Adrenergic blocking agent

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

Adrenergic blocking agents treat certain diseases through blocking the adrenergic receptor,^[2][3] preventing it from being activated by noradrenaline and adrenaline. As a result, it stops the body from producing the fight-or-flight response.

There are drugs that are approved by the US Food and Drug Administration (FDA), whereas there are some off-label uses as well.

The alpha blockers mostly act in our smooth muscles, especially the ones that control the size of vessels.^[3] Thus, alpha1 blockers can dilate blood vessels and decrease the blood pressure.^[3] Depending on its site of action, it can be used to treat different diseases.^[3] They can be used to treat signs and symptoms of benign prostatic hyperplasia, hypertension (but not as first line agent), pheochromocytoma, extravasation management and reversal of local anesthesia.^[3]

There are some off- label use as well, such as chronic prostatitis and lower urinary tract symptoms in males, ureteral calculus expulsion, ureteral stent-related urinary symptoms.^[3] It can be used in post-traumatic stress disorder, Raynaud phenomenon, hypertensive crisis, extravasation of sympathomimetic vasopressors, problem with urine related to neurogenic bladder, functional outlet obstruction and partial prostate obstruction.^[3]

Alpha-2 blockers reduce the transmission of neurotransmitters circulating around the body, which contributes to contraction of smooth muscle.^[4] Instead of treating diseases, they are used as antidotes for reversing overdose of alpha-2 agonist, reducing the toxic effect of the agonist.^[4] Only limited indications are present for this drug. More research is in progress to investigate the possible use of alpha2 blockers.^[4]

Since beta-1 receptors are mainly located in the heart, most beta-1 blockers take abnormalities associated with the heart as the target.^[5] It treats medical conditions like hypertension, arrhythmias, heart failure, chest pain, and myocardial infarction. It treats other symptoms unrelated to heart like migraines and anxiety.^[5]

Beta-2 blockers promote vasodilation in some tissues as mentioned above (arterioles in skeletal muscles or ciliary muscle in the eye etc.). Currently, there is no beta-2 blocker with FDA approval.^[6] Butoxamine, an example of beta-2 blocker, has no clinical use but is used in research.^[6]

Due to the relatively limited study on the beta-3 receptor, there is not much development of beta-3 blockers. Therefore, beta-3 blockers has no clinical use.^[7]

Some drugs, being non-selective, can exert actions on 2 or more different receptors. Examples include non-selective beta blocker, which block both beta-1 receptor and beta-2 receptor as well.^[2]

The adverse effects of non-selective alpha blockers are caused by the autonomic response to the systemic changes induced by the adrenergic blocking agents.^[3] The common adverse effects of alpha blockers are due to the blockade of alpha-1 adrenergic receptors in tissue that requires high level of alpha adrenergic sympathetic input such as arterial resistance, vascular capacitance and the outflow tract of the urinary bladder.^[8] The undesirable symptoms are mentioned in the following 'selective alpha-1 blocker' part.

With the vasodilation and smooth muscle relaxation caused by alpha-1 blockers,^[9] around 10 to 20% of patients present undesirable effects of asthenia(weakness), dizziness, faintness and syncope.^[8] Other adverse outcomes that are even more uncommon include headache, drowsiness, palpitations, urinary incontinence and priapism.^[8] Mild body weight gain of 1–2 kg, which may be associated with secondary hyperaldosteronism, is also observed in some patients.^[8]

The alpha-1 blockers are associated with the first-dose effect, which refers to the tachycardia response and orthostatic hypotension that caused by the systemic vasodilation at the initial administration of alpha-1 blockers.^[3] After the first administration, patients may experience a short period of orthostatic hypotension with a sensation of intense faintness, which is aggravated by upright posture, intravascular volume depletion or concurrent administration of other antihypertensive medications.^[8]

Apart from increasing the noradrenaline release, the selective alpha-2 blockers have the potential to bind with other receptors such as the 5-HT receptor.^[10] However, the serotonin receptor antagonism has side effects such as weight gain and impaired movement.^[11] Hence, alpha-2 blockers are not used clinically due to its extensive binding.

