Alpha-1 blocker

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Alpha-1 blockers (also called alpha-adrenergic blocking agents or alpha-1 antagonists) constitute a variety of drugs that block the effect of catecholamines on alpha-1-adrenergic receptors. They are mainly used to treat benign prostatic hyperplasia (BPH), hypertension and post-traumatic stress disorder. [1] Alpha-1-adrenergic receptors are present in vascular smooth muscle, the central nervous system, and other tissues. When alpha blockers bind to these receptors in vascular smooth muscle, they cause vasodilation.

Contents

Over the last 40 years, a variety of drugs have been developed from non-selective alpha-1 receptor antagonists to selective alpha-1 antagonists and alpha-1 receptor inverse agonists. [2] [3] The first drug that was used was a non-selective alpha blocker, named phenoxybenzamine and was used to treat BPH. [2] Currently, several relatively selective alpha-1 antagonists are available. As of 2018, prazosin is the only alpha-1 blocker known to act as an inverse agonist at all alpha-1 adrenergic receptor subtypes; [3] [4] whereas tamsulosin is a selective antagonist for all alpha-1 subtypes. [3] [5] Drugs that act as selective antagonists at specific alpha-1 adrenergic receptor subtypes have also been developed.

Medical uses

Benign prostatic hyperplasia

Benign prostatic hyperplasia (BPH) is an enlarged prostate gland. Alpha-1 blockers are the most commonly used medicine to treat BPH. [6] Alpha-1 blockers are first line treatment for the symptoms of BPH in men. [1] [2] [7] [8] Doxazosin, terazosin, alfuzosin, and tamsulosin have all been well established in treatment to reduce lower urine tract symptoms (LUTS) caused by benign prostatic hyperplasia. They are all believed to be similarly effective for this purpose. First generation alpha-1 blockers, like prazosin are not recommended to treat lower urinary tract symptoms because of their blood-pressure-lowering effect. Later generation drugs in this class are used for this purpose. [1] [9] In some cases alpha-1 blockers have been used in combined therapy with 5α-reductase inhibitors. Dutasteride and tamsulosin are on the market as combined therapy and results have shown that they improve symptoms significantly versus monotherapy. [9] [10]

Hypertension

Alpha-1 blockers are used as second line treatment for high blood pressure. They are not thought to be good as first line treatment because there are other more selective agents, although they can be good for treating men with hypertension and BPH. [11] Doxazosin has been shown to improve symptoms of BPH in the elderly and reduce blood pressure at the same time. BPH and hypertension are both very common in men over 60 years old. [12]

In patients with neurogenic hypertension who fail in achieving blood pressure control with angiotensin converting enzyme inhibitors (ACEi), Angiotensin receptor blockers (ARB) and calcium channel blockers (CCB), alpha- and beta- adrenergic receptor blockers constitute the main treatment options. This is supported by studies that show surprisingly though consistently that neither alpha- nor beta-blocker mono- therapy reduces sympathetically mediated blood pressure reactivity to acute experimental stressors. Studies of combined oral alpha- and beta-blockade using an alpha-blocker (e.g., doxazosin or terazosin) in combination with a nonlipophilic beta-blocker with more reliable bioavailability (e.g., betaxolol, bisoprolol, atenolol and others) have shown a larger antihypertensive effect. [13] [14] [15] This approach also enables separate titration of alpha- and beta-blocking effects. In these studies, doxazosin was prescribed at the low dose of 1–2 mg. [16] [17] [18]

Post-traumatic stress disorder (PTSD) and nightmares

Post-traumatic stress disorder (PTSD) is a disabling mental condition that can develop following a traumatic experience; for example, it is especially common in military veterans and sexual assault survivors. Prazosin is commonly used as an antihypertensive, but because alpha-1-adrenergic activity has been connected to fear and startle responses, it sees use as a PTSD treatment. [19] [20] Prazosin has been established as an effective and safe centrally active alpha-1-adrenergic receptor antagonist. It can be used to treat trauma-related nightmares, sleep disturbance, and other chronic PTSD symptoms. [21]

Adverse effects

As Alpha-1a blockers affect the symptoms of BPH more specifically than non-selective Alpha-1 blockers, the adverse effects seem to be more linked to the reproductive system while minimizing the effect on the blood pressure system. [22] [23] Hypotension and its complications (e.g., weakness, dizziness) are a constant risk, however, even though selective alpha-1a blockers are being used. It is therefore important when starting treatment with an alpha-1 blocker to monitor blood pressure to minimize the risk for adverse effects connected to low blood pressure.

