In this article, we will study the important pharmacological aspects of alpha and beta blockers such as classification, pharmacokinetics, mechanism of action, important actions on various organ systems, clinical uses and toxicity.
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Space-filling model of phentolamine

Image: “Space-filling model of phentolamine” by NZLS11 – Own work. License: CC0 1.0


Definition of Alpha and Beta Blockers

These drugs are also called adrenergic blockers or adrenergic antagonists. Another name for these drugs is sympatholytics. They block the functions of the sympathetic nervous system. These drugs bind to adrenoceptors reversibly or irreversibly, preventing the binding of endogenous catecholamines.

Classification of Alpha and Beta Blockers

Adrenoceptor blockers are classified based upon their selectivity towards adrenoreceptors.

Alpha blockers

Phenoxybenzamine chemical structure

Image: “Chemical Structure of Phenoxybenzamine” by Yikrazuul – Own Work. License: Public Domain

  • Non-selective: phenoxybenzamine, phentolamine
  • α1-selective: prazosin, terazosin, doxazosin, alfuzosin, indoramin, urapidil, bunazosin, tamsulosin
  • α2-selective: yohimbine

Beta Blockers

  • Non-selective: nadolol, penbutolol, pindolol, propranolol, timolol, sotalol, metapranolol, cartelol, carvedilol*, labetalol*
  • β1- selective: acebutolol, atenolol, bisoprolol, esmolol, metoprolol, betaxolol, nebivolol
  • β2- selective: butoxamine

Mnemonics to remember this classification:

α-blockers generally end with -in.

β-blockers generally end with –olol.

Important:

  • Phenoxybenzamine is a long acting irreversible α-blocker.
  • Phentolamine is a short acting reversible α-blocker.
  • *Carvedilol and labetalol also block α-receptors.

Always remember: In the sympathetic nervous system, the transmitter in effector organs is norepinephrine, while, in the parasympathetic nervous system, the transmitter in effector organs is acetylcholine (Ach). Alpha and beta blockers have an antagonistic action on the sympathetic nervous system.

Adrenoceptors – Alpha and Beta Receptors

 α1 Receptors

  • Located at GI tract and bladder sphincter, vascular smooth muscles of skin and splanchnic regions, and radial muscle of iris.
  • Function: generally produce smooth muscle constriction.
  • Mechanism of action: they act via stimulation of IP3/Ca3+

α2 Receptors

  • Present in presynaptic nerve terminals, platelets, fat cells and the wall of the GI tract.
  • Function: generally produce relaxation/dilation.
  • Mechanism of action: they act via inhibition of adenylate cyclase and decreasing the concentration of cAMP (cyclic adenosine monophosphate).

β1 Receptors

  • Located on heart SA, AV node, atrial and ventricular muscle, His-Purkinje, and kidney.
  • Mechanism of action: they act via stimulation of adenylate cyclase and decreasing the concentration of cAMP (cyclic adenosine monophosphate).

β2 Receptors

  • Located on smooth vessels of skeletal muscle, blood vessels, GIT, uterus, liver and urinary tract.
  • Mechanism of action: they act via stimulation of adenylate cyclase and decreasing the concentration of cAMP (cyclic adenosine monophosphate).

Effect of Adrenoceptors on Organ Systems

It is suggested to first learn and memorize the action of alpha and beta receptors on various organ systems. If the action of alpha and beta receptors is known, then it is easy to remember the effect of alpha and beta blockers on those organ systems because they have the opposite actions to the alpha/beta agonists.

Receptor/organ system Actions
α1 receptors
Eyes Contraction (mydriasis) of the iris dilator muscle.
Bladder Constriction of bladder sphincter,

Control of micturition and urine flow.

Note: α-blockers increase the urine flow by promoting the relaxation of the bladder muscles.

Prostate Cause ejaculation by prostate contraction.

