Autonomic Nervous System

Nervous system is very important to maintain the homeostasis (balance) of the human body.
It controls and coordinates the human body and it gives the quick response to our body.
Functions:-

 Sensory- information goes to brain

 Motor- response from brain to body

 Integration- analysis the sensory input.

The human nervous system consists of the Central Nervous System (CNS) and the Peripheral
Nervous System(PNS).
 CNS is composed of the brain (located in the cranial cavity) and the spinal
cord (located in the vertebral cavity), which serve as the main control
centers for all body activities.

 PNS is composed of nerves derived from the brain and spinal cord (12 pairs
of cranial nerves and 31 pairs of spinal nerves) which serve as linkage
between the CNS and the body.

ANS can be divided into sympathetic and parasympathetic branches where in general
sympathetic nerves stimulate activities of the effect or organs (except digestive organs) and
parasympathetic nerves inhibit activities of the effect or organs (except digestive organs).
  ANS together with the endocrine system controls the body's internal organs.
 It innervates smooth muscles, cardiac muscle , and glands , controlling the circulation of
blood , activity of the G.I . Tract and body temp.
 Generally stimulates the effector organ (except in digestive tract).

 It is activated in emergencies, flight– or– fight reaction, in thesense that the

body can either quickly flee or "take a stand".

Neuron : it is the basic element of the nervous system. It transmit information to the other
nerve cells , muscle, glands, etc.
Neurotransmitter:
Neuro: neuron
Transmitter: transfer the information
Sympathetic: Adrenergic
Parasympathetic: Cholinergic
Both adrenergic and cholinergic division work antagonistically to maintain homeostasis.

Sympathetic system:
Occurrence : Sympathetic fibers originate from the thoracolumbar region of the spinal cord (T1
– L2). Most postganglionic fibers produce norepinephrine (noradrenalin) and are called
adrenergic fibers (exceptions are the sweat glands and blood vessels in skin).
Adrenergic system produces CATECHOLAMINES which are as:
Dopamine :pleasure,, addiction, movement and motivation. People repeat behaviours that lead
to dopamine release.
Epinephrine(Adrenaline): fight or flight mode in stressful situation, increase heart rate, blood
flow leading to physical boost and high awareness.
Nor-epinephrine(Nor Adrenaline): concentration in brain, ctract blood vessels and increased
blood flow.

Catecholamines
Catecholamines are characterized by a catechol group (a benzene ring with two hydroxyl
groups) to which is attached an amine (nitrogen-containing) group.
Among the catecholamines are dopamine, epinephrine (adrenaline), and norepinephrine
(noradrenaline).

Catechol Ring Catecholamines

 Biosynthesis of catecholamines:

Storage and release of catecholamines:

 Nor adrenaline stored in vesicles in the form of ATP complex. After diffusing out in
cytoplasm it gets methylated into adrenaline.
 Then it enters into chromaffin granules and get stored.
 Now it releases from vesicles and bind with receptor and produces its action.
Catabolism of catecholamines:
 SYMPATHOMIMETIC AGENTS
Sympathomimetics are substances that mimic or modify the actions of endogenous
catecholami es of the sympathetic nervous system. Direct agonists directly activate adrenergic
receptors while indirect agonists en ance the actions of endogenous catecholamines.

Receptors: These are G Protein coupled receptor.

1. Alpha receptor
2. Beta receptor

Alpha (α) receptor

α2
α1
present on pre and post
present on post synaptic synaptic recptor sites
recptor sites
Func:
Func:
inhibit neurotransmitter
vasoconstriction release
gland secretion, decrease insulin release
glucose synthesis platelet aggregation
( glycogenolysis) inhibitory res[ponse
excitatory response

NE or epinephrine binding to alpha- receptors is stimulatory while their binding to

beta-receptors is inhibitory.

