SYMPATHOLYTIC

NIKITA PANCHAL
 INTRODUCTION
PRESENTATION TITLE

• Sympatholytic are those which block the actions of norepinephrine on

adrenergic receptors.
• They are also called as anti-adrenergic agents or adrenergic blocking
agents or adrenoceptor antagonists.

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 CLASSIFICATION OF
ADRENERGIC
ANTAGONISTS

Nonselective α Non-selective
Selective Selective Selective Mixed α,
(α1 + α2) – β (β1 + β2) –
α1-blockers α2-blockers β1-blockers β-blockers
blockers blockers

Drugs without intrinsic Drugs with intrinsic

sympathomimetic sympathomimetic
activity (pure activity (partial
antagonists) agonists)

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 SELECTIVE α1-BLOCKERS
• Prazosin is a prototype of this class. It causes peripheral vasodilation
and decreases blood pressure.
• As α1 receptors are also present in prostate gland, prostatic urethra
and urinary bladder neck, blocking α1 receptors in these organs
cause smooth muscle relaxation and hence improves urine flow in
cases of benign prostatic hypertrophy (BPH).
• It is used in hypertension and in BPH.

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 • Terazosin and doxazosin are similar to prazosin but with a longer
duration of action. Their uses are similar as of prazosin
• Tamsulosin and alfuzosin are more selective for α1A-receptors (found in
prostate gland, prostatic urethra and bladder neck) rather than
α1B-receptors which are mainly located on blood vessels.
• Thus, they are first line drugs for the treatment of BPH with little effect
on blood pressure.

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 2. Selective α2-blockers
• Yohimbine is an indole alkaloid obtained from Pausinystalia
yohimbe.
• It has been used for a variety of research projects and rarely
prescribed for erectile dysfunction in men.

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 3. NONSELECTIVE α (α1 + α2) -
BLOCKERS
• Because of non-selectivity at α-receptors and side effects like
increased gastric secretion, their use is limited to treating the
symptoms of pheochromocytoma.

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 SYNTHESIS OF TOLAZOLINE
PRESENTATION TITLE

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 4. SELECTIVE β1-BLOCKERS
• Most of the β1-blockers (cardio selective) also have some
β2-blocking properties (contraindicated in asthma) at the higher
therapeutic doses.
• These agents are used in hypertension and in cardiac
arrhythmia.
• As esmolol is methyl ester, it is rapidly inactivated by plasma esterase
(plasma half-life is < 10 min). So it is administered by i.v. infusion.
• Celiprolol is also having weak β2-agonistic activity, so it is safe in
asthmatics (due to bronchodilation).

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Acebutolol is also partial agonist at β1-receptor
 5. Non-selective β (β1 + β2) – blockers

• Like selective β1-blockers, drugs of this class also are used in

hypertension.
a) Drugs without intrinsic sympathomimetic activity (pure antagonists)
These pure antagonists are contraindicated in asthma (due to blockade
of β2-mediated bronchodilation) and in bradycardia (due to blockade of
β1-mediated positive inotropic effect).
Propranolol is the most lipophilic drug of the available β-blockers. As
more lipophilic drugs are primarily cleared by the liver, it is not suitable
for patients suffering from liver disease.
Timolol is also used in glaucoma.

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 SYNTHESIS OF PROPRANOLOL

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 • b) Drugs with intrinsic sympathomimetic activity (partial agonists)
Partial agonistic activity on β-receptors is advantageous in patients
suffering from bradycardia (due to positive inotropic effect) and or
asthma (due to bronchodilation).
Pindolol

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 6. Mixed α, β-blockers
• It is carbazole derivative,
administered as racemic mixture.
• S-(–)-enantiomer has α1-, β1- and
β2-blocking activity, while Carvedilol
R-(+)-enantiomer has only α1-
blocking activity.
• Labetalol is also administered as its
racemate.
Labetalol
• 1R, 2R isomer has β1, β2-blocking
activity with minimal α1-blocking
16 activity, while 1R, 2S isomer has only
α1-blocking activity.
 SAR OF β-BLOCKERS
• In 1958, Powell and Slater described the β-blocking activity of
dichloroisoprenaline (DCI). The structure of DCI is similar to that of
isoprenaline, except that the catechol hydroxyl groups have been
replaced by two chloro groups.

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 • This simple structural modification has provided the basis to design
and synthesize therapeutically useful β-blockers.
• Unfortunately, DCI is not a pure antagonist but a partial agonist. This
precluded its development as a clinically useful drug.
• Pronethalol was the next important β-blocker to be discovered.
Although it was much less partial agonist than DCI, it was withdrawn
from clinical testing as it caused thymic cancer in mice.

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 • Within two years of this report, Black and Stephenson described the
β-blocking activity of propranolol, a close structural analogue of
pronethalol.
• Propranolol belongs to the group of β-blockers known as
aryloxypropanolamines.

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 This reflects that the -OCH2- group has been incorporated between
the aromatic ring and the ethanolamine side chain of pronethalol to
discover propranolol.

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 • As this structural feature (aryloxypropanolamine) is frequently found
in β-blockers, it was assumed that the -OCH2- group is responsible for
the antagonistic activity.
• Later, it became found that, the -OCH2- group is solely not
responsible for β blocking activity. It is the nature of the aromatic
ring and its substituents that determine β-blocking activity.
• The nature of aromatic ring also determines the β1 selectivity of
the antagonists. One common structural feature of selective
β1-blockers is the presence of a para substituent on the aromatic
ring.
• Amino group in the side chain must be a secondary amine for
optimal β-blocking activity.
• The β-blockers exhibit high stereoselectivity in producing antagonistic
activity. The configuration of the hydroxyl bearing carbon of the
oxypropanolamine side chain must be the (S) for optimal activity.
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