Adrenergic Agonists dependent norepinephrine transporter

(NET) that can be inhibited by tricyclic

Direct-acting agonists: directly activate antidepressants (TCAs), such as
adrenergic receptors imipramine, by serotonin
Indirect-acting agonists: enhancing release norepinephrine reuptake inhibitors
or blocking reuptake of norepinephrine such as duloxetine, or by cocaine.

Adrenergic neurons - links between ganglia Norepinephrine also binds to presynaptic

and the effector organs receptors (mainly 2 subtype) that modulate
the release of the neurotransmitter.
Neurotransmission involves the following
steps: Reuptake of norepinephrine into the
presynaptic neuron is the primary
1. synthesis - Tyrosine is hydroxylated to mechanism for termination of its effects
dihydroxyphenylalanine (DOPA) by
tyrosine hydroxylase. This is the rate- Once norepinephrine reenters the adrenergic
limiting step. DOPA is then neuron, it may be taken up into synaptic
decarboxylated by the enzyme vesicles via the amine transporter system
aromatic I-amino acid decarboxylase and be sequestered for release by another
to form dopamine in the presynaptic action potential, or it may persist in a
neuron. protected
2. Storage - Dopamine is transported by pool in the cytoplasm.
an amine transporter system. This
carrier system is blocked by Alternatively, norepinephrine can be oxidized
reserpine. Dopamine is next by monoamine oxidase (MAO) present in
hydroxylated to form norepinephrine neuronal mitochondria.
by the enzyme dopamine -
hydroxylase. adrenergic agonists
3. release- An action potential triggers 1. epinephrine
an influx of calcium ions causing 2. norepinephrine
synaptic vesicles to fuse with the cell 3. isoproterenol.
membrane and to undergo exocytosis Adrenoceptors
to expel their contents into the 1. alpha - epinephrine norepinephrine
synapse. Drugs such as guanethidine >> isoproterenol
block this release. 1. a1 - higher affinity for phenylephrine
4. receptor binding of norepinephrine - present in postsynaptic membrane
binds to postsynaptic receptors on the constriction of smooth muscles
effector organ or to presynaptic activation of phospholipase C
receptors on the nerve ending. This inositol-1,4,5-triphosphate and
diacylglycerol.
results in production of transducers or
IP3 initiates release of Ca2+ into
second messenger system cAMP
cytosol
phosphatidlyinositol cycle.
vasoconstriction (particularly in
5. removal of the neurotransmitter from
skin and abdominal viscera)
the synaptic gap 1.) diffuse out of
2. a2 - clonidine selectively binds to 2
the synaptic space and enter the
receptors
systemic circulation; 2) be
- located on presynaptic nerve
metabolized to inactive metabolites by
endings and control release of
catechol-O-methyltransferase (COMT)
norepi
in the synaptic space; or 3) undergo
- when adrenergic nerve is
reuptake back into the neuron. The
stimulated, some of the norepi
reuptake involves a (Na+/Cl-)-
 reacts with the presynaptic neuron heart - predominantly 1 receptors.
in order to inhibit more release of
norepi, thus regulating its release. Desensitization - Prolonged exposure to
(Inhibitory autoreceptors) catecholamines reduces the responsiveness

- it can also interact with of the receptors.

