Pharmacology_Katzung

Pharmacology_Katzung. A. Treatment of Acute Hypotension Acute hypotension may occur in a variety of settings such as severe hemorrhage, decreased blood volume, cardiac arrhythmias, neurologic disease or accidents, adverse reactions or overdose of medications such as antihypertensive drugs, and infection. If cerebral, renal, and cardiac perfusion is maintained, hypotension itself does not usually require vigorous direct treatment. Rather, placing the patient in the recumbent position and ensuring adequate fluid volume while the primary problem is determined and treated is usually the correct course of action. The use of sympathomimetic drugs merely to elevate a blood pressure that is not an immediate threat to the patient may increase morbidity. However, sympathomimetics may be required in cases of sustained hypotension with evidence of tissue hypoperfusion.


Pharmacology_Katzung

Pharmacology_Katzung. Shock is a complex acute cardiovascular syndrome that results in a critical reduction in perfusion of vital tissues and a wide range of systemic effects. Shock is usually associated with hypo-tension, an altered mental state, oliguria, and metabolic acidosis. If untreated, shock usually progresses to a refractory deteriorating state and death. The three major forms of shock are septic, cardiogenic, and hypovolemic. Volume replacement and treatment of the underlying disease are the mainstays of the treatment of shock. If vasopressors are needed, adrenergic agonists with both α and β activity are preferred. Pure β-adrenergic stimulation increases blood flow but also increases the risk of myocardial ischemia. Pure α-adrenergic stimulation increases vascular tone and blood pressure but can also decrease cardiac output and impair tissue blood flow. Norepinephrine provides an acceptable balance and is considered the vasopressor of first choice: it has predominantly α-adrenergic properties,


Pharmacology_Katzung

Pharmacology_Katzung. decrease cardiac output and impair tissue blood flow. Norepinephrine provides an acceptable balance and is considered the vasopressor of first choice: it has predominantly α-adrenergic properties, but its modest β-adrenergic effects help to maintain cardiac output. Administration generally results in a clinically significant increase in mean arterial pressure, with little change in heart rate or cardiac output. Dopamine has no advantage over norepinephrine because it is associated with a higher incidence of arrhythmias and mortality. However, dobutamine is arguably the inotropic agent of choice when increased cardiac output is needed.


Pharmacology_Katzung

Pharmacology_Katzung. B. Chronic Orthostatic Hypotension On standing, gravitational forces induce venous pooling, resulting in decreased venous return. Normally, a decrease in blood pressure is prevented by reflex sympathetic activation with increased heart rate, and peripheral arterial and venous vasoconstriction. Impairment of autonomic reflexes that regulate blood pressure can lead to chronic orthostatic hypotension. This is more often due to medications that can interfere with autonomic function (eg, imipramine and other tricyclic antidepressants, α blockers for the treatment of urinary retention, and diuretics), diabetes, and other diseases causing peripheral autonomic neuropathies, and less commonly, primary degenerative disorders of the autonomic nervous system, as in the case study described at the beginning of the chapter.


Pharmacology_Katzung

Pharmacology_Katzung. Increasing peripheral resistance is one of the strategies to treat chronic orthostatic hypotension, and drugs activating α receptors can be used for this purpose. Midodrine, an orally active α1 agonist, is frequently used for this indication. Other sympathomimetics, such as oral ephedrine or phenylephrine, can be tried. A novel approach to treat orthostatic hypotension is droxidopa, a synthetic (L-threo-dihydrophenylserine, L-DOPS) molecule that has been approved by the FDA to treat neurogenic orthostatic hypotension. It is a prodrug that is converted to norepinephrine by the aromatic L-amino acid decarboxylase (dopa-decarboxylase), the enzyme that converts L-dopa to dopamine. C. Cardiac Applications Epinephrine is used during resuscitation from cardiac arrest. Current evidence indicates that it improves the chance of returning to spontaneous circulation, but it is less clear that it improves survival or long-term neurologic outcomes and this is an area of active investigation.


Pharmacology_Katzung

Pharmacology_Katzung. Dobutamine is used as a pharmacologic cardiac stress test. Dobutamine augments myocardial contractility and promotes coronary and systemic vasodilation. These actions lead to increased heart rate and increased myocardial work and can reveal areas of ischemia in the myocardium that are detected by echocardiogram or nuclear medicine techniques. Dobutamine can thus be used in patients unable to exercise during the stress test. D. Inducing Local Vasoconstriction Reduction of local or regional blood flow is desirable for achieving hemostasis during surgery, for reducing diffusion of local anesthetics away from the site of administration, and for reducing mucous membrane congestion. In each instance, α-receptor activation is desired, and the choice of agent depends on the maximal efficacy required, the desired duration of action, and the route of administration.


Pharmacology_Katzung

Pharmacology_Katzung. Effective pharmacologic hemostasis is often necessary for facial, oral, and nasopharyngeal surgery. Epinephrine is usually applied topically in nasal packs (for epistaxis) or in a gingival string (for gingivectomy). Cocaine is still sometimes used for nasopharyngeal surgery because it combines a hemostatic effect with local anesthesia. Combining α agonists with some local anesthetics greatly prolongs their duration of action; the total dose of local anesthetic (and the probability of systemic toxicity) can therefore be reduced. Epinephrine, 1:200,000, is the favored agent for this application. Systemic effects on the heart and peripheral vasculature may occur even with local drug administration but are usually minimal. Use of epinephrine with local anesthesia of acral vascular beds (digits, nose, and ears) has not been advised because of fear of ischemic necrosis. Recent studies suggest that it can be used (with caution) for this indication.


Pharmacology_Katzung

Pharmacology_Katzung. Alpha agonists can be used topically as mucous membrane decongestants to reduce the discomfort of allergic rhinitis or the common cold by decreasing the volume of the nasal mucosa. These effects are probably mediated by α1 receptors. Unfortunately, rebound hyperemia may follow the use of these agents, and repeated topical use of high drug concentrations may result in ischemic changes in the mucous membranes, probably as a result of vasoconstriction of nutrient arteries. Constriction of the latter vessels may involve activation of α2 receptors, and phenylephrine or the longer-acting oxymetazoline are often used in over-the-counter nasal decongestants. A longer duration of action—at the cost of much lower local concentrations and greater potential for cardiac and CNS effects—can be achieved by the oral administration of agents such as ephedrine or one of its isomers, pseudoephedrine.


Pharmacology_Katzung

Pharmacology_Katzung. One of the most important uses of sympathomimetic drugs is in the therapy of asthma and chronic obstructive pulmonary disease (COPD; discussed in more detail in Chapter 20). Beta2-selective drugs (albuterol, metaproterenol, terbutaline) are used for this purpose to reduce the adverse effects that would be associated with β1 stimulation. Short-acting preparations can be used only transiently for acute treatment of asthma symptoms. For chronic asthma treatment in adults, long-acting β2 agonists should only be used in combination with steroids because their use in mono-therapy has been associated with increased mortality. Long-acting β2 agonists are also used in patients with COPD. Indacaterol, olodaterol, and vilanterol, new ultralong β2 agonists, have been approved by the FDA for once-a-day use in COPD. Nonselective drugs are now rarely used because they are likely to have more adverse effects than the selective drugs.


Pharmacology_Katzung

Pharmacology_Katzung. Anaphylactic shock and related immediate (type I) IgE-mediated reactions affect both the respiratory and the cardiovascular systems. The syndrome of bronchospasm, mucous membrane congestion, angioedema, and severe hypotension usually responds rapidly to the parenteral administration of epinephrine, 0.3–0.5 mg (0.3–0.5 mL of a 1:1000 epinephrine solution). Intramuscular injection may be the preferred route of administration, since skin blood flow (and hence systemic drug absorption from subcutaneous injection) is unpredictable in hypotensive patients. In some patients with impaired cardiovascular function, intravenous injection of epinephrine may be required. The use of epinephrine for anaphylaxis precedes the era of controlled clinical trials, but extensive experimental and clinical experience supports its use as the agent of choice. Epinephrine activates α, β1, and β2 receptors, all of which may be important in reversing the pathophysiologic processes underlying anaphylaxis. It is


Pharmacology_Katzung

Pharmacology_Katzung. supports its use as the agent of choice. Epinephrine activates α, β1, and β2 receptors, all of which may be important in reversing the pathophysiologic processes underlying anaphylaxis. It is recommended that patients at risk for anaphylaxis carry epinephrine in an autoinjector (EpiPen, Auvi-Q) for self-administration. Recent price-gouging increases in the cost of the EpiPen in the USA have raised fears that high costs will limit access to this drug.


Pharmacology_Katzung

Pharmacology_Katzung. Phenylephrine is an effective mydriatic agent frequently used to facilitate examination of the retina. It is also a useful decongestant for minor allergic hyperemia and itching of the conjunctival membranes. Sympathomimetics administered as ophthalmic drops are also useful in localizing the lesion in Horner’s syndrome. (See Box: An Application of Basic Pharmacology to a Clinical Problem.) Glaucoma responds to a variety of sympathomimetic and sympathoplegic drugs. (See Box: The Treatment of Glaucoma, in Chapter 10.) Both α2-selective agonists (apraclonidine and brimonidine) and β-blocking agents (timolol and others) are common topical therapies for glaucoma.


Pharmacology_Katzung

Pharmacology_Katzung. As noted above, β2-selective agents (eg, terbutaline) relax the pregnant uterus. In the past, these agents were used to suppress premature labor. However, meta-analysis of older trials and a randomized study suggest that β-agonist therapy has no significant benefit on perinatal infant mortality and may increase maternal morbidity.


Pharmacology_Katzung

Pharmacology_Katzung. The amphetamines have a mood-elevating (euphoriant) effect; this effect is the basis for the widespread abuse of this drug group (see Chapter 32). The amphetamines also have an alerting, sleep-deferring action that is manifested by improved attention to repetitive tasks and by acceleration and desynchronization of the electroencephalogram. A therapeutic application of this effect is in the treatment of narcolepsy. Modafinil, a new amphetamine substitute, is approved for use in narcolepsy and is claimed to have fewer disadvantages (excessive mood changes, insomnia, and abuse potential) than amphetamine in this condition. Amphetamines have appetite-suppressing effects, but there is no evidence that long-term improvement in weight control can be achieved with amphetamines alone, especially when administered for a relatively short course. A final application of the CNS-active sympathomimetics is in the attention deficit hyperactivity disorder (ADHD), a behavioral syndrome consisting of


Pharmacology_Katzung

Pharmacology_Katzung. when administered for a relatively short course. A final application of the CNS-active sympathomimetics is in the attention deficit hyperactivity disorder (ADHD), a behavioral syndrome consisting of short attention span, hyperkinetic physical behavior, and learning problems. Some patients with this syndrome respond well to low doses of methylphenidate and related agents. Extended-release formulations of methylphenidate may simplify dosing regimens and increase adherence to therapy, especially in school-age children. Slow or continuous-release preparations of the α2 agonists clonidine and guanfacine are also effective in children with ADHD. The norepinephrine reuptake inhibitor atomoxetine is sometimes used in ADHD. Clinical trials suggest that modafinil may also be useful in ADHD, but because the safety profile in children has not been defined, it has not gained approval by the FDA for this indication.