α-blockers are used to treat benign prostatic hyperplasia (BPH) induced urinary obstructions because it causes the relaxation of the bladder muscles (the opposite actions to the alpha agonists).

α-blockers also produce impaired ejaculation due to their α-receptor antagonism.

Kidney Decrease renin secretion.
Veins and arterioles (skin) Contraction of smooth muscles of the peripheral blood vessels.
α2 receptors
Platelets Increase the platelet aggregability.
β1 receptors
Heart Increase heart rate, conduction velocity, contractibility and AV node conduction.
β2 receptors
Veins and arterioles Promote dilation of arterioles and veins. Consequently a decrease in TPR, BP, afterload.

Beta blockers are used in the treatment of hypertension.

Bladder In contrast to the receptors, these stimulate bladder relaxation.

No effect on the ejaculation.

Bronchioles Bronchiolar smooth muscle relaxation
Kidney Increase the renin secretion
Liver Increased glycogenolysis

 

Αlpha Adrenergic Blocking Agents

These drugs block the action of alpha adrenoceptors. They are commonly used in the treatment/management of hypertension, and benign prostatic hyperplasia (BPH).

Phenoxybenzamine and phentolamine are two non-selective alpha adrenergic blocking agents. Thus, they act at both α1 and α2 receptors.

Phenoxybenzamine binds covalently with the adrenergic receptors (irreversible and non-competitive). Due to irreversible binding, phenoxybenzamine has a longer duration of action. It decreases the BP by the prevention of the constriction of the peripheral blood vessels. However, due to increased cardiac output, it doesn’t cause a prolonged drop in BP, thus it is not widely used for this purpose.

Phentolamine is a reversible and competitive type of alpha adrenergic blocking agents. It has a shorter duration of action and it is used in the treatment of pheochromocytoma.

Prazosin, terazosin, doxazosin, and tamsulosin have selective antagonistic action on α1 receptors.

Prazosin: It has 1000 times more selectivity action on α1 receptors. Due to selectivity in action, a marked orthostatic hypotension and tachycardia is generally observed with non-selective alpha adrenergic blocking agents such as phenoxybenzamine and phentolamine are comparatively less with α1 selective alpha blockers.

Prazosin is an important drug in the treatment of hypertension and BPH. Terazosin and doxazosin have similar actions. Terazosin (80%) has a higher bioavailability than prazosin (50%).

Tamsulosin: Postural hypotension is not observed with this drug.

Yohimbine: Before the discovery of phosphodiesterase-5-inhibitors such as sildenafil, it was used to treat impotency (ED) in men, but, nowadays, it is not used for the treatment of ED due to the availability of more safer and effective alternatives.

Please note: Alpha blockers (both selective and non-selective) are not recommended as monotherapy in hypertension due to the availability of other effective anti-hypertensives.

Adverse Effects of Alpha Adrenergic Blocking Agents

Adverse effects of alpha blockers are mainly due to their antagonistic action/blocking effects of α receptors.

  • Orthostatic hypotension: This results due to the pooling of blood in the veins of the legs. Fainting can also result due to the reduced supply of blood to the brain. It is the most common side-effect with alpha blockers. It is more marked with the use of non-selective alpha blockers and less marked with the use of α1 selective blockers.
  • Dizziness and headache.
  • Reflex tachycardia: Increased heart rate due to the stimulation of baroreceptors.
  • Drowsiness.
  • Nasal stiffness due to alpha receptor blockage.
  • Since alpha receptors have a role in the contraction of smooth muscle of prostate which induce ejaculation in males, blockage of alpha receptors inhibits the ejaculation process in males.

Beta Adrenergic Blocking Agents

All the beta blockers or beta adrenoceptor blockers antagonize the action of beta receptors.

A simple trick to remember the actions of beta blockers on various organ systems is to first memorize the action of beta agonists on the organ system. Beta blockers always have an opposite action on organ systems to the beta agonist.

