Dr. Nadia Haress
Adrenergic Agents
Adrenergic
drugs
are
those
chemical
agents
that
exert
their
pharmacological and therapeutical effects by acting at the peripheral sites of the
sympathetic division of the autonomic nervous system.
These agents or drugs act by either enhancing the sympathetic nervous
activity, i.e. produce effects similar to stimulation of sympathetic nervous activity
(Fight or Flight responses, e.g. an increase in heart rate, rise in blood pressure
and dilating of eye pupils) and they are known as sympathomimetics,
adrenomimetics, or adrenergic stimulants. Or inhibiting the sympathetic
nervous activity and are known as sympatholytics, antiadrenergics, or
adrenergic blocking agents.
Adrenergic Neurotransmitters
The adrenergic neurotransmitter that is liberated from postganglionic
sympathetic neurons – as a result of sympathetic nerve stimulation – is
norepinephrine (NE). After the release of NE from the sympathetic nerve ending
into the synaptic cleft, it interacts with specific postsynaptic receptors on the
effector organ (e.g., a gland, smooth muscle or cardiac muscle) resulting in
muscle contraction or relaxation, glandular secretion, or any physiological
response that is characteristic of the effector organ or tissue.
1
The action of NE at adrenergic receptors is terminated by a combination
of processes including:
1.
Uptake into neurons and extraneuronal tissues.
2.
Diffusion away from the synapse.
3.
Metabolism.
Epinephrine is also an endogenous adrenergic neurotransmitter but it is
not released from sympathetic nerve endings as NE. Epinephrine is synthesized
and stored in adrenal medulla from which it is released into circulation to
various organs and tissues where it exerts its effects at adrenergic receptor sites;
and is often known as neurohormone.
Termination of epinephrine activity occurs mostly via metabolism.
Chemistry of Adrenergic Neurotransmitters:
NE and epinephrine contain catechol function (3,4-dihydroxyphenyl
moiety) in their structure, and they belong to a class known as catecholamines.
They contain both acidic (aromatic hydroxyls OH’s) and basic (aliphatic
amine) functional groups.
At physiological pH (7.4), NE and epinephrine have been found to exist in
more than 95% in the cationic form in which nitrogen is protonated. This largely
accounts for the higher degree of water solubility of these chemicals.
2
HO
HO
CH CH2 NH2
CH CH 2 NHCH3
OH
OH
HO
HO
Epinephrine
Norepinephrine
HO
CH CH 2 NH 2 R
OH
HO
R = H or CH 3
Cationic Form of NE and Epinephrine
Biosynthesis of Catecholamines:
Catecholamines biosynthesis takes place in adrenergic and dopaminergic
neurons in the central nervous system, in sympathetic neurons in autonomic
nervous system and in adrenal medulla.
The biosynthetic steps, substrates and enzymes involved are shown in the
following figure:
Norepinephrine biosynthesis takes place by a three-step process:
3
1.
Conversion of tyrosine to L-dihydroxyphenylalanine (L-DOPA)
catalyzed by tyrosine hydroxylase. This step is the rate-limiting
process in catecholamine biosynthesis. Tyrosine hydroxylase is
inhibited by α-methyltyrosine (metyrosine).
2.
Decarboxylation of L-DOPA to produce dopamine catalyzed by
L-aromatic amino acid decarboxylase (DOPA decarboxylase) and is
inhibited by Methyldopa.
3.
Stereospecific hydroxylation of dopamine to produce NE catalyzed
by dopamine β-hydroxylase which is inhibited by disulfiram.
In the adrenal medulla , a 4th biosynthetic reaction takes place by which
NE
is
converted
to
epinephrine
catalyzed
by
phenylethanolamine
N-methyltransferase (PNMT).
Metabolism of Catecholamines:
Two principal enzymes involved in catecholamines metabolism are the
monoamine oxidase (MAO) and catechol O-methyltransferase (COMT).
MAO has role in the metabolism of intraneuronal catecholamines,
whereas COMT acts primarily upon catecholamines that enter the circulation and
the extraneuronal tissues.
MAO acts via oxidative deamination of catecholamines.
R
CH2 NH2
R
CH NH
4
R
CHO + NH4
COMT methylates almost exclusively the meta-hydroxyl group of
catecholamines.
The following scheme demonstrates the different metabolic pathways of
catecholamines (Norepinephrine and Epinephrine):
Metabolism of Norepinephrine : MAO, monoamine oxidase; COMT,
catechol-O-methyltransferase; DOPGAL, 3,4-dihydroxyphenylglycolaldehyde; AR,
aldehyde reductase; AD, aldehyde dehydrogenase.
Norepinephrine is initially metabolized to DOPGAL by monoamine
oxidase and to normetanephrine by catechol-O-methyltransferase. Each of the
initial products may, in turn, be further metabolized and these metabolites are
subject to further metabolism via phase II conjugation.
Adrenergic Receptors
Careful analysis of different drugs acting on the sympathetic nervous
system either as agonists or antagonists have revealed that there are two types
5
of adrenergic receptors: α- and β-receptors which are further subclassified into
α1 and α2 receptors and β1 and β2 receptors, respectively.
Postganglionic sympathetic neuron, synaptic cleft, and effector cell.
The receptors activation may result in:
1.
α1-Adrenergic Receptors: ↑ Vasoconstriction so they ↑ B.P. (used
in treatment of hypotension) relaxation of GIT smooth muscle,
salivary secretion and hepatic glycogenolysis.
2.
α2-Adrenergic Receptors:  Transmitter release, including Ach,
NE from the autonomic nerves, i.e., it  sympathetic responses
(used in treatment of hypertension i.e.  B.P.).
3.
β1-Adrenergic Receptors: ↑ Cardiac rate and force (used in
treatment of heart failure and shock) and relaxation of GIT smooth
muscle.
4.
β2-Adrenergic Receptors:
↑ Bronchodilatation, vasodilatation
and smooth muscle relaxation (used in treatment of asthma). Also

