Chapter 2

Drugs acting on autonomic nervous system

By Melkamu.A

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 Overview of Nervous System

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Motor nerves
 Without motor nerves:

 No breathing.
 Digestion.
 Excretion.
 Muscle movement.
 Control of body temperature.
 Heart problems.

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Motor nerves
1. Somatic motor NS:
 carry messages from CNS to the skeletal muscles.
 Acetylcholine is the neurotransmitter.

 Lead to muscle contraction.

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 Cont’d…
2. Autonomic motor NS:
 Carry messages from the CNS to smooth muscle,
cardiac muscle and adrenal medulla.
 Two subsystems:
I. 1. Parasympathetic nerves:
 From CNS to smooth muscles.
 Acetylcholine is the N.T.
II. 2. Sympathetic nerves:
 To the cardiac muscles and most of internal organs.
 Using Noradrenalin and Acetylcholine as N.T

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 Cont’d…
Autonomic nervous system (ANS)
 Acts on smooth muscles & glands
 Controls and regulates the heart, respiratory system, GI tract, bladder, eyes and
salivary glands, etc .

 ANS has two sets of neurons

1. Afferent (sensory) neurons : sends impulses to the CNS for interpretation
2. Efferent neurons: receive impulses (info.) from the brain and transmits from the spinal cord to
the effector organ cells
ANS has also two branches that produce opposite effects:- sympathetic and parasympathetic
nervous system

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 Adrenaline action

– increase heart rate.

– Relax GIT and UT muscles.
– Decrease salivation.
– Vasoconstriction of peripheral blood vessels.

Fight or Flight

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 Cont’d…
3. Enteric NS:
– Located in the wall of intestine.
– Use serotonin, neuropeptide, Acetylcholine and Dopamine are among
many other neurotransmitters take part in this system

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 Cont’d…

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 Cont’d…

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 Cont’d…

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 SAR for acetylcholine

Quaternary nitrogen is essential

O O

CMe3 NMe2
H3C O H3C O

Bad for activity

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 Cont’d…

• Distance from quaternary nitrogen to ester is important

• Ethylene bridge must be retained

O O

H 3C O H 3C O
NMe3 NMe3

Bad for activity

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 Cont’d…

Ester is important

NMe3 NMe3
H 3C O H 3C

Bad for activity

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 Cont’d…

Minimum of two methyl groups on quaternary nitrogen

O Et
O Et
N Me
N Et H 3C O
H 3C O Me
Et

Lower activity Active

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 Cont’d…

Methyl group of acetoxy group cannot be extended

H 3C
NMe3
O

Much lower activity

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 Cont’d…

Conclusions:
• Tight fit between Ach and binding site
• Methyl groups fit into small hydrophobic pockets
• Ester interacting by H-bonding
• Quaternary nitrogen interacting by ionic bonding

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 Binding site (muscarinic)

hydrophobic
pocket Trp-307
Asp311
CH3 CH3
CO2

N CH3
hydrophobic
O O
pockets
CH3
Trp-616 Trp-613
H
H
O N hydrophobic
pocket

Asn-617

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 Cont’d…

vdw Trp-307
Asp311
CH3 CH3
CO2
Ionic bond
N CH3 vdw
O O
H-bonds CH3 vdw
Trp-616 Trp-613
H
H
O N

Asn-617

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Cholinergic Agents
 Direct acting - act on the receptors to activate a tissue response
 Indirect acting - inhibit the action of the enzyme
Acetylcholinesterase:

 Major uses = Stimulate bladder & GI tone, constrict pupils (miosis),

neuro-muscular transmission

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 Cont’d…

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Hydrolysis of Acetylcholine

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 Acetylcholine (Ach)

Acetyl Choline

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Cholinergic receptors
1. Muscarinic receptors:
 Found in smooth muscles and cardiac muscles.
 Related to muscarine.

2. Nicotinic receptors:
 Found in skeletal muscles.
 Related to nicotine.

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Subtypes of M1 M2 M3 M4 M5
M- receptor Neural Cardiac Glandular,
smooth muscles
Main CNS, Gastric & Heart , GIT, Gastric & CNS CNS
location salivary glands CNS salivary glands,
GIT, Eye
Cellular Increase IP3, Decrease in Increase IP3, As M2 As M3
response DAG, a) cAMP Ca++
Depolarization, inhibition, conductance,
excitation, b) Ca++
increase conductance,
potassium
conductance Increase K+
conductance
Functional CNS excitation, Cardiac Gastric & saliva Enhanced Not
responses gastric secretion inhibition, secretion, GI locomotion
known
neural smooth muscle
inhibition contraction,
occular
accomodation
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 Cholinergic agonists

Acetylcholine as an agonist

Advantages
• Natural messenger
• Easily synthesised

Disadvantages
• Easily hydrolysed in stomach (acid catalysed hydrolysis)
• Easily hydrolysed in blood (esterases)
• No selectivity between receptor types
• No selectivity between different target organs

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 L-serine ethanolamine

choline Acetylcholine

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Biological hydrolysis of Ach

