Steps of neurotransmissionSteps of neurotransmission

Steps of cholinergic Steps of cholinergic neurotransmissionneurotransmission

Transduction systemTransduction system

Cholinergic Cholinergic neurotransmissionneurotransmission

Transduction systemTransduction system

Agonist Agonist (acetylcholine(acetylcholine))

Receptor Receptor (M)(M) G-protein G-protein (Gs, Gi)(Gs, Gi) Effector enzyme Effector enzyme

(phospholipase C, (phospholipase C, PLC)PLC)

Second messenger Second messenger (IP3, DAG)(IP3, DAG)

Drug actionDrug action

Muskarínový receptorMuskarínový receptor

Interaction with Interaction with receptorsreceptors

Receptors:Receptors:

- adrenergic: - adrenergic: αα - - αα1, 1, αα2 2

ββ – – ββ1, 1, ββ22

- cholinergic: M (M1-M-3)- cholinergic: M (M1-M-3)

NN

Cholinergic receptorsCholinergic receptors - muskarinic- muskarinic - nicotinic - nicotinic

Nicotinic receptorsNicotinic receptors

Nicotinic receptorsNicotinic receptors

  Muscular typ Ganglionic typ CNS typ

Localization Neuromuscular junction

Vegetative ganglions

Brain

membrane effects

Excitation increase of permeability for Na/K

Excitation increase of permeability for Na/K

Excitation: increase of permeability for Ca++

agonists AcetylcholineNicotine  

AcetylcholineNicotine 

AcetylcholineNicotine

antagonists Tubocurarine DimecamineMecamylamíne

Mecamylamine - conotoxine

Characteristic of muscarinic receptorsCharacteristic of muscarinic receptors

Typ M1 (neural) M2 (cardial) M3 (glandular)

Localization CNS, cortex, hipokampus,Parietal cells  

Heart, Smooth muscle (GIT)CNS

Exocrine glands

Effects Excitation CNS,Increase of HCL

Cardial inhibition,neural inhibition,

Increase of secretion, contraction GIT, vasodilatation miosis

Antagonists AtropineDicycloverineIpratropiumPyrenzepine

AtropineDicycloverineIpratropium

AtropineDicycloverineIpratropium

Functions of the autonomic nervous system

1. Sympathetic: activated in response to stressful situations (trauma, fear, hypoglycemia, cold, or exercise).

I "fight or flight2. Parasympathetic system Dominant over the sympathetic system in

"rest or digest" situations.

Groups of drugs influencing Groups of drugs influencing

vegetative systemvegetative system

Muscarinic agonists Muscarinic agonists ParasympathomimeticsParasympathomimetics

Representative: Representative: acetylcholineacetylcholine

Effects of Effects of parasympathomimeticsparasympathomimetics

Cardiovascular effets (M2):Cardiovascular effets (M2): cardiac slowing and (reduced automaticity)cardiac slowing and (reduced automaticity) decreased force of contraction (mainly in atria)decreased force of contraction (mainly in atria) inhibition of AV conductioninhibition of AV conduction

Smooth muscleSmooth muscle (except vascular smooth muscle (except vascular smooth muscle contracts in response to muscarinic agonistscontracts in response to muscarinic agonists peristaltic activity of GIT increaseperistaltic activity of GIT increase bladder and bronchial smooth muscle also contractbladder and bronchial smooth muscle also contract

Vascular smooth muscleVascular smooth muscle acetylcholine acetylcholine produces vasodilatation - mediator is NOproduces vasodilatation - mediator is NO

Exocrinne glandsExocrinne glands stimulation of gastric acid secretion (M1)stimulation of gastric acid secretion (M1) sweating, lacrimation, salivation, bronchial secretion (M3)sweating, lacrimation, salivation, bronchial secretion (M3)

Effects on eyeEffects on eye lower the intraocular pressure, myosislower the intraocular pressure, myosis

Mechanismof vasodilatation after Mechanismof vasodilatation after ACHACH

Groups of Groups of parasympathomimeticsparasympathomimetics

Directly actingDirectly actinga. Acetylcholinea. Acetylcholine - - rapid rapid

destructiondestruction nonselective effect (M nonselective effect (M

and N)and N) b. More stable derivates of b. More stable derivates of

Ach:Ach: Metacholine, Betanechol, Metacholine, Betanechol,

CarbacholCarbacholc.c. Alkaloids:Alkaloids: muscarine muscarine (Amanita (Amanita

muscaria), muscaria), pilocarpine pilocarpine (Pilocarpus jaborandi)(Pilocarpus jaborandi)

They have no significant They have no significant nicotinic effectnicotinic effect

muscarine - toxicologic muscarine - toxicologic interest onlyinterest only

Indirectly actingIndirectly actinga.a. Reversible Reversible

anticholinesterasesanticholinesterases- short-acting drugs - short-acting drugs

(edrophonium, ambenonium)(edrophonium, ambenonium)- medium-duration - medium-duration

anticholinesterasesanticholinesterases (neostigmine, (neostigmine,

pyridostigmine, pyridostigmine, physostigmine)physostigmine)

b. Irreversible b. Irreversible anticholinesterases anticholinesterases (organophosphates)(organophosphates)

tabun, sarin. somantabun, sarin. somanpesticides, as well as war gasespesticides, as well as war gases::-are usually high lipid-soluble-are usually high lipid-solublecompounds and are rapidly compounds and are rapidly absorbed through mucous absorbed through mucous

membrane, unbroken skinmembrane, unbroken skin

Clinical usesClinical usesand side effects of and side effects of

parasympathoparasympathomimeticmimeticssClinical usesClinical uses myasthenia gravismyasthenia gravis - -

