Autonomic Pharmacology

 Nervous system
CNS Peripheral nervous system
Brain and spinal cord autonomic and somatic
ANS

 Independent not under direct conscious

control
 Visceral control
 Sympathetic and Parasympathetic system
 Sympathetic --- Thoracolumbar outflow
 Parasympathetic ---- Craniosacral outflow
CHOLINOCEPTOR AGONISTS
( Cholinomimetics )
Parasympathomimetics

Dr Waqar Ahmed Siddiqui

Associate professor
CMH LMC IOD
HOD Pharmacology
Learning Outcome

 At the end of session students should be

able to
 Describe the mechanism of acetylcholine
release and actions
 Explain Location of Parasympathetic
receptors and functions
 Classify Parasympathomimetic drugs
Synthesis of acetylcholine

 From Acetyl-CoA and choline

 Acetyl-CoA ---synthesized in Mitochondria
 Choline is transported from extracellular fluid
by choline transporter CHT
 Choline acetytransferase (ChAT)
 Ach is transported into vesicle by vesicle
associated transporter (VAT) driven by proton
efflux
Release

 Vesicles are concentrated on the inner

surface of nerve terminal ---SNNARE
proteins
 Physiologic release of transmitter is
dependent on extracellular Ca
 Action potential reaches the terminal and
influx of Ca occur
 Ca interact with VAMP stnaptotagmin –cause
fusion of vesicle with terminal membrane
Degradation

 After release ---degraded by

acetylcholinesterase AChE
 Splits acetylcholine into choline and acetate
 Half life of acetylcholine is fraction of second
 ACHE is found in RBC
 Butyrylcholinesterase or
pseudocholinesterase –blood, plasma, liver,
glia
Cholinergic receptor location
Muscarinic M1 CNS neurons, IP3 Formation
parietal cells
Muscarinic M2 Myocardium Smooth Opening of potassium
Muscle , some channels
presynaptic sites
Muscarinic M3 Exocrine glands, Like M1 receptor
Vessels, CNS neurons
Muscarinic M4 CNS neurons Like M2 receptor
Muscarinic M5 Vascular endothelium Like M1 receptor
(cerebral vessels)
Nicotinic Nn Postganglionic neurons Opening of Na+, K +
presynaptic cholinergic channels
Nicotinic Nm Skeletal neuro Opening of Na+, K +
muscular junction channels
M1

M2

M3

M4

M5

Nm

Nn
 MUSCARINIC RECEPTOR SITES

ON PLASMA MEMBRANE OF CELLS

 In the CNS
 Of effector organs innervated by
parasympathetic nerves
 Tissue with no cholinergic innervation

(endothelium)
 Tissues innervated by postganglionic
sympathetic cholinergic nerves
NICOTINIC RECEPTOR SITES
 ON PLASMA MEMBRANES

 Of
postganglionic cells in all autonomic
ganglia

 Ofmuscles innervated by somatic motor

fibers

 Some central nervous system neurons

 CHOLINOCEPTOR STIMULANTS CLASSIFIED

 1.By Spectrum of action depending on type of

receptor activated
 MUSCARINIC
 NICOTINIC

 By Mechanism of action
 DIRECTLY ACTING
 INDIRECTLY ACTING
CLASSIFICATION

I: Directly Acting Agonists:

( A ) : Choline-Esters
1. Acetylcholine.
2. Methacholine.
3. Carbachol.
4. Bethanichol.
( B ) : Cholinomimetic Alkaloids:
a). Quaternary Compounds.
1. Muscarine.

b). Tertiary Compounds.

1. Pilocarpine. 2. Nicotine.
3. Lobeline.
c).
Used in Alzheimer’s Disease:
1. Donepezil.
2. Rivastigmine.
3. Galantamine.
4. Tacrine.
II.Indirectly Acting Drugs
( Anticholinesterases ).

( A ). Reversible Anticholinesterases:
a). Alcohol:
1. Edrophonium.
b). Carbamates:
1. Neostigmine. 2. Physostigmine.
3. Pyridostigmine. 4. Distigmine.
5. Carbaryl. 6. Ambenonium
7. Demecarium.
( B ). Irreversible Anticholinesterases:
1. Echothiophate.
2. Parathion.
3. Malathion.
4. Diflurophosphate.
5. Soman
6. Sarin
7. Tabun
III. Nicotinic Agonists.
( A ).Nn :
1. Nicotine
2. Lobeline.

