate R; are located in somatic neuroefector

synapses NN receptors = neuronal R / ganglia R;

are located in interneuronal synapses from all ganglia of the autonomic (parasympathetic, sympathetic) nervous system and

medulosuprarenal

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Localisation of Nicotinic Receptors

Skeletal muscle

ACh (Nicotinic)

Somatic eferent

Spinal cord

exocrin glands

ACh (Muscarinic)ACh (Nicotinic)

ParasimpatheticGanglia

{Simpathetic

Blood vasselsNoradrenalineACh (Nicotinic)

Ganglia

{ Sweat glands

ACh (Muscarinic)

s.muscles

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Pentameric ()

Comutator dezvoltare

2 biding sites of ACh

Receptor ~ 250 kDa

ordine

2 binding sites for Ch on interference

selective cationic channel

Structure of muscular receptor (NM)

K+ Na+ Ca2+

A A

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ACh

ACh

Acetat+ Cholina

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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

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B. Parasympatholitics1.Naturales: a) Atropine b) Scopolamine2. Sinthetics: a) Pirenzepine, Telenzepine,

Propanteline, Oxifenciclimine, Butilscopolamine

b) Homatropine, Tropicamide, Ciclopentolat

c) Trihexifenidil

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A. Parasympathomimetics substances that produce similar effects of parasympathetic stimulation and activation of muscarinic and nicotinic neuroeffector cholinergic synapses

direct parasympathomimetics;

indirect parasympathomimetics (anticholinesterases)

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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

1. DIRECT PARASYMPATHOMIMETICS

– mechanism of action

colinergic receptors – increase the permeability of cells membrane for some ions

on excitoconductor heart tissue – increase the permeability for 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 exocrine glands (sweat, salivary (M)) – increases the permeability for Ca+ - gland secretion

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Muscarinic effects colinergici R from the postsynaptic membrane of

the effectors cells; on small doses. This effects are antagonised by Atropine.

a) cardiovascular system : depression heart depression:

decreses atrial contraction force (negativ inotrop effect)

bradicardia by depression of sinusal node (negativ cronotrop)

decreasing of atrio-ventricular driving by depression of A-V node and Hiss fasciculum (negativ dromotrop)

vessels: vasodilation (decrease BP) by releasing of NO

(nitric oxid) from endothelial cells

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Muscarinic effects

b) respiratory system : bronchoconstriction bronchial gland hypersecretion crisis of dyspnea expiratory (in

asthmatics)

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c) digestiv sysytem: stimulation of g-i smooth muscle increses of digestive glands secretion;

gastric acid hypersecretion sphincters relaxation 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 stimulationg) exocrine glands (salivary, sweat, tears):

stimulation → hypersecretion

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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.

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2. Nicotinic effectsnicotinic R –

autonomic ganglia and motor end plates; high doses (experimentaly

conditions)

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Matural esters of choline - ACETYLCHOLINETherapeutic Uses:

- local ophthalmology - Miochol (acetYlcholine), eye drops 1% - Systemic administration - TPSV- Intracoronary - heart surgery

Contraindications- Asthma- Thyrotoxicosis - Peptic Ulcers

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Synthetic esters of choline representatives :

Carbachol Metacholine Betanechol

Farmacokinetics: cholinei esters are hydrolysed:

very rapid: Acetylcholine (not use as medicine)

more slow: Metacholine not hydrolised in the body (Carbachol,

Betanechol) → persistent effectMechanism of action: Ach-like.

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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%.

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Methacholine - is hydrolysed more slowly

Pharmacodynamic Action: - predominant cardiovascular action.

Therapeutic Uses: paroxysmal tachycardia arteritis Raynaud's syndrome

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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.

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Pilocarpinealkaloid from din leaf of Pilocarpus 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)

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PilocarpineTherapeutics 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).

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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

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2. INDIRECT PARASYMPATHOMIMETICS –(Anticholinesterases)

Mechanism of action: 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

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Reversible indirect parasimpathomimeticsNeostigmine - 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)

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NeostigmineTherapeutic 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‰.

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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 administrationDosage forme: eye drops 0,5% şi 1% (4 - 6 x 1

drop/day).

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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)

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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

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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

miosisSalivary, bronchial hypersecretionnausea, vomiting, diarrheabronchospasm with respiratory disorders → asphyxia,

bradycardiahypertension then hypotension

Nicotinic Symptomsfascicular skeletal muscle contractions, convulsionsHigh doses cause death by respiratory depression

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Treatment of intoxication with organophosphate compounds

Antidots:

Atropine i.v. 2 → 4 amp Cholinesterase reactivators:

TOXOGONINE (obidoxima) i.v. – in first 6 hours

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Indirectly ireversible parasimpathomimetic (organofosfate derivatives)

Therapeutic use: purely local in glaucoma due to increased toxicityEcotiophate - pressure-lowering effect of intense

and lasting eye lasting 1-2 weeksSides effects:

specific cataract after prolonged treatment with high doses.