What makes acetylcholine exceptionally prone to hydrolysis

is the possibility of folding to form an intramolecular dipole
bond that will increase the positive charge of the ester carbonyl

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 Cholinergic agonists

Nicotine and muscarine as cholinergic agonists

Advantages

• More stable than Ach

• Selective for main cholinergic receptor types
• Selective for different organs

Disadvantages
• Activate receptors for other chemical messengers
• Side effects
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 Requirements for cholinergic agonists

• Stability to stomach acids and esterases

• Selectivity for cholinergic receptors
• Selectivity between muscarinic and nicotinic receptors
• Knowledge of binding site
• SAR for acetylcholine

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 Uses of cholinergic agonists

Nicotinic selective agonists

Treatment of myasthenia gravis
- lack of acetylcholine at skeletal muscle causing weakness

Muscarinic selective agonists

• Treatment of glaucoma
• Switching on GIT and urinary tract after surgery
• Treatment of certain heart defects. Decreases heart muscle activity and decreases
heart rate

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 Design of cholinergic agonists

Use of steric shields

Bulky groups
Rationale

• Shields protect ester from nucleophiles and enzymes

• Shield size is important

• Must be large enough to hinder hydrolysis

• Must be small enough to fit binding site

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 Acetylcholine analogues
 To overcome the instability of Ach:
 Steric shield: add large group to change the conformation of Ach:

 3X more stable than Ach.

 More selective on muscarinic over nicotinic receptors.
 S-enantiomer is more active than the R-enantiomer

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 Acetylcholine analogues

 Carbamate more stable ester toward hydrolysis.

 NH2 and CH3 are equal sizes. Both fit the hydrophobic pocket
 Long acting cholinergic agonist.
 Can be administered orally.
 Not selective…… just used topically in glaucoma.

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 Acetylcholine analogues

 More stable.
 More selective on muscarinic receptor.
 Used to stimulate GIT and urinary bladder after
surgery.

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 Muscarinic agonists

 Clinical uses:
 Treatment of glaucoma.
 Stimulate GIT and UT after surgery.
 In some heart defects.

 Pilocarpine:

 An alkaloids from Pilocarpus shrubs.

 Used in glaucoma.
 Topically only.

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 Cont’d…
 Oxotremorine and Arecoline:

 Act on the muscarinic receptors in brain.

 Used in Alzheimer’s disease.

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 Nicotinic agonists
•

Clinical use:
 Varenicline is indicated for smoking cessation, as an alternative to bupropion
and nicotine patches.
 Time of treatment, with a maintenance dose of 1 mg twice daily, is 12 weeks.

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 Acetylcholinesterase Inhibitors (AChEIs)

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 Cont’d…
 Reversible AChEIs are composed of:
 Substrates for AChE which acylate the enzyme followed by deacylation.
 Most of these agents are carbamates, not esters, and form carbamylated
AChE and are more resistant to hydrolysis.
 Substrates with greater binding affinity for AChE than ACh, but do not
acetylate the enzyme.
 Irreversible AChEIs (echothiophate iodide) are: commonly phosphate
esters, which phosphorylate AChE and only slowly dephosphorylate
and, as a result, have high potential toxicity.

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 Cont’d…
 Echothiophate iodide is indicated for treatment of open-angle
glaucoma
 Edrophonium chloride is recommended for diagnosis of myasthenia
gravis, but its short duration of action is a limiting factor for its use.
 On the other hand, neostigmine methylsulfate and pyridostigmine
bromide are used to control myasthenia gravis, with the former being
administered SC or IM while the latter is effective orally
 The four remaining drugs rivastigmine tartrate, donepezil and tacrine
hydrochloride, and galantamine hydrobromide have been approved for
treatment of mild to moderate dementia including Alzheimer’s type.

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 Cont’d…
 Organophosphate insecticides irreversible AChEIs with varying
degrees of human toxicity

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 Cholinergic Antagonists
 Of two types:
 Muscarinic antagonists:
 The prototype drug here is Atropine

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SAR of cholinergic antagonists

 The prototype of atropine or scopolamine is reflected in the structures of

tiotropium, trospium, ipratropium, glycopyrrolate, and oxybutynin.
 R1 is commonly a second aryl group or a carbocyclic group.
 The size of substituents on either ring is limited suggesting steric hindrance
during binding to the mAChR.
 Hydrophobic binding appears to be outside of the ACh binding region.
 R2 is a tertiary hydroxyl or a hydroxymethyl group, which appears to increase
the potency by participating in a hydrogen bond interaction at the receptor.
 A cationic amine appears to be involved in binding to the muscarinic receptor
with small alkyl substituents (e.g., methyl, ethyl, or isopropyl).
 The distance between the ring-substituted carbon and the N is not critical,
although two methylenes or equivalent distance is common.
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 Cont’d…
 Antagonist is a molecule that can bind to a receptor without
eliciting a response:
 It does not activate the receptor
 It will block the binding site
 Prevents the entrance of the natural ligand of that
receptor

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 Based on this definition
 The chemical structure of receptor antagonist does not
necessarily mimic the natural ligand structure;
Antagonist is generally bulkier, having extra
binding groups compared to the natural ligand

Different binding mode, means no formation of

the receptor active conformer…no response
 Muscarinic Antagonists

Clinical Effects

• Decrease of saliva and gastric secretions

• Relaxation of smooth muscle
• Decrease in motility of GIT and urinary tract
• Dilation of pupils
 Muscarinic Antagonists

Uses
• Shutting down digestion for surgery
• Ophthalmic examinations
• Relief of peptic ulcers
• Treatment of Parkinson’s Disease
• Anticholinesterase poisoning
• Motion sickness
• Treatment of overactive bladder.