uterine
contraction
(during
glycogenolysis and muscle tremors.
6
premature
laour),
hepatic
7
Adrenergic Agonists (Sympathomimetics)
According to the mechanism of action, sympathomimetic agents may be
classified – as producing their effects – into:

Direct-acting Agents that elicit their response by interacting directly
with adrenergic receptors.

Indirect-acting Agents which initiate the release of NE from adrenergic
nerve terminals resulting in activation of the receptors.

Mixed Function agonists that interact directly with adrenergic receptors
and initiate the release of NE.
Direct-Acting Sympathomimetics (SAR):

Prototypical direct-acting sympathomimetics are NE, epinephrine and
isoproterenol.

These compounds are phenylethanolamine derivatives (phenethylamine) that contain the appropriate substituents.

They have the following structural features:
meta
CH CH2 NH2
para


8
1. Catechol hydroxyl groups in the meta- and para-positions of the
aromatic ring relative to the phenethylamine moiety.
2. β-Hydroxyl group on the ethylamine portion of the molecule.
3. Amino group is essential, either primary or secondary, but the tertiary
analogues are poor direct agonists.
4. Two carbon atoms separating the amino group from the aromatic ring
for providing optimal activity.
5. Methyl substitution on the α-carbon increases the duration of action of
phenethylamine agonists by making the compound resistant to
metabolic deamination by MAO.
6. Proper stereochemistry of the β-hydroxyl group enhances the activity
of NE and other catecholamines since it is involved in the binding of
the compound with the adrenoreceptor, e.g. (-) NE is more active than
the other enantiomer (stereoselectivity).
Interaction of the Enantiomers of Epinephrine with Adrenergic Receptors
Interaction of epinephrine isomers with adrenoreceptors
9
Notice that the (-) isomer can fit itself via three points of interaction with
the receptor, while (+) isomer has only two. Hence, the (-) isomer has higher
affinity and activity.
Direct-acting Sympathomimetic Classification:
a)
Non-selective (α, β-Agonists)
These agents show no selectivity towards different types of adrenergic
receptors.
The general medicinal use of these agents relies on their
vasoconstricting activity.
b)
Selective (α1, α2, β1 and β2)
These agents show a certain selectivity towards different types of
receptors.
a)
Direct Non-selective Agonists:
*Norepinephrine
OH
2
HO
3
HO
4
NH2
1
6
5
[R(-)-2-amino-1-(3,4-dihydroxyphenyl)ethanol]

NE has limited clinical application because of its nonselective action, which
causes both vasoconstriction and cardiac stimulation. In addition, it must be
given intravenously because it has no oral activity (poor oral bioavailability)
10
as a result of its rapid metabolism by intestinal and liver COMT and MAO.
This rapid metabolism also limits its duration of action (1 or 2 minutes).