Dosage form: eye drops 0,03 - 0,25% de 1-2x/d.

Fluostigmine – effects like ecotiophate Duration of eye pressure lowering effect - 1

weekDosage form: ointment, eye drops

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ParasympatholiticsClasificationNatural 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

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ParasympatholiticsClasificationSemisynthetic and synthetic compounds tertiary amines indicated for the treatment of

gastrointestinal and genitourinary tract disorders 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

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ParasympatholiticsClasificationSemisynthetic 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

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ParasympatholiticsClasificationSemisynthetic and synthetic compounds

antimuscarinic used in ophthalmology to produce mydriasis for diagnostic Homatropine Ciclopentolate Tropicamide

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ParasympatholiticsParasimpaticoliticele are substances that oppose the effects of

Ach and muscarinic excitation of parasympathetic effects1. Natural parasympatholiticsa) 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: Atropine in an competitiv antagonist 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

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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

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Pharmacodynamic action:c) Renal/excretory system diminish the tone and amplitude of ureteral

contractions and bladder smooth fibers → moderate antispasmodic effect.

d) Respiratory system 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.

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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

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f) CNSDepending 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)

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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 retentionContraindication: closed-angle glaucoma prostate adenoma pyloric stenosis

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Acute poisoning with atropine (symptoms): mydriasis, photophobia Tachycardia, dysphagia, constipation urinary retention (peripheral effect); agitation, hallucinations, convulsions, coma (central effect)

hyperthermia

Treatment of poisoning: Specifically: physostigmine i.v.; Symptomatic: benzodiazepines (diazepam) during the

excitation.

Dosage form: ATROPINE SULFAT amp. 1‰ şi 0,25‰ (s.c., i.m., i.v. slowly); Eye drops included in standard preparations

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b) Scopolamine - It is an alkaloid extracted from Datura stramonium.

Pharmacodynamic effect: parasimpaticolitice atropine-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.

Therapeutic use: the preanesthesia (in combination with hydromorphone,

morphine); the motion sickness; in Parkinson (Atropine increased as the tremor).

Dosage form: SCOPOLAMINE BROMHIDRATE amp.; SCOPODERM TTSpatch applied retroauricular, maintain max. 3 days, the motion sickness.

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2. Synthetic Parasimpatholitics - parasimpaticolitice are drugs with selective actions

a) Gastric Anti-secretivesparasimpatholitics - 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: hyperacidity gastritis; gastric ulcer.

Side effects: atropinic-like, but lower.

Dosage form: PROPANTELINA, dg.

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Pirenzepine Does gastric antisecretory action intense. Selectivity for

gastric acid secretion is probably due to muscarinic M1 receptor blockade.Therapeutic efficacy of cimetidine ulcer is close.

Therapeutic use: peptic ulcer, reflux esophagitis, Zollinger-Ellison syndrome

(high dose). Atropinic unwanted effects are more rare than other

anticholinergics.Dosage forme: GASTROZEPIN, tb. (de 2 x /zi).

Telenzepine Parasympathcolitic potent gastric anti-secretoary 4-10

times Pirenzepine.Oxifenciclimine Atropinic like antisecretory action lasting effect (6-8

hours), relatively well tolerated.

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Ipratropium early asthma. in bronchial asthma with long-term trend, producing an

increase in viscosity of bronchial secretions with bronchial collapse.

Oxibutinine improving bladder spasms after surgery It is also indicated in children with meningomyelocele or

other neurological disorders urinary incontinence. Oxybutynine is administered orally or as instilaţii

bladder catheter (bladder continence increases, reduce the risk of infection and renal damage).

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b) Anticholinergic mydriatic - are predominantly acting anticholinergic mydriatic substances.

Pharmacodynamic action: produce mydriasis and cycloplegic effect shorter than

atropine.Therapeutic use: in ophthalmology for retinal examination

and preoperative for cataract.Homatropine, eye drops 1% Mydriasis and cycloplegia are fast and durază 1-3 days.Ciclopentolate, eye drops 1% Mydriasis and cycloplegia durază 24 h.Tropicamide Mydriasis and cycloplegia maintained ~ 6 hours. Dosage forme: MYDRIUM, eye drops

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