NC Hwang 2011
Catecholamines and Sympathomimetic agents
Sympathomimetic agents
•drugs that mimic the actions of adrenaline or
noradrenaline
•can be grouped by
•mode of action
•the spectrum of receptors that they effect
•chemical structure
•Classification by modes of action
•direct action
•agents directly interact with and activate
adrenoceptors
•indirect action
•actions depend upon
•displacement of stored catecholamines
from the adrenergic nerve endings
(amphetamine, tyramine)
•inhibition of reuptake of released
catecholamines (cocaine, tricyclic
antidepressants)
•Classification by receptor types
•alpha
•beta
•dopamine
•alpha adrenoceptor agonists
•potency series
•adrenaline  noradrenaline >> isoprenaline
(Ahlquist, 1948)
•2 major groups
•alpha1 (prazosin), alpha2 (yohimbine), both
receptor types (dihydroergocryptine)
•subtypes
•1A, 1B, 1D, 1L, 2A, 2B, 2C
•subtypes distinguished based on their
affinities for a variety of a variety of
drugs and experimental compounds
•beta adrenoceptor agonists
•potency series
•isoprenaline > adrenaline  noradrenaline
•subtypes
•β1 (affinity: adrenaline = noradrenaline)
•β2 (affinity: adrenaline > noradrenaline)
•β3 (affinity: noradrenaline > adrenaline),
selective agonist BRL37344, antagonist
bupranolol
•effect of β adrenoceptor activation
•increase cAMP, common to all subtypes
•lipolysis with β3
•dopamine adrenoceptor agonists
•distinct from α and β receptor agonists
•of particular importance in the brain, and in the
splanchnic and renal vasculature
•subtypes
•D1-5
•effects of dopamine adrenoceptor activation
•D1, D5: increase cAMP
•D2: decrease cAMP, opening of K+ channel and
decrease calcium influx
•D3, D4: decrease cAMP
•Classification by chemical structure
•catecholamines
•naturally occurring: adrenaline, noradrenaline,
dopamine
•synthetic: isoprenaline, dobutamine, dopexamine
•non-catecholamines: ephedrine, methoxamine,
metaraminol
β 
•Chemistry and pharmacokinetics -CH2-CH2-NH2
•phenylethylamine
•benzene ring with ethylamine side chain
•2 carbon atoms separate the aromatic ring & the
amino group
•considered the parent compound from which
sympathomimetic drugs are derived
•modification of phenylethylamine
•changes the affinity of the agent for α
and β receptors
•influences the intrinsic activity to
activate the receptors
•structural activity – C3, C4 of benzene ring
•C3, C4 substitution by OH groups yields catecholamines
•inactivated by catechol-O-methyltransferase
•catecholamines have maximal  and β activity
•noncatecholamines sympathomimetic agents are agents
without -OH groups at C3 and C4
•e.g. ephedrine and amphetamine, both have
absence of OH groups at C3 and C4 position
•with absence of one or both -OH groups
•bioavailability after oral administration is
increased
•duration of action is prolonged
•distribution of the molecule to the central
nervous system is increased
•OH at C3 but absence of OH at C4 promotes α1
selectivity.
•e.g. phenylephrine.  activity decreased by 100-
fold and β activity almost negligible at very high
concentrations, therefore phenylephine
considered a pure α agonist

•structural activity - amino group
•bulky amine substitution
•reduces α-receptor activity
•increases β-receptor activity
•too bulky for amine reuptake
•MAO unable to oxidise agent
•β2 selective agonists generally require a large amino
substituent group
•methyl (adrenaline) and isopropyl substitution
(isoprenaline)
2
•Mechanism of action
•G proteins
•G (guanine nucleotide regulatory) proteins couple
adrenoceptors to various effector proteins whose activities
are regulated by the receptors
•each G protein is a heterotrimer consisting of , β and 
subunits
•classified on the basis of the α subunit
•Gs: activates adenylyl cyclase
•Gi: inhibits adenylyl cyclase
•Gq: activates phospholipase C

