AUTONOMIC NERVOUS SYSTEM

U N I V ER S I TY O F M O S U L
C O L L EG E O F D E N TI S TR Y

Endogenous Catecholamines 2020-2021

Dopamine

By:
Assist.prof. Dr.
Faehaa Azher Al-Mashhadaneh
‫د فيحاء ازهر المشهداني‬.‫م‬.‫ا‬ Department of
Basic Dental
Sciences
 U N I V ER S I TY O F M O S U L
C O L L EG E O F D E N TI S TR Y
Cardiovascular effects
2020-2021
Dopamine interacts with various receptor types to influence
vascular function, and it is used therapeutically for maintaining
renal function in cases of shock associated with compromised
cardiac output.

Department of
Basic Dental
Sciences
With moderate doses, dopamine was thought to act at myocardial β1-adrenergic receptors to
increase contractile force.

At higher doses, dopamine also stimulates α1-adrenergic receptors, which produces

vasoconstriction.

As with all catecholamines, excessive doses of dopamine can cause tachycardia and generate
arrhythmias.
In addition to stimulating α1 and β1 receptors directly, dopamine in moderate to high doses
causes the release of norepinephrine from sympathetic nerve terminals.
• In addition, D1 and D2 dopaminergic receptors, distinct from the α- and β-adrenergic receptors,
occur in the peripheral mesenteric and renal vascular beds, where binding of dopamine produces
vasodilation. D2 receptors are also found on presynaptic adrenergic neurons, where their
activation interferes with norepinephrine release.
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α-Adrenergic Receptor Agonists 2020-2021

These drugs stimulate α-adrenergic receptors, but have low
affinity for β-adrenergic receptors.

Department of
Basic Dental
Sciences
Phenylephrine and methoxamine differ from
epinephrine and norepinephrine by being
selective agonists at α1adrenergic
receptors.
 Phenylephrine and methoxamine

Their primary pharmacologic effect is to cause contraction of

vascular smooth muscle, resulting in an increase in systolic and diastolic
blood pressures and reflex bradycardia.
The α2-adrenergic receptor agonists clonidine,
guanabenz, guanfacine, and methyldopa
effectively enter into the CNS and selectively
stimulate α2-adrenergic receptors in the brain.
Methyldopa enters into the nerve terminal and is converted into the α2 receptor– selective agonist
α-methylnorepinephrine.

Α Methylnorepinephrine is nearly equipotent to norepinephrine as a vasoconstrictor in humans.

This agent has been developed as the drug levonordefrin, which is used as a vasoconstrictor in some
local anesthetic solutions.
 Department of: U N I VER SI T Y O F M O SU L

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C O L LEGE O F D E NT IS T RY

β-Adrenergic Receptor Agonists

Isoproterenol
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Isoproterenol, a synthetic 020-2021

catecholamine, is a potent
nonselective β-receptor
agonist.
It does not appreciably
distinguish among the β1,
β2, and β3 receptor
subtypes
 Cardiac and vascular effects
The actions of isoproterenol on the cardiovascular system are based solely on the stimulation of β-
adrenergic receptors. It causes a marked decrease in diastolic blood pressure from β2 receptor–
mediated vasodilation, primarily caused by relaxation of blood vessels in skeletal muscle, with some
additional vasodilation in the renal and mesenteric vascular beds

There is also an increase in systolic blood pressure largely resulting from the increase in cardiac
output caused by β1 receptor stimulation of contractility.

Because of the effects on systolic (slight increase) and diastolic (decrease) pressures, the mean
arterial blood pressure is usually decreased.
 Effects on bronchial smooth muscle

As an agonist of β2-adrenergic receptors, isoproterenol relaxes

bronchial smooth muscle in the lungs to relieve or prevent
bronchoconstriction.
Disadvantages of the use of isoproterenol for relief of bronchospastic
disorders that limit its clinical use are its nonselectivity for β-
adrenergic receptor subtypes (which can result in β1 receptor–
induced tachycardia,palpitation, and arrhythmias) and the
development of tolerance with frequent use.
 Metabolic and other effects

Although the β receptor agonist activity of isoproterenol stimulates glycogenolysis and

gluconeogenesis in the liver, it is not as effective as epinephrine in elevating plasma
glucose.

Isoproterenol stimulates the secretion of saliva that is rich in amylase and other proteins.
The drug is also capable of causing CNS excitation at doses higher than used clinically.

