Adrenergic Blockers

Intended
learning outcomes

At the end of the
lecture the students will be able to

• Categorize adrenergic blockers

• State the specific uses for the various blockers

• Outline the synthesis of Tolazoline

Contents

• Categorize adrenergic blockers

• The specific uses for the various blockers

• The synthesis of Tolazoline

Adrenergic
blocking agents

• Adrenergic blockers are also called as antiadrenergic
drugs or sympatholytics

• Adrenergic blocking agents prevent the response of effector
organs to endogenous as well as exogenous adrenaline and noradrenaline

• These drugs block the actions of adrenergic drugs at alpha
(α) or beta (β) adrenergic receptors

• Useful in medicine, particularly in the treatment of
cardiovascular diseases

Mechanism
of Action of α -Adrenergic Blockers

• α -Adrenergic receptor response in clinical relevance
include α1 receptor mediated contraction of arterial and venous smooth muscle.

• α2 adrenergic receptors are involved in suppressing
sympathetic output, increasing vagal tone, facilitating platelet aggregation,
inhibiting the release of norepinephrine, and acetylcholine

• From nerve endings.

• Blockade of α1 receptors inhibits vasoconstriction induced
by endogenous catecholamines

• Vasodilatation may occur in both arteriolar resistance
vessels and veins.

• α 2 receptor regulates both central and peripheral
sympathetic neurons.

• Acceleration of presynaptic α2 receptors inhibits the
norepinephrine release.

• In some vascular beds, these drugs promote vasodilatation
through the release of nitric oxide (endothelial relaxing factor).

• Phenoxybenzamine inhibits the uptake of catecholamine from
the nerve terminals.

• Phentolamine and tolazoline are competitive α adrenergic antagonists
and block the receptor for 5-HT and it causes the release of histamine from the
mast cells, which is a potent vasodilator.

Mechanism
of Action of β-Adrenergic Receptor Blockers

• β adrenergic receptor antagonists slow the heart rate and
decrease the myocardial contractility, these prolongs the systolic conduction
and disturbs the ventricular fibres.

• Dimensions of the ventricle is decreased, oxygen
consumption is decreased, and thereby decreases the heart rate and aortic
pressure.

• In blood vessels, these drugs reduces the noradrenaline
release from the sympathetic terminals and decrease the renin from kidney due
to the blockade of β receptors

Classification:
Adrenergic blocking agents

I.     Alpha receptor blocking agents:

a.    Beta halo alkyl amines:

i.      Dibenamine

ii.     Phenoxy
benzamine

b. Natural and
dehydrogenated ergot alkaloids:

i.     Ergotamine

ii.  Ergocristine

iii. Ergocriptine

iv.   Ergocornine

c. Imidazole
derivatives:

i.Tolazoline

ii.Phentolamine

d. Quinazolines:

i.Prazosin

ii.Terazosin

iii.Doxazosin

e. Miscellaneous

i.Indoramine

ii.Yohimbine

iii.Chlorpromazine

II.
Beta-receptor blocking agents

a. β-Blockers with
membrane stabilizing activity and intrinsic sympathomimetic property:

i.Oxprenalol

ii.Pindalol

b. Specifi c
β-blockers:

i.Timolol

ii.Nodalol

c. β-blockers with
membrane stabilizing activity

i.Propranolol

d. β-blockers with
cardio selective action

i. Acebutolol

ii. Atenolol

iii.Metaprolol

Tolazoline

Synonym: Priscoline

Chemical Structure

• Chemically it is 2-benzyl-4,5-dihydro-1H-imidazole

• Tolazoline is a member of the class of imidazoles that is
4,5-dihydro-1H-imidazole substituted by a benzyl group

Properties: It is
a white, bitter taste, crystalline compound with a slight aromatic odour,
soluble in water, alcohol, and chloroform, but sparingly soluble in ether.

Medicinal Uses:

• An alpha-adrenergic antagonist

• An antihypertensive agent and

• A vasodilator agent

Tolazoline Synthesis

It is prepared by condensation of an aminoether (obtained by
methanolysis of phenylacetonitrile) with ethylene diamine.

Phentolamine:

• Phentolamine is a synthetic imidazoline with alpha-
adrenergic antagonist activity

• Chemically it is
3-[N-(4,5-dihydro-1H-imidazol-2-ylmethyl)-4- methylanilino]phenol

Properties: It is
a white, odourless, bitter powder, soluble in water and alcohol

Medicinal Uses:

• A nonselective alpha-adrenergic antagonist

• It is used in the treatment of hypertension and
hypertensive emergencies

Phenoxybenzamine
(Dibenzyline)

• Phenoxybenzamine is a synthetic, dibenzamine alpha
adrenergic antagonist with antihypertensive and vasodilatory properties.

• Phenoxybenzamine non-selectively and irreversibly blocks
the postsynaptic alpha-adrenergic receptor in smooth muscle, thereby preventing
vasoconstriction, relieving vasospasms, and decreasing peripheral resistance.

• Reflex tachycardia may occur and may be enhanced by
blockade of alpha-2 receptors which enhances norepinephrine release.

• Phenoxybenzamine is reasonably anticipated to be a human carcinogen.

• Phenoxybenzamine is an aromatic amine.

Properties:
Colourless, crystalline compound soluble in alcohol, water, and chloroform.

Medicinal uses:

• A major use of phenoxybezamine is in the treatment of pheochromocytoma
(tumours of the adrenal medulla)

• It is used to treat peripheral vascular diseases, suchas
Raynaud’s syndrome

• It has also been used in the case of shock and frostbite
to improve blood flow to peripheral tissues

• Used in the treatment of shock and in the treatment of
pulmonary oedema

Prazosin:
(Minipress, Prazopress)

• It belongs to the class of drugs known as alpha-1 blockers

• Prazosin is an alpha-Adrenergic Blocker. The mechanism of
action of prazosin is as an Adrenergic alpha-Antagonist.

Properties: It is
a white crystalline powder, soluble in water and alcohol. A selective
α-antagonist,

Medicinal uses:

• prazosin, reduces peripheral vascular resistance and
lowers arterial blood pressure in both supine and erect patients.

• Used to treat hypertension of any degree.

• It has been used in decreasing cardiac overload

Dihydroergotamine

• Dihydroergotamine is an Ergotamine Derivative. The
chemical classification of dihydroergotamine is Ergotamines.

• Ergot alkaloids are widely used for therapy of acute
migraine headaches and include ergotamine and dihydroergotamine, both of which
act by causing vasoconstriction of the carotid artery beds.

• Ergot alkaloids have multiple side effects, but have
little effect on the liver and have not been clearly linked to instances of
clinically apparent acute liver injury.

• A 9,10alpha-dihydro derivative of ERGOTAMINE.

• It is used as a vasoconstrictor, specifically for the
therapy of MIGRAINE DISORDERS.

Methysergide

• An ergot derivative that is a congener of LYSERGIC ACID DIETHYLAMIDE

• It antagonizes the effects of serotonin in blood vessels
and gastrointestinal smooth muscle, but has few of the properties of other
ergot alkaloids

• Methysergide is used prophylactically in migraine and
other vascular headaches and to antagonize serotonin in the carcinoid syndrome

• Chemically it is
(6aR,9R)-N-[(2S)-1-hydroxybutan-2-yl]-4,7-dimethyl-
6,6a,8,9-tetrahydroindolo[4,3-fg]quinoline-9-carboxamide is an ergoline
alkaloid.