Selectivity Adverse effects Main hepatic pathway
Prazosin Alpha-1Dizziness, headache, drowsiness, asthenia, weakness, palpitations, nausea, vomiting, diarrhea, constipation, edema, hypotension, dyspnea, vertigo, nervousness, rash, blurred vision CYP1A1 [24]
Terazosin Alpha-1Nervousness, vertigo, palpitations, tachycardia, chest pain, hypotension, dyspnoea, nausea, constipation, diarrhoea, vomiting, pruritus, rash, back pain, impotence, dizziness, asthenia, oedema, headache, pain (extreme) CYP3A1 [25]
Doxazosin Alpha-1Hypotension (dizziness and weakness), priapism (prolonged erection), floppy iris syndrome during cataract surgery, vertigo, palpitation/tachycardia, bronchitis, cough, dyspnea, pruritus, back pain, cystitis, asthenia, peripheral oedema, retrograde ejaculationCYP3A4 [26]
Silodosin Alpha-1aProblem with ejaculation/orgasm, hypotension, dizziness, nasal congestion, diarrhoeaCYP3A4 [27]
Alfuzosin Alpha-1aDizziness (due to hypotension), upper respiratory tract infection, headache, fatigue, impotence, pain in whole body, bronchitis, gastro-intestinal pain, swelling, rash, difficulty swallowing or breathing, chest pain, fainting, hoarsingCYP3A4 [28]
Tamsulosin Alpha-1aHypotension, problem with ejaculation/orgasm, disorientation, headache, floppy iris syndrome during cataract surgeryCYP3A4 & CYP2D6 [29]

By reducing alpha-1-adrenergic activity of the blood vessels, these drugs may cause hypotension (low blood pressure) and interrupt the baroreflex response. In doing so, they may cause dizziness, lightheadedness, or fainting when rising from a lying or sitting posture (known as orthostatic hypotension or postural hypotension). For this reason, it is generally recommended that alpha blockers should be taken at bedtime. The risk of first dose phenomenon may be reduced or eliminated by gradual-dose titration, since the adverse effects of Prazosin are dose-related. [7] This is also the case for Tamsulosin and it may be assumed that the others alpha-1 blockers work in a similar manner, since Tamsulosin is an alpha-1-a blocker and Prazosin is an alpha-1 blocker. [30] The risk for floppy iris syndrome during cataract surgery is elevated when the patient is using an alpha-1 blocker. This is especially the case for Tamsulosin and other alpha-1-a blockers, since alpha-1-a receptors are present also in the iris dilator muscle, which allows unopposed action of the parasympathetically innervated iris constrictor muscle and loss of iris tone. [31] This however can be treated if the eye surgeon is experienced and has knowledge of the use of alpha-1 blocker.

Interactions and contraindication

Contraindication : Allergies or hypersensitivity to alpha-1 blockers or any of the active ingredient, that includes angiodema induced by the drug. Patients with a history of orthostatic hypotension or severe hepatic impairment. [32] [33]

Interactions : No interactions were recorded when administered with atenolol (beta blocker), enalapril (ACE inhibitor) and theophylline. [32] Furosemide has drop effect on plasma level for tamsulosin, and a rise in plasma level with cimetidine. No dose adjustment needs to be done when the levels are in normal range. Drugs that inhibit CYP3A4 (for example, itraconazole, ketoconazole, and ritonavir) can increase drug exposure for tamsulosin, alfuzosin, doxazosin, and silodosin. Grapefruit is also a powerful inhibitor of the CYP3A4 enzyme, so concurrent use is not recommended as it may increase the plasma levels of the Alpha-1 blockers which are metabolised by the CYP3A4 enzyme. [34] Some drugs; such as Fluoxetine, Paroxetine and Ritonavir are strong inhibitors of the CYP2D6 enzyme and therefore it is not recommended to use at the same time as tamsulosin, as it may increase plasma levels of tamsulosin and increase the risk of adverse effects. [35]

Warfarin and diclofenac can increase the elimination rate for tamsulosin, but has not shown an effect on alfuzosin hydrochloride. Co-administration of alpha-1 inhibitor can cause hypotension. [32] [33]

Since alpha-1 blockers may cause orthostatic hypotension, co-administration with antihypertensives and vasodilators must be evaluated with regards to risk-benefit as the risk for low blood pressure is greatly increased.