Always remember: cardioselective β-blockers (atenolol, metoprolol, acebutolol, esmolol, bisoprolol, betaxolol) have selective action on β1 receptors.

Advantage of cardioselective β-blockers: They are safer in asthma (don’t cause bronchoconstriction), diabetes, and peripheral vascular disease.

Important: Beta blockers do not cause postural hypotension as they don’t have any action on α receptors.

Beta blockers act by reducing the cardiac output (volume of blood pumped by the heart per minute); thus, a decrease in the volume of blood pumped from the heart also reduces the BP.

Pharmacological Actions of Propranolol (Prototype Drug)

Propranolol is described as a prototype drug here. It is a non-selective beta blocker. Important indications and side effects of other beta blockers will be discussed in the next sections.

Effects of Beta Adrenergic Blocking Agents

Effect on Cardiovascular System

  • cardiac output
  • ↓ heart rate (produce bradycardia)
  • ↓ force of contraction
  • total peripheral resistance (TPR)
  • Negative chronotropic and inotropic actions
  • also decrease the renin release from the kidneys, which is thought to be their mechanism of action in reducing the BP

Always remember:

Action by beta blockers on β2 receptors is considered as undesired because non-selective beta blockers cause bronchoconstriction, decrease insulin secretion and glycogenolysis.

Cardioselective beta blockers always act on β1 receptors.

Effect on Pulmonary System

Non-selective beta blockers such as propranolol can produce bronchoconstriction or can exacerbate asthma in asthmatics.

Due to this, propranolol should be avoided in asthmatics and patients suffering from COPD.

Always remember: Beta blockers always show effects opposite to beta agonists.

β1 agonists such as salmeterol and salbutamol have a bronchodilatory effect on the lungs.

Effects on the Eyes

Acute angle closure glaucoma

Image: “Photograph showing acute angle-closure glaucoma which is a sudden elevation in intraocular pressure that occurs when the iris blocks the eye’s drainage channel—the trabecular meshwork.” by Jonathan Trobe, M.D. – The Eyes Have It. License: CC BY 3.0

Beta blockers reduce the intraocular pressure. Thus, they are used to treat glaucoma. They also reduce the production of aqueous humour in the eyes (timolol).

Metabolic effects

They increase the levels of insulin in the body ­− if a beta blocker is given to a diabetic patient who is on insulin therapy, there could be a drastic hypotension. Thus, beta blockers are contraindicated in diabetes.

Beta blockers also block glycogenolysis and gluconeogenesis.

Clinical uses of beta adrenergic blocking agents

  • Hypertension (carvedilol, labetalol, propranolol)
  • Angina pectoris (propranolol)
  • Myocardial infarction (propranolol and esmolol)
  • Glaucoma (timolol, betaxolol, cartelol – applied topically)
  • Migraine (propranolol)
  • Performance anxiety (propranolol)
  • Hyperthyroidism (propranolol)

Adverse effects and toxicity of beta blockers

  • Bradycardia
  • AV blockage
  • Severe asthma attacks (propranolol)
  • Hypoglycemia
  • Arrhythmias (upon abrupt stoppage of therapy with beta blockers)
  • Sexual dysfunction (propranolol)
  • Fatigue
  • Vivid dreams (propranolol)

Review Questions on Alpha and Beta Blockers

The correct answers can be found below the references.

1. Which of the following alpha blocker was once used for the treatment of erectile dysfunction?

A.    Prazosin

B.     Doxazosin

C.     Yohimbine

D.    Propranolol

E.     Nadolol

2. Which of the following drug causes orthostatic hypotension as a side effect?

A.     Prazosin

B.     Propranolol

C.     Nadolol

D.     Atenolol

E.      Metoprolol

3. Which of the following beta-blocker is not a cardioselective in its action?

A.     Propranolol

B.     Atenolol

C.     Bisoprolol

D.     Esmolol

E.      Acebutolol

 

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