adrenergic agents as per PCI Syllabus

1. AS PER PCI SYLLABUS
B PHARMACY FOURTH SEMESTER
By: Somashekhar M Metri
SATVIK PUBLICATIONS VIJAYAPUR-586103

2. Chapter 2.Adrenergic Agents
Drugs acting on Autonomic Nervous System; Adrenergic Neurotransmitters: Biosynthesis
and catabolism of catecholamine, adrenergic receptors (Alpha & Beta) and their distribution.
Sympathomimetic agents: SAR of Sympathomimetic agents, Direct acting: Nor-epinephrine,
Epinephrine, Phenylephrine*, Dopamine, Methyldopa, Clonidine, Dobutamine, Isoproterenol,
Terbutaline, Salbutamol*, Bitolterol, Naphazoline, Oxymetazoline and Xylometazoline. Indirect
acting agents: Hydroxyamphetamine, Pseudoephedrine, Propylhexedrine. Agents with mixed
mechanism: Ephedrine, Metaraminol. Adrenergic Antagonists: Alpha adrenergic blockers:
Tolazoline*, Phentolamine, Phenoxybenzamine, Prazosin, Dihydroergotamine, Methysergide.
Beta adrenergic blockers: SAR of beta blockers, Propranolol*, Metibranolol, Atenolol,
Betazolol, Bisoprolol, Esmolol, Metoprolol, Labetolol, Carvedilol.

3. INTRODUCTION
The Autonomic Nervous System consists of motor neurons that:
•Innervate smooth and cardiac muscle and glands
•Make adjustments to ensure optimal support for body activities
•Operate via subconscious control
Other names
•Involuntary nervous system
•General visceral motor system
Central nervous system (CNS) Peripheral nervous system (PNS)
Motor (efferent) divisionSensory (afferent)
division
Somatic nervous
system
Autonomic nervous
system (ANS)
Sympathetic
division
Parasympathetic
division
Definition: “Adrenergic drugs are chemical agents that exert their principal pharmacological and therapeutic
effects by either enhancing or reducing the activity of the various components of the sympathetic division of
the autonomic nervous system”.

4. Skeletal muscle
Cell bodies in central
nervous system Peripheral nervous system Effect
+
+
Effector
organs
ACh
ACh
Smooth muscle
(e.g., in gut),
glands, cardiac
muscle
Ganglion
Adrenal medulla Blood vessel
ACh
ACh
ACh
NE
Epinephrine and
norepinephrine
Acetylcholine (ACh) Norepinephrine (NE)
Ganglion
Heavily myelinated axon
Lightly myelinated
preganglionic axon
Lightly myelinated
preganglionic axons
Neuro-
transmitter
at effector
Unmyelinated
postganglionic
axon
Unmyelinated
postganglionic axon
Stimulatory
Stimulatory
or inhibitory,
depending
on neuro-
transmitter
and
receptors
on effector
organs
Single neuron from CNS to effector organs
Two-neuron chain from CNS to effector organs
SOMATIC
NERVOUS
SYSTEM
AUTONOMICNERVOUSSYSTEM
PARASYMPATHETICSYMPATHETIC

6. Sympathetic Nervous System- Preganglionic Neuron May:
•terminate on postganglionic neuron in the sympathetic chain ganglia
•ascend or descend to higher or lower ganglia and terminate on postganglionic neuron in the sympathetic
chain ganglia
•pass through the sympathetic chain to prevertebral ganglia (celiac, inferior or superior mesenteric)
•pass through the sympathetic chain ganglia to adrenal medulla

7. •In general, substances that produce effects similar to stimulation of sympathetic nervous activity
are known as sympathomimetics or adrenergic stimulants. Those that decrease sympathetic
activity are referred to as synipatholytics or anti-adrenergics or adrenergic blocking agents.
Because of the important role that the sympatholytics nervous system plays in the normal
functioning of the body, adrenergic drugs find wide use in the treatment of a number of diseases.
•In addition to their effects on sympathetic nerve activity, a number of adrenergic agents produce
important effects on the central nervous system (CNS). Norepinephrine (NE) is the
neurotransmitter of the postganglionic sympathetic neurons. As a result of sympathetic nerve
stimulation, it is released from sympathetic nerve endings in to the synaptic cleft, where it
interacts with specific presynaptic and postsynaptic adrenergic receptors.
Another endogenous adrenergic receptor agonist is epinephrine. This compound is not released
from peripheral sympathetic nerve endings, as is NE. Rather, it is synthesized and stored in the
adrenal medulla, from which it is released into the circulation. Thus
•Epinephrine is often referred to as a neuro-hormone. Epinephrine is also biosynthesized in
certain neurons of the CNS. Where Epinephrine and Nor-Epinephrine serve as neurotransmitters

