Adrenergic Agents Dr.Noor H.

Aldabagh \\
And related compounds PhD. Pharmaceutical Chemist ry
------------~- ...::-~ l-:-\/ _I 10 -

Adrenergic Receptors
The diverse physiological responses of CAs (Catecholamines), · are
mediated via a 1, a h and ,8-adrenoceptors, which are further divided into a
number of subtypes. They all belong to the superfamily of (G-protein)
coupled receptors (GPCR). Elucidation of the characteristics of these
receptors and the biochemical and physiological pathways they regulate has
increased our understanding of the seemingly contradictory and variable
effects of CAs on various organ systems. Although structurally related,
different receptors regulate distinct physiological process by controlling the
synthesis or release of various second messengers. An important factor in
the response of any cell or organ to adrenergic drugs is the density and
proportion of a- and ,B-adrenoceptors. The various adrenoceptor types and
subtypes are not uniformly distributed with certain tissues conlaining more
of one type than another.

a-Adrenergic Receptors
the discovery that ce1iain adrenergic agonists and antagonists exhibited
various degrees of selectivity fo r presynaptic and postsynaptic a recepto rs
led to the proposal Lhal pustsynaptic u. -receptors be designated o: 1 and that
presynaptic a-receptors be referred to as a2 . Later, a functional
classification of the a-receptors was proposed wherein o: 1-receptors were
designated as those that were excitatory, while arreceptors purportedly
mediated inhibitory responses (Activation of a 2-receptors leads to a
reduction in the ·catalytic activity of CAs ).
a-Receptors of the CNS and in peripheral tissues perform a number of
important physiological functions. In particular, a-receptors are involved in
control of the cardiovascular system. For example, constriction of vascular
smooth muscle is mediated by both a 1and a2 receptors, though the
 Adrenergic Agents Dr.Noor H. Aldabagh
And related co_m pounds -Ph.D. Pharmaceutical Chemisffy .
~--~~
- ~--- -
- - -~

predominant ~eceptor_ mediating this effect is o: 1. In the heart, activation of

a 1-receptors results in a selective inotropic response with little or no change
in heart rate. This is in contrast to the ,Brreceptor, which is the predominant
receptor in the heart, mediating both inotropic and chronolropic effects. In
the brain, activation of postjunctional o:rreceptors reduces sympathetic
outflow from the CNS, which in tum causes a lowering of blood pressure.
The prototypical o:rreceptor is the presynaptic a-receptor found on the
tenninal sympathetic neuron . Interaction of this receptor with agonists such
as NE and E results in inhibition of NE release from -the neuron. The o:r
receptors not only play a role in the regulation of NE release but also
regulate the release of other NTs, such as acetylcholine and serotonin. Both
o. 1- and o:rreceptors also play an important role in the regulation of several

metabolic processes, such as insulin secretion and glycogenolysis.