presynaptic parasympathetic 1. sequestration of the receptors so that
neuron to controlrelease of Ach they are unavailable for interaction
(Inhibitory heteroreceptors) with the ligand
- mediated by inhibition of adenlyl 2. down-regulation, that is, a
cyclase and fall in cAMP levels disappearance of the receptors either
3. There are further subdivisions such by destruction or by decreased
as a1a tamsulosin is selective to synthesis
this receptor to treat benign 3. an inability to couple to G protein,
prostatic hyperplasia with fewer because the receptor has been
cardiovascular effects because it phosphorylated on the cytoplasmic
targets subtype in urinary tract and side.
prostate gland and does not affect
the a1b subtype CHARACTERISTICS OF ADRENERGIC
2. beta isoproterenol > epinephrine > AGONISTS
norepinephrine
- activation of adenylyl cyclase and Most of the adrenergic drugs are derivatives
increased concentrations of cAMP of -phenylethylamine (Substitutions on the
1. b1 - equal affinities for epinephrine benzene ring or on the ethylamine side
and norepinephrine chains for varying abilities to differentiate
- cardiac stimulation (increase between a and b receptors and ability to
in heart rate and contractility) penetrate CNS)
2. b2 - higher affinity for epinephrine
than for norepinephrine Two important structural features of these
predominance in vasculature of drugs are:
skeletal muscle (this is why it is 1) the number and location of OH
response to effects from adrenal substitutions on the benzene ring
medulla) 2) the nature of the substituent on the amino
vasodilation (in skeletal muscle nitrogen.
vascular beds) and smooth
muscle relaxation Catecholamines - amines that contain the
3. b3 lipolysis and effects on the 3,4-dihydroxybenzene group (such as
detrusor muscle of the bladder. epinephrine, norepinephrine, isoproterenol, and
vasculature of skeletal muscle 1 and 2 dopamine)
receptors, but the 2 receptors predominate. 1. High potency for a and b receptors -
 (with OH groups in the 3 and 4 used in therapy. Epinephrine, norepinephrine
positions on the benzene ring and dopamine are natural and dobutamine is
2. Rapid inactivation - metabolized by synthetic.
COMT
postsynaptically and by MAO intraneuronally, In the adrenal medulla, norepinephrine
as well as by COMT and MAO in the gut wall, is methylated to yield epinephrine, which is
and by MAO in the liver. Rapid inactivation IV stored in chromaffin cells along with
and ineffective orally. norepinephrine. Adrenal medulla releases
3. Poor penetration into the CNS about 80% epinephrine and 20%
because they are polar but still have a norepinephrine.
bit of CNS effects (anxiety, tremor, and
headaches) Epinephrine interacts with both and
receptors. At low doses, effects
Noncatecholamines - Compounds lacking the (vasodilation) on the vascular system
catechol hydroxyl groups (phenylephrine, predominate, whereas at high doses,
ephedrine, and amphetamine) effects (vasoconstriction) are the strongest.
1. longer halflives - because they are not 1. Cardiovascular major actions here.
inactivated by COMT and poor +Strengthens the contractility of the
substrates for MAO myocardium (positive inotrope: 1
2. Increased lipid solubility - due to lack action)
of polar hydroxyl groups so can +Increases its rate of contraction
penetrate the CNS (positive chronotrope: 1 action).
+Cardiac output increases
epinephrine with a CH3 substituent on the + Increase oxygen demand on the
amine nitrogen, is more potent at receptors mycocardium
than norepinephrine, which has an + activates 1 receptors on the kidney
unsubstituted to cause renin release.
amine. + constricts arterioles in the skin,
isoproterenol, which has an isopropyl mucous membranes, and viscera (
substituent effects)
CH (CH3)2 on the amine nitrogen is a strong + dilates vessels going to the liver and
agonist with little activity skeletal muscle (2 effects).
+ Renal blood flow is decreased
Mechanism of action of adrenergic agonists causing increase in systolic blood
pressure, coupled with a slight
1. Direct-acting agonists: bind to decrease in diastolic pressure due to
adrenergic receptors on effector 2 receptormediated vasodilation in
organs without interacting with the the skeletal muscle vascular bed
presynaptic neuron. Widely used =Renin is an enzyme involved in the
clinically. production of angiotensin II, a potent
epinephrine, norepinephrine, vasoconstrictor.
isoproterenol, and phenylephrine. 2. Respiratory - bronchodilation by
2. Indirect-acting agonists: These acting directly on bronchial smooth
agents may block the reuptake of muscle (2 action)
norepinephrine (cocaine) or cause the + inhibits the release of allergy
release of norepinephrine vesicles mediators such as histamines from
