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					Principles of Pharmacology

July 25, 2002

9:10- 10:00 am

Aneesa Niravel

                                        ADRENERGIC AGONISTS

(Starting from the bottom of page 6)
c. Isoproterenol (Isuprel)
Isoproterenol is an synthetic catecholamine that is a strong agonist at R, and R2 receptors with virtually
no effect at alpha receptors. It increases both heart rate and force of contraction through its R, effects.
Cardiac output increases. Myocardial oxygen demands also increase. Having no alpha activity, 02
mediated vasodilation of skeletal muscle vasculature results in a fall in diastolic blood pressure. Increased
cardiac output tends to offset the drop in peripheral resistence such that systolic blood pressure is either
only slightly increased or slightly decreased. Mean blood pressure is decreased.
Although a catecholamine, isoproterenol is a marginal substrate for COMT and is resistant to MAO. As
such, it has a parenteral half-life of 2 hours.
Isoproterenol has been used in the acute treatment of asthma in the past, but has been replaced by the
selective (32 agonists that have fewer cardiac effects. In this application, it was given by the inhalation
route.
Isoproterenol is still utilized in the temporary emergency management of complete heart block or cardiac
arrest. Electronic pacemakers are safer and more effective in heart block. If the heart block is continuous,
isoproterenol should only be administered until the pacemaker can be inserted. Isoproterenol increases
myocardial oxygen demands on already ischemic tissue. It can easily cause arrhythmias in this situation.
*Isoproterenol has a much longer half life than epinephrine
* Use of of isoproterenol in shock patients leads to death

d. Dopamine (Intropin)
Dopamine is an endogenous catecholamine that is far less potent at alpha and beta receptors than
epinephrine or norepinephrine. It does bind potently to D, and DZ dopamine receptors which are distinct
from alpha and beta receptors. Dz receptors are found presynaptically and block release of transmitter. D,
receptors are found on the renal vasculature where dopamine causes vasodilation and increases (or
preserves in the case of shock) renal blood flow. Higher concentrations of dopamine stimulates R,
receptors, increasing heart rate and force of contraction. At extremely high concentrations, dopamine can
activate alpha receptors and produce vasoconstriction.
Dopamine is only administered intravenously. Dopamine is metabolized by MAO and COMT and has a
short half-life.
The only therapeutic indication for the use of dopamine is in the treatment of shock. As described above
(See epinephrine), volume replacement and treating the underlying disease are currently favored over the
use of sympathomimetics in the treatment of shock. Norepinephrine and epinephrine can completely shut
down blood flow to the kidney through their alpha effects. Dopamine causes vasodilation of the renal
vasculature through its D, effects. This vasodilation opposes the strong sympathetic drive on the renal
vasculature that normally accompanies shock.

e. Dobutamine (Dobutrex)
Dobutamine is a synthetic catecholamine that is a relatively selective R, agonist. Dobutamine has
relatively more inotropic than chronotropic effects on the heart than isoproterenol. It produces primarily
increased force of contraction and increased cardiac output.
Dobutamine is only administered intravenously. Dobutamine is metabolized by MAO and COMT and has
a short half-life of only 2 minutes.
Dobutamine is used in the short-term treatment of cardiac decompensation that follows cardiac surgery or
in patients with congestive heart failure or acute myocardial infarction. It increases force of contraction
and cardiac output with little increase in heart rate in these patients. Usually, increases in blood pressure
are modest. It is not used continuously for more than a few days due the rapid development of tolerance
to its effects.
*Dobutamine doesn’t increase myocardial oxygen demands, unlike other catecholamines *

2. Alpha, agonists
a. Phenylephrine (Neo-Synephrine)
Phenylephrine is primarily an a, agonist that is 100 fold less potent than epinephrine. Nonetheless, in
sufficient doses it does produce significant a, activity. It is resistant metabolism by COMT, but not MAO. It
has a longer half-life than the catecholamines. It is orally active and does penetrate the blood brain
barrier. Its subjective CNS effects are considered to be undesirable. It increases diastolic and systolic
blood pressure and elicits a reflex bradycardia.
It is used as an nasal decongestant, mydriatic in ophthalmic preparations, for the treatment chronic
orthostatic hypotension, and in combination with local anesthetics to prevent their diffusion away from the
injection site. Phenylephrine is superior to epinephrine in this last usage because its lacks the cardiac
stimulant properties of epinephrine and systemic absorption following local injection will not increase
heart rate.
*No Beta activity

b. Methoxamine (Vasoxyl)
Methoxamine is an alpha agonist that is relatively selective for a, receptors. It increases blood pressure
and elicits reflexive bradycardia. Methoxamine is used to treat chronic orthostatic hypotension.

