M1 Secretory salivation, stomach acid, sweating, lacrimation

glands

M2 Heart Decreases heart rate bradycardia

M3 Smooth Contraction of smooth muscles (some)

muscle diarrhea, bronchospasm, urination
(GI/Resp)
M3 Pupil and Contracts Miosis
ciliary Increased flow of aqueous humor
muscle
Nm Skeletal Contraction of skeletal muscle
muscle end
plate
Nn Autonomic Secretion of Epinephrine
ganglia, Controls ANS
Adrenal
Medulla
ATP+Acetate+Co-enzymeA
Acetate activating reaction
Acetyl coEn-A
Choline
choline acetylase
Acetyl choloine +
Co En. A
Generalized Cholinergic Junction
SITE TYPE OF Selective Selective
RECEPT. agonist antagonist
All postganglionic Muscarinic Muscarine Atropine
parasymp.
b. Few postganglionic
symp. (sweat)
Glands, BV

Gangla (both symp. And Nicotinic DMPP Hexamethoniu

parasymp). (NN) m
Adrenalmedulla
Skeletal Muscle Nicotinic PTMA CURARE
(NM)
CNS (CORTEX BASAL G Muscarinic Muscarine/ Atropine
ANGLIA, SPINALCORD.) Oxotremorine
DMPP-Dimethyl phenyl
piperazinium
PTMA-PhenyI trimethyl Nicotonic Carbacol Curare
ammonium
M1 M2 M3
Autonomic SA node: Viseral smooth
ganglia: (late Hyperpolarizatiory muscle:
EPSP):Depolarization Decrease rate of contraction.Exocrine
Gaslric impulse generation glands secration,
glands: acid secretion, AV node: Decr. velocity EDRF
Hist. release, of conduction (NO)vesodialation
CNS: Learning, Atrium: shorteirng of
memory, APD, contractility
motor functions Ventricle: contractility
GPCR GPCR GPCR

IP3/DAG K+ CH. Opening, IP3/DAG

decr.cAMP
(Agonist)Oxotremorine Methacholine Bethanecol
Antagonist: Pirenzapine, Methotramine, Derifenacin
telenzapine tripitamine
 Nm Nn
Location and Neuromuscular junction: Autonomic ganglia:
function depolarization of muscle end depolarization
plate, contraction of skeletal Adrenal medulla: Adr
muscle release.
CNS: Site specific:
excitation or
inhibition.
Nature Intrinsic ion channel Intrinsic ion channel
Transducer Opening of Na+, K+ channel Opening of Na+, Ca+
mechanism (Cation) +, K+ channel
(Cation)
Agonists PTMA, Nicotine DMPP, Nicotine
Antagonists Tubocurarine Hexamethonium,
Trimethophan.
 Choline esters: Acetyl choline,

Methacholine, Carbacol, Bethanecol.

Alkaloids: Muscarine, Pilocarpine, Arecoline.

 Intracellular signaling triggered by acetylcholine in the smooth muscle

Main molecular players: M3, Heterotrimeric protein Gq, PLC/IP3, Ca(2+), MLCK
 Intracellular signaling triggered by acetylcholine in the Heart

Main molecular players: M2, heterotrimeric G Protein Gi, Adenylyl cyclase

 Cholinergic action (molecular mechanism)
Intracellular signaling triggered by acetylcholine in the endothelium

eNOS
Nitric oxide synthase

L-Arg
eNOS
L-Citruline

NO

Major molecular players: M3, heterotrimeric G Protein Gq, Ca(2+)-CaM, eNOS, NO

 Cholinergic action (molecular mechanism)
acetylcholine mediated endothelium-dependent vasodilation

Start Here
+ACh
NO probe - ACh
NO probe
 Sites of Cholinergic Activity
-Preganglionic synapses of both sympathetic and parasympathetic ganglia

- Parasympathetic postganglionic neuroeffector junctions

- All somatic motor end plates on skeletal muscles

RECEPTOR M2 M4 M1 M3 M5

Gi Go Gq
INTRACELLULAR
TRANSDUCER Adenylyl cyclase Phospholipase C
cAMP Diacyl-glycerol IP3

ELECTRICAL Hyperpolarization (heart)