By reducing α1-adrenergic activity of the blood vessels, these drugs may cause hypotension (low blood pressure) and interrupt the baroreflex response. In doing so, they may cause dizziness, lightheadedness, or fainting when rising from a lying or sitting posture (known as orthostatic hypotension or postural hypotension). For this reason, it is generally recommended that alpha blockers should be taken at bedtime. Additionally, the risk of first dose phenomenon may be reduced by starting at a low dose and titrating upwards as needed.

Because these medications may cause orthostatic hypotension, as well as low blood pressure in general, these agents may interact with other medications that increase risk for low blood pressure, such as other antihypertensives and vasodilators.

As discussed above, tamsulosin may have less risk for low blood pressure and orthostatic hypotension due to its selectivity for α1a-adrenergic receptors. On the other hand, the drug (a) elevates risk for floppy iris syndrome, and (b) might show adverse drug reactions (ADRs) characteristic of the sulfa related drugs.

List of alpha-1 blockers

Alpha-1 inhibitorStructureUseBrand nameSelectivity
PrazosinHypertension, PTSD and nightmaresMinipress, Vasoflex, Lentopres and Hypovase.Alpha-1
TerazosinHypertension and BPHHytrin, Zaysel and TerazosinAlpha-1
DoxazosinHypertension and BPHCardura and CarduranAlpha-1
SilodosinBPHRapaflo, Silodyx, Rapilif, Urief, Trupas, UrorecAlpha-1a
AlfuzosinBPHUroxatral, Xat, Xatral, Prostetrol and Alfural.Alpha-1a
TamsulosinBPHAlna, Flomax, OmnicAlpha-1a

Silodosin shows high affinity and selectivity for alpha-1a adrenergic receptors found in the prostate which ensures that it works quickly and effectively to relieve the symptoms of BPH. Silodosin's low affinity for alpha-1b receptors in the blood vessels is thought to be reflected in its low incidence of orthostatic and vasodilatory side effects. [36]

The beta blocker Carvedilol is also an alpha-1 blocker. [37]

Pharmacokinetics

Absorption: Bioavailability of tamsulosin and terazosin is around 90% during oral administration in fasting state. Food can have effect on absorption for tamsulosin if it has been ingested shortly before, Tmax for fasting state is 2,9–5,6 hours compared to 5,2–7 hours in fed state. Food has no effect on absorption of terazosin but can delay plasma level concentration for 1 hour, peak plasma level are around 1–2 hours. [38] [32] [39] Alfuzosin bioavailability under fed state is around 49%. Tmax is 8 hours in fed state. [40] [33] Tamsulosin Cmax range was 13.9–18,6 ng/mL fastest and in fed state 7,2–15,6 ng/mL, Cmax for alfuzion is 13,6 mg/mL. [41] [32]

Distribution: Tamsulosin is 99% bound to plasma and distribution volume is low 0.2L/kg. [32] Alfuzosin is 90% bound to plasma and distribution volume is 2.5L/kg. [40] [33] Terazosin is 90–94% bound to plasma. [39]

Elimination: Elimination half-life for alfuzosin is around 8 hours, alfuzosin is metabolised mainly via liver. 75–91% is excreted in feces and 35% in unchanged form. Distribution volume and excretion increases with renal impairment due to less protein binding, but the half-life elimination rate is unchanged. therefore no dose adjustment is needed for low to moderate renal impairment. Delay in elimination half-life, peak concentration in plasma is double and bioavailability is changed in hepatic impairment patients. Alfuzosin should not be used for patients with renal impairment. [40] [33] Tamsulosin is excreted via urine and 9% of that is unchanged on its active form, elimination half-life for tamsulosin is between 9–13 hours for healthy volunteers. The elimination half-life for target patients is around 14–15 hours. No dose adjustment is needed for patients with renal impairment and moderate hepatic impairment. [38] [32] 10–20% of terazosin is excreted unchanged in urine and feces during oral administration. 40% is eliminated in urine and 60% in feces. Eliminations half-life for terazosin is between 8–13 hours. No dose adjustment is needed for patients with renal impairment. Terazosin is metabolised by the liver and is excreted by the biliary tract, so patients with moderate hepatic impairment should receive titrated doses of terazosin witch caution. Patients with severe hepatic impairment should not take terazosin due to lack of clinical data. [39] [42]