•activation of G protein coupled receptors

•e.g. salbutamol (tertiary butyl group) •upon activation by an extracellular ligand, the receptor
triggers the activation of a G protein located on the
cytoplasmic face of the plasma membrane
•GDP dissociates from the α subunit, followed by binding
of GTP to G protein
•N-methylation increases the potency of the primary
amines •GTP-bound α subunit then dissociates from the β- unit
•α activity of adrenaline > isoprenaline and regulate the activity of its effector (adenylyl cyclase,
cGMP phosphodiesterase, phospholipase C, and ion
•structural activity - alpha carbon
channels), which then changes the concentration of the
•catecholamines do not have methyl compounds at -
intracellular second messenger (cyclic adenosine-3’,5’-
carbon
monophosphate (cAMP), Ca++, or phosphoinositides)
• methyl compounds aka phenylisopropylamines
•by resisting oxidation by monoamine oxidase, •α subunit is inactivated by hydrolysis of the bound GTP
the action of these agents (ephedrine and to GDP and Pi, and the subsequent reassociation of the α
amphetamine) is prolonged, enhancing the ability subunit with the β subunit
of these indirectly acting sympathomimetics to
•β subunit may act directly on ion channels and other
displace catecholamines from storage sites in
enzymes
noradrenergic nerves
•a portion of their action depends upon
the presence of normal noradrenaline
stores in the body

•structural activity - beta carbon

•direct-acting agonists typically have a β-hydroxyl group
(except dopamine)
•hydroxyl group may be important for storage of
sympathomimetic amines in the neural vesicles

•isomerism
•conferred by substitution on either of the ethyl C atoms
•levorotatory substitution at the β-C atom
produces naturally occurring noradrenaline and
adrenaline
•both are > 10 times as potent as their d-isomers
•dextrorotatory substitution at the α-C atom
generally confers greater potency in stimulation
of the central nervous system
•e.g. d-amphetamine
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•activation of alpha1 receptor •in smooth muscle
•phosphorylation of myosin light chain kinase to
an inactive form promotes relaxation of smooth
muscle
•promotes entry of K+ into cells via Na+/K+
ATPase pump
•modifies gene expression
•by phosphorylating cAMP response element
binding protein

•Receptor regulation - desensitization

•aka tachyphylaxis, refractoriness, tolerance
•occurs after long-term usage of β-adrenergic agonist and
is reversible with removal of agonist
•3 mechanisms
•α1 receptors also activate mitogen-activated kinase (MAP •receptor sequestration, a rapid and transient
kinases) and polyphosphoinositol-3-kinase (PI-3-kinase) event wherein the receptors are made temporarily
unavailable for activation by agonists
•these pathways may have importance for the α1-
•down-regulation, disappearance of the receptors
receptor mediated stimulation of cell growth
from the cell, may take place by the action of
•activation of alpha2 receptor enzymes on the receptor or decreased synthesis
•phosphorylation of the receptor on the
cytoplasmic side by protein kinase A or β-
adrenergic receptor kinase βARK may impair
coupling of β-adrenoceptors with Gs

•activation of beta receptor

•in the liver

•activation of glycogen phosphorylase, with
increased glycogenolysis
•release of K+ from liver
•in the heart
•increase in cAMP results in increase Ca++ influx
across the cell membrane and its sequestration
inside the cell
•β adrenoceptor may activate voltage-sensitive
calcium channels independent of changes in
cAMP concentration via Gs-mediated
enhancement

•Synthesis of noradrenaline and adrenaline
•Termination of action
•actions of adrenaline and noradrenaline are terminated by
three processes
•presynaptic re-uptake into the nerve terminal
•dilution by diffusion from the junctional cleft
and uptake at non-neuronal sites, and
•metabolic transformation
•COMT for methylation
•MAO for oxidative deamination
•Metabolism
•COMT & MAO distributed widely throughout the body,
including the brain
•highest concentrations in liver and kidney
•different cytosolic locations,
•MAO located on the outer surface of
mitochondria, especially in adrenergic neurones
•COMT located in cytoplasm, and some in
membranes
•no selective association with adrenergic
nerves
4
Noncatecholamine sympathomimetics
•with few exceptions the actions of the noncatecholamines
fit within the framework of α and β receptors
•mechanisms of action
•direct agonist activity (phenylephrine (),
ephedrine (β2)
•uptake into the adrenergic nerve terminal, with
subsequent stoichiometric displacement of
noradrenaline from storage sites (uptake &
displacement hypothesis of Burn & Rand, 1958)
•agents that release noradrenaline have
predominantly α actions
•elimination of non-catecholamines
•pathways for metabolism include
•p-hydroxylation
•N-demethylation
•deamination
•conjugation in the liver
•substantial fractions of these drugs are eliminated
unchanged in the urine
•renal excretion of amphetamine (pKa = 9.9), and many
other non-catecholamine's is profoundly influenced by
urinary pH
•large number of noncatecholamines have pKa
between 9.0 to 10.3
•therefore excretion is enhanced by acidification
of the urine
•although these agents are resistant to the actions of the
MAO inhibitors, they provoke the release of noradrenaline
and may cause hypertensive crises if administered
concurrently
•Beta adrenergic agonists

