Katzung & Trevor's Pharmacology Examination and Board Review, 9th Edition

Chapter 10. Adrenoceptor Blockers

Adrenoceptor Blockers: Introduction

Alpha- and beta-adrenoceptor-blocking agents are divided into primary subgroups on the basis of their receptor selectivity. All of these agents are pharmacologic antagonists or partial agonists. Because  and  blockers differ markedly in their effects and clinical applications, these drugs are considered separately in the following discussion.

High-Yield Terms to Learn

Competitive blocker A surmountable antagonist (eg, phentolamine); one that can be overcome by increasing the dose of agonist Epinephrine reversal Conversion of the pressor response to epinephrine (typical of large doses) to a blood pressure-lowering effect; caused by  blockers Intrinsic sympathomimetic activity (ISA) Partial agonist action by adrenoceptor blockers; typical of several  blockers (eg, pindolol, acebutolol) Irreversible blocker A nonsurmountable inhibitor, usually because of covalent bond formation (eg, phenoxybenzamine) Membrane stabilizing activity (MSA) Local anesthetic action; typical of several  blockers (eg, propranolol) Orthostatic hypotension Hypotension that is most marked in the upright position; caused by venous pooling (typical of  blockade) or inadequate blood volume (caused by blood loss or excessive diuresis) Partial agonist A drug (eg, pindolol) that produces a smaller maximal effect than a full agonist and therefore can inhibit the effect of a full agonist Pheochromocytoma A tumor consisting of cells that release varying amounts of norepinephrine and epinephrine into the circulation

Alpha-Blocking Drugs

Classification

Subdivisions of the  blockers are based on selective affinity for 1 versus 2 receptors or a lack thereof. Other features used to classify the -blocking drugs are their reversibility and duration of action.

Irreversible, Long-Acting

Phenoxybenzamine is the prototypical long-acting, irreversible  blocker. It is only slightly 1 selective.

Reversible, Shorter-Acting

Phentolamine is a competitive, reversible blocking agent that does not distinguish between 1 and 2 receptors.

Alpha1-Selective

Prazosin is a highly selective, reversible pharmacologic 1 blocker. Doxazosin, terazosin, and tamsulosin are similar drugs. The advantage of 1 selectivity is discussed in the following text.

Alpha2-Selective

Yohimbine and rauwolscine are 2-selective competitive pharmacologic antagonists. They are used primarily in research applications.

Pharmacokinetics

Alpha-blocking drugs are all active by the oral as well as the parenteral route, although phentolamine is rarely given orally. Phenoxybenzamine has a short elimination half-life but a long duration of action—about 48 h—because it binds covalently to its receptor. Phentolamine has a duration of action of 2-4 h when used orally and 20-40 min when given parenterally. Prazosin and the other 1-selective blockers act for 8-24 h.

Mechanism of Action

Phenoxybenzamine binds covalently to the  receptor, thereby producing an irreversible (insurmountable) blockade. The other agents are competitive pharmacologic antagonists—that is, their effects can be surmounted by increased concentrations of agonist. This difference may be important in the treatment of pheochromocytoma because a massive release of catecholamines from the tumor may overcome a reversible blockade.

Effects

Nonselective Blockers

These agents cause a predictable blockade of -mediated responses to sympathetic nervous system discharge and exogenous sympathomimetics (ie, the  responses listed in Table 9-1). The most important effects of nonselective blockers are those on the cardiovascular system: a reduction in vascular tone with a reduction of both arterial and venous pressures. There are no significant direct cardiac effects. However, the nonselective  blockers do cause baroreceptor reflex-mediated tachycardia as a result of the drop in mean arterial pressure (see Figure 6-4). This tachycardia may be exaggerated because the 2 receptors on adrenergic nerve terminals in the heart, which normally reduce the net release of norepinephrine, are also blocked (see Figure 6-3).

Epinephrine reversal (Figure 10-1) is a predictable result of the use of this agonist in a patient who has received an  blocker. The term refers to a reversal in the blood pressure effect of large doses of epinephrine, from a pressor response (mediated by  receptors) to a depressor response (mediated by 2 receptors). The effect is not observed with phenylephrine or norepinephrine because these drugs lack sufficient 2 effects. Epinephrine reversal is occasionally seen as an unexpected (but predictable) effect of drugs for which  blockade is an adverse effect (eg, some phenothiazine tranquilizers, antihistamines).

