Adrenergic agonist

An adrenergic agonist is a drug that stimulates a response from the adrenergic receptors. The five main categories of adrenergic receptors are: α₁, α₂, β₁, β₂, and β₃, although there are more subtypes, and agonists vary in specificity between these receptors, and may be classified respectively. However, there are also other mechanisms of adrenergic agonism. Epinephrine and norepinephrine are endogenous and broad-spectrum. More selective agonists are more useful in pharmacology.

An adrenergic agent is a drug, or other substance, which has effects similar to, or the same as, epinephrine (adrenaline). Thus, it is a kind of sympathomimetic agent. Alternatively, it may refer to something which is susceptible to epinephrine, or similar substances, such as a biological receptor (specifically, the adrenergic receptors).

Receptors

Directly acting adrenergic agonists act on adrenergic receptors. All adrenergic receptors are G-protein coupled, activating signal transduction pathways. The G-protein receptor can affect the function of adenylate cyclase or phospholipase C, an agonist of the receptor will upregulate the effects on the downstream pathway (it will not necessarily upregulate the pathway itself).

The receptors are broadly grouped into α and β receptors. There are two subclasses of α-receptor, α₁ and α₂ which are further subdivided into α_1A, α_1B, α_1D, α_2A, α_2B and α_2C. The α_2C receptor has been reclassed from α_1C, due to its greater homology with the α₂ class, giving rise to the somewhat confusing nomenclature. The β receptors are divided into β₁, β₂ and β₃. The receptors are classed physiologically, though pharmacological selectivity for receptor subtypes exists and is important in the clinical application of adrenergic agonists (and, indeed, antagonists).

From an overall perspective, α₁ receptors activate phospholipase C (via G_q), increasing the activity of protein kinase C (PKC); α₂ receptors inhibit adenylate cyclase (via G_i), decreasing the activity of protein kinase A (PKA); β receptors activate adenylate cyclase (via G_s), thus increasing the activity of PKA. Agonists of each class of receptor elicit these downstream responses.^[1]

Uptake and storage

Indirectly acting adrenergic agonists affect the uptake and storage mechanisms involved in adrenergic signalling.

Two uptake mechanisms exist for terminating the action of adrenergic catecholamines - uptake 1 and uptake 2. Uptake 1 occurs at the presynaptic nerve terminal to remove the neurotransmitter from the synapse. Uptake 2 occurs at postsynaptic and peripheral cells to prevent the neurotransmitter from diffusing laterally.

There is also enzymatic degradation of the catecholamines by two main enzymes - monoamine oxidase and catechol-o-methyl transferase. Respectively, these enzymes oxidise monoamines (including catecholamines) and methylate the hydroxal groups of the phenyl moiety of catecholamines. These enzymes can be targeted pharmacologically. Inhibitors of these enzymes act as indirect agonists of adrenergic receptors as they prolong the action of catecholamines at the receptors.^[2]

Structure–activity relationship

In general, a primary or secondary aliphatic amine separated by 2 carbons from a substituted benzene ring is minimally required for high agonist activity.^[3]

Mechanisms

A great number of drugs are available which can affect adrenergic receptors. Each drug has its own receptor specificity giving it a unique pharmacological effect. Other drugs affect the uptake and storage mechanisms of adrenergic catecholamines, prolonging their action. The following headings provide some useful examples to illustrate the various ways in which drugs can enhance the effects of adrenergic receptors.^[4][5][6]

Direct action

These drugs act directly on one or more adrenergic receptors. According to receptor selectivity they are two types:

• Non-selective: drugs act on one or more receptors; these are:
  • Adrenaline (almost all adrenergic receptors).
  • Noradrenaline (acts on α₁, α₂, β₁).
  • Isoprenaline (acts on β₁, β₂, β₃).
  • Dopamine (acts on α₁, α₂, β₁, D₁, D₂).
• Selective: drugs which act on a single receptor only; these are further classified into α selective & β selective.
  • α1 selective: Phenylephrine, Methoxamine, Midodrine, Oxymetazoline.
  • α2 selective: α-Methyl dopa, clonidine, brimonidine.
  • β1 selective: Dobutamine.
  • β2 selective: Salbutamol, Albuterol, Terbutaline, Salmeterol, Formoterol, Pirbuterol.

Indirect action

(agents that increase neurotransmission in endogenous chemicals in this case Epinephrine and Norepinephrine)

• Amphetamines
• Cocaine
• Methylenedioxymethamphetamine (MDMA)
• Tyramine
• Nicotine
• Caffeine
• Methylphenidate

Mixed action

• Ephedrine
• Pseudoephedrine

See also

• Adrenergic receptor

References

1. Siegel, George J; et al. (2006). Basic Neurochemistry 7e. Elsevier.
2. Rang, H.P.; et al. (2003). Pharmacology. Churchill Livingstone.
3. Medicinal Chemistry of Adrenergics and Cholinergics
4. Laurence Pharmacology 9th edition , page 450
5. Katzung Pharmacology 12th edition page 131-133
6. Lippincott's Pharmacology 5th edition page 69-85

External links

• Virtual Chembook article on adrenergic drugs
• adrenergic agonists at the US National Library of Medicine Medical Subject Headings (MeSH)