P-Adrenergic Receptors
Three ,B-receptor subtypes have been cloned, including /Ji, /J2, ·and /J3 . The
/J-adrenoceptor subtypes also differ in terms of the rank order of potency of
the adrenergic receptor agonists NE, E. The ,8 1-receptors are located mainly
in the heart, where they mediate the positive inotropic and chronotropic
effects of the CAs. They are also found on the juxtaglomerular cells of the
kidney, where they are involved in increasing renin secretion. The /Jr
receptors are located on smooth muscle throughout the body, where they
are involved in relaxation of the smooth muscle, producing such effects as
bronchodilation and vasodilation. They are also found in the liver, where
they promote glycogenolysis. The /J3-receptor is located on brown adipose
tissue and is involved in the stimulation of lipolysis.
 Adrenergic Agents Dr.Noor H. A ldab agh
And related compounds Ph.D. Pharmaceutical Chemist1y
~~~~~~~~~~ ~

Sympathomimetic Agents
Sympathomimetic agents produce effects resembling those produced by
stimulation of the sympathetic nervous system. They may be classified as
agents that produce effects by a direct, indirect, or mixed mechani sm of
action. Direct-acting agents elicit a sympathomimetic response by
interacting directly with adrenergic receptors. Indirect-acting agents
produce effects primarily by causing the release of NE from adrenergic
nerve terminals; the NE that is released by the indirect-acting agent
activates the receptors to produce the response. Compounds with a mixed
mechanism of action interact directly with adrenergic receptors and
indirectly cause the release of NE. The mecnanism by which an agent
produces its sympathomimetic effect is related intimately to its chemical
structure.

(I) Direct-Acting Sympathomimetic

Structure-Activitv Relationships,·
The parent structure with the features m common for many of the
adrenergic drugs is /J- phenylethylamine. The manner in which /J-
phcny lethy lam ine is substituted on the meta- and para-pos itions of the
aromatic ring, on the amino (R 1), and on a-(R2), and /J-positions of the
ethylamine side chain influences;
• Their mechanism of action. • Metabolism, degradation,
.... . . .· • The receptor selectivity . arid thus duration of action-

• Absorption. (DOA).

• Oral activity.
For the direct-acting sympathomimetic amines, maximal activity is seen in
/J-phenylethylamine derivatives containing (a) a catechol and (b) a (lR)-OH
group on the ethylamine portion of the molecule. Such structural features
are seen in the prototypical direct-acting compounds NE, E, and ISO.
 Adrenergic Agents Dr.Noor H. Aldabagh
And related compo_
u n_d_s_ _ _ _ _ _ _ _ _ _ _
Ph_D_.P_h_a_rm_aceutical Chemistry . ',
- -. -1 13
A critical ·factor in the interaction of adrenergic agonists with their
receptors is stereoselectivity. Substitution on either carbon-1 or carbon-2
yields optical isomers. (JR, 2S) isomers seem correct configuration for
direct-acting ·activity.
It appears that for all direct-acting, phenylethylamine-derived agonists that
are structurally similar to NE, the more potent enantiomer is capable of
assuming a conformation that results in the ·arrangement in space of the
catechol group, the amino group, and the (lR)-OH group in a fashion
resembling that of ( lR)-NE. This explanation of stereoselectivity is based
on the presumed interaction of these three critical pharmacophoric groups
with three complementary binding areas on the receptor and is known as
the "Easson-Stedman hypothesis". This was illustrated in the following
figure;

OH
OH .......

Asp 113

Separation ofAromatic Ring and Amino Group.

The greatest adrenergic activity occurs when two carbon atoms separate the
aromatic ring from the amino group, as in E and NE. This rule applies with
few exceptions to all types of activities.
 \ .

.'
Adrenergic Agents Dr.Noor H. Aldabagh ·\
And related compounds Ph.D. Pharmaceutical Chemistry
~~~~~~~~~~- ~

. -\
\
RI, Substitution on the Amino Nitrogen Determines o.- or P-Receptor
Selectivity.
The amine is normally ionized at physiological pH. Thi s is impo1iant for
direct agonist activity, because replacing nitrogen with carbon results in a
large decline in activity. The activity is also affected by the number of
substituents on the nitrogen. Primary and secondary amines have good
adrenergic activity, whereas tertiary amines and quaternary ammonium
salts do not. The nature of the amino substituent also dramatically affects
the receptor selectivity of the compound. As the size of the nitrogen
substituent increases, a-receptor agonist activity generally decreases and /J-
receptor agonist activity increases. Thus, NE has more rx-activity than /]-
activity and E is a potent agonist at a-, /31-, and /Ji-receptors. Isoprotrenol
(ISO), however, is a potent /J 1- and /Jragonist but has little affinity for ex-
receptors .
. These results indicate that the ~-receptor has a larger lipophilic binding
pocket adjacent to the amine-binding aspartic acid residue Lhan Jo lhe a-
receptors.