FIGURE 10-1

The effects of an  blocker, for example, phentolamine, on the blood pressure responses to epinephrine (epi) and phenylephrine. The epinephrine response exhibits reversal of the mean blood pressure change from a net increase (the  response) to a net decrease (the 2 response). The response to phenylephrine is suppressed but not reversed, because phenylephrine is a "pure"  agonist without  action.

Selective  Blockers

Because prazosin and its analogs block vascular 1 receptors much more effectively than the 2-modulatory receptors associated with cardiac sympathetic nerve endings, these drugs cause much less reflex tachycardia than the nonselective  blockers when reducing blood pressure. These drugs also have important effects on smooth muscle in the prostate.

Clinical Uses

Nonselective  Blockers

Nonselective  blockers have limited clinical applications. The best-documented application is in the presurgical management of pheochromocytoma. Such patients may have severe hypertension and reduced blood volume, which should be corrected before subjecting the patient to the stress of surgery. Phenoxybenzamine is usually used during this preparatory phase; phentolamine is sometimes used during surgery. Phenoxybenzamine also has serotonin receptor-blocking effects, which justify its occasional use in carcinoid tumor; and H1 antihistaminic effects, which lead to its use in mastocytosis.

Accidental local infiltration of potent  agonists such as norepinephrine may lead to tissue ischemia and necrosis if not promptly reversed; infiltration of the ischemic area with phentol-amine is sometimes used to prevent tissue damage. Overdose with drugs of abuse such as amphetamine, cocaine, or phenylpropanolamine may lead to severe hypertension because of their indirect sympathomimetic actions. This hypertension usually responds well to blockers. Sudden cessation of clonidine therapy leads to rebound hypertension (Chapter 11); this phenomenon is often treated with phentolamine.

Raynaud's phenomenon sometimes responds to  blockers, but their efficacy is not well documented in this condition. Phentolamine or yohimbine has been used by direct injection to cause penile erection in men with erectile dysfunction.

Selective  Blockers

Prazosin, doxazosin, and terazosin are used in hypertension (Chapter 11). These 1 blockers, tamsulosin, and silodosin are also extensively used in the management of urinary hesitancy and prevention of urinary retention in men with benign prostatic hyperplasia.

Toxicity

The most important toxicities of the  blockers are simple extensions of their -blocking effects. The main manifestations are orthostatic hypotension and, in the case of the nonselective agents, marked reflex tachycardia. Tachycardia is less common and less severe with 1-selective blockers. Phentolamine also has some non-alpha-mediated vasodilating effects. In patients with coronary disease, angina may be precipitated by the tachycardia. Oral administration of some of these drugs can cause nausea and vomiting. The 1-selective agents are associated with an exaggerated orthostatic hypotensive response to the first dose in some patients. Therefore, the first dose is usually small and taken just before going to bed.

Beta-Blocking Drugs

Classification, Subgroups, and Mechanisms

All of the  blockers used clinically are competitive pharmacologic antagonists. Propranolol is the prototype. Drugs in this group are usually classified into subgroups on the basis of 1 selectivity, partial agonist activity, local anesthetic action, and lipid solubility (Table 10-1).

TABLE 10-1 Properties of several -adrenoceptor-blocking drugs.

Drug Selectivity Partial Agonist Activity Local Anesthetic Activity Lipid Solubility Elimination Half-Life Acebutolol 1

Yes Yes Low 3-4 h Atenolol 1

No No Low 6-9 h Carvedilol a

None No No Moderate 7-10 h Esmolol 1

No No Low 10 min Labetalol a

None Yesb

Yes Low 5 h Metoprolol 1

No Yes Moderate 3-4 h Nadolol None No No Low 14-24 h Pindolol None Yes Yes Moderate 3-4 h Propranolol None No Yes High 3.5-6 h Timolol None No No Moderate 4-5 h

aAlso causes -receptor blockade.

bPartial agonist effect at 2 receptors.

Modified, with permission, from Katzung BG, editor: Basic & Clinical Pharmacology, 11th ed., McGraw-Hill, 2009: p. 157.

Receptor Selectivity

Beta1-receptor selectivity (1 block > 2 block) is a property of acebutolol, atenolol, esmolol, metoprolol, and several other  blockers. This property may be an advantage when treating patients with asthma. Nadolol, propranolol, and timolol are typical nonselective  blockers.

Labetalol and carvedilol have combined - and -blocking actions. These drugs are optically active, and different isomers have - or -blocking action.