NE is used to ↑ blood pressure in acute hypotension.
*Epinephrine
OH
HO
H
N
CH3
HO
[R(-)-1-(3,4-dihydroxyphenyl)-2-(N-methylamino) ethanol]

Epinephrine is similar to NE in its limited clinical application. In
addition to ↑ B.P. in acute hypotension, it is used intravenously and in
inhalers to relieve the bronchioconstriction in asthma and in
anaphylactic reactions (β2 activity).

Due to its significant α-activity epinephrine is used in nasal
decongestants ( constriction of the dilated nasal blood vessels).
b)
Direct Selective α1-Agonists:
*Phenylphrine
[R(-)-1-(3-hydroxyphenyl)-2-(N-methylamino)ethanol]

It is potent vasoconstrictor and orally active because it is not substrate
for COMT, consequently, its duration of action is longer than NE.
11

Uses
1. ↑ B.P.
2. Nasal decongestant
3. Dilate the pupil during eye surgery.
*Methoxamine
OH
NH2
HO
HO
CH3O
CH3

It is less potent than phenylephrine in vasoconstriction.

Uses: Maintains B.P. with spinal anesthesia.
*Metaraminol
Uses: Maintains B.P. with spinal anesthesia similar to methoxamine.
c)

2-Arylimidazoline Selective α1-Agonists:
Some imidazoline derivatives, are also selective 1-agoists and
therefore, are called vasoconstrictors/vasopressors.

Uses: Decongestive agents, in the form of hydrochloride salts and eye
drops.
12
*Xylometazoline Hydrochloride (Otrivin)

HCl
2-(4-t-Butyl-2,6-dimethylbenzyl)-2-imidazoline monohydrochloride
*Naphazoline Hydrochloride (Prisoline, Naphcon)
2-(1-Naphthylmethyl)-2-imidazoline HCl
*Oxymetazoline Hydrochloride (Afrin, Visine)
d)
2-Aminoimidazoline and Other Related Selective 2-Agonists:
* Clonidine (Catapres, Captopress)
2-(2,6-Dichloroanilino)-2-imidazoline
or
N-(2,6-dichlorophenyl)-4,5-dihydroimidazole-2-amine
13

Clonidine was originally synthesized as a vasoconstricting nasal
decongestant but, in early clinical trials was found to have dramatic
hypotensive effects. This is due to that clonidine not only has some 1agonist (vasoconstrictive) properties but also it is a powerful central
2-agonist causing inhibition of the sympathetic outflow.

So, the initial dose of clonidine may produce a transient
vasoconstriction causing transient ↑ B.P. but it is soon overcome by
vasodilatation as clonidine penetrates the blood brain barrier (BBB)
and interacts with 2-receptors causing  B.P. (antihypertensive or
hypotensive).

The imidazoline nucleus is not required for 2-agonist activity, since
guanidine derivatives, guanabenz and guanfacine; both of which
produce hypertensive effects as the result of activation of 2-receptors
in the central nervous system.

They are considered as ring-opened analogues of clonidine.

They have the same mechanism of action and use i.e.  B.P.
(antihypertensive).
14
* Methyldopa (Aldomet)

Although structurally unrelated to the aminoimidazolines or
guanidines the prodrug L--methyldopa (methyldopa) is an 2agonist
acting
in
the
CNS
via
its
active
metabolite,
-methylnorpinephrine.

Uses: Antihypertensive i.e.  B.P.

It acts as
1. False transmitter
2. 2-Agonist
3. Inhibits biosynthesis of NE through decarboxylation inhibition.