MECHANICAL Depolarization
Cardiac inhibition
PHYSIOLOGICAL Smooth muscle contraction
Antagonism of smooth
RESPONSES Glandular secretion
muscle relaxation
 Muscarinic receptor types
experiments that led to their discovery

M1 - Neurotransmission in Cortex and Ganglia

(-/-) mice - abrogation of pilocarpine induced seizures

M2 - Agonist-mediated bradycardia, tremor, autoinhibition of release in several

brain regions
(-/-) mice - loss of oxytremorine-induced tremors; loss of
agonist-induced bradycardia; diminished hypothermia

M3 - Smooth muscle contraction, gland secreation, pupil dilation, food intake

and possibly weight gain
(-/-) mice - loss of agonist-induced bronchoconstriction,
higher basal pupil dilation, reduction of
agonist-induced salivation

M4 and M5 Central Nervous System (CNS) roles.

 Classes of cholinergic stimulants

Direct-acting Indirect-acting

Receptor agonists Cholinesterase inhibitors

Carbamates
PHYSOSTIGMINE Phosphates
Choline esters NEOSTIGMINE ISOFLUROPHATE
ACETYLCHOLINE Alkaloids PYRIDOSTIGMINE Antidote
BETHANECOL PILOCARPINE PRALIDOXIMINE
EDROPHONIUM
Quaternary ammonium

Tertiary amine
 Chewing pilocarpus caused salivation

Amazon

Experiments performed in Brazil in 1874, isolated in 1875, methacholine and

carbachol studies in 1911
- Eyes: contraction of ciliary muscle and smooth
muscle of the iris sphincter (miosis) aqueous
humor outflow, drainage of the anterior chamber

- Cardiovascular: Bradycardia (possibly preceded

by tachycardia), vasodilation (all vascular beds
including pulmonary and coronary M3) and
hypotension, reduction of the contraction
strength (atrial and ventricular cells, IK+ , ICa2+
diastolic depolarization , NO-inhibitable ATP?),
negative chronotropic effect (inhibition of
adrenergic activation).
- GI - increases in tone, amplitude of contractions, and
peristaltic activity of the stomach and intestines,
enhances secretory activity of the gastrointestinal
tract.
- Urinary bladder - increase ureteral peristalsis,
contract the detrusor muscle of the urinary bladder,
increase the maximal voluntary voiding pressure, and
decrease the capacity of the bladder.
- Other effects Increased secretion from all glands
that receive parasymphatetic enervation (salivary,
lacrimal, tracheobronchial, digestive and exocrine
sweat glands)

- IMPORTANT - BROCHOCONSTRICTION
 Bethanechol chloride (carbamylmethylcholine chloride; URECHOLINE)

Stimulant of the smooth muscle of the GI tract and the urinary bladder.

Postoperative abdominal distension and gastric retention or

gastroparesis.

Urinary retention and inadequate emptying of the bladder when organic

obstruction is absent:

- postoperative
- postpartum urinary retention
- certain cases of chronic hypotonic or neurogenic bladder.

-alternative to pilocarpine to promote salivation Xerostomia (dryness of the

mouth).

-Sjogren syndrome (immunologic disorder with destruction of the

exocrine glands) leading to mucosal dryness
 Bethanechol should be administered only by the oral or subcutaneous route for
systemic effects; they also are used locally in the eye.

Antidote - atropine.

Epinephrine may be used to overcome severe cardiovascular or

bronchoconstrictor responses.

Among the major contra-indications to the use of the choline esters are asthma,
hyperthyroidism, coronary insufficiency, and acid-peptic disease.

Bronchoconstrictor action could precipitate an asthmatic attack

Hyperthyroid patients may develop atrial fibrillation.

Hypotension induced by these agents can severely reduce coronary blood flow,
especially if it is already compromised.

The gastric acid secretion produced by the choline esters can aggravate the
symptoms of acid-peptic disease.

POSSIBLE SIDE EFFECTS : sweating (very common), abdominal cramps, a sensation

of tightness in the urinary bladder, difficulty in visual accommodation for far
vision, headache, and salivation.
 Carbachol usually is not employed for these
purposes
because of its relatively larger component of
nicotinic
action at autonomic ganglia.

The unpredictability of the intensity of response has

virtually eliminated the use of methacholine or other
cholinergic agonists as vasodilators and cardiac
vagomimetic agents.