OH
I 11 •• •• ••
HO ...__~ / ' - . _ / N.;_ ':
• .• H .•

HO
.
•

\,_ ••••
. I

Norepinephrine (NE) Epinephrine (E)

a > f3 agonist a , J3 1 and f3z agonist
a. agonist nonselective a and jj agonist

The nature of the substituents can also affect /3 1- and /Jr receptor
selectivity. In several instances, it has been shown that N-tert-butyl group
enhances /3z-selectivity. For example, N-tert-butylnorepinephrine (Colterol)
 A d renergic Agents Dr.Noor H. A ldabagh
A nd related compounds Ph.D. Pharmaceutical Chemistry
- _. _-_- - - - - -_- - -
__ ~ .

· is 9 to 10 times more potent as an agonist at tracheal ..Brreceptors than at

cardiac ..B 1-receptors.
OH H •.•
HO N.y_.-\.
HO :'- .• . ••. :

lso pro terenol ( ISO) N ~ r - B u ty l n o rep inephr i.n e (Colterol)

~1 1
and 13 2 agon ists
nonselective 13 agonist selective 13 2 agonist

Increasing the length of the alkyl chain offers no advantage, but if a polar
functional group is placed at the end of the alkyl group, the situation
changes. In particular, adding a phenol group to the end of alkyl chain
results in a dramatic rise in activity, indicating that an extra polar-binding
region has been accessed, which can take part in H-bonding. Large
subs tituents on the amino group also protect the amino group fro m
undergoing oxidative deamination by MAO.

Exten sion analog

ll l
Extra bind ing interaction

R2, Substitution on the a-Carbon (Carbon-2).

Substitution by small alkyl group (e.g., CH3 - or C2H 5-) slows metabolism
by MAO but has little overall effect on DOA of catechols because they
remain substrates for COMT. However, the resistance to MAO activity is
more important in noncatechol indirect-acting phenylethylamines. The
DOA of drugs such as ephedrine or amphetamine is thus measured in hours
rather than in minutes. Because addition of small alkyl group increases the

6
 Adrenergic Agents Dr.Noor H. Aldabagh
And related compounds PhD. Phannaceutical Chemistry

~
resistance to metabolism and lipophilicity, such compounds often exhibit
enhanced oral effectiveness and greater CNS activity than their
counterparts that do not contain an o:-alkyl group.

Ephed ri ne (Log P = 1.05) Methamphetamine (log P = 1.97)

more o. and [3 activity less lX and ~ activity
less lipophilic -f less CNS activity more lipophilic -f more CNS activity

In addition, compounds with an o:-methyl substituent persist in the nerve

terminals and are more likely to release NE from storage sites . .For
example, metaraminol is an u.-agonist and also exhibits a greater degree of
indirect sympathomimetic activity.
OH

HO NH;,

~ ~ "'~.

~,CH;i.:

Metaraminol

Methyl or ethyl substitution on the a -carbon of the ethylamine side chain

reduces direct agonist activity at both a- and ,B-receptors. a-Substitution
also significantly affects receptor selectivity. An ethyl group in this
position diminishes a-activity far more than ,B-activity, affording
compounds with ,B-selectivity (e.g. , ethylnorepinephrine and isoetharine ).
OH
H .
HO
NYCH3
,. •· ··•·. a-ethyl group results in:
:' '. CH3
HO ( CH3;
~2 activity< ISO
resistant to MAO metabolism

lsoetharine

1·
 Adrenergic Agents Dr.Noor H. Aldabagh
And related compounds Ph.D. Phannaceutical Chemistry
.----. ~

In the case of ,B-receptors, for example, a-ffiethyl or ethyl substitution

results in compounds toward the ,Brselectivity, whereas in the case of a-
receptors, a-methyl substitution gives compounds toward the a 2-
selectivity. Another effect of a-substitution is the introduction of a chiral
center, which has pronounced effects on the stereochemical requirements
for activity. For example, with a-methylnorepinephrine, it is the erythro
( 1R,2S) isomer that possesses significant activity at o:rreceptors.

