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Medication

Image : “Packages of medication” by Ralf Roletschek. License: CC BY-SA 3.0


Definition

Alpha-blockers generally help relax the muscles, which in turn can lead to the opening of blood vessels for smooth circulation. Alpha-blockers work by keeping the hormones of norepinephrine or noradrenaline at bay, leading to smoother blood flow through open veins.

Beta-blockers work by blocking the hormone called epinephrine (better known as adrenaline). This hormone often causes increased heart rate, which can lead to increased blood pressure levels. Beta-blockers prevent this from happening by reducing the heart rate, thereby reducing blood flow. Blood pressure is decreased because of the dilation of blood vessels.

Classification

Adrenoceptor blockers are classified based upon their selectivity toward adrenoreceptors.

Alpha-Blockers

  • alpha-blockersNon-selective: phenoxybenzamine, phentolamine
  • α1-selective: prazosin, terazosin, doxazosin, alfuzosin, indoramin, urapidil, bunazosin, tamsulosin
  • α2-selective: yohimbine
α-Methyldopa (Aldomet) Clonidine
Decreases central sympathetic outflow Decreases central sympathetic outflow
Prodrug; metabolized to methylnorepinephrine
Decreases central sympathetic outflow, cardiac output, and vascular resistance Decreases central sympathetic outflow, cardiac output, and vascular resistance
Compensatory reaction: salt retention Compensatory reaction: salt retention
Idiosyncratic reaction:

  • Hematologic immunotoxicity (positive Coombs test) → hemolytic anemia
  • Sedation
Idiosyncratic reaction:

  • Rebound hypertension if discontinued (restart it, or use phentolamine, an alpha blocker)
  • Sedation
Previously used extensively for pregnancy; second most common Not used in pregnancy

Beta-Blockers

beta-blocker

  • Non-selective: nadolol, penbutolol, pindolol, propranolol, timolol, sotalol, metoprolol, carteolol, carvedilol*, labetalol*
  • β1-selective: acebutolol, atenolol, bisoprolol, esmolol, metoprolol, betaxolol, nebivolol
  • β2-selective: butoxamine
Notable β-Blocker
Propranol

  • Prototypical β-blocker
  • Short-acting, poor blood pressure control
  • Used in anxiety and stage fright
  • Can be used to fool a lie detector test!
Metoprolol

  • Prototypical cardiac β-blocker
  • Used twice daily
  • Most commonly used in myocardial infarction period
  • More β1 selective, less blood pressure control
Labetalol

  • Nonselective 3rd generation
  • Wide therapeutic margin (200–2,400 mg/day)
  • Excellent blood pressure control
  • Most used blood pressure medication in pregnancy
Bisoprolol

  • Once daily β-blocker
  • More β1 selective, used post-MI
  • Good blood pressure control
β-Blockers with additional activity
Nebivolol

  • “Novel” 3rd-generation selective β-blocker
  • β1 selective
  • Also has nitric oxide activity — direct vasodilator
  • Excellent blood pressure control
  • Caution: endothelial dysfunction
Carvedilol

  • Nonselective 3rd-generation β-blocker
  • Also has alpha activity
  • Used in heart failure
  • Poor blood pres control

Note:

  • The names of α-blockers generally end with -in, while those of β-blockers generally end with –olol.
  • Phenoxybenzamine is a long-acting irreversible α-blocker.
  • Phentolamine is a short-acting reversible α-blocker.
  • 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

  • Location: at the gastrointestinal 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: act via stimulation of IP3/Ca3+

α2-receptors

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

β1-receptors

  • Location: sinoatrial node, atrioventricular node, atrial and ventricular muscle, His-Purkinje system, and kidney
  • Mechanism of action: act via stimulation of adenylate cyclase and thereby increasing the concentration of cAMP (cyclic adenosine monophosphate)

β2-receptors

  • Location: smooth vessels of skeletal muscle, blood vessels, gastrointestinal tract, uterus, liver, and urinary tract
  • Mechanism of action: act via stimulation of adenylate cyclase and increasing the concentration of cAMP

Effect of Adrenoceptors on Organ Systems

Understanding the action of alpha- and beta-receptors on various organ systems will aid in remembering the effect of alpha- and beta-blockers on those organ systems because they have 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 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 they cause 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 and consequently a decrease in temperature, pulse, respiration, blood pressure, and afterload

Beta-blockers are used in the treatment of hypertension.

Bladder In contrast to receptors, these stimulate bladder relaxation

No effect on 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 and management of hypertension and benign prostatic hyperplasia (BPH).

  • Phenoxybenzamine and phentolamine are 2 nonselective alpha-adrenergic blocking agents. Thus, they act as 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 blood pressure by preventing constriction of the peripheral blood vessels. However, due to increased cardiac output, phenoxybenzamine does not cause a prolonged drop in blood pressure, so 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 is used in the treatment of pheochromocytoma.
  • Prazosin, terazosin, doxazosin, and tamsulosin have selective antagonistic action on α1 receptors.
  • Prazosin has 1,000 times more selectivity action on α1 receptors. Due to selectivity in action, marked orthostatic hypotension and tachycardia are generally observed with nonselective alpha-adrenergic blocking agents such as phenoxybenzamine and phentolamine.
  • Prazosin is an important drug in the treatment of hypertension and benign prostatic hyperplasia  Terazosin and doxazosin have similar actions. Terazosin has a higher bioavailability (80%) than prazosin (50%).
  • Postural hypotension is not observed with tamsulosin.
  • Before the discovery of phosphodiesterase-5-inhibitors such as sildenafil, yohimbine was used to treat impotence (erectile dysfunction) in men, but safer and effective alternatives are now available.

