Alpha blockers, also known as α-blockers or α-adrenoreceptor antagonists, are a class of pharmacological agents that act as antagonists on α-adrenergic receptors (α-adrenoceptors).
Historically, alpha-blockers were used as a tool for pharmacologic research to develop a greater understanding of the autonomic nervous system. Using alpha blockers, scientists began characterizing arterial blood pressure and central vasomotor control in the autonomic nervous system. Today, they can be used as clinical treatments for a limited number of diseases.
Alpha blockers can treat a small range of diseases such as hypertension, Raynaud's disease, benign prostatic hyperplasia (BPH) and erectile dysfunction. Generally speaking, these treatments function by binding an α-blocker to α receptors in the arteries and smooth muscle. Ultimately, depending on the type of alpha receptor, this relaxes the smooth muscle or blood vessels, which increases fluid flow in these entities.
Classification
α1-blockers act on α1-adrenoceptors α2-blockers act on α2-adrenoceptors When the term "alpha blocker" is used without further qualification, it can refer to an α1 blocker, an α2 blocker, a nonselective blocker (both α1 and α2 activity), or an α blocker with some β activity. However, the most common type of alpha blocker is α1.
Non-selective α-adrenergic receptor antagonists include: Phenoxybenzamine Phentolamine Tolazoline Trazodone
Selective α1-adrenergic receptor antagonists include: Alfuzosin Doxazosin Prazosin (inverse agonist) Tamsulosin Terazosin Silodosin
Selective α2-adrenergic receptor antagonists include: Atipamezole Idazoxan Mirtazapine Yohimbine
Finally, the agents carvedilol and labetalol are both α and β-blockers.
Below are some of the most common drugs used in the clinic.
Drug NameCommon BrandsStructureMechanism of ActionEffectsClinical ApplicationsToxicityPhenoxybenzamineDibenzylineNonselective covalent binding to α1 and α2 receptors.
Irreversibly binds.Lowers blood pressure by decreasing peripheral resistance.
Blocks alpha induced vasconstriction. Pheochromocytoma Excess catecholamine release Orthostatic hypotension Tachycardia Nausea Vomiting PhentolamineRegitineCompetitive blocking of α1 and α2 receptors.
4 hours of action after initial administration.Reversal of epinephrine induced effects.
Lowers blood pressure by decreasing peripheral resistance. Pheochromocytoma Reflex cardiac stimulation Tachycardia Arrhythmia Anginal pain PrazosinMinipressInverse agonist of α1 receptor.Lowers blood pressure. Hypertension Benign prostatic hyperplasia (BPH) Posttraumatic stress disorder (PTSD) First dose effect Orthostatic hypotension Nasal congestion Dizziness Lack of energy Headache Drowsiness DoxazosinCardura Cardura XLCompetitive blocking of α1 receptor.Lowers blood pressure. Hypertension Benign prostatic hyperplasia First dose effect Orthostatic hypotension Nasal congestion Dizziness Lack of energy Headache Drowsiness TerazosinHytrinCompetitive blocking of α1 receptor.Lowers blood pressure. Hypertension Benign prostatic hyperplasia (BPH) First dose effect Orthostatic hypotension Nasal congestion Dizziness Lack of energy Headache Drowsiness TamsulosinFlomaxA blocker selective for α1 receptors, with relative preference for the α1A (and α1D) subtypes over α1B.Relaxation of prostatic smooth muscle. Benign prostatic hyperplasia Orthostatic hypotension YohimbineYoconBlocks α2 receptor, and increases norepinephrine release, thus increasing CNS activity.Raises blood pressure and heart rate. Sexual stimulation Male erectile dysfunction Hypotension May cause anxiety Central Nervous System stimulationLabetalolTrandateBlocks some α1 receptor activity, but binds more strongly to β receptors.Lowers blood pressure, increases heart rate slightly. Hypertension May cause tachycardia CarvedilolCoreg Coreg CRBlocks some α1 receptor activity, but binds more strongly to β receptors.Can interfere with noradrenergic mechanisms. Congestive heart failure(CHF) Fatigue
Medical uses While there are limited clinical α-blocker uses, in which most α-blockers are used for hypertension or benign prostatic hyperplasia, α-blockers can be used to treat a few other diseases, such as Raynaud's disease, congestive heart failure (CHF), pheochromocytoma, and erectile dysfunction.
Furthermore, α-blockers can occasionally be used to treat anxiety and panic disorders, such as posttraumatic stress disorder (PTSD) induced nightmares. Studies have also had great medical interest in testing alpha blockers, specifically α2 blockers, to treat type II diabetes and psychiatric depression.
Hypertension Hypertension is due to an increase in vascular resistance and vasoconstriction. Using α1 selective antagonists, such as prazosin, has been efficacious in treating mild to moderate hypertension. This is because they can decrease vascular resistance and decrease pressure. However, while these drugs are generally well tolerated, they have the potential to produce side effects such as orthostatic hypotension and dizziness. However, unlike other treatments for hypertension such as ACE inhibitors, ARBs, calcium channel blockers, thiazide diuretics or beta blockers, alpha blockers have not demonstrated the same mortality and morbidity benefits, and are therefore not generally used as first or even second line agents.
Another treatment for hypertension is using drugs that have both α1 blocking activity, as well as nonselective β activity, such as Labetalol or carvedilol. In low doses, labetalol and carvedilol can decrease the peripheral resistance and block the effects of isoprenaline to reduce hypertensive symptoms.
