Overview Adrenergic drugs stimulate the same receptors as
norepinephrine and epinephrine. Drugs that stimulated the
adrenergic receptors are also called sympathomimetics. Drugs that
block the adrenergic system are called sympathoplegics. Drugs that
directly stimulate the receptor are called direct acting agonist
and drugs that block the reuptake or enhance the release of
catecholamines are called indirect acting agonists.
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Adrenergic Receptors Alpha 1: Vasoconstriction, increased
peripheral resistance, increased blood pressure, mydriasis,
increased closure of bladder sphincter Alpha 2: Inhibition of
norepinephrine release, inhibition of acetylcholine release,
inhibition of insulin release Beta 1: Tachycardia, increased
myocardial contractility, increased release of renin Beta 2:
Vasodilation, decreased peripheral resistance, bronchodilation,
increased release of glucagon, relaxed uterine smooth muscle. Beta
3: Enhancement of lipolysis in adipose tissue and thermogenesis in
skeletal muscle.
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Synthesis of Epinephrine The synthesis of norepinephrine begins
with the transport of tyrosine into the adrenergic neuron. Tyrosine
is then hydroxylated to dihydroxyphenylalanine (DOPA) by tyrosine
hydroxylase. This is the rate limiting step. DOPA is then
decarboxylated by the aromatic I-amino acid decarboxylase to form
dopamine in the presynaptic neuron. Dopamine is then transported to
the synaptic vesicles where dopamine beta- hydroxylase hydrolates
dopamine to norepineprhrine. Norepinephrine is acted on by
phenyethanolamine N Methyl Transferase to form Epinephrine.
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Removal of Catecholamines Catecholamines have a half-life of a
few minutes when circulating in the blood. They are degraded either
by methylation by catechol-O-methyltransferases (COMT) or by
deamination by monoamine oxidases (MAO). Norepinephrine may 1.
Diffuse out of the presynaptic cleft, 2) Be metabolized by COMT in
the synaptic cleft, 3) re-uptaked by the presynaptic neuron. Once
in the presynaptic neuron it may be degraded in the mitochondria by
MAO
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MAO A & MAO B MAO A : Monoamine oxidase A is an isoform of
monoamine oxidase. It deaminates norepinephrine (noradrenaline),
epinephrine, serotonin, and dopamine (which is equally deaminated
by MAO-A and MAO-B). High-activity variants of the MAOA gene is
associated with major depressive disorder MAO B: This protein
preferentially degrades benzylamine and phenylethylamine. Like
MAOA, it also degrades dopamine. Alzheimer's disease and
Parkinson's disease are both associated with elevated levels of
MAO-B in the brain. The normal activity of MAO-B creates reactive
oxygen species, which directly damage cells.
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Monoamine Oxidase Inhibitor (MA0I) Monoamine oxidase inhibitors
(MAOIs) inhibit the monoamine oxidase enzyme. These drugs are
effective in treating atypical depression. They can also be used to
treat Parkinsons disease. These drugs can have potentially lethal
dietary and drug interactions, and often are used as drugs of last
resort for depression. MAOIs can also treat panic disorder,
agoraphobia, social phobia, atypical depression, anxiety,
depression, bulimia, and post-traumatic stress disorder, and with
limited efficacy borderline personality disorder
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Characteristics of Adrenergic Agonists When we look at the
agonists epinephrine, norepinephrine and isoproterenol we have to
take a look at their comparative potency at receptors. At the
receptor the relative potency is: Epinephrine > Norepinephrine
>> Isoproterenol. At the receptor the relative potency is :
Isoproterenol > Epinephrine > Norepinephrine
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Non-Specific Direct Acting Adrenergic Agonists Epinephrine: is
both a neurotransmitter and hormone. Pharmacological doses of
epinephrine stimulate 1, 2, 1, 2, and 3 receptors of the
sympathetic nervous system. It is used to treat cardiac arrest,
anaphylaxis, superficial bleeding and croup. It is also a backup
for 2 agonist failure in asthma. Epinephrine can produce retrograde
enhancement of long-term memory. Adverse affects: palpitations,
tachycardia, arrhythmia, anxiety, panic attack, headache, tremor,
hypertension, and acute pulmonary edema. Half-Life 2 minutes
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Non-Specific Direct Acting Adrenergic Agonists Epinephrine in
croup it works by stimulation of the -adrenergic receptors in the
airway, with resultant mucosal vasoconstriction and decreased
subglottic edema, and by stimulation of the -adrenergic receptors
in the bronchial smooth muscles with resultant relaxation of the
bronchial smooth muscle. In cardiac arrest epinephrine actions are
to increase peripheral resistance via 1receptor-dependent
vasoconstriction and to increase cardiac output by binding to 1
receptors. The goal of reducing peripheral circulation is to
increase coronary and cerebral perfusion pressures.