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

Adverse Effects of Alpha-Adrenergic Blocking Agents

The adverse effects of alpha-blockers are mainly due to their antagonistic action/blocking effects on alpha-receptors.

  • Orthostatic hypotension: This results from the pooling of blood in the veins of the legs. Fainting can also result due to the reduced supply of blood to the brain. This is the most common side effect of alpha-blockers. It is more common with the use of nonselective than selective alpha-blockers.
  • Dizziness and headache
  • Reflex tachycardia: increased heart rate due to the stimulation of baroreceptors
  • Nasal stiffness: 0ccurs due to alpha-receptor blockage.
  • Since alpha-receptors have a role in the contraction of smooth muscle of the prostate, which induces ejaculation in males, blockage of alpha-receptors inhibits the ejaculation process in males.

Beta-Adrenergic Blocking Agents

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

Understanding the action of beta-blockers on various organ systems will aid in remembering the effect of beta-agonists on those organ systems because they have opposite actions to the beta-agonists.

Note:

  • Cardioselective β-blockers (atenolol, metoprolol, acebutolol, esmolol, bisoprolol, betaxolol) have a selective action on β1-receptors.
  • Cardioselective β-blockers are safer to use in patients with asthma (as they don’t cause bronchoconstriction), diabetes, and peripheral vascular disease.
  • Beta-blockers do not cause postural hypotension as they do not have any action on alpha receptors.
  • Beta-blockers act by reducing cardiac output (volume of blood pumped by the heart per minute), thereby reducing blood pressure.

Effects of Beta-Adrenergic Blocking Agents

Effect on Cardiovascular System

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

Always remember:

  • Action by beta-blockers on β2-receptors is considered to be undesired because nonselective beta-blockers cause bronchoconstriction and decrease insulin secretion and glycogenolysis.
  • Cardioselective beta-blockers always act on β1 receptors.

Effect on Pulmonary System

Nonselective beta-blockers such as propranolol can produce bronchoconstriction or exacerbate asthma in asthmatics. Due to this, propranolol should be avoided in asthmatics and patients suffering from COPD.

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

Metabolic Effects

Beta-blockers increase the levels of insulin in the body, so if given to a diabetic patient who is on insulin therapy, drastic hypotension may result. Thus, beta-blockers are contraindicated in diabetes.

Beta-blockers also block glycogenolysis and gluconeogenesis.

Clinical Uses of Beta-Adrenergic Blocking Agents

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)

The Renin-Angiotensin-Aldosterone System

Blockers of the renin-angiotensin-aldosterone system

Beta-blockers control and regulate blood pressure. The kidney and the central nervous system are the critical components of this action. Peripheral baroreceptors and the autonomic nervous system also play important roles.

Medical Therapy for Myocardial Infarction Patients: ACE Inhibitors (ACEI) and Angiotensin Receptor Blockers (ARBs)

ACE inhibitors and ARBs decrease blood pressure and decrease the work of the heart by dilating arteries. Side effects include cough, dizziness, and low blood pressure. Pregnancy is contraindicated.

The kidney is crucial to blood pressure regulation via the juxtaglomerular apparatus and renin release. Renin initiates a biochemical sequence that eventually converts angiotensinogen, which is produced in the liver, into angiotensin, a strong vasoconstrictor. Angiotensin stimulates the release of aldosterone from the adrenal gland, which causes the kidney to retain salt and water. Angiotensin stimulates the release of antidiuretic hormone from the pituitary gland, which causes the kidney to retain water.

ACE inhibitors may lower blood pressure too much and cause allergic reactions. This system is part of the body’s defense against dehydration and/or blood loss. Blood volume should be restored to normal as quickly as possible.

Commonly Used ACEI and AII blockers Initial Daily Dose(s) Target Dose
Captopril 6.25 mg tid 50 mg tid
Enalapril 2.5 mg bid 10–20 mg bid
Fosinopril 5–10 mg daily 40 mg daily
Lisinopril 2.5–5 mg daily 20–40 mg daily
Perindopril 2 mg daily 8–16 mg daily
Quinapril 5 mg bid 20 mg bid
Ramipril 1.25–2.5 mg daily 10 mg daily
Trandolapril 1 mg daily 4 mg daily
Candesartan 4–8 mg daily 32 mg daily
Losartan 25–50 mg daily 50–100 mg daily
Valsartan 20–40 mg bid 160 mg bid

AEs with ACEI and ARB: first-line Rx

Summary

  1. Alpha-blockers work on the blood muscles to open up the blood vessels, while beta-blockers work on the heart to ease the flow of blood.
  2. Alpha-blockers work on norepinephrine or noradrenaline, while beta-blockers work on epinephrine or adrenaline.
  3. Alpha-blockers affect only blood pressure levels, while beta-blockers affect both the heart and blood pressure.
  4. Beta-blockers can cause weight gain, while alpha-blockers do not.
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5 thoughts on “Class 2 Alpha- and Beta-Blockers — Antiarrhythmic Drugs

  • Stanley Oiseth

    Thanks for pointing this out. The corrections have been made. Please accept our apologies for not fixing it earlier!
    Stan Oiseth, MD

  • paras kansal

    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).

    again this is increasing the conc. of cAMP CORRECT IT

    1. paras kansal

      it is inhibiting the adenylate cyclase then consequently decreasing the con. of cAMP

    2. Olivaldo Paz

      These comments are almost 1 year old, and they haven’t corrected it yet

  • paras kansal

    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).

    it is increasing the conc. of cAMP correct it please