Methacholine chloride (acetyl-b-methylcholine

chloride;
PROVOCHOLINE) may be administered for diagnosis
of bronchial hyperreactivity and asthmatic
conditions.
 Carbnmates Acridine REVERSIBLE
Physostigmine(Eserine) Tacrine
Neostigmine
Pyridostigmine
Edrophonium
Rivasti gmine, Donepezil
Galantamin

Organophosphates Carbamates IRREVERSIBLE

Carbaryl*
Dyflos (DFP) Propoxor
Echothiophate
Parathion*, Malathion*
Diazinon*
(tIK-20)
Tabun, Sarin, Soman
 The anti-ChEs react with the enzyme
essentially
in the same way as ACh.
The carbamates and phosphates
respectively carbamylate and
phosphorylate the esteratic site of the
enzyme.
 Whereas the acetylated enzyme reacts with water
extremely rapidly and the esteratic site is freed in a
fraction of a millisecond,

the carbamylated enzyme (reversible inhibitors) reacts

slowly.
and the phosphorylated enzyme (irreversible inhibitors)
reacts extremely slowly or not at all

lt is noteworthy that edrophonium and tacrine attach

only to the anionic site of the enzyme, while
organophosphates attach only to the esteratic site.
 Lipid-soluble agents (physostigmine and
organophosphates) have more marked

muscarinic and CNS effects; stimulate

ganglia but action on skeletal muscles is
less prominent.
 Lipid-insoluble agents (neostigmine and
other quatemary ammonium compounds)
produce more marked effect on the
skeletal muscles (direct action on muscle
endplate cholinoceptors as well),
stimulate ganglia,

but muscarinic effects are less prominent.

The
Ganglia Local hydrolysis of ACh is less
important in ganglia: inactivation occurs
partly by diffusion and hydrolysis in
plasma.

Anti-ChEsstimulate ganglia primarily

through muscarinic receptors present
there.

High doses cause persistent depolarization

of the ganglionic nicotinic receptors and
blockade of transmission
 CVS Cardiovascular effects are complex.
Whereas muscarinic action would produce
bradycardia and hypotension, ganglionic
stimulation would tend to increase heart
rate and BP
Skeletal muscles After treatment with

antiChEs, the Ach released by a single

nerve impulse is not immediately
destroyed-rebinds to the same receptor,
diffuses to act on neighbouring receptors
and activates prejunctional fibres.
 repetitive firing

twitching and fasciculation

Force of contraction in partially curarized and

myasthenic muscles is increased. Higher
doses cause persistent depolarization of
endplates resulting in blockade of
neuromuscular transmission

weakness and paralysis

 Exageration of all symptoms of muscarinic
agonism
Significance: Higher consumption of wild
mushrooms (culinary)

A. muscaria

30-60 minutes, salivation, lacrimation, excessive sweating, nausea, vomiting

diarrhea, bronchospasm, headache, visual disturbances, abdominal colic,
bradychardia, hypotension, shock

ALL SYMPTOMS REVERTED BY ATROPINE1 - 2 mg intramuscular

 Amanita phalloides deadly nightcap
Inhibits mRNA synthesis 24 h symptom free period followed by
liver and
kidney malfunction, death within 4-7 days

A. phalloides A. muscaria
 CLASSIFICATION
1. Natural alkaloids: Atropine, Hyoscine
(Scopolamine).
2. Semisynthetic derivatives: Homatropine,

Atropine methonitrate, Hyoscine butyl

bromide
Ipratropium bromide, Tiotropiumbromide.
3. Synthetic compounds
(a) Mydriatics: Cyclopentolate, Tropicamide
(b) Anti secretory-anti spasmodics:
i) Quaternary compounds: Propanthelin
Oxyphenonium, Clidinium, Pipenzolate,
methylbromide, Isopropamide, Glycopyrolate.
(ii) Tertiary amines: Dicyclomine,
Valethama:.
Pirenzepine.

(c) Vasicoselective: Oxybutynin,

Flavoxate.
Tolterodine.

(d) Antiparkinsonian: Trihexyphenidyl

(Benzhexol), Procyclidine, Biperiden.
 CNS : Atropine has an overall CNS stimulant
action. However, these effects are not
appreciable at low doses which produce only

peripheral effects because of restricted entry

into the brain.
Hyoscine produces central effects (depressant)

even at low dose.