Methyldopa Bioactivation:
Methyldopa (L--methyldopa) crosses the BBB, where it is
decarboxylated by aromatic L-amino acid decarboxylase to methyldopamine, which is converted stereospecifically to (1R: 2S)-methylnorepinephrine by dopamine -hydroxylase.
15

Of the three chemicals shown, only methyldopa can cross the BBB
because of its lipophilicity while the other two are hydrophilic.
16
Direct Selective -Agonists (either 1 or 2)
Example: Isoproterenol
[R(-)-1-(3,4-dihydroxyphenyl)-2-(isopropylamino)ethanol]

The nature of the nitrogen substituent determines whether the
adrenergic agonist will act at - or -receptors.

In general, as the bulk of the nitrogen substituent increases ↑ , the
-receptor agonist activity decreases  and the -receptor activity
increases ↑ because the bulkiness of the N-alkyl group appears to hinder
the interaction of the compound with -receptors. Also, -receptors have
large lipophilic binding pocket adjacent to the amino group binding site
which is absent in the -receptors.

Thus isoproterenol is a potent non-selective -adrenergic agonist with no
effect on -receptors (bulkiness of isopropylamino group).

Isoproterenol acts equally or 1 or 2-receptors, thus, reducing the
therapeutic utility of the drug for treatment of bronchial asthma as the
bronchiodilatation effect (2-receptors stimulation) is associated by
undesirable cardiac stimulation effect (↑ cardiac output; 1-receptors
stimulation).
17

Disadvantages of Isoproterenol:
1. Short duration of action.
2. Inactive orally.
3. ↑ Cardiac output (1-receptors).

