alpha blocker

File:GPCR and itegrin signaling diagram.png

• 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 usually an α₁ blocker.

Non-selective α-adrenergic receptor antagonists include:

• Phenoxybenzamine
• Phentolamine
• Tolazoline
• Trazodone

Selective α₁-adrenergic receptor antagonists include:

• Alfuzosin{{cite journal | vauthors = McKeage K, Plosker GL | title = Alfuzosin: a review of the therapeutic use of the prolonged-release formulation given once daily in the management of benign prostatic hyperplasia | journal = Drugs | volume = 62 | issue = 4 | pages = 633–653 | date = 2002-03-01 | pmid = 11893233 | doi = 10.2165/00003495-200262040-00009 | s2cid = 250307179 }}
• Doxazosin{{cite journal | vauthors = Nash DT | title = Alpha-adrenergic blockers: mechanism of action, blood pressure control, and effects of lipoprotein metabolism | journal = Clinical Cardiology | volume = 13 | issue = 11 | pages = 764–772 | date = November 1990 | pmid = 1980236 | doi = 10.1002/clc.4960131104 | s2cid = 24619863 | doi-access = free }}
• Prazosin (inverse agonist){{cite journal | vauthors = Green B | title = Prazosin in the treatment of PTSD | journal = Journal of Psychiatric Practice | volume = 20 | issue = 4 | pages = 253–259 | date = July 2014 | pmid = 25036580 | doi = 10.1097/01.pra.0000452561.98286.1e | s2cid = 40069887 }}
• Tamsulosin{{Cite web|date=|title=Tamsulosin Monograph for Professionals|url=https://www.drugs.com/monograph/tamsulosin.html|url-status=live|archive-url=https://web.archive.org/web/20210120045327/https://www.drugs.com/monograph/tamsulosin.html |archive-date=2021-01-20 |access-date=29 January 2021|website=Drugs.com}}
• Terazosin{{cite journal | vauthors = Lepor H, Henry D, Laddu AR | title = The efficacy and safety of terazosin for the treatment of symptomatic BPH | journal = The Prostate | volume = 18 | issue = 4 | pages = 345–355 | date = 1991-01-01 | pmid = 1711689 | doi = 10.1002/pros.2990180408 | s2cid = 37160206 }}
• Silodosin{{Cite journal| vauthors = Michel MC |title=The Pharmacological Profile of the α1A-Adrenoceptor Antagonist Silodosin|journal=European Urology Supplements|volume=9|issue=4|pages=486–490|doi=10.1016/j.eursup.2010.03.006|year=2010}}

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.

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.{{cite journal | vauthors = Roehrborn CG, Schwinn DA | title = Alpha1-adrenergic receptors and their inhibitors in lower urinary tract symptoms and benign prostatic hyperplasia | journal = The Journal of Urology | volume = 171 | issue = 3 | pages = 1029–1035 | date = March 2004 | pmid = 14767264 | doi = 10.1097/01.ju.0000097026.43866.cc }}{{cite journal | vauthors = Messerli FH | title = Doxazosin and congestive heart failure | journal = Journal of the American College of Cardiology | volume = 38 | issue = 5 | pages = 1295–1296 | date = November 2001 | pmid = 11691497 | doi = 10.1016/s0735-1097(01)01534-0 | doi-access = free }}{{cite journal | vauthors = Ernst E, Pittler MH | title = Yohimbine for erectile dysfunction: a systematic review and meta-analysis of randomized clinical trials | journal = The Journal of Urology | volume = 159 | issue = 2 | pages = 433–436 | date = February 1998 | pmid = 9649257 | doi = 10.1016/s0022-5347(01)63942-9 }}

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 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.{{cite journal | vauthors = Laurent S | title = Antihypertensive drugs | journal = Pharmacological Research | volume = 124 | pages = 116–125 | date = October 2017 | pmid = 28780421 | doi = 10.1016/j.phrs.2017.07.026 | s2cid = 251991 }} 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.{{cite journal | vauthors = Brogden RN, Heel RC, Speight TM, Avery GS | title = Labetalol: a review of its pharmacology and therapeutic use in hypertension | journal = Drugs | volume = 15 | issue = 4 | pages = 251–270 | date = April 1978 | pmid = 25757 | doi = 10.2165/00003495-197815040-00002 | s2cid = 42161040 }} In low doses, labetalol and carvedilol can decrease the peripheral resistance and block the effects of isoprenaline to reduce hypertensive symptoms.

