Alpha-receptor antagonists (overview)

α receptor antagonists (alpha blockers) act as competitive antagonists at the α receptors. The effect of adrenaline and noradrenaline is thereby cancelled out. Alpha-receptor antagonists are used as second-choice agents in hypertension. They have further indications in the therapy of benign prostatic hyperplasia (prazosin, alfuzosin, tamsulosin) and Raynaud's syndrome (prazosin is the most commonly used).

Alpha-receptor antagonists (alpha blockers) include:

• ergot alkaloids (e.g.: ergotamine; ergocornin)
• non-selective alpha-receptor antagonists of the phentolamine and phenoxybenzamine type
• selective alpha-receptor antagonists (e.g. prazosin, terazosin, doxazosin, urapidil)

_______________________________________________________________________________________

The following substances are classified as non-selective alpha-receptor antagonists (antagonisation of alpha1 and alpha2 receptors)

• Phenoxybenzamine
• Phentolamine

The following substances are classified as selective alpha1 receptor antagonists

• Urapidil
• Prazosin
• Doxazosin
• Alfuzosin
• Terazosin
• Tamsulosin

Urapidil also has an agonistic effect on serotonin receptors (5-HT1A). It is important to note that receptor antagonists can only act if the corresponding receptor is tonically activated. However, this state is true for the alpha1 receptors of the resistance vessels. Thus they act as blood pressure reducers.

Adrenoreceptors of the alpha type, alpha receptors for short, are subdivided into alpha1 and alpha2 receptors. There are 3 subtypes of both alpha-receptor types:

• α1A receptor
• α1B- Receptor
• α1D- Receptor

The alpha1-adrenoreceptors belong to the adrenoceptors(G-protein-coupled receptors) and can be detected mainly in the presynaptic membrane of sympathetic and also parasympathetic neurons, but also on the cell membrane of adipocytes. They are activated by accumulation of catecholamines(adrenalin and noradrenalin).

α 1-adrenoreceptors contribute to the regulation of sympathetic nervous system activity and influence a number of sympathetic responses, for example to smooth muscle in vessels, bronchial tubes, hair follicles (goose bumps), the urogenital tract and the gastrointestinal tract. They unfold their effect via the Gq-protein (see below G-protein coupled receptors see below adrenoreceptors). This leads to an activation of the phospholipase C (type β). This lipase cleaves membrane lipids such as phosphatidylinositol-4,5-bisphosphate (PIP2) to diacylglycerol (DAG) and inositoltrisphosphate (IP3).

The α2 adrenoceptors can be further subdivided into α2C/D, α2B and α2C receptors.

• α2A- Receptor
• α2B- Receptor
• α2C- Receptor

Due to the lack of selective antagonists, the subtypes of both receptor types are not precisely characterized. It is known that the α1A receptor subtype mediates vasoconstriction, the α1B receptor subtype causes the known positive inotropic effect at the heart of the α1 receptor.

The vasoconstriction mediated by the presynaptic α2 receptor is mediated by the α2B receptor.

The activation of the α2C-receptor leads to the activation of a Gi-protein (= inhibitory G-protein) which inhibits the adenylate cyclase (AC) and thus leads to a reduction of the cAMP levels.

The antagonization of α1-receptors (selective α1-receptor antagonists) lowers the peripheral resistance and blood pressure.

The antagonization of presynaptic α2-receptors interrupts the important control circuit for the exocytotic release of noradrenaline.

In therapeutic doses phenoxybenzamine inhibits both α1 and α2 receptors. Phentolamine is also a dual blocker of the α1 and α2 receptors.

For pharmacotherapy, however, only therapy with selective alpha1-receptor antagonists has become established. Non-selective α receptor antagonists have only very limited indications (Graefe KH et al. 2016).

Indications (selective alpha1 receptor antagonists):

• Arterial hypertension (in this indication, however, they do not belong to first-line therapy)
• Raynaud's syndrome: Prazosin is the main drug used in this indication
• Benign prostatic hyperplasia (prazosin, alfuzosin, tamsulozin). Alpha1-receptor antagonists can reduce muscle tone in the bladder neck.
• Contraindicated are alpha1-receptor antagonists in pregnancy and lactation, in heart failure and in children <12 years of age.

Indications (non-selective alpha-receptor antagonists):

• S.u. Phenoxybenzamine(pheochromocytoma and neurogenic bladder voiding disorders) and phentolamine (for intoxications caused by indirect sympathomimetic drugs such as cocaine, amphetamine and amphetamine-like substances as an antidote; further for erectile dysfunction and as a phentolamine inhibition test)