8. •Epinephrine and NE belong to the chemical class of substances known as the catecholamine’s.
This name was given to these compounds because they contain an amino group attached to an
aromatic ring that contains two hydroxyl groups situated ortho to each other, the same
arrangement of hydroxyl groups as found in catechol.
•Aromatic compounds that contain such an arrangement of hydroxyl substituents are highly
susceptible to oxidation. Catecholamine’s such as epinephrine and NE. undergo oxidation in the
presence of oxygen (air) or other oxidizing agents to produce ortho-quinone-like compounds.
•Which undergo further reactions to give mixtures of colored products Hence Sodium of
catecholamine drugs often is stabilized by the addition of an antioxidant (reducing agent) such as
ascorbic acid or sodium bisulfite.
•Catecholamines are polar substances that contain the acidic and basic functional groups.
•The action of NE at adrenergic receptors is terminated by a combination of processes, including
uptake into the neuron and into extra neuronal tissues, diffusion away from the synapse and
metabolism. Usually, the primary mechanism for termination of the action of NE is reuptake of
the catecholamine into the nerve terminal.
•This process is termed uptake-I and involves a Na /C1-dependent Trans membrane, transporter
that has a high affinity for NE.

10. •The two principal enzymes involved in catecholamine metabolism are monoamine oxidase
(MAO) and catechol ortho methyl transferase COMT).
•Both of these enzymes are distributed throughout the body with high concentrations found in the
liver and kidneys MAO is associated primarily with the outer membrane of the mitochondria
while COMT is found primarily in the cytoplasm.

12. •The wide tissue distribution of MAO and COMT indicates that both act on catecholamine’s that enter the
circulation and the extra neuronal tissues after being released from nerves or the adrenal gland. In addition,
the fact that COMT is not present in sympathetic neurons whereas the neuronal mitochondria do contain
MAO indicates that MAO also has a role in the metabolism of intra neuronal catecholamines.
Fight or Flight Response:
•These catecholamine hormones facilitate immediate physical reactions These include the following:
•Acceleration of heart and lung action･Inhibition of stomach and intestinal action
•Constriction of blood vessels in many parts of the body
•Dilation of blood vessels for muscles
•Inhibition of tear glands and salivation
•Dilation of pupil
•Relaxation of bladder
•Inhibition of erection
Neurotransmission
Nerve impulses elicit responses in smooth, cardiac, and skeletal muscles, exocrine glands, and postsynaptic
neurons by liberating specific chemical neurotransmitters.
Steps Involved in Neurotransmission
AxonalConduction
•At rest, the interior of the typical mammalian axon is approximately 70 mV negative to the exterior.
The resting potential is essentially a diffusion potential based chiefly on the 40 times higher concentration of
K+ in the axoplasm as compared with the extracellular fluid and the relatively high permeability of the

14. •resting axonal membrane to K+. Na+ and Cl- are present in higher concentrations in the extracellular fluid
than in the axoplasm, but the axonal membrane at rest is considerably less permeable to these ions; hence
their contribution to the resting potential is small.
•These ionic gradients are maintained by an energy-dependent active transport mechanism, the Na+K+-
ATPase
Junctional Transmission
•The arrival of the action potential at the axonal terminals initiates a series of events that trigger transmission
of an excitatory or inhibitory impulse across the synapse or neuro effecter junction.
Storage and release of the transmitter
•The non-peptide (small molecule) neurotransmitters are largely synthesized in the region of the axonal
terminals and stored there in synaptic vesicles.
•Peptide neurotransmitters (or precursor peptides) are found in large dense-core vesicles that are transported
down the axon from their site of synthesis in the cell body.
•Neurotransmitter transport into the vesicle is driven by an electrochemical gradient generated by the
vacuolar proton pump.
•Neurotransmitters also can modulate the permeability of K+ and Ca2+ channels indirectly. In these cases, the
receptor and channel are separate proteins, and information is conveyed between them by G proteins.
•Other receptors for neurotransmitters act by influencing the synthesis of intracellular second messengers and
do not necessarily cause a change in membrane potential.
Initiation of postjunctional activity
•If an EPSP (exitory post synaptic potential) exceeds a certain threshold value, it initiates a propagated action
potential in a postsynaptic neuron or a muscle action potential in skeletal or cardiac muscle by activating
voltage-sensitive channels in the immediate vicinity.
•In certain smooth muscle types in which propagated impulses are minimal, an EPSP may increase the rate of
spontaneous depolarization, cause Ca2+ release, and enhance muscle tone; in gland cells, the EPSP initiates
secretion through Ca2+ mobilization.
•An IPSP (inhibitory post synaptic potential), which is found in neurons and smooth muscle but not in
skeletal muscle, will tend to oppose excitatory potentials simultaneously initiated by other neuronal sources.

