The Adrenergic System

The neurotransmitters of the adrenergic system are catecholamines -

adrenaline and noradrenaline.

They are synthesized in the cytoplasm of cells adrenergic neurons from

tyrosine which converts in dopa, an amino acid which then transforms into
dopamine. Dopamine is converted into norepinephrine (noradrenaline) which
is converted into epinephrine (adrenaline).

Catecholamines are released from the deposit granules by exocytosis.

From the synaptic cleft it diffuses and stimulate specific receptors - adrenergic
receptors.

Termination of the effect of catecholamines is done by passive diffusion,

reuptake and metabolism by 2 enzymes - monoamine oxidase (MAO) and
catechol-O-methyltransferase (COMT).

Adrenergic receptors are G protein coupled receptors and are of two

types - α and β.

• α-adrenergic receptors:
o postsynaptic α1 receptors
o presynaptic, postsynaptic and extrasinaptic α2 receptors.
• β-adrenergic receptors - β1, β2, β3.

α1 receptors are coupled with Gq proteins.

α2 receptors are coupled with Gi proteins.

β-adrenergic receptors are coupled with Gs proteins with an increase
in intracellular cAMP.
Effects of adrenergic receptor stimulation

α1 receptors:
o vasoconstriction,
o decreased bronchial secretion,
o mydriasis,
o spleen capsule contraction,
o piloerection,
o decreased insulin secretion.

presynaptic α2 receptors:
o decreases the release of norepinephrine into the synaptic cleft -
feedback mechanism.

α2 postsynaptic receptors:
o Vasoconstriction

extrasynaptic α2 receptors:
o stimulates platelet aggregation.

β1 receptors:
o increases the activity of the heart (increases contractility, A-V
conduction, excitability)
o stimulates renin secretion

β2 receptors:
o vasodilation,
o bronchodilation,
o relaxes uterine muscles,
o tremor,
o agitation,
o nervousness,
o increases gluconeogenesis and glycogenolysis,
o increases insulin secretion

β3 receptors:
o lipolysis and glycogenolysis.
 Sympathomimetics

Direct sympathomimetics are substances that have affinity for

adrenergic receptors and intrinsic activity.

Adrenaline stimulates all adrenergic receptors.

Effects: anxiety, insomnia, nervosity, vasoconstriction in the
subcutaneous, splanchnic and renal territories and vasodilation in the muscular,
cardiac and cerebral territories, stimulation of the heart. Systolic blood pressure
rises, diastolic blood pressure does not change. Bronchodilation.
Indications.
- anaphylactic shock.
- acute asthma attack.
- cardiac arrest
- antihemorrhagic in association with local anesthetics.
Side effects: increased blood pressure with strokes, severe heart
arrhythmias, ventricular fibrillation, worsening of ischemic heart disease,
myocardial infarction, tremor of the extremities, anxiety, psychomotor
agitation.

Noradrenaline stimulates α adrenergic receptors; no β adrenergic

effects.
Effects: vasoconstriction in all territories, contraction of the spleen
capsule. Increases blood pressure, both systolic and diastolic.
Indications - hypovolemic shock with collapse - administration by
intravenous infusion.

Dopamine stimulates adrenergic and dopaminergic receptors.

Effects: vasodilation in the splanchnic and renal territory. In high doses
the drug can stimulate β1 adrenergic receptors by increasing heart activity and
α adrenergic receptors by increasing blood pressure.
Indications: selected cases of shock in intravenous infusion.
 Isoprenaline – selective β1 and β2 receptors agonist.
Effects: bronchodilation, heart stimulation, vasodilation, decreases
diastolic blood pressure and increases systolic blood pressure.
Side effects - worsening of ischemic heart disease, acute myocardial infarction,
ventricular fibrillation, tachycardia, palpitations, extremity tremor,
psychomotor agitation, anxiety.

Selective α1 sympathomimetics - phenylephrine, ethylephrine -

produce vasoconstriction; used in the treatment of particular types of shock or
as a decongestant of the nasal or conjunctival mucosa (local applications).

Selective α2 sympathomimetics - clonidine - lowers blood pressure -

is used to treat high blood pressure.

Selective β1 sympathomimetics - dobutamine - increases the

contraction force of the myocardium, increases the cardiac output; used in
cardiogenic shock.

Selective β2 sympathomimetics (salbutamol, phenoterol,

orciprenaline, terbutaline, salmeterol) produce bronchodilation, vasodilation
and relaxation of the uterine smooth muscles. Indications: treatment of asthma,
treatment of painful uterine contractions in pregnant women. Low-intensity
cardiac side effects, tremor of the extremities, increased excitability of the
central nervous system, anxiety.

Indirect sympathomimetics increase the availability of catecholamines

in the synaptic cleft, by increasing the release (ephedrine, amphetamine),
preventing the reuptake of catecholamines from the synaptic cleft (cocaine,
tricyclic antidepressants) or inhibiting their metabolism (antidepressants
IMAO).
 Ephedrine increases the release of catecholamines into the synaptic
cleft. It is effective in oral administration and crosses the blood-brain barrier.
Nafazolin - mechanism of action identical to that of ephedrine, used as
a decongestant of the nasal mucosa.
Amphetamine is another indirect sympathomimetic that has virtually
all the effects of ephedrine but the effects on the central nervous system are
much more intense.
Cocaine is a local anesthetic that prevents the reuptake of
catecholamines from the synaptic cleft. It produces adrenergic side effects, and
on the central nervous system it produces phenomena similar to those produced
by amphetamine.
Tricyclic antidepressants increase the availability of catecholamines
in the synaptic cleft by preventing their reuptake from the synaptic cleft.
IMAO antidepressants block catecholamine metabolization by
blocking MAO enzymes.

Sympatholytics

Sympatholytics are substances that prevent the effects of sympatho-

adrenergic stimulation.
Direct sympatholytics have affinity for adrenergic receptors without
intrinsic activity.

Tolazoline, phentolamine non-selectively block both α1 and α2

receptors, producing vasodilation with decreased blood pressure and reflex
tachycardia. Are used in the diagnosis and treatment of pheochromocytoma.

Selective blockers of α1 adrenergic receptors - prazosin, doxazosin,

tamsulosin produce vasodilation without reflex tachycardia. Are used in the
treatment of hypertension and benign prostatic hypertrophy.
 β Adrenergic receptor blockers. Decrease the heart activity by
blocking the β1 adrenergic receptors and aggravate asthma by blocking the β2
adrenergic receptors.
Indications: treatment of hypertension, angina pectoris and cardiac
arrhythmias, prevention of migraine attacks (propranolol), tremor of the
extremities in conditions of anxiety (propranolol), treatment of glaucoma
(timolol) in local administration.
Side effects: excessive hypotension, bradycardia, atrioventricular block,
worsening of asthma or peripheral vascular-spastic diseases.
β non-selective blockers – propranolol
β1 selective blockers - atenolol, metoprolol, acebutolol. They have the
same indications and the same efficacy as non-selective blockers but can also
be used in patients with asthma or peripheral ischemia syndromes.

Indirect sympatholytics - neurosympatholytics, or blockers of

sympathetic endings, prevent the accumulation of catecholamines in the
synaptic cleft. It works by decreasing the release of the neurotransmitter in the
synaptic cleft - guanethidine or by depleting catecholamine deposits -
reserpine.