Pharmacology_Katzung

Pharmacology_Katzung. Although the primary use of the α2 agonist clonidine is in the treatment of hypertension (see Chapter 11), the drug has been found to have efficacy in the treatment of diarrhea in diabetics with autonomic neuropathy, perhaps because of its ability to enhance salt and water absorption from the intestine. In addition, clonidine has efficacy in diminishing craving for narcotics and alcohol during withdrawal and may facilitate cessation of cigarette smoking. Clonidine has also been used to diminish menopausal hot flushes and is being used experimentally to reduce hemodynamic instability during general anesthesia. Dexmedetomidine is an α2 agonist used for sedation under intensive care circumstances and during anesthesia (see Chapter 25). It blunts the sympathetic response to surgery, which may be beneficial in some situations. It lowers opioid requirements for pain control and does not depress ventilation. Clonidine is also sometimes used as a premedication before anesthesia. Tizanidine is


Pharmacology_Katzung

Pharmacology_Katzung. be beneficial in some situations. It lowers opioid requirements for pain control and does not depress ventilation. Clonidine is also sometimes used as a premedication before anesthesia. Tizanidine is an α2 agonist closely related to clonidine that is used as a “central muscle relaxant” (see Chapter 27), but many physicians are not aware of its cardiovascular actions, which may lead to unanticipated adverse effects.


Pharmacology_Katzung

Pharmacology_Katzung. Horner’s syndrome is a condition—usually unilateral—that results from interruption of the sympathetic nerves to the face. The effects include vasodilation, ptosis, miosis, and loss of sweating on the affected side. The syndrome can be caused by either a preganglionic or a postganglionic lesion, and knowledge of the location of the lesion (preganglionic or postganglionic) helps determine the optimal therapy. A localized lesion in a nerve causes degeneration of the distal portion of that fiber and loss of transmitter contents from the degenerated nerve ending—without affecting neurons innervated by the fiber. Therefore, a preganglionic lesion leaves the postganglionic adrenergic neuron intact, whereas a postganglionic lesion results in degeneration of the adrenergic nerve endings and loss of stored catechol-amines from them. Because indirectly acting sympathomi-metics require normal stores of catecholamines, such drugs can be used to test for the presence of normal adrenergic nerve


Pharmacology_Katzung

Pharmacology_Katzung. of stored catechol-amines from them. Because indirectly acting sympathomi-metics require normal stores of catecholamines, such drugs can be used to test for the presence of normal adrenergic nerve endings. The iris, because it is easily visible and responsive to topical sympathomimetics, is a convenient assay tissue in the patient. If the lesion of Horner’s syndrome is postganglionic, indirectly acting sympathomimetics (eg, cocaine, hydroxy-amphetamine) will not dilate the abnormally constricted pupil because catecholamines have been lost from the nerve endings in the iris. In contrast, the pupil dilates in response to phenylephrine, which acts directly on the αreceptors on the smooth muscle of the iris. A patient with a preganglionic lesion, on the other hand, shows a normal response to both drugs, since the postganglionic fibers and their catecholamine stores remain intact in this situation.


Pharmacology_Katzung

Pharmacology_Katzung. • Midodrine Activates phospholipase C, resulting in increased intracellular calcium and vasoconstriction Vascular smooth muscle contraction increasing blood pressure (BP) Oral • prodrug converted to active drug with a 1-h peak effect • Toxicity: Supine hypertension, piloerection (goose bumps), and urinary retention Phenylephrine: Can be used IV for short-term maintenance of BP in acute hypotension and intranasally to produce local vasoconstriction as a decongestant α-Methyldopa, guanfacine, and guanabenz: Also used as central sympatholytics Dexmedetomidine: Prominent sedative effects and used in anesthesia Tizanidine: Used as a muscle relaxant


Pharmacology_Katzung

Pharmacology_Katzung. Dexmedetomidine: Prominent sedative effects and used in anesthesia Tizanidine: Used as a muscle relaxant Apraclonidine and brimonidine: Used topically in glaucoma to reduce intraocular pressure `2 AGONISTS •ClonidineInhibits adenylyl cyclase and interacts with other intracellular pathways Vasoconstriction is masked by central sympatholytic effect, which lowers BP Hypertension Oral•transdermal•peakeffect1–3h•t1/2 oforaldrug~12h•producesdrymouthand sedation •Dobutamine1 Activates adenylyl cyclase, increasing myocardial contractility Positive inotropic effect Cardiogenic shock, acute heart failure IV•requiresdosetitrationtodesiredeffect 1Dobutamine has other actions in addition to β1-agonist effect. See text for details. Amphetamine, racemic mixture Generic 1:1:1:1 mixtures of amphetamine sulfate, amphetamine aspartate, dextroamphetamine sulfate, and dextroamphetamine saccharate Adderall Dextroamphetamine Generic, Dexedrine Dobutamine Generic, Dobutrex Dopamine Generic, Intropin


Pharmacology_Katzung

Pharmacology_Katzung. Dextroamphetamine Generic, Dexedrine Dobutamine Generic, Dobutrex Dopamine Generic, Intropin Epinephrine Generic, Adrenalin Chloride, Primatene Mist, Bronkaid Mist, EpiPen, Auvi-Q Hydroxyamphetamine Paremyd (includes 0.25% tropicamide) Isoproterenol Generic, Isuprel Methylphenidate Generic, Ritalin, Ritalin-SR Modafinil Provigil Naphazoline Generic, Privine Norepinephrine Generic, Levophed Olodaterol Striverdi respimat Oxymetazoline Generic, Afrin, Neo-Synephrine 12 Hour, Visine LR Phenylephrine Generic, Neo-Synephrine Pseudoephedrine Generic, Sudafed Tetrahydrozoline Generic, Visine Tizanidine Zanaflex Callaway CW: Epinephrine for cardiac arrest. Curr Opin Cardiol 2013;28:36. Cotecchia S: The α1-adrenergic receptors: Diversity of signaling networks and regulation. J Recept Signal Transduct Res 2010;30:410. DeWire SM, Violin JD: Biased ligands for better cardiovascular drugs: Dissecting G-protein-coupled receptor pharmacology. Circ Res 2011;109:205.


Pharmacology_Katzung

Pharmacology_Katzung. DeWire SM, Violin JD: Biased ligands for better cardiovascular drugs: Dissecting G-protein-coupled receptor pharmacology. Circ Res 2011;109:205. Gurevich EV et al: G-protein-coupled receptor kinases: More than just kinases and not only for GPCRs. Pharmacol Ther 2012;133:40. Hawrylyshyn KA et al: Update on human alpha1-adrenoceptor subtype signaling and genomic organization. Trends Pharmacol Sci 2004;25:449. Hollenberg SM: Vasoactive drugs in circulatory shock. Am J Respir Crit Care Med 2011;183:847. Holmes A, Lachowicz JE, Sibley DR: Phenotypic analysis of dopamine receptor knockout mice: Recent insights into the functional specificity of dopamine receptor subtypes. Neuropharmacology 2004;47:1117.


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Pharmacology_Katzung. Insel PA: β(2)-Adrenergic receptor polymorphisms and signaling: Do variants influence the “memory” of receptor activation? Sci Signal 2011;4:pe37. Johnson JA, Liggett SB: Cardiovascular pharmacogenomics of adrenergic receptor signaling: Clinical implications and future directions. Clin Pharmacol Ther 2011;89:366. Johnson M: Molecular mechanisms of β2-adrenergic receptor function, response, and regulation. J Allergy Clin Immunol 2006;117:18. Lefkowitz RJ, Shenoy SK: Transduction of receptor signals by beta-arrestins. Science 2005;308:512. Minzenberg MJ, Carter CS: Modafinil: A review of neurochemical actions and effects on cognition. Neuropsychopharmacology 2008;33:1477. Philipp M, Hein L: Adrenergic receptor knockout mice: Distinct functions of 9 receptor subtypes. Pharmacol Ther 2004;101:65. Sandilands AJ, O’Shaughnessy KM: The functional significance of genetic variation within the beta-adrenoceptor. Br J Clin Pharmacol 2005;60:235.


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Pharmacology_Katzung. Sandilands AJ, O’Shaughnessy KM: The functional significance of genetic variation within the beta-adrenoceptor. Br J Clin Pharmacol 2005;60:235. Simons FE: Anaphylaxis. J Allergy Clin Immunol 2008;121:S402. Vincent J-L, De Backer D: Circulatory shock. N Engl J Med 2013;369:1726. Whalen EJ, Rajagopal S, Lefkowitz RJ: Therapeutic potential of β-arrestinand G protein-biased agonists. Trends Mol Med 2011;17:126. Xylometazoline Generic, Otrivin *α2 Agonists used in hypertension are listed in Chapter 11. β2 Agonists used in asthma are listed in Chapter 20. Norepinephrine transporter inhibitors are listed in Chapter 30.


Pharmacology_Katzung

Pharmacology_Katzung. The clinical picture is that of autonomic failure. The best indicator of this is the profound drop in orthostatic blood pressure without an adequate compensatory increase in heart rate. Pure autonomic failure is a neurodegenerative disorder selectively affecting peripheral autonomic fibers. Patients’ blood pressure is critically dependent on whatever residual sympathetic tone they have, hence the symptomatic worsening of orthostatic hypotension that occurred when this patient was given the α blocker tamsulosin. Conversely, these patients are hypersensitive to the pressor effects of α agonists and other sympathomimetics. For example, the α agonist midodrine can increase blood pressure signifi-cantly at doses that have no effect in normal subjects and can be used to treat their orthostatic hypotension. Caution should be observed in the use of sympathomimetics (includ-ing over-the-counter agents) and sympatholytic drugs. David Robertson, MD, & Italo Biaggioni, MD*


Pharmacology_Katzung

Pharmacology_Katzung. David Robertson, MD, & Italo Biaggioni, MD* A 38-year-old man has been experiencing palpitations and headaches. He enjoyed good health until 1 year ago when spells of rapid heartbeat began. These became more severe and were eventually accompanied by throbbing headaches and drenching sweats. Physical examination revealed a blood pressure of 150/90 mm Hg and heart rate of 88 bpm. During the physical examination, palpation of the abdomen elicited a sudden and typical episode, with a rise in blood pressure to 210/120 mm Hg, heart rate to 122 bpm, profuse sweating, and facial pallor. This was accompanied by severe headache. What is the likely cause of his episodes? What caused the blood pressure and heart rate to rise so high during the examination? What treatments might help this patient?


Pharmacology_Katzung

Pharmacology_Katzung. Catecholamines play a role in many physiologic and pathophysiologic responses, as described in Chapter 9. Drugs that block their receptors therefore have important effects, some of which are of great clinical value. These effects vary dramatically according to the drug’s selectivity for α and β receptors. The classification of adrenoceptors into α1, α2, and β subtypes and the effects of activating these receptors are discussed in Chapters 6 and 9. Blockade of peripheral dopamine receptors is of limited clinical importance at present. In contrast, blockade of central nervous system (CNS) dopamine receptors is very important; drugs that act on these receptors are discussed in Chapters 21 and 29. This chapter deals with pharmacologic antagonist drugs whose major effect is to occupy α1, α2, or β receptors outside the CNS and prevent their activation by catecholamines and related agonists.


