Drugs acting on Autonomic Nervous System, Sympathomimetic drugs (Adrenergic Agonist) Sympatholytic drugs (Adrenergic Antagonist) Alpha Blockers Beta Blockers B. PHARM SEMESTER IV (2nd Year 2nd Sem.)

1. Drugs acting on
Autonomic Nervous System
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Sympathomimetic drugs (Adrenergic Agonist)
Sympatholytic drugs (Adrenergic Antagonist)
Alpha Blockers
Beta Blockers
B. PHARM SEMESTER IV (2nd Year 2nd Sem.)
S.SEETARAM SWAMY, M.Pharm.,
Assoc. professor,
Dept. of Pharmaceutical Chemistry,
E-mail: seetaram.443@gmail.com

2. The nervous system is a complex network of nerves and cells that carry
messages to and from the brain and spinal cord to various parts of the
body.
The Central nervous system is made up of the brain and spinal cord and
The Peripheral nervous system is made up of the Somatic and the
Autonomic nervous systems.
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3. Adrenergic Neurotransmitters:
Naturally occur in our body
Both Agents that activate adrenergic receptors are called Sympathomimetics
The agents that block the activation of adrenergic receptors are called
Sympatholytics
Adrenergic Neurotransmitters are 3 types
Collectively called catecholamines
1. Noradrenaline (NA) - at postganglionic sympathetic sites(except
sweat glands, hair follicles) & in certain areas of brain.
2. Adrenaline(Adr) - secreted by adrenal medulla
3. Dopamine(DA)- transmitter in basal ganglia, limbic system, CTZ,
anterior pituitary.
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4. Steps in the synthesis of
Catecholamines (CAs)
- Synthesis of CAs
- Storage of CAs
- Release of CAs
- Uptake of CAs
- Metabolism of CAs
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6. Biosynthesis of Catecholamine
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7. Metabolism of neurotransmitter:
• Endogenous & exogenous catecholamines are metabolised mainly
by two enzymes, monoamine oxidase & catechol-O-methyl transferase
(COMT).
• MAO occurs within cells bound to surface membrane of mitochondria,
abundant in noradrenergic nerve terminals.
• COMT a widespread enzyme that occurs in both neuronal and nonneuronal
tissues, acts on both catecholamines & its deaminated products, produced by
action of MAO.
• Main final metabolite of adrenaline & noradrenaline is 3-methoxy-
4-hydroxymandelic acid (VMA).
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8. Catabolism of Catecholamine
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9. All belong to super family of G-protein-coupled receptors.
Adrenergic receptors are classified into two types
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10. Adrenergic drugs are medications that stimulate certain nerves in your
body. They do this either by mimicking the action of the chemical
messengers epinephrine and norepinephrine or by stimulating their
release. These drugs are used in many life-threatening conditions, including
cardiac arrest, shock, asthma attack, or allergic reaction.
Sympathomimetic agents that partially or completely mimic the actions of
norepinephrine (NE) or Epinephrine (Epi).
They are also called as Sympathomimetic drugs / Adrenomimetic Drugs /
Adrenergic Agonist / Adrenoreceptor Agonists
Sympathomimetic drugs / Adrenergic Agonist
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11. Classification of Sympathomimetic Drugs
They could be classified on two different basis
1) Chemical Classification
2) Based on the mechanism of Action
1. Chemical Classification:
They are chemically classified into two main categories
A) Catecholamines
B) Non-catecholamines
A) Catecholamines:
They contain catechol (3, 4-dihydroxy benzene ring) nucleus.
Exp: Nor-epinephrine, Epinephrine, Dopamine, Dobutamine, Isoproterenol
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13. B) Non-catecholamines:
They do not contain catechol nucleus and have prolonged duration of action,
because they are not inactivated by COMT.
Exp: Ephedrine, Phenylephrine, Terbutaline, Oxymetazoline,
Pseudoephedrine, Clonidine, Amphetamine
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14. 2. Based on the mechanism of Action
Sympathomimetic Drugs
Direct acting:
Nor-epinephrine
Epinephrine
Phenylephrine
Dopamine
Methyldopa
Clonidine
Naphazoline
Oxymetazoline
Xylometazoline
Dobutamine
Isoproterenol
Terbutaline
Salbutamol
Bitolterol
Indirect acting agents:
Hydroxyamphetamine
Pseudoephedrine
Propylhexedrine
Mixed Agents:
Ephedrine
Metaraminol
Direct Acting agents: Directly act as agonist on α & β
or both.
Indirect acting agents: Acts on adrenergic neuron to
release N.A
Mixed Agents: They act directly or indirectly.
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15. SAR of Adrenergic Agonists / β-phenylethylamines
/ Sympathomimetic Agents/ Arylethanolamines
1. Structure required for Activity
a) Phenyl Ethylamine as parent compound
b) Catechol or Aromatic Ring
c) β-carbon hydroxy & amino terminal
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16. SAR of Sympathomimetic agents was studied by 3 different substituents
1. Phenyl Ring Substitution
2. Substitution at carbon in side chain
3. Substitution at nitrogen
1. Phenyl ring substitution
 3-hydroxy substitution is required for α - activity
 4-hydroxy substitution is required for β – activity
 3, 4 –dihydroxy substitution is required for both α & β - activity
 Replacement of catechol by resorcinol increases β2 selectivity and also
decreases metabolism by COMT and produce longer duration of action.
Exp:- Terbutaline
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17.  Replacement of meta hydroxyl of catechol increases β2 selectivity and
decreases metabolism by COMT.
Exp:- Salbutamol
 Removal of para hydroxyl group from epinephrine produce selective α1
agonist.
Exp: - Phenylephrine
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18. 2. Substitution at carbon in side chain