(amphetamine) mast cells.
3. Mixed-action agonists: Ephedrine and 3. Hyperglycemia - increased
its stereoisomer, pseudoephedrine, glycogenolysis in the liver (2 effect)
+ increased release of glucagon (2
There are four catecholamines commonly effect)
 + a decreased release of insulin (2
effect).
4. Lipolysis - agonist activity on the
receptors of adipose tissue.
+ Increased levels of cAMP stimulate a
hormone-sensitive lipase, which
hydrolyzes triglycerides to free fatty
acids and glycerol.
Therapeutic uses
1. Bronchospasm - treatment of acute
asthma and anaphylactic shock (subQ
administration)
+ selective 2 agonists, such as
albuterol, are favored in the chronic
treatment of asthma because of a
longer duration of action and minimal
cardiac stimulatory effects.
2. Anaphylactic shock - treatment of type
I hypersensitivity reactions
3. Cardiac arrest - restore cardiac
rhythm
4. Anesthetics low concentrations (for most
example, 1:100,000 parts) of epi
because it increases the duration of
local anesthesia by producing
vasoconstriction at the site of
injection so not absorbed into
systemic circulation.
+ topically to vasoconstrict mucous
membranes and control oozing of
capillary blood.
Pharmacokinetics rapid onset, brief
duration
IM (anterior thigh) bc rapid
absorption
IV if emergency (most rapid)
subcutaneously, by
endotracheal tube, and by
inhalation
metabolites metanephrine and
vanillylmandelic acid are
excreted in urine
Adverse effect - CNS effects - anxiety, fear,
tension, headache, and tremor.
cardiac arrhythmias (esp if px is
taking digoxin)
pulmonary edema
enhanced cardiovascular
actions in patients with
hyperthyroidism so dose is
lowered
If px has hyperthyroidism, they
may have increased production
of adrenergic receptors in the
vasculature so there is
hypersensitivity
Inhalation anesthetics sensitize
the heart so may lead to
tachycardia
increase release of glucose so
insulin dose may be increased
Nonselective -blockers prevent
vasodilatory effects of
epinephrine on 2 receptors,
leaving receptor stimulation
unopposed. This may lead to
increased peripheral resistance
and increased blood pressure.
Norepinephrine affects a receptors the
Cardiovascular actions
1. Vasoconstriction of vascular beds
including kidney (a1) causing rise in
peripheral resistance
+ systolic and diastolic blood
pressures increase
+ Norepinephrine causes greater
vasoconstriction than epinephrine,
because it does not induce
compensatory vasodilation via 2
receptors on blood vessels supplying
skeletal muscles.
+ The weak 2 activity of
norepinephrine also explains why it is
not useful in the treatment of asthma
or anaphylaxis.
2. Baroreceptor reflex - increases blood
pressure, and this stimulates the
baroreceptors, inducing a rise in vagal
activity which in turn causes reflex
bradycardia
+ This bradycardia counteract the
local actions of norepinephrine on the
heart, although the reflex
compensation does not affect the
positive inotropic effects of the drug.
+ When atropine, which blocks the
transmission of vagal effects, is given
before norepinephrine, stimulation of
 the heart by norepinephrine is evident
as tachycardia.
Therapeutic effects - treat shock, because it
increases vascular resistance and, therefore,
increases blood
pressure.
Pharmakonetics IV duration 1-2 mins Actions
Adverse effects same as epinephrine
potent vasoconstrictor and may
cause blanching and sloughing of
skin along an injected vein
If extravasation (leakage of drug
from the vessel into tissues
surrounding the injection site)
occurs, it can cause tissue
necrosis
not administered in peripheral
veins
Impaired circulation caused by
norepi may be treated with a
receptor antagonist, phentolamine.
Isoproterenol
direct-acting synthetic catecholamine shock and is given by continuous infusion
that stimulates both 1- and 2-
adrenergic receptors
rarely used bc nonselective
intense stimulation of the heart,
increasing heart rate, contractility,
and cardiac output (as active as
epinephrine)
dilates the arterioles of skeletal
muscle (2 effect), resulting in
decreased peripheral resistance.
Increase systolic blood pressure
slightly, but it greatly reduces mean
arterial and diastolic blood pressures
bronchodilator
use has been largely replaced with
other drugs but can still be useful in
atrioventricular (AV) block
A/E similar to epinephrine
Dopamine
immediate metabolic precursor of Adverse effects sympathetic stimulation
norepinephrine
occurs naturally in the CNS in the
basal ganglia, and adrenal medulla
higher doses, vasoconstriction (a1)
lower doses, B1
D1 and D2 in peripheral mesenteric
and renal vascular beds causing
vasodilation
D2 receptors are also found on
presynaptic adrenergic neurons,
where their activation interferes with
norepinephrine release.