Pharmacology_Katzung

Pharmacology_Katzung. For pharmacologic research, α1and α2-adrenoceptor antagonist drugs have been very useful in the experimental exploration of autonomic function. In clinical therapeutics, nonselective α antagonists are used in the treatment of pheochromocytoma * The authors thank Dr. Randy Blakely for helpful comments, Dr. Brett English for improving tables, and our students at Vanderbilt for advice on conceptual clarity. (tumors that secrete catecholamines), and α1-selective antagonists are used in primary hypertension and benign prostatic hyperplasia. Beta-receptor antagonist drugs are useful in a much wider variety of clinical conditions and are firmly established in the treatment of hypertension, ischemic heart disease, arrhythmias, endocrinologic and neurologic disorders, glaucoma, and other conditions. Mechanism of Action


Pharmacology_Katzung

Pharmacology_Katzung. Mechanism of Action Alpha-receptor antagonists may be reversible or irreversible in their interaction with these receptors. Reversible antagonists dissociate from receptors, and the block can be surmounted with sufficiently high concentrations of agonists; irreversible drugs do not dissociate and cannot be surmounted. Phentolamine and prazosin (Figure 10–1) are examples of reversible antagonists. These drugs and labetalol—drugs used primarily for their antihypertensive effects—as well as several ergot derivatives (see Chapter 16) are also reversible α-adrenoceptor antagonists or partial agonists. FIGURE 10–1 Structure of several α-receptor–blocking drugs. Phenoxybenzamine forms a reactive ethyleneimonium intermediate (Figure 10–1) that covalently binds to α receptors, resulting in irreversible blockade. Figure 10–2 illustrates the effects of a reversible drug in comparison with those of an irreversible agent.


Pharmacology_Katzung

Pharmacology_Katzung. As discussed in Chapters 1 and 2, the duration of action of a reversible antagonist is largely dependent on the half-life of the drug in the body and the rate at which it dissociates from its receptor: The shorter the half-life of the drug in the body, the less time it takes for the effects of the drug to dissipate. In contrast, the effects of an irreversible antagonist may persist long after the drug has been cleared from the plasma. In the case of phenoxybenzamine, the restoration of tissue responsiveness after extensive α-receptor blockade is dependent on synthesis of new receptors, which may take several days. The rate of return of α1-adrenoceptor responsiveness may be particularly important in patients who have a sudden cardiovascular event or who become candidates for urgent surgery. A. Cardiovascular Effects


Pharmacology_Katzung

Pharmacology_Katzung. Because arteriolar and venous tone are determined to a large extent by α receptors on vascular smooth muscle, α-receptor antagonist drugs cause a lowering of peripheral vascular resistance and blood pressure (Figure 10–3). These drugs can prevent the pressor effects of usual doses of α agonists; indeed, in the case of agonists with both α and β2 effects (eg, epinephrine), selective α-receptor antagonism may convert a pressor to a depressor response (Figure 10–3). This change in response is called epinephrine reversal; it illustrates how the activation of both α and β receptors in the vasculature may lead to opposite responses. Alpha-receptor antagonists often cause orthostatic hypotension and reflex tachycardia; nonselective (α1= α2, Table 10–1) blockers usually cause significant tachycardia if blood pressure is lowered below normal. Orthostatic hypotension is due to antagonism of sympathetic nervous system stimulation of α1 receptors in vascular smooth muscle; contraction of veins is


Pharmacology_Katzung

Pharmacology_Katzung. if blood pressure is lowered below normal. Orthostatic hypotension is due to antagonism of sympathetic nervous system stimulation of α1 receptors in vascular smooth muscle; contraction of veins is an important component of the normal capacity to maintain blood pressure in the upright position since it decreases venous pooling in the periphery. Constriction of arterioles in the legs also contributes to the normal orthostatic response. Tachycardia may be more marked with agents that block α2-presynaptic receptors in the heart, since the augmented release of norepinephrine will further stimulate β receptors in the heart.


Pharmacology_Katzung

Pharmacology_Katzung. B. Other Effects Blockade of α receptors in other tissues elicits miosis (small pupils) and nasal stuffiness. Alpha1 receptors are expressed in the base of the bladder and the prostate, and their blockade decreases resistance to the flow of urine. Alpha blockers, therefore, are used therapeutically for the treatment of urinary retention due 0 50 100 100 50 0 2.4 20 160 1.2 10 80 Percent of maximum tension Percent of maximum tension Control 20 µmol/L 10 µmol/L Control 0.4 µmol/L 0.8 µmol/L Competitive antagonist Irreversible antagonist


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Pharmacology_Katzung. FIGURE 10–2 Dose-response curves to norepinephrine in the presence of two different α-adrenoceptor–blocking drugs. The tension produced in isolated strips of cat spleen, a tissue rich in α receptors, was measured in response to graded doses of norepinephrine. Left: Tolazoline, a reversible blocker, shifted the curve to the right without decreasing the maximum response when present at concentrations of 10 and 20 μmol/L. Right: Dibenamine, an analog of phenoxybenzamine and irreversible in its action, reduced the maximum response attainable at both concentrations tested. (Adapted, with permission, from Bickerton RK: The response of isolated strips of cat spleen to sympathomimetic drugs and their antagonists. J Pharmacol Exp Ther 1963;142:99.)


Pharmacology_Katzung

Pharmacology_Katzung. FIGURE 10–3 Top: Effects of phentolamine, an α-receptor–blocking drug, on blood pressure in an anesthetized dog. Epinephrine reversal is demonstrated by tracings showing the response to epinephrine before (middle) and after (bottom) phentolamine. All drugs given intravenously. BP, blood pressure; HR, heart rate. TABLE 10–1 Relative selectivity of antagonists for adrenoceptors. to prostatic hyperplasia (see below). Individual agents may have other important effects in addition to α-receptor antagonism (see below). Phenoxybenzamine binds covalently to α receptors, causing irreversible blockade of long duration (14–48 hours or longer). It is somewhat selective for α1 receptors but less so than prazosin (Table 10–1). The drug also inhibits reuptake of released nor-epinephrine by presynaptic adrenergic nerve terminals. Phenoxybenzamine blocks histamine (H1), acetylcholine, and serotonin receptors as well as α receptors (see Chapter 16).


Pharmacology_Katzung

Pharmacology_Katzung. The pharmacologic actions of phenoxybenzamine are primarily related to antagonism of α-receptor–mediated events. The most significant effect is attenuation of catecholamine-induced vasoconstriction. While phenoxybenzamine causes relatively little fall in blood pressure in normal supine individuals, it reduces blood pressure when sympathetic tone is high, eg, as a result of upright posture or because of reduced blood volume. Cardiac output may be increased because of reflex effects and because of some blockade of presynaptic α2 receptors in cardiac sympathetic nerves.


Pharmacology_Katzung

Pharmacology_Katzung. Phenoxybenzamine is absorbed after oral administration, although bioavailability is low; its other pharmacokinetic properties are not well known. The drug is usually given orally, starting with dosages of 10 mg/d and progressively increasing the dose until the desired effect is achieved. A dosage of less than 100 mg/d is usually sufficient to achieve adequate α-receptor blockade. The major use of phenoxybenzamine is in the treatment of pheochromocytoma (see below). Most adverse effects of phenoxybenzamine derive from its α-receptor–blocking action; the most important are orthostatic hypotension and tachycardia. Nasal stuffiness and inhibition of ejaculation also occur. Since phenoxybenzamine enters the CNS, it may cause less specific effects including fatigue, sedation, and nausea. Because phenoxybenzamine is an alkylating agent, it may have other adverse effects that have not yet been characterized.


Pharmacology_Katzung

Pharmacology_Katzung. Phentolamine is a potent competitive antagonist at both α1 and α2 receptors (Table 10–1). Phentolamine reduces peripheral resistance through blockade of α1 receptors and possibly α2 receptors on vascular smooth muscle. Its cardiac stimulation is due to antagonism of presynaptic α2 receptors (leading to enhanced release of norepinephrine from sympathetic nerves) and sympathetic activation from baroreflex mechanisms. Phentolamine also has minor inhibitory effects at serotonin receptors and agonist effects at muscarinic and H1 and H2 histamine receptors. Phentolamine’s principal adverse effects are related to compensatory cardiac stimulation, which may cause severe tachycardia, arrhythmias, and myocardial ischemia. Phentolamine has been used in the treatment of pheochromocytoma. In addition, it is sometimes used to reverse local anesthesia in soft tissue sites; local anesthetics are often given with vasoconstrictors that slow their removal. Local phentolamine permits reversal at the end


Pharmacology_Katzung

Pharmacology_Katzung. it is sometimes used to reverse local anesthesia in soft tissue sites; local anesthetics are often given with vasoconstrictors that slow their removal. Local phentolamine permits reversal at the end of the procedure. Unfortunately oral and intravenous formulations of phentolamine are no longer consistently available in the United States.


Pharmacology_Katzung

Pharmacology_Katzung. Prazosin is a competitive piperazinyl quinazoline effective in the management of hypertension (see Chapter 11). It is highly selective for α1 receptors and typically 1000-fold less potent at α2 receptors. This may partially explain the relative absence of tachycardia seen with prazosin compared with that of phentolamine and phenoxybenzamine. Prazosin relaxes both arterial and venous vascular smooth muscle, as well as smooth muscle in the prostate, due to blockade of α1 receptors. Prazosin is extensively metabolized in humans; because of metabolic degradation by the liver, only about 50% of the drug is available after oral administration. The half-life is normally about 3 hours.


Pharmacology_Katzung

Pharmacology_Katzung. Terazosin is another reversible α1-selective antagonist that is effective in hypertension (see Chapter 11); it is also approved for use in men with urinary retention symptoms due to benign prostatic hyperplasia (BPH). Terazosin has high bioavailability but is extensively metabolized in the liver, with only a small fraction of unchanged drug excreted in the urine. The half-life of terazosin is 9–12 hours. Doxazosin is efficacious in the treatment of hypertension and BPH. It differs from prazosin and terazosin in having a longer half-life of about 22 hours. It has moderate bioavailability and is extensively metabolized, with very little parent drug excreted in urine or feces. Doxazosin has active metabolites, although their contribution to the drug’s effects is probably small.


Pharmacology_Katzung

Pharmacology_Katzung. Tamsulosin is a competitive α1 antagonist with a structure quite different from that of most other α1-receptor blockers. It has high bioavailability and a half-life of 9–15 hours. It is metabolized extensively in the liver. Tamsulosin has higher affinity for α1A and α1D receptors than for the α1B subtype. Evidence suggests that tamsulosin has relatively greater potency in inhibiting contraction in prostate smooth muscle versus vascular smooth muscle compared with other α1-selective antagonists. The drug’s efficacy in BPH suggests that the α1A subtype may be the most important α subtype mediating prostate smooth muscle contraction. Furthermore, compared with other antagonists, tamsulosin has less effect on standing blood pressure in patients. Nevertheless, caution is appropriate in using any α antagonist in patients with diminished sympathetic nervous system function (see http://www .bmj.com/content/347/bmj.f6320). Recent epidemiologic studies suggest an increased risk of orthostatic


Pharmacology_Katzung

Pharmacology_Katzung. any α antagonist in patients with diminished sympathetic nervous system function (see http://www .bmj.com/content/347/bmj.f6320). Recent epidemiologic studies suggest an increased risk of orthostatic hypotension shortly after initiation of treatment. A recently recognized and potentially serious adverse effect of oral tamsulosin in patients undergoing cataract surgery is that they are at increased risk of the intraoperative floppy iris syndrome (IFIS), characterized by the billowing of a flaccid iris, propensity for iris prolapse, and progressive intra-operative pupillary constriction. These effects increase the risk of cataract surgery, and complications are more likely in the ensuing 14 days if patients are taking these agents.


