| Alpha blockers α-blockers | |
|---|---|
| Drug class | |
| Class identifiers | |
| Use | • Hypertension • Vasoconstriction • BPH • Raynaud's Disease • Pheochromocytoma • CHF • Erectile Dysfunction |
| Mechanism of action | • Receptor antagonist • Inverse agonist • Neutral antagonist |
| Biological target | α-adrenoceptors |
| In Wikidata | |
Specific locations and functions of the α receptors. Image from Basic and Clinical Pharmacology by Bertram Katzung, et al.
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.
Although alpha blockers can only treat a small range of diseases,
some of them have clinical uses, such as having the ability to treat hypertension, Raynaud's disease, and erectile dysfunction.
Generally speaking, all of 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
Schematic of G Protein Coupled Receptor Signaling, representing Gi GPCR signaling, Gs GPCR signaling, and Gq GPCR signaling.
- 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:
Selective α1-adrenergic receptor antagonists include:
Selective α2-adrenergic receptor antagonists include:
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.
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
An
image of a patient with pheochromocytoma. In patients with this
disease, a catecholamine secreting tumor is formed, and causes excess
CNS stimulation, such as excess sweating and tachycardia. Nonselective
alpha blockers, such as phenoxybenzamine or phentolamine, can be used to
mitigate this disease.
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 alpha-1 and alpha-2 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.
Benign
prostate hyperplasia, a disease in which urinary retention becomes an
issue. Alpha-1 blockers can be used, but it can result in side effects
such as increased urination and retrograde ejaculation.
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
Patients
with Raynaud's syndrome experience cut off blood flow from the fingers
causing a large decrease in oxygen, which leads to the discoloration of
the fingers. Using alpha blockers aids in restoring blood flow and
treating the syndrome by stimulating the dilation of blood vessels.
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.
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.
Other side effects
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.
Contraindications
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. 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.
Drug interactions
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.
Mechanism of action
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. 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 Gq GPCRs, signaling through Phospholipase C to increase IP3 and DAG, thus increasing the release of calcium. Meanwhile, α2 receptors are labeled as Gi GPCRs, which signal through adenylyl cyclase to decrease cAMP.
Because the α1 and α2 receptors have different mechanisms of action, their antagonists also have different effects. 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.