HO

HO

(1 Ft 2S}-a-Methylnorepinephrine
active isomer
selective a,2 agonist

OH substitution on the P-carbon (carbon-1)

Generally decreases CNS activity largely because it lowers lipid solubility.
Ho wever, such substitution greatly enhances agonist activity at both ,B- and
a -receptors. For example, ephedrine is less potent than methamphetamine
as a central stimulant, but it is more powerful in dilating bronchioles and
increasing blood pressure and heart rate. Compounds lacking the ,B-OH
group (e.g. DA) have a greatly reduced adrenergic receptor activity. Some
of the activity is retained, indicating that the OH group is important but not
·-
essential. The R-enantiomer of NE is more active than the S-enantiomer,
indicating that the secondary alcohol is involved in an H-bonding
interaction.
 Adrenergic Agents Dr.Noor H. Aldabagh
And related compounds Ph.D. Pharmaceutical Chemis ll
~~~~~~~~~~ ~

Substitution on the Aromatic Ring.

Maximal a- and ,8-activity also depends on the presence of 3' and 4' OH
groups . Tyramine, which lacks two OH groups, has no affinity for
adrenoceptors , indicating the importance of the OH groups. Studies of ,8-
adrenoceptor structure suggest that the OH groups on serine residues 204
and 207 probably form H-bonds with the catechol OH groups at positions
3' and 4', respectively.
Although the catechol moiety is an important structural feature in terms of
yielding compounds with maximal agonist activity at adrenoceptors, it can
be replaced with other substituted phenyl moieties to provide selective
Rdrenergic agonists . This approach has been used in particular in the des igL
of selective ,Bragonists. For example, replacement of the catechol function
of ISO with the resorcinol structure gives a selective ,Bragonist,
metaproterenol. Furthermore, because the resorcinol ring is not a substrate
for COMT, ,8-agonists that contain this ring structure tend to have better
. absorption characteristics and a longer DOA than their catechol-containing
counterpaiis. ln another approach, replacement of the meta-OH of the
catechol structure with a hydroxymethyl group gives Rgents, such as
albuterol , \vhich sho 'v sel ecli vity tu the /J2-receptor. Uecausc they arc not
catechols , these agents are not metabolized by COMT and thus show
improved oral bioavailability and longer DOA.
OH

HOy·
.
OH
.. ~

HO
••!! .....
'~
( CH10H.) OH
...........

Metaproterenol Albuterol Resorcinal

selective 02 agonist selective B2 agonist
not metabolized by COMT ~ not metabolized by COMT ~
better absorption & longer DOA better oral bioavailability
 Adrenergic Agents Dr.Noor H. Alda bagh ,,
And related compounds Ph. D. Pharmaceutical Chemistry
- - - -_- _
-- · - - - _- _- __- - - - -~---

Modifrcation of the catechol ring can also bring about selectivity at a-

receptors as it appears that the catechol moiety is more important for o.r
activity than for o. 1-activity. For example, removal of the p-OH group from
E (Epinephrin), gives phenylephrine, which, in contrast to E, is selective
for the a 1-receptor. Phenylephrine is less potent than E at both a- and /3-
receptors, with ,Bractivity almost completely absent.

Phenylephrine
less a and Bactivity than NE
selective a 1 agonist
almost no p activity

However, the OH group can be replaced by other groups capable of

interacting with the binding site by H-bonding. This is particularly true for
the meta-OH group, which can be replaced by CH2 0H, l\THMe, NHCOR,
NMe 2, or NHS0 2R group .

Catecho!am;nes (CA) w;thout OH Groups.

Phenylethylamines that lack OH groups on the ring and the /3-0H group on
the side chain act almost exclusively by causing the release of NE from
sympathetic nerve terminals and thus results in a loss of .direct
sympathomimetic activity. Because substitution of OH groups on the
phenylethylamine structure makes the resultant compounds less lipophilic,
unsubstituted or alkylsubstituted compounds cross the BBB more readily
and have more central activity. Thus, amphetamine and methamphetamine
exhibit considerable CNS activity. CAs per oral have only a brief DOA and
are almost inactive, because they are rapidly inactivated in the intestinal

(o
 Adrenergic Agents Dr. Noor H. A lda bagh
\·
I

A nd related compounds Ph.D. Phannaceutical Chemistry

·1·' t.,
~ \
mucosa and in the liver before reaching the systemic circulation. Jn
contrast, compounds without one or both phenolic OH substituents are,
however, not metabolized by COMT, and they are orally active and have
longer DOA.

!111idazolines and a-Adrenergic Agonists.

Al though nearly all ,B-agonists are ,B-phenylethanolamine derivati ves, it is
o:-adrenoceptors that exhibit a far more diverse assortment of structures. A
second chemical class of o:-agonists, the imidazolines, which give rise to a
agonists and are thus vasoconstrictors. These imidazolines can be
nonselective, or they can be selective for either al- or a2-receptors.
Structurally, most imidazolines have their heterocyclic imidazoline nucleus
li11ked to a substituted aromatic moiety via some type of bridging unit.
The optimum bridging unit (X) is usually a single methylene group or
amino group . Although modification of the imidazoline ring generally
. results in compounds with significantly reduced agonist activity, there are
examples of so-called open-ring imidazolines that are highl y active. The
nature of the aromatic moiety, as well as how it is substituted, is quite
t1exible. Ho \veve r, J.gonisl activily is enhance<l when Lhe aromatic ring is
substituted with halogen substituents like chlorine (Cl) or small alkyl
groups like methyl group, particularly when they are placed in the two
· ortho positions. Because the SARs of the imidazolines are quite different
from those of the ,8-phenylethylamines, it has been postulated that the
imidazolines interact with a-receptors differently from the way the ,B-
phenylethylamines do, particularly with regard to the aromatic moiety.

Aromatic moiety { Ar-x-{J }

............... H
lmidazoline ring
.
Bridging unit
X::; usually CH 2 (a 1 agonrsts) or NH (a 2 agonists)

//
 Adrenergic Agents Dr.Noor H. Aldabagh .
And related compounds Ph.D. Phannaceutical Chemistry
-- -- _- - - - - - -_
-_
- _- - ----- - I ?l_, --~

- Xylometazoline; Oxymetazofinq, Tetrahydrozoline, and ·Naphazuline.

These agents are 2-arylimidazolines with a 1-agonists, used for their
vasoconstrictive effects as nasal and ophthalmic decongestants. They have
limited access to the CNS , because they essentially exist in an ionized form
at phys iological pH caused by the very basic nature of the imidazoline ring
(pKa =10-11).

lmidazoline molty
pKa 9-10
Limited access to the CNS

Naphazoline

Tetrahydrozoline R=

C(CH3}3
Oxymetazoline

Xylometazoline

r z__
 Adrenergic Agents Dr.Noor H. Aldabagh
And related compounds Ph.D. Pharmaceu_ tical Chemistry
~~~~~~~~~----------i...::_

