UN IVERS ITY OF M OSUL

C OLLEGE OF D E NTISTRY

AUTONOMIC 2020-2021

NERVOUS SYSTEM
Lecture 3

Adrenergic Antagonists
By: Department of
Assist.prof. Dr. Basic Dental
Faehaa Azher Al-Mashhadaneh
‫ينادهشمال رهزا ءاحيف د‬.‫م‬.‫ا‬ Sciences
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SELECTIVE α1-ADRENENERGIC
RECEPTOR ANTAGONISTS
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α1-adrenergic receptors are located predominantly

on the post junctional membranes of glands and smooth muscle.

The α1-adrenergic receptors associated with smooth muscle of

arteries and veins play an important role in promoting vasoconstriction

The α1-adrenergic receptors are also important in regulating

the tone of nonvascular smooth muscle, such as in the neck of the
urinary bladder and capsule of the prostate.
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The first therapeutically useful α1-

adrenergic receptor antagonist
developed was prazosin .

Terazosin and doxazosin are structural

analogues that were subsequently
introduced. Although these agents differ in
pharmacokinetic properties, their
mechanism of action is the same.
 As a result of blocking smooth muscle α1- U N IVE R SITY O F M O SU L

adrenergic receptors, prazosin dilates arterioles C O L LE GE O F D E NTIS TRY

and veins.

Each of these actions contributes to the

hypotension seen with this drug. Blockade of
arterial smooth muscle produces hypotension
by reducing peripheral resistance.

prazosin causes less tachycardia, a smaller

increase in cardiac output, and less renin
release.
 Therapeutic uses
➢Prazosin, terazosin, and doxazosin can be used in monotherapy for the treatment of hypertension
➢Terazosin and doxazosin, which are given once a day, may have advantages over prazosin, which
requires more frequent administration.
➢prazosin is effective for treating nightmares and improving sleep and reducing the severity of
posttraumatic stress disorder.
 Norepinephrine has a role in the pathophysiology of Post-traumatic
stress disorder (PTSD). Higher norepinephrine cerebrospinal fluid
concentrations have been found in patients with PTSD and are
associated with greater severity of PTSD symptoms.
This increased central nervous system noradrenergic statecontributes
to the disruption of normal rapid eye movement sleep,in turn
contributing to nightmares. Thus, blocking postsynapticadrenergic
receptors is a possible pharmacologic approach to the treatmentof
PTSD-associated nightmares.
Prazosin is a lipid-soluble α1-adrenergic receptor antagonist that
crosses the blood-brain barrier and decreases the sympathetic
outflow in the brain.
 Adverse effects
Orthostatic or postural hypotension is a concern with prazosinanalogues.
The effect is most likely to occur with initial administration and is known as
“first-dose” syncope.
Hypotension ensues when the systemic arterial blood pressure decreases by
more than 20 mm Hg on standing. In this situation, cerebralperfusion
decreases, and an individual may become lightheaded, dizzy, or faint. In
changing from the supine to the standing position, gravity tends tocause
blood to pool in the lower extremities. However, several reflexes, including
sympathetically mediated venoconstriction, minimize this pooling, and
maintain cerebral perfusion.
NONSELECTIVE α-ADRENERGIC RECEPTOR ANTAGONISTS
 The nonselective α-adrenergic receptor–blocking drugs prevent the action of
adrenergic transmitters and sympathomimetic agonists at all α-adrenergic receptors.
Although many drugs exhibit some α-blocking activity, only
phentolamine and phenoxybenzamine
are currently used clinically for their nonselective α- adrenoceptor
antagonist action.
 More recently, phentolamine mesylate has been approved forthe
reversal of soft tissue anesthesia after administration of local
anesthetics with vasoconstrictors for nonsurgical dentalprocedures.
The drug is formulated in dental cartridges
(0.4 mg/1.7-mL cartridge) and is injected in the same manneras the
local anesthetic when pain relief is no longer needed. The median
duration of post treatment anesthesia in the upper and lower lips of
adults and children is reduced by 85 minutes when phentolamine
mesylate is injected at the end of restorative and dental hygiene
procedures lasting about 45 minutes. Return of normal function
(e.g., speaking, smiling, drinking) occurs in concert with return of
normal sensation.
 It is unlikely that the phentolamine is acting
by reversing the vasoconstrictor effect of injected epinephrine, which
should have already disappeared from the local tissues.
Instead, the phentolamine probably increases local blood flow by
blocking sympathetic tone, which hastens the removal of the local
anesthetic from local neurons.
Doses of phentolamine used for this purpose (0.2 to 0.8 mg) (0.5 to
2.0 cartridges), are approximately 10 times less than doses
injected intravenously for treatment of hypertensive
emergencies.
 β-ADRENERGIC RECEPTOR ANTAGONISTS

The β-adrenergic receptor antagonists, also called β-adrenergic

receptor blockers or simply β blockers are an important and
versatile class of drugs widely used in cardiovascular
therapeutics.

The β blockers are also used to treat numerous non-

cardiovascular disorders.
 First-Generation β-Adrenergic Receptor Blockers,
Nonselective Antagonists

These drugs are competitive antagonists with equal affinity at both the
β1-adrenergic and β2-adrenergic receptors and as such are referred to
as nonselective β blockers.
Propranolol was the first β-blocking drug to be approved in the United
States and is considered the prototype for this class of compounds.
The beneficial effects of propranolol and
other nonselective β blockers are mostly attributable to blockade of
the β1-adrenergic receptor.
 Second-Generation β-Adrenergic Receptor Blockers,
β1-Selective Antagonists

Metoprolol, the first selective β1 receptor antagonist, and its successors (e.g.,
atenolol, acebutolol, and esmolol) have attracted considerable attention because of
their relative freedom from the unwanted effects of β2-adrenergic receptor
blockade.
This β1 selectivity is relative with existing agents, and these drugs lose much of their
selectivity at higher doses.

Presently, both nonselective and selective β blockers are used clinically.

Third-Generation β-Adrenergic Receptor Blockers, Antagonists with Additional
Actions

As typified by labetalol and carvedilol, these drugs not only block

the β-adrenergic receptors but have additional actions such as
blockade of the α1-adrenergic receptor, generation of nitric oxide,
and decrease in reactive oxygen species, which contribute to their
unique pharmacologic actions.
 Cont.
❑Labetalol combines nonselective β-blocking properties with α1-
adrenergic antagonism.
❑It is five to seven times more potent at blocking β-adrenergic
receptors compared to α1 receptors.
❑Because of actions at β-adrenergic and α1-adrenergic receptors,
labetalol decreases peripheral resistance and blood pressure.
❑The drug has some direct vasodilatory properties not mediated by
interaction at adrenergic receptors.
❑Because of these actions, labetalol can be used to treat hypertensive
emergencies.
 Cont.
Carvedilol, is the second drug to be marketed with α1- and β-blocking
activities.
Carvedilol is also much more selective for β-adrenergic receptorsthan
labetalol.

Carvedilol was initially approved for use as an antihypertensive (because

of its ability to block α1 and β receptors), but more recent clinical
studies have shown that it is particularly useful in decreasing morbidity
and mortality associated with heart failure.
 Cont,
The pharmacologic actions that make carvedilol useful in
treating heart failure are probably the result of blockade
of both α1-adrenergic and β-adrenergic receptors. The
vasodilatory actions of carvedilol that occur as a result of
α1 receptor blockade decrease peripheral resistance
and, as a result, the workload of the heart.
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THE END 2020-2021