BETA ADRENERGIC RECEPTOR BLOCKERS

BETA ADRENERGIC RECEPTOR BLOCKERS

 

II. Beta Adrenergic Receptor Blockers

A. Introduction

1. Cardiovascular effects of Beta Blockers

a. Since catecholamines have positive inotropic and chronotropic effects on the heart, beta blockers slow the heart rate, and decrease myocardial contractility. When sympathetic activation is low, these drugs have modest effects. However, when sympathetic activation is high, such as during exercise and stress, beta blockers attenuate the expected increase in heart rate, and diminish cardiac output. Blockade of vascular Beta 2 receptors results in increased total peripheral resistance. Blood flow to most organs other than the brain is reduced. With long term use total peripheral resistance returns toward normal by unclear mechanisms. Beta blockers tend to decrease the capacity to work. Exercise performance is impaired less by selective Beta 1 blockers. Beta blockers have important effects on cardiac rhythm and automaticity. They reduce the sinus rate, decrease the rate of depolarization of ectopic pacemakers, and slow conduction in the atria and AV node. Lots more on this topic during lectures on antiarrhythmic drugs. Beta blockers do not lower blood pressure in normal man, however they do reduce blood pressure in hypertensive man. The mechanism of this effect has not been satisfactorily explained. Chronic prophylactic therapy with a beta blocker in patients who have had a myocardial infarct appears to help prevent the recurrence of a second fatal myocardial infarct.

2. Pulmonary effects of Beta Blockers

a. Beta blockade usually has little effect on pulmonary function in normal man, however in asthmatics they can cause life threatening bronchoconstriction. Although Beta 1 selective blockers may be less likely to cause respiratory problems in asthmatics, these drugs should be used with great caution, if at all in patients with bronchospastic disease since even relatively selective blockers have some affinity for the beta 2 receptor.

3. Metabolic effects of Beta Blockers

a. Catecholamines promote glycogenolysis and mobilize glucose in response to hypoglycemia. Non-selective Beta blockers adversely effect recovery from hypoglycemia in insulin dependent diabetics. Nonselective Beta blockers must therefore be used with great caution in diabetics. A selective Beta 1 blocker is usually preferable in this case. Beta blockers (Beta 3 receptor) attenuate the lipolytic response to sympathetic nervous system activation which is an important energy source for exercising muscle. Selective beta 1 antagonists may cause these effects less fequently than non-selective antagonists.

 

B. Pharmacology of Nonselective Beta Blockers

1. Propranolol

a. After oral administration, propranolol is almost completely absorbed, but undergoes extensive first pass metabolism in the liver. The extent of clearance by the liver varies radically across patients however and results in as much as a 20 fold difference in plasma concentration of the drug after oral administration to different persons. This has obvious significance in patients with liver disease. 90% of the drug in the circulation is bound to plasma proteins. When used as an antihypertensive agent, the full response on the blood pressure may not develop until after several weeks of administration. Abrupt withdrawal of propranolol after chronic therapy can lead to the develpment of withdrawal symptoms. Side effects include GI distress (relatively unopposed parasympathetic nervous system), and CNS effects such as nightmares, insomnia, and depression.

2. Nadolol

a. Nadolol is a nonselective beta blocker with a long duration of action. Nadolol is poorly lipid soluble, and incompletely absorbed from the GI tract. Interindividual variability in its bioavailability is less than with propranolol. It is not extensively metabolized, and is excreted intact in the urine. As such kidney disease is a cause for concern, and may result in an accumulation of nadolol. Because nadolol is poorly lipid soluble, it is thought that there will be lower concentrations of nadolol in the brain, and this may contribute to a lower incidence of CNS side effects seen with this drug.