Isoproterenol stimulates the secretion of saliva

Explain
 Selective β2-Adrenergic Receptor Agonists
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2020-2021
Metaproterenol, terbutaline, albuterol, levalbuterol,
pirbuterol, and salmeterol are relatively
selective β2 receptor agonists that are effective in decreasing
airway resistance without causing as much cardiac
acceleration These drugs are usually inhaled; however, oral
administration of metaproterenol, albuterol, and terbutaline
may be useful under certain limited conditions. Systemic
adverse effects are usually greater by the oral route.
 Mixed-Acting and Indirect-Acting Adrenergic Agonists

Numerous adrenergic agonist drugs produce some or all of their effects by causing the release of
norepinephrine from adrenergic nerve terminals.

They do so by being transported into the adrenergic nerve ending or adrenal chromaffin cells, where
these drugs displace catecholamines from the vesicular storage sites into a cytoplasmic pool in the
nerve endings or chromaffin cells. This cytoplasmic pool is distinct from that of the storage vesicles
from which release occurs during nerve stimulation.

These drugs have a pharmacologic profile similar to that of norepinephrine. In contrast to

norepinephrine, these drugs are generally not subject to rapid inactivation and are usually effective
by the oral route.
Ephedrine is an example of an orally active, mixed-acting drug.
In addition to releasing norepinephrine, ephedrine is a direct α and
β receptor agonist. It can cause bronchodilation, vasoconstriction,
increased heart rate, and modest CNS stimulation.
 U N I V ER S I TY O F M O S U L
C O L L EG E O F D E N TI S TR Y

2020-2021
β-Adrenergic Receptor
Agonists

GENERAL THERAPEUTIC USES

Department of
Basic Dental
Sciences
Clinical applications of the adrenergic agonists can be divided into eight major
categories:
✓local vasoconstriction,
✓vasoconstriction in the treatment of hypotension and shock,
✓bronchodilation,
✓Relaxation of uterine smooth muscle,
✓ophthalmic uses,
✓ relief of allergic states (including anaphylaxis),
✓CNS stimulation,
✓and control of hypertension.
 Local Vasoconstriction

Various drops, sprays, aerosols, and oral dosage forms of several adrenergic
agonists have proved useful in providing temporary symptomatic relief of
nasal congestion.
These compounds are agonists at α receptors (α1 or α2 or both) and have
minimal CNS stimulant effects.
Common examples include phenylephrine, pseudoephedrine, and
oxymetazoline.
 Cont.
An adverse effect associated with the local administration of nasal decongestants is rebound congestion, a
chronic swelling of the nasal mucous membranes after the effect of the drugs wears off.

This response is more likely with the longer acting α2 receptor–selective nasal decongestants.

Imidazoline derivatives, such as tetrahydrozoline and oxymetazoline, can paradoxically produce

drowsiness, comatose sleep with hypotension, and bradycardia.

These effects are thought to be caused by the entry of the drugs into the CNS, where they stimulate central
α2-adrenergic receptors. Children and infants are especially prone to these adverse effects.
• The rebound effect, or rebound phenomenon, is the emergence or re-
emergence of symptoms that were either absent or controlled while
taking a medication, but appear when that same medication is
discontinued, or reduced in dosage. In the case of re-emergence, the
severity of the symptoms is often worse than pretreatment levels.
 Rebound congestion
• Immediate relief of nasal congestion is offered by a group of drugs called decongestants.
Preparations available for clinical use include α1-adrenergic agonists (e.g. phenylephrine),
α2- adrenergic agonists [e.g. amines (xylometazoline), imidazoles (oxymetazloine)],
noradrenaline releasers (ephedrine and pseudoephedrine) and drugs that prevent the re-
uptake of noradrenaline (cocaine, tricyclic anti-depressants).
• α2-adrenergic agonists are contained in many of the ‘over the counter’ preparations.
Oxymetazoline has a longer duration of action than xylometazoline and appears more
likely to cause rebound nasal congestion.
 Cont.
Adrenergic agonists are often used to produce hemostasis for surgery and to enhance local
anesthesia. Whether applied topically or administered by injection with or without a local
anesthetic, adrenergic agonists can significantly improve visibility in the operative field in
certain situations.

Because vasoconstriction is temporary, the use of these drugs is no substitute for the adequate
surgical control of bleeding.