Atropine stimulates many medullary centres
-veagal, respiratory, vasomotor.

It depresses vestibular excitation and has

antimotion sickness property.
 By blocking the relative cholinergic over
activity
in basal ganglia, it suppresses tremor
and rigidity of parkinsonism.

High doses cause cortical excitation,

restlessness, disorientation, hallucinations and
delirium followed by respiratory depression
and coma.
 2. CVS
Heart The most prominent effect of atropine is
to cause tachycardia. It is due to blockade of M 2

receptors on SA node through which vagal tone

decreases HR.
Higher the existing vagal tone more marked is

the tachycardia (maximum in young adults, less

in children and elderly) because of M1recpt. In
brain.

BP Since cholinergic impulses are not involved

in maintenance of vascular tone, atropine does
not have any consistent or marked effect on BP
 Eye The autonomic control of iris muscles
and the action of mydriatics as well as

miotics. Topical instillation of atropine

causes mydriasis, abolition of light reflex
and cycloplegia lasting 7-10 days. This
results
in photophobia and blurring of near

vision.
The ciliary muscles recover somewhat

earlier than sphincter pupillae.

 4. Smooth muscles: All visceral smooth
muscles that receive parasympathetic motor
innervation are relaxed by atropine (M3
blockade).

Tone and amplitude of contractions of

stomach and intestine are reduced; the
passage of chyme is slowed-constipation may
occur, spasm may be relieved
However, peristalsis is only incompletely
suppressed because it is primarily regulated

by local reflexes and other

neurotransmitters (5HT,enkephalin, etc.) as
well as hormones are involved.
 Atropine causes bronchodilatation and
reduces airway resistance, especially in
COPD and
asthma patients.

Atropine has relaxant action on ureter and

urinary bladder; urinary retention can occur in
older males with prostatic hypertrophy.

However,the same can be beneficial for

increasing bladder capacity and controlling
detrusor hyper reflexia in neurogenic
bladder/enuresis.
 5. Glands: Atropine markedly decreases saliv
ary, tracheobronchial and lacnmal secration :
(M3 blockade). Skin and eyes become dry ,

talking and swallowing maybe difficult.

Atropine decreases secretion of acid, pepsin

and mucus in the stomach.

Bodytemperature occurs at higher doses. It is

due to both inhibitor of sweating as well as
stimulation of temperatureregulating centre
in the hypothalamus.
 Local anesthetic action: Atropine has an
local anaesthetic action on the cornea.
Attropa belladona
 Atropa belladona - used in the renaissance
Deadly nightshade - used in the middle ages to produce
polonged poisoning

Jimson plant leaves burned in India to treat Asthma (1800)

purification of atropine (1831)
 ATROPINE

SCOPOLAMINE
 ATROPINE

SCOPOLAMINE Attropa belladona

- Atropine and Scopolamine are belladona alkaloids

(competitive inhibitors)

-Drugs differ in their CNS effects, scopolamine permeates the

blood-brain barrier

-At therapeutic doses atropine has negligible effect upon the CNS,
scopolamine even at low doses has prominent CNS effects.
- Competitively block muscarinic receptors
- Salivary, bronchial, and sweat glands are
most sensitive to atropine
- Smooth muscle and heart are intermediate
in responsiveness
- In the eye, causes pupil dilation and difficulty for
far vision accomodation
- Relaxation of the GI, slows peristalsis
 ORGAN DRUG APPLICATION
CNS Benztropine Treat Parkinsons disease
Scopolamine Prevent/Reduce motion
sickness

Eye Atropine Pupil dilation

Bronchi Ipatropium Bronchodilate in Asthma, COPD

GI Methscopolamine Reduce motility/cramps

GU Oxybutinin Treat transient cystitis

Postoperative bladder spasms
 DRY AS BONE, RED AS A BEET, MAD AS HATTER.