15. Destruction or dissipation of the transmitter
•When impulses can be transmitted across junctions at frequencies up to several hundred per second, it is
obvious that there should be an efficient means of disposing of the transmitter following each impulse.
•At cholinergic synapses involved in rapid neurotransmission, high and localized concentrations of
acetylcholinesterase (AChE) are available for this purpose.
•On inhibition of AChE, removal of the transmitter is accomplished principally by diffusion. Under these
circumstances, the effects of released ACh are potentiated and prolonged.
Nonelectrogenic functions
•The continual release of neurotransmitters in amounts insufficient to elicit a postjunctional response
probably is important in the transjunctional control of neurotransmitter action.
•The activity and turnover of enzymes involved in the synthesis and inactivation of neurotransmitters, the
density of presynaptic and postsynaptic receptors, and other characteristics of synapses probably are
controlled by trophic actions of neurotransmitters or other trophic factors released by the neuron or the target
cells.
Adrenergic Receptors
•Located throughout the body are receptors for the sympathetic neurotransmitters?
•Alpha-adrenergic receptors: respond to NE
•Beta-adrenergic receptors: respond to EPI (Exocrine pancreatic insufficiency)
Types of -adrenergic receptor
•-adrenergic receptors are adrenergic receptors that respond to nor-epinephrine and to such blocking
agents as phenoxybenzamine.
•They are subdivided into two types:
•1, found in smooth muscle, heart, and liver, with effects including vasoconstriction, intestinal
relaxation, uterine contraction and pupillary dilation,
•2, found in platelets, vascular smooth muscle, nerve termini, and pancreatic islets, with effects
including platelet aggregation, vasoconstriction, and inhibition of nor-epinephrine release and of
insulin secretion.

16. NH3
COOH
Gq
Phospho-
lipase C
(+)
PIP2
IP3 Diacylglycerol
Increase Ca2+ Activate Protein
KinaseC
Response
Receptor agonists activate signal transduction pathways
1 adrenergic
receptor
HO
HO CH
OH
CH2 NH2
Norepinephrine

17. -receptor types
•-adrenergic receptors respond particularly to epinephrine and to such blocking agents as propranolol.
•There are three known types of beta receptor, designated β1, β2 and β3.
•β1-Adrenergic receptors are located mainly in the heart
•β2-Adrenergic receptors are located mainly in the lungs, gastrointestinal tract, liver, uterus, vascular smooth
muscle, and skeletal muscle
•β3-receptors are located in fat cells
•Agonists of the 2 receptors are used in the treatment of asthma (relaxation of the smooth muscles of the
bronchi)

18. Receptor antagonists block agonist binding to the receptor
NH3
COOH
Gq
Phospho-
lipase C
Antagonist
HO
HO CH
OH
CH2 NH2
Norepinephrine
What effect would an antagonist
alone have on receptor activation?