1. Cardiovascular stimulatory effects
(B1)
- v high doses, a1
vasoconstiction
2. Renal and visceral - dilates renal and
splanchnic arterioles by activating
dopaminergic receptors, thereby
increasing blood flow to the kidneys
and other viscera
- treatment of shock, in which
significant increases in
sympathetic activity might
compromise renal function bc D
receptors are not affected by a and
b-blocking drugs
Therapeutic use cardiogenic and septic
raises blood pressure by
stimulating the 1 receptors on the
heart to increase cardiac output
and 1 receptors on blood vessels
to increase total peripheral
resistance
enhances perfusion to the kidney
and splanchnic areas
enhances the glomerular filtration
rate and causes diuresis.
Treat hypotension and severe heart
failure, in patients with low or
normal peripheral vascular
resistance and in patients who
have oliguria.
dopamine is far superior to
norepinephrine, which diminishes
blood supply to the kidney and may
cause renal shutdown.
but short-lived bc rapidly metabolized
Fenoldapam agonist of D1
vasodilator to treat severe
hypertension
 acting on coronary arteries, kidney
arterioles, and mesenteric arteries
racemic but R-isomer is the active one
extensive first-pass metabolism and
has a 10-minute elimination half-life
after IV infusion
causes Headache, flushing, dizziness,
nausea, vomiting, and tachycardia
(due to vasodilation)
Dobutamine synthetic B1 agonist
increases cardiac rate and output with
few vascular effects
used to increase cardiac output in
acute heart failure, as well as for
inotropic support after cardiac surgery Clonidine - 2 agonist that is used for the
advantage - does not significantly
elevate oxygen demands of the
myocardium
caution in atrial fibrillation, because it
increases AV conduction
adverse effects are similar to
epinephrine
Tolerance may develop with prolonged
use
Oxymetazoline synthetic a1 and a2 agonist
found in many over-the-counter short-
term nasal spray decongestants, as
well as in ophthalmic drops for the
relief of redness of the eyes
associated with swimming, colds, and agonists used primarily as bronchodilators
contact lenses.
stimulates receptors on blood
vessels supplying the nasal mucosa
and conjunctiva, thereby producing
vasoconstriction and decreasing
congestion.
It is absorbed in the systemic
circulation regardless of the route of
administration
produce nervousness, headaches, and
trouble sleeping.
Local irritation and sneezing may
occur with intranasal administration.
Rebound congestion and dependence
are observed with long-term use.
Phenylephrine synthetic a1 agonist
vasoconstrictor that raises both
systolic and diastolic blood pressures
no effect on the heart itself but, rather,
induces reflex bradycardia when given
parenterally.
Treat hypotension, especially to those
with a rapid heart rate
Large doses can cause hypertensive
headache and cardiac irregularities
nasal decongestant when applied
topically or taken orally (replacing
pseudoephedrine wc has been
misused/used to make
methamphetamine)
ophthalmic solutions for mydriasis
treatment
of hypertension
minimize the symptoms that
accompany withdrawal from opiates,
tobacco smoking, and
benzodiazepines.
acts centrally on presynaptic 2
receptors to produce inhibition of
sympathetic vasomotor centers
S/E: lethargy, sedation, constipation,
and xerostomia
abrupt discontinuance causes
hypertension
Albuterol and Terbutaline - short-acting 2
and administered
by a metered-dose inhaler
Albuterol is the short-acting 2 agonist
of choice for the management of acute
asthma
Terbutaline is no longer available in US
Terbutaline is also used off-label as a
uterine relaxant to suppress
premature labor
S/E: tremor (but px can develop
tolerance), restlessness,
apprehension, and anxiety
orally, they may cause tachycardia or
arrhythmia (due to 1 receptor
activation
Monoamine oxidase inhibitors (MAOIs)
also increase the risk of adverse
cardiovascular effects, and
 concomitant use should be avoided. precipitate serious vasopressor
episodes
Salmeterol and formoterol longacting same action as amphetamine
agonists (LABAs) that are 2 selective
bronchodilation over 12 hours, Cocaine - block the sodium-chloride (Na+/Cl-)
compared with less than 3 hours for dependent norepinephrine transporter
albuterol required for cellular uptake of norepinephrine
salmeterol has a somewhat delayed small doses of the catecholamines
onset of action produce greatly magnified effects
not rec for monotherapy but with in an individual taking cocaine
corticosteroids increase blood pressure by 1
treating nocturnal asthma in agonist actions and stimulatory
symptomatic patients taking other effects
asthma medications
LABA increase risk of asthma-related MIXED-ACTION ADRENERGIC
deaths AGONISTS