Beta (ß)receptors
ß1 ß2 ß3
present in cardiac tissue present in smooth muscle cells present in
(myocardium), kidney and gland cells,bronchi, blood adipose tissue
Func: vessels, uterus, liver, g.i.t. and urinary
bladder
increased heart rate, Func:
Func:
release of renin results in bronchodilation, vasodilation,
increased B.P. relaxation . lipolysis and
urinary bladder
excitatory response. inhbitory in nature relaxation
 SAR of Sympathomimetic agents

I. Phenyl ring substitution

• Substitution on the meta and para positions of the aromatic amino, α, and β positions of
the ethylamine side chain ring and on the influences the mechanism of sympathomimetic
action and the receptor selectivity of the drug.

• Maximal activity is seen in β-phenyl ethylamine derivatives, containing hydroxyl groups in

the meta and para positions of the aromatic ring (catechol) and a β-hydroxyl group of the
correct stereochemical configuration on the ethylamine portion of the molecule.

•
• Unsubstitution gives CNC activity by increasing BBB.

Amphetamine
• Although the catechol moiety is an important structural feature to obtain maximal agonistic
activity at adrenergic receptors, it can be replaced with other substituted phenyl moieties to
provide selective adrenergic agonism.
• For example, replacement of the catechol function of isoproterenol with the resorcinol
structure gives the drug metaproterenol, which is a selective β2- receptor agonist.
• In another approach, replacement of the meta hydroxyl of the catechol structure with a
hydroxymethyl group afforded Salbutamol, which shows selectivity to the β2 receptor.
• The naturally occurring noradrenaline has 3, 4-dihydroxy benzene ring (catechol) active at
both α and β receptors. However, it has poor oral activity because it is rapidly metabolized by
COMT, the change in substitution pattern3, 5-dihydroxy as in metaproterenol gives good oral
activity. This is due to its resistance to metabolism by COMT. It also provides selectivity for
β2 receptors.

II. Substitution at nitrogen

• Amino group in phenylethylamines is important for direct agonistic activity.
• The amino group should be separated from the aromatic ring by two carbon atoms found
among the potent direct-acting agonists.
• As the bulk of the nitrogen substituent increases, α-receptor agonistic activity decreases and
β-receptor activity increases. Thus, NE that is an effective β1- receptor agonist is also a potent
α-agonist, while epinephrine is a potent agonist at α, β1, and β2 receptors. N-tertiary butyl
group enhances β2 selectivity. As the
size increases from hydrogen in noradrenaline to methyl in adrenaline,
isopropyl in isoproterenol, the activity of α receptor decreases and β receptorincreases.

• Primary and secondary amines are more potent direct-acting agonists than 3°or 4° amines.

Salbutamol

Isoprenaline(Isoproterenol)
III. Substitution on the carbon side chain
Methyl or ethyl substitution on the α-carbon of the ethylamine side chain reduces direct
receptor agonist activity at both α and β receptors.
-OH group on ß carbon decreases the cns activity, increases α, ß receptor activity.

Importantly, an α-alkyl group increases the duration of action of the

phenylethylamine agonist by making the compound resistant to metabolic deamination by
MAO.
 α-substitution also significantly affects receptor selectivity.
 Another effect of α-substitution is the introduction of a chiral centre, which has
pronounced effects on the stereo-chemical requirements for activity.

Amphetamine

Classification of sympathomimetic drugs:

SYMPATHOMIMETIC
DRUGS

DIRECT ACTING DRUGS INDIRECT ACTING MIXED ACTING

DRUGS DRUGS
NOR EPINEPHRINE
EPINEPHRINE HYDROXYAMPHETAMINE
EPHEDRINE
PHENYLEPHRINE PSEUDOEPHEDRINE
DOPAMINE PROPYLHEXEDRINE METARAMINOL
METHYL DOPA CLONIDINE
DOBUTAMINE
ISOPRENALINE
TERBUTALINE
SALBUTAMOL
BITOLTEROL
NAPHAZOLINE
OXYMETAZOLINE
XYLOMETAZOLINE
 Sympathomimetic drugs/ Adrenergic drugs

Drugs Mechanism of Uses

action

Norepinephrine Nonelective Adrenergic agent, vasopressor drug

adrenergic agonist

4-[(1R)-2-amino-1-
hydroxyethyl]benzene-1,2-diol

Epinephrine Bronchodilator
Cardiostimulant
Glaucoma treatment
Mydriatic (dilation of pupil)