Pharmacology_Katzung

Pharmacology_Katzung. Alfuzosin is an α1-selective quinazoline derivative that is approved for use in BPH. It has a bioavailability of about 60%, is extensively metabolized, and has an elimination half-life of about 5 hours. It may increase risk of QT prolongation in susceptible individuals. Silodosin resembles tamsulosin in blocking the α1A receptor and is also used in the treatment of BPH. Indoramin is another α1selective antagonist that also has efficacy as an antihypertensive. It is not available in the USA. Urapidil is an α1 antagonist (its primary effect) that also has weak α2-agonist and 5-HT1A-agonist actions and weak antagonist action at β1 receptors. It is used in Europe as an antihypertensive agent and for BPH. Labetalol and carvedilol have both α1-selective and β-antagonistic effects; they are discussed below. Neuroleptic drugs such as chlorpromazine and haloperidol are potent dopamine receptor antagonists but are also antagonists at α receptors. Their antagonism of α receptors probably


Pharmacology_Katzung

Pharmacology_Katzung. discussed below. Neuroleptic drugs such as chlorpromazine and haloperidol are potent dopamine receptor antagonists but are also antagonists at α receptors. Their antagonism of α receptors probably contributes to some of their adverse effects, particularly hypotension. Similarly, the antidepressant trazodone has the capacity to block α1 receptors. Ergot derivatives, eg, ergotamine and dihydroergotamine, cause reversible α-receptor blockade, probably via a partial agonist action (see Chapter 16).


Pharmacology_Katzung

Pharmacology_Katzung. Yohimbine is an α2-selective antagonist. It is sometimes used in the treatment of orthostatic hypotension because it promotes norepinephrine release through blockade of α2 receptors in both the CNS and the periphery. This increases central sympathetic activation and also promotes increased norepinephrine release in the periphery. It was once widely used to treat male erectile dysfunction but has been superseded by phosphodiesterase-5 inhibitors like sildenafil (see Chapter 12). Yohimbine can greatly elevate blood pressure if administered to patients receiving norepinephrine transport-blocking drugs. Yohimbine reverses the anti-hypertensive effects of α2-adrenoceptor agonists such as clonidine. It is used in veterinary medicine to reverse anesthesia produced by xylazine, an α2 agonist used to calm animals. Although yohimbine has been taken off the market in the USA solely for financial reasons, it is available as a “nutritional” supplement and through compounding pharmacies.


Pharmacology_Katzung

Pharmacology_Katzung. Pheochromocytoma is a tumor of the adrenal medulla or sympathetic ganglion cells. The tumor secretes catecholamines, especially norepinephrine and epinephrine. The patient in the case study at the beginning of this chapter had a left adrenal pheochromocytoma that was identified by imaging. In addition, he had elevated plasma and urinary norepinephrine, epinephrine, and their metabolites, normetanephrine and metanephrine. The diagnosis of pheochromocytoma is confirmed on the basis of elevated plasma or urinary levels of norepinephrine, epinephrine, metanephrine, and normetanephrine (see Chapter 6). Once diagnosed biochemically, techniques to localize a pheochromocytoma include computed tomography and magnetic resonance imaging scans and scanning with radiomarkers such as 131I-meta-iodobenzylguanidine (MIBG), a norepinephrine transporter substrate that is taken up by tumor cells and is therefore a useful imaging agent to identify the site of pheochromocytoma.


Pharmacology_Katzung

Pharmacology_Katzung. The major clinical use of phenoxybenzamine is in the management of pheochromocytoma. Patients with this tumor have many symptoms and signs of catecholamine excess, including intermittent or sustained hypertension, headaches, palpitations, and increased sweating. Release of stored catecholamines from pheochromocytomas may occur in response to physical pressure, chemical stimulation, or spontaneously. When it occurs during operative manipulation of pheochromocytoma, the resulting hypertension may be controlled with α-receptor blockade or the vasodilator nitroprusside. Nitroprusside is preferred because its effects can be more readily titrated and it has a shorter duration of action.


Pharmacology_Katzung

Pharmacology_Katzung. Alpha-receptor antagonists are most useful in the preoperative management of patients with pheochromocytoma (Figure 10–4). Administration of phenoxybenzamine in the preoperative period helps to control hypertension and tends to reverse chronic changes resulting from excessive catecholamine secretion such as plasma volume contraction, if present. Furthermore, the patient’s operative course may be simplified. Oral doses of 10 mg/d can be increased at intervals of several days until hypertension is controlled. Some physicians give phenoxybenzamine to patients with pheochromocytoma for 1–3 weeks before surgery. Other surgeons prefer to operate on patients in the absence of treatment with phenoxybenzamine, counting on modern anesthetic techniques to control blood pressure and heart rate during surgery. Phenoxybenzamine can be very useful in the chronic treatment of inoperable or metastatic pheochromocytoma. Although there is less experience with alternative drugs, hypertension in patients


Pharmacology_Katzung

Pharmacology_Katzung. surgery. Phenoxybenzamine can be very useful in the chronic treatment of inoperable or metastatic pheochromocytoma. Although there is less experience with alternative drugs, hypertension in patients with pheochromocytoma may also respond to reversible α1selective antagonists or to conventional calcium channel antagonists. Beta-receptor antagonists may be required after α-receptor blockade has been instituted to reverse the cardiac effects of excessive catecholamines. Beta antagonists should not be used prior pressure reflects excess circulating concentrations of α agonists, eg, in pheochromocytoma, overdosage of sympathomimetic drugs, or clonidine withdrawal. However, other drugs are generally preferable, since considerable experience is necessary to use α-adrenoceptor antagonist drugs safely in these settings.


Pharmacology_Katzung

Pharmacology_Katzung. Members of the prazosin family of α1-selective antagonists are efficacious drugs in the treatment of mild to moderate systemic hypertension (see Chapter 11). They are generally well toler ated, but they are not usually recommended as monotherapy for hypertension because other classes of antihypertensives are more effective in preventing heart failure. Their major adverse effect is orthostatic hypotension, which may be severe after the first few doses but is otherwise uncommon. Prazosin and related drugs may also be associated with dizziness. Orthostatic changes in treated for hypertension. Nonselective α antagonists are not used in primary systemic hypertension. It is interesting that the use of α-adrenoceptor antagonists such as prazosin has been found to be associated with either no changes in plasma lipids or increased concentrations of high-density lipoproteins (HDL), which could be a favorable alteration. The mechanism for this effect is not known.


Pharmacology_Katzung

Pharmacology_Katzung. FIGURE 10–4 Effects of phenoxybenzamine (Dibenzyline) on blood pressure in a patient with pheochromocytoma. Dosage of the drug was begun in the fourth week as shown by the shaded bar. Supine systolic and diastolic pressures are indicated by the circles, and the standing pressures by triangles and the hatched area. Note that the α-blocking drug dramatically reduced blood pressure. The reduction in orthostatic hypotension, which was marked before treatment, is probably due to normalization of blood volume, a variable that is sometimes markedly reduced in patients with longstanding pheochromocytoma-induced hypertension. (Adapted, with permission, from Engelman E, Sjoerdsma A: Chronic medical therapy for pheochromocytoma. Ann Intern Med 1964;61:229.) to establishing effective α-receptor blockade, since unopposed β-receptor blockade could theoretically cause blood pressure elevation from increased vasoconstriction.


Pharmacology_Katzung

Pharmacology_Katzung. Pheochromocytoma is sometimes treated with metyrosine (α-methyltyrosine), the α-methyl analog of tyrosine. This agent is a competitive inhibitor of tyrosine hydroxylase, the rate-limiting step in the synthesis of dopamine, norepinephrine, and epinephrine (see Figure 6–5). Metyrosine is especially useful in symptomatic patients with inoperable or metastatic pheochromocytoma. Because it has access to the CNS, metyrosine can cause extrapyramidal effects due to reduced dopamine levels. The α-adrenoceptor antagonist drugs have limited application in the management of hypertensive emergencies, but labetalol has been used in this setting (see Chapter 11). In theory, α-adrenoceptor antagonists are most useful when increased blood


Pharmacology_Katzung

Pharmacology_Katzung. Alpha-receptor–blocking drugs do not seem to be effective in the treatment of peripheral vascular occlusive disease characterized by morphologic changes that limit flow in the vessels. Occasionally, individuals with Raynaud’s phenomenon and other conditions involving excessive reversible vasospasm in the peripheral circulation do benefit from prazosin or phenoxybenzamine, although calcium channel blockers may be preferable for most patients. Benign prostatic hyperplasia is common in elderly men. Various surgical treatments are effective in relieving the urinary symptoms of BPH; however, drug therapy is efficacious in many patients. The mechanism of action in improving urine flow involves partial reversal of smooth muscle contraction in the enlarged prostate and in the bladder base. It has been suggested that some α1-receptor antagonists may have additional effects on cells in the prostate that help improve symptoms.


Pharmacology_Katzung

Pharmacology_Katzung. Prazosin, doxazosin, and terazosin are all efficacious in patients with BPH. These drugs are particularly useful in patients who also have hypertension. Considerable interest has focused on which α1-receptor subtype is most important for smooth muscle contraction in the prostate: subtype-selective α1A-receptor antagonists like tamsulosin may have improved efficacy and safety in treating this disease. As indicated above, even though tamsulosin has less blood pressure–lowering effect, it should be used with caution in patients susceptible to orthostatic hypotension and should not be used in patients undergoing eye surgery.


Pharmacology_Katzung

Pharmacology_Katzung. Sildenafil and other cGMP phosphodiesterase inhibitors are drugs of choice for erectile dysfunction (see Chapter 12). Other effective but now largely abandoned approaches have included a combination of phentolamine with the nonspecific smooth muscle relaxant papaverine; when injected directly into the penis, these drugs may cause erections in men with sexual dysfunction. Long-term administration may result in fibrotic reactions. Systemic absorption may also lead to orthostatic hypotension; priapism may require direct treatment with an α-adrenoceptor agonist such as phenylephrine. Alternative therapies for erectile dysfunction include prostaglandins (see Chapter 18) and apomorphine. Applications of Alpha2 Antagonists


Pharmacology_Katzung

Pharmacology_Katzung. Applications of Alpha2 Antagonists Alpha2 antagonists have relatively little clinical usefulness. They have definite but limited benefit in male erectile dysfunction. There has been experimental interest in the development of highly selective antagonists for treatment of type 2 diabetes (α2 receptors inhibit insulin secretion) and for treatment of psychiatric depression. It is likely that better understanding of the subtypes of α2 receptors will lead to development of clinically useful subtype-selective α2 antagonists.


