Adrenergic agonist

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).

Beta blockers block the action of epinephrine and norepinephrine in the body. Adrenergic drugs either stimulate a response (agonists) or inhibit a response (antagonists). The five categories of adrenergic receptors are: α1, α2, β1, β2, and β3, 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.

Receptors
For more info see adrenergic receptor

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 α1A, α1B, α1D, α2A, α2B and α2C. The α2C receptor has been reclassed from α1C, 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 Gq), increasing the activity of protein kinase C (PKC). α2 receptors inhibit adenylate cyclase (via Gi), decreasing the activity of protein kinase A (PKA). β receptors activate adenylate cyclase (via Gs), thus increasing the activity of PKA. Agonists of each class of receptor elicit these downstream responses.

Uptake and Storage
Indirectly acting adrenergic agonists affect on 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 two 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 targetted pharmacologically. Inhibitors of these enzymes act as indirect agonists of adrenergic receptors as they prolong the action of catecholamines at the receptors.

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.

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.

Direct action

 * Alpha-adrenergic agonist
 * Beta-adrenergic agonist

Indirect action

 * Amphetamine
 * Cocaine
 * Methylenedioxymethamphetamine (MDMA)
 * Tyramine

Mixed action

 * Ephedrine
 * Pseudoephedrine