Beta Adrenoceptor Blockers

Most of the commonly used drugs nowadays are the beta adrenoceptor blockers. They were discovered during the 1960s and are extensively used for the treatment of various cardiovascular diseases as well as other uses.

They act on the beta 1 and beta 2 receptors (causing relaxation of smooth muscles of blood vessels, bronchi and bronchioles, producing an inhibitory effect).

The earlier drugs were non-selective and were not good for asthma patients. Now selective drugs have been developed. We classify the beta blockers on this basis into:

1. Selective
2. Non-selective

Classification:

According to Pharmacodynamics

1. Non-selective (beta1, beta2) blockers:

a. Pure Blockers (with no ISA)

Sotalol

Timolol

Nadolol

b. With membrane stabilizing activity (MSA)(local anesthetic activity)

Propanolol

c. With intrinsic sympathetic activity (ISA, partial agonists –can activate beta receptors)

Pindolol (MSA ±)

Carteolol

Penbutalol

d. With ISA and MSA

Oxyprenolol

2. Cardio selective (beta 1 blockers)

a. Pure blockers

Atenolol

Bisoprolol (most selective)

Esmolol (shortest action)

b. With MSA

Metaprolol

Tolamolol

Betaxolol

c. With ISA

Practolol (clinically not used now)

Celiprolol

d. With ISA and MSA

Acebutolol

Beta 2 blockers

Butoxamine

Drugs that block both alpha and beta receptors

Labetalol

Carvedilol

Bucindolol

Based on Pharmacokinetic Pattern

Two groups are found:

1. Water soluble beta blockers
2. Lipid soluble beta blockers

 

Lipid soluble (extensive first pass metabolism)

Propanolol

Timolol

Metoprolol

Penbutolol

Water Soluble

Nadolol

Atenolol

Acebutolol

Lipid soluble drugs

Lipid soluble drugs cross the blood brain barrier, thus are rapidly absorbed and undergo extensive first pass metabolism. They have a shorter half life of about 4 hours. They produce a decrease in blood flow to the liver and decrease their own metabolism after prolonged use. Three times increase in half life is observed after prolonged use.

Disadvantages:

1. CNS effects like nightmares may be produced because drugs cross the BBB.
2. Plasma levels after oral intake are variable due to first pass metabolism (not related to dose)
3. If given in higher doses, liver metabolizing capacity is saturated, thus their levels rise.

Water soluble drugs:

1. Water soluble drugs do not undergo first pass metabolism
2. They are excreted in unchanged form
3. Half life is longer (about 8-10 hrs)
4. Not for patients having renal diseases
5. Produce no CNS effects as are unable to cross BBB.

Based on Duration of Action

Ultra short acting                                Half life

Esmolol                                                           9 minutes

(rapidly metabolized because of esterases due to presence of ester linkage)

Intermediate acting

Propranolol                                                      3 – 5 hours

Timolol                                                            3 – 5 hours

Pindolol                                                           3 – 4 hours

Metaprolol                                                       3 – 4 hours

Long acting

Nadolol                                                           10 – 20 hours

Atenolol                                                          5 – 8 hours

Bisoprolol                                                        11 – 17 hours

Newer Classification

1^st generation drugs

Beta non selective drugs

2^nd generation drugs

Cardio selective drugs (beta 1 selective)

3^rd generation drugs

Drugs with other activities as well

Other Activities

1.      NO mediated vasodilatation –antihypertensive activity (cardio protective)
2.      Alpha 1 blockage
3.      Potassium channel opening
4.      Calcium channel blockage
5.      Beta 2 agonist activity
6.      Antioxidant activity

Mechanism of Action

Mechanism of action depends upon the affinity for receptors. They have affinity for receptors but no intrinsic activity, as they resemble the agonists. They chemically resemble isoprenaline and competitively block the effect of catecholamines at receptors. Their effects are reversible and depend upon the concentration.

1. Antagonize the effects of agonists i.e. negative ionotropic and chronotropic effect decreasing cardiac output and blood pressure (beta 1). After some time, cardiac output returns to normal, but blood pressure remains decreased due to absence of renin.
2. Block beta 1 receptors on JG cells, decreasing renin and blood pressure.
3. Presynaptically decrease the release of norepinephrine.
4. Central action by blocking beta 1 receptors in vasomotor center, decreasing sympathetic activity.
5. Natriuretic peptide secretion, leading to decreased blood pressure.
6. Producing sedation

Pharmacological Actions

1. CVS

Beta 1 receptors are found in the heart located in two main regions:

1. Myocardium, exhibiting positive ionotropic effect. When they are blocked, negative ionotropic effect is observed, resulting in decreased force of contraction and decreased cardiac output.
2. SA node, In nodes produce chronotropic effect, when blocked result in decreased work load and decreased oxygen demand.