Small alkyl group (methyl or ethyl) present at α carbon decreases the
metabolism by MAO (Mono amine oxidase )
 Ethyl group present at α carbon decreases the activity.
 OH (hydroxyl) group substitution on the β carbon is essential for activity.
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19. 3. Substitution at nitrogen
The nature of amino substituent determines α / β receptor selectivity.
As the size of alkyl group on nitrogen increases, activity at α-receptor
decreases and activity at β -receptor increases.
Exp:- Isoproterenol
 Primary & secondary amines have good adrenergic activity
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20. SAR of Non-catecholamines:
1. Bridging Unit (X) :
Usually a single methylene group / amino group is essential for agonist
activity
Exp: - X = CH2 (α1 agonist) – Clonidine
= NH (α2 agonist ) – Oxymetazoline
2. Imidazoline rings are highly active α- agonist activity
3. Aromatic ring:
Agonist activity is enhanced when the aromatic ring is substituted with
halogen or small alkyl groups (methyl).
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21. Synthesis of Phenylephrine
- Selective α1-Agonist
- Phenylephrine increases BP by the vasoconstrictor Action
- Locally it is used as Nasal Decongestant
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22. Synthesis of Salbutamol
- Selective β2-agonist
- It is used as a bronchodilator and is the drug of choice in the
treatment of Bronchial Asthma
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24. Therapeutic Uses of Sympathomimetic Agents
A – Anaphylactic Shock – Exp: Epinephrine
B – Bronchial Asthma – Exp: Salbutamol, Terbutaline, Isoprenaline,
Epinephrine
C – Cardiogenic shock – Exp: Dobutamine / Cardiac Arrest - Exp:
Epinephrine
D – Delay of Parturition – Exp: Terbutaline, Ritodrine / Delay
absorption of Local Anesthetics – Exp: Adrenaline
H – Hypertension – Exp: Clonidine
M – Migraine – Exp: Clonidine
N – Used as CNS stimulant in Narcolepsy – Exp: Amphetamine
N – Nasal Decongestion – Exp: Ephedrine, Phenylephrine,
Methoxamine
P – Premature labor – Exp: Salbutamol
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25. Sympatholytic drugs / Adrenergic Antagonist
Alpha & Beta Antagonists are prevent the interaction of endogenous
neurotransmitter NE or Sympathomimetics with corresponding
adrenergic receptors.
Bind specifically to alpha receptors and interfere with catecholamine and
Sympathomimetic action.
Role of Alpha-1 & Alpha-2 Antagonists
Alpha-1:
-Vasoconstriction
- Increased peripheral resistance
- Increased blood pressure
Alpha-2:
-Inhibition of Norepinephrine release
- Inhibition of insulin release
Alpha adrenergic blockers / Alpha Antagonists
The agents which antagonise the action of Sympathomimetic agents
or sympathetic stimulations are called Sympatholytic agents.
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26. Alpha Blockers
Non-Selective
Irreversible
Phenoxybenzamine
Reversible
Phentolamine
Tolazoline
Selective
Alpha 1 Blocker
Prazosin
Terazosin
Doxazosin
Alfuzosin
Alpha 2 Blocker
Yohimbine
Miscellaneous
Miscellaneous
Ergot Alkaloids
Dihydroergotamine
Methysergide
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28. It is a imidazoline Derivative
Non-selective α-adrenergic blocker
It is used in the treatment of Reynaud's Disease, Cerebral Vascular Accidents.
Synthesis of Tolazoline
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29. • Hypertension - alpha-1 selective
• Pheochromocytoma (Conditions associated with increased
sympathetic activity)
• Hemodynamic shock
• Peripheral vascular disease – Raynaud’s
• Congestive heart failure (CHF)
• Benign prostatic hyperplasia (BPH)
• Pulmonary hypertension – tolazoline
Therapeutic Uses of Alpha-Adrenergic Blockers
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31. Bind selectively to beta receptors
Interfere with ability of catecholamines or Sympathomimetics to
provoke beta receptors (heart, smooth muscle of airway and blood vessel).
Propranolol is standard beta antagonist drug to which all beta
antagonists are compared.
Role of Beta-1 & Beta-2 Antagonists
Beta-1:
-Tachycardia
- Increased lipolysis
- Increased myocardial contractility
Beta-2:
- Vasodilation
- Bronchodilation
- Increased release of glucagon
Beta adrenergic blockers / Beta Antagonists
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32. Classification of Beta Blockers
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34. Synthesis of Propranolol
- Non-selective β-blocker
- It is used in hypertension, Arrhythmiasis, Angina Pectoris, Coronary artery
disease & open angle glucoma.
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35. SAR of Beta Blockers / Adrenergic Antagonists /
Sympatholytic Agents/ Aryloxy Propanolamines
1. - OCH2 group is placed between the aromatic ring and ethanolamino
side chain, which is essential for the activity.
2. The hydroxyl bearing carbon of the aryloxy prpanolamine side chain
play critical role in the interaction of β-antagonist drugs with β-receptor.
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36. 3. Alkyl Amino group is must be a secondary amine for optimal activity.
4. Isopropyl and t-butyl groups present on the amino group provides
nucleophilicity to the amino group. E.g: Atenolol
5. The two carbon chains are essential for activity.
6. N, N-disubstitution decreases the beta blocking activity.
7. The aromatic ring and it substituent is the primary determinant of β1
antagonist activity.
8. Alkenyl groups present in the ortho position on aryl ring gives good beta
antagonist activity. E.g: Oxprenolol, Alprenolol
9. Most of the derivatives have different aryl group like Phenyl,
Naphthalene & Indole. E.g: Atenolol, Propranolol & Pindolol
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Therapeutic Uses of Beta-Adrenergic Blockers

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