( B ).Nm:
1. Succinylcholine ( initially ).
RECEPTOR MECHANISMS

Muscarinic Receptors:
Serpentine-Seven Trans membrane
Segments,

G - Protein-linked
when activated:
M1. M3 .M 5
Interact with G-protein ( Gq ) which in turn
activates Phospholipase C

This yields DAG and IP3

which causes increase intracellular Ca 2+ .
This Ca2+ will
increase secretion or contraction of SM

M1 In CNS are stimulatory ,block K+ channels

M2. interact with Gi which inhibits
Adenylyl Cyclase,
↓ cAMP synthesis
& increases K+ conductance
leading to decrease in heart rate &
force of contraction.

( M4 ) inhibits synthesis of cAMP

Nicotinic Receptors:
Nm.
A Pentamer of Four types of Glycoprotein
Subunits ( two alpha, one beta, gamma & delta )
& acts as a ligand-gated channel.

Two molecules of A.Ch. activate its two

α-subunits & open a central trans membrane ion
channel through which Na+ enters into the cell
leading to NMJ depolarization.
Nn.
Only α & β subunits
( each has four segments ).

When activated, channel opens to allow

Na+ & K+ and there is depolarization of
nerve cell.
 Pharmacokinetics

Choline-esters:
Positively charged & Hydrophilic.
Alkaloids:
Tertiary compounds are lipid soluble.

Carbamates:
only Neostigmine is +vly charged & less lipid sol.

Organophosphorus Comp.: Highly lipid sol.

 Choline esters properties:
Choline Susceptibility to Muscarinic Nicotinic
esters Cholinesterase Receptors Receptors

A.Ch. ++++ +++ +++

Methacholine + ++++ None

Carbachol -/+ ++ +++

Bethanichol -/+ ++ None

↓ ACTIVITY AT
NICOTINIC SITES
Organ System Effects
( Pharmacological Effects )
 ORGAN RESPONSE
EYE

HEART

BLOOD VESSELS
LUNG

GASTROINTESTINAL TRACT

URINARY BLADDER

GLANDS
Vagus
Nerve
EYE. (M3)
Circular
&
Radial
Muscles
of Iris
i). Contraction of Circular, Sphincter, Constrictor
Muscles of iris → MIOSIS & iris is
pulled away from the angle of the
anterior chamber.

ii). Contraction of Ciliary Muscles

opens the trabecular meshwork at its
base

Both effects facilitate out flow of aqueous

humor into Canal of Schlemm →
decreased intra-ocular pressure.
ACCOMODATION

Ciliary
Body

Suspensory
Ligaments
EFFECT ON ACCOMODATION

 Ciliary muscle contracts

 Suspensary ligament is relaxed

 Lens becomes more globular

 EYE IS FIXED FOR NEAR VISION

Accommodation
EYE is fixed for near vision.
 Heart ( M2 )

i). Direct Effects: (M2)

Intravenous doses briefly

decrease: the Pacemaker Rate,(HR)
↓ Atrial Contraction,
↓ Slight Ventricular Contraction
↓ Cardiac Output,
↓ Atrial Refractory Period,
↓ Conduction Velocity of AV-node
but increase
Refractory Period of AV-node.
Achieved by M2 → ↑ K+ EFLUX
 IN atrial muscle cells
 Cells of sinoatrial node
 Cells of the Atrioventricular node
 ↓ in slow inward Ca2+ current in heart
cells

 DECREASE
THE PACE MAKER RATE
&
CONTRACTILITY OF ATRIAL CELLS
DIRECT EFFECT OF Ach ON BV
Dilation of Arteries & Veins
via EDRF( NITRIC OXIDE ) →↑ cGMP levels
→ decreased peripheral vascular resistance

↓ In sinoatrial rate & AV conductioin also reduce the

blood pressure

Opposed by reflex sympathetic discharge

Resultant sympathetic –parasympathetic interaction

is complex because of muscarinic modulation of
sympathetic influences
RESPIRATORY SYSTEM. ( M3 )

M3 recepors activated

Contraction of bronchial smooth muscles

Increased tracheobronchial mucosal

glandular secretions —
Narrowing of the air passages;
Can cause symptoms in asthmatics
 GASTROINTESTINAL TRACT.( M3 )

Increased secretory & motor activity of gut

Contraction of (due to ↑ Ca2+ influx in SM)
longitudinal & circular muscles →
Increased
peristalsis , but Sphincters are relaxed.
M3 receptors cause direct activation of SM
M2 ↓ the cAMP formation
&
↓ relaxation caused by sympathomimetics
 Exocrine Glands. ( M3 )
increased
salivary, gastric secretions ( via M1 )
pancreatic & intestinal secretions (less)
lachrimal,
Nasopharyngeal,
bronchial,
( also thermoregulatory sweat )
 GENITOURINARY TRACT. ( M3 )

M2 & M3 receptors
Contraction of Detrusor muscles &
relaxation of trigone & sphincter →voiding.