How to increase 2-agonist selectivity?
Direct Selective 2-Agonists
Several structure modifications on the chemical composition of
isoproterenol have been achieved to improve (enhance) 2-agonist selectivity.
Yet, cardiovascular effects are still there but in small proportion. These changes
include:
1-
Replacement of catechol moiety by resorcinol which is not
substrate of COMT (longer duration).
Example metaproterenol (Alupent);
[R(-)-1-(3,5-dihydroxyphenyl)-2-(isopropylamino) ethanol]
Metaproterenol exhibits significant 2-adrenoreceptor selectivity, so it
does not produce cardiovascular effect similar to isoproterenol. It is not
metabolized by COMT.
Uses: Metaproterenol is used in tablet, syrup (orally) and inhalation
forms for management of bronchial asthma.
18
2-
Replacement of meta-OH by –CH2OH.
Example: Albuterol; Salbutamol (Ventolin)
[R (-)-1-(4-hydroxy-3-hydroxymethylphenyl)-2-(t-butylamino)ethanol]
The hydroxymethyl group has a blocking effect towards the action of
COMIT which leads to a longer duration of action. It is more selective 2-agonist
and  cardiac stimulation.
Uses: Treatment of bronchospasm associated with asthma.
3-
Substitution of isopropyl moiety by tert-butyl.
Example: Albuterol (Ventolin) and Terbutaline (Bricanyl)
[R(-)-1-(3,5-dihydroxyphenyl)-2-(t-butylamino) ethanol]
Terbutaline has been designed with implication of resorcinol moiety
instead of catechol (catechol causes poor oral bioavailability and short duration)
and t-butyl instead of isopropyl. Thus it acts preferentially at 2-receptor sites.
Uses: It is given orally for treatment of asthma.
19
4-
Insertion of C2H5 (ethyl) at α-Carbon.
Example: Isotharine
Another molecular modification that enhances 2-agonist selectivity is the
presence of ethyl group on the carbon adjacent to the nitrogen. Isoetharine is the
-ethyl derivative of isoproterenol.
Uses : Treatment of bronchial asthma .
Selective β2-Agonists:
*Pirbuterol (Maxair)
Pibuterol is an interesting analogue of albuterol (Salbutamol) in which the
benzene ring has been replaced by a pyridine ring, i.e. isostere of salbutamol.
Uses: Selective 2 agonist; used in treatment of bronchial asthma.
*Bitolterol
20
Bitolterol is a prodrug of the 2-selective agonist colterol which is the Nt-butyl analogue of NE-in which the catechol OH hydroxyl groups have been
converted to 4-methylbenzoic (p-tolyl) acid esters – producing increased lipid
solubility and prolonged duration of action.
Bitolterol is hydrolyzed by esterases in the lung tissue to produce the
active agent colterol which is metabolized by COMIT and by conjugation.
Uses: It is administered by inhalation as a long acting agent for bronchial
asthma.
*Ritodrine (Yutopar)
Ritodrine is a selective 2-receptor agonist that it is used exclusively for
relaxing uterine muscle and inhibiting the contractions of premature labour.
Uses: It is used by intravenous infusion to stop premature labour and it
may be given orally.
Long-acting 2-Adrenergic Agonists
*Salmeterol (Serevent)
It has very long duration of action (12 hours) due to high lipophilicity of
the phenyl and alkyl groups on the nitrogen atom. Also, it results (long duration)
21
from a specific binding interaction (anchoring) of the phenyl group at the end of
the extended lipophilic side chain of the 2-receptor.
Uses: Used in the treatment of severe persistent asthma.
22
Direct Selective 1-Agonists:
*Dobutamine (Dobutrex)
4-[2-[3-(4-hydroxyphenyl)-1-methylpropyl)amino]ethyl]-1,2-benzenediol
It is a catecholamine analogue with bulky aralkyl group.
Uses: As a cardiac stimulant for heart failure (IV only).
*Dopamine (Inotropin)
Dopamine is not strictly an adrenergic drug, but it is a biosynthetic
precursor of NE. It is used in the treatment of shock, and in contrast with the
usual catecholamines, it increases blood flow to the kidney causing dilatation of
renal blood vessels via acting on specific dopaminergic receptors, rather than on
-receptors. Dopamine also stimulates cardiac 1-receptors to increase ↑ cardiac
output
in
congestive
heart
failure
23
,trauma
and
shock.
Indirect-acting Sympathomimetics
Mode of Action:
Indirect adrenergic agonists are taken up by pre-synaptic neurons, where
they cause the release of NE.
SAR:
This class of adrenergic agonists possess the following structural features:
1.
Absence of catechol hydroxyl groups that results in increase of oral
absorption and better penetration through blood brain barrier
(BBB). COMT has no activity on these drugs.
2.
-Hydroxyl group may be present or not. Its stereochemistry is
less important. Its absence provides more lipophilic agents with
central stimulating activity.
3.
-CH3 in the phenethylamine structure provides more resistance
to MAO.
4.
The amino nitrogen may be primary, secondary or part of the
heterocyclic ring.
24
Examples:
*Amphetamine
It is the prototype of this class of adrenergic agonists.
Uses: CNS stimulation and appetite suppressant effects.
*Methamphetamine
It is the N-methyl derivative of amphetamine.
*Pseudophedrine
Threo
Direct
Inactive
Active
Indirect
(S:S)-Threo--[ℓ-methylamino)ethyl]benzyl alcohol

Pseudophedrine is the threo-diastereomer of ephedrine.

It has no direct activity i.e., no direct stimulation on the receptor.
25

Uses: Nasal decongestant.
Mixed – Function Adrenergic Agonists:
*Ephedrine
The prototype of this group is the natural alkaloid ephedrine. It does not
have any substituent on the phenyl ring, giving it good oral activity because it is
not a substrate for COMT similar to indirect adrenergic agonists. In addition,
ephedrine is less polar than other catechol derivatives and thus, it can cross BBB.
Ephedrine has four stereoisomers in a pair of diastereoisomers. The
threo-pair of enantiomers is known as pseudoephedrine (indirect-acting
adrenergic agonist; ψ-ephedrine) and the erythro racemate is known as
ephedrine.
Erythro
Direct
Active
Active
Indirect
Thus, the drug ephedrine is a mixture of the erythro-enantiomers (1R:2S)
and (1S:2R).
26
Uses: The erythro racemate of ephedrine is used I.V., I.M. or locally as
bronchiodilator, cardiac stimulant and nasal decongestant.
27
Adrenergic Antagonists “Blocking Agents”
A.