File:Pheochromocytoma.jpg

Pheochromocytoma is a disease in which a catecholamine secreting tumor develops.{{cite journal | vauthors = Bravo EL | title = Pheochromocytoma: an approach to antihypertensive management | journal = Annals of the New York Academy of Sciences | volume = 970 | issue = 1 | pages = 1–10 | date = September 2002 | pmid = 12381537 | doi = 10.1111/j.1749-6632.2002.tb04408.x | s2cid = 222084372 | bibcode = 2002NYASA.970....1B }} 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.{{Cite journal| vauthors = Das S, Kumar P, Kiran U, Airan B |date= January 2017 |title=Alpha blockers: A relook at phenoxybenzamine|journal=Journal of the Practice of Cardiovascular Sciences|language=en|volume=3|issue=1|pages=11|doi=10.4103/jpcs.jpcs_42_16|doi-access=free}} 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.

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.{{cite journal | vauthors = Bristow MR | title = beta-adrenergic receptor blockade in chronic heart failure | journal = Circulation | volume = 101 | issue = 5 | pages = 558–569 | date = February 2000 | pmid = 10662755 | doi = 10.1161/01.CIR.101.5.558 | doi-access = free }} 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.

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.{{cite journal | vauthors = Lue TF | title = Erectile dysfunction | language = EN | journal = The New England Journal of Medicine | volume = 342 | issue = 24 | pages = 1802–1813 | date = June 2000 | pmid = 10853004 | doi = 10.1056/nejm200006153422407 }}

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.

File:BPH.png

Phenoxybenzamine, a non-competitive α₁ and α₂ blocker was used by Dr. Giles Brindley in the first intracavernosal pharmacotherapy for erectile dysfunction.{{cite book | chapter = A Description of the Pioneering Work That Led to the First Approved Agents for ED: Giles Brindley, the Needle, and the Penis (Phenoxybenzamine) |date=2007 | title =Key Clinical Trials in Erectile Dysfunction |pages=4–7 | veditors = Carson CC |place=London |publisher=Springer |language=en |doi=10.1007/978-1-84628-428-1_2 |isbn=978-1-84628-428-1}}

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.{{cite journal | vauthors = Chapple CR | title = Selective alpha 1-adrenoceptor antagonists in benign prostatic hyperplasia: rationale and clinical experience | journal = European Urology | volume = 29 | issue = 2 | pages = 129–144 | date = January 1996 | pmid = 8647139 }} 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.

File:Raynaud's Syndrome.jpg

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.{{cite journal | vauthors = Bakst R, Merola JF, Franks AG, Sanchez M | title = Raynaud's phenomenon: pathogenesis and management | journal = Journal of the American Academy of Dermatology | volume = 59 | issue = 4 | pages = 633–653 | date = October 2008 | pmid = 18656283 | doi = 10.1016/j.jaad.2008.06.004 }}

Patients with posttraumatic stress disorder (PTSD) have often continued to be symptomatic despite being treated with PTSD-specific drugs.{{cite journal | vauthors = Koola MM, Varghese SP, Fawcett JA | title = High-dose prazosin for the treatment of post-traumatic stress disorder | journal = Therapeutic Advances in Psychopharmacology | volume = 4 | issue = 1 | pages = 43–47 | date = February 2014 | pmid = 24490030 | pmc = 3896131 | doi = 10.1177/2045125313500982 }} 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.