Pharmacodynamics
•effect on blood vessels
•α receptor agonists increase arterial resistance
•β2 receptor agonists promote smooth muscle relaxation
•overall effects of a sympathomimetic agent
depend on the relative activities of that drug at α
and β receptors and the anatomic sites of the
vessels affected
•e.g. skin vessels have predominant α receptors,
constrict with adrenaline and noradrenaline
•D1 receptor agonists promote vasodilatation of renal,
splanchnic, coronary, and cerebral arteries
•effects on the heart
•direct effects are determined largely by β1 receptors,
though β2 and to a less extent α receptors are also involved
•β receptor activation results in increased calcium influx in
cardiac cells
•chronotropy - pacemaker activity (sinoatrial
node and Purkinje fibres) is increased
•dromotropy - conduction velocity in
atrioventricular node is increased
•inotropy - intrinsic contractility is increased
•lusitropy - accelerated relaxation
•effects on blood pressure
•explained on the basis of the action on the heart,
peripheral vascular resistance and venous return
•pure α agonist, (phenylephrine) increases peripheral
vascular resistance and decreases venous capacitance,
leading to a marked rise in blood pressure
•with intact baroreceptor-mediated response,
vagal tone increases resulting in bradycardia
•cardiac output may not decrease with increased
venous return, and modest positive inotropic
effect
•pure β agonist, (isoprenaline) decreases peripheral
vascular resistance
•net effect is increased cardiac output with
maintained or slightly increased systolic pressure,
and a decrease in diastolic pressure
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•effects on the eye
•mydriasis
•radial pupillary dilator muscles of the iris
contains α receptors, activation (by
phenylephrine) causes mydriasis
•aqueous humour
•outflow increased by α agonists
•production decreased by β agonists, (treatment
of glaucoma)
•decrease in accommodation
•β receptor activation relaxes the ciliary muscle to
a minor degree causing insignificant decrease in
accommodation
•effects on the respiratory tract
•bronchodilation
•mediated by β2 receptors on smooth muscle cells
•decongestion of upper respiratory tract mucosa
•blood vessels of the upper respiratory tract
mucosa contains α1 receptors, activation results in
decongestion
•effects on the gastrointestinal tract
•relaxation of the gastrointestinal smooth muscle
•β receptors located on smooth muscle cells and
mediate relaxation via hyperpolarisation and
decreased spike activity in these cells
•α agonists, especially α2 selective agonists
decrease muscle activity indirectly by
presynaptically reducing the release of
acetylcholine and possibly other stimulants within
the enteric nervous system
•α response probably of greater pharmacologic
significance than β response
•α2 receptors may also decrease salt and water flux into the
lumen of the intestine
•effects on the genitourinary tract
•relaxation of uterus
•uterus contains both α and β2 receptors, β
receptors mediate relaxation
•urinary incontinence
•bladder base, urethral sphincter, and prostate
contain α receptors that mediate contraction
•relaxation of bladder wall
•mediated by β2 receptors of bladder wall
effects on the exocrine glands
•dry mouth
•central α2 activity
•increased sweat production by apocrine sweat glands
(palm of hands)
•these are nonthermoregulatory apocrine glands
usually associated with psychologic stress
•in contrast with diffusely distributed
thermoregulatory eccrine sweat glands which are
regulated by sympathetic cholinergic
postganglionic nerves that activate muscarinic
cholinoceptors
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•metabolic effects •endocrine actions
•lipolysis •modulation of renin, insulin & pituitary
•increased by β3 receptor activation hormones
•inhibited by α2 receptor activation, via decreased •CNS actions
intracellular cAMP •stimulation of respiration
•glycogenolysis in the liver •some agents increase psychomotor activity &
•enhanced by sympathomimetic drugs (β>α1), wakefulness, and decreased appetite
leading to increased glucose release into the
circulation and hyperglycaemia Specific sympathomimetic agents
•hypokalaemia •Adrenaline
•by promoting uptake of potassium into skeletal •rise in blood pressure due to
muscle cells via Na+/K+ ATPase pump •positive inotropic and chronotropic actions on
•metabolic acidosis the heart (b1)
•effects on endocrine and other functions •vasoconstriction induced in many vascular beds
•insulin secretion ()
•stimulated by β2 receptor activation •vasodilatation in
•decreased by 2 receptor activation •skeletal muscle blood vessels (b2)
•renin secretion •total peripheral resistance may actually fall due to fall in
•stimulated by β1 receptors diastolic blood pressure
•inhibited by 2 receptors •vascular effects of adrenaline
•modulate secretion of parathyroid hormone, calcitonin,
thyroxine, and gastrin
•but physiologic significance unclear
•leukocytosis, with high concentrations of adrenaline
•in part, by promoting demargination of white
blood cells sequestrated away from the general
circulation
•effects on the central nervous system
•depend on the ability to cross the blood-brain barrier
•phenylisopropylamines, the most commonly
used noncatecholamines are widely distributed in
tissues and readily cross the blood brain barrier,
therefore have pronounced effects on the central
nervous system •smooth muscle effects of adrenaline
•catecholamines
