Pharmacology of

Autonomic Nervous
System
 Chemical Transmitors

Acetylcholine Noradrenaline

Cholinergic fibers Adrenergic fibers

Cholinergic Receptors Adrenergic Receptors

Nicotinic Muscurinic
(N)
Alpha/beta
(M)
Pharmacology of
parasympathetic
system
Types of cholinesterase
1. True-cholinesterase
2. Pseudo-cholinesterase
 Cholinergic Receptors
(Cholinoceptors)
Classified into 2 principal types

1- Nicotinic
receptors
2- Muscarinic
receptors
 Cholinergic Receptors
Nicotinic receptors
(Na+ channels)

NN NM

Supra-renal medulla
NN
AutonomicNganglions
N NMJ in skeletal
(symp & parasymp) muscles

NM
 Cholinergic Receptors
Muscarinic receptors
(G-proteins-coupled)

M1 M2 M3 M4 M5

Smooth muscles
Vascular
CNS Heart CNS CNS
endothelium
Exocrine glands
Pharmacological modification of
parasympathetic system
Medications

Mimic Block

Agonist Antagonist
 Parasympathomimetics

Direct agonists Indirect agonists

Drugs stimulating muscarinic Drugs stimulating muscarinic
receptors directly receptors indirectly by inhibition of
the cholinesterase enzyme, thus
preventing hydrolysis of acetylcholine
Acetylcholine leading to its accumulation

Anti-cholinesterases
Pilocarpine

1. Reversible anticholinesterases:
• Neostigmine
• Neostigmine substitutes
2. Irreversible anticholinesterases:
• Organophosphorus compounds
 DIRECT CHOLINERGIC AGONISTS

Pharmacological actions

Stimulation of Stimulation of
muscarinic nicotinic
receptors receptors

The muscarinic actions are blocked by atropine.

Pilocarpine exhibits muscarinic activity and doesn’t affect nicotinic

receptors.
 DIRECT CHOLINERGIC AGONISTS
Stimulation of muscarinic receptors
Heart

Vagal stimulation
 (-) chronotropic (↓ HR)
 (-) inotropic (Atria) (↓ atrial contraction)
 (-) dromotropic (↓ conduction)
 DIRECT CHOLINERGIC AGONISTS
Stimulation of muscarinic receptors
Gastrointestinal tract (GIT)

Stimulation Relaxation
Tone Sphincters
Motility
Secretion
Exocrine glandes
Stimulation of lachrymal, salivary, gastric, bronchial,
& sweat secretions
 DIRECT CHOLINERGIC AGONISTS
Stimulation of muscarinic receptors

Urinary tract (UT)

Stimulation Relaxation

Evacuation of
bladder
 DIRECT CHOLINERGIC AGONISTS
Stimulation of muscarinic receptors

Bronchi
• Broncho-constriction
• Augmentation of bronchial secretions
 DIRECT CHOLINERGIC AGONISTS
Stimulation of muscarinic receptors
Eyes
 Myosis due to stimulation of constrictor pupillae
muscle
 Accommodation for near vision due to stimulation
of ciliary muscle
Pupillary diameters
Normal

Miosis Mydriasis
DIRECT CHOLINERGIC AGONISTS
Stimulation of nicotinic receptors

Skeletal muscle (NM)

Enabling skeletal muscle actions.

 Anti-cholinesterases

Reversible Irreversible
Competitive inhibition Loose bond
Loose & temporary 6-8 hours
Firm
bond Permanent inactivation

Organo-phosphorous
• Neostigmine esters
• Edrophonium
• Pyridostigmine
• Donepezil

Effect on Eye, Respiratory Tract,

Gastrointestinal Tract, and Urinary Tract as
direct agonists
 Anti-cholinesterases
Effect on Neuromuscular Junction
Therapeutic concentrations moderately prolong and intensify
the actions of the physiologically released acetylcholine. This
increases the strength of contraction, especially in muscles
weakened by the competitive neuromuscular blocking agents or
by Myasthenia Gravis.

Neostigmine has an additional direct nicotinic agonist effect at

the NMJ. This may contribute to its effectiveness in therapy for
myasthenia Gravis.
 Reversible Anti-cholinesterases

Don’t pass BBB Pass BBB

Anti-cholinesterase action Anti-cholinesterase action
Direct stimulant action on NMJ Mainly central

1. Paralytic ileus Treatment of Alzheimer’s

2. Urinary retention disease (mild to moderate
3. Antidote to curare cases)
(Anesthetic adjuvant)
4. Treatment of MG
Therapeutic Uses of Cholinergic Agonists

GIT & UT
Paralytic ileus Urinary retention
 Therapeutic Uses of Cholinergic Agonists

GIT

Severe dry mouth

Pilocarpine
Therapeutic Uses of Cholinergic Agonists

Neuromuscular
Edrophonium
Diagnosis
2 mg IV, If muscle fatigue is ameliorated, then it
is MG

Pyridostigmine
Treatment
Alone or with immunosuppressant drugs
(corticosteroids and azathioprine)
 Therapeutic Uses of Cholinergic Agonists

Neuromuscular

Anesthetic adjuvant =
Antidote to NMBs
Neostigmine
 Therapeutic Uses of Cholinergic Agonists