Mechanism of action

Mechanism of action.jpg

Alpha-1 blockers inhibit the activation of post-synaptic alpha-1 receptors by norepinephrine thus opposing blood vessel contraction. Alpha-1 blockers have no effect on renin release or cardio output. [43]

Benign prostatic hyperplasia

Alpha-1 blocker, blocks alpha receptors and it relaxes the smooth muscles in the bladder. It helps the urine to flow smoothly and it can lessen the pain caused by the bladder pressing on the prostate. [44] [45] Selective alpha-1 blockers are better tolerated than non-selective alpha blockers in the body and therefore works better on BPH. [2] Terazosin, tamsulosin and doxazosin are prime drug for BPH because they have a long half-life and modified release formulation. Tamsulosin is primarily used because it doesn't affect the blood pressure and the side effects of vasodilation is minimum. [44] [45] [2]

Hypertension

Alpha-1 blocker lowers the blood pressure by blocking alpha-1 receptors so norepinephrine cannot bind the receptor, causing the blood vessels to dilate. Without the resistance in the blood vessels the blood runs more freely. [46] [47] Alpha-1 blockers have a good effect on lipoproteins in plasma, insulin resistance and it causes the glucose levels in blood to lower. [46] [47] [48]

Structure activity relationship (SAR)

By changing the furan ring in prazosin to tetrahydrofuran ring (as in alfuzosin) the half-life is greatly increased, allowing once-a-day dosing. Silodosin is the most selective for alpha-1a receptors. [49] The affinity and selectivity for alpha-1 receptors seems to be determined by structure between the quinazoline and the furan ring. Piperazine is present in prazosin, terazosin and doxazosin which seems to contribute to the non-selective inhibition of alpha-1 receptors. [50]

Comparison between prazosin, terazosin, and alfuzosin. The conversion of the furan ring to a tetrahydrofuran ring (colored purple) contributed to an increase in half-life of terazosin. The conversion of piperazine to aminopropyl (colored red) increases the selectivity for Alpha-1a receptors. SAR alpha 1 blocker.png
Comparison between prazosin, terazosin, and alfuzosin. The conversion of the furan ring to a tetrahydrofuran ring (colored purple) contributed to an increase in half-life of terazosin. The conversion of piperazine to aminopropyl (colored red) increases the selectivity for Alpha-1a receptors.

Doxazosin 2,4-diamino-6,7-dimethoxyquinazoline variations for in vitro and in vivo performance. A key factor in these structures were the derivations from 2,4-diamino-6,7-dimethoxyquinazoline nucleus that was replaced for norepinephrine. And N-1 which protonated quinazoline was also a key factor. [51]

Variation of structure 2,4-diamino-6,7-dimethoxyquinazoline., Where X = CH, N Alpha-1-blocker-SAR.jpg
Variation of structure 2,4-diamino-6,7-dimethoxyquinazoline., Where X = CH, N

Tamsulosin is most potent alpha 1 blocker and has the most selectivity for alpha 1a receptors. It has no beta-blocking activity. [52]

History

The first effective treatment for benign prostatic hyperplasia (BPH) was a non-selective alpha blocker phenoxybenzamine which was irreversible. Dibenzyline was the first brand name marketed. Today phenoxybenzamine is not the first choice due to many side effects like lowering blood pressure. [2]

First selective alpha-1 blocker that was approved to treat hypertension was prazosin. Prazosin was synthesized in 1974 when Constantin and Hess were trying to discover a vasodilator which had a minimal effect on cardiac activity. [7] Prazosin was a much better tolerated drug than phenoxybenzamine but the problem still remained that it lowered the blood pressure more than desired for a BPH treatment. [2] [8]