(-)-3,4-Dihydroxy-α-
[2(methylamino)ethyl]benzyl
alcohol

Phenylephrine α1-adrenergic Marked arterial vasoconstrictor effect

agonist Nasal decongestant
Mydriatic
Prolongs local anaesthetics

(R)-3-[-1-hydroxy-2-
(methylamino)ethyl]phenol

Naphazoline Reduces swelling of nasal and ocular

mucus membrane
Potent vasoconstrictor
Nasal decongestant

2-(naphthalen-1-ylmethyl)-4,5-
dihydro-1H-imidazole
Oxymetazoline Long acting vasoconstrictor
Nasal decongestant

3-(4,5-Dihydro-1H-imidazol-2-
ylmethyl)-2,4-dimethyl-6-tert-
butyl-phenol

Xylometazoline Nasal and ophthalmic decongestant

2-[(4-tert-butyl-2,6-
dimethylphenyl)methyl]- 4,5-
dihydro-1H-imidazole

Metaraminol Used in hypotensive states in patients

with general and spinal anaesthetics,
septicemia and adverse drug reaction
(ADRs) in medication

(1R,2S)-3-[-2-amino-1-hydroxy-
propyl]phenol

Methyldopa α2-adrenergic Antihypertensive drug

agonist

(S)-2-amino-3-(3,4-
dihydroxyphenyl)-2-methyl-
propanoic acid

Clonidine Used in hypertension

Side effect sedation used in elderly
people

N-(2,6-Dichlorophenyl)-4,5--1H-
imidazol-2-amine
 Propylhexedrine α-adrenergic Adrenergic vasoconstrictor
agonist. Nasal decongestant

(±)-1-cyclohexyl-N-
methylpropan-2-amine

Dopamine ß1-adrenergc agonist Cardiotonic drug

Antihypertensive drug

Dobutamine Myocardial contractility

Heart failure
Cardiotonic

4-(2-aminoethyl)benzene-1,2-
diol

Terbutaline ß2-adrenergic Bronchodilator

agonist. Critical treatment of asthma
Tocolytic agent(parturition and
obstetrics)

(RS)-5-[2-(tert-Butylamino)-1-
hydroxyethyl]benzene-1,3-diol

Salbutamol Drug of choice in bronchial asthma

Potent bronchodilator
Severe mayocardial infarction
Acute left ventricular failure
Premature labour
ocular hypotension
(RS)-4-[2-(tert-Butylamino)-1-
hydroxyethyl]-2-
(hydroxymethyl)phenol

Bitolterol Potent bronchodilator

(RS)-[4-(1-Hydroxy-2-tert-
butylamino-ethyl)-2-(4-
methylbenzoyl)oxy-phenyl] 4-
methylbenzoate

Isoproterenol Non selective ß In bronchial asthma

adrenergic agonist. Antiarrythmic agent
Increase heart rate
In cardiac shock
Bronchodilator

(RS)-4-[1-hydroxy-2-
(isopropylamino)ethyl]benzene-
1,2-diol

Ephedrine mixed adrenergic Allergic conditions

agonist. Colds
Narcolepsy
Hypotensive conditions
Bronchidilator
2-(methylamino)-1-
Enuresis
phenylpropan-1-ol Mydriasis

Hydroxyamphetamine indirect acting Mydriatic

sympathomimetic
amine drug

4-(2-aminopropyl)phenol

Pseudoephedrine Nasal decongestant

(1R,2R)-2-methylamino-1-
phenylpropan-1-ol
 Adrenergic antagonists/blockers(sympatholytics )

Classification:

Alpha Adrenergic blockers Beta Adrenergic blockers

Tolazoline Propranolol
Phentolamine Metibranolol
Phenoxybenzamine Atenolol
Prazosin Betaxolol
Dihydroergotamine Bisoprolol
Methysergide Esmolol
Metoprolol
Labetalol
Carvedilol

Drugs Mechanism of Uses

action

Tolazoline Nonselective α- Vasodilator;

adrenergic antagonist. It exhibits sympathomimetic
effect so it stimulates heart to
increase BP
Effective as α2 antagonist
hence antagonizes the
2-Benzyl-4,5-dihydro-1H-imidazole overdoses of clonidine.
Antihypertensive