(neostigmine, (neostigmine, pyridostigmine,)pyridostigmine,)

glaucomaglaucoma (physostigmine), (physostigmine), antidoteantidote - in atropine poisoning - in atropine poisoning

(physostigmine)(physostigmine)- in curare-like drug-- in curare-like drug-

induced muscle paralysis induced muscle paralysis (neostigmine), (neostigmine),

urinary tracturinary tract stimulant stimulant (neostigmine)(neostigmine)

GIT GIT postoperative postoperative abdominal distension abdominal distension (neostigmine)(neostigmine)

Side effectsSide effects- flush, - salivation,- flush, - salivation,-

nausea, -vomiting, -nausea, -vomiting, -diarrhea, -hypotension –diarrhea, -hypotension –bronchoconstriction - bronchoconstriction - asthmatic attackasthmatic attack

Intoxication by organophosphatesIntoxication by organophosphates

SymptomsSymptomsa. Effects on autonomic a. Effects on autonomic

cholinergic synapses (M)cholinergic synapses (M) Glands, GIT, Glands, GIT,

bronchoconstrictionbronchoconstriction Bradycardia, hypotension, Bradycardia, hypotension,

disturbancies in visiondisturbancies in visionb. Effects on the b. Effects on the

neuromuscular junction neuromuscular junction (N)(N)

Muscle contraction, in large Muscle contraction, in large doses (poisoning) doses (poisoning) depolarisation of depolarisation of membrane membrane

neuromuscular blockneuromuscular blockc. Effects on the CNSc. Effects on the CNSExcitation,- convulsion - Excitation,- convulsion -

depresion - respiratory depresion - respiratory failurefailure

TreatmentTreatment

1. first step - remove the 1. first step - remove the source to prevent source to prevent further exposure,further exposure,

2. most muscarinic 2. most muscarinic symptoms are blocked symptoms are blocked by atropine,by atropine,

3. to restore 3. to restore acetylcholinesterase acetylcholinesterase activity activity oximes oximes

pralidoxime, pralidoxime, trimedoxime, trimedoxime, obidoxime.obidoxime.

Muscarinic antagonistsMuscarinic antagonists(parasympatholitics)(parasympatholitics)

Representative: atropineRepresentative: atropine

Atroppa belladonaAtroppa belladona

Groups of muscarinic antagonistsGroups of muscarinic antagonists(parasympatholitics)(parasympatholitics)

1. 1. Tertiary ammonium compoundsTertiary ammonium compounds:: - - Alkaloids Alkaloids - atropine and scopolamine,- atropine and scopolamine, atropine - (Atropa belladonna), scopolamine (Datura atropine - (Atropa belladonna), scopolamine (Datura

stramonium)stramonium)

- Semisynthetic Semisynthetic derivate of atropine - homatrapine derivate of atropine - homatrapine - - Selective M1Selective M1 - pirenzepine and dicyclomine - - pirenzepine and dicyclomine - benztropine and trihexyphenidyl – (CNS- antiparkinsonic benztropine and trihexyphenidyl – (CNS- antiparkinsonic

drugs)drugs)

2. 2. Quarternary Quarternary syntheticsynthetic deivates of atropine deivates of atropine - Atropine methonitrate - peripheraly very - Atropine methonitrate - peripheraly very

similar to atropine but it dos not cross blood-similar to atropine but it dos not cross blood-brain barrier - lacks central actionsbrain barrier - lacks central actions

PropanthelinePropantheline - methscopolamine, - methscopolamine, ipratropiumipratropium

Effects of muscarinic antagonistsEffects of muscarinic antagonists

Inhibition of secretionInhibition of secretion Effects on heart rateEffects on heart rate Effects on the eyeEffects on the eye – – mydriasis, pmydriasis, paralysis of aralysis of

accomodation, cycloplegia) accomodation, cycloplegia) disturbances disturbances of near vision, of near vision, -intraocular pressure may rise-intraocular pressure may rise

Effects on the GITEffects on the GIT – inhibition of motility – inhibition of motility Effects on other smooth muscleEffects on other smooth muscle -bronchial, biliary and urinary tract smooth -bronchial, biliary and urinary tract smooth

muscle are all relaxed muscle are all relaxed Effects on CNSEffects on CNS -atropine produced mainly excitatory effects on -atropine produced mainly excitatory effects on

CNSCNS (low doses - mild restlessness(low doses - mild restlessness

Clinical uses of muscarinic Clinical uses of muscarinic antagonistsantagonists

Premedication for anesthesiaPremedication for anesthesia --inhibition of bronchial and salivary secretion, inhibition of bronchial and salivary secretion,

inhibition of reflex bronchoconstrictioninhibition of reflex bronchoconstriction -reduced bradycardia after some anesthetics-reduced bradycardia after some anesthetics GI disordersGI disorders - to reduce gastric acid secretion - to reduce gastric acid secretion

(pirenzepine),(pirenzepine), to reduce gastrointestinal motility to reduce gastrointestinal motility

(dicyclomine)(dicyclomine) OphthalmologyOphthalmology -pupilary dilatation - -pupilary dilatation - homatropinehomatropine is often is often

usedused

Clinical uses of muscarinic Clinical uses of muscarinic antagonists (cont.)antagonists (cont.)