Human uterine smooth muscles insensitive

But
pregnant uterus contracts
Penis erection
 CENTRAL NERVOUS SYSTEM.
( M1 M2 Nn )

In Brain: Muscarinic dominant,

M1→ epileptic seizures( block K+ channels)

M2→ tremor, hypothermia, antinociception (↑ K + eflux)

M3 in hypothalmus → appetite & ↑ body fat mass

So both Excitatory & Inhibitory Effects

In Cortex & Brain stem Nn (Nicotine ,Lobeline)

Cause Mild alertness

tremors ,
emesis,
respiratory center stimulation &
convulsions terminating into fatal coma.
NICOTINE used as an insecticide
 PERIPHERAL NERVOUS SYSTEM.
( Nn )

Nn on Autonomic Ganglia ( Nicotine)

both sympathetic & parasympathetic activated.

On CVS sympathetic effects predominate

 Hypertension, alternating tachycardia & bradycardia.

 OnGIT & Urinary tract parasympathetic predominate

Nausea, vomiting, diarrhea and voiding of urine.

 Prolonged exposure → depolarization blockade of

autonomic ganglia
Nm at NMJ:
Similar but not identical to Nn of autonomic ganglia

 Activated by Ach & Nicotine

.
 Both Produce end plate depolarization

 Fasciculations or strong contraction of entire muscles.

Nicotine not rapidly hydrolyzed → depolarization block

→persistent depolarization
→ flaccid paralysis.
 PILOCARPINE:
( Pilocarpus jaborandi ):
M-receptors only.
Tertiary amine — CNS-stimulates ( M1 )
with larger doses inhibits ( M2 ).
Actions:
EYE ( mainly ):
I.O. pressure decreases rapidly.
Actions last for 4-6 hours.;
.
Uses: Topically useful
a). Drug of choice in emergency lowering of intraocular
pressure in narrow & wide- angle glaucoma.
b).Synachiae ? c). Xerostomia.
D) Sweat collection in Sjögren's syndrome

Adverse Effects:
Intense salivation, sweating, Nausea, vomiting,
abdominal pain & diarrhea;
CNS disturbances;
heart block or pulmonary edema in severe cases.
 BETHANICHOL

Mainly on Muscarinic receptors.

It is not hydrolysed by AChE
Can be given oral or IV
DOA 30 mins -2 hrs

Actions:
principal effect on GIT, Urinary Bladder.
Uses:
No Topical use
Paralytic Ileus, Atonic Bladder ( Postpartum /Postoperative )
Side Effects:
exaggerated muscarinic effects.
 Contraindications:urinary retention d/t stone,
obstruction, BPH, GIT obstruction,
Parkinson’s D
 CARBACHOL
Both on M & N receptors.
Highly Potent; Long-acting

Actions:
GIT / CVS profound M & Nn
stimulation at autonomic ganglia.
Miosis as local effects.

Uses: Topically for Glaucoma,

Systemically urinary retention, Paralytic Ileus,
Raynauds Disease.

Side Effects on GIT, Eye, Urinary Tract.

 Methacholine

 Can be degraded by AChE

 No therapeutic effect
 Used to detect bronchial hyperactivity ( act
as an allergen)
 Can be given via inhalational route
 Nicotine

Direct acting nicotinic stimulant

 Alkaloid
 Lipid soluble
 Can be used as nicotine gum and
transdermal patches
 1-6 hrs
 Smoking cessation--- act on nicotinic rec
 Not degraded by AChE, fatal dose 40mg.
 Acute toxicity:
 Convulsions  comma  death
 Respiratory paralysis
 Hypertension  cardiac arrhythmias

Treatment:-
Symptomatic, atropine , diazepam, ventilatory
support,
Quick metabolism 4hr,
Vereniciline

 Act on nicotinic rec (partial agonist at α4β2)

 Lipid soluble
 Smoking cessation
 DOA—12 -24 hrs
 Not degraded by AChE
 S/E: nausea, insomnia, psychiatric illness,
suicidal ideation.
ANTICHOLINESTRASES

Produce inhibition of the enzyme by attaching

with the enzyme at Two Sites:
i). at the esteratic site:

a): by hydrogen & electrostatic bond

( as in Edrophonium ) — lasts 2 -10 min.;

b): by covalent-carbamoylated-enzyme- bond

( as in Neostigmine / Physostigmine )
lasts for ½ - 6 hours.
c): by covalent-phosphorous-enzyme-
bond
( as in Organophosphorous
comp.)

lasts for hundreds of hours.

