Adrenergic blocking agent

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Adrenergic blocking agents are a class of drugs that exhibit its pharmacological action through inhibiting the action of the sympathetic nervous system[1] 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.[1] 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.[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, the heart rate and contractile force increase when 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 epinephrine. As a result, it stops the body from producing the "fight-or-flight" responses.

Medical Uses

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

Alpha 1 blocker

Main article: Alpha-1 blocker

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]

benign prostatic hyperplasia
Manifestation of Raynaud phenomenon

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 blocker

Main article: Alpha-2 blocker

Alpha2 blocker reduces 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]

Beta 1 blocker

Main article: Beta blocker
Myocardial infarction (heart attack)

Since beta 1 receptor 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, myocardial infarction. It treats other symptoms unrelated to heart like migraines and anxiety.[5]

Beta 2 blocker

Beta2 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]

Beta 3 blocker

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 now.[7]

Adverse Effect

Selectivity

Main article: Selectivity (pharmacology)

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]

Non-selective alpha blocker

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.

Selective alpha 1 blocker

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]

Demonstration of orthostatic hypotension

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]

Selective alpha 2 blocker

Apart from increasing the noradrenaline release, the selective alpha-2 blockers have the potential to bind with other receptors such as the 5-HT serotonin 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]

Non-selective beta blocker

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]

Selective beta 1 blocker

heart failure

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]

Selective beta 2 blocker

Demonstration of thickening of airway

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]

Selective beta 3 blocker

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.

Contraindications

Alpha 1 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]

Alpha 2 blocker

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

Beta 1 blocker

Damaged alveoli of a chronic obstructive pulmonary disease patient

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

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]

Beta 3 blocker

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 effects

Alpha 1 blocker

Overview of Parasympathetic Nervous System

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

Alpha 2 blocker

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

Beta 1 blocker

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]

Beta 2 blocker

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

Beta 3 blocker

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.

Drug Interaction

Alpha 1 blocker

CYP3A4 inhibitors

Main article: CYP3A4

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]

Alpha 2 blocker

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

Beta 1 blocker

Antihypertensive drugs

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]

Hypertensive drugs

Ibuprofen as an NSAID, can cause drug interaction with beta-1 blocker

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]

Beta 2 blocker

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

Beta 3 blocker

Since beta-3 blocker is still under development, there is a lack of information on drug interaction about beta-3 blocker.

Mechanism of Action

Alpha 1 blocker

Mechanism of Action of Alpha -1 blocker

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.

Mechanism of Action of Alpha-2 blocker

Alpha 2 blocker

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

Beta1 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 blocker

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.

Remarks: It has to be noted that 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

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]

History

Alpha Blocker

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]

Beta Blocker

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]

Beta 3 blocker

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

Agents

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)

Non-selective alpha blocker

  • Phenoxybenzamine
  • Phentolamine

Selective alpha 1 blocker

  • Prazosin
  • Tamsulosin

Selective alpha 2 blocker

  • Yohimbine

Non-selective beta blocker

  • Propranolol
  • Timolol

Selective beta 1 blocker

  • Atenolol
  • Metoprolol

Selective beta 2 blocker

  • Butaxamine

Selective beta 3 blocker

  • Still under development

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