Similar to the alpha-1 blocker, the alpha-2 family will also present the first-dose effect, but it is generally less pronounced compared with the alpha-1 blockers.^[3]

The Central Nervous System (CNS) side effects of beta blockers including sleep impairment, dreaming, nightmares and hallucinations are generally small. Also, the effects on short-term memory are minimal.^[12]

The cardio-selective beta-1 blockers could cause adverse effects including bradycardia, reduced exercise ability, hypotension, atrioventricular nodal blockage and heart failure.^[5] Other possible adverse effects include nausea and vomiting, abdominal discomfort, dizziness, weakness, headache, fatigue, and dryness in mouth and eye.^[5] Sexual impairment, memory loss, and confusion are regarded as rare side effects.^[5] For diabetic patients, there is an extra risk of masking hypoglycemia-induced tachycardia, while a continuous hypoglycemia could cause acute brain damage.^[5]

The blockade of beta-2 receptors will result in vasoconstriction and smooth muscle constriction,^[6] and the effects are similar to the agonism of alpha-1 receptors. The side effects include hypertension, tachycardia, arrhythmia and subcutaneous ischemia at the site of injection.^[3] Other possible side effects include Raynaud phenomenon, hypoglycemia during exercise, muscle cramps, and increase of airway resistance.^[6]

Due to the relatively limited study on beta-3 receptor, there is not much development of beta-3 blocker. Therefore, there is limited information on the adverse effects caused by beta-3 blocker.

As alpha 1 blocker will dilate blood vessels, it lowers the blood pressure.^[3] Thus, it contraindicate to patients with a history of orthostatic hypotension and in current use of phosphodiesterase inhibitors.^[3] Moreover, alpha 1 blocker should not be given to patients with heart failure since it expands blood volume.^[13]

There are limited information about the contraindication of alpha-2 blocker, since it has limited clinical uses.

Traditionally, Beta-1 blocker has several contraindications, including, recent history of fluid retention without use of diuretics, and complete or second degree of heart block.^[5] Whilst some studies suggest that there are only minor differences in terms of adverse effect between asthma patients and non-asthma patients, beta-1 blockers are generally not prescribed to asthma patients or patients with chronic obstructive pulmonary disease, due to its potential blockage of beta 2 receptors.^[5] Additionally, beta1 blocker should not be given to patients with peripheral vascular diseases, diabetes mellitus, since blockage of beta-2 receptors may lead to vasoconstriction and delayed response to hypoglycemia respectively.^[5]

Beta 2 blocker should be avoided for patients with asthma, COPD as it causes bronchoconstriction.^[6] It may also increase the chance of hypoglycemic comas in diabetic patients.^[6]

Due to the relatively limited study on beta-3 receptor, there is not much development of beta-3 blocker. Therefore, beta-3 blocker has no clinical use. The contraindications of beta-3 blocker can not be observed.

Overdose of alpha-1 blocker will lead to an unopposed parasympathetic activity.^[3] Symptoms include bradycardia, hypotension, miosis and sedation.

There is a lack of information regarding toxicity caused by overdose of alpha-2 blocker, due to its limited clinical uses.

Toxicity of beta-1 blocker will contribute to symptoms including bradycardia, hypotension, due to its extensive blockage of beta-1 receptor.^[5] Moreover, overdose of beta-1 blocker may lead to the loss of their selectivity and bind to beta-2 receptor, causing bronchopulmonary symptoms.^[5] Overdose of lipophilic beta-1 blocker can disturb neurologic functioning, which eventually lead to altered mental states.^[5]

To mitigate the toxicity of Beta-1 blocker, glucagon, salts like calcium and sodium bicarbonate, magnesium sulfate are used to reverse beta-1-blocker effect and treating hypotension respectively.^[5]

Similar to alpha-2 blocker, there is a lack of information about beta-2 blocker's toxicity, due to its limited clinical uses.

Due to the relatively limited study on beta-3 receptor, there is not much development of beta-3 blocker. Therefore, there is not much information regarding the toxic effect of beta-3 blocker.