Soman sarin. (nerve gases).

ii). at anionic site:

inactive site;
only A.Ch. binds electrostatically .
A.Ch. Metabolism by Cholinesterase
Entire Process occurs in 150 micro seconds
CHOLINESTRASE
Estratic site Anionic site
“ ACTIVE SITE ”
O

+ (CH3)3
CH3 --- C—O—CH2---CH2—N
( Acetyl part ) ( Nitrogen part )
G

( covalent bond ) ( ionic bond )

H2O ( REACTION )
H O

G ( free enzyme ) CH3 — C — OH ( acetic acid )

Phosphorylated-enzyme complex,

Initially phosphorous enzyme bond can be splitted by

OXIMES, i.e. PRALIDOXIME
the acetylcholinesterase regenerators
but later on the binding undergoes
“AGING ” (breaking of oxygen –phosphorous bond
of inhibitor & strengthening of enzyme
phosphorous bonds)

a process leading to further strengthening of the

inhibition of the enzyme by the organophosphate.
 EDROPHONIUM

Quaternary alcohol
short duration of action ( 10 – 20 min. ).

Uses:
i). Diagnosis of Myasthenia Gravis, 3 mg i.v. →
rapid increase in the SK muscles strength.

ii).Differentiate between Myasthenic crisis & Cholinergic

crisis

Adverse Effects: Insomnia, Seizures.

 PHYSOSTIGMINE

Non-polar; Tertiary
CNS( stimulation );duration of action: 2-4 hours.
Uses:
i). Atony of Intestines & Urinary Bladder.
ii). Glaucoma( locally ).
iii). Anticholinergics Poisoning,
iv). Alzheimer's Disease
V. Reversal of atropine poisoning.

Adverse Effects:
CNS-stimulation --- convulsions; bradycardia;
NMJ --- Paralysis..
NEOSTGMINE

Polar, Quaternary, mainly peripheral effects.

Uses: Tubocurarine paralysis reversal.

Atonic Bladder, Paralytic ileus,

& Myasthenia Gravis,

( Atropine is also given to block
muscarinic effects of Neostigmine ).

PYRIDOSTIGMINE:
used in the management of Myasthenia Gravis.
 ISOFLUROPHATE

Generalized cholinergic stimulation,

CNS stimulation --- convulsions;
persistent depolarization of NMJ ---
paralysis of skeletal muscles.
Uses: topically;
chronic open-angle glaucoma.

ECHOTHIOPHATE:
used for Glaucoma, effects last for 100 hr.
 Toxicity of
Organ phosphorous compounds
Chronic Toxicity:
Fluorine containing compounds can cause
“delayed” neurotoxicity --- severe
polyneuritis

After several days of exposure of:

a single large dose or cumulative
amounts.
a). Mild sensory disturbances, ataxia,
weakness
& fatigability of legs, tenderness on
b). In severe cases the weakness may
progress to complete flaccid paralysis.

After many weeks or months

this paralysis is changed to “spastic
paralysis”
with exaggeration of reflexes.
Muscles become wasted.

Recovery occurs after 2 or more years.

Acute Toxicity:
occupational - exposure
by dermal & pulmonary routes.

In non-occupational poisoning
oral is most common.
a). Local Effects:

i). Ocular Effects:

Marked miosis, ocular pain, brow-ache with
watery nasal discharge.

ii). Respiratory Effects:

Tightness & wheezing in chest due to
broncho-constriction & increased bronchial
secretions.
iii). G.I.T: ( after ingestion ).
Anorexia, nausea, vomiting,
abdominal -cramps & diarrhea.

iv). Skin: ( local absorption ).

Local sweating,
muscular fasciculation.
b). Systemic Effects:
( after systemic absorption ).

i). Muscarinic Effects:

extreme salivation, lacrimation,
sweating,
bradycardia & hypotension.
Involuntary defecation & urination.
ii). Nicotinic Effects:
Skeletal Muscles:
fatigability, general weakness,
involuntary twitching,
scattered fasciculations and even
paralysis;

“respiratory muscle paralysis is

serious ”
CNS:
depression of vasomotor & other
centers
in the medulla ----severe
hypotension.

confusion, ataxia, slurred speech,

cheyne-stokes breathing,

generalized convulsions, coma &

central respiratory paralysis.
TIME OF DEATH:
( after a single acute exposure ).
3 min. – 24 hours.
depending upon
Dose, Route, Agent
& other factors.
CAUSE OF DEATH:

Respiratory Failure:
due to:
 CNS- depression,
 Paralysis of diaphragm &
other intercostal muscles,
 Brochospasm & increased bronchial
secretions
 Severe fall in blood pressure.
TREATMENT

Initial:
Inj. Atropine 2-4 mg i.m. or i.v.
repeated after every 3-10 min. until
muscarinic symptoms disappear.