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.{{cite book|title=Pharmacology Made Easy| vauthors = Manning L, Rayfield S |publisher=ICAN|location=Bossier City, LA|page=38}}

One of the most common side effects with alpha blockers is the first dose effect.{{cite journal | vauthors = Hodsman GP, Isles CG, Murray GD, Usherwood TP, Webb DJ, Robertson JI | title = Factors related to first dose hypotensive effect of captopril: prediction and treatment | journal = British Medical Journal | volume = 286 | issue = 6368 | pages = 832–834 | date = March 1983 | pmid = 6403103 | pmc = 1547159 | doi = 10.1136/bmj.286.6368.832 }} 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.{{Cite book| vauthors = Elliott HL |pages=1019–1025|language=en-us|doi=10.1016/b978-0-323-03961-1.50085-4|title = Comprehensive Hypertension|year = 2007|isbn = 9780323039611|chapter = Alpha Adrenoreceptor Antagonists}}

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.{{cite journal | vauthors = Lepor H, Lepor NE, Hill LA, Trohman RG | title = The QT Interval and Selection of Alpha-Blockers for Benign Prostatic Hyperplasia | journal = Reviews in Urology | volume = 10 | issue = 2 | pages = 85–91 | date = Spring 2008 | pmid = 18660858 | pmc = 2483321 }} Alpha blockers that may have these side effects include yohimbine, phenoxybenzamine, and phentolamine.

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.{{cite journal | vauthors = Lepor H | title = Alpha blockers for the treatment of benign prostatic hyperplasia | journal = Reviews in Urology | volume = 9 | issue = 4 | pages = 181–190 | date = Fall 2007 | pmid = 18231614 | pmc = 2213889 }} However, these alpha blockers can produce the exact opposite side effect, in which edema, or abnormal fluid retention, occurs.{{Cite journal|date=July 2011|title=Alpha-blockers: their properties and use in hypertension|journal=Prescriber|volume=22|issue=13–14|pages=38–39|doi=10.1002/psb.779|doi-access=free}}

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.{{cite journal | vauthors = Debruyne FM | title = Alpha blockers: are all created equal? | journal = Urology | volume = 56 | issue = 5 Suppl 1 | pages = 20–22 | date = November 2000 | pmid = 11074198 | doi = 10.1016/s0090-4295(00)00744-5 }} 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.

Finally, there are other general side effects that can be caused by most alpha blockers (however, more frequently in alpha-1 blockers). Such side effects include dizziness, drowsiness, weakness, fatigue, psychiatric depression, and dry mouth.

Priapism, an unwanted, painful long term erection not brought on by sexual arousal and lasting several hours has been associated with alpha blocker use. While this is extremely rare, particularly with tamsulosin, it can cause permanent impotence if not treated in a hospital setting. Male patients should be made aware of this as it can result from a single dose or develop over time.

There is only one compelling indication for alpha blockers, which is for benign prostatic hyperplasia. Patients who need alpha blockers for BPH, but have a history of hypotension or postural heart failure, should use these drugs with caution, as it may result in an even greater decrease in blood pressure or make heart failure even worse. The most compelling contraindication is urinary incontinence and overall fluid retention.{{Cite web|url=http://www.bhsoc.org/pdfs/therapeutics/Alpha-Adrenoceptor%20Antagonists%20(Alpha-Blockers).pdf|title=Alpha-Adrenoceptor Antagonists (Alpha-Blockers)|website=British Hypertension Society|archive-url=https://web.archive.org/web/20170829020552/http://www.bhsoc.org/pdfs/therapeutics/Alpha-Adrenoceptor%20Antagonists%20(Alpha-Blockers).pdf|archive-date=2017-08-29|url-status=dead}}{{Cite web|url=http://cvpharmacology.com/vasodilator/alpha|title=CV Pharmacology {{!}} Alpha-Adrenoceptor Antagonists (Alpha-Blockers)|website=cvpharmacology.com|access-date=2017-11-15}} To combat such fluid retention, patients can take a diuretic in combination with the alpha-blocker.

In the absence of compelling indications or contraindications, patients should take alpha blockers as a step 4 therapy to reduce blood pressure, but only if the use of ACE inhibitors, angiotensin-II receptor blockers, calcium channel blockers, or thazide diuretics (in full dose or in combinations) have not been efficacious.