The anticholinergics tiotropium, ipratropium, aclidinium, and umeclidinium are used for the
long-term maintenance treatment of bronchospasms (long-acting muscarinic antagonists)
(LAMAs) seen in chronic obstructive pulmonary disease (COPD) as well as chronic bronchitis.
Scopolamine, in the form of a transdermal patch, is used for the prevention of motion sickness
 Cholinergic Antagonists
 Nicotinic antagonists:
 The nicotine antagonists fall into two subclasses – the ganglionic blocking
agents and the NM blocking agents
 The prototype drug is tubocurarine

MeO

Me
N
HO Me
H CH2
O

CH2
H
Me
O
H N OH

OMe

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 Cont’d…

Clinical uses:
 NM blocking agents are used primarily as an adjunct to general anesthesia.
 They produce skeletal muscle relaxation that facilitates operative procedures such as abdominal
surgery and reduce the depth requirement for general anesthetics, thus decreasing the overall risk
of a surgical procedure and shortens the postanesthetic recovery time.

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 Adrenergic Agents

 The term adrenergic comes from the word “adrenaline,” a synonym for
epinephrine (Epi), the N-methylated analog of the neurotransmitter
norepinephrine (NE).
Endogenous Adrenergics:
 NE is the adrenergic neurotransmitter produced and released from presynaptic terminals
 Epi, a neurohormone, is produced in and secreted by the adrenal medulla.
 The precursor of both endogenous adrenergics is L-tyrosine.

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 Cont’d…
 Note that stimulation of sympathetic nervous system uses what is
known as “Fight or flight” response .
These effects include:
 Increased rate and force of heart contraction
 Increased blood pressure
 Increased blood flow to brain, heart and skeletal muscles
 Increase in blood glucose levels (through gluconeogenesis and glycogenolysis) for energy
 Pupil and bronchiole dilation
 Stimulants such as Epinephrine does this by its effects on alpha and
beta receptors that are found in many animals

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 Cont’d…

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 Biosynthesis of epinephrine and NE

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 Direct adrenergic drug action (Adrenergic agonists)

 Excellent for cardiac stimulant and vasoconstrictive effects in cardiac arrest, and also
added to local anesthetic to be used for treatment of Anaphylaxis, and glaucoma
 Serious side effects include cerebral hemorrhage and cardiac arrhythmias

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 Cont’d…
2. Isuprel (isoproterenol)
 It is a synthetic drug and a direct acting adrenergic receptor agonists or β-
receptor agonists (or it binds to both β-1 and β-2 receptors without selectivity)
 Stimulates heart, dilates blood vessels in skeletal muscle and causes
bronchodilation.
 No alpha stimulation or has low affinity to α-receptors.

 Used in heart blocks (when pacemaker not available) and as a bronchodilator

Administration: Oral, parenteral, local (inhaled);
Uses: It also is used for treatment of asthma, chronic obstructive pulmonary Disease
(COPD) and cardio stimulant

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 Cont’d…

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 Cont’d…
4. Dopamine (Intropin)
 Direct acting adrenergic receptor agonists: β1 receptors.

5. Clonidine
 Direct acting adrenergic receptor agonists: selective α2 receptors.

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 Cont’d…
 SAR of the phenylethylamine and arylimidazoline adrenergic agonist.

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 Indirect adrenergic drug action
 Occurs by stimulation of postsynaptic α-1, β1 and β2 receptors.
 Cause release of endogenous norepinephrine (NE) (naturally occurring
hormone) from the adrenergic nerve terminals into the synapse of
nerve endings which then stimulates the receptor.
 Act by blocking and reversing norepinephrine transporter (NET)
activity
 Some examples of indirect acting drugs are amphetamine,
pseudoephedrine, ephedrine, phenylpropanolamine, tyramine, Tricyclic
antidepressants (TCAs)

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 Cont’d…

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 Cont’d…

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 Cont’d…

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 Cont’d…

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 Cont’d…

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Antiadrenergic drugs/Sympatholytic agents/
Adrenergic blocking drugs
Block or decrease the effects of sympathetic nerve stimulation, endogenous
catecholamines and adrenergic drugs.

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 Cont’d…

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 Cont’d…
Structure of some commercial α-blockers

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 Cont’d…

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 Cont’d…

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 Cont’d…

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 Cont’d…

 Selective (β1 selective) β-blockers

Examples of non-selective β-blockers which also antagonize at the α1 receptor

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