Alpha-2 adrenergic agonists

Localization of $\alpha_2$-adrenergic receptors

These receptors are found in the body in two main locations:

• Vascular: Located in the arterioles of the skin, mucous membranes, coronary vessels, and veins. Their distinctive feature is a predominantly extrasynaptic arrangement.
• Neuronal: Located on postsynaptic membranes and, most importantly, on presynaptic membranes (on varicosities of adrenergic and cholinergic nerves).

Additionally, $\alpha_2$-receptors are present on platelets (their stimulation causes aggregation), in the gastrointestinal tract (reducing tone and secretion), and in pancreatic $\beta$-cells (decreasing insulin production).

Mechanisms of action: from receptor to effect

The effects of $\alpha_2$-adrenergic agonists depend on the location of the activated receptor.

1. In vascular smooth muscle (contraction):

Receptor binding activates the $G_{i/0}$ protein, which inhibits adenylyl cyclase. This reduces cAMP levels and protein kinase A activity. As a result, the activity of myosin light-chain kinase (facilitating actin-myosin interaction) and phospholamban increases. Phospholamban inhibits sarcoplasmic reticulum $Ca^{2+}$-ATPase, causing calcium to accumulate in the cytoplasm, which leads to vasoconstriction.

1. On presynaptic membranes (inhibition):

This operates via negative feedback. Activation of the $G_{i/0}$ protein decreases protein kinase A activity, opens potassium channels (hyperpolarization), and disrupts voltage-gated calcium channels. Less calcium enters the nerve terminal, which decreases the exocytosis of vesicles containing the neurotransmitter (norepinephrine or acetylcholine).

Classification and pharmacological effects

Drugs in this group are divided into topical and centrally acting agents.

Topical agents (imidazoline derivatives): Naphazoline, Oxymetazoline, Xylometazoline, Tetryzoline. Their main objective is to induce pronounced vasoconstriction. They are used in ENT practice to relieve nasal mucosal edema (effect lasts longer than that of $\alpha_1$-agonists) and in ophthalmology (Tetryzoline) for eye irritation.

Centrally acting agents: Clonidine, Guanfacine, Methyldopa, Tizanidine. They act on neurons of the nucleus tractus solitarii. Their stimulation produces central effects:

• Hypotensive (blood pressure reduction);
• Analgesic;
• Sedative;
• Hypothermic.

Clonidine additionally stimulates imidazoline $I_1$-receptors, enhancing the inhibition of the sympathetic nervous system.

Application features and side effects

Topical formulations: Should not be used more than 3 times a day. Prolonged use (more than 5 days) leads to tachyphylaxis (tolerance), and discontinuation causes rebound vasodilation (secondary nasal congestion). Systemic absorption may increase blood pressure.

Central formulations: Used primarily to treat arterial hypertension (Clonidine for hypertensive crises, Guanfacine has a longer duration of action). Tizanidine acts as a central muscle relaxant, reducing skeletal muscle tone.

Common side effects of central agents:

• Dry mouth (xerostomia);
• Bradycardia;
• Drowsiness, slowed reaction time;
• Constipation, fluid retention;
• Withdrawal syndrome (upon abrupt cessation).

Class and exam questions

What else to study on this topic

• The role of phospholamban in smooth muscle contraction
• Mechanism of tachyphylaxis development during decongestant use
• The connection between $\alpha_2$-receptors and imidazoline receptors (Clonidine)
• Use of clonidine in the treatment of opioid dependence
• Central muscle relaxants: mechanism of action of tizanidine

Other topics in the section "Drugs Acting on Adrenergic Synapses"

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