Beta blockers

History

Beta blockers are widely used drugs, indicated in many heart-related conditions. In 1964. Scottish pharmacologist James Black synthesized beta blocker known as propranolol, which later became the best selling drug in the world. This was considered to be one of the greatest discoveries in the pharmacology of the 20th century. The original idea of Sir James Black was to manage the chest pain in angina pectoris. He succeeded, as his contribution was even bigger, because beta blockers lower the death rates beside managing the symptoms, and now they are used to treat various disorders, not only the heart-related ones.

Beta receptors

Beta receptors, along with alpha receptors are the adrenergic receptors that are activated by catecholamines, mainly by epinephrine (adrenaline) and norepinephrine (noradrenaline), which are produced in the human organism. Although the dopamine is also a catecholamine, it activates different receptors. Epinephrine is primarily produced in adrenal glands, acting as a hormone, as opposed to norepinephrine which is mainly used by the sympathetic nervous system, as a neurotransmitter.

Beta receptors

Beta receptors are divided into 3 subtypes (β12, and β3).

The main location of  β1 receptors is in the heart and in the kidneys. Activation of β1 receptors in the heart causes increased cardiac output, acting positive inotropic (stronger contractions), positive chronotropic (increased heart rate), positive dromotropic (faster electrical conductivity), and positive bathmotropic (enhanced excitability of heart’s cells). In the juxtaglomerular apparatus of the kidney, they induce the renin release, leading to angiotensin II synthesis, which is a powerful vasoconstrictor, meaning that it’s narrowing blood vessels.

Predominant localization of β2receptors is in vascular smooth muscles, where they cause vasodilation (widening of the blood vessels), and in bronchi, where they ease the respiration by relaxation of the smooth muscles in airways. They are also present in the liver, eyes, gastrointestinal tract, and skeletal muscles.

The less exposed β3 receptors are based in fat tissue mostly, and they are involved in lipolysis, a disintegration of the fat tissue.

Mechanism of action

Beta blockers are competitive antagonists of catecholamines. They bind to the same receptors without activating them, preventing catecholamines to initiate their function. Epinephrine or norepinephrine can displace bound beta blockers if they’re in higher concentration.

beta blockers mechanism of action

Types of beta blockers

The main difference in beta blockers distinction is their selectivity. Beta blockers can be selective or nonselective. They can also be divided by their solubility, being lipid-soluble or water-soluble.

Selective β1 beta blockers

Selective beta blockers only act on β1 receptors, if they are given in adequate concentrations, as the higher concentrations also block the β1 receptors. Cardioselective beta blockers are generally safer than the nonselective ones. Low doses of this type can be given in stable asthma or COPD. In people with peripheral vascular disease, where the blood in peripheral tissues is lowered, selective beta blockers can be given, as they don’t cause additional vasoconstriction opposed to nonselective drugs. Selective beta blockers could also be used in people with diabetes. Some examples of these drugs are atenolol, betaxolol, bisoprolol, metoprolol, nebivolol, esmolol, and others.

Nonselective beta blockers

Nonselective beta blockers act on both β1 and β2 receptors. They include propranolol, carvedilol, labetalol, nadolol, sotalol, timolol, and others.

Lipid-soluble beta blockers

Lipid-soluble beta blockers are metabolized in the liver, so they should be avoided in hepatic failure. They can also pass in the brain through the blood-brain barrier, and act on the central nervous system. They include propranolol and labetalol.

Water-soluble beta blockers

Water-soluble beta blockers are metabolized in the kidneys, and they should be avoided in kidney failure. They include atenolol, nadolol, and sotalol.

Indications

indications of beta blockers

Beta blockers are often prescribed in heart-related conditions such as angina, hypertension, heart failure, arrhythmia, heart attack, and in other disorders such as glaucoma, migraine, anxiety, essential tremor, and pheochromocytoma (tumor of the adrenal gland).

Angina

Angina resembles a chest pain or pressure, mainly caused due to ischemic heart disease. Beta blockers represent the basic drugs used in stable angina treatment. Their positive effects in angina are described by competitive blocking of β receptors, which is decreasing the heart’s oxygen needs. Mechanisms of these effects are lowered blood pressure, heart contractility, heart rate, and increased blood flow in poorly supplied, ischemic zones. The time of heart filling is prolonged, thus more blood flows through the heart.

Hypertension

Hypertension is high blood pressure with values higher than 140 / 90 mm Hg. Although the beta blockers aren’t as effective as other antihypertensives in hypertension as a disease on itself, they are highly effective in treating hypertension associated with other heart diseases such as angina, heart failure, arrhythmia, and heart attack. The main mechanism of action is the blocking of β1 receptors in the heart, decreasing cardiac output, along with blocking of β1 receptors in juxtaglomerular apparatus in kidneys, which is causing a decrease of the renin release. It is important to note that the quitting of beta blockers therapy must be done gradually, because they can induce an increased heart rate, elevated blood pressure, acute angina attack, or even a myocardial infarction. The reason for this is the increased number of heart’s β receptors, as an organism’s natural reaction to continual receptor blocking.

Heart failure

Heart failure is a condition, characterized by the heart’s inability to provide enough oxygen and nutrient-rich blood to organs and peripheral tissues. At first, it was thought that the beta blockers are worsening this condition, because of their negative effect on contractility of the already weakened heart, but it is proved, that they are actually helpful because they lower the mortality while managing the symptoms. Activated sympathetic system is responsible for many harmful effects on heart, including increased oxygen demand, propagation of inflammation and heart remodeling. With their effects on heart, beta blockers manage those destructive events. It is very important to begin the beta blockers therapy on “dry hearth“, meaning that they should be prescribed after the elimination of fluid buildups (edema) of the organism.