Terazosin was the first long-lasting alpha 1 blocker approved by FDA to treat BPH. Doxazosin and Tamsulosin were approved after. The first-line treatment choice today to treat BPH is tamsulosin. It is not better tolerated, nor does it have greater efficacy than the previous drugs, however, it requires minimal dose titration in comparison. Alfuzosin SR (sustained release) was the fourth alpha 1 selective blocker to be approved by FDA and requires no dose titration. [2] [47]

Related Research Articles

<span class="mw-page-title-main">Benign prostatic hyperplasia</span> Noncancerous increase in size of the prostate gland

Benign prostatic hyperplasia (BPH), also called prostate enlargement, is a noncancerous increase in size of the prostate gland. Symptoms may include frequent urination, trouble starting to urinate, weak stream, inability to urinate, or loss of bladder control. Complications can include urinary tract infections, bladder stones, and chronic kidney problems.

<span class="mw-page-title-main">Beta blocker</span> Medications for abnormal heart rhythms

Beta blockers, also spelled β-blockers, are a class of medications that are predominantly used to manage abnormal heart rhythms (arrhythmia), and to protect the heart from a second heart attack after a first heart attack. They are also widely used to treat high blood pressure, although they are no longer the first choice for initial treatment of most patients.

Antihypertensives are a class of drugs that are used to treat hypertension. Antihypertensive therapy seeks to prevent the complications of high blood pressure, such as stroke, heart failure, kidney failure and myocardial infarction. Evidence suggests that reduction of the blood pressure by 5 mmHg can decrease the risk of stroke by 34% and of ischaemic heart disease by 21%, and can reduce the likelihood of dementia, heart failure, and mortality from cardiovascular disease. There are many classes of antihypertensives, which lower blood pressure by different means. Among the most important and most widely used medications are thiazide diuretics, calcium channel blockers, ACE inhibitors, angiotensin II receptor antagonists (ARBs), and beta blockers.

<span class="mw-page-title-main">Atenolol</span> Beta blocker medication

Atenolol is a beta blocker medication primarily used to treat high blood pressure and heart-associated chest pain. Although used to treat high blood pressure, it does not seem to improve mortality in those with the condition. Other uses include the prevention of migraines and treatment of certain irregular heart beats. It is taken orally or by intravenous injection. It can also be used with other blood pressure medications.

<span class="mw-page-title-main">Doxazosin</span> Group of stereoisomers

Doxazosin, sold under the brand name Cardura among others, is a medication used to treat symptoms of benign prostatic hyperplasia, hypertension, and post-traumatic stress disorder (PTSD). For high blood pressure, it is a less preferred option. It is taken by mouth.

<span class="mw-page-title-main">Prazosin</span> Antihypertensive drug

Prazosin, sold under the brand name Minipress among others, is a medication used to treat high blood pressure, symptoms of an enlarged prostate, and nightmares related to post-traumatic stress disorder (PTSD). It is an α1 blocker. It is a less preferred treatment of high blood pressure. Other uses may include heart failure and Raynaud syndrome. It is taken by mouth.

<span class="mw-page-title-main">Alfuzosin</span> Chemical compound alfa1-blocker

Alfuzosin, sold under the brand name Uroxatral among others, is a medication of the α1 blocker class. It is used to treat benign prostatic hyperplasia (BPH).

<span class="mw-page-title-main">Phenoxybenzamine</span> Alpha blocker medication

Phenoxybenzamine is a non-selective, irreversible alpha blocker.

Nocturia is defined by the International Continence Society (ICS) as "the complaint that the individual has to wake at night one or more times for voiding ". The term is derived from Latin nox – "night", and Greek [τα] ούρα – "urine". Causes are varied and can be difficult to discern. Although not every patient needs treatment, most people seek treatment for severe nocturia, waking up to void more than 2 or 3 times per night.

<span class="mw-page-title-main">Tamsulosin</span> Medication

Tamsulosin, sold under the brand name Flomax among others, is a medication used to treat symptomatic benign prostatic hyperplasia (BPH) and chronic prostatitis and to help with the passage of kidney stones. The evidence for benefit with a kidney stone is better when the stone is larger. Tamsulosin is taken by mouth.