Mirabegron - 3 agonist that relaxes the
detrusor
smooth muscle and increases bladder
capacity
for patients with overactive bladder
increase blood pressure
increases levels of digoxin and also
inhibits the CYP2D6 isozyme, which
may enhance the effects of other
medications metabolized by this
pathway (for example, metoprolol).
INDIRECT-ACTING ADRENERGIC
AGONISTS
potentiate the effects of epinephrine or
norepinephrine produced endogenously, but
do not directly affect postsynaptic receptors
Amphetamine - increase blood pressure
significantly by 1 agonist action on the
vasculature, as well as 1-stimulatory effects
on the heart.
CNS stimulant
Tyramine - not a clinically useful drug, but it
is important
because it is found in fermented foods, such
as aged cheese and Chianti wine
normal by-product of tyrosine
metabolism
oxidized by MAO in the
gastrointestinal tract, but, if the
patient is taking MAOIs, it can
Ephedrine and pseudoephedrine are not
catechols and are poor substrates for
COMT and MAO
excellent absorption orally and
penetrate into the CNS, but
pseudoephedrine has fewer CNS effects
Ephedrine is eliminated largely
unchanged in urine, and
pseudoephedrine undergoes incomplete
hepatic metabolism before elimination
in urine
Ephedrine raises systolic and diastolic
blood pressures by vasoconstriction
and cardiac stimulation and can be
used to treat hypotension.
Ephedrine produces bronchodilation,
but it is less potent and slower acting
than epinephrine or isoproterenol.
(previously used for astham but now
replaced)
Ephedrine produces a mild stimulation
of the CNS. This increases alertness,
decreases fatigue, and prevents sleep.
It also improves athletic performance.
The clinical use of ephedrine is
declining because of the availability of
better, more potent agents that cause
fewer adverse effects.
Ephedrine-containing herbal
supplements (mainly ephedra-
containing products) have been
banned by the U.S. Food and Drug
Administration because of
 lifethreatening cardiovascular
reactions.
Pseudoephedrine is primarily used
orally to treat nasal and sinus
congestion.
Pseudoephedrine has been illegally
used to produce methamphetamine.

[SUMMARY OF THERAPEUTIC USES IN

BOOK]