Alpha-1 blockers such as alfuzosin, doxazosin, tamsulosin, and silodosin involve CYP450 enzyme metabolism, particularly by CYP3A4.^[14] Alpha-1 blockers will conjugate in glucuronidation during metabolism. CYP3A4 inhibitors inhibit glucuronidation and hence reduce the glucuronide-conjugated metabolite.^[15] Hence, potent CYP3A4 inhibitors can potentially increase their exposure to those alpha blockers. However, there are no clinically significant evidence supporting the drug interaction between alpha-1 blocker and CYP3A4 inhibitors.^[16]

Since alpha-2 blocker has limited clinical uses, there is a lack of information on drug interaction regarding alpha-2 blocker.

Additional hypotensive effects may occur when patients are taking beta-1 blockers with other antihypertensive drugs such as nitrates, PDE inhibitors, ACE inhibitors and calcium channel blockers.^[17] The combination of beta blockers and antihypertensive drugs will work on different mechanism to lower blood pressure.^[17] For example, the co-administration of beta-1 blocker atenolol and ACE inhibitor lisinopril could produce a 50% larger reduction in blood pressure than using either drug alone.^[18]

Antihypertensive drugs and hypertensive drugs affect blood pressure in an opposite way.^[19] The most common hypertensive drugs in the UK are NSAIDs and steroids.^[19] NSAIDs inhibit the synthesis of prostaglandin, which increases the blood pressure and potentially reduce the efficacy of several antihypertensive drugs.^[20]

Since beta-2 blocker has limited clinical uses, there is a lack of information on drug interaction regarding beta-2 blocker.

Since beta-3 blockers are still under development, there is a lack of information on drug interactions.

Alpha 1 blocker exerts its action on alpha-1 receptor, dilating the smooth muscles.^[3] Alpha-1 receptor is a Gq type G-protein coupled receptor.^[3] When it is activated, it will lead to activation of phospholipase C, raising the intracellular level of IP3 and DAG.^[3] As a result, a higher intracellular concentration of Calcium is achieved, contributing to smooth muscle contraction and glycogenolysis.^[3] Alpha 1 blockers, in contrast, bind to and act as inhibitors of alpha-1 receptors, hence preventing the downstream action mentioned(increase of phospholipase C, IP3 and DAG hence increase of Ca Concentration).^[3] As a result, the contraction of smooth muscle is suppressed.

The alpha-2 blocker acts on alpha-2 receptors. The alpha-2 receptor is a G-protein coupled receptor as well, which exert its action by Gi function, leading to an inhibition of adenylyl cyclase and thus reducing synthesis of cAMP.^[3]  It lowers the amount of calcium inside the cell.^[3] Ultimately, release of noradrenaline and epinephrine will be inhibited and smooth muscles tend to dilate.^[3] Alpha-2 blocker stops the downstream signaling pathway (inhibit adenylyl cyclase, reduce cAMP and Ca), thus lead to release of the mentioned neurotransmitters(noradrenaline and epinephrine) and contraction of smooth muscle eventually.^[3]

Beta-1 blocker will stop the action of beta-1 receptor via occupying the beta-1 receptor without any activation.^[5] The beta-1 receptor is a G-protein-coupled receptor with Gs alpha subunit as its main communication method.^[5] By signaling Gs, adenylyl cyclase is recruited to activate a cAMP pathway, which potentiates the receptor.^[5] This kind of receptor is located at the heart, kidney and adipose tissue.^[5] Eventually, a higher cardiac output(or an increased amount of perfusion to organs) will be resulted.^[5] Moreover, more renin is released from the kidney to produce more angiotensin II, increasing the blood volume.^[5] Moreover, it encourages lipolysis in adipose tissue. Beta-1 blocker blocks the beta-1 receptor and stops the action mentioned above. (signaling Gs, thus activate cAMP pathway by recruiting adenylyl cyclase, leading to higher cardiac output, renin release and lipolysis)

Beta-2 blockers cease action of beta-2 receptor by blocking the receptor and preventing it from being activated.^[6] Similar to beta-1 receptor, the activated beta-2 receptor will lead to the detach of alpha subunit of Gs protein and attachment of adenylate cyclase.^[6] Adenosine triphosphate(ATP), is then catalyzed to form cAMP.^[6] cAMP will facilitate release of protein kinase A as well as reduction of intracellular calcium level, relaxing the smooth muscles.^[6] Beta-2 blockers stops the above-mentioned signaling pathway, (formation of cAMP, release of protein kinase A, reduction of intracellular calcium level) by blocking the receptor.

