Adrenergic Agonists

The adrenergic drugs affect receptors that are stimulated by norepinephrine or epinephrine. Some adrenergic drugs act directly on the adrenergic receptor (adrenoceptor) by activating it and are said to be sympathomimetic.  block the action of the neurotransmitters at the receptors (sympatholytics), whereas still other drugs affect adrenergic function by interrupting the release of norepinephrine from adrenergic neurons. This chapter describes agents that either directly or indirectly stimulate adrenoceptors .

  • The Adrenergic Neuron 
Adrenergic neurons release norepinephrine as the primary neurotransmitter. These neurons are found in the central nervous system (CNS) and also in the sympathetic nervous system, 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 

Figure : Sites of actions of adrenergic agonists.

  •  Characteristics of Adrenergic Agonists 

Most of the adrenergic drugs are derivatives of β-phenylethylamine 

 Substitutions on the benzene ring or on the ethylamine side chains produce a great variety of compounds with varying abilities to differentiate between α and β receptors and to penetrate the CNS. Two important structural features of these drugs are the number and location of OH substitutions on the benzene ring and the nature of the substituent on the amino nitrogen.

A. Catecholamines

Sympathomimetic amines that contain the 3,4-dihydroxybenzene group (such as epinephrine, norepinephrine, isoproterenol, and dopamine) are called catecholamines. These compounds share the following properties:

1. High potency: Drugs that are catechol derivatives (with –OH groups in the 3 and 4 positions on the benzene ring) show the highest potency in directly activating α or β receptors. 

2. Rapid inactivation: Not only are the catecholamines metabolized by COMT postsynaptically and by MAO intraneuronally, they are also metabolized in other tissues. For example, COMT is in the gut wall, and MAO is in the liver and gut wall. Thus, catecholamines have only a brief period of action when given parenterally, and they are ineffective when administered orally because of inactivation.

 3. Poor penetration into the CNS: Catecholamines are polar and, therefore, do not readily penetrate into the CNS. 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-lives, because they are not inactivated by COMT. These include phenylephrine, ephedrine, and amphetamine. Phenylephrine, an analog of epinephrine, has only a single –OH at position 3 on the benzene ring, whereas ephedrine lacks hydroxyls on the ring but has a methyl substitution at the α-carbon. 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 the noncatecholamines (due to lack of polar hydroxyl groups) permits greater access to the CNS.  [Note: Ephedrine and amphetamine may act indirectly by causing the release of stored catecholamines.] 

C. Substitutions on the amine nitrogen 

The nature and bulk of the substituent on the amine nitrogen is important in determining the β selectivity of the adrenergic agonist. For example, epinephrine, with a –CH3 substituent on the amine nitrogen, is more potent at β receptors than norepinephrine, which has an unsubstituted amine. Similarly, isoproterenol, with an isopropyl substituent –CH(CH3)2 on the amine nitrogen, is a strong β agonist with little α activity.

D. Mechanism of action of the adrenergic agonists

1. Direct-acting agonists: These drugs act directly on α or β receptors, producing effects similar to those that occur following stimulation of sympathetic nerves or release of the hormone epinephrine from the adrenal medulla 

Figure : Sites of action of direct-, indirect-, and mixed-acting adrenergic agonists.

 Examples of direct-acting agonists include epinephrine, norepinephrine, isoproterenol, and phenylephrine. 

2. Indirect-acting agonists: These agents, which include amphetamine, cocaine and tyramine, may block the uptake of norepinephrine (uptake blockers) or are taken up into the presynaptic neuron and cause the release of norepinephrine from the cytoplasmic pools or vesicles of the adrenergic neuron. As with neuronal stimulation, the norepinephrine then traverses the synapse and binds to the α or β receptors. Examples of uptake blockers and agents that cause norepinephrine release include cocaine and amphetamines, respectively. 

