Medical University of Sofia, Faculty of Medicine

Department of Pharmacology and Toxicology

ADRENERGIC DRUGS
(Sympathomimetics,
Adrenomimetics)

Assoc. Prof. Ivan Lambev

E-mail: itlambev@mail.bg

The sympathetic preganglionic fibers leave the

CNS through the thoracic and lumbar spinal nerves.
The sympathetic preganglionic neurons (first
neurons) project from the intermediolateral
column of the spinal gray matter to the paired
paravertebral ganglionic chain lying alongside
the vertebral column and to unpaired prevertebral
ganglia. These ganglia represent sites of synaptic
contact between preganglionic axons (1st neurons)
and nerve cells (2nd neurons) that emit postganglionic axons terminating on cells in various end
organs. In addition, there are preganglionic neurons
that project either to peripheral ganglia in end organs
or to the adrenal medulla.

ADRENERGIC AND DOPAMINERGIC NERVES

Activation of the
Sympathetic Nervous
System can be
considered a means
by which the body
achieves a state of
maximal work capacity
as required in fight
or flight situations.

Whereas ACh serves as the chemical transmitter at

ganglionic synapses between first and second neurons,
Norepinephrine (NE, noradrenaline) is the mediator at
synapses of the second neuron. Excitation of the neuron
leads to activation of a larger aggregate of effector cells,
although the action of released NE may be confined to
the region of each junction. Excitation of preganglionic
neurons innervating the adrenal medulla causes a
liberation of ACh. This, in turn, elicits a secretion
of epinephrine (adrenaline) into the blood, by
which it is distributed to body tissues as a hormone.

Adrenoceptors fall into two major

groups, designated alpha (1, 2)
and beta (1, 2, 3) within
each of which further subtypes can be
distinguished pharmacologically. The
different adrenoceptors are differentially
distributed according to region and
tissue. Agonists at adrenoceptors
(direct adrenomimetics) mimic the
actions of the naturally occurring catecholamines, NA and epinephrine, and
are used for various therapeutic effects.

Within the varicosities, NE is stored in small

membrane-enclosed vesicles (granules,
0.05 to 0.2 m in diameter). In the axoplasm,
L-tyrosine is converted via two intermediate
steps to dopamine (DA), which is taken up into
the vesicles and there converted to NE by
DA-beta-hydroxylase.
When stimulated electrically, the sympathetic
nerve discharges the contents of part of its
vesicles, including NE, into the extracellular
space. Liberated NE reacts with adrenoceptors
located postjunctionally on the membrane of
effector cells or prejunctionally on the membrane of
varicosities. Activation of presynaptic 2-receptors
inhibits NE (regulative negative feedback).

Presynaptic receptors in adrenergic synapse

and their role in the regulative negative and
positive feedback

Presynaptic regulation of transmitter release from

noradrenergic and cholinergic nerve terminal

The effect of released NE wanes quickly,

because approximately 90% is actively
transported back into the axoplasm, then
into storage vesicles (neuronal re-uptake).
Small portions of NE are inactivated by the
enzyme catechol-O-methyltransferase
(COMT, present in the cytoplasm of
postjunctional cells, to yield normetanephrine), and monoamine oxidase
(MAO, present in mitochondria of nerve
cells and postjunctional cells) to yield
3,4-dihydroxymandelic acid).

The liver is richly endowed with

COMT and MAO. It therefore contributes significantly to the degradation
of circulating NE and epinephrine.
The end product of the combined
actions of MAO and COMT is
vanillylmandelic acid.

Antiparkinsonian dopaminergic drugs

moclobemide and selegiline block MAO.

Action on alpha-adrenoceptors
Contraction of arterioles and veins: raise in BP (1)
Contraction of radial muscules of iris: mydriasis and
decreased aqueous secretion (1)
GIT: intestinal relaxation, contraction of sphincters
Bladder trigone: contraction
Uterus: contraction
Splenic capsule: contraction
Neuromuscular transmission: increased ACh release
Insulin secretion: inhibited (2 dominant)
Mail sex organs: ejaculation
Salivary glands: K+ and water secretion (1)
Nictitating membrane in cats: contraction (1)

Noradrenaline (a1)
(+)

Ex
Gs

PLC

PIP2
IP3

DAG
ADP

Ca2+

ATP

PKC

In

 PLC (phospholipase C) catalyses the

formation of two intracellular messengers - InsP3 and DAG, from membrane phospholipids.
InsP3 (inositol-triphosphate) increases
free cytosolic calcium by releasing
Ca2+ from endoplasmic reticulum.
Free calcium initiates contractions, secretion, membrane hyperpolarization
DAG activates protein kinase C.