3. Timolol

a. It is a nonselective blocker with a short duration of action. It is well absorbed from the gut and is subject to moderate first pass metabolism. It is metabolized by the liver and only a small fraction is excreted by the kidney in unchanged form. Timolol is an example of a beta blocker which is used in glaucoma to reduce the rate of synthesis of aqueous humor. The ocular form of timolol is well absorbed into the circulation and adverse effects can occur in patients with asthma or congestive heart failure.

b. Other new drugs with similar mechanisms of action include Bopindol, Carteolol, oxprenolol, penbutolol, sotalol etc etc

 

4. Labetolol

a. It is an example of a nonselective beta blocker which also blocks alpha 1 receptors. It also inhibits uptake of NE from the synaptic cleft (a cocaine-like effect). Its pharmacokinetics are like those of Propranolol discussed above, ie well absorbed, highly metabolized and very variably so on first pass through liver, mainly metabolized by liver. It is used in the treatment of pheochromocytoma and hypertensive emergency, where its alpha 1 effects promote vasodilation and hypotension, while its beta 1 effect helps reduce reflex tachycardia.

b. Other new drugs with a similar mechanism of action include Carvedilol, Medroxalol, Bucindolol

 

C. Pharmacology of Selective Beta Blockers

 

1. Metaprolol

a. It is a selective Beta 1 antagonist, whose pharmacokinetics are like propranolol.

2. Atenolol

a. It is also a selective Beta 1 antagonist. It is a poorly lipid soluble drug. About half of an oral dose is absorbed, but most of this reaches the systemic circulation ie there is no first pass metabolism in the liver. As a result, peak concentrations of this drug in the plasma are not so variable across patients. It is excreted unchanged in the urine. It has a somewhat longer duration of action than metaprolol.

3. Esmolol

a. it is a selective Beta 1 antagonist with a very very short duration of action. It is given by iv infusion. It has a half life of about 8 minutes in plasma, and is metabolized by plasma esterases. It is used only for the treatment of atrial tachycardia.

b. Other new drugs with a similar mechanism of action include Bisoprolol, Nebivolol, Betaxolol

 

D. Toxic Effects of Beta Blockers

 

1. Patients with impaired cardiac function have high levels of sympathetic activation of the heart to provide support for cardiac performance. In these patients, beta blockers may provoke an acute incident of congestive heart failure. In fact use of beta blockers in heart failure was once contraindicated.

a. Despite this fact, beta antagonists are currently being used for the treatment of mild to moderate degrees of congestive heart failure. Not all beta blockers are equally efficacious, however metoprolol appears to be useful. The mechanisms which underly this beneficial effect are poorly understood at this time.

2. Arrhythmias, especially bradyarrhythmias .

3. Bronchoconstriction, especially in asthmatics

4. CNS effects include sleep disturbances & depression

5. Metabolic effects include delayed recovery from insulin induced hypoglycemia.

 

E. Drug Interactions

 

1. Drugs that induce hepatic drug metabolizing enzymes will reduce the plasma concentrations of beta blockers that are extensively metabolized by the liver. These include barbiturates, many miscellaneous sedative hypnotic drugs, phenytoin (diphenylhydantoin), as well as smoking.

 

F. Therapeutic Uses of Beta Blockers

 

1. Used as Antihypertensives especially in mild cases where they are less likely than other agents to provoke postural hypotension.

2. In the treatment of ischemic heart disease

a. In angina, beta blockers reduce cardiac work and oxygen consumption. This reduces the frequency of anginal episodes.

b. Long term prophylactic use of nonspecific beta blockers helps prevents the recurrence of a fatal second myocardial infarct in patients who survived an initial attack. The mechanism of this effect is not known.

3. In the treatment of mild to moderate degees of congestive heart failure, chronic treatment with certain beta-1 blockers prolong the life expectancy.

4. Beta blockers are antiarrhythmics. More in other lectures. Here, only mentioned their ability to block atrial tachycardia.

5. In glaucoma, beta blockers decrease the rate of synthesis of aqueous humors.

6. Many of the signs and symptoms of hyperthyroidism are due to sympathetic nervous system activation. Beta blockers reduce these symptoms.

7. Beta blockers are useful in the prophylaxis of migraine, but not in treatment.