Adrenergic agonists must often be used with special caution during general anesthesia
because certain inhalation anesthetics (e.g., halothane) predispose the heart to the
arrhythmogenic action of the adrenergic agonists.
 Treatment of Hypotension and Shock

Shock is a condition caused by inadequate tissue perfusion. It is

usually associated with a decrease in arterial blood pressure and,
if not treated, may quickly lead to multiorgan system failure.
Adrenergic agonists may prove useful in restoring blood pressure
and in correcting the distribution of blood flow, especially to the
vital organs, whenever shock develops under normovolemic
conditions
 Cont,

α-Adrenergic receptor agonists (e.g., phenylephrine), which increase

blood pressure by causing vasoconstriction, are most useful during
episodes of inadequate sympathetic nervous system function that
may result from spinal anesthesia or hypotensive drug overdose.

Such drugs are less beneficial in other shock states associated with
hypotension, however, because they may impair blood flow to the
kidneys and mesenteric organs.
 Cont.
Dopamine has often been used for initial therapy
of cardiogenic shock because it causes less generalized vasodilation than typical β receptor
agonists, increases contractile force in the heart without increasing heart rate, and, through
stimulation of dopamine receptors, may improve renal and mesenteric perfusion.

Dobutamine, similar to dopamine, can increase the force of myocardial contraction without
producing significant changes in heart rate and is also used inpatients with heart failure.
 Bronchodilation

Acute and chronic obstructive pulmonary diseases are marked by

increased inspiratory and expiratory resistance, and the adrenergic
agonists have historically played an important role in the relief of
these conditions.
Currently, the adrenergic agents most useful in the treatment of
bronchospastic disease are agonists with selectivity for β2-
adrenergic receptors because they produce marked bronchodilation
with less effect on the heart than nonselective β receptor agonists
 Cont.
The selective β2 receptor agonists used for bronchodilation include metaproterenol, terbutaline,
albuterol, levalbuterol, pirbuterol, salmeterol,and formoterol.

Salmeterol and formoterol have durations of action of about 24 hours.

Other long-acting β2-adrenergic receptor agonists are arformoterol, indacaterol, olodaterol, and
vilanterol.
These extended durations can be of significant benefit in treating patients with asthma and
chronic obstructive pulmonary disease (COPD).

The shorter acting drugs are used to reverse acute bronchoconstriction, whereas longer acting
drugs are used prophylactically to prevent bronchoconstriction and alleviate COPD, bronchitis,
and other chronic lung conditions.
 Ophthalmic Uses

The two major ocular indications for adrenergic agonists are for the production of mild mydriasis
and the reduction of intraocular pressure. The former is mediated by stimulation of α1-
adrenergic receptors in the radial muscle of the eye.

Although muscarinic receptor antagonists such as atropine produce a much stronger pupillary
dilation, adrenergic agonists are useful because they cause mydriasis without paralyzing the
ciliary muscle (cycloplegia).
 Treatment of Allergic States

Adrenergic agonists, especially epinephrine, are especially useful in

reversing the effects of histamine and other mediators associated with
allergic reactions.

In contrast to the antihistamines, adrenergic

agonists are physiologic antagonists, producing responses opposite
to the acute effects produced by histamine and associated autacoids.
 Cont.
For acute allergic reactions such as urticaria, subcutaneous injection of 0.1 to 0.5 mL of 1:1000 (i.e.,
1mg/mL) epinephrine should be adequate. Fulminating disturbances such as anaphylactic shock
require a faster absorption of epinephrine than provided by subcutaneous injection, especially if
circulation is impaired.

Intramuscular (intralingual)injection of 0.3 to 0.5 mL of 1:1000 epinephrine or, if the patient has
previously been prepared for intravenous injections, slow intravenous administration of 1:10,000
epinephrine (0.1 mg in 5 minutes) is recommended.

With this latter route of administration, there is a considerable risk of precipitating serious cardiac
arrhythmias and ventricular fibrillation. Because of the rapid metabolism of epinephrine,
reinjection at intervals of 5 to 15 minutes may be required. Subcutaneous administration
generally provides the longest duration of action, and intravenous injection provides the
shortest.
 Central Nervous System Stimulation
For many years, selected adrenergic agonists have been used clinically
because of their ability to produce stimulation of certain functions of the
CNS that result in increased alertness and attention span and decreased
sense of fatigue. Another potentially therapeutic effect of these agents is
stimulation of the lateral hypothalamus and satiation of the food drive.