Pharmacology_Katzung

Pharmacology_Katzung. Beta-receptor antagonists share the common feature of antagonizing the effects of catecholamines at β adrenoceptors. Beta-blocking drugs occupy β receptors and competitively reduce receptor occupancy by catecholamines and other β agonists. Most β-blocking drugs in clinical use are pure antagonists; that is, the occupancy of a β receptor by such a drug causes no activation of the receptor. However, some are partial agonists; that is, they cause partial activation of the receptor, albeit less than that caused by the full agonists epinephrine and isoproterenol. As described in Chapter 2, partial agonists inhibit the activation of β receptors in the presence of high catecholamine concentrations but moderately activate the receptors in the absence of endogenous agonists. Finally, evidence suggests that some β blockers (eg, betaxolol, metoprolol) are inverse agonists—drugs that reduce constitutive activity of β receptors—in some tissues. The clinical significance of this property is not


Pharmacology_Katzung

Pharmacology_Katzung. that some β blockers (eg, betaxolol, metoprolol) are inverse agonists—drugs that reduce constitutive activity of β receptors—in some tissues. The clinical significance of this property is not known.


Pharmacology_Katzung

Pharmacology_Katzung. The β-receptor–blocking drugs differ in their relative affinities for β1 and β2 receptors (Table 10–1). Some have a higher affinity for β1 than for β2 receptors, and this selectivity may have important clinical implications. Since none of the clinically available β-receptor antagonists are absolutely specific for β1 receptors, the selectivity is dose-related; it tends to diminish at higher drug concentrations. Other major differences among β antagonists relate to their pharmacokinetic characteristics and local anesthetic membrane-stabilizing effects. Chemically, most β-receptor antagonist drugs (Figure 10–5) resemble isoproterenol to some degree (see Figure 9–4). Pharmacokinetic Properties of the Beta-Receptor Antagonists A. Absorption Most of the drugs in this class are well absorbed after oral administration; peak concentrations occur 1–3 hours after ingestion. Sustained-release preparations of propranolol and metoprolol are available. B. Bioavailability


Pharmacology_Katzung

Pharmacology_Katzung. B. Bioavailability Propranolol undergoes extensive hepatic (first-pass) metabolism; its bioavailability is relatively low (Table 10–2). The proportion of drug reaching the systemic circulation increases as the dose is increased, suggesting that hepatic extraction mechanisms may become saturated. A major consequence of the low bioavailability of propranolol is that oral administration of the drug leads to much lower drug concentrations than are achieved after intravenous injection of the same dose. Because the first-pass effect varies among individuals, there is great individual variability in the plasma concentrations achieved after oral propranolol. For the same reason, bioavailability is limited to varying degrees for most β antagonists with the exception of betaxolol, penbutolol, pindolol, and sotalol. C. Distribution and Clearance


Pharmacology_Katzung

Pharmacology_Katzung. The β antagonists are rapidly distributed and have large volumes of distribution. Propranolol and penbutolol are quite lipophilic and readily cross the blood-brain barrier (Table 10–2). Most β antagonists have half-lives in the range of 3–10 hours. A major exception is esmolol, which is rapidly hydrolyzed and has a half-life of approximately 10 minutes. Propranolol and metoprolol are extensively metabolized in the liver, with little unchanged drug appearing in the urine. The CYP2D6 genotype is a major determinant of interindividual differences in metoprolol plasma clearance (see Chapters 4 and 5). Poor metabolizers exhibit threefold to tenfold higher plasma concentrations after administration of metoprolol than extensive metabolizers. Atenolol, celiprolol, and pindolol are less completely metabolized. Nadolol is excreted unchanged in the urine and has the longest half-life of any available β antagonist (up to 24 hours). The half-life of nadolol is prolonged in renal failure. The


Pharmacology_Katzung

Pharmacology_Katzung. metabolized. Nadolol is excreted unchanged in the urine and has the longest half-life of any available β antagonist (up to 24 hours). The half-life of nadolol is prolonged in renal failure. The elimination of drugs such as propranolol may be prolonged in the presence of liver disease, diminished hepatic blood flow, or hepatic enzyme inhibition. It is notable that the pharmacodynamic effects of these drugs are sometimes prolonged well beyond the time predicted from half-life data.


Pharmacology_Katzung

Pharmacology_Katzung. Pharmacodynamics of the Beta-Receptor Antagonist Drugs Most of the effects of these drugs are due to occupation and blockade of β receptors. However, some actions may be due to other effects, including partial agonist activity at β receptors and local anesthetic action, which differ among the β blockers (Table 10–2). A. Effects on the Cardiovascular System Beta-blocking drugs given chronically lower blood pressure in patients with hypertension (see Chapter 11). The mechanisms FIGURE 10–5 Structures of some β-receptor antagonists. involved are not fully understood but probably include suppression of renin release and effects in the CNS. These drugs do not usually cause hypotension in healthy individuals with normal blood pressure.


Pharmacology_Katzung

Pharmacology_Katzung. Beta-receptor antagonists have prominent effects on the heart (Figure 10–6) and are very valuable in the treatment of angina (see Chapter 12) and chronic heart failure (see Chapter 13) and following myocardial infarction (see Chapter 14). The negative inotropic and chronotropic effects reflect the role of adrenoceptors in regulating these functions. Slowed atrioventricular conduction with an increased PR interval is a related result of adrenoceptor blockade in the atrioventricular node. In the vascular system, β-receptor blockade opposes β2-mediated vasodilation. This may acutely lead to a rise in peripheral resistance from unopposed α-receptor–mediated effects as the sympathetic nervous system discharges in response to lowered blood pressure due to the fall in cardiac output. Nonselective and β1-blocking drugs antagonize the release of renin caused by the sympathetic nervous system.


Pharmacology_Katzung

Pharmacology_Katzung. Overall, although the acute effects of these drugs may include a rise in peripheral resistance, chronic drug administration leads to a fall in peripheral resistance in patients with hypertension. B. Effects on the Respiratory Tract Blockade of the β2 receptors in bronchial smooth muscle may lead to an increase in airway resistance, particularly in patients with asthma. Beta1-receptor antagonists such as metoprolol and atenolol may have some advantage over nonselective β antagonists when blockade of β1 receptors in the heart is desired and β2-receptor blockade is undesirable. However, no currently available β1selective antagonist is sufficiently specific to completely avoid interactions with β2 adrenoceptors. Consequently, these drugs should generally be avoided in patients with asthma. However, some TABLE 10–2 Properties of several beta-receptor–blocking drugs. 1Carvedilol and labetalol also cause α1-adrenoceptor blockade. 2β3 agonist. 3Bioavailability is dose-dependent.


Pharmacology_Katzung

Pharmacology_Katzung. TABLE 10–2 Properties of several beta-receptor–blocking drugs. 1Carvedilol and labetalol also cause α1-adrenoceptor blockade. 2β3 agonist. 3Bioavailability is dose-dependent. patients with chronic obstructive pulmonary disease (COPD) may tolerate β1-selective blockers, and the benefits, for example in patients with concomitant ischemic heart disease, may outweigh the risks. C. Effects on the Eye Beta-blocking agents reduce intraocular pressure, especially in glaucoma. The mechanism usually reported is decreased aqueous humor production. (See Clinical Pharmacology and Box: The Treatment of Glaucoma.) D. Metabolic and Endocrine Effects Beta-receptor antagonists such as propranolol inhibit sympathetic nervous system stimulation of lipolysis. The effects on carbohydrate metabolism are less clear, although glycogenolysis in the human liver is at least partially inhibited after β2-receptor blockade. 0.5 mg/kg


Pharmacology_Katzung

Pharmacology_Katzung. 0.5 mg/kg FIGURE 10–6 The effect in an anesthetized dog of the injection of epinephrine before and after propranolol. In the presence of a β-receptor–blocking agent, epinephrine no longer augments the force of contraction (measured by a strain gauge attached to the ventricular wall) nor increases cardiac rate. Blood pressure is still elevated by epinephrine because vasoconstriction is not blocked. (Reproduced, with permission, from Shanks RG: The pharmacology of β sympathetic blockade. Am J Cardiol 1966;18:312. Copyright Elsevier.)


Pharmacology_Katzung

Pharmacology_Katzung. Glucagon is the primary hormone used to combat hypoglycemia; it is unclear to what extent β antagonists impair recovery from hypoglycemia, but they should be used with caution in insulin-dependent diabetic patients. This may be particularly important in diabetic patients with inadequate glucagon reserve and in pancreatectomized patients since catecholamines may be the major factors in stimulating glucose release from the liver in response to hypoglycemia. Beta1-receptor–selective drugs may be less prone to inhibit recovery from hypoglycemia. Beta-receptor antagonists are much safer in those type 2 diabetic patients who do not have hypoglycemic episodes.


Pharmacology_Katzung

Pharmacology_Katzung. The chronic use of β-adrenoceptor antagonists has been associated with increased plasma concentrations of very-low-density lipoproteins (VLDL) and decreased concentrations of HDL cholesterol. Both of these changes are potentially unfavorable in terms of risk of cardiovascular disease. Although low-density lipoprotein (LDL) concentrations generally do not change, there is a variable decline in the HDL cholesterol/LDL cholesterol ratio that may increase the risk of coronary artery disease. These changes tend to occur with both selective and nonselective β blockers, although they may be less likely to occur with β blockers possessing intrinsic sympathomimetic activity (partial agonists). The mechanisms by which β-receptor antagonists cause these changes are not understood, although changes in sensitivity to insulin action may contribute. E. Effects Not Related to Beta-Blockade


Pharmacology_Katzung

Pharmacology_Katzung. E. Effects Not Related to Beta-Blockade Partial β-agonist activity may have been considered desirable to prevent untoward effects such as precipitation of asthma or excessive bradycardia. Pindolol and other partial agonists are noted in Table 10–2. However, these drugs may not be as effective as the pure antagonists in secondary prevention of myocardial infarction. Clinical trials of partial β-agonist drugs in hypertension have not confirmed increased benefit.


Pharmacology_Katzung

Pharmacology_Katzung. Local anesthetic action, also known as “membrane-stabilizing” action, is a prominent effect of several β blockers (Table 10–2). This action is the result of typical local anesthetic blockade of sodium channels (see Chapter 26) and can be demonstrated experimentally in isolated neurons, heart muscle, and skeletal muscle membrane. However, it is unlikely that this effect is important after systemic administration of these drugs, since the concentration in plasma usually achieved by these routes is too low for the anesthetic effects to be evident. The membrane-stabilizing β blockers are not used topically on the eye, because local anesthesia of the cornea, eliminating its protective reflexes, would be highly undesirable. Sotalol is a nonselective β-receptor antagonist that lacks local anesthetic action but has marked class III antiarrhythmic effects, reflecting potassium channel blockade (see Chapter 14).