-Adrenergic Antagonists
a)
Non-Selective -Blockers:
I.
Imidazolines
Some imidazoline derivatives act as -antagonists by competitive
(reversible) blocking action. They are structurally similar to the imidazoline
-agonists such as, naphazoline and xylometazoline.

They are not useful antihypertensive agents as they are nonspecific
-antagonists, so they are used for treatment of peripheral vasospasm.
*Tolazoline
2-Benzyl-2-imidazoline
*Phentolamine
28
Uses: The clinical application of tolazoline and phentolamine are limited
to treating the hypertension in patients of pheochromocytoma.
N.B. : Pheochromocytoma is a tumour of the chromaffin cells of the adrenal
medulla which produces large amounts of epinephrine and NE into the blood
stream causing hypertension.
2-
-Haloalkylamines
The -haloalkylamines comprise a group of nonselective -adrenergic
antagonists that produce a long-lasting (irreversible) blockade that involves the
formation of an intermediate aziridinium ion (ethylene iminium cation). This
positively charged electrophile reacts with a nucleophilic group on the receptor,
resulting in the formation of a covalent bond between the drug and the receptor.
This alkylation of the receptor through the formation of a covalent bond results
in the prolonged -receptor blockade. Phenoxybenzamine is a member of this
class.
*Phenoxybenzamine
29
Uses: It produces tachycardia and used for treatment of hypertension of
pheochromocytoma .
b)
Selective 1-Antagonists (Blockers):
It includes compounds like prazosin, terazosin and doxazosin.
Mechanism of Action and Uses:
They inhibit 1-receptors:
 In blood vessels producing vasodilatation, thus, they are used as
antihypertensive agents.
 In prostate gland and urinary bladder, so used in treatment of
benign prostatic hyperplasia (BPH).
N.B.: All 1-blockers possess the first dose effect (also known as rust-dose
phenomena) which produces orthostatic hypotension (characterized by
dizziness and palpitations). The 1st dose effect can be treated by administering
the first doses of the antihypertensive agent (1-blocker) at bedtime.
*Prazosin (Minipress)
1-(4-Amino-6,7-dimethoxy-2-quinazolinyl)-4-(2-furanylcarbonyl)
piperazine.