The principal sympathomimetic drugs that cross the blood–brain barrier are
ephedrine, amphetamines, and methylphenidate.

Because of the history of abuse of amphetamine-like drugs, their use are

strictly controlled.
 Treatment of Hypertension

Four centrally acting α2-adrenergic receptor–selective agonists are

used for the treatment of hypertension:
clonidine, guanabenz, guanfacine, and methyldopa.
They act on central α2 receptors that are involved in the autonomic
regulation of the cardiovascular system.
 THERAPEUTIC USES IN DENTISTRY
Vasoconstrictors are widely often used in local anesthetic solutions.
The vasoconstrictor most commonly used in dentistry is epinephrine,
with levonordefrin (the l isomer of nordefrin) being used less
frequently, usually with mepivacaine.
 Cont.
Vasoconstrictors serve several useful purposes when used with local anesthetic solutions. First, they
prolong the duration of local anesthesia several-fold and may improve the frequency of successful nerve
block.

Second, systemic toxicity of the local anesthetic may be minimized by reducing the peak blood
concentration of the anesthetic agent.

Third, when anesthetic solutions are given by infiltration, vasoconstrictors tend to reduce blood loss
associated with surgical procedures
 U N I VER SI T Y O F M O SU L

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One issue of potential toxicity is the systemic effects of vasoconstrictors after

intraoral injection
Department of: in patients with cardiovascular disease.
HERE
Some older reports recommend that cardiac patients be given local anesthetics
with vasoconstrictors if needed for adequate anesthesia because the benefits of
satisfactory pain control were greater than the risks of small amounts of
vasoconstrictor.

The validity of this statement depends on the level of stress on the patient and
the amount, rate, and manner in which the epinephrine-containing solution is
injected.
 Cont.
It is often necessary to produce gingival retraction for operative
procedures on teeth and for making impressions.

Besides astringents such as zinc and aluminum salts, retraction cord impregnated With epinephrine,
containing as much as
1.2 mg of drug per inch of cord, is commercially available.

Systemic absorption is marked by signs of anxiety, elevated blood pressure, increased heart rate, and
occasional arrhythmias.

These effects can be extremely serious in a patient with cardiovascular disease or in a patient who is taking
medication that reduces the uptake or otherwise enhances the
activity of adrenergic agents.

Because of this concern, epinephrine-impregnated retraction cord is used much less often than other types
of retraction cord.
gingival retraction cord
 Cont.

Various products are available to control capillary bleeding

occurring with surgical procedures on gingival tissues.

Topical epinephrine hydrochloride (1:1000) and phenylephrine

(1:100) are most common.
 U N I VER SI T Y O F M O SU L

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ADVERSE EFFECTS
Department of:
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Almost all adverse adrenergic agonists are dose related.
Toxic reactions can result from
❑ the administration of too large a dose,
❑accidental intravascular injection,
❑ impaired uptake of the drug,
❑ a heightened sensitivity or number of adrenergic receptors,
❑or therapeutic doses given to a patient with preexisting cardiovascular disease.
 U N I VER SI T Y O F M O SU L

C O L LEGE O F D E NT IS T RY

Most serious of the toxic effects of epinephrine are cardiac disturbances, with
Department
increased stimulation of:heart leading to myocardial ischemia, possibly heart
of the
attack,HERE
and arrhythmias, including ventricular fibrillation.

Patients with a history of uncontrolled hyperthyroidism, hypertension, or angina

pectoris are particularly susceptible.
Drugs with primarily α-adrenergic receptor stimulation can cause excessive
vasoconstriction in overdose.
Local tissue necrosis may result from any vasoconstrictor injected into a region
where ischemia is likely, such as the digits of the hands or feet.
 Department of: U N I VER SI T Y O F M O SU L

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Cont.
CNS reactions to classic sympathomimetic drugs
include nervousness, excitability, insomnia, dizziness,
and tremors.

The most common side effects of centrally acting α2-

agonist antihypertensive agents are dizziness,
drowsiness, and xerostomia.

The xerostomia seems to be most severe with

clonidine and guanabenz. Constipation, sexual
dysfunction, CNS disturbances, bradycardia, and
excessive hypotension have also been reported.