If they are given to normal people, little effect is seen. Profound effect is observed only when an increase in sympathetic activity is observed. Normally when given to patients, initial rise in peripheral vascular resistance is noted, then it comes to normal.

When beta 2 receptors are blocked, catecholamines act on alpha 1 receptors to cause vasoconstriction, so a rise in vascular resistance takes place due to unopposed effect of alpha 1. After a few days to a few months, it returns to normal.

2. Respiratory System

Only beta 2 receptors are present, when blocked bronchoconstriction is noted. Thus beta blockers are not used in bronchial asthma. We can use beta 1 selective drugs.

3. Kidneys

Receptors are mainly present in JG apparatus, releasing rennin. When blocked, decrease in renin release takes place, resulting in decreased angiotensin and decreased aldosterone.

4. Metabolic Effects

a. Blood Glucose

Adrenaline increases blood glucose. Beta blockers decrease it and antagonize the action, resulting in decreased gluconeogenesis, decreased glycogenolysis and decreased release of glucagon.

This is of important significance in diabetics.

1. Release of catecholamines maintains glucose, if hypertensive or diabetic and take beta blockers, further decrease in glucose levels are seen, no sympathetic compensation occurs.
2. Patient taking beta blocker if develops hypoglycemia, symptoms of hypoglycemia occur only due to sympathetic response (palpitations, tachycardia), he takes sugar, etc. If sympathetic system is blocked, no symptoms occur and the person directly goes into comma. Thus unnoticed hypoglycemia is seen.

b. Lipid Metabolism

Beta blockers cause an increase in plasma lipids, triglycerides, LDLs and cholesterol, while causing a decrease in HDLs. This is stabilized after 6 months to one year and is not significant.

5. CNS

Beta blockers cross the blood brain barrier (lipid soluble), thus can cause CNS symptoms, nightmares, hallucinations and disturbances of sleep.

6. PNS

They cause a decrease in essential tremors.

7. Eye

a. They cause a decrease in intraocular pressure, thus are used in treatment of glaucoma.

b. Also produce a decrease in the synthesis of aqueous humor.

8. Ankle Jerk

In ankle jerk, relaxation time is prolonged. If the patient has hypothyroidism, again it is prolonged. Thus in cases of myxedema, it is difficult to diagnose.

 

Beta blockers are given by oral route of administration. They can also be given parentally. They are widely distributed.

Therapeutic Uses

Cardiovascular diseases

1. Hypertension (Cardio-protective)

Sole agents used in mild to moderate hypertension, also used in combination with other antihypertensive drugs

2. Angina pectoris (Prophylaxis)

Pain, especially due to exertion (may even be emotional), because of decreased blood supply. Beta blockers have a negative ionotropic and negative chronotropic effect. They increase the exercise tolerance and anxiety tolerance, decreasing the requirement of nitroglycerin.

They can also decrease the size of infarct.

This is because during infarction, some area undergoes necrosis immediately. But some cells at periphery can still be revived. If their ischemia is reversed, ultimate size of infarct can be decreased.

The bad point is that as diastole duration is increased, increased filling leads to decreased effects of beta blockers.

Beta 1 blockers decrease cardiac activity:

1. decreasing oxygen consumption
2. increasing diastolic phase, increasing life spam of myocardium

3.  Myocardial infarction

1. Primary prevention
2. Limit the size of infarct (Esmolol given as short lived, cardio depression will be short lived)
3. Secondary prevention –Timolol, Metoprolol, Propanolol

Beta blockers have an important effect especially because patients are anxious during MI, leading to further release of catecholamines and further progression. Beta blockers reduce catecholamines thus having cardio protective effect.

4. Cardiac arrhythmias (Class II antiarrhythmic)

Beta blockers are used in supraventricular arrhythmias (atrial fibrillation, flutter, sinus tachycardia), especially in patients suffering from anxiety induced arrhythmias or during exercise.

Beta blockers are antiarrhythmic due to:

1. Negative ionotropic and chronotropic effect
2. Decrease in AV conduction
3. Increase in refractory period
4. Diminish or decrease the phase 4 of depolarization

Due to this there is decrease in automaticity

5. Some beta blockers have MSA (resemble class 1) due to blockage of Na+ channels
6. Some beta blockers (sotalolol) cause increase in refractory period (have property like class III)

Drugs Used

Propanolol (wide range, start from 10 mg, may be increased to 100 mg, depending on conditions)

Esmolol has short duration. It is given I/V in emergency and operations where there is fear of arrhythmias.