Pharmacology_Katzung

Pharmacology_Katzung. Propranolol is the prototypical β-blocking drug. As noted above, it has low and dose-dependent bioavailability. A long-acting form of propranolol is available; prolonged absorption of the drug may


Pharmacology_Katzung

Pharmacology_Katzung. Glaucoma is a major cause of blindness and of great pharmacologic interest because the chronic form often responds to drug therapy. The primary manifestation is increased intraocular pressure not initially associated with symptoms. Without treatment, increased intraocular pressure results in damage to the retina and optic nerve, with restriction of visual fields and, eventually, blindness. Intraocular pressure is easily measured as part of the routine ophthalmologic examination. Two major types of glaucoma are recognized: open-angle and closed-angle (also called narrow-angle). The closed-angle form is associated with a shallow anterior chamber, in which a dilated iris can occlude the outflow drainage pathway at the angle between the cornea and the ciliary body (see Figure 6–9). This form is associated with acute and painful increases of pressure, which must be controlled on an emergency basis with drugs or prevented by surgical removal of part of the iris (iridectomy). The open-angle


Pharmacology_Katzung

Pharmacology_Katzung. is associated with acute and painful increases of pressure, which must be controlled on an emergency basis with drugs or prevented by surgical removal of part of the iris (iridectomy). The open-angle form of glaucoma is a chronic condition, and treatment is largely pharmacologic. Because intraocular pressure is a function of the balance between fluid input and drainage out of the globe, the strategies for the treatment of open-angle glaucoma fall into two classes: reduction of aqueous humor secretion and enhancement of aqueous outflow. Five general groups of drugs—cholinomimetics, α agonists, β blockers, prostaglandin F2α analogs, and diuretics—have been found to be useful in reducing intraocular pressure and can be related to these strategies as shown in Table 10–3. Of the five drug groups listed in Table 10–3, the prostaglandin analogs and the β blockers are the most popular. This popularity results from convenience (onceor twice-daily dosing) and relative lack of adverse effects


Pharmacology_Katzung

Pharmacology_Katzung. listed in Table 10–3, the prostaglandin analogs and the β blockers are the most popular. This popularity results from convenience (onceor twice-daily dosing) and relative lack of adverse effects (except, in the case of β blockers, in patients with asthma or cardiac pacemaker or conduction pathway disease). Other drugs that have been reported to reduce intraocular pressure include prostaglandin E2 and marijuana. The use of drugs in acute closed-angle glaucoma is limited to cholinomimetics, acetazolamide, and osmotic agents preceding surgery. The onset of action of the other agents is too slow in this situation.


Pharmacology_Katzung

Pharmacology_Katzung. occur over a 24-hour period. The drug has negligible effects at α and muscarinic receptors; however, it may block some serotonin receptors in the brain, although the clinical significance is unclear. It has no detectable partial agonist action at β receptors. Metoprolol, atenolol, and several other drugs (Table 10–2) are members of the β1-selective group. These agents may be safer in patients who experience bronchoconstriction in response to pro pranolol. Since their β1 selectivity is rather modest, they should be used with great caution, if at all, in patients with a history of asthma. However, in selected patients with COPD, the benefits may exceed the risks, eg, in patients with myocardial infarction. Beta1-selective antagonists may be preferable in patients with diabetes or peripheral vascular disease when therapy with a β blocker is required, since TABLE 10–3 Drugs used in open-angle glaucoma.


Pharmacology_Katzung

Pharmacology_Katzung. TABLE 10–3 Drugs used in open-angle glaucoma. Drugs Mechanism Methods of Administration β2 receptors are probably important in liver (recovery from hypoglycemia) and blood vessels (vasodilation). Nebivolol is the most highly selective β1-adrenergic receptor blocker, although some of its metabolites do not have this level of specificity. Nebivolol has the additional quality of eliciting vasodilation. This is due to an action of the drug on endothelial nitric oxide production. Nebivolol may increase insulin sensitivity and does not adversely affect lipid profile. Agents of this type are sometimes referred to as third-generation β-blocking drugs because they activate nitric oxide synthase. In patients with metabolic syndrome, for an equivalent reduction of blood pressure and heart rate, metoprolol, but not nebivolol, decreased insulin sensitivity and increased oxidative stress.


Pharmacology_Katzung

Pharmacology_Katzung. Timolol is a nonselective agent with no local anesthetic activity. It has excellent ocular hypotensive effects when administered topically in the eye. Nadolol is noteworthy for its very long duration of action; its spectrum of action is similar to that of timolol. Levobunolol (nonselective) and betaxolol (β1-selective) are also used for topical ophthalmic application in glaucoma; the latter drug may be less likely to induce bronchoconstriction than nonselective antagonists. Carteolol is a nonselective β-receptor antagonist.


Pharmacology_Katzung

Pharmacology_Katzung. Pindolol, acebutolol, carteolol, bopindolol, * oxprenolol, * celiprolol, * and penbutolol are of interest because they have partial β-agonist activity. They are effective in the major cardiovascular applications of the β-blocking group (hypertension and angina). Although these partial agonists may be less likely to cause bradycardia and abnormalities in plasma lipids than are antagonists, the overall clinical significance of intrinsic sympathomimetic activity remains uncertain. Pindolol, perhaps as a result of actions on serotonin signaling, may potentiate the action of traditional antidepressant medications. Acebutolol is also a β1-selective antagonist. Celiprolol is a β1-selective antagonist with a modest capacity to activate β2 receptors. There is limited evidence suggesting that celiprolol may have less adverse bronchoconstrictor effect in asthma and may even promote bronchodilation.


Pharmacology_Katzung

Pharmacology_Katzung. Labetalol is a reversible adrenoceptor antagonist available as a racemic mixture of two pairs of chiral isomers (the molecule has two centers of asymmetry). The (S,S)and (R,S)-isomers are nearly inactive, the (S,R)-isomer is a potent α blocker, and the (R,R)isomer is a potent β blocker. Labetalol’s affinity for α receptors is less than that of phentolamine, but labetalol is α1-selective. Its β-blocking potency is somewhat lower than that of propranolol. Hypotension induced by labetalol is accompanied by less tachycardia than occurs with phentolamine and similar α blockers.


Pharmacology_Katzung

Pharmacology_Katzung. Carvedilol, medroxalol, * and bucindolol * are nonselective β-receptor antagonists with some capacity to block α1-adrenergic receptors. Carvedilol antagonizes the actions of catecholamines more potently at β receptors than at α1 receptors. The drug has a half-life of 6–8 hours. It is extensively metabolized in the liver, and stereoselective metabolism of its two isomers is observed. Since metabolism of (R)-carvedilol is influenced by polymorphisms in CYP2D6 activity and by drugs that inhibit this enzyme’s activity (such as quinidine and fluoxetine, see Chapter 4), drug interactions may occur. Carvedilol also appears to attenuate oxygen free radical–initiated lipid peroxidation and to inhibit vascular smooth muscle mitogenesis independently of adrenoceptor blockade. * Not available in the USA. These effects may contribute to the clinical benefits of the drug in chronic heart failure (see Chapter 13).


Pharmacology_Katzung

Pharmacology_Katzung. * Not available in the USA. These effects may contribute to the clinical benefits of the drug in chronic heart failure (see Chapter 13). Esmolol is an ultra-short–acting β1-selective adrenoceptor antagonist. The structure of esmolol contains an ester linkage; esterases in red blood cells rapidly metabolize esmolol to a metabolite that has a low affinity for β receptors. Consequently, esmolol has a short half-life (about 10 minutes). Therefore, during continuous infusions of esmolol, steady-state concentrations are achieved quickly, and the therapeutic actions of the drug are terminated rapidly when its infusion is discontinued. Esmolol may be safer to use than longer-acting antagonists in critically ill patients who require a β-adrenoceptor antagonist. Esmolol is useful in controlling supraventricular arrhythmias, arrhythmias associated with thyrotoxicosis, perioperative hypertension, and myocardial ischemia in acutely ill patients.


Pharmacology_Katzung

Pharmacology_Katzung. Butoxamine is a research drug selective for β2 receptors. Selective β2-blocking drugs have not been actively sought because there is no obvious clinical application for them; none is available for clinical use.


Pharmacology_Katzung

Pharmacology_Katzung. The β-adrenoceptor–blocking drugs have proved to be effective and well tolerated in hypertension. Although many hypertensive patients respond to a β blocker used alone, the drug is often used with either a diuretic or a vasodilator. Despite the short half-life of many β antagonists, these drugs may be administered once or twice daily and still have an adequate therapeutic effect. Labetalol, a competitive α and β antagonist, is effective in hypertension, although its ultimate role is yet to be determined. Use of these agents is discussed in greater detail in Chapter 11. There is some evidence that drugs in this class may be less effective in the elderly and in individuals of African ancestry. However, these differences are relatively small and may not apply to an individual patient. Indeed, since effects on blood pressure are easily measured, the therapeutic outcome for this indication can be readily detected in any patient.


Pharmacology_Katzung

Pharmacology_Katzung. Beta-adrenoceptor blockers reduce the frequency of anginal episodes and improve exercise tolerance in many patients with angina (see Chapter 12). These actions are due to blockade of cardiac β receptors, resulting in decreased cardiac work and reduction in oxygen demand. Slowing and regularization of the heart rate may contribute to clinical benefits (Figure 10–7). Multiple large-scale prospective studies indicate that the long-term use of timolol, propranolol, or metoprolol in patients who have had a myocardial infarction prolongs survival (Figure 10–8). At present, data are less compelling for the use of other than the three mentioned β-adrenoceptor antagonists for this indication. It is significant that surveys in many populations have indicated that β-receptor antagonists are underused, leading to unnecessary morbidity and mortality. In addition, β-adrenoceptor antagonists are strongly indicated in the acute phase of a myocardial infarction. In this setting, relative


Pharmacology_Katzung

Pharmacology_Katzung. are underused, leading to unnecessary morbidity and mortality. In addition, β-adrenoceptor antagonists are strongly indicated in the acute phase of a myocardial infarction. In this setting, relative contraindications include bradycardia, hypotension,


Pharmacology_Katzung

Pharmacology_Katzung. FIGURE 10–7 Heart rate in a patient with ischemic heart disease measured by telemetry while watching television. Measurements were begun 1 hour after receiving placebo (upper line, red) or 40 mg of oxprenolol (lower line, blue), a nonselective β antagonist with partial agonist activity. Not only was the heart rate decreased by the drug under the conditions of this experiment, it also varied much less in response to stimuli. (Adapted, with permission, from Taylor SH: Oxprenolol in clinical practice. Am J Cardiol 1983;52:34D. Copyright Elsevier.) .30 .25 .20 .15 .10 .05 .00


Pharmacology_Katzung

Pharmacology_Katzung. Placebo Timolol p = 0.0028 lated rates of mortality from all causes over 6 years among 1884 patients surviving myocardial infarctions. Patients were randomly assigned to treatment with placebo (dashed red line) or timolol (solid blue line). (Reproduced, with permission, from Pedersen TR: Six-year follow-up of the Norwegian multicenter study on timolol after acute myocardial infarction. N Engl J Med 1985;313:1055. Copyright © 1985 Massachusetts Medical Society.) moderate or severe left ventricular failure, shock, heart block, and active airways disease. It has been suggested that certain polymorphisms in β2-adrenoceptor genes may influence survival among patients receiving antagonists after acute coronary syndromes.


Pharmacology_Katzung

Pharmacology_Katzung. Beta antagonists are often effective in the treatment of both supraventricular and ventricular arrhythmias (see Chapter 14). It has been suggested that the improved survival following myocardial infarction in patients using β antagonists (Figure 10–8) is due to suppression of arrhythmias, but this has not been proved. By increasing the atrioventricular nodal refractory period, β antagonists slow ventricular response rates in atrial flutter and fibrillation. These drugs can also reduce ventricular ectopic beats, particularly if the ectopic activity has been precipitated by catecholamines. Esmolol is particularly useful against acute perioperative arrhythmias because it has a short duration of action and can be given parenterally. Sotalol has antiarrhythmic effects involving ion channel blockade in addition to its β-blocking action; these are discussed in Chapter 14.