Clonidine (Catapres/RJ
Differs from 2-arylimidazoline o: 1-agonists mainly by the presence of 0-
chlorine groups and a NH bridge. The 0-chlorine groups afford better
activity than 0-methyl groups at o:2 sites. Importantly, clonidine contains a
NH bridge (aminoimidazolines) instead of CH2 bridge in 2-arylimidazoline.
The uncharged form of clonidine exists as a pair of tautomers as shown
below. Clonidine is an example of a (phenylimino) imidazolidine
derivative that possesses central o:2-selectivity.
a 2 agonistic activity
guanidine group
I Cl ----------
t
Cl t

R
-Q-N =< J ~ R__r{_~!{J
~- CN
\ct a Under certain conditions,
such as intravenous infusion, clonidine can briefly exhibit vasoconstrictive
activity as a result of stimulation of peripheral a-receptors. However, this
hypertensive effect, if it occurs, is followed by a much longer-lasting
hypotensive effect as a result of the ability of clonidine to enter into the
CNS and stimulate o:rreceptors located in regions of the brain. Stimulation
of these arreceptors brings about a decrease in sympathetic outflow from
the CNS , which in turn leads to decreases in pcriphc.ral vascular resistance
and blood pressure. This pharmacological actions have made clonidine
quite useful in the treatment of hypertension. The ability of clonidine and
its analogs to exert an antihypertensive effect depends on the ability of
these compounds not only to interact with the o:z-receptor in the brain but
also to gain entry into the CNS. For example, in the case of clonidine, the
basicity of the guanidine group (typically pKa = 13.6) is decreased to 8.0
(pKa of clonidine) because of the inductive and resonance -effects of the
dichlorophenyl ring. Thus, at physiological pH, clonidine will exist to a
significant extent in the nonionized form required for passage into the
CNS. It has an oral bioavailability of more than 90%.