Bronchial disordersBronchial disorders - - ipratropium bromideipratropium bromide is useful is useful

in treatment of asthmain treatment of asthma Motion sicknessMotion sickness - - scopolaminescopolamine is used in is used in

preventing motion sicknesspreventing motion sickness OtherOther - Parkinson´s disease - Parkinson´s disease

((benztropinebenztropine),antidote, diarrhea),antidote, diarrhea

Side effectsSide effectsAtropine like effectAtropine like effect

-blurred vision, -blurred vision,

-tachycardia, -tachycardia,

-dry mouth, -dry mouth,

-constipation, -constipation,

-urinary retention, --urinary retention, -

--mydriasismydriasis

Atropine poisoningAtropine poisoning

mainly in youg mainly in youg children who eat children who eat deadly nightshade deadly nightshade berriesberries

excitement and excitement and irritability irritability hyperactivity and rise hyperactivity and rise body temperature body temperature result of blocking result of blocking muscarinic receptors muscarinic receptors in the brainin the brain

they are opposed by they are opposed by anticholinesterase anticholinesterase drugs drugs (physostigmine)(physostigmine)

MyorelaxantsMyorelaxants

Classification of myorelaxantsClassification of myorelaxants I. drugs that act I. drugs that act

presynapticallypresynaptically by inhibiting of by inhibiting of ACH ACH

synthesis: synthesis: hemicholiniumhemicholinium

by inhibiting by inhibiting ACH ACH release: botulinum release: botulinum toxin, bungarotoxin toxin, bungarotoxin (venom of various (venom of various snakes (cobra family)snakes (cobra family)

by by inhibiting of inhibiting of calcium entrycalcium entry ((magnesium ion, magnesium ion, aminoglycoside ATBaminoglycoside ATB),),

II. drugs that act II. drugs that act postsynapticallypostsynaptically

interfering with interfering with the postsynaptic the postsynaptic action of ACH: action of ACH:

non-depolarising non-depolarising agents agents tubocurarine, tubocurarine, pancuronium, pancuronium, gallaminegallamine

depolarising agents depolarising agents succinylcholinesuccinylcholine

Non-depolarisingNon-depolarising agents - agents -

ttubocurarineubocurarine EffectsEffects Paralysis Paralysis small muscles of the face and eye are small muscles of the face and eye are

paralyzed first, paralyzed first, limb, neck and trunk limb, neck and trunk then intercostal then intercostal

muscles are affected muscles are affected diaphragm muscles. diaphragm muscles. Other effectsOther effects - - release of histamine release of histamine vasodilatation vasodilatation

fall in blood pressure,fall in blood pressure, - bronchospasm - bronchospasm consequence of consequence of

histamine release histamine release asthma, asthma, - neuromuscular blockade last from 20 min - neuromuscular blockade last from 20 min

to 1 hour.to 1 hour.

Non-depolarisingNon-depolarising agents – agents – ttubocurarine (cont.)ubocurarine (cont.)

Terapeutic usesTerapeutic uses

are used therapeutically as are used therapeutically as adjuvant in surgical anesthesia,adjuvant in surgical anesthesia,

strychnine intoxication,strychnine intoxication,

tetanus,tetanus,

diagnosis of myasthenia gravis,diagnosis of myasthenia gravis,

adjunct relaxation during adjunct relaxation during maximal electroshock therapy.maximal electroshock therapy.

Depolarizing agents - Depolarizing agents - succinylcholinesuccinylcholine

EffectsEffects muscular fasciculation last only a few minutes (3 – 5 muscular fasciculation last only a few minutes (3 – 5

min),min), paralysis is slightly different than in non-depolarising paralysis is slightly different than in non-depolarising

drugs, but paralysis of respiratory muscles is the last,drugs, but paralysis of respiratory muscles is the last, does not produce ganglionic block,does not produce ganglionic block, has weak histamine-releasing action,has weak histamine-releasing action,

Unwanted effectsUnwanted effects bradycardiabradycardia increased intraocular pressureincreased intraocular pressure prolonged paralysis by genetic differences of cholinesterase prolonged paralysis by genetic differences of cholinesterase

activity activity malignat hyperthermiamalignat hyperthermia - sudden rise in body temperature - sudden rise in body temperature usually treated by dantrolene (prevention of calcium release from usually treated by dantrolene (prevention of calcium release from

sarcoplasmatic reticulum) + rapid coolingsarcoplasmatic reticulum) + rapid cooling