Adrenergic Agonists
Direct-acting adrenergic agonists: Albuterol, Clonidine, Dobutamide, Dopamine, Epinephrine,
Formoterol, Isoproterenol, Metaproterenol, Methoxamie, Norepinephrine, Phenylephrine, Piruterol,
Salmeterol, Tamsulosine, Terbutaline, alpha-Methyldopa, Oxymethazoline, Salbutamol
Indirect-acting adrenergic agonists: Amphetamine, Tyramine, Cocaine
Direct and indirect acting (mixed action): Ephedrine, Metaraminol
The adrenergic neuron
Adrenergic neurons release NE as the neurotransmitter. These neurons are found in the CNS and also in
the SNS, where they serve as links between ganglia and the effector organs.
The adrenergic neurons and receptors, located either presynaptically on the neuron or postsynaptically
on the effector organ, are the sites of action of the adrenergic drugs.
A. Neurotransmission at adrenergic neurons
The process involves 5 steps: synthesis, storage, release and receptor binding of the NE, followed by
removal of the neurotransmitter from the synaptic cleft.
The rate limiting step in the formation of NE is the hydroxylation of tyrosine to dihydroxyphenylalanine
(DOPA) by tyrosine hydroxylase.
Catechol O-methyltransferase (COMT) in the synaptic space metabolizes NE to inactive metabolites.
The reuptake by the neuronal membrane involves a Na/K activated ATPase that can be inhibited by
tricyclic antidepressants, such as imipramine or by cocaine.
Alternatively, NE can be oxidized by monoamine oxidase (MAO), present in neuronal mitochondria.
The inactive products of NE metabolism are excreted in the urine as vanillylmandelic acid,
metanephrine, and normetanephrine.
B. Adrenergic receptors (adrenoceptors)
Two families of receptors, designated α and β, were initially identified on the basis of their responses to
the adrenergic agonists apinephrine, NE, and isoproterenol.
The α receptors show a weak response to the synthetic agonist isoproterenol, but are responsive to the
naturally occurring epi and NE. For α receptors, the rank order of potency is epinephrine – NE –
isoproterenol.
The alpha1 receptors have a higher affinity for phenylephrine than do the alpha2 receptors. Conversely,
the drug clonidine selecctively binds to alpha2 receptors and has less effect on alpha1 receptors.
α 1 Receptors: these receptors are present on the postsynaptic membrane of the effector organs and
mediate many of the classic effects, involving constriction of smooth muscle. They act through PLC →
DAG, IP3 → Ca2+ release.
α2 receptors: located primarily on presynaptic nerve endings and on other cells, such as the beta cells of
the pancreas, control adrenergic neuromediator and insulin output, respectively. The modulator function
acts by negative feedback on the neuronal membrane. The effects are mediated by inhibition of
adenylylcyclase and a fall in the levels of intracellular cAMP.
The α1 and α2 receptors are further divided. This extended classification is necessary to understand the
selectivity of some drugs.
For example, tamsulosine is a selective alpha1A antagonist that us used to treat benign prostate
hypertrophy.
β receptors are characterized by a strong response to isoproterenol, with less sensitivity to epi an NE.
Isoproterenol – epi - NE
β1 receptors have approximately equal affinities for epinephrine and NE, whereas β2 receptors have a
higher affinity for epi than for NE.
The effects of these receptors are mediated by an increase in the cAMP levels.
The heart contains predominantly β1 receptors.
α1: vasoconstriction, increased peripheral resistance, increased blood pressure, mydriasis, increased
closure of internal sphincter of the bladder
α2: inhibition of NE release, inhibition of insulin release
β1: tachycardia, increased lipolysis, increased myocardial contractility, increased release of rennin
β2: vasodilation (in skeletal vascular beds), slightly decreased peripheral resistance, bronchodilation,
increased muscle and liver glycogenolysis, increased release of glucagons, relaxed uterine smooth
muscle
, Prolonged exposure to the catecholamines reduces the responsiveness of these receptors, a phenomenon
known as desensitization.
Characteristics of Adrenergic Agonists
Most of the adrenergic drugs are derivatives of beta phenylethylamine.
A. Catecholamines
Sympathomimetic amines that contain the 3,4-dihydroxybenzene group are called catecholamines.
Catecholamines include epinephrine, norepinephrine, isoproterenol, dopamine, dobutamide.
Catecholamines have a rapid onset of action, brief duration of action, are not administered orally and do
not penetrate the BBB.
High potency
Rapid inactivation by MAO and COMT and therefore only a brief period of action when given
parenterally, and are ineffective when administered orally because of inactivation.
Poor penetration into the CNS: because they are polar. Nevertheless, most of these drugs have some
clinical effects (anxiety, tremor, and headaches) that are attributable to action on the CNS.