3. Mixed-action agonists: Some agonists, such as ephedrine, pseudoephedrine and metaraminol, have the capacity both to stimulate adrenoceptors directly and to release norepinephrine from the adrenergic neuron

  •  Direct-Acting Adrenergic Agonists 

Direct-acting agonists bind to adrenergic receptors without interacting with the presynaptic neuron. The activated receptor initiates synthesis of second messengers and subsequent intracellular signals. As a group, these agents are widely used clinically. 

H. Methoxamine

Methoxamine [meth-OX-a-meen] is a direct-acting, synthetic adrenergic drug that binds primarily to α receptors, with α1 receptors favored over α2 receptors. Methoxamine raises blood pressure by stimulating α1 receptors in the arterioles, causing vasoconstriction. This causes an increase in total peripheral resistance. Because of its effects on the vagus nerve, methoxamine is used clinically to relieve attacks of paroxysmal supraventricular tachycardia. It is also used to overcome hypotension during surgery involving halothane anesthetics. In contrast to most other adrenergic drugs, methoxamine does not tend to trigger cardiac arrhythmias in the heart, which is sensitized by these general anesthetics. Adverse effects include hypertensive headache and vomiting.

 I. Clonidine Clonidine [KLOE-ni-deen] is an α2 agonist that is used in essential hypertension to lower blood pressure because of its action in the CNS .It can be used to minimize the symptoms that accompany withdrawal from opiates or benzodiazepines. Clonidine acts centrally to produce inhibition of sympathetic vasomotor centers, decreasing sympathetic outflow to the periphery

J. Metaproterenol Metaproterenol [met-a-proe-TER-a-nole], although chemically similar to isoproterenol, is not a catecholamine, and it is resistant to methylation by COMT. It can be administered orally or by inhalation. The drug acts primarily at β2 receptors, producing little effect on the heart. Metaproterenol produces dilation of the bronchioles and improves airway function. The drug is useful as a bronchodilator in the treatment of asthma and to reverse bronchospasm .

 K. Albuterol, pirbuterol, and terbutaline Albuterol [al-BYOO-ter-ole], pirbuterol [peer-BYOO-ter-ole], and terbutaline [ter-BYOO-te-leen] are short-acting β2 agonists used primarily as bronchodilators and administered by a metered-dose inhaler. Compared with the nonselective β-adrenergic agonists, such as metaproterenol, these drugs produce equivalent bronchodilation with less cardiac stimulation.

Figure : Onset and duration of bronchodilation effects of inhaled adrenergic agonists.

 L. Salmeterol and formoterol Salmeterol [sal-ME-ter-ole] and formoterol [for-MOH-ter-ole] are β2-adrenergic selective, long-acting bronchodilators. A single dose by a metered-dose inhalation device, such as a dry powder inhaler, provides sustained bronchodilation over 12 hours, compared with less than 3 hours for albuterol. Unlike formoterol, however, salmeterol has a somewhat delayed onset of action  .These agents are not recommended as monotherapy and are highly efficacious when combined with a corticorsteroid. Salmeterol and formoterol are the agents of choice for treating nocturnal asthma in symptomatic patients taking other asthma medications. 

  • Indirect-Acting Adrenergic Agonists 
Indirect-acting adrenergic agonists cause norepinephrine release from presynaptic terminals or inhibit the uptake of norepinephrine

Figure :Sites of action of direct-, indirect-, and mixed-acting adrenergic agonists.

They potentiate the effects of norepinephrine produced endogenously, but these agents do not directly affect postsynaptic receptors. 

A. Amphetamine
The marked central stimulatory action of amphetamine [am-FET-a-meen] is often mistaken by drug abusers as its only action. However, the drug can increase blood pressure significantly by α-agonist action on the vasculature as well as βstimulatory effects on the heart. Its peripheral actions are mediated primarily through the blockade of norepinephrine uptake and cellular release of stored catecholamines; thus, amphetamine is an indirect-acting adrenergic drug. The actions and uses of amphetamines are discussed under stimulants of the CNS . The CNS stimulant effects of amphetamine and its derivatives have led to their use for treating hyperactivity in children, narcolepsy, and appetite control. Its use in pregnancy should be avoided because of adverse effects on development of the fetus.