<span class="mw-page-title-main">Labetalol</span> Medication used to treat high blood pressure

Labetalol is a medication used to treat high blood pressure and in long term management of angina. This includes essential hypertension, hypertensive emergencies, and hypertension of pregnancy. In essential hypertension it is generally less preferred than a number of other blood pressure medications. It can be given by mouth or by injection into a vein.

<span class="mw-page-title-main">Fenoldopam</span> Antihypertensive agent, also used in hypertensive crisis

Fenoldopam mesylate (Corlopam) is a drug and synthetic benzazepine derivative which acts as a selective D1 receptor partial agonist. Fenoldopam is used as an antihypertensive agent. It was approved by the Food and Drug Administration (FDA) in September 1997.

Intraoperative floppy iris syndrome (IFIS) is a complication that may occur during cataract extraction in certain patients. This syndrome is characterized by a flaccid iris which billows in response to ordinary intraocular fluid currents, a propensity for this floppy iris to prolapse towards the area of cataract extraction during surgery, and progressive intraoperative pupil constriction despite standard procedures to prevent this.

<span class="mw-page-title-main">Silodosin</span> Chemical compound

Silodosin, sold under the brand name Urief among others, is a medication for the symptomatic treatment of benign prostatic hyperplasia. It acts as an alpha-1 adrenergic receptor antagonist.

<span class="mw-page-title-main">Adrenergic antagonist</span> Type of drug

An adrenergic antagonist is a drug that inhibits the function of adrenergic receptors. There are five adrenergic receptors, which are divided into two groups. The first group of receptors are the beta (β) adrenergic receptors. There are β1, β2, and β3 receptors. The second group contains the alpha (α) adrenoreceptors. There are only α1 and α2 receptors. Adrenergic receptors are located near the heart, kidneys, lungs, and gastrointestinal tract. There are also α-adreno receptors that are located on vascular smooth muscle.

A sympatholytic (sympathoplegic) drug is a medication that opposes the downstream effects of postganglionic nerve firing in effector organs innervated by the sympathetic nervous system (SNS). They are indicated for various functions; for example, they may be used as antihypertensives. They are also used to treat anxiety, such as generalized anxiety disorder, panic disorder and PTSD. In some cases, such as with guanfacine, they have also shown to be beneficial in the treatment of ADHD.

The first-dose phenomenon is a sudden and severe fall in blood pressure that can occur when changing from a lying to a standing position the first time that an alpha blocker drug is used or when resuming the drug after many months off. This postural hypotension usually happens shortly after the first dose is absorbed into the blood and can result in syncope (fainting). Syncope occurs in approximately 1% of patients given an initial dose of 2 mg prazosin or greater. This adverse effect is self-limiting and in most cases does not recur after the initial period of therapy or during subsequent dose titration.

<span class="mw-page-title-main">Alpha blocker</span> Class of pharmacological agents

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).

Adrenergic blocking agents are a class of drugs that exhibit its pharmacological action through inhibiting the action of the sympathetic nervous system in the body. The sympathetic nervous system(SNS) is an autonomic nervous system that we cannot control by will. It triggers a series of responses after the body releases chemicals named noradrenaline and epinephrine. These chemicals will act on adrenergic receptors, with subtypes Alpha-1, Alpha-2, Beta-1, Beta-2, Beta-3, which ultimately allow the body to trigger a "fight-or-flight" response to handle external stress. These responses include vessel constriction in general vessels whereas there is vasodilation in vessels that supply skeletal muscles or in coronary vessels. Additionally, the heart rate and contractile force increase when SNS is activated, which may be harmful to cardiac function as it increases metabolic demand.

Adrenergic neurone blockers, commonly known as adrenergic antagonists, are a group of drugs that inhibit the sympathetic nervous system by blocking the activity of adrenergic neurones. They prevent the action or release of catecholamines such as norepinephrine and epinephrine. They are located throughout the body, causing various physiological reactions including bronchodilation, accelerated heartbeat, and vasoconstriction. They work by inhibiting the synthesis, release, or reuptake of the neurotransmitters or by antagonising the receptors on postsynaptic neurones. Their medical uses, mechanisms of action, adverse effects, and contraindications depend on the specific types of adrenergic blockers used, including alpha 1, alpha 2, beta 1, and beta 2.

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