D-Sotalol is preferred in ventricular arrhythmias as it also has K+ channel blocking activity. Beta blockers are more useful in atrial disorders because of their prominent action on AV node.

5. Congestive cardiac failure

In CCF, decreased cardiac pumping leads to over activity of sympathetics, thus increased work load on heart further damages the tissues. Compensation leads to decompensation.

• beta1 selective e.g. Metoprolol & bisoprolol
• non selective e.g. Carvedolol

Normally beta blockers are contraindicated because they block the activity of heart further. But in mild congestive failure, beta blockers are beneficial because:

a. They decrease the motility rate.

b. They cause bradycardia (negative ionotropic and chronotropic)

c. Cause up regulation of beta receptors

Beta blockers are given in slow doses, in severe congestive cardiac failure, beta blockers are contraindicated.

6. Obstructive Cardiomyopathies

1. Hypertrophic sub aortic stenosis (obstruction of left ventricular outflow)
2. Fallot’s teratology (congenital defect, obstruction of right ventricular outflow)

7. Dissecting aneurysm of aorta

In patients suffering from severe hypertension, tears in walls of aorta occur and dilatation of aorta occurs. Ultimate treatment is surgery but before that patients may be stabilized with beta blockers, which decrease the workload.

8.  Portal hypertension

In conditions like cirrhosis of liver, beta blockers decrease blood flow about 30%, thus decreasing portal hypertension (otherwise hemorrhage or gastroesophageal varices develop)

Propanolol or Nadolol decrease first incidence of bleeding. Nadolol and isosorbide momonitrate decrease the second incidence of esophageal bleeding.

9. Sub arachnoid hemorrhage

Sub arachnoid hemorrhage occurs in patients suffering from hypertension, sometimes even without hypertension. Beta blockers decrease work load and blood pressure.

How beta blockers decrease blood pressure?

1. Beta blockers decrease the release of renin from JG apparatus.
2. They have negative ionotropic and negative chronotropic effect.
3. They decrease the release of noradrenaline from adrenergic nerve terminals.
4. By central mechanism, they cross the BBB and block beta 1 mediated vasomotor center, blocking central sympathetic outflow and produce sedation.
5. They cause about 2-3 times increase in natriuretic peptides in kidney. (reduce sodium levels)

Non-Cardiovascular Uses

Conditions associated with sympathetic over activity

1. Thyrotoxicosis

In hyperthyroidism, increased sympathetic activity occurs. Thyroxine increases the effects of catecholalmines (sensitizes effects of catecholamines on beta receptors). Thus patients may suffer from  hypertension, cardiac arrhythmias (positive ionotropic and chronotropic effect).

These effects can be controlled by beta blockers. They are used in various phases of thyrotoxicosis to control the symptoms due to increased sympathetic activity because of:

1. prevention of conversion of T4 to T3
2. Negative ionotropic effect
3. Negative chronotropic effect
4. Decrease in tremors

a. Pregnancy

During pregnancy, antithyroid drugs are replaced by beta blockers because they are not safe, having teratogenic effect (causing goiter formation in fetus).

b. Ultimate treatment of thyrotoxicosis is surgery. In preparation for surgery for removal of adenoma of thyroid, beta blockers can be given.

c. Treatment of thyroid crisis

In acute hyperthyroidism, beta blockers are given to save life along with anti-thyroid drugs.

 2. Acute anxiety states (Panic syndromes)

Symptoms due to increased sympathetic activity include palpitations, tachycardia, and tremors. These symptoms can be controlled by beta blockers.

3. Childhood phobias

Propanolol may be used in 20-40 mg dose to control anxiety states.

 4. Acute porphyria

Congenital disorder resulting in increased production of porphyrin. Symptoms are aggravated by enzyme inducing drugs, which cause increase in sympathetic activity. Beta blockers may be used.

 5. Drug withdrawal syndrome

In addicts, beta blockers may be given to control symptoms due to increased sympathetic activity.

6. Pheochromocytoma (along with alpha blockers)

Beta blockers can be used to control increase in catecholamines due to tumor of adrenal medulla causing hypertension and cerebrovascular attacks.

One drug is never used as catecholamines may act on alpha receptors or if alpha receptors are blocked, on beta receptors.

Miscellaneous

1. Glaucoma (Simple open angle)

Levobunolol, Betaxolol, Timolol

Beta blockers are also used in treatment of glaucoma. Beta blockers are used which are devoid of MSA. They are topically instilled in the form of drops. MSA activity produces local anesthesia, reflex actions are lost and foreign body or dust may cause damage.