19. •Antagonists of the 1 receptors are used in the treatment of hypertension and angina (slow heart and reduce
force of contraction)
•Antagonists of the 1 receptors are known to cause lowering of the blood pressure (relaxation of smooth
muscle and dilation of the blood vessels)
Stimulation of alpha-adrenergic receptors on smooth muscles results in:
•Vasoconstriction of blood vessels
•Relaxation of GI smooth muscles
•Contraction of the uterus and bladder
•Male ejaculation
•Decreased insulin release
•Contraction of the ciliary muscles of the eye (dilated pupils)
Stimulation of beta2-adrenergic receptors on the airways results in:
•Bronchodilation (relaxation of the bronchi)
•Uterine relaxation
•Glycogenolysis in the liver
Stimulation of beta1-adrenergic receptors on the myocardium, AV node, and SA node results in cardiac
stimulation:
•Increased force of contraction (positive inotropic effect)
•Increased heart rate (positive chronotropic effect)
•Increased conduction through the AV node (positive dromotropic effect) automaticity
Anorexiants: adjuncts to diet in the short-term management of obesity
Examples: Benzaphetamine, Phentermine, Dextroamphetamine, Dexedrine
Bronchodilators: Treatment of asthma and bronchitis
Agents that stimulate beta2-adrenergic receptors of bronchial smooth muscles causing relaxation
Examples: Albuterol Ephedrine Epinephrine Isoetharine Isoproterenol Levalbuterol
Metaproterenol Salmeterol Terbutaline

20. Reduction of intraocular pressure and mydriasis (pupil dilation): treatment of open-angle glaucoma
Examples: Epinephrine and Dipivefrin
Nasal decongestant:
Intranasal (topical) application causes constriction of dilated arterioles and reduction of nasal blood flow,
thus decreasing congestion.
Examples: Epinephrine Ephedrine Naphazoline Phenylephrine
Tetrahydrozoline
Ophthalmic relieving conjunctival congestion
Examples: Epinephrine, Naphazoline, Phenylephrine ,Tetrahydrozoline
Vasoactive sympathomimetics also called cardio selective sympathomimetics Used to support the heart
during cardiac failure or shock.
Examples: Dobutamine, Dopamine, Ephedrine, Epinephrine, Fenoldopam
Isoproterenol, Methoxamine , Norepinephrine, Phenylephrine
Sympathomimetic Agents
•Sympathomimetic drugs usually mimic stimulation of the peripheral endings of the sympathetic or
‘adrenergic’ nerves, the action being exerted on the effector cells supplied by postganglionic endings.
•There is now enough evidence to show that the neurohormone directly concerned with such an action is
noradrenaline.
•It is, however, interesting to observe that a good number of sympathomimetics in fact do not really mimic
the actions of noradrenaline or adrenaline at the effector receptor.
•They merely induce the release of noradrenaline from the sympathetic postganglionic adrenergic nerves.
Such sympathomimetics which exert their action indirectly are comparatively less effective in patients treated
with noradrenaline depleting drugs, for instance, the rauwolfia alkaloids, or other adrenergic neuron blockers.

21. Structure—Activity Relationships
NH2
alpha
beta
para
meta
2-phenylethanamine
•Structure—activity relationships for α- and β-adrenergic receptor agonists have been reviwed
•The parent structure for many of the sympathomimetic drugs is β-phenylethylamine.
•The manner in which β-phenylethylamine is substituted on the Meta and Para positions of the aromatic ring.
•The ethylamine side chain influences not only the mechanism of sympathomimetic action but also the
receptor selectivity of the drug.
•For the direct-acting sympathomimetic amines. Maximal activity is seen in β-phenylethylamine derivatives
containing hydroxyl groups in the Meta and Para positions of the aromatic ring (a catechol) and α-hydroxyl
group of the correct stereochemical configuration on the ethylamine portion of the molecule.
•Such structural features are seen in the prototypical direct-acting compounds NE. epinephrine and
isoproterenol.
Direct acting agents: Nor-epinephrine, Epinephrine, Phenylephrine*, Dopamine, Methyldopa, Clonidine,
Dobutamine, Isoproterenol, Terbutaline, Salbutamol*, Bitolterol, Naphazoline, Oxymetazoline and
Xylometazoline.

24. Indirect acting agents: Hydroxyamphetamine, Pseudoephedrine, Propylhexedrine.
Agents with mixed mechanism: Ephedrine, Metaraminol.

25. Adrenergic Antagonists:
Alpha adrenergic blockers: Tolazoline*, Phentolamine, Phenoxybenzamine, Prazosin, Dihydroergotamine,
Methysergide.

26. Beta adrenergic blockers: SAR of beta blockers, Propranolol*, Metipranolol, Atenolol, Betazolol,
Bisoprolol, Esmolol, Metoprolol, Labetolol, Carvedilol.