 B. Tyramine
Tyramine [TIE-ra-meen] is not a clinically useful drug, but it is important because it is found in fermented foods, such as ripe cheese and Chianti wine . It is a normal byproduct of tyrosine metabolism. Normally, it is oxidized by MAO in the gastrointestinal tract, but if the patient is taking MAO inhibitors, it can precipitate serious vasopressor episodes. Like amphetamines, tyramine can enter the nerve terminal and displace stored norepinephrine. The released catecholamine then acts on adrenoceptors.

 C. Cocaine
Cocaine [koe-KANE] is unique among local anesthetics in having the ability to block the Na+/K+-activated ATPase (required for cellular uptake of norepinephrine) on the cell membrane of the adrenergic neuron. Consequently, norepinephrine accumulates in the synaptic space, resulting in enhancement of sympathetic activity and potentiation of the actions of epinephrine and norepinephrine. Therefore, small doses of the catecholamines produce greatly magnified effects in an individual taking cocaine as compared to those in one who is not. In addition, the duration of action of epinephrine and norepinephrine is increased. Like amphetamines, it can increase blood pressure by α-agonist actions and β-stimulatory effects.

  •  Mixed-Action Adrenergic Agonists 
Mixed-action drugs induce the release of norepinephrine from presynaptic terminals, and they activate adrenergic receptors on the postsynaptic membrane.

-Ephedrine and pseudoephedrine

Ephedrine [e-FED-rin], and pseudoephedrine [soo-doe-e-FED-rin] are plant alkaloids, that are now made synthetically. These drugs are mixed-action adrenergic agents. They not only release stored norepinephrine from nerve endings but also directly stimulate both α and β receptors. Thus, a wide variety of adrenergic actions ensue that are similar to those of epinephrine, although less potent. Ephedrine and pseudoephedrine are not catechols and are poor substrates for COMT and MAO; thus, these drugs have a long duration of action. Ephedrine and pseudoephedrine have excellent absorption orally and penetrate into the CNS; however, pseudoephedrine has fewer CNS effects.

Ephedrine is eliminated largely unchanged in the urine, and pseudoephedrine undergoes incomplete hepatic metabolism before elimination in the urine. Ephedrine raises systolic and diastolic blood pressures by vasoconstriction and cardiac stimulation. Ephedrine produces bronchodilation, but it is less potent than epinephrine or isoproterenol in this regard and produces its action more slowly. It is therefore sometimes used prophylactically in chronic treatment of asthma to prevent attacks rather than to treat the acute attack. Ephedrine enhances contractility and improves motor function in myasthenia gravis, particularly when used in conjunction with anticholinesterases .

 Ephedrine produces a mild stimulation of the CNS. This increases alertness, decreases fatigue, and prevents sleep. It also improves athletic performance. Ephedrine has been used to treat asthma, as a nasal decongestant (due to its local vasoconstrictor action), and to raise blood pressure. Pseudoephedrine is primarily used to treat nasal and sinus congestion or congestion of the eustachian tubes. [Note: The clinical use of ephedrine is declining due to the availability of better, more potent agents that cause fewer adverse effects. Ephedrine-containing herbal supplements (mainly ephedra-containing products) were banned by the U.S. Food and Drug Administration in April 2004 because of lifethreatening cardiovascular reactions. Pseudoephedrine has been illegally converted to methamphetamine. Thus, products containing pseudoephedrine have certain restrictions and must be kept behind the sales counter.]

Figure : Some adverse effects observed with adrenergic agonists.

Figure : Summary of β- adrenergic receptors

Figure : Summary of the therapeutic uses of adrenergic agonists.

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