Transcript Therapeutic Uses

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
Acetylcholine
Nicotinic Receptors
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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
4
 There are two types of cholinergic
receptors :
 muscarinic receptors (M)
 nicotinic receptors (N)
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HO
H3C
CH3
+N CH3
CH3
N
N
CH 3
Nicotine
tobacco
Muscarine
Amanita muscaria
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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
Spinal cord
ACh (Nicotinic)
Skeletal muscle
Somatic eferent
Simpathetic
{
ACh (Nicotinic)
Ganglia
Parasimpathetic
{
ACh (Nicotinic)
Ganglia
Noradrenaline
Blood vassels
Sweat glands
ACh (Muscarinic)
ACh (Muscarinic)
exocrin glands
s.muscles
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Structure of muscular receptor (NM)
K+ Na + Ca 2+
a
g/e
a
Pentameric (2a,b,d,g/e)
Comutator dezvoltare g/e
A
A
b
d
2 biding sites of ACh
Receptor ~ 250 kDa
ordine agadb (abadg)
2 binding sites for Ch on
interference ag (ae) si ad
selective cationic channel
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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. Parasympatholitics
1. Naturales:
 a) Atropine
 b) Scopolamine
2. 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
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 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
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 stimulation
g) 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 effects
 nicotinic R –
 autonomic ganglia
 and motor end plates;
 high doses (experimentaly
conditions)
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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
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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 effect
Mechanism 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 hypersecretion
Ex: 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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Pilocarpine
alkaloid 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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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).
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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 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:
 stimulate digestive tract motility and urinary bladder

nicotinic effect :
 selective contracting striated muscle (small doses)
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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‰.
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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 administration
Dosage forme: eye drops 0,5% şi 1% (4 - 6 x 1
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drop/day).
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
miosis
Salivary, bronchial hypersecretion
nausea, vomiting, diarrhea
bronchospasm with respiratory disorders → asphyxia,
bradycardia
hypertension then hypotension
 Nicotinic Symptoms
 fascicular skeletal muscle contractions, convulsions
 High 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 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 drops 0,03 - 0,25% de 1-2x/d.
Fluostigmine – effects like ecotiophate
 Duration of eye pressure lowering effect - 1
week
Dosage form: ointment, eye drops
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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
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Parasympatholitics
Clasification
Semisynthetic 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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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
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Parasympatholitics
Clasification
Semisynthetic and synthetic compounds
 antimuscarinic used in ophthalmology to produce
mydriasis for diagnostic
 Homatropine
 Ciclopentolate
 Tropicamide
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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:
 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:
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.
c)
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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) 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)
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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 treatmentciclitelor irido
Side effects:




dry mouth
constipation
cycloplegic mydriasis, Photophobia
urinary retention
Contraindication:
 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-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:
 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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