CNS

Alzheimer’s Ac
disease h

Mild/moderate
cases
It can delay but does not stop the
Donepezil
progression of the disease.
Therapeutic Uses of Cholinergic Agonists
Pilocarpine
Pharmacological actions:
Local application on eyes:
• Myosis
• Ciliary muscle spasme
accommodation for near vision
Decrease of the intraoccular pressure by
Closed angle
augmentation glaucoma
of aqueous humour(Acute)
drainage
 Therapeutic Uses of antimuscarinics
Organophosphorus poisoning
treatment
1. Atropine 2 mg IV, IM/ 5-10 min
2. Cholinesterase reactivators: Oximes:
pralidoxime (PAM), diacetyl monoxime (DAM) (IV
infusion) = Early within 6-8 hrs ?????
3. Anticonvulsants: Diazepam
4. Care of respiration
5. Gastric lavage
6. Contaminated skin should be washed with
NaHCO3
 Pharmacology of
parasympatholytics
CHOLINERGIC ANTAGONISTS

Muscarinic receptors

Antimuscarinic
drugs
 Antimuscarinics/anticholinergics

Naturel belladonna alkaloids Synthetic substitutes of atropine

Atropine Selective

Hyoscine
(scopolamine)

Non-selective

Blockage of all muscarinic receptors

M1, M2 and M3

Many antihistaminics, antidepressants &

antipsychotics have atropine-like actions
 Atropine & scopolamine
Mechanism of action

Block of all muscarinic receptors M1,

M2 and M3 by competing with Ach for
binding to these receptors

Centrally & peripherally

 Atropine
Parasympathetic depressant action

CVS
Vagolytic effect
 (+) chronotropic ( HR)

 (+) dromotropic ( conduction)

No effect on blood pressure

 Atropine
Parasympathetic depressant action

Exocrine
GITGlandes

Reduction of lachrymal, salivary, gastric,

bronchial, & sweat secretions
 Gastrointestinal tract (GIT)

Relaxation
Tone Stimulation
Motility
Sphincters
Secretion
 Atropine
Parasympathetic depressant action

Urinary tract
Relaxation Stimulation

Detrusor Internal urethral

muscle sphincter

Retention of urine
 Bronchi
Bronchodilatation and reduction of
bronchial secretion.
Atropine flush Atropine fever
 Atropine
Parasympathetic depressant action

Eyes [topical (7-10 days)/ systemic (4 hrs)]

A
1. Passive Mydriasis
2. Light reflex abscent
3. Cycloplegia
(Lost Accommodation for near vision)
B
4. Increase IO Pressure
5. Inhibition of lachrymation
 Atropine
Action on CNS
Therapeutic doses
Depressant action =
Sedation (minimal)

- Tremor & rigidity (Parkinson's disease)

- Central Excitation of OPC poisoning
Toxic doses
Excitation, hallucinations &
coma
 Hyoscine (Scopolamine)
Therapeutic doses
Depressant action =
Sedation
• More marked sedation
• Amnesia
• Antiemetic action

Toxic doses
Excitation, hallucinations
& coma
Therapeutic Uses of antimuscarinics
1. CNS disorders

Parkinson’s disease

Benztropine

Central
 Therapeutic Uses of antimuscarinics
1. CNS disorders

Motion sickness prophylaxis

Scopolamine

Half an hour before the trip. The patch formulation

provides protection for up to 3 days
 Therapeutic Uses of antimuscarinics
2. Respiratory disorders
Pre-anesthetic medication

Atropine

Decrease airway secretions

Protect the heart from excessive vagal tone caused by

some anesthetics
Therapeutic Uses of antimuscarinics
2. Respiratory disorders

Bronchial asthma

Ipratropium
Tiotropium
Therapeutic Uses of antimuscarinics
3. CVS disorders
Bradycardia
Vasovagal attack

Heart block

Atropine
Therapeutic Uses of antimuscarinics
4. GI disorders
Intestinal, renal &
biliary colics

Atropine
Hyoscine butyl bromide
(Buscopan)
Therapeutic Uses of antimuscarinics
5. Ophthalmologic Disorders
Mydriasis with cycloplegia
Therapeutic Uses of antimuscarinics
6. Urinary disorders
Urinary urgency/bladder spasm
Urinary incontinence

Oxybutynin
Therapeutic Uses of antimuscarinics
7. Antidote for cholinergic Poisoning
Organophosphorus
poisoning

Atropine
+ Insecticides
Oximes
Chemical war gases
 Organophosphorus poisoning

Muscarinic excess signs

CNS involvement

confusion
 Therapeutic Uses of antimuscarinics
Organophosphorus poisoning
treatment
1. Atropine 2 mg IV, IM/ 5-10 min
2. Cholinesterase reactivators: Oximes:
pralidoxime (PAM), diacetyl monoxime (DAM) (IV
infusion) = Early within 6-8 hrs ?????
3. Anticonvulsants: Diazepam
4. Care of respiration
5. Gastric lavage
6. Contaminated skin should be washed with
NaHCO3
 Antimuscarinics
Adverse effects
1. Mydriasis & cycloplegia with blurred
vision.’’Acute glaucoma may be precipitated’’
2. Dry mouth
3. Hot & flushed skin.’’Atropine fever’’
4. Tachycardia
5. In toxic doses, scopolamine, and to a lesser
extent atropine, can cause agitation,
hallucinations, and coma.
 Contraindications

1. Glaucoma
 Antimuscarinics

2. In children