B. Noncatecholamines
Compounds lacking the catechol hydroxyl groups have longer half-lifes because they are not inactivated
by COMT.
Noncatecholamines include phenylephrine, methoxamine, clonidine, metaproterenol, terbutaline,
albuterol, salmeterol, formoterol, amphetamine and ephedrine. These drugs have longer duration of
action and they can all be administered orally.
These are poor substrates for MAO and, thus, show a prolonged duration of action, because MAO is an
important route of detoxification.
Increased lipid solubility of many of these drugs permits greater access to the CNS.
Ephedrine and amphetamine may act indirectly by causing the release of stored catecholamines.
C. Mechanism of action of the adrenergic agonists
Direct acting: act directly on alpha or beta receptors, producing effects similar to those that occur
following physiologic stimulation. Examples are epi, NE, isoproterenol and phenylephrine.
Indirect acting: amphetamine and tyramine, cause the release of NE from the cytoplasmic pools or
vesicles of the adrenergic neuron.
Mixed action: ephedrine and metaraminol
Direct-acting Adrenergic Agonists
Bind to adrenergic receptors without interacting with the presynaptic neuron.
A. Epinephrine
At low doses, beta effects (vasodilation) on the vascular system predominate, whereas at high doses,
alpha effects (vasoconstriction) are strongest.
1. Actions
CV: the major actions of epi are on the CV system.
Epi strengthens the contractility of the myocardium (positive inotropic beta1 action) and increases the
rate of contraction (positive chronotropic, beta1 action). Cardiac output therefore increases.
With these effects come increased oxygen demands on the myocardium.
Epi constricts arterioles in the skin, mucous membranes, and viscera (alpha effects), and dilates vessels
going to the liver and skeletal muscle (beta2).
Renal blood flow is decreased.
Therefore, the cumulative effect is an increase in systolic blood pressure, coupled with a slight decrease
in diastolic pressure.
Respiratory:
Powerful bronchodilation (beta2). This action relieves all known allergic or histamine induced
bronchoconstriction. In the case of anaphylactic shock, this can be lifesaving.
In individuals suffering from an acute asthmatic attack, epi rapidly relieves the dyspnea and increases
the tidal volume.
Hyperglycemia: increase glycogenolysis in the liver (beta2), increased release of glucagons (beta2), and
a decreased release of insulin (alpha2).
Lipolysis: beta1.
Dilation of the pupils (mydriasis)
2. Biotransformations
, Metabolized by COMT and MAO which has S adenosylmethionine as a cofactor. The final metabolites
found in the urine are metanephrine and vanillylmandelic acid.
3. Therapeutic uses
Bronchospasm: the primary drug used in the emergency treatment of any condition of the respiratory
tract when bronchoconstriction has resulted. Thus, in treatment of acute asthma and anaphylactic shock,
epi is the drug of choice and the result is seen within a few minutes.
However, selective beta2 agonists, such as albuterol, are presently favored in the chronic treatment of
asthma because of a longer duration of action and minimal cardiac stimulatory effect.
Glaucoma: used topically to reduce intraocular pressure by vasoconstriction of the ciliary blood vessels.
Anaphylactic shock: the drug of choice for the treatment of type I hypersensitivity reactions.
Administered SC to treat bronchospasm, congestion, angioedema and cardiovascular collapse.
In anesthetics: in local anesthetics to increase the duration of the local anesthesia and to prevent
systemic toxicity (by vasoconstriction).
4. Pharmacokinetics
Rapid onset but brief duration of action.
In emergency situations, epi is given IV for the most rapid onset of action.
It may also be given SC, by endotracheal tube, by inhalation, or topically to the eye.
Oral administration is ineffective, because epi and the other catecholamines are inactivated by intestinal
enzymes.
5. Adverse effects
CNS disturbances: anxiety, fear, tension, headache and tremor
Hemorrhage: cerebral hemorrhage as a result of marked elevation in blood pressure
Cardiac arrythmias: particularly if patient is receiving digitalis
Epinephrine increases coronary blood flow as a result of increased cardiac workload; it may precipitate
angina in patients with coronary insuffisciency.
Pulmonary edema
6. Interactions
Hyperthyroidism: the dose of epi must be reduced because of the possible enhanced CV actions in these
patients.
Cocaine: epi produces exaggerated CV actions. This is due to the ability of cocaine to prevent reuptake
of catecholamines into the adrenergic neuron.
TCAs block catecholamine reuptake and may potentiate the effects of NE and epi.
Some halogenated anesthetic agents and digitalis may sensitize the heart to beta receptor stimulants,
resulting in ventricular arrhythmias.
B. Norepinephrine
When the drug is given in therapeutic doses to humans, the alpha adrenergic receptor is most affected.