Pharmacology_Katzung

Pharmacology_Katzung. Clinical trials have demonstrated that at least three β antagonists— metoprolol, bisoprolol, and carvedilol—are effective in reducing mortality in selected patients with chronic heart failure. Although administration of these drugs may worsen acute congestive heart failure, cautious long-term use with gradual dose increments in patients who tolerate them may prolong life. Although mechanisms are uncertain, there appear to be beneficial effects on myocardial remodeling and in decreasing the risk of sudden death (see Chapter 13).


Pharmacology_Katzung

Pharmacology_Katzung. Beta-receptor antagonists have been found to increase stroke volume in some patients with obstructive cardiomyopathy. This beneficial effect is thought to result from the slowing of ventricular ejection and decreased outflow resistance. Beta antagonists are useful in dissecting aortic aneurysm to decrease the rate of development of systolic pressure. Beta antagonists have been claimed to prevent adverse cardiovascular outcomes resulting from non-cardiac surgery, but this is controversial. Glaucoma (See Box: The Treatment of Glaucoma)


Pharmacology_Katzung

Pharmacology_Katzung. Systemic administration of β-blocking drugs for other indications was found serendipitously to reduce intraocular pressure in patients with glaucoma. Subsequently, it was found that topical administration also reduces intraocular pressure. The mechanism appears to involve reduced production of aqueous humor by the ciliary body, which is physiologically activated by cAMP. Timolol and related β antagonists are suitable for local use in the eye because they lack local anesthetic properties. Beta antagonists appear to have an efficacy comparable to that of epinephrine or pilocarpine in open-angle glaucoma and are far better tolerated by most patients. While the maximal daily dose applied locally (1 mg) is small compared with the systemic doses commonly used in the treatment of hypertension or angina (10–60 mg), sufficient timolol may be absorbed from the eye to cause serious adverse effects on the heart and airways in susceptible individuals. Topical timolol may interact with orally


Pharmacology_Katzung

Pharmacology_Katzung. or angina (10–60 mg), sufficient timolol may be absorbed from the eye to cause serious adverse effects on the heart and airways in susceptible individuals. Topical timolol may interact with orally administered verapamil and increase the risk of heart block.


Pharmacology_Katzung

Pharmacology_Katzung. Betaxolol, carteolol, levobunolol, and metipranolol are also approved for the treatment of glaucoma. Betaxolol has the potential advantage of being β1-selective; to what extent this potential advantage might diminish systemic adverse effects remains to be determined. The drug apparently has caused worsening of pulmonary symptoms in some patients. Excessive catecholamine action is an important aspect of the pathophysiology of hyperthyroidism, especially in relation to the heart (see Chapter 38). The β antagonists are beneficial in this condition. The effects presumably relate to blockade of adrenoceptors and perhaps in part to the inhibition of peripheral conversion of thyroxine to triiodothyronine. The latter action may vary from one β antagonist to another. Propranolol has been used extensively in patients with thyroid storm (severe hyperthyroidism); it is used cautiously in patients with this condition to control supraventricular tachycardias that often precipitate heart failure.


Pharmacology_Katzung

Pharmacology_Katzung. Propranolol reduces the frequency and intensity of migraine headache. Other β-receptor antagonists with preventive efficacy include metoprolol and probably also atenolol, timolol, and nadolol. The mechanism is not known. Since sympathetic activity may enhance skeletal muscle tremor, it is not surprising that β antagonists have been found to reduce certain tremors (see Chapter 28). The somatic manifestations of anxiety may respond dramatically to low doses of propranolol, particularly when taken prophylactically. For example, benefit has been found in musicians with performance anxiety (“stage fright”). Propranolol may contribute to the symptomatic treatment of alcohol withdrawal in some patients.


Pharmacology_Katzung

Pharmacology_Katzung. Beta-receptor antagonists have been found to diminish portal vein pressure in patients with cirrhosis. There is evidence that both propranolol and nadolol decrease the incidence of the first episode of bleeding from esophageal varices and decrease the mortality rate associated with bleeding in patients with cirrhosis. Nadolol in combination with isosorbide mononitrate appears to be more efficacious than sclerotherapy in preventing rebleeding in patients who have previously bled from esophageal varices. Variceal band ligation in combination with a β antagonist may be more efficacious.


Pharmacology_Katzung

Pharmacology_Katzung. In the current era of repurposing established drugs that are well tolerated, unexpected benefits can emerge. Infantile hemangiomas are the most common vascular tumors of infancy, which can disfigure or impair vital functions. Propranolol at 2 mg/kg/d has been found to reduce the volume, color, and elevation of infantile hemangioma in infants younger than 6 months and children up to 5 years of age, perhaps displacing more toxic drugs such as systemic glucocorticoids, vincristine, and interferon-alfa.


Pharmacology_Katzung

Pharmacology_Katzung. Propranolol is the standard against which newer β antagonists for systemic use have been compared. In many years of very wide use, propranolol has been found to be a safe and effective drug for many indications. Since it is possible that some actions of a β-receptor antagonist may relate to some other effect of the drug, these drugs should not be considered interchangeable for all applications. For example, only β antagonists known to be effective in stable heart failure or in prophylactic therapy after myocardial infarction should be used for those indications. It is possible that the beneficial effects of one drug in these settings might not be shared by another drug in the same class. The possible advantages and disadvantages of β-receptor partial agonists have not been clearly defined in clinical settings, although current evidence suggests that they are probably less efficacious in secondary prevention after a myocardial infarction compared with pure antagonists.


Pharmacology_Katzung

Pharmacology_Katzung. Many adverse effects have been reported for propranolol but most are minor. Bradycardia is the most common adverse cardiac effect of β-blocking drugs. Sometimes patients note coolness of hands and feet in winter. CNS effects include mild sedation, vivid dreams, and rarely, depression. Discontinuing the use of β blockers in any patient who develops psychiatric depression should be seriously considered if clinically feasible. It has been claimed that β-receptor antagonist drugs with low lipid solubility are associated with a lower incidence of CNS adverse effects than compounds with higher lipid solubility (Table 10–2). Further studies designed to compare the CNS adverse effects of various drugs are required before specific recommendations can be made, although it seems reasonable to try the hydrophilic drugs nadolol or atenolol in a patient who experiences unpleasant CNS effects with other β blockers.


Pharmacology_Katzung

Pharmacology_Katzung. The major adverse effects of β-receptor antagonist drugs relate to the predictable consequences of β blockade. Beta2-receptor blockade associated with the use of nonselective agents commonly causes worsening of preexisting asthma and other forms of airway obstruction without having these consequences in normal individuals. Indeed, relatively trivial asthma may become severe after β blockade. However, because of their lifesaving potential in cardiovascular disease, strong consideration should be given to individualized therapeutic trials in some classes of patients, eg, those with chronic obstructive pulmonary disease who have appropriate indications for β blockers. While β1-selective drugs may have less effect on airways than nonselective β antagonists, they must be used very cautiously in patients with reactive airway disease. Beta1-selective antagonists are generally well tolerated in patients with mild to moderate peripheral vascular disease, but caution is required in patients


Pharmacology_Katzung

Pharmacology_Katzung. in patients with reactive airway disease. Beta1-selective antagonists are generally well tolerated in patients with mild to moderate peripheral vascular disease, but caution is required in patients with severe peripheral vascular disease or vasospastic disorders.


Pharmacology_Katzung

Pharmacology_Katzung. Beta-receptor blockade depresses myocardial contractility and excitability. In patients with abnormal myocardial function, cardiac output may be dependent on sympathetic drive. If this stimulus is removed by β blockade, cardiac decompensation may ensue. Thus, caution must be exercised in starting a β-receptor antagonist in patients with compensated heart failure even though long-term use of these drugs in these patients may prolong life. A life-threatening adverse cardiac effect of a β antagonist may be overcome directly with isoproterenol or with glucagon (glucagon stimulates the heart via glucagon receptors, which are not blocked by β antagonists), but neither of these methods is without hazard. A very small dose of a β antagonist (eg, 10 mg of propranolol) may provoke severe cardiac failure in a susceptible individual. Beta blockers may interact with the calcium antagonist verapamil; severe hypotension, bradycardia, heart failure, and cardiac conduction abnormalities have all been


Pharmacology_Katzung

Pharmacology_Katzung. in a susceptible individual. Beta blockers may interact with the calcium antagonist verapamil; severe hypotension, bradycardia, heart failure, and cardiac conduction abnormalities have all been described. These adverse effects may even arise in susceptible patients taking a topical (ophthalmic) β blocker and oral verapamil.


Pharmacology_Katzung

Pharmacology_Katzung. Patients with ischemic heart disease or renovascular hypertension may be at increased risk if β blockade is suddenly interrupted. The mechanism of this effect might involve up-regulation of the number of β receptors. Until better evidence is available regarding the magnitude of the risk, prudence dictates the gradual tapering rather than abrupt cessation of dosage when these drugs are discontinued, especially drugs with short half-lives, such as propranolol and metoprolol.


Pharmacology_Katzung

Pharmacology_Katzung. The incidence of hypoglycemic episodes exacerbated by β-blocking agents in diabetics is unknown. Nevertheless, it is inadvisable to use β antagonists in insulin-dependent diabetic patients who are sub-compared with that in diabetics receiving nonselective β-adrenoceptor ject to frequent hypoglycemic reactions if alternative therapies are antagonists. There is considerable potential benefit from these drugs available. Beta1-selective antagonists offer some advantage in these in diabetics after a myocardial infarction, so the balance of risk versus patients, since the rate of recovery from hypoglycemia may be faster benefit must be evaluated in individual patients.


Pharmacology_Katzung

Pharmacology_Katzung. •Propranolol•Nadolol•TimololBlock β1 and β2 LowerHRandBP•reducerenin Hypertension•anginapectoris•arrhythmias•migraine•hyperthyroidism•glaucoma(topical timolol) Oral,parenteral•Toxicity: Bradycardia•worsenedasthma•fatigue•vividdreams•coldhands•Metoprolol•Atenolol•Betaxolol•NebivololBlock β1 > β2 LowerHRandBP•reducerenin•maybesaferinasthma Anginapectoris•hypertension•arrhythmias•glaucoma(topicalbetaxolol) Toxicity: Bradycardia•fatigue•vividdreams•coldhands•Butoxamine1 Blocks β2 > β1 Increases peripheral resistance No clinical indication Toxicity: Asthma provocation •Pindolol•Acebutolol•Carteolol•Bopindolol1 •Oxprenolol1 •Celiprolol1 •Penbutololβ1, β2, with intrinsic sympathomimetic (partial agonist) effect LowerBP•modestlylowerHR Hypertension•arrhythmias•migraine•mayavoidworseningof bradycardia Oral•Toxicity: Fatigue•vividdreams•coldhands•Carvedilol•Medroxalol1 •Bucindolol1 (see labetalol above) β > α1 block Heart failure Oral,longhalf-life•Toxicity: Fatigue 1Not available in the USA.