Dry is a consequence of decreased sweating,

salivation and lacrimation

Red is a result of reflex peripheral (cutaneous)

vasodilation to dissipate heat (hyperthermia)

Mad is a result of the CNS effects of muscarinic

inhibition which can lead to sedation, amnesia
(hypersensitivity), or hallucination
 Classification and examples of direct and
indirect acting Cholinergic agonists
Brief discussion of few of the above
examples
Pathophysiology, diagnosis, and
Management of
Myasthenia gravis and tensilon test
Glaucoma
Alzheimer's disease
Organo Phosphorus compound poisoning
 Heart: Cardiac suppressantBradycardia,
hypotension,
Eye: Miosis, cycloplegia, facilitates aqueous
humour drainage, lacrimation
Bronchospasm
Excess secretion from glands.salivary,
bronchial, lacrimal glands etc..
GIT /bladder smooth muscle contraction and
relaxation of sphincters, increased motility,
diarrhea, vomiting , increased micturation
(urinary urgency)
 Often called parasympathomimetic drugs,
because their action mimics the action of
the PSNS commonly
Also called as Cholinergic drugs or

cholinomimetric
Cholinergic agonists are two types :
1. Direct acting

2. Indirect acting
 They act by binding directly to cholinoceptors

Acetylcholine (Synthetic analogue of ACH)

Carbachol

Bethanechol

Pilocarpine (naturally occurring alkaloid)

 They act through inhibition of Acetyl
cholinesterase enzyme.so increases
Acetylcholine level in the synapse

Reversible (Carbamates):
Neostigmine
Irreversible(Organoph
Physostigmine
Pyridostigmine osphates) :
Edrophonium
Ecothiophate
Tacrine
Danopezil Malathion
Parathion
Sarin
 It is a quaternary ammonium compound so
Cannot penetrate the membrane
Does not have any therapeutic
importance, because of multiplicity of
actions & rapid inactivation by
acetylcholinesterases
It has both Muscarinic & Nicotinic actions
Neurotransmitter for pre-ganglionic neuron
 Not hydrolyzed by acetylcholinesterases
It has strong Muscarinic action & no Nicotinic action
Actions
Directly stimulates M receptors causing increased
intestinal motility & tone
It stimulates detrusor muscle of the bladder while
trigone & sphincters are relaxed causing expulsion of
urine
Therapeutic Uses:
Paralytic ileus
Urinary retentions
An alkaloid, lipid soluble & is stable to hydrolysis by
cholinsterases It has Muscarinic activity only .
Actions-
When applied locally to cornea Produces rapid
miosis & contraction of ciliary muscle produces
of spasm of accommodation & vision is fixed at
particular distance making it impossible to focus
for far situated objects
Therapeutic Use : In Glaucoma
It opens trabecular meshwork around schlemms
canal
causes drainage of aqueous humor
IOP immediately decreases.
 Cholinesterase inhibitors. Can be reversible or
irreversible.
Reversable:
Neostigmine
Physostigmine
Edrophonium
Tacrin
Danopezil
Irreversible
Malathion and Parathion
Sarin
Ecothiopate

 Neostigmine in M.gravis
Physostigmine in Glaucoma, atropine overdose
Ecothiopate in glaucoma
Edrophonium in M.gravis to test
Tacrin, Danopezil in Alzheimer's
Malathion, Parathion as insecticides
 An autoimmune process causes production of
antibodies that decrease the number of functional
nicotinic receptors on the postjunctional end plates.
Frequent findings are
Double vision. diplopia,
Drooping of eyelids. ptosis,
Dysarthria Difficulty in speaking
Dysphagia ..difficulty swallowing,
Difficult in Daily routines
limb weakness increases.
Difficulty in respiration Severe disease may affect all
the muscles, including those necessary for respiration.
Death
 Immunosuppressant drugs
Thymectomy
Acetyl Cholinesterase inhibitors
Neostigmine
Pyridostigmine
Ambenonium
Edrophonium
Other supportive measures
 Neostigmine Has a strong influence at the
neuromuscular junction
Pyridostigmine: Has a longer duration of
action than neostigmine
Ambenonium :Available only in oral form;
cannot be used if patient is unable to swallow
tablets
Edrophonium: Diagnostic agent for
myasthenia gravis and to diffrentiate
myasthenic and cholinergic crisis (Tensilon
test )
 Clinical situations in which severe myasthenia
(myasthenic crisis) must be distinguished from
excessive drug therapy (cholinergic crisis) usually
occur in very ill myasthenic patients
If excessive amounts of cholinesterase inhibitor
have been used, patients may become
paradoxically weak because of nicotinic
depolarizing blockade of the motor end plate.
Small doses of edrophonium (12 mg
intravenously) will produce no relief or even
worsen weakness if the patient is receiving
excessive cholinesterase inhibitor therapy.
On the other hand, if the patient improves with
edrophonium, an increase in cholinesterase
inhibitor dosage may be indicated.
 A progressive disorder involving neural
degeneration in the cortex
Leads to a marked loss of memory and of
the ability to carry on activities of daily
living
Cause of the disease is not yet known
?????? There is a progressive loss of ACh-
producing neurons and their target neurons
 Tacrine
Side effect: HepatoToxicity