Action on beta-adrenoceptors
Dilatation of arterioles and veins (2): fall in BP
Cardiac stimulation (1): increased heart rate,
force and conduction velocity
Bronchodilation (2)
Eye: enhanced aqueous secretion
GIT: intestinal relaxation (2)
Bladder detrusor: relaxation
Uterus: relaxation (2)
Neuromuscular transmission: tremor (2)
Augmented insulin and glucagon secretion (2)
Liver: glycogenolysis (2)
Fat lipolysis (3), Kidney renin release (1)
Posterior pituitary: ADH secretion (1)

Adr (b1&b2)
(+)

Ex
Gs

AC

In
cAMP
PKA

ATP
Effects

b-adrenoceptor
7 subunits

Agents which increase cAMP

(adrenaline, salbutamol
and other beta-adrenoceptor
agonists) inhibit histamine
secretion and produce
bronchodilation
(antiasthmatic effect).

Autonomic
control
of pupil (A)
and site
of action of
mydriatics (B)
and
miotics (C)

Chemical structure of catecholamines

and affinity for - and -receptors

Norepinephrine (noradrenalne):
1, 2, 1 and 3, but not 2 action
Epinephrine (adrenaline):
1, 2, 1 and 2 and weak 3 action
Isoproterenol (isoprenaline):
1 and 2, but not action
-------------------------------------------------Clonidine: presynaptic 2 agonist
(with antihypertensive action)

 Direct-acting adrenomimetics
-adrenomimetics (activators of phospholipase C)
- antihypotensive drugs: Etilefrin (Effortil), NE
- local nasal decongestants: Naphazoline,
Oxymetazoline, Xylometazoline (0.1% nasal drops)
- eye drops in glaucoma: Phenylephrine
Cardioselective 1-adrenomimetics: Dobutamine
DA-ergic adrenomimetics: Dopamine
Selective 2-adrenomimetics: Fenoterol, Hexoprenaline,
Salbutamol, Salmeterol, Terbutaline
Non-selective -adrenomimetics: Iso- and Orciprenaline
- and -adrenomimetics: Adrenaline (antiallergic):
amp. 0,1% 1 ml s.c.; Anapen (0,3 mg/03 ml i.m.)

Indirect-acting adrenomimetics
Antihypotensive drugs
Ephedrine, Mephentermine, Midodrine

Reactive hyperemia due to -adrenomimetics

(naphazoline, oxymetazoline, xylometazoline)
e.g., following decongestion of nasal mucosa

Some important catecholamines

NB: isoproterenol (isoprenaline)

BP blood pressure, HR heart rate

Effects of intravenous infusion of norepinephrine,

epinephrine, or isoproterenol in humans

Isolated aortic strip

Isolated bronchial
smooth muscle

Dose-response curves of Adr (adrenaline), NA (noradrenaline)

and Iso (isoprenaline) on isolated aortic strip and isolated bronchial smooth muscle illustrating two distinct rank orders of potencies respectively for - and -adrenergic receptors.

Effect after 3 to 5 min

and duration 46 h:
Salbutamol
Fenoterol
Effect after 1520 min
and duration 12 h:
Salmeterol

FACTORS THAT EXACERBATE ASTHMA

Primarily sites of bronchodilation action of inhaled 2-adrenergic

agonists is mainly bronchiolar smooth muscle. Atropinic drugs
cause bronchodilation by blocking cholinergic constrictor tone,
act primarily in large airways.

Selective 2-adrenomimetics with tocolytic effect

Fenoterol (Partusisten: tab. 5 mg)
Hexoprenaline
Salbutamol (Salbupart)
Terbutaline

Ephedra
equsetina
- Ephedrine
with antihypotensive
and antiasthmatic
effects
AR: tachyphyllaxis

Indirect
sympathomimetics
with central
stimulant
activity and
abuse potential
Amphetamine
Cocaine

Erythroxylon
coca L.