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 (α1, α2)
and beta (β1, β2, β3) 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 µm 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 α2-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 (α1)
•Contraction of radial muscules of iris: mydriasis and
decreased aqueous secretion (α1)
•GIT: intestinal relaxation, contraction of sphincters
•Bladder trigone: contraction
•Uterus: contraction
•Splenic capsule: contraction
•Neuromuscular transmission: increased ACh release
•Insulin secretion: inhibited (α2 dominant)
•Mail sex organs: ejaculation
•Salivary glands: K+ and water secretion (α1)
•Nictitating membrane in cats: contraction (α1)
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 (β2): fall in BP
•Cardiac stimulation (β1): increased heart rate,
force and conduction velocity
•Bronchodilation (β2)
•Eye: enhanced aqueous secretion
•GIT: intestinal relaxation (β2)
•Bladder detrusor: relaxation
•Uterus: relaxation (β2)
•Neuromuscular transmission: tremor (β2)
•Augmented insulin and glucagon secretion (β2)
•Liver: glycogenolysis (β2)
•Fat – lipolysis (β3), Kidney – renin release (β1)
•Posterior pituitary: ADH secretion (β1)
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 α- and β-receptors
Norepinephrine (noradrenalne):
α1, α2, β1 and β3, but not β2 action
Epinephrine (adrenaline):
α1, α2, β1 and β2 and weak β3 action
Isoproterenol (isoprenaline):
β1 and β2, but not α action
-------------------------------------------------Clonidine: presynaptic α2 agonist
(with antihypertensive action)
 Direct-acting adrenomimetics
α-adrenomimetics (activators of phospholipase C)
- antihypotensive drugs: Etilefrinе (Effortil), NE
- local nasal decongestants: Naphazoline,
Oxymetazoline, Xylometazoline (0.1% nasal drops)
- eye drops in glaucoma: Phenylephrine
Cardioselective α1-adrenomimetics: Dobutamine
DA-ergic adrenomimetics: Dopamine
Selective β2-adrenomimetics: Fenoterol, Hexoprenaline,
Salbutamol, Salmeterol, Terbutaline
Non-selective β-adrenomimetics: Iso- and Orciprenaline
α- and β-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 α-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 α- and β-adrenergic receptors.
Effect after 3 to 5 min
and duration 4–6 h:
•Salbutamol
•Fenoterol
Effect after 15–20 min
and duration 12 h:
•Salmeterol
FACTORS THAT EXACERBATE ASTHMA
Primarily sites of bronchodilation action of inhaled β2-adrenergic
agonists is mainly bronchiolar smooth muscle. Atropinic drugs
cause bronchodilation by blocking cholinergic constrictor tone,
act primarily in large airways.
Selective β2-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.