2. Migraine (Prophylaxis)

Beta blockers reduce the recurrence and intensity of attacks. They act by blocking the beta 2 mediated vasodilatation of cerebral blood vessels.

3. Familial Tremors

4. Torti Collis

Spasm of sternocleidomastoid is known as torti collis. Beta blockers relieve this condition by unknown mechanisms.

Drugs Preferred

1. Drugs with no MSA are used in glaucoma.
2. Drugs with ISA are preferred in bradycardia and in patients with poor cardiac reserves.
3. Beta 1 selective drugs are preferred in diabetes mellitus and asthma (do not block beta 2)
4. In peripheral vascular diseases (raynaud’s disease) beta 1 selective drugs are used (disease aggravated by vasoconstriction due to beta 2 blockage)
5. Short acting drugs are used in patients in emergency and during surgery (esmolol has half life of 9 minutes), when they are withdrawn effects are minimal.

Adverse effects

Adverse effects are the aggravation of therapeutic effects. They are opposite to the sympathomimetic drugs.

1. CVS

• Cardio depression, Bradycardia,
• Heart Blocks, Cardiac Failure
• Cold extremities (due to decreased C.O and decreased peripheral blood flow)
• Worsening of Peripheral Vascular Disease

2. Respiration

Bronchospasm (beta 2)

3. CNS

Sleep disturbances, Nightmares (lipid soluble beta blockers only)

4. Metabolic

• Masking of Hypoglycemia (patients may directly go into coma)
• Increased TGs, Reduced HDL (return to normal in 6 months to one year)

5. Male Sexual Dysfunction(due to blockage of sympathetic system)

6. Rashes(allergic response), Diarrhea(due to blockage of sympathetic system), Muscle cramps(due to decreased blood flow and cardiac output)

7. Oculomucocutaneous syndrome- practolol

Condition involving eye, mucous membrane and skin allergic reactions. Spots appear on the skin and mucous membranes.

Drugs Interactions

1. Enzyme inhibitors – Cimetidine

Metabolism decreases while half life and plasma concentration increases in case of lipid soluble beta blockers, water soluble are excreted as such.

2. Chlorpromazine, hydralazine, furesimide

Decrease blood flow from liver, decreasing the metabolism of lipid soluble beta blockers.

3. Enzyme inducers(Phenytoin, Barbiturates)

Increase the metabolism of lipid soluble beta blockers, decreasing their plasma concentration

4. Sympathomimetics

In people taking antagonists, up regulation of receptors occur. When beta blockers are taken over prolonged periods, up regulation occurs, and if sympathomimetics are taken, they have enhanced effects.

In people taking nasal decongestants, like alpha agonist drugs (adrenaline, ephedrine), up regulation of beta receptors occurs, which may lead to severe rise in blood pressure.

In patients taking local anesthetics combined with sympathomimetics, if use beta blockers, up regulation occurs leading to severe rise in blood pressure.

5. Prazosin

Alpha blocker. Acute fall in blood pressure occurs on first dose. Increased incidence occurs if taking beta blocker (as beta blockers cause fall in blood pressure)

6. Clonidine

Clonidine is antihypertensive. If patient is taking beta blockers and clonidine is suddenly withdrawn, hypertension crisis occurs.

7. Lignocaine

Lignocaine is a local anesthetic and antiarrhythmic drug (I/V route), if taking beta blockers clearance is decreased by decreased blood flow to liver and plasma levels of lignocaine rise.

8. Calcium channel blockers

Used in treatment of cardiac arrhythmias (Verapamil), beta blockers reduce AV conduction leading to severe bradycardia.

9. NSAIDs e.g. Indomethacin

Indomethacin may decrease effects of beta blockers, because acts mainly be blocking prostaglandins, especially those present in the kidneys (which are vasodilators), thus their contributing effects are not present. May also cause salt and water retention.

10. Antihypertensives

Beta blockers potentiate effects of antihypertensives, thus have a beneficial effect and are usually combined.

Treatment Of Over dosage

1. Atropine

Parasympatholytic and vagolytic control of bradycardia –physiological antagonism

2. Beta adrenoceptor agonists e.g. isoprenaline, dobutamine, dopamine

Until the heart rate is 50-70 per minute, they are given by IV infusion.

3. Glucagon

Glucagon increases blood glucose and has positive ionotropic and chronotropic effects. IV infusion is used to control the toxicity.

Contraindications

1. Hyperkalemia
2. Hyperlipidemia
3. Hypoglycemia
4. Hypotensive shock
5. Heart block
6. Asthma
7. Severe bradycardia
8. Decreased cardiac reserves (decompensated heart failure, unstable patients)
9. Peripheral vascular disease
10. Diabetes type II

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