Partial Agonist Activity

Partial agonist activity ("intrinsic sympathomimetic activity") may be an advantage in treating patients with asthma because these drugs (eg, pindolol, acebutolol )—at least in theory—are less likely to cause bronchospasm. In contrast, full antagonists such as propranolol are more likely to cause severe bronchospasm in patients with airway disease.

Local Anesthetic Activity

Local anesthetic activity ("membrane-stabilizing activity") is a disadvantage when  blockers are used topically in the eye because it decreases protective reflexes and increases the risk of corneal ulceration. Local anesthetic effects are absent from timolol and several other  blockers that are useful in glaucoma.

Pharmacokinetics

Most of the systemic agents have been developed for chronic oral use, but bioavailability and duration of action vary widely (Table 10-1). Esmolol is a short-acting ester  blocker that is used only parenterally. Nadolol is the longest-acting  blocker. Acebutolol, atenolol, and nadolol are less lipid-soluble than other  blockers and probably enter the central nervous system (CNS) to a lesser extent.

Effects and Clinical Uses

Most of the organ-level effects of  blockers are predictable from blockade of the -receptor-mediated effects of sympathetic discharge. The clinical applications of  blockade are remarkably broad (Table 10-2). The treatment of open-angle glaucoma involves the use of several groups of autonomic drugs as well as other agents (Table 10-3). The cardiovascular applications of  blockers—especially in hypertension, angina, and arrhythmias—are extremely important. Treatment of chronic (not acute) heart failure has become an important application of  blockers. Several large clinical trials have shown that that some, but not all,  blockers can reduce morbidity and mortality when used properly in heart failure (see Chapter 13). Labetalol, carvedilol, and metoprolol appear to be beneficial in this application. Pheochromocytoma is sometimes treated with combined - and -blocking agents (eg, labetalol), especially if the tumor is producing large amounts of epinephrine as well as norepinephrine.

TABLE 10-2 Clinical applications of  blockers.

Application Drugs Effect Hypertension Atenolol, propranolol, metoprolol, timolol, others Reduced cardiac output, reduced renin secretion, other Angina pectoris Propranolol, others Reduced cardiac rate and force Arrhythmia prophylaxis after myocardial infarction Propranolol, metoprolol, timolol Reduced automaticity of all cardiac pacemakers Supraventricular tachycardia Propranolol, esmolol, acebutolol Slowed or blocked atrioventricular conduction velocity; blocked reentry Heart failure Carvedilol, labetalol, metoprolol Decreased mortality, mechanism poorly understood Hypertrophic cardiomyopathy Propranolol Slowed rate of cardiac contraction Migraine prophylaxis Propranolol Mechanism not understood Familial tremor, other types of tremor, "stage fright" Propranolol Reduced 2 alteration of neuromuscular transmission; possible CNS effects

Thyroid storm, thyrotoxicosis Propranolol, esmolol Reduced cardiac rate and arrhythmogenesis; reduced conversion of T4 to T3

Glaucoma a

Timolol, others (topical) Reduced secretion of aqueous humor

aSee Table 10-3 for other drugs used in glaucoma.

TABLE 10-3 Drugs used in glaucoma.

Group, Drugs Mechanism Method of Administration Beta blockers Timolol, others Decreased secretion of aqueous humor from the ciliary epithelium Topical drops Prostaglandins Latanoprost, others Increased aqueous outflow Topical drops Cholinomimetics Pilocarpine, physostigmine Ciliary muscle contraction, opening of trabecular meshwork, increased outflow Topical drops or gel, plastic film slow-release insert Alpha agonists Nonselective: epinephrine Increased outflow via uveoscleral veins Topical drops (obsolete) Alpha2-selective agonists Apraclonidine, brimonidine Decreased aqueous secretion Topical drops Carbonic anhydrase inhibitors Acetazolamide, dorzolamide Decreased aqueous secretion due to lack of HCO3 -

Oral (acetazolamide) or topical (others) Osmotic agents Mannitol Removal of water from eye IV (for acute closed angle glaucoma)

Modified and reproduced, with permission, from Katzung BG, editor: Basic & Clinical Pharmacology, 11th ed. McGraw-Hill, 2009, p. 160.