If they reappear,
repeat the dose ( maximum 50 mg ).
Tab Atropine 1-2 mg is given when
required if muscarinic symptoms persist.

(when dilated pupils start constricting again)

Then:
Inj. Pralidoxime 1G i.v. over 2 min.;
repeat the dose if muscle weakness
persist / recurs after 20 min.

Pralidoxime Chloride: reacts directly with the

organophosphorous compound –enzyme
complex & decomposes it.
phosphorylated - oxime is released &
the enzyme is regenerated.
It only reverses the symptoms of skeletal
muscles
it does not cross BBB
Other Measures:
General supportive measures;
Artificial Respiration + O2.
Inj. Diazepam / Thiopentone
Also treat the shock.

Contraindications: poisoning with:

neostigmine /physostigmine /
carbachol.
 Clinical Uses
A). EYE:

Galucoma:
i). Acute angle-closure glaucoma — initially both
Pilocarpine & Physostigmine, then Iridectomy
ii). Chronic open-angle glaucoma — Drugs +
laser techniques. Surgery not helpful.
iii). Secondary glaucoma, due to trauma, surgery
or inflammation — drugs.
Esotropia:
( strabismus / squint due to hypermetropia )
directly - acting agonists.

Posterior or Anterior Synechia:?

B). GASTROINTESTINAL TRACT:
( Depressed smooth muscles activity without
obstruction ).

i). Post-operative Paralytic ileus.

ii). Congenital Mega colon.
iii). Gastric atony / stasis.
Initially pass “Rectal Tube”
& then give Cholinomimetics.
iv). Reflux esophagitis — Bethanichol,
Neostigmine.
C). SALIVARY SECRETIONS:
Sjogren syndrome ( xerostomia with
connective tissue disorder like SLE, Rh.
Arthritis etc.) Pilocarpine, Cevimeline.

D). URINARY TRACT:

i). Urinary Retention
Post operative / postpartum if No Obstruction
ii). Neurogenic Bladder
due to injury / disease of spinal cord ---
Bethanichol, Neostigmine
E). NEUROMUSCULAR JUNCTION:

Myasthenia Gravis
weakness after use of smaller groups of muscles
Indirectly-acting drugs( directly acting less effective)
Pyridostigmine, Ambenonium, Neostigmine
- muscarinic symptoms -due to excessive use of
anticholinestrases TOLERANCE DEVELOPS RAPIDLY

Edrophonium — for Diagnosis & to differentiate

Myasthenic crisis from Cholinergic Crisis
For Reversal of Neuromuscular Blockade

Most common use

of
neostigmine
To reverse the flaccid paralysis produced by
neuromuscular blocking drugs like Tubocurarine
& Pancuronium after the operation is over
F). HEART:

Supraventricular Tachyarrhythmia's
Edrophonium

BUT

Adenosine / Ca2+ Blockers preferred.

G). ANTIMUSCARINIC DRUGS
INTOXICATION:

( Atropine, TCAs, Phenothiazines, etc. )

Accidental or Overdoses —
Give Physostigmine ( For Raised Body Temp
& Supraventricular Tachycardia )
BUT
Central Toxic effects of Physostigmine itself
are also dangerous.
 H). CENTERAL NERVOUS SYSTEM

 ALZHEIMER,S DISEASE
 Tacrine (hepatic toxicity)

 NEWER, MORE SELECTIVE,CHOLINESTERASE
INHIBITORS.
 Donepezil long t1/2 & not hepatotoxic
 Galantamine
 Rivastigmine
 Varenicline : use in smoking cessation treatment
 Toxicity of Cholinomimetics

A). Muscarinic-agonists:
( excessive activity ).
 Nausea, vomiting, diarrhea, increased
salivation & acidity;
 Sweating, cutaneous vasodilatation,
bronchial constriction.
 Bradycardia & increased urination may
also be seen.
.
B). Nicotinic agonists:
CNS Stimulation:
convulsions, coma, respiratory arrest.

Skeletal Muscles Blockade

constant stimulation .
Muscles weakness., respiratory
paralysis,
Hypertension, cardiac arrhythmias.
Contraindications:
 Bronchial asthma,
 Peptic ulcer,
 Cardiac Arrhythmias ---
hyperthyroidism.
 Mechanical Obstruction of GIT &
Urinary Bladder.