•nervousness
•feeling of impending disaster
•noncatecholamines
•alerting, with improved attention to boring tasks
•elevation of mood, insomnia, euphoria, and
anorexia
•psychotic behaviour
•probably represent enhancement of dopamine-
mediated processes in the central nervous system
•summary of effects
•peripheral excitatory action on certain types of smooth
muscle
•blood vessels supplying the skin and mucous
membranes
•gland cells, including the salivary & sweat
•peripheral inhibitory action on certain types of smooth •Noradrenaline
muscle •similar effects with adrenaline on β1 and  receptors
•the wall of the gut and bronchial tree •positive inotropic and chronotropic actions on
•the blood vessels supplying skeletal muscle the heart (β1)
•a cardiac excitatory effect, increase in rate and force of •vasoconstriction induced in many vascular beds
contraction ()
•metabolic actions, including, •relatively little effect on β2 receptors
•increased rate of glycolysis in muscle & liver, •actions lead to increase in total peripheral resistance,
and diastolic and systolic blood pressure
•the liberation of free fatty acids from adipose •compensatory vagal reflexes
tissue •tend to overcome direct positive chronotropic
effects, but positive inotropic effect is maintained
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•Isoprenaline •Phenylephrine
•extremely potent β receptor agonist, little effect on  •relatively pure  agonist
receptor •acts directly on receptors
•positive chronotropic and inotropic action •noncatecholamine, therefore not metabolised by COMT
•potent vasodilator •longer duration of action than catecholamines
•actions lead to marked increase in cardiac output •applications
associated with •mydriasis
•a fall in diastolic and mean arterial pressure •nasal decongestant
•a lesser decrease or slight increase in systolic •pressor agent
pressure •side effects
•Dopamine •rebound hyperaemia
0.1-2 μg/kg/min •mucosal ischaemia
•D1 activation, increasing renal and splanchnic blood flow,
•Ephedrine
urine output and sodium excretion
•noncatecholamine phenylisopropylamine
•D2 activation, inhibiting noradrenaline release and
•mixed-action mechanism of action
resulting in vasodilatation
•stimulates both alpha and beta receptors and its
1-5 μg/kg/min
peripheral actions are due partly to release of
•activation of β1 receptors, increasing myocardial
stored noradrenaline and partly to direct effect on
contractility
receptors
•tachycardia, arrhythmias and increased cardiac work with
•has 1, 2, β1, β2 adrenergic receptor-agonist properties.
higher dose ranges
•40% of the thermogenic activity of ephedrine is
>6 μg/kg/min
reported to be due to the activation of the β3
•activation of  receptors, causing peripheral
adrenoreceptors in the adipose tissues
vasoconstriction, reducing splanchnic and renal blood
•also stimulates thyroid function
flows
•absorption
•Dobutamine
•active by oral route, with high bioavailability
•relatively β1-selective synthetic catecholamine
•rapidly and completely absorbed following
•2 isomers, administered as racemic mixtures
parenteral injection
•(+) isomer is potent β1 agonist and an 1 receptor
•distribution
antagonist
•access into brain, is a mild stimulant
•(-) isomer is a potent α1 agonist, capable of
•central effects of ephedrine are overshadowed to
causing vasoconstriction when administered alone
a large extent by its peripheral actions
•effects
•increases oxygen consumption and metabolic
•increase in stroke volume and left ventricular
rate as a probable result of central stimulation
dP/dt
•long duration of action
•reduction in LVEDP, PAWP, and SVR
•pressor and cardiac responses to ephedrine
•dose range: 2-15 μg/kg/min, but tolerance develops after
persist for one hour following intramuscular or
6-8 hours of infusion, probably due to downregulation
subcutaneous administration of 25 to 50 mg
•pharmacokinetics
•may deplete norepinephrine stores in
•Vd 0.2 L/kg
sympathetic nerve endings, so that tachyphylaxis
•clearance 60 ml/min/kg
to cardiac and pressor effects of the drug may
•t½β 2.5 minutes
develop
•Dopexamine
•metabolism
•synthetic catecholamine, structurally related to dopamine
•small amounts of ephedrine are slowly
and dobutamine
metabolized in the liver
•produces a combination of D1 and β2and β1 receptor
•p-OHephedrine, p-OHnorephedrine,
agonist activity
norephedrine, and conjugates of these
•compared with dopamine, one-third potency at
compounds
D1 receptors but 60x more at β2 adrenoceptors
•elimination
•relative selectivity for β2:β1-receptors about 9.8:1
•the drug and its metabolites are excreted in the
•inhibitory action in neuronal catecholamine uptake
urine, mostly as unchanged ephedrine
•more potent than dopamine
•rate of urinary excretion is dependent on urinary
•this likely accounts for the positive inotropic
pH
action of the agent
•as a weak base, excretion is accelerated
•dose range 0.5-4 μg/kg/min: preferential systemic,
by acidification of urine
mesenteric and renal vasodilatation; t ½ about 7 minutes
•elimination half-life of the drug has
•dose range >4 μg/kg/min: tachycardia and hypotension
been reported to be about 3 hours when
•in patients with severe congestive cardiac failure
the urine is acidified to pH 5 and about 6
•profound reduction in afterload with increased
hours when urinary pH is 6.3
cardiac output (mainly rate)
•applications
•mild positive inotropy (5-10%)
•nasal decongestant
•increased renal blood flow
•pressor agent
•tachyphylaxis may occur