Only 55-60% bioavailable after oral administration
30
*Terazosin (Hytrin)
1-(4-Amino-6,7-dimethoxy-2-quinazolinyl)-4-(2-tetrahydrofuranylcarbonyl)piperazine.
Terazosin structure differs from that of prazosin only in having a
tetrahydrofuran ring instead of a furan ring leading to an increase in lipophilicity
and resulting in an improvement of bioavailability up to 70% compared to the
55-60% of prazosin.
*Doxazosin
1-(4-Amino-6,7-dimethoxy-2-quinazolinyl)-4-(2-benzodioxanylcarbonyl)piperazine.
Substitution of the dihydrofuran ring by a benzodioxane ring resulted in a
dramatic increase in bioavailability (90%) of doxazosin.
31
B.
-Adrenergic Antagonists
-adrenergic blocking agents bear structural similarity to the prototype
agonist NE, and they have the following general formula:
Connection between A and B may be direct or through oxymethylene
bridge (-OCH2-).
So, they are either arylethanolamines or aryloxypropanol-
amines.
Structure-Activity Relationships SAR
Ar
X
CH CH2
NH
R
OH
1)
R is a -directing group (isopropyl t-butyl, aralkyl)  also  polarity.
2)
Carbinol carbon is asymmetric for optimal activity. Stereochemistry
depends on X (Note: in agonists, R is most active).
3)
X (spacer group) is either nothing or an –OCH2- group.
32
(i)
Arylethanolamines X = nothing
 Optimal stereochemistry is R.
 All compounds in this class are nonselective.
(ii)
Aryloxypropanolamines X = -OCH2-
Ar
O
CH2
CH
CH2
NH
R
OH
 Increased distance between aryl nucleus and N.
 Most active isomer is S (Note: groups are in the same relative
position, but substituents change the absolute configuration).
4)
Aryl Nucleus (Ar)
(i)
Non-substituted Phenyl results in nonselective -antagonism (
lipid levels and  hydrophilicity).
(ii)
Substituted Phenyl
 Para-substituted phenyl results in 1-selectivity (has less effect on
lipid levels).
 Small ortho-substituted phenyl retain 1 selectivity.
 Other substituent patterns result in nonselective -antagonism.
33
(iii)
Naphthyl or Substituted Naphthyl (Non Selective)
(iv)
Heteroaromatic Rings
 Indole: e.g., Pindolol (nonselective).
 Thiadiazole: e.g., Timolol (nonselective).
Mechanism of Action:
-Blockers are competitive antagonists on 1- (heart) and 2- (blood
vessels) receptor, i.e., decrease  contractility and  heart rate.
Influence of the Lipophilic Character:
1.
Site Effects
As log P increases, penetration of BBB increases, resulting in increased
CNS side effects (vertigo, fatigue, insomnia, nightmares and psychoses). So,
compounds with high log P should be avoided in patients with depression and
mental confusion.
2.
Duration of Action (DOA)
 High log P: results in rapid and extensive first pass effect, practicing
inactive metabolites.
 Low log P:
results in excretion of the hydrophilic compound
unchanged (in kidneys).
 Intermediate log P: Escapes extensive first, pass effect (in liver).
Therefore, increases its duration of action DOA. It may need further
metabolism before excretion.
34
a)
Non-Selective -Blockers: Arylethanolamines
*Sotalol (Betapace)
Uses: Treatment of ventricular arrhythmias.
SAR Notes
 -Directing group on N (isopropyl).
 p-Substituent, but not 1-selective because the general structure of the
molecule is arylethanolamine, not aryloxypropanolamine.
 Polar group ion the aromatic ring (hydrophilic -blocker), excreted
mainly by the kidneys. It has  CNS side effects.
a’)
Non-Selective -Blockers: Aryloxypropanolamines
*Propranolol (Inderal) (Prototype; lead)
()-1-(Isopropylamino)-3-(1-naphthyloxy)-2-propanol
35
Uses: Treatment of cardiac arrhythmias, angina pectoris, hypertension
and migraine. It is contraindicated in asthmatic or bronchitis conditions due to
blockade of β2-receptors in the respiratory tract.
SAR Notes:
 The (-) (levorotatory) isomer is 100 times more active that (+) (dextro)
isomer but it is marketed as the racemic () mixture.
 Aromatic ring (napthylene)  nonselective.
 Lipophilicity increases  CNS side effects (avoid in patients with
depression and mental confusion).
Synthesis:
CH2
O
OH
CH2
+
O
O
Cl
K2CO3
CH3
H2N
CH3
Propranolol
Metabolism:
 Propranolol is well absorbed after oral administration but it undergoes
extensive hepatic “first pass” metabolism before it reaches the systemic
circulation due to its relative lipophilicity resulting in a decrease in DOA.
This extensive first-pass metabolism of propranolol accounts for the fact, that
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when it is given I.V., much smaller doses are required to achieve a therapeutic
effect than when it is given orally.
 It has been found that the pharmacological effects of propranolol may persist
for two or three days after discontinuation of the drug. Why? It has been
proposed that propranolol glucuronide, which is the main metabolite
formed during long-term therapy, may serve as a storage pool in the tissues