Pheochromocytoma
Pheochromocytoma is a disease in which a catecholamine secreting tumor develops. Specifically, norepinephrine and epinephrine are secreted by these tumors, either continuously or intermittently. The excess release of these catecholamines increases central nervous system stimulation, thus causing blood vessels to increase in vascular resistance, and ultimately giving rise to hypertension. In addition, patients with these rare tumors are often subject to headaches, heart palpitations, and increased sweating.
Phenoxybenzamine, a nonselective α1 and α2 blocker, has been used to treat pheochromocytoma. This drug blocks the activity of epinephrine and norepinephrine by antagonizing the alpha receptors, thus decreasing vascular resistance, increasing vasodilation, and decreasing blood pressure overall.
Congestive heart failure Blockers that have both the ability to block both α and β receptors, such as carvedilol, bucindolol, and labetalol, have the ability to mitigate the symptoms in congestive heart failure. By binding to both the α and β receptors, these drugs can decrease the cardiac output and stimulate the dilation of blood vessels to promote a reduction in blood pressure.
Erectile dysfunction Yohimbine, an α2 blocker derived from the bark of the Pausinystalia johimbe tree, has been tested to increase libido and treat erectile dysfunction. The proposed mechanism for yohimbine is blockade of the adrenergic receptors that are associated with neurotransmitters inhibition, including dopamine and nitric oxide, and thus aiding with penile erection and libido. By doing so, they can alter the blood flow in the penis to aid in achieving an erection. However, some side effects can occur, such as palpitation, tremor, elevated blood pressure, and anxiety. Yohimbe bark contains both α1 and α2 adrenergic receptors blocking alkaloids.
Phentolamine, a non-selective alpha blocker, has also been tested to treat erectile dysfunction. By reducing vasoconstriction in the penis, there appears to be increased blood flow that aids in penile erection. Side effects associated with phentolamine include headache, flushing, and nasal congestion.
Phenoxybenzamine, a non-competitive α1 and α2 blocker was used by Dr. Giles Brindley in the first intracavernosal pharmacotherapy for erectile dysfunction.
Benign prostatic hyperplasia In benign prostatic hyperplasia (BPH), men experience urinary obstruction and are unable to urinate, thus leading to urinary retention. α1 specific blockers have been used to relax the smooth muscle in the bladder and enlarged prostate. Prazosin, doxazosin, and terazosin have been particularly useful for patients with BPH, especially in patients with hypertension. In such patients, these drugs can treat both conditions at the same time. In patients without hypertension, tamsulosin can be used, as it has the ability to relax the bladder and prostate smooth muscle without causing major changes in blood pressure.
Raynaud's disease
Both α1 blockers and α2 blockers have been examined to treat Raynaud's disease. Although α1 blockers, such as prazosin, have appeared to give slight improvement for the sclerotic symptoms of Raynaud's disease, there are many side effects that occur while taking this drug. Conversely, α2 blockers, such as yohimbine, appear to provide significant improvement of the sclerotic symptoms in Raynaud's Disease without excessive side effects.
Post traumatic stress disorder Patients with posttraumatic stress disorder (PTSD) have often continued to be symptomatic despite being treated with PTSD-specific drugs. In addition, PTSD patients often have debilitating nightmares that continue, despite their treatments. High doses of the α1 blocker, prazosin, have been efficacious in treating patients with PTSD induced nightmares due to its ability to block the effects of norepinephrine.
Adverse effects of prazosin to treat PTSD nightmares include dizziness, first dose effect (a sudden loss of consciousness), weakness, nausea, and fatigue.
Adverse effects Although alpha blockers have the ability to reduce some disease pathology, there are some side effects that come with these alpha blockers. However, because there are several structural compositions that make each alpha blocker different, the side effects are different for each drug. Side effects that arise when taking alpha blockers can include the first dose effect, cardiovascular side effects, genitourinary side effects, as well as other side effects.
First dose effect One of the most common side effects with alpha blockers is the first dose effect. This is a phenomenon in which patients with hypertension take an alpha blocker for the first time, and suddenly experience an intense decrease in blood pressure. Ultimately, this gives rise to orthostatic hypotension, dizziness, and a sudden loss of consciousness due to the drastic drop in blood pressure.
Alpha blockers that possess these side effects include prazosin, doxazosin, and terazosin.
Cardiovascular side effects There are some alpha blockers that can give rise to changes in the cardiovascular system, such as the induction of reflex tachycardia, orthostatic hypotension, or heart palpitations via alterations of the QT interval. Alpha blockers that may have these side effects include yohimbine, phenoxybenzamine, and phentolamine.
Genitourinary side effects When alpha blockers are used to treat BPH, it causes vasodilation of blood vessels on the bladder and the prostate, thus increasing urination in general. However, these alpha blockers can produce the exact opposite side effect, in which edema, or abnormal fluid retention, occurs.
In addition, due to the relaxation of the prostate smooth muscle, another side effect that arises in men being treated for BPH is impotence, as well as the inability to ejaculate. However, if any ejaculation activity does occur, oftentimes, it results in a phenomenon called retrograde ejaculation, in which semen flows into the urinary bladder instead of exiting through the urethra.
Drugs that may produce such side effects include prazosin, terazosin, tamsulosin, and doxazosin.
Other side effects