1. CV actions
Vasoconstriction: NE causes a rise in peripheral resistance due to intense vasoconstriction of most
vascular beds, including the kidney (alpha1). Both systolic and diastolic blood pressure increases.
NE causes greater vasoconstriction than does epi because it does not induce compensatory vasodilation
via beta2 receptors of blood vessels supplying skeletal muscles.
The weak beta2 activity of NE also explains why it is not useful in the treatment of asthma.
Baroreceptor reflex: in isolated cardiac tissue, NE stimulates cardiac contractility, however, in vivo, it is
not noted. This is due to the increased blood pressure that induces a reflex rise in vagal activity by
stimulating the baroreceptors. This bradycardia is sufficient to counteract the local actions of NE on the
heart, although the reflex compensation does not affect the positive inotropic effects of the drug.
Effect of atropine pre-treatment: if atropine, which blocks the transmission of vagal effects, is given
before NE, then NE stimulation of the heart is evident as tachycardia.
2. Therapeutic uses
NE is used to treat shock, because it increases vascular resistance and, therefore, increases blood
pressure.
However, metaraminol is favored, because it does not reduce blood flow to the kidney, as does NE.
Other actions of NE are not considered to be clinically significant.
C. Isoproterenol
Predominantly stimulates both beta1 and beta2 receptors.
Its nonselectively is one of its drawbacks.
Its action on alpha receptors is insignificant.
1. Actions
, CV:
Intense stimulation of the heart to increase its rate and force of contraction, causing increased cardiac
output. It is therefore useful in the treatment of atrioventricular block and cardiac arrest.
It also dilates the arterioles of skeletal muscle (beta2), resulting in a decreased peripheral resistance.
Because of its cardiac stimulatory action, it may increase systolic blood pressure slightly, but it greatly
reduces mean arterial and diastolic blood pressure.
Pulmonary:
A profound and rapid bronchodilation is produced by the drug (beta2). Isoproterenol is as active as epi
and rapidly alleviates an acute attack of asthma when taken by inhalation. The action lasts about one
hour.
2. Therapeutic uses
Now rarely used as a bronchodilator in asthma. It can be employed to stimulate the heart in emergency
situations.
3. Pharmacokinetics
Can be absorbed systemically by the sublingual mucosa but is more reliably absorbed when given
parenterally or as an inhaled aerosol.
4. Adverse effects
Similar to those of epi.
D. Dopamine
DA can activate alpha and beta receptors. For example, at higher doses, it can cause vasoconstriction by
activating alpha receptors, whereas at lower doses, it stimulates beta1 cardiac receptors.
In addition, dopaminergic receptors occurring in the mesenteric and renal vascular beds, where binding
of DA produces vasodilation.
1. Actions
CV: stimulatory effects on the beta1 receptors of the heart, having both inotropic and chronotropic
effects. At very high doses, DA activates alpha receptors on the vasculature, resulting in
vasoconstriction.
Renal and visceral: dilates renal and splanchnic arterioles and thereby increasing blood flow to the
kidneys and other viscera. These receptors are useful in the treatment of shock, in which significant
increases in sympathetic activity might compromise renal function.
2. Therapeutic uses
Shock: drug of choice in shock, and is given by continuous infusion. It raises the blood pressure by
stimulating the heart and in addition, it enhances perfusion to the kidney and splanchnic areas.
An increased blood flow to the kidney enhances the GFR and causes sodium diuresis. In this regard,
dopamine is far superior to NE, which diminishes the blood supply to the kidney and may cause renal
shutdown.
3. Adverse effects
An overdose produces the same effects as sympathetic stimulation.
The adverse effects including nausea, hypertension and arrythmias are short-lived because dopamine is
rapidly metabolized.
E. Dobutamine
Actions: a beta1receptor agonist that increases cardiac rate and output with few vascular effects. No
effect on DA receptors.
Therapeutic uses: used to increase cardiac output in congestive heart failure. The drug increases cardiac
output with little change in heart rate, and does not significantly elevate oxygen demands of the
myocardium, a major advantage over other sympathomimetic drugs.
Dobutamine is administered IV because of its short half life (about 2 minutes).
Dobutamine should be used in caution in atrial fibrillation, because the drug increases atrioventricular
conduction.
Tolerance may develop on prolonged use.
F. Phenylephrine
A direct acting, synthetic adrenergic drug that binds primarily to alpha receptors and favors alpha1
receptors over alpha2 receptors.
It is a vasoconstrictor that raises both systolic and diastolic blood pressures.
It has no effect on the heart itself but rather induces reflex bradycardia when given parenterally.
It is most often used topically on the nasal mucous membranes as a nasal decongestant and in
ophthalmic solutions for mydriasis.
Large doses can cause hypertensive headache and cardiac irregularities.