Arrhythmia

Heart arrhythmia is a group of diseases, where the heartbeat is irregular and abnormal. Beta blockers are decreasing the heart rate and prolonging the time of electrical impulse conductivity through the atrioventricular node, which is electrically connecting atria and ventricles. They are used in atrioventricular related arrhythmia, and in the treatment of atrial fibrillation.  The blood pressure and heart electrical activity need to be monitored, as beta blockers could induce bradycardia (heart rate < 60 beats per minute), and hypotension (dramatically low blood pressure < 90 / 60 mm Hg).

Heart attack

A heart attack occurs when the part of the heart is cut off from the blood supply, or the blood flow is dramatically decreased, causing the death of heart cells. Beta blockers are used in primary prevention (before a heart attack) and in secondary prevention (after the survived heart attack) of the heart attack. They are lowering the blood pressure, heart rate, and heart’s oxygen demand, thus reducing its workload.

Contraindications

contraindication

Beta blockers should be avoided in some cases, as they can be dangerous if used in certain conditions.

Bradycardia

Bradycardia sometimes doesn’t show any symptoms, but the usual ones are lightheadedness, fatigue, fainting, and dizziness. As beta blockers slow down the heart, extremely slowed heart rate can be dangerous for a patient.

Hypotension

As beta blockers are antihypertensives, they can additionally lower the already low blood pressure, inducing even a life-threatening condition manifested with confusion, cold and pale skin, and tachypnea (fast and shallow breathing) called shock.

Second and third degree atrioventricular block

Atrioventricular block is a disease characterized by disrupted electrical conductivity between atria and ventricles. In second degree AV block, some of the impulses sent from atria fail to reach to ventricles, and it rarely shows up any symptoms. Sometimes lightheadedness, dizziness, and fainting follow it. In third degree AV block, the transmission between atria and ventricles is completely blocked. Ventricles are activated by an accessory pacemaker, creating so-called escape rhythm. The heart rate and blood pressure are extremely low. Beta blockers should not be used, as they can worsen those symptoms, causing dangerous and abnormal heart rhythm problems.

Decompensated heart failure

Beta blockers shouldn’t be used in decompensated heart failure due to their negative effect on heart contractility, and increasing effect on fluid retention. When the fluid excess is eliminated, a low dose of a beta blocker can be introduced, gradually increasing for 2 – 3 weeks.

Asthma and chronic obstructive pulmonary disease

Asthma and COPD are diseases characterized by difficulty of breathing, coughing, and chest discomfort. Therapy of these conditions is based on widening and relaxation of airways. Beta blockers do exactly the opposite, causing the narrowing of bronchi, worsening the symptoms, sometimes requiring the hospitalizations. Cardioselective beta blockers can sometimes be used in well-regulated asthma and COPB.

Raynaud’s disease

Raynaud’s disease is a disorder where some body part such as fingers and toes suffer reduced blood flow, caused by narrowing of smaller arteries that are supplying them. In severe Raynaud’s disease, use of beta blockers can worsen the symptoms by decreasing the rate at which the blood is delivered to these body parts.

Side effects

Side effects of beta blockers
Side effect of beta blockers

Like all other drugs, beta blockers can induce some side effects including:

  • bradycardia – heart rhythm can fall below 40 beats per minute.
  • hypotension – the blood pressure can be lowered significantly, causing symptoms.
  • bronchoconstriction – narrowing of bronchi can induce an asthma attack.
  • cold hands, feet – blocking of β2 in skeletal muscle can lower the blood flow through the periphery tissue inducing these effects.
  • fatigue – fatigue is a common, but temporary side effect of beta blockers,  which goes away after some time. It is induced by lowered cardiac output, blood supply of organs and peripheral tissues.
  • dizziness – similar to fatigue, this side effect is caused due to lowered blood perfusion of the brain.
  • erectile dysfunction, loss of sex drive – a possible side effect of many antihypertensives.
  • upset stomach – a possible side effects of almost any drug.
  • sleeping disturbances – certain beta blockers can cause trouble with sleeping.
  • hypoglycemia unawareness – signs of dangerously low concentration of blood sugar like tremor and rapid heart rate, may be concealed by effects of beta blockers.
  • AV block – a disrupted transmission of electrical impulses from atria to ventricles.
  • hypoglycemia – β receptors are involved in glucose release from the liver.
  • hyperglycemia – beta blockers can disrupt the regulation of blood sugar, especially if they are used for a long time, combined with thiazide diuretics.

Interactions

Warning!!! Beta blockers may interact with a lot of other cardiac drugs

Like any other drugs, beta blockers can interact with other medications, so it’s important to tell which drugs you are taking to your doctor or your pharmacist.

Calcium channel inhibitors

Calcium channel inhibitors are also used to treat many heart-related diseases. They are lowering the heart rate and decreasing the electrical conductivity as well as the beta blockers, so if they are combined, serious bradycardia or a life-threatening atrioventricular block may occur.

Antiarrhythmics

Certain types of antiarrhythmics, such as the ones of Class I agents and amiodarone can also enhance the negative inotropic effect, and AV block.

NSAID

Nonsteroidal anti-inflammatory drugs can lower the antihypertensive effects of beta blockers. This can be explained by their effects on lowering of prostaglandin synthesis, thus interfering with renal blood pressure management, while also causing fluid retention, which increases blood pressure.