As with any drug, there are drug interactions that can occur with alpha blockers. For instance, alpha blockers that are used for the reduction of blood pressure, such as phenoxybenzamine or phentolamine can have synergy with other drugs that affect smooth muscle, blood vessels, or drugs used for erectile dysfunction (i.e. sildenafil, tamsulosin, etc.). This stimulates exaggerated hypotension.

Alternative alpha blockers, such as prazosin, tamsulosin, doxazosin, or terazosin can have adverse interactions with beta blockers, erectile dysfunction drugs, anxiolytics, and antihistamines. Again, these interactions can cause dangerous hypotension. Furthermore, in rare cases, drug interactions can cause irregular, rapid heartbeats or an increase blood pressure.

Yohimbine can interact with stimulants, hypertension drugs, naloxone, and clonidine. Interactions with such drugs can cause either an unintended increase in blood pressure or potentiate an increase in blood pressure.

Finally, in drugs with both alpha and beta blocking properties, such as carvedilol and labetalol, interactions with other alpha or beta blockers can exaggerate a decrease in blood pressure. Conversely, there are also drug interactions with carvedilol or labetalol in which blood pressure is increased unintentionally (such as with cough and cold medications). Finally, there may also be some alpha/beta blocker drug interactions that can worsen previous heart failure.

Alpha blockers work by blocking the effect of nerves in the sympathetic nervous system. This is done by binding to the alpha receptors in smooth muscle or blood vessels.{{Cite web|url=https://patient.info/health/alpha-blockers|title=Alpha-blockers| vauthors = Knott L |date=2015-06-27|website=Patient}} α-blockers can bind both reversibly and irreversibly.

There are several α receptors throughout the body where these drugs can bind. Specifically, α₁ receptors can be found in most vascular smooth muscle, the pupillary dilator muscle, the heart, the prostate, and pilomotor smooth muscle. On the other hand, α₂ receptors can be found in platelets, cholinergic nerve terminals, some vascular smooth muscle, postsynaptic CNS neurons, and fat cells.

The structure of α receptors is a classic G protein–coupled receptors (GPCRs) consisting of 7 transmembrane domains, which form three intracellular loops and three extracellular loops. These receptors couple to heterotrimeric G proteins composed of α, β, and γ subunits. Although both of the α receptors are GPCRs, there are large differences in their mechanism of action. Specifically, α₁ receptors are characterized as G_q GPCRs, signaling through Phospholipase C to increase IP₃ and DAG, thus increasing the release of calcium. Meanwhile, α₂ receptors are labeled as G_i GPCRs, which signal through adenylyl cyclase to decrease cAMP.{{cite journal | vauthors = Pierce KL, Premont RT, Lefkowitz RJ | title = Seven-transmembrane receptors | journal = Nature Reviews. Molecular Cell Biology | volume = 3 | issue = 9 | pages = 639–650 | date = September 2002 | pmid = 12209124 | doi = 10.1038/nrm908 | s2cid = 23659116 }}

Because the α₁ and α₂ receptors have different mechanisms of action, their antagonists also have different effects.{{cite journal | vauthors = Bylund DB | title = Subtypes of alpha 1- and alpha 2-adrenergic receptors | journal = FASEB Journal | volume = 6 | issue = 3 | pages = 832–839 | date = February 1992 | pmid = 1346768 | doi = 10.1096/fasebj.6.3.1346768 | s2cid = 83827013 | doi-access = free }} α₁ blockers can inhibit the release of IP₃ and DAG to decrease calcium release, thus, decreasing overall signaling. On the other hand, α₂ blockers prevent the reduction of cAMP, thus leading to an increase in overall signaling.

• Beta blocker
• Adrenergic receptor
• Adrenergic antagonist
• Sympathetic nervous system

{{reflist}}

{{Receptor agonists and antagonists}}

{{Alpha blockers}}

{{Drugs used in benign prostatic hypertrophy}}