Nursing Pharmacology:  Autonomic Pharmacology Adrenergic Drugs

ß-Adrenergic Antagonists

Introduction

• Clinical uses for β-adrenoceptor antagonists

  • Non-selective (blocks both β₁ and β₂ type β receptors).

    •  Hypertension

    •  Angina

    •  Arrhythmias

    •  Glaucoma

    •  Mgraine

  • β₁-Selective

    • Arrhythmias

    • Hypertension

• ß-Adrenergic Antagonists are clinically important drugs, used in treatment of hypertension, coronary vascular disease and arrhythmias.

• Propranolol is an example of a non-selective ß-adrenergic receptor blocker, i.e. capable of blocking both ß₁ and ß₂ receptor subtypes.

• Metoprolol (Lopressor) and atenolol (Tenormin) are examples of ß₁ selective drugs, having a greater affinity for ß₁ compared to ß₂ receptor subtypes.

  • The selectivity is not absolute in that a "ß₁ selective" drug will interact with ß₂ sites. 

• ß₁ selective antagonists are cardioselective.

• ß receptor blockers exert most of their therapeutic actions on the cardiovascular system.

• ß receptor blockers: Effects on the heart: 

  • Decrease heart rate

  • Reduce contractility

  • Decrease conduction velocity in atria and AV node

  • Decrease phase 4 depolarization

  • Reduce myocardial oxygen demand

  • Increased refractory period of the AV node

• ß receptor blockers: Antihypertensive Effects:

  • β_- receptor blockers reduce blood pressure in patients with hypertension (not in normal subjects)

  •  β-receptor blockers are effective in reducing blood pressure in both "high-renin" and "low-renin" patients.

  • Renin release in response to sympathetic stimulation is blocked by ß receptor blockers.

  • A long-term reduction in peripheral resistance, in addition to a reduction in cardiac output, contributes to the antihypertensive effects of β receptor blockers. (mechanism for reduction in peripheral resistance is unknown)

  • Some antihypertensive ß receptor blockers also exhibit α -receptor blocking properties, e.g. labetalol. In this case reduction in peripheral resistance is explained by α -receptor blocking properties

•  Pulmonary Effects

  • In asthmatic patients or patients with COPD (chronic obstructive pulmonary disease) ß receptor blockers cause dangerous bronchiolar constriction.

    • This effect is particularly prominent with nonselective ß receptor blockers, such as propranolol.

• Metabolic Actions

  • ß adrenergic receptor antagonists influence carbohydrate and lipid metabolism.

  • Catecholamines increase glycogenolysis and glucose availability in hypoglycemia: this response is reduced by ß adrenergic receptor antagonists.

  •  In insulin-dependent diabetes, adrenergic receptor antagonists impede recovery from hypoglycemia.

  •  Adrenergic receptor antagonists may mask symptoms of hypoglycemia.

    • This property interfers with the patients ability to anticipate a hypoglycemic episode.

  •  Circulating free fatty acids are utilized by exercising muscle.

    • Increasing availability of free fatty acids may be mediated by ß₃ adrenergic receptor subtypes. ß adrenergic receptor antagonists interfere with this metabolic response.

  • ß adrenergic receptor agonists decrease plasma K⁺ concentration by promoting transport into cells, primarily muscle.

    • In exercise, serum K⁺ increases.

      • Catecholamines are involved in regulating serum levels.

    • ß adrenergic receptor antagonists interfere with this K⁺ regulation mechanism.

  • Other Effects

    • ß adrenergic receptor antagonists block catecholamine-induced tremor and mast-cell degranulation.

• Nonselective-ß adrenergic receptor antagonists

  • Propranolol (Inderal) is a nonselective ß adrenergic receptor antagonist.

    • Effective in treating

      • Essential hypertension

      • Angina

      • Certain arrhythmias

    • Propranolol (Inderal) decreases amide local anesthetic clearance by:

      • Decreasing hepatic blood flow

      • Inhibiting hepatic metabolism

        • Bupivacaine (Marcaine): 35% decrease in clearance -- probably due to metabolic effects since bupivacaine is a low extraction drug (not sensitive to hepatic blood flow changes)

      •  Possible increases in systemic toxicity of bupivacaine (Marcaine) (and other amide local anesthetics) when the anesthetics are administered concurrently with propranolol (Inderal).

    • Propranolol (Inderal) (after chronic administration) reduces pulmonary first-pass uptake of fentanyl (Sublimaze).

      • As a consequence: immediately after fentanyl (Sublimaze) administration, 2X to 4X more injected Fentanyl (Sublimaze) into the systemic circulation

        • Possible mechanism: propranolol (a basic, lipophilic amine) inhibits the pulmonary uptake of a second basic lipophilic amine (fentanyl)

  • Nadolol (Corgard): nonselective ß adrenergic receptor antagonist

    • Long half-life

    • May accumulate in patient with renal dysfunction

  • Timolol (Blocadren): nonselective ß adrenergic receptor antagonist

    • Ocular use: treatment of glaucoma

    • Systemic effects common after ocular application

      • Bradycardia and hypotension refractory to atropine effects may occur during anesthesia in pediatric and adult patients receiving topical timolol (Blocadren).

      • Timolol may impair neonatal ventilation resulting in an unexpected postoperative apnea. (Blood-brain barrier immaturity in the neonate may faciliate the drug's access to the brain, promoting this effect.)

      • Contraindicated in patients

        • With congestive heart failure.

        • Cardiac conduction abnormalities (partial heart block)

        • Asthma

  • Labetalol (Trandate, Normodyne) α₁ AND ß₁ adrenergic receptor antagonist.