which is cleaved to slowly release the active metabolite  increase DOA and
slow accumulation of propranolol.
*Nadolol (Corgard)
Uses: Indicated in angina pectoris and hypertension.
SAR Notes
 Substituted napthyl ring  nonselective -antagonist.
 Primarily excreted unchanged (kidney) i.e., hydrophilic drug   CNS
side effects.
 Due to its lack of metabolism it is administered once daily (long DOA).
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*Timolol (Timoptic)
Uses:
used as an ophthalmic solution in treating glaucoma by 
decreasing the ocular hypertension.
SAR Notes
 Hydrophilic compared to propranolol.
 Given topically, so it avoids first pass metabolism (DOA 24 hrs) i.e.,
slow to penetrate the eye.
*Pindolol (Visken)
1-(Isopropylamino)-3-[indole-4-yl)oxy]-2-propanol.
Uses: Treatment of hypertension.
SAR Notes
 Indole ring  nonselective -blocker.
 Increased  polarity   CNS side effects.
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1-Selective Blockers (Aryloxypropanolamines):
b)
As previously mentioned, propranolol is contraindicated in presence of
conditions of asthma or bronchitis due to the blockade at 2-receptors. Chemical
modification in the aryloxypropanolamine compounds has resulted in 1selective antagonists that are used therapeutically.
*Metoprolol (Lopressor)
1-(Isopropylamino)-3-[p-methoxyethyl)phenoxy]-2-propanol.
Uses:
in treatment of hypertension, angina pectoris and myocardial
infarction.
SAR Notes
 p-Substituted phenyl  1-selective antagonist at therapeutic dose
(low dose).
 Changes in the p-substituent (e.g., esmolol and betaxolol) retain 1selectivity.
N.B.: Cardioselectivity is lost at higher dose so not indicated for patients with
asthma.
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*Esmolol (Brevibloc)
Esmolol is the methyl ester of metoprolol, which make it liable to
hydrolysis by plasma estrases. For this reason, it is administered I.V. only and not
orally.
Uses: Due to its very short DOA (8 minutes), it is used to control
tachycardia during surgery when a short-acting 1-blocker is needed.
*Betaxolol (Betoptic)
Uses: indicated as ophthalmic solution for  ocular hypertension in
glaucoma.
SAR Notes
 It only differs from metoprolol by having a cyclopropyl ring on the
terminal end of p-substituent.
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 Topical agent (Betoptic) has an advantage over Timolol because it is
1-selective (fewer side effects). So it is the drug of choice for patients
with pre-existing CHF(cardiac heart failure).
*Acebutolol (Sectral)
N-{3-Acetyl-4-[2-hydroxy-3-isopropylamino)propoxy]phenyl}butanamide.
Uses: indicated in hypertension and ventricular arrhythmias.
SAR Notes:
 Butanamide N is conjugated with aromatic ring. Potency might be
decreased.
 p- and o-Substituted phenyl group, still retain 1-selectivity.
 Remove p-substituent or add additional substituent and you get
nonselective -blocker.
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*Atenolol (Tenormin)
4-[2-Hydroxy-3-isopropylamino)propoxy]benzene-acetamide.
Uses: indicated in angina pectoris and hypertension.
SAR Notes
 More 1-selective than metoprolol.
 Hydrophilic  more polar  mostly excreted unchanged (kidney).
 Acetamide NH2 (p-substituent) may form a hydrogen bond with
1-receptor. (This is hypothesized since the dimethyl acetamide is
inactive).
Synthesis:
HO
COOH
+
CH3
H+
OH
OCH3
HO
O
O
i)
Cl
ii) Piperidine
NH3
NH2
HO
iii) H2N
Atenolol
O
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(C)
Mixed /-Adrenergic Antagonists:
They are antihypertensives with 1-, 1- and 2-blocking activity and they
have the advantage over 1 or 1 selective blockers in that they inhibit the reflex
tachycardia caused by vasodilatation (via 1-blockade).
*Labetalol
Uses:
in treatment of moderate hypertension, essential or renal
hypertension.
 Chemically, labetalol contains 2 chiral centres and the preparation
that is used clinically is a mixture of 4 isomers.
 The active isomers are (RR) and (SR) while (SS) and (RS) are inactive.
 (RR) ⇒ -blocker with minimal 1-blocking activity and (SR) ⇒ 1antagonist (selective).
 (RR) alone is known as dilevalol.
SAR Notes:
 The -methyl substituent attached to the N-aralkyl group is
responsible for -adrenergic blocking effect.
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 Carboxamide function is responsible for some -antagonism and also
gives the molecule some 2-agonism ⇒ provides a safety margin in
patients with asthma, however, still nonselective.
*Carvedilol
Uses: as labetalol and is also effective in the treatment of ischemic heart
diseases.
 Carvedilol is administered as its racemate.
 Its S(-) enantiomer is / mixed antagonist (nonselective -blocker).
 Its R(+) enantiomer is an 1-selective blocker.
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