ADRENERGIC DRUGS

(Sympathomimetics,
Adrenomimetics)
Assoc. Prof. I. Lambev
Medical University of Sofia
E-mail: itlambev@mail.bg
www.medpharm-sofia.eu
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 postgan-
glionic 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.
(NOR)ADRENERGIC AND DOPAMINERGIC NERVES

NE
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
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.
 Adrenergic
receptors:
α1
α2
β1
β2
β3
Adrenergic
(catecholamine)
neurotransmitters
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 regulatory 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-ortho-methyltransferase
(COMT, present in the cytoplasm of
postjunctional cells, to yield normeta-
nephrine), and monoamine oxidase
(MAO, present in the mitochondria of nerve
cells and postjunctional cells) to yield
3,4-dihydroxymandelic acid).
The liver is richly endowed with
COMT and MAO. It therefore contrib-
utes 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
•Arterioles and veins (α1): contraction and rise in BP
•Eye (α1): decreased aqueous secretion
•GIT (α1): contraction of sphincters
•Bladder trigone (α1): contraction
•Uterus (α1): contraction
•Insulin secretion (α2): inhibited
•Mail sex organs: ejaculation
•Salivary glands (α1): water secretion
•Nictitating membrane in cats (α1): contraction
 Noradrenaline (1)
(+)
Ex
Gs PLC
In
PIP2
IP3 DAG
ADP
Ca2+ ATP PKC
• PLC (phospholipase C) catalyses the
formation of two intracellular messen-
gers  InsP3 and DAG, from memb-
rane phospholipids.
• InsP3 (inositol-triphosphate) increases
free cytosolic calcium by releasing
Ca2+ from the endoplasmic reticulum.
• Free calcium initiates contractions, se-
cretion, membrane hyperpolarization
• DAG activates protein kinase C.
Action on beta-adrenoceptors
•Arterioles and veins (β2): dilation and fall in BP
•Heart (β1): increased heart rate,
force, and conduction velocity
•Lung (β2): bronchodilation
•Eye (β2): enhanced aqueous secretion
•GIT (β2): intestinal relaxation
•Bladder detrusor (β2): relaxation
•Uterus (β2): relaxation
•Liver (β2): glycogenolysis
•Insulin and glucagon secretion (β2): augmented
•Fat (β3): lipolysis
•Kidney (β ): renin release
Adr (1&2)
(+)
Ex
Gs AC
In
cAMP ATP

PKA Effects
-ad-
reno-
ceptor
•7 sub-
units
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 (noradrenaline):
α1, α2, β1 and β3, but no β2 action
Epinephrine (adrenaline):
α1, α2, β1 and β2, and weak β3 action
Isoproterenol (isoprenaline):
β1 and β2, but no α action
--------------------------------------------------
Clonidine: presynaptic α2 agonist
(with antihypertensive action)
 Direct-acting adrenomimetics
α-adrenomimetics (activators of phospholipase C)
- antihypotensive drugs: Etilefrinе, Midodrine, NE
- local nasal decongestants: Naphazoline,
Oxymetazoline, Xylometazoline (0.1% nasal drops)
- eye drops in glaucoma: Phenylephrine
Cardioselective β1-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 or Epipen (0,3 mg/03 ml i.m.)

 Indirect-acting adrenomimetics
Antihypotensive drugs
Ephedrine, Mephentermine
 I.M.

Pre-filled syringes: Anapen® and EpiPen®: I.M.

http://www.youtube.com/watch?v=ZR5c5VP2rOs
Reactive hyperemia due to α-adrenomimetics
(naphazoline, oxymetazoline, xylometazoline)
e.g., following decongestion of nasal mucosa
 Some important catecholamines
Isoproterenol (USAN) = Isoprenaline (INN)
BP – blood pressure, HR – heart rate
 Isolated aortic strip Isolated bronchial
smooth muscle

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

and Iso (isoprenaline) on isolated aortic strip and isolated bron-
chial smooth muscle illustrating two distinct rank orders of po-
tencies 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
The primary site 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
(indirect adreno-
mimetic with
antihypotensive
and
antiasthmatic
effects
ADR: tachy-
phyllaxis
 Indirect
sympathomimetics
with central
stimulant
activity and
abuse potential

•Amphetamine
•Cocaine
Erythroxylum
coca L.