First drug to treat Alzheimers dementia

Rivastigmine
Available in solution for swallowing ease

Donepezil
Has once-a-day dosing advantage
 Only Ecothipate is used clinically in
Glaucoma. This is the long acting drug used
in glaucoma
Rest of the drugs are used as pesticides or war
gases or poisons: Malathion and Parathion
 The dominant initial signs are those of
muscarinic excess: miosis, salivation, sweating,
bronchial constriction, vomiting, and diarrhea.
Central nervous system involvement usually
follows rapidly, accompanied by peripheral
nicotinic effects, especially depolarizing
neuromuscular blockade.
(1) maintenance of vital signsrespiration in particular may
be impaired;
(2) decontamination to prevent further absorptionthis may
require removal of all clothing and washing of the skin in
cases of exposure to dusts and sprays; and
(3) Atropine parenterally in large doses, given as often as
required to control signs of muscarinic excess stimulation .

(4)Therapy often also includes treatment with pralidoxime

(Acetylcholinesterase reactivator)
 Irreversible cholinesterate inhibitor.
LONG acting
Used in Glaucoma
 Direct/indirect acting cholinergic drugs
actions, adverse effects, toxicity features
of OP poisoning
In OP poisoning atropine used to reverse
only the muscarinic effects..
Pralidoxime used to reactivate the enzyme
 Miosis
Excessive salivation
Bradycardia
Bronchospasm
Abdominal cramps, vomiting, diarrhea,
urination
Sweating
 Group of diseases characterized by a
progressive form of optic nerve damage.

Associated with raised I.O.T.(more than

21mm Hg.)
Types of Glaucoma:
1. Open Angle Glaucoma Excessive production of
Aqueous Humour
2. Closed Angle Glaucoma (40-60mm.Hg.) Outflow
obstruction of Aqueous Humour
Two Therapy aimed at:
1. Reduce (Production, Synthesis or Secretion)
Dorzolamide, Acetazolamide, Timolol, Betoxolol and
Apraclonidine
2.Facilitate the drainage: Pilocarpine, Carbachol,
Ecothiopate ,Mannitol and Latanoprost
Courtesy : Katzung
 Mannitol
reduces IOP by reducing vitreous volume by
inhibiting the enzyme carbonic anhydrase
Reduces the secretion/synethesis
Timolol topical eye drops Non-selective
blockade
Betaxolol eye drops Selective 1 blockade
Reduces the synthesis
Acetazolamide (oral), Dorzolamide (topical ) :
reduces the synthesis of aqueous humour,
inhibits the enzyme carbonic anhydrase
2 receptor agonist (apraclonidine 1%, topical
drops).
1. Pilocarpine, Carbachol, Ecothiopate and

Physostigmine :Causes Ciliary muscle contraction,

increases Irido-corneal angle and open trabecular

meshwork.

2. Prostaglandins : Latanoprost : increase the outflow

through uveoscleral meshwork

 Excessive adrenergic receptor mediated
production and secretion of aqueous humor
from the ciliary body epithelium.
Best treated with betablockers
 Results from obstruction of canal of
Schlemm through which aqueous humor
was supposed to be filtrated out .
Caused by
1. Mydriatics : Anti-cholinergic drugs
2. Antidepressants : SSRI drugs

Treatment: Pilocarpine, Carbachol , ecothiopate

and physostigmine
 Natural alkaloids: Atropine, Hyoscine
(Scopolamine)
Semisynthetic derivatives: Homatropine,
Atropine methonitrate, Hyoscine butylbromide,
Ipratropium bromide
Synthetic compounds

Mydritics: Cyclopentolate, Tropicamide.

Antisecretory-Atispasmodics:Propanthalin,
Oxyphenonium,Dicyclomin, Oxybutynin,
Procyclidine, Biperiden.
 CNS: Stimulant action. Vegal, repiratory,
vasomotor.