    • This drug decreases blood pressure in hypertensive patients.

    • α₁ blocking action decreases vascular smooth muscle tone.

    • ß₁ adrenergic receptor antagonism reduces heart rate.

    • ß₂ adrenergic receptor agonist property also promotes vascular relaxation.

    • Labetalol may be used to reduce heart rate and blood-pressure increases in anesthetized patients,  who are reacting to a rapid increase in the level of painful surgical stimulation.

  • Interaction of β-adrenergic receptor antagonists with anesthetics:

    • Additive myocardial depression between anesthetics and β-adrenergic antagonist is not excessive; β-adrenergic treatment may be maintained, safely, throughout the perioperative period.

      •  Exception: timolol (Blocadren)

        • Substantial bradycardia observed in presence of inhaled anesthetics

    • Additive cardiovascular effects with inhaled anesthetics with β-adrenergic receptor blockade drugs:

      • Greatest: enflurane (Ethrane)

      • Intermediate: halothane (Fluothane)

      • Least: isoflurane (Forane) (also, sevoflurane (Sevorane, Ultane) and desflurane (Suprane))

    • When using anesthetic drugs such as ketamine (Ketalar) that increase sympathetic nervous system activity or when excessive sympathetic activities is present (e.g.hypercarbia), β-receptor blockade may unmask the drug's negative inotropic property, thereby decreasing systemic blood-pressure and cardiac output.

• Selective-ß₁ adrenergic receptor antagonists

  • Metoprolol (Lopressor)

    • Metoprolol is a cardioselective ß₁ adrenergic receptor antagonist.

    • Effective in treating essential hypertension

    • Effective in treating symptoms of coronary artery disease

    • Contraindicated in management of acute myocardial infarction if heart rates are < 45 bpm.

  • Esmolol (Brevibloc)

    • Esmolol is also a cardioselective ß₁ adrenergic receptor antagonist.

    • Very short duration of action

    • I.V. administration

    • Effective in rapid termination of paroxymal supraventricular arrhythmias

    • Short duration of action (plasma esterases, not plasma cholinesterases) is beneficial in management of intraoperative adverse BP/heart rate increases associated with noxious stimulation (e.g. during tracheal intubation)

      • IV esmolol administration before direct laryngoscopy in tracheal intubation protects against heart rate in systolic blood pressure increases which is typically associated with tracheal intubation.

    • Perioperative hypertension and tachycardia may also be generally prevented by esmolol (Brevibloc) administration over a 15 second period before anesthesia induction.

    • Esmolol (Brevibloc) , IV, administered to patients undergoing electroconvulsive treatment and anesthetized with methohexital (Brevital) and succinylcholine (Anectine) is associated with reduced positive chronotropic effects and reduced duration of electrically-induced seizures

    • Other esmolol (Brevibloc) uses:

      • Reduced catecholamine release during anesthesia in patients with hypertrophic obstructive cardiomyopathy.

      • Reduced catecholamine release in patients experiencing hypercyanotic spells (associated with tetralogy of Fallot)

    • Esmolol (Brevibloc) reduces plasma propofol concentration needed to prevent patient movement upon surgical skin incision-- unknown mechanism

  • Atenolol (Tenormin)

    • Most cardioselective ß₁ adrenergic receptor antagonist

    • Used in treating hypertension

    • Somewhat longer action compared to metoprolol

    • Atenolol may have special benefit for patients undergoing noncardiac surgery but having significant underlying coronary artery disease:

      • Preoperative IV atenolol (Tenormin) , postoperative IV atenolol (Tenormin) , and oral therapy during hospitalization reduce mortality and incidence of cardiovascular complications.

      • Perioperative atenolol (Tenormin) for high-risk patients (CHD): reduces postoperative myocardial ischemia incidence.

• Adverse Effects of ß adrenergic receptor antagonists

  • Cardiovascular

    • Congestive heart failure (due to negative chronotropic/inotropic effects)

    • Bradycardia

    • Abrupt discontinuation may cause angina and increases the risk of sudden death

  • Pulmonary

    • Bronchoconstriction due to blockade of ß₂ adrenergic receptors

    • ß adrenergic receptor antagonist contraindicated in asthma

  • CNS

    • Fatigue

    • Sleep disturbances

    • Depression

  • Metabolic Effects

    • Delays recovery from insulin-induced hypoglycemia

    • Decreases awareness of onset of hypoglycemic symptoms.

    • Increases blood lipid levels

• Therapeutic Uses for β-adrenergic receptor antagonists (Blockers)

  • Hypertension

  • Supraventricular arrhythmias

  • Ventricular arrhythmias

  • Myocardial infarction (decreases myocardial oxygen demand)

  • Acute dissecting aortic aneurysm (reduced inotropism)

  • Hypertrophic obstructive cardiomyopathy

  • symptoms of hyperthyroidism

  • Prophylaxis of migraine (propranolol, metoprolol, timolol)

  • Acute panic disorder

  • Stage fright (performance anxiety)

  • Gaucoma (timolol)

  • Essential tremor

Hoffman, B.B and Lefkowitz, R.J, Catecholamines, Sympathomimetic Drugs, and Adrenergic Receptor Antagonists, In, Goodman and Gillman's The Pharmacologial Basis of Therapeutics, (Hardman, J.G, Limbird, L.E, Molinoff, P.B., Ruddon, R.W, and Gilman, A.G.,eds) The McGraw-Hill Companies, Inc.,1996, pp.232-242.

Stoelting, R.K., "Sympathomimetics", in Pharmacology and Physiology in Anesthetic Practice, Lippincott-Raven Publishers, 1999, pp. 293-301