1.3
 Adrenergic Agents Dr.Noor H. Aldabagh
A_n(j. related compounds _ PhD. P(iannaceutica1 CJ:ief!Listry
- =
=====-==~====== ~ ------

-(JI) lnditect~Acting Sympathomimetics -

Indirect-acting sympathomimetics act by releasing endogenous NE. They
also enter the nerve ending by way of the active-uptake process and
displace NE from its storage granules.

Structure activity Relationship,·

• As \Vith the direct-acting agents, the presence of the catechol OH
groups enhances the potency of indirect-acting phenylethylamines.
However, the indirect-acting drugs that are used therapeutically are
not catechol derivatives and, in most cases, do not even contain an
__ OH moiety.
• In contrast with the direct-acting agents, the presence of a ,B-hydroxyl
group decreases, and an a-methyl group increases, the effectiveness
of indirect-acting agents.
• The presence of nitrogen substituents decreases indirect activity,
with substituents larger than methyl groups rendering the compound
virtually inactive. Phenylethylamines that contain a tertiary amino
group are also ineffective as NE-releasing agents.
Hydroxvamphetamine is an effective, indirect-acting sympathomimetic
drug. It differs from amphetamine in the presence of p-OH group and so it
has little or no CNS-stimulating action. It is used to dilate the pupil for /
diagnostic eye examinations ·and for surgical procedures on the eye. It is
sometimes used with cholinergic blocking drugs like atropine to produce a
mydriatic effect, which is more pronounced than that produced by either
drug alone.

HO
 Adrener[Jic Agents Dr.Noor H. Aldabagh
And related compounds PfLD. Pharmaceutical Chemistry
~~~~~~~~~-~

L -(+) -Pseudoephedrine. Is - the (-1 S,2S) diastereoisomer of ephedrine.

Whereas ephedrine has a mixed mechanism of action, L-(+)-
pseudoephedrine acts mostly by an indirect mechanism and has virtually no
direct activity. The structural basis for this difference in mechanism is the
stereochemistry of the carbon atom possessing the ,B-OH group. In
pseudoephedrine, this carbon atom possesses the (S) configuration, the
wrong stereochemistry at this center for a direct-acting effect at
adrenoceptors. This agent is found in many OTC nasal decongestant and
cold medications.

(Ill) Sympathomimetics with a Mixed Mechanism of Action

Those phenylethylamines considered to have a mixed mechanism of ~ction
.usually have no hydroxyls on the aromatic ring but do have a ,B-hydroxyl
group.
D-{-)-Ephedrine. The phannacological activity of ( 1R,2S)-D-(-)-ephedrine
resembles th at of E. The drug acts on both o.- and ,B-receptors. Its ab ility to
activate ,B-receptors probably accounled for its earlier use in asthma. It is
the classic example of a sympathomimetic with a mixed mechanism of
action.

(~
 Adrene'rgic Agents . Dr.Noor'H. Aldaqagh
And related co mpounds PhD. Pharmaceutical Chemis try
===-=-=-==~=~""""""""""'_,,.,,,,,,..,... ........ -~ ----

Adrenergic Receptor Antagonists (Blockers)

P-Blockers:
Structure Activity Relationshin·
,8-Blockers are among the most widely employed antihypertensives and are
also considered the first-lin e treatment fo r glaucoma. Most of ,8-blockers
are in the chemical class of "aryloxypropanolamines ".
Propranolol belongs to the group of ,8-blockers known as
ary loxypropanolamines. This term reflects the fact that an -OCHr group
has been incorporated into the molecule between the aromatic ring and the
ethylamino side chain. Because this structural feature is frequently found in
,8-blockers, the assumption is made that the -OCHr group is responsible for
the antagonistic properties of the molecules. However, this is not true; in
fact,_the -OCHr group is present in several compounds that are potent ,8-
agonists.
The nature of the aromatic ring and its substituents that is · the primary
determinant of ,8-antagonistic activity. The aryl group also affects the
absorption, excretion, and metabolism of the ,8-blockers. The nature of the
aro matic ring is also a determ inant in their ,Brselectivity. One common
structural feature of many cardioselective ~ 1 -blockers is the presence of a
para-substituent of sufficient size on the aromatic ring along with the
absence of meta-substituents.
Like ,8-agonists, ,8-directing tert-butyl and isopropyl · groups, are normally
found on the amino function of the aryloxypropanolamine ,8-blockers. It
must be a secondary amine for optimal activity. For arylethanolamine
adrenergic agonists, the ,8-0H substituted carbon must be in the R absolute
configuration for maximal direct activity. However, for ,8-blockers, the ,B-
OB-substituted carbon must be in the S absolute configuration for maximal
,8-blocking activity.
_ Adrenergic Agents P r.Noo{ H. Aldabagh
And .related compounds PhD. Pharmaceutical Chemist ry
~~~~~~~~~-~