Toxicity

Cardiovascular adverse effects, which are extensions of the  blockade induced by these agents, include bradycardia, atrioventricular blockade, and heart failure. Patients with airway disease may suffer severe asthma attacks. Beta blockers have been shown experimentally to reduce insulin secretion, but this does not appear to be a clinically important effect. However, premonitory symptoms of hypoglycemia from insulin overdosage, for example, tachycardia, tremor, and anxiety, may be masked by  blockers, and mobilization of glucose from the liver may be impaired. CNS adverse effects include sedation, fatigue, and sleep alterations. Atenolol, nadolol, and several other less lipid-soluble  blockers are claimed to have less marked CNS action because they do not enter the CNS as readily as other members of this group. Sexual dysfunction has been reported for most of the  blockers in some patients.

Skill Keeper: Partial Agonist Action

(See Chapter 2)

Draw a concentration-response graph showing the effect of increasing concentrations of albuterol on airway diameter (as a percentage of maximum) in the presence of a large concentration of pindolol. On the same graph, draw the curves for the percentage of receptors bound to albuterol and to pindolol at each concentration. The Skill Keeper Answer appears at the end of the chapter.

Skill Keeper Answer: Partial Agonist Action

(See Chapter 2)

Because pindolol is a partial agonist at  receptors, the concentration-response curve will show a bronchodilating effect at zero albuterol concentration. As albuterol concentration increases, the airway diameter also increases. The binding curves will show pindolol binding starting at 100% of receptors and going to zero as albuterol concentration increases, with albuterol binding starting at zero and going to 100%.

Checklist

When you complete this chapter, you should be able to:

 Describe and compare the effects of an  blocker on the blood pressure and heart rate responses to epinephrine, norepinephrine, and phenylephrine.

 Compare the pharmacodynamics of propranolol, labetalol, metoprolol, and pindolol.

 Compare the pharmacokinetics of propranolol, atenolol, esmolol, and nadolol.

 Describe the clinical indications and toxicities of typical  and  blockers.

Drug Summary Table: Adrenoceptor Blockers

Subclass Mechanism of Action Clinical Applications Pharmacokinetics Toxicities, Interactions Nonselective blockers Phentolamine Competitive pharmacologic antagonism at  receptors Pheochromocytoma, antidote to overdose of  agonists Oral, IV; short half-life Duration: 2-4 h Orthostatic hypotension, reflex tachycardia Phenoxybenzamine Irreversible (covalent) binding to  receptors Pheochromocytoma,carcinoid, mastocytosis, Raynaud’s phenomenon Oral, short half-life but long duration of action (24-48 h) Orthostatic hypotension, reflex tachycardia; gastrointestinal irritation 1-Selective blockers Prazosin Competitive antagonism at 1 receptors

Hypertension, benign prostatic hyperplasia Oral Duration: 8 h Orthostatic hypotension (especially first dose), but little reflex tachycardia Doxazosin, terazosin: Like prazosin; longer duration of action (12-24 h) Tamsulosin, silodosin: Like prazosin, approved only for benign prostatic hyperplasia 2-Selective blockers Yohimbine Competitive antagonism at 2 receptors

Obsolete use for erectile dysfunction; research use Oral, parenteral Tachycardia, gastrointestinal upset Nonselective blockers Propranolol Competitive block of  receptors, local anesthetic effect Angina, arrhythmias (treatment and prophylaxis), hypertension, tremor, stage fright, migraine Oral and IV Duration: 4-6 h. Ready entry into CNS Excessive  blockade: bronchospasm (can be fatal in asthmatics), atrioventricular block, heart failure; CNS sedation, lethargy, sleep disturbances Timolol, betaxolol: Lack local anesthetic action; useful in glaucoma Pindolol: Partial agonist action; possibly safer in asthma Nadolol: Like propranolol but longer action (up to 24 h) and less CNS effect 1-Selective blockers Atenolol Competitive block of 1 receptors

Hypertension, angina, arrhythmias Oral Duration: 6-9 h Like propranolol with somewhat less danger of bronchospasm Esmolol: IV agent for perioperative and thyroid storm arrhythmias, hypertensive emergency Metoprolol: Like atenolol, oral, shown to reduce mortality in heart failure Nebivolol: New oral 1-selective blocker with additional vasodilating action 2-Selective blockers Butoxamine Competitive block of 2 receptors

None; research use only — Bronchospasm  +  blockers Labetalol Four isomers; 2 bind and block both  and  receptors Hypertension, hypertensive emergencies (IV) Oral and IV Duration: 5 h Like atenolol Carvedilol: Like labetalol, 2 isomers; shown to reduce mortality in heart failure



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