c. Midodrine (ProAmatine)
Midodrine is a newer orally active alpha agonist used to treat chronic orthostatic hypotension.

d. Xylometazoline (Otrivin, Neo-Synephrine) Oxymetazoline (Afrin, Neo-Synephrine 12 Hour)
Xylometazoline and oxymetazoline are alpha agonists that are used as topical decongestants. Topical
application causes vasoconstriction of the nasal mucosa and a decongestant effect.
*Just be able to recognize these drug names, no need to memorize

3. Alpha2 agonists
a. Clonidine (Catapres)
Clonidine is a selective a2 agonist that is used primarily as an antihypertensive agent. Theoretically,
presynaptic agonist effects would decrease release of norepinephrine from postganglionic sympathetic
neurons which should lower blood pressure. This mechanism contributes little to the antihypertensive
effect of clonidine. Clonidine's major hypotensive mechanism is to decrease central outflow of impulses
in the sympathetic nervous system by activating a2 receptors in the brainstem. Clonidine is also used to
decrease the increased sympathetic activity that accompanies opiate withdrawal.

b. Guanabenz (Wytensin)
Guanfacine (Tenex)
Guanabenz and guanfacine are a2 agonists that are used to lower blood pressure through a central
mechanism like clonidine.

c. Apraclonidine (lopidine)
Apraclonidine is a selective a2 agonist that is used topically to lower intraocular pressure in patients with
glaucoma. The mechanism seems to involve decreased secretion of aqueous humor.

4. Beta, agonists
a. Dobutamine (Dobutrex)
See above.

5. Beta2 agonists
In general, R2 agonists are not completely selective and do possess some weak R, agonist activity. They
are used for their bronchodilator effects in the treatment of asthma or bronchospasm. Inhalation tends to
reduce their R, effects on the heart. In doses used to treat asthma or bronchospasm, they produce far
less cardiac stimulation than isoproterenol or epinephrine. These drugs also are used to reduce
contractions in premature labor. The cardiovascular effects are usually mild. R2 induced vasodilation of
skeletal muscle vasculature decreases diastolic pressure which elicits a reflexive tachycardia. The slight
direct R, effects on the heart also contributes to the tachycardia.

a. Albuterol (Ventolin)
Albuterol is a relatively selective R2 agonist that can be administered orally or by inhalation. Its primary
use is in the long-term treatment of obstructive airway diseases or emergency treatment of
bronchospasm. It can also be used to delay premature delivery (See Ritodrine below.)

b. Terbutaline (Brethine)
Terbutaline is a relatively selective R2 agonist that can be administered orally, subcutaneously or by
inhalation. Its primary use is in the long-term treatment of obstructive airway diseases or emergency
treatment of bronchospasm. It can be given parenterally in the emergency treatment of status
asthmaticus.       It can also be used to delay premature delivery (See Ritodrine below.)

c. Ritodrine (Yutopar)
Ritodrine is a relatively selective 02 agonist is used to reduce uterine contractions in premature labor. It is
given intravenous to initially control contractions. If labor is delayed, it can be given orally if further
pharmacological intervention is necessary. Albuterol and terbutaline are used "off label" for the same
purpose.

6. Miscellaneous adrenergic agonists
Many of these miscellaneous adrenergic agonists are indirect acting agonists, causing the release of
norepinephrine from presynaptic terminals or blocking the uptake of norepinephrine. Some have direct
sympathomimetic activity. Many of these agents readily cross the blood brain barrier and produce central
effects, some of which are therapeutic.
*Some are abused

a. Ephedrine (generic)
Ephedrine is a natural alkaloid found in numerous plants that has been used in China for over 2000
years. It was introduced in this country as the first orally active sympathomimetic over 70 years ago.
Ephedrine acts primarily by causing the release of stored catecholamines, but does have some direct
adrenergic activity. It is a nonselective sympathomimetic with a spectrum of activity that resembles
epinephrine. Ephedrine has a high oral bioavailability and long duration of action (half-life 3-6 hrs). It does
cross the blood brain barrier and produces CNS stimulation. Ephedrine raises heart rate and cardiac
output through its beta effects and increases peripheral resistence through its alpha effects. Blood
pressure is usually increased.
Most of ephedrine's applications have been replaced by newer, more selective agents. Currently the use
of ephedrine is limited to clinical situations when a long acting, orally active sympathomimetic is desired
for decongestant or pressor effects. Still, the use of ephedrine in these capacities carries the risk of
hypertension and arrhythmias. It also can cause insomnia.

b. Pseudoephedrine (Sudafed)
Pseudoephedrine is actually one of 4 ephedrine stereoisomers. It is less potent the ephedrine in
producing tachycardia, increased blood pressure and CNS stimulation, but still can, particularly in
sensitive individuals. It is found in OTC decongestants either alone or with an antihistamine.