The alpha-1 receptor has an opposite action when it is compared with beta 2 receptor. However, the location of the two receptors differs in different tissues, which gives rise to different action of smooth muscle.^[21] For example, in the eye, under stimulation of sympathetic nervous system, radial muscles of the iris contract through activation of alpha-1 receptor to allow more light to enter, while the ciliary muscle in the eye relaxes through activation of beta-2 receptor to allow far vision.^[21] In the arterioles of skeletal muscle, there is only mild constriction under activation of SNS, due to the balance between alpha-1 and beta-2 receptors.^[21][1]

Beta-3 blocker will inactivate beta-3 receptor and stops the following action.^[7] Beta 3 receptor is a G-protein coupled receptor, similar to beta-1 and beta-2 receptors.^[7] The receptor is involved in G-as activation.^[7] The receptor will also stimulate adenylyl cyclase.^[7] Eventually, it will lead to effects like increase of tryptophan and 5-hydroxytryptamine level, increase of lipolysis in adipose tissue.^[7] Beta-3 blocker will antagonize the receptor, which will stop the signaling pathway(G-as activation, stimulation of adenylyl cyclase).^[7]

In 1978, a successful alpha blocker, phenoxybenzamine was confirmed to be clinically beneficial through a randomized, placebo-controlled study.^[22] It was the first alpha blocker which was used for treating Benign Prostatic Hyperplasia.^[22]

Another Alpha Blocker Prazosin, which was the first drug selective to alpha 1 receptor, was developed in 1987^[22] for the therapy of Benign Prostatic Hyperplasia. Other alpha blockers are then introduced for several diseases.^[22]

The first beta blocker, propranolol, was introduced in the early 1960s by the winner of The Nobel Prize in Physiology or Medicine 1988- Sir James W. Black.^[23] The drug was originally developed in order to induce a calm effect on the heart by blocking the beta receptor for adrenaline, treating a range of cardiovascular disorders.^[23]

Unlike other subtypes of receptor, beta 3 receptors were more recently discovered in 1989.^[7] Therefore, Beta 3 blockers are still under development.

The following examples are the common adrenergic blocking agents used clinically.

Drug	Chemical structure	Drug class	Clinical uses	Brand Name
Phenoxybenzamine		Non-selective alpha blocker	Paroxysmal hypertension, pheochromocytoma-induced sweating[24]	Dibenzyline[25]
Phentolamine		Non-selective alpha blocker	Reversal agent for unnecessary prolonged local analgesia[26]	Regitine[27]
Prazosin		Selective alpha-1 blocker	Hypertension, benign prostatic hyperplasia, PTSD associated nightmares and Raynaud phenomenon[28]	APO-PRAZO [29]
Tamsulosin		Selective alpha-1 blocker	Benign prostatic hypertrophy[30]	HARNAL D [31]
Yohimbine		Selective alpha-2 blocker	Not used clinically, but available for treatment of male erectile dysfunction[32]	PMS-YOHIMBINE [33]
Propranolol		Non-selective beta blocker	Migraine prophylaxis[34]	APO-PROPRANOLOL[35]
Timolol		Non-selective beta blocker	Glaucoma and ocular hypertension[36]	APO-DORZO-TIMOP[37]
Atenolol		Selective beta-1 blocker	Hypertension, angina and acute myocardial infarction[38]	ALONET[39]
Metoprolol		Selective beta-1 blocker	Angina, heart failure, myocardial infarction, atrial fibrillation and hypertension[40]	BETALOC[41]
Butaxamine		Selective beta-2 blocker	Not used clinically, use in animal and tissue experiments[42]	(not used clinical)

• Phenoxybenzamine
• Phentolamine

• Prazosin
• Tamsulosin

• Yohimbine

• Propranolol
• Timolol

• Atenolol
• Metoprolol

• Butaxamine

• Still under development