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Non-Specific Direct Acting Adrenergic Agonists Norepinephrine
is a hormone and neurotransmitter. Pharmacological doses of
norepinephrine stimulate 1, 2, 1, 2, and 3 receptors.
Norepinephrine is primarily used to treat severe hypotension. Its
effects are often limited to the increasing of blood pressure
through agonist activity on 1 and 2 receptors, and causing a
resultant increase in peripheral vascular resistance. At high doses
it can lead to limb ischemia and limb death
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Non-Specific Direct Acting Agonists Isoproterenol is a 1- and
2-adrenoreceptor agonist which was commonly used to treat asthma
before the more widespread use of albuterol, which has more
selective effects on the airways. Its route of administration is
either intravenous, oral, intranasal, subcutaneous, or
intramuscular, depending on use medication used for the treatment
of bradycardia, A.V. heart block, Torsades de pointes. -receptors
are not that sensitive to isopreterenol. This medication not be
administered to patients with myocardial ischemia. Half Life 2
minutes
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Dopamine Type Direct Acting Adrenergic Agonists Dopamine: can
activate both and receptors. At higher levels it stimulates 1
receptors at lower levels it stimulates 1 receptors. Dopamine also
stimulates the D1 and D2 receptors where they produce vasodilation.
D1 and D2 receptors are found in the mesentery and renal areas.
Dopamine is the drug of choice for cardiogenic and septic shock. It
is given continuously by IV. Not only does it stimulate the heart
and raise blood pressure it enhances perfusion to the kidney and
splanchnic areas. The break down product of dopamine is
homovanillic acid. Side effects for: headache, flushing, nausea,
hypotension, reflex tachycardia, and increased intraocular pressure
Fenoldopam: acts as a partial agonist on the D1 receptor causing
vasodilation and can be used to treat hypertensive crisis.
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Alpha 1 & Alpha 2 Direct Acting Adrenergic Agonists
Oxymetazoline: is a selective - 1 agonist and partial - 2 agonist.
It is used as a decongestant and to treat nosebleeds. Rebound
congestion known as rhinitis medicamentosa can occur. Half-Life is
5-6 hours.
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Alpha-2 Direct Acting Adrenergic Agonists Clonidine: Clonidine
is a sympatholytic medication that is an agonist at the - 2
receptor. It is used to treat high blood pressure, attention
deficit hyperactivity disorder, anxiety disorders, withdrawal (from
either alcohol, opioids, or smoking), migraine, menopausal
flushing, and diarrhea. Methyldopa: is an -2 -adrenergic agonist
pro-drug used as a sympathoplegic medication. It is converted to
-methylnorepinephrine by dopamine beta-hydroxylase (DBH). This
binds to the -2 receptor. This medication is used in gestational
hypertension. Rebound hypertension, depression, sexual dysfunction,
memory impairment and tolerance may be significant.
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Alpha-1 Direct Acting Adrenergic Agonists Phenylephrine is a
selective 1-adrenergic receptor agonist used primarily as a
decongestant, and also to dilate the pupils, and to increase blood
pressure. Phenylephrine is marketed as an alternative for the
decongestant pseudoephedrine, though clinical studies suggest that
phenylephrine is less effective than pseudoephedrine. Phenylephrine
is used to abort priapism. It is diluted with normal saline and
injected directly into the corpora cavernosa; causing constriction
of the blood vessels. Side effects: Hypertension, rebound
bradycardia, rebound congestion. Half Life 2.1 3.4 hours.