                         c. Amphetamine (generic)
                         Methamphetamine (generic)
                         Phenmetrazine (generic)
                         Methylphenidate (Ritalin)
                         Pemoline (Cylert)

As a group, all of these drugs are orally active, indirect acting sympathomimetics that cross the blood
brain barrier and are long acting. They all are strong CNS stimulants that are often abused. All but
methylphenidate act by causing the release of stored catecholamines. Methylphenidate acts by blocking
the uptake of dopamine. Their CNS stimulant effects are due to the release of dopamine or dopamine
uptake blockade.

In the periphery, these agents act as nonspecific sympathomimetics due to the release of
catecholamines. As a group, these agents increase diastolic and systolic blood pressure, heart rate can
be increased, but may be reflexively slowed, and finally, cardiac output may increased or unchanged.
They can cause arrhythmias. Methylphenidate again is the exception. Because it only blocks the uptake
of dopamine, methylphenidate lacks peripheral sympathomimetic effects. As a group, these drugs are
contraindicated in patients receiving monoamine oxidase inhibitors (MAOIs). MAOIs result in a build up
norepinephrine in presynaptic terminals. Indirect acting sympathomimetics will release this massive build
up of norepinephrine which can lead to hypertensive crisis and death.

All of these drugs suppress appetite (produce anorexia). Amphetamine, methamphetamine and
phenmetrazine have been extensively utilized in the past and still are used to promote weight loss.
Anorexia is a side effect of methylphenidate or pemoline treatment of attention deficit hyperactivity
disorder (ADHD) in children. Tolerance develops to anorexic effects of these agents, limiting their
effectiveness in weight reduction. In addition, weight loss tends not to be permanent after these drugs are
discontinued. Coupled with adverse cardiovascular effects and potential for abuse, the use of these drugs
for weight loss is of questionable value.

All of these drugs can be used to treat narcolepsy. Narcolepsy is characterized by hypersomnia with
sudden daytime attacks of sleep.

All of these drugs can be used in the treatment of ADHD disorder in children. This syndrome is
characterized by excessive motor activity, difficulty in sustaining attention and poor impulse control. By
far, methylphenidate is the most widely utilized, most likely due to its lack of peripheral sympathomimetic
effects and the stigma attached to more abused drugs in the group.

c. Phenylpropanolamine (generic)
Phenylpropanolamine is an orally active, indirect acting sympathomimetic that resembles ephedrine in
pharmacological spectrum and potency, but does not seem to produce the same degree of CNS
stimulation. It is available OTC in numerous weight loss preparations. Its effectiveness in weight loss is no
more than that of the CNS stimulants above. It is also found in combination with antihistamines in OTC
cold remedies where it is used for its decongestant effects. Although it is alleged to be safe is
recommended dosage, it has been associated with significant elevation of blood pressure and target
organ damage in patients ingesting large doses. It is currently the target of a class action lawsuit.

d. Tyramine
Tyramine is not a drug, but rather an indirect acting sympathomimetic found in various fermented foods
and beverages such as cheese and red wine. It causes release of catecholamines from storage sites and
slight sympathomimetic effects under normal conditions. However, if an individual has been taking a
MAGI, tyramine can cause a massive release of norepinephrine and hypertensive crisis.

e. Cocaine
Cocaine is a local anesthetic that produces both CNS stimulation and peripheral sympathetic stimulation.
CNS stimulation is due to blockade of dopamine uptake. Sympathetic stimulation is due uptake blockade
of norepinephrine. At doses used for its euphoric effects, cocaine can cause significant elevation of blood
pressure and tachycardia. Toxic doses can produce convulsions, arrhythmias and death.

f. Tricyclic antidepressants
Tricyclic antidepressants comprise a large group of drugs and produce their antidepressant effects
through the blockade of norepinephrine and/or serotonin in the CNS. Those that block norepinephrine
uptake can cause indirect sympathomimetic effects.
D. Adverse Effects
Adverse effects of sympathomimetic drugs are extensions of their receptor effects in the cardiovascular
and central nervous systems. Marked elevation of blood pressure (a,) can cause cerebral hemorrhage or
pulmonary edema. R, agonists can increase cardiac work load and oxygen demand and can precipitate
severe angina or myocardial infarction. R, agonists can also cause sinus arrhythmias and can provoke
severe ventricular arrhythmias. Sympathomimetics must be used with caution in elderly patients or in
patients with hypertension or coronary artery disease.
CNS toxicity is not observed with catecholamines. With drugs like phenylephrine, CNS toxicity is generally
mild. Amphetamines can cause anxiety, restlessness, tremor, insomnia and eventually a paranoid
psychosis. Cocaine can cause convulsions, cerebral hemorrhage, arrhythmias or myocardial infarction.

				
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