•Pseudoephedrine
•one of the 4 enantiomers of ephedrine
•use as nasal decongestant
•treatment of stress incontinence in women
•side effects
•hypertension
•dysrhythmias
•angina
•hyperglycaemia
•contraindications
•people prone to hypertension, heart disease,
hyperglycemia, hyper-thyroidism, prostate
disease
•Amphetamine
•noncatecholamine phenylisopropylamine
•enters central nervous system even more readily than
ephedrine
•has a more marked stimulant effect on mood and alertness
and a depressant effect on appetite
•peripheral actions mediated through release of
catecholamine
•Cocaine
•local anaesthetic with peripheral sympathomimetic action
•inhibition of dopamine and noradrenaline
reuptake at the noradrenergic synapses, enhances
the effects of the catecholamines
•readily enters the central nervous system produces
amphetamine-like effect but
•shorter lasting and more intense
•heavily abused drug as it can be inhaled as well as
injected
•by inhibiting neuronal uptake of amine, also inhibits the
effects of the noncatecholamines
8
•Clinical applications of sympathomimetic agents
•correction of hypotension
•correction of hypertension (clonidine, methyldopa)
•aid haemostasis
•mucous membrane decongestion
•emergency management of complete heart block
(isoprenaline), cardiac arrest (adrenaline) acute right heart
failure (isoprenaline)
•management of congestive heart failure (adrenaline,
dobutamine, prenalterol)
•treatment of bronchial asthma
•management of anaphylaxis, anaphylactic shock and
related immediate (type I) IgE-mediated reactions
•syndrome of bronchospasm, mucous membrane
congestion, angioedema, cardiovascular collapse
responds rapidly to subcutaneous administration
of adrenaline 0.3-0.5 mg (stimulation of α, β1,
and β2 receptors)
•ophthalmic applications
•mydriasis to facilitate examination of retina
•conjunctival decongestant
•treatment of glaucoma (alpha effects increase
outflow and beta effects decrease production of
aqueous humour)
•genitourinary applications
•relaxation of uterus to suppress premature labour
•treatment of stress incontinence
•central nervous system applications
•treatment of narcolepsy
•appetite suppressant
•treatment of attention-deficit hyperkinetic
syndrome
•Toxicity of sympathomimetics
•severe hypertension
•angina
•myocardial infarction
•arrhythmias (sinus tachycardia, ventricular arrhythmias)
•tissue ischaemia if extravasation has occurred (treat with
alpha antagonist)
•restlessness, tremor, anxiety, insomnia, convulsions,
cerebra haemorrhage with agents that access the brain