Beta Adrenergic Antagonist

Overview
  • Beta-adrenergic antagonists, commonly known as beta blockers, are all reversible antagonists of beta adrenergic receptors. The primary pharmacological and therapeutic uses of these drugs are cardiovascular and they represent some of the most commonly used strategies for medical management of heart disease and hypertension. A variety of these compounds have been synthesized with variable specificity for beta1 versus beta2 receptors along with different pharmacokinetic properties that yield specialized clinical applications. For medical students an intimate knowledge of the differences and clinical applications of beta blockers is unnecessary and we present a generalized picture below. We briefly discuss a few specific properties of particular drugs at the end. Almost all beta blockers end in the suffix "-olol" except for labetalol and carvedilol.
Pharmacological Actions
  • Cardiac Effects
    • Sympathetic tone on cardiac beta1 receptors results in increased contractility as well as heart rate by enhancing SA nodal rate and conduction through the AV node (See: Autonomic Cardiac Regulation). Consequently, blockade of beta receptors yields decreased cardiac contractility and heart rate, together yielding reduced total cardiac output. When cardiac activity is already at a low baseline in a resting healthy individual, these effects are relatively mild. However, beta blockers can profoundly blunt the inotropic and chronotropic effects of catecholamines, thus reducing cardiac oxygen demand in contexts of sympathetic stimulation.
  • Vascular Effects
    • Blockade of vasodilatory beta2 receptors results in a mild vasoconstriction and thus increased systemic vascular resistance (SVR). This tendency to boost SVR is also enhanced by endogenous reflex responses triggered from reduced cardiac output described above. However, in most patients SVR returns to normal within a few days.
  • Blood Pressure Effects
    • Beta blockers are some of the most frequently prescribed anti-hypertensives; however, the precise mechanism by which they reduce systemic arterial pressure is not well understood. Whatever the process it is not simply due to a reduction in cardiac output. It has been suggested that reduced sodium resorption in the kidneys due to inhibition of beta1 receptors may also contribute (See: SNS - Renal Effects).
  • Pulmonary Effects
    • Blockade of bronchodilatory beta2 receptors can result in bronchoconstriction. This is of little consequence in healthy individuals, but in those with COPD or asthma it can precipitate a bronchspastic crisis. Although Beta1-secific beta-blockers are less likely to cause these effects their clinical use in susceptible patients is still done with great caution.
  • Metabolic Effects
    • Beta adrenergic receptors normally cause increased blood glucose by triggering hepatic glycogenolysis; therefore, use of beta-blockers can reduce the liver's capacity to mobilize glucose. Normally, this is of little clinical significance but can lead to devastating hypoglycemia in contexts of labile Type I Diabetes Mellitus following insulin injection. Type II Diabetics are much less to prone to this adverse effect.
Therapeutic Uses
  • Hypertension
    • Beta-blockers are some of the most commonly prescribed anti-hypertensives; however, as described above the precise mechanism by which they exert their anti-hypertensive effects remains unclear.
  • Ischemic Heart Disease
    • By reducing cardiac output, beta blockers are potent reducers of cardiac oxygen demand especially in contexts of increased sympathetic outflow to the heart. In patients with stable angina or those experiencing an outright myocardial infarction, this reduction in cardiac oxygen demand is highly beneficial in reducing myocardial ischemia. Consequently, beta-blockers are critical during the medical management of an acute ischemic event.
    • Beta-blockers are also administered as maintenance therapy for those with stable angina and CHF secondary to ischemic heart disease. While their capacity to reduce cardiac output probably contributes, beta-blockers also appear to display anti-remodelling properties that make up the bulk of their usefulness in these contexts. However, it is important to avoid administration of beta-blockers during acute exacerbations of CHF as reductions in cardiac output are devastating in this context.
  • Anti-arrhythmic
    • The anti-choronotropic effects of beta-blockers provide excellent anti-arrhythmic properties especially in contexts of supra-ventricualar tachycardias. Here, inhibition of AV nodal conduction by beta-blockers reduces the frequency by which supra-ventricular impulses travel through the AV node and thus can maintain fairly normal ventricular rates.
  • Migraine
    • Beta-blockers have been successfully used for migraine headache prophylaxis although are not useful during acute attacks. Their activity in this context may arise from the fact that vascular dysfunction may be a component of migraine pathophysiology.
  • Hyperthyroidism
    • Beta-blockers are used in contexts of acute hyperthyroid crises due to their ability to blunt sympathetic hyperactivity to the heart which is arrhythmogenic.
  • Glaucoma
    • Blockade of beta-receptors appears to reduce secretion of the aqueous humor and thus beta blockers are effective in medical management of Open-angle glaucoma.
Adverse Effects
  • Cardiovascular Adverse Effects
    • Because beta-blockers reduce cardiac output, they are contraindicated in contexts of an acute CHF exacerbation when cardiac output is already pathologically low. However, as described previously beta-blockers are prescribed for maintenance therapy in compensated CHF to reduce cardiac remodeling.
    • Beta-blockers can cause bradycardia in some and may exacerbate conduction delays in patients with heart block and should be used with caution in these contexts
    • Finally, abrupt discontinuation of beta-blockers after long-term maintenance therapy can precipitate sudden death and angina through still emerging mechanisms
  • Respiratory Adverse Effects
    • As mentioned, non-specific beta-blockers antagonize beta2 receptors, resulting in bronchoconstriction. This is of little significance in healthy individuals but can be catastrophic in patients with bronchospastic disease such as those with asthma or COPD.
  • Metabolic Adverse Effects
    • As mentioned above, beta-blockers reduce hepatic glycogenolysis and may lead to catastrophic hypoglycemia in patients with labile diabetes following injection of insulin.
Specific Compounds
  • Overview
    • A large number of beta-blockers exist and can be divided into several classes depending on their selectivity for beta1 versus beta2 receptors. Additionally, certain beta-blockers exert antagonism toward alpha1 receptors which provide useful clinical benefits.
  • Non-selective Beta Antagonists: Propanolol, Timolol, Nadolol
    • These drugs antagonize beta1 and beta2 adrenergic receptors equally and are thus more likely to cause bronchospastic adverse effects
    • Timolol is frequently used in treatment of glaucoma
  • Beta1 Selective Antagonists: Atenolol, Metoprolol, Esmolol, Acetbutolol
    • These drugs have significant specificity for beta2 receptors and display relatively little antagonism of beta2 receptors, yielding fewer bronchospastic side effects
    • Esmolol has an especially short half life of 10 minutes
  • Beta Antagonists with Anti-alpha Properties: Labetalol, Carvedilol
    • These drugs are non-specific beta blockers that also have some antagonism toward alpha1 receptors. By antagnozing alpha1 receptors these drugs somewhat attenuate the vasoconstrictive properties resulting from beta2 blockade. Consequently, labetaolol and carvedilol are thought to be slightly better anti-hypertensives.