Phentolamine Vasodilator
Adjunct in Treatment of
sudden shock, heart failure.
Antihypertensive drug

3-[(4,5-Dihydro-1H-imidazol-2-
ylmethyl)(4-
methylphenyl)amino]phenol
Phenoxybenzamine Prolonged duration of action
Sudden shock
Pulmonary oedema
In preparative management of
patients suffering from
pheochromocytoma, peripheral
(RS)-N-Benzyl-N-(2-chloroethyl)- vascular disease(frostbite) to
1-phenoxypropan-2-amine prevent circulation of blood in
the body

Propranolol Nonselective ß-adrenergic Antihypertensive drug

antagonist. (Critical suppression of rennin
release from kidney
Lowered cardiac output )

(RS)-1-(1-methylethylamino)-3-(1-
naphthyloxy)propan-2-ol

Metipranolol Antihypertensive drug

Antiglaucoma agent

(RS)-4-{[-2-hydroxy-3-
(isopropylamino)propyl]oxy}-2,3,6-
trimethylphenyl acetate

Prazosin α1-antagonist. Antihypertensive drug

Minimizes the cardiac
overload

[4-(4-Amino-6,7-dimethoxy-2-
quinazolinyl)-1-piperazinyl](2-
furyl)methanone

Dihydroergotamine Ergot alkaloid. Antimigraine agent

(2R,4R,7R)-N-[(1S,2S,4R,7S)-7-
benzyl-2-hydroxy-4-methyl-5,8-
dioxo-3-oxa-6,9-
diazatricyclo[7.3.0.02,6]dodecan-
4-yl]-6-methyl-6,11-
diazatetracyclo[7.6.1.02,7.012,16]he
xadeca-1(16),9,12,14-tetraene-4-
carboxamide

Methysergide Serotonin antagonist. Antimigraine agent

(6aR,9R)-N-[(2S)-1-Hydroxybutan-
2-yl]-4,7-dimethyl-6,6a,8,9-
tetrahydroindolo[4,3-fg]quinoline-
9-carboxamide

Atenolol ß1-adrenergic antagonist Antihypertensive drug

(mostly Used in old age)

(RS)-2-{4-[2-Hydroxy-3-(propan-
2-
ylamino)propoxy]phenyl}acetami
de).

Betaxolol Antihypertensive drug

Antiglaucoma agent

(RS)-1-{4-[2-
(cyclopropylmethoxy)ethyl]-
phenoxy}-3-
(isopropylamino)propan-2-ol
 Bisoprolol Antihypertensive drug

(RS)-1-{4-[(2-
Isopropoxyethoxy)methyl]phenoxy
}- 3-(isopropylamino)propan-2-ol

Esmolol Antiarrythmic agent

methyl (RS)-3-{4-[2-hydroxy-3-
(propan-2-
ylamino)propoxy]phenyl}propanoat
e

Metoprolol Antianginal drug

Antihypertensive drug
Antiarrythmic class II agent

(RS)-1-[4-(2-
Methoxyethyl)phenoxy]-3-
[(propan-2-yl)amino]propan-2-ol

Labetolol Mixed α/ß blocker. Antihypertensive drug

2-hydroxy-5-[1-hydroxy-2-[(1-
methyl-3-
phenylpropyl)amino]ethyl]benza
mide

Carvedilol Mixed α/ß blocker. Antihypertensive drug

Congestive Heart
Failure(CHF)

(±)-[3-(9H-carbazol-4-yloxy)-2-
hydroxypropyl][2-(2-
methoxyphenoxy)ethyl]amine
 SYNTHESIS OF TOLAZOLINE:

SYNTHESIS OF PROPRANOLOL

Epichlorhydrin
α- Naphthol

Propranolol
 SAR of Beta Blockers

1. Amino nitrogen should be secondary for optimum activity for ionic bonding.
2. Branched and bulky group provides nucleophilicity as it helps in binding.
3. Alcohol group required for increased activity.
4. Two methy groups for stability.
5. –OCH2 essential for activity.
6. Substitution at 4th position of naphtha ring leads to 4 hydroxy propranolol which is more
potent to propranolol.