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Alpha-1 & Beta 2 Direct Acting Adrenergic Agonists
Pseudoephedrine acts on -1 and 2-adrenergic receptors, to causing
vasoconstriction and bronchodilation. Pseudoephedrine is often used
as a decongestant from the common cold and allergies. It reduces
tissue hyperemia, edema, and nasal congestion. Some studies suggest
that it increases the drainage of sinus secretions, and opening of
obstructed Eustachian tubes. May also be used for priapism. Side
effects insomnia, nervousness, excitability, dizziness and anxiety,
hypertension. Half Life 4.3 8 hours.
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Beta -1 Direct Acting Adrenergic Agonists Dobutamine is
predominantly a 1-adrenergic agonist, with weak 2 activity, and 1
selective activity. Dobutamine is used to treat acute but
potentially reversible heart failure, which can occur during
cardiac surgery or in cases of septic or cardiogenic shock,
increasing ionotropic action Dobutamine can also be used in cases
of congestive heart failure to increase cardiac output. It is
indicated when parenteral therapy is necessary for inotropic
support in the short-term treatment of patients with cardiac
decompensation due to depressed contractility. Does not significant
increase the energy needs of the heart. Side effects are
hypertension, angina, arrhythmia, and tachycardia. Half Life 2
minutes
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Beta-2 specific Direct Acting Adrenergic Agonists Albuterol:
(salbutamol) is a short acting -2 Agonist used to treat asthma and
chronic obstructive pulmonary disease. The most common side effects
are a fine tremor, anxiety, headaches, muscle cramps, dry mouth,
and palpitations. Terbutaline: is used as a fast-acting
bronchodilator and as a tocolytic to delay premature labor. The
inhaled form of terbutaline starts working within 15 minutes and
can last up to 6 hours. Side effects are tachycardia, anxiety,
nervousness, tremors, headache, hyperglycemia, hypokalemia,
hypertension and, rarely, pulmonary edema. Albuterol is a little
faster acting but shorter acting.
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Beta-2 specific Direct Acting Adrenergic Agonists Salmeterol:
is a long-acting 2 -adrenergic receptor agonist drug used in the
maintenance and prevention of asthma symptoms and maintenance of
chronic obstructive pulmonary disease (COPD) symptoms. It is also
used to prevent exercise induce asthma. Side effects: The common
side effects of salmeterol are dizziness, sinus infection, and
migraine headaches. Half-Life 5 Hours Formoterol: This medication
is similar to salmeterol and has a half-life of 10 hours. Though it
has a longer half-life than salmeterol it has a shorter onset of
action due to a much lower volume of distribution.
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Indirect Acting Adrenergic Agonists Cocaine acts as a
serotoninnorepinephrinedopamine reuptake inhibitor, also known as a
triple reuptake inhibitor (TRI). At higher levels it can also block
the sodium channel causing sudden death. Topical cocaine can be
used as a local numbing agent to help with procedures in the mouth
or nose. It is appetite inhibitor also. Cocaine can also be used as
part of cauterize to stop bleeding of the nose. Side effects drug
can cause itching, fast heart rate, hallucinations, and paranoid
delusions. Overdoses can cause hyperthermia, a marked elevation of
blood pressure, and cardiac arrhythmias
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Indirect Acting Adrenergic Agonists Amphetamine: This drug
stimulates the release of catecholamines and is a weak inhibitor of
MAO. It is used in the treatment of attention deficit hyperactivity
disorder (ADHD) and narcolepsy. Half-Life 11 hours Tyramine: is a
naturally occurring compound. stimulates the release of
catecholamines. It is unable to cross the blood-brain barrier,
resulting in only nonpsychoactive peripheral sympathomimetic
effects. A hypertensive crisis can result from ingestion of
tyramine-rich foods in conjunction with monoamine oxidase
inhibitors (MAOIs).
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Mixed Action Adrenergic Agonists. Ephedrine: The mechanism of
action relies on its indirect stimulation of the adrenergic
receptor system by increasing the activity of norepinephrine at the
postsynaptic - and -receptors. It is a natural medicine used to
treat asthma and in combination with caffeine is used by
professional body builders to cut fat. Side effects acne,
tachycardia, insomnia, restlessness Pseudoephedrine:
Pseudoephedrine acts on and 2 adrenergic receptors, to cause
vasoconstriction and relaxation of smooth muscle in the bronchi. It
is used as a decongestant and does not cause rebound congestion.
Side effects: hypertension, sweating, insomnia, and anxiety.