Selective $\alpha_1$-blockers
This group includes drugs such as prazosin (Minipress), doxazosin (Cardura), and terazosin. Doxazosin stands out as a long-acting agent.
Their primary target is postsynaptic $\alpha_1$-adrenoceptors located in blood vessels. By blocking these receptors, the drugs completely abolish the stimulating effect of the sympathetic nervous system on vascular tone.
How this affects hemodynamics:
- In arterioles (resistance vessels): the lumen widens, total peripheral vascular resistance (TPVR) drops, and consequently, blood pressure decreases.
- In veins (capacitance vessels): their dilation leads to a drop in venous pressure, significantly reducing cardiac preload.
Compensatory reactions and adverse effects
The antihypertensive effect of $\alpha_1$-blockers inevitably triggers a cascade of reflex regulatory mechanisms. The body attempts to compensate for the drop in pressure:
- Reflex tachycardia. Initiated by baroreceptors that detect vasodilation and signal a moderate increase in heart rate.
- Activation of the renin-angiotensin-aldosterone system (RAAS). Due to reduced blood supply (perfusion) of the renal parenchyma, renin secretion increases compensatorily.
- Orthostatic (postural) hypotension. When a patient abruptly assumes an upright position, blood pools in the dilated veins, causing a sudden drop in blood pressure. This phenomenon is most pronounced upon taking the very first tablet, which is why clinical pharmacology refers to it as the "first-dose effect".
Use in comorbid conditions
Selective $\alpha_1$-blockers offer a unique advantage in treating comorbid patients. They are the drugs of choice when arterial hypertension is combined with benign prostatic hyperplasia (adenoma).
The mechanism behind this clinical benefit is that these drugs relax the smooth muscle of the prostatic urethra and the bladder neck. As a result, the patient's spasm is relieved, and urination is significantly facilitated. It is important to remember that other antihypertensive agents (e.g., calcium channel blockers such as diltiazem, verapamil, and amlodipine) do not affect prostate receptors.
Non-selective drugs and pheochromocytoma
Non-selective $\alpha_1$- and $\alpha_2$-receptor blockers include phentolamine and phenoxybenzamine. Today, they are not used for the treatment of ordinary (essential) hypertension. There are two reasons for this:
- Short duration of action. Blockade of presynaptic $\alpha_2$-receptors disrupts the negative feedback mechanism, leading to increased norepinephrine release.
- Marked tachycardia. It occurs via two mechanisms: reflexively (in response to lowered blood pressure) and directly (due to removing the "brake" on neurotransmitter release in the heart).
However, phentolamine is indispensable in the diagnosis and management of secondary arterial hypertension caused by pheochromocytoma, an adrenal tumor that secretes adrenaline and noradrenaline.
Here, the drug causes the phenomenon of "epinephrine reversal" (reversal of the pressor effect). Phentolamine blocks postsynaptic $\alpha_1$-receptors and extrasynaptic $\alpha_2$-receptors in blood vessels. Against the background of such total $\alpha$-blockade, circulating adrenaline can only stimulate $\beta_2$-adrenoceptors. Result: instead of the expected vasoconstriction, vasodilation and a drop in pressure occur.
Briefly: answers to topical questions
Which alpha-blockers are used to manage a hypertensive crisis?
Proroxan is used to manage hypertensive crises.
- Proroxan (Proroxan) is a drug that blocks central and peripheral $\alpha_1$- and $\alpha_2$-adrenoceptors. This leads to peripheral vasodilation (predominantly of arterioles and precapillaries) and a decrease in blood pressure. The drug is also used for sympathoadrenal crises associated with hypothalamic syndrome.
What are the bioavailability and half-life of doxazosin?
The bioavailability of doxazosin is 60–70%, and its half-life is 19–22 hours.
The drug has good systemic absorption when taken orally (80–90%), but undergoes presystemic hepatic metabolism (the "first-pass" effect), which reduces its final bioavailability. The long half-life allows for a convenient dosing regimen. Doxazosin is extensively metabolized in the liver, and its metabolites are excreted primarily through the intestines.
Which drugs belong to uroselective alpha-1 adrenergic blockers?
Uroselective $\alpha_1$-adrenergic blockers include tamsulosin and alfuzosin.
These drugs are used for benign prostatic hyperplasia:
- Tamsulosin causes selective blockade of $\alpha_{1A}$-adrenergic receptors in the smooth muscle of the prostate and the bladder neck.
- Alfuzosin is also used for benign prostatic hyperplasia.
Tamsulosin does not have a significant effect on vascular tone and systemic blood pressure.
To understand the "reversal" of adrenaline's effect in pheochromocytoma, imagine a scale with two pans: $\alpha$ (constriction) and $\beta_2$ (dilation). Phentolamine tightly blocks the $\alpha$ pan, so all the adrenaline presses on the $\beta_2$ pan, causing the blood vessels to dilate.
Class and exam questions
Why do non-selective alpha blockers cause severe tachycardia?
They block presynaptic $\alpha_2$-receptors, which disrupts negative feedback. This removes the "brake" on norepinephrine release, which directly stimulates the heart, plus reflex tachycardia is added in response to the drop in blood pressure.
What is the "first-dose effect"?
This is a sharp drop in blood pressure (orthostatic hypotension) upon transitioning to a vertical position. The phenomenon occurs due to venous dilation and blood pooling in the veins, and is most pronounced precisely after taking the first dose of the drug.
How do alpha blockers help with prostate adenoma?
They relax the smooth muscles of the bladder neck and the prostatic urethra. This removes the obstruction to urine outflow and facilitates urination in comorbid patients.
Can the effects of doxazosin and nebivolol be confused?
No, because these are drugs from different pharmacological groups. Doxazosin ($\alpha_1$-blocker) causes reflex tachycardia in response to vasodilation, while nebivolol ($\beta$-blocker) slows the heart rate, causing bradycardia.
What else to study on this topic
- Detailed mechanism of the baroreceptor reflex during pharmacologically induced vasodilation.
- The role of renin and RAAS activation in response to decreased renal perfusion.
- Functional differences between presynaptic and postsynaptic adrenergic receptors.
- Pharmacodynamics of adrenaline during isolated interaction with vascular $\beta_2$-receptors.
- Differential diagnosis of antihypertensive agents (differences from calcium channel blockers).
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