Pharmacology_Katzung

Pharmacology_Katzung. GENERIC NAME AVAILABLE AS ALPHA BLOCKERS Alfuzosin Uroxatral Doxazosin Generic, Cardura Phenoxybenzamine Dibenzyline Phentolamine Generic Prazosin Generic, Minipress Silodosin Rapaflo Tamsulosin Flomax Terazosin Generic, Hytrin Tolazoline Priscoline BETA BLOCKERS Acebutolol Generic, Sectral Atenolol Generic, Tenormin Betaxolol Oral Kerlone Ophthalmic Generic, Betoptic Bisoprolol Generic, Zebeta Carteolol Oral Cartrol Ophthalmic Generic, Ocupress PREP AR A TIONS A V AIL ABLE*GENERIC NAME AVAILABLE AS Carvedilol Coreg Esmolol Brevibloc Labetalol Generic, Normodyne, Trandate Levobunolol Betagan Liquifilm, others Metipranolol OptiPranolol Metoprolol Generic, Lopressor, Toprol Nadolol Generic, Corgard Nebivolol Bystolic Penbutolol Levatol Pindolol Generic, Visken Propranolol Generic, Inderal Sotalol Generic, Betapace Timolol Oral Generic, Blocadren Ophthalmic Generic, Timoptic TYROSINE HYDROXYLASE INHIBITOR Metyrosine Demser * In the USA.


Pharmacology_Katzung

Pharmacology_Katzung. Ambrosio G et al: β-Blockade with nebivolol for prevention of acute ischaemic events in elderly patients with heart failure. Heart 2011;97:209. Arnold AC et al: Combination ergotamine and caffeine improves seated blood pressure and presyncopal symptoms in autonomic failure. Front Physiol 2014;5:270. Ayers K et al: Differential effects of nebivolol and metoprolol on insulin sensitivity and plasminogen activator inhibitor in the metabolic syndrome. Hypertension 2012;59:893. Bell CM et al: Association between tamsulosin and serious ophthalmic adverse events in older men following cataract surgery. JAMA 2009;301:1991. Berruezo A, Brugada J: Beta blockers: Is the reduction of sudden death related to pure electrophysiologic effects? Cardiovasc Drug Ther 2008;22:163.


Pharmacology_Katzung

Pharmacology_Katzung. Berruezo A, Brugada J: Beta blockers: Is the reduction of sudden death related to pure electrophysiologic effects? Cardiovasc Drug Ther 2008;22:163. Bird ST et al: Tamsulosin treatment for benign prostatic hyperplasia and risk of severe hypotension in men aged 40-85 years in the United States: Risk window analyses using between and within patient methodology. BMJ 2013;347:f6320. Blakely RD, DeFelice LJ: All aglow about presynaptic receptor regulation of neurotransmitter transporters. Mol Pharmacol 2007;71:1206. Blaufarb I, Pfeifer TM, Frishman WH: Beta-blockers: Drug interactions of clinical significance. Drug Saf 1995;13:359. Boyer TD: Primary prophylaxis for variceal bleeding: Are we there yet? Gastroenterology 2005;128:1120. Brantigan CO, Brantigan TA, Joseph N: Effect of beta blockade and beta stimulation on stage fright. Am J Med 1982;72:88. Bristow M: Antiadrenergic therapy of chronic heart failure: Surprises and new opportunities. Circulation 2003;107:1100.


Pharmacology_Katzung

Pharmacology_Katzung. Bristow M: Antiadrenergic therapy of chronic heart failure: Surprises and new opportunities. Circulation 2003;107:1100. Cleland JG: Beta-blockers for heart failure: Why, which, when, and where. Med Clin North Am 2003;87:339. Eisenhofer G et al: Current progress and future challenges in the biochemical diagnosis and treatment of pheochromocytomas and paragangliomas. Horm Metab Res 2008;40:329. Ellison KE, Gandhi G: Optimising the use of beta-adrenoceptor antagonists in coronary artery disease. Drugs 2005;65:787. Fitzgerald JD: Do partial agonist beta-blockers have improved clinical utility? Cardiovasc Drugs Ther 1993;7:303. Freemantle N et al: Beta blockade after myocardial infarction: Systematic review and meta regression analysis. BMJ 1999;318:1730. Hogeling M, Adams S, Wargon O: A randomized controlled trial of propranolol for infantile hemangiomas. Pediatrics 2011;128:e259. Jacobs DS: Open-angle glaucoma: Treatment. UpToDate.com 2013, topic 15695.


Pharmacology_Katzung

Pharmacology_Katzung. Jacobs DS: Open-angle glaucoma: Treatment. UpToDate.com 2013, topic 15695. Kamp O et al: Nebivolol: Haemodynamic effects and clinical significance of combined β-blockade and nitric oxide release. Drugs 2010;70:41. Kaplan SA et al: Combination therapy using oral β-blockers and intracavernosal injection in men with erectile dysfunction. Urology 1998;52:739. Kyprianou N: Doxazosin and terazosin suppress prostate growth by inducing apoptosis: Clinical significance. J Urol 2003;169:1520. Lanfear DE et al: β2-Adrenergic receptor genotype and survival among patients receiving β-blocker therapy after an acute coronary syndrome. JAMA 2005;294:1526. Lepor H et al: The efficacy of terazosin, finasteride, or both in benign prostate hyperplasia. N Engl J Med 1996;335:533. Maggio PM, Taheri PA: Perioperative issues: Myocardial ischemia and protection– beta-blockade. Surg Clin North Am 2005;85:1091.


Pharmacology_Katzung

Pharmacology_Katzung. Maggio PM, Taheri PA: Perioperative issues: Myocardial ischemia and protection– beta-blockade. Surg Clin North Am 2005;85:1091. McVary KT: Alfuzosin for symptomatic benign prostatic hyperplasia: Long-term experience. J Urol 2006;175:35. Nickel JC, Sander S, Moon TD: A meta-analysis of the vascular-related safety profile and efficacy of alpha-adrenergic blockers for symptoms related to benign prostatic hyperplasia. Int J Clin Pract 2008;62:1547. Nickerson M: The pharmacology of adrenergic blockade. Pharmacol Rev 1949;1:27. Okamoto LE et al: Nebivolol, but not metoprolol lowers blood pressure in nitric oxide-sensitive human hypertension. Hypertension 2014;64:1241. Perez DM: Structure-function of alpha1-adrenergic receptors. Biochem Pharmacol 2007;73:1051. Pojoga L et al: Beta-2 adrenergic receptor diplotype defines a subset of salt-sensitive hypertension. Hypertension 2006;48:892.


Pharmacology_Katzung

Pharmacology_Katzung. Pojoga L et al: Beta-2 adrenergic receptor diplotype defines a subset of salt-sensitive hypertension. Hypertension 2006;48:892. Raj SR et al: Propranolol decreases tachycardia and improves symptoms in the postural tachycardia syndrome: Less is more. Circulation 2009;120:725. Robertson D et al: Primer on the Autonomic Nervous System, 3rd ed. Cambridge, MA: Academic Press, 2012. Roehrborn CG, Schwinn DA: Alpha1-adrenergic receptors and their inhibitors in lower urinary tract symptoms and benign prostatic hyperplasia. J Urol 2004;171:1029. Schwinn DA, Roehrborn CG: Alpha1-adrenoceptor subtypes and lower urinary tract symptoms. Int J Urol 2008;15:193. Shibao C et al: Comparative efficacy of yohimbine against pyridostigmine for the treatment of orthostatic hypotension in autonomic failure. Hypertension 2010;56:847. Tank J et al: Yohimbine attenuates baroreflex-mediated bradycardia in humans. Hypertension 2007;50:899.


Pharmacology_Katzung

Pharmacology_Katzung. Tank J et al: Yohimbine attenuates baroreflex-mediated bradycardia in humans. Hypertension 2007;50:899. Wilt TJ, MacDonald R, Rutks I: Tamsulosin for benign prostatic hyperplasia. Cochrane Database Syst Rev 2003;1:CD002081.


Pharmacology_Katzung

Pharmacology_Katzung. The patient had a pheochromocytoma. This tumor secretes cat-echolamines, especially norepinephrine and epinephrine, result-ing in increases in blood pressure (via α1 receptors) and heart rate (via β1 receptors). The pheochromocytoma was in the left adrenal gland and was identified by meta-iodobenzylguanidine (MIBG) imaging, which labels tissues that have norepinephrine transporters on their cell surface (see text). In addition, he had elevated plasma and urinary norepinephrine, epinephrine, and their metabolites, normetanephrine and metanephrine. The catecholamines made the blood pressure surge and the heart rate increase, producing a typical episode during the examina-tion, perhaps set off in this case by external pressure as the phy-sician palpated the abdomen. His profuse sweating was typical and partly due to α1 receptors, although the large magnitude of drenching sweats in pheochromocytoma has never been fully explained. Treatment would consist of preoperative pharma-cologic


Pharmacology_Katzung

Pharmacology_Katzung. was typical and partly due to α1 receptors, although the large magnitude of drenching sweats in pheochromocytoma has never been fully explained. Treatment would consist of preoperative pharma-cologic control of blood pressure and normalization of blood volume if reduced, followed by surgical resection of the tumor. Control of blood pressure extremes might be necessary during surgery, probably with nitroprusside.


Pharmacology_Katzung

Pharmacology_Katzung. Neal L. Benowitz, MD A 35-year-old man presents with a blood pressure of 150/95 mm Hg. He has been generally healthy, is sedentary, drinks several cocktails per day, and does not smoke cigarettes. He has a family history of hypertension, and his father died of a myocardial infarction at age 55. Physical examination is remarkable only for moderate obesity. Total cholesterol is 220, and high-density lipoprotein (HDL) cholesterol level is 40 mg/dL. Fasting glucose is 105 mg/dL. Chest X-ray is normal. Electrocardiogram shows left ven-tricular enlargement. How would you treat this patient?


Pharmacology_Katzung

Pharmacology_Katzung. Hypertension is the most common cardiovascular disease. In a National Health and Nutrition Examination Survey (NHANES) carried out in 2011 to 2012, hypertension was found in 29% of American adults and 65% of adults age 65 years or older. The prevalence varies with age, race, education, and many other variables. According to some studies, 60–80% of both men and women will develop hypertension by age 80. Sustained arterial hypertension damages blood vessels in kidney, heart, and brain and leads to an increased incidence of renal failure, coronary disease, heart failure, stroke, and dementia. Effective pharmacologic lowering of blood pressure has been shown to prevent damage to blood vessels and to substantially reduce morbidity and mortality rates. However, NHANES found that, unfortunately, only one-half of Americans with hypertension had adequate blood pressure control. Many effective drugs are available. Knowledge of their antihypertensive mechanisms and sites of action allows


Pharmacology_Katzung

Pharmacology_Katzung. only one-half of Americans with hypertension had adequate blood pressure control. Many effective drugs are available. Knowledge of their antihypertensive mechanisms and sites of action allows accurate prediction of efficacy and toxicity. The rational use of these agents, alone or in combination, can lower blood pressure with minimal risk of serious toxicity in most patients.


Pharmacology_Katzung

Pharmacology_Katzung. The diagnosis of hypertension is based on repeated, reproducible measurements of elevated blood pressure (Table 11–1). The diagnosis serves primarily as a prediction of consequences for the patient; it seldom includes a statement about the cause of hypertension. Epidemiologic studies indicate that the risks of damage to kidney, heart, and brain are directly related to the extent of blood pressure elevation. Even mild hypertension (blood pressure TABLE 11–1 Classification of hypertension on the basis of blood pressure. From the Joint National Committee on prevention, detection, evaluation, and treatment of high blood pressure. JAMA 2003;289:2560.