29. OH
+ Cl
O
Condensed
- HCl
O
O
NH2
CH3
CH3
ClH
O
OH
NH
CH3
CH3
naphthalen-1-
ol
2-(chloromethyl)oxira
ne 2-[(naphthalen-1-yloxy)methyl]oxira
ne
propan-2-amine
1-(naphthalen-1-yloxy)-3-(propan-2-ylamino)propan-
2-ol Propranolol
SYNTHESIS
Propranolol
(+ -})-1-Isopropylamino-3-(1-naphthyloxy) propan-2-ol-hydrochloride: 2-Propanol, -1-[(1-
methylethyl) amino]-3-(1-naphthalenyloxy)-hydrochloride
Interaction of 1-naphthol with epichlorohydrin affords a glycidic ether which upon treatment with
isopropylamine aids in the opening of the Oxygen ring yielding the propranolol base and this on being treated
with a known quantity of hydrochloric acid gives the official compound.

30. • Propranolol has been reported to exhibit quinidine-like antiarrhythmic actions which are quiet
independent of beta-adrenergic blockade.
• Hence, these pharmacological properties are usually employed to suppress ventricular tachycardia,
digitalis-induced tachy arrhythmias, paroxysml a trial tachycardia and lastly ventricular and a trial extra-
systoles.
• It is also currently receiving a lot of attention in the treatment and management of essential
hypertension.
• Dose: Oral, adult, for arrhythmias, 10 to 30 mg 3 to 4 times daily.
Salbutamol
Salbutamol can be prepared from an acetophenone derivative which is itself derived from salicylic acid
(hence the “sal” in salbutamol) Salbutamol was first made in 1967 in Britain and became commercially
available in the UK in 1969. It was approved for medical use in the United States in 1982. It is on the World
Health Organization's List of Essential Medicines,
O
CH3
OH
O O CH3
Br2
NH
CH3
CH3
CH3
OH
O
N
CH3CH3
CH3
H2
LiAlH 4
OH
OH
NH
CH3
CH3
CH3
OH
ethyl
5-acetyl-2-hydrox
ybenzoate
N-benzyl-2-methy
lpropan-2-amine
2-[benzyl(tert-butyl)a
mino]-1-(4-hydroxyp
henyl)ethanone
4-[2-(tert-butylamino)-1-h
ydroxyethyl]-2-(hydroxym
ethyl)phenol
(Salbutamol)
Dose: 5 mg BID

31. The tertiary butyl group in salbutamol makes it more selective for β2 receptors, which are the predominant
receptors on the bronchial smooth muscles. Activation of these receptors causes adenylyl cyclase to convert
ATP to cAMP, beginning the signalling cascade that ends with the inhibition of myosin phosphorylation and
lowering the intracellular concentration of calcium ions (myosin phosphorylation and calcium ions are
necessary for muscle contractions). The increase in cAMP also inhibits inflammatory cells in the airway, such
as basophils, eosinophils, and most especially mast cells, from releasing inflammatory mediators and
cytokines. Salbutamol and other β2 receptor agonists also increase the conductance of channels sensitive to
calcium and potassium ions, leading to hyperpolarization and relaxation of bronchial smooth muscles.
Tolazoline
Tolazoline is a non-selective competitive α-adrenergic receptor antagonist. It is a vasodilator that is used to
treat spasms of peripheral blood vessels (as in acrocyanosis). It has also been used (in conjunction with
sodium nitroprusside) successfully as an antidote to reverse the severe peripheral vasoconstriction which can
occur as a result of overdose with certain 5-HT2A agonist drugs
CN
C2H5OH
NH
O
CH3
NH2
NH2
N
H
N
phenylacetonitrile ethyl
2-phenylethanimi
doate
2-benzyl-4,5-dihydro-
1H-imidazole
ethane-1,2-diamine
4 mg/kg
Phenylephrine
Phenylephrine is a selective α1-adrenergic receptor agonist of the phenethylamine class used primarily as
a decongestant, as an agent to dilate the pupil, to increase blood pressure, and to relieve hemorrhoids.
Phenylephrine is marketed as an alternative for the decongestant pseudoephedrine, although clinical
trials show phenylephrine, taken orally at the recommended dose.

32. OH
OH
CH3
+ CH3 NH2
OH
OH
NH
CH3
3-(1-hydroxypro
pyl)phenol
methanamine
3-[1-hydroxy-2-(methyla
mino)ethyl]phenol
heat
PhenylephrineDose: 2 to 5 mg IM/SC every 1 to 2 hours as needed
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