Q-Blockers can be classified according to their selectivity,·

(I) Nonselective P-Blockers
Propranolol (Inderal) is nonselective ,B-blocker. It blocks the /Ji- and /Jr
receptors with equal affinity, and does not block a -receptors. Propranolol,
like the other ,B-blockers discussed, is a competitive blocker whose
receptor-blocking actions can be reversed with sufficient concentrations of
/J-agonists . Propranolol is approved for use in the United States for
hypertension, cardiac arrhythmias, angma pectoris, postmyocardial
infarction, hypertrophic cardiomyopathy, pheochromocytoma, m1grame
prophylaxis, and essential tremor. In addition, because of its high
lipophilicity and thus its ability to penetrate the CNS , propranolol has
found use in treating anxiety and is under investigation for the treatment of
a variety of other conditions, including schizophrenia, alcohol withdrawal
syndrome, and aggressive behavior.

..
· (-~~NliCH(CH3)2
·-·····1

o5 §

Propranolo l
Oli

(II) Selective fh.-Blockers

Cardioselective /J 1-blockers are drugs that have a greater affinity for the /J 1-
receptors of the heart than for /Jr receptors in other tissues.
Such cardioselective agents should provide two important therapeutic
advantages;
1. The lack of a blocking effect on the /Jrreceptors in the bronchi.
Theoretically, this would make /Ji-blockers safe for use in patients
who have bronchitis or bronchial asthma.

IT
 Adrenergic Agents Dr.Noor H Aldabagh
And related compounds Ph D. Pharmaceutic({l ~h_emi$t!Y .
-- ---- ~~~~~==~...........,... _ _..........___ _ _ ~ - -

2. The ab'.Jence of blockade of the vascular .Br receptors, which mediate

vasodilation. This would be expected to reduce or eliminate the
increase in peripheral resistance that sometimes occurs after the
administration of nonselective ,8-blockers.
U nfo rtunately, cardioselectivity is usually observed with ,8 1-blockers at
only relatively low doses. At normal therapeutic doses, much of the
selectivity is lost.

O~NHCH(CH3}i O~NHCH(CH3}i
A OH
OH

y
/ CHzCONH2

Atenolol: antihypertensive
CH20 CH2CH20CH(CH3f.!

Bisoprolol: antihypertensive Metoprolol: antihypertensive

O~NHCH(CH3}i
A
/
OH

y CH2CH 20CH2--<:J
Betaxolol: antihypertensive & antiglaucoma Esmolol: short-a cting antihypertensive

Examples of p1 selective antagonists

I~