CURRENT DRUG THERAPY DONALD G. VIDT, MD AND ALAN BAKST, PharmD, EDITORS Alpha^ and beta^blocking agents: pharmacology and properties PROFESSOR B.N.C. PRICHARD • Adrenergic receptors have been separated into alpha and beta groups, which have then been further subdivided. Agents have been developed that block each type of receptor with varying degrees of specificity between the sub-types, leading to differences in pharmacodynamic profile. A more recent innovation has been the development of multiple action beta-blocking drugs, ie, those not only blocking the beta receptors but also posessing a peripheral vasodilator effect that may be due to alpha blockade, beta-2 stimulation, or a vasodilator action independent of either alpha or beta receptors. • INDEX TERMS: ALPHA BLOCKERS; BETA BLOCKERS; HYPERTENSION • CLEVE CLIN ] MED 1991; 58:33 7-350 HE CONCEPT that binding of Rosenblueth suggested that a transmitter released at catecholamines to receptors leads to differ- sympathetic nerve endings produced either inhibitory ing responses was first described by Langley, or excitatory responses as a result of combination with who in 1905 noted that a cell may make sympathin I or sympathin E at the receptor.3 Tmotor or inhibitory substances or both, and that "the The current classification of alpha and beta respon- effect of a nerve impulse depends upon the proportion ses is based on the classic work of Ahlquist,4 who of the two kinds of receptive substance which is af- studied six sympathomimetic amines and found two fected by the impulse."1 In 1906, Dale reported that patterns of reactivity. One group of actions, mediated ergot blocked the excitatory but not the inhibitory ac- by what were termed "alpha receptors," were principally tions of adrenaline.2 In 1933, Cannon and excitatory. The excitatory actions included vaso- constriction, as well as contraction of the uterus, ureter, and nictitating membrane. But alpha actions also in- cluded inhibitory actions, such as dilator pupillae and From the Department of Clinical Pharmacology, University Col- lege and Middlesex School of Medicine, University College Lon- intestinal relaxation. The most potent agent at these don, England. receptors was adrenaline, followed by noradrenaline. Address reprint requests to B.N.C.P., Head, Department of Clini- In the second group, mediated by what were termed cal Pharmacology, University College London, 5 University Street "beta receptors," inhibitory actions predominated. (The Rayne Institute), London WCIE 6JJ, England. This article was produced by Consultants in Medical Education, These inhibitory actions included vasodilation; and Inc., Manhasset, New York, under an educational grant from relaxation of the uterus and bronchial smooth muscle. Schering-Plough International. There was also an important beta-excitatory action, JULY • AUGUSTDownloaded 1991 from www.ccjm.org on September 27, 2021. For personal use only. All otherCLEVELAN uses requireD CLINI permission.C JOURNAL OF MEDICINE 337 ALPHA AND BETA BLOCKERS • PRICHARD TABLE I nism, inhibiting noradrena- EFFECTS OF RECEPTOR STIMULATION AND BLOCKADE line release, contain pre- synaptic receptors of the al- Organ/Iissue Receptor Stimulation causes Blockade causes pha-2 subtype.5 More re- Blood vessels Constriction Dilatation cently, investigations using (resistance vessels) Constriction Dilatation animals have identified fur- Dilatation Constrictio? n Heart Contractile forcet ther subtypes of alpha re- Heart rateî Bradycardia ß,>ß2 ceptors, as well as alpha-la, AV conduction? AV conduction! Contractile forceî Contractile force! alpha-lb, alpha-2a, and Spleen «i Contraction Relaxation alpha-2b receptors.6 M sphincter pupillae «2 Dilatation Contraction Thrombocytes <x2 Aggregation The distribution of re- Adenylcyclase Hyperglycemia Hypoglycemia ceptors is not the same in + Free fatty acidT Free fatty acid! ßi ß2 Intestine Relaxation all species or all organs. For Bronchi Relaxation Constriction Uterus Relaxation Constriction example, in some vascular §2>ß, Skeletal muscle Tremor Anti-tremor beds, such as the cerebral arteries of the dog, alpha-2 From van Zweiten.11 AV, atrioventricular; Î, increase; !, decrease receptors are more numer- ous than alpha-1 receptors.7 By comparison, the human TABLE 2 ALPHA AGONIST AND ANTAGONIST SELECTIVITY forearm has both alpha-1 and alpha-2 receptors.8 Receptor stimulated Receptors also vary in Agents or blocked Application their tissue and synaptic lo- Agonists cations. The receptors in Noradrenaline (neurotransmitter) + + Vasoconstrictor (a, + 0i2) «2 vascular smooth muscle Adrenaline (neurotransmitter) + a2 + | Vasoconstrictor (at + <X2) Phenylephrine >a, Vasoconstrictor (a,), decongestant (a2) that mediate the nerve im- Clonidine Antihypertensive (central a2) Guanfacine >a, pulses are postsynaptic re- Azepexole (B-HT 933) ceptors of the alpha-1 sub- B-HT 920 Antiglaucomatous (experimental) UK-14, 304 Experimental pharmacology type, whereas the receptors that mediate contraction in Antagonists Phentolamine a. + a, Pheochromocytoma preoperative response to hormonal stim- phase (a, + a2) ulation are extrasynaptic Tolazoline XX, Vasodilator (af + 0i2) 5 Prazosin Antihypertensive (peripheral Ctj) alpha-2 receptors. In vas- Doxazosin cular smooth muscle, the Terazosin alpha-1 receptors are lo- Trimazosin + Antihypertensive (peripheral Olj + ßj & ß2) Labetalol ß, ß2 cated in the adventitial lay- Corynanthine Experimental pharmacology er; the alpha-2 receptors are Rauwolscine diastereoisomers Yohimbine || found closer to the interior, Idazoxan where they respond to cir- 9 From van Zweiten." culating catecholamines. In the central nervous system, different functions cardiac stimulation (Table I). Isoprenaline was the have been identified for alpha-1 and alpha-2 receptors. most potent stimulant at the beta receptor; adrenaline The adrenergic postsynaptic receptors in the central was also effective. nervous system are predominantly alpha-2. Stimulation Subsequently, the alpha and beta receptors were fur- of these receptors produces a fall in blood pressure and ther delineated. The alpha receptors were subdivided bradycardia. Central alpha-1 receptors, demonstrated into alpha-1 and alpha-2 receptors. Both alpha-1 and by receptor-binding techniques,8 may mediate alpha- 2 receptors are found on the postsynaptic mem- baroreceptor reflex function. Alpha-1 blockade of these brane, where vasoconstriction is mediated. The nerve central receptors may be the reason that the alpha-1 endings that function as a negative feedback mecha- blocker prazosin does not produce reflex tachycardia.10 338 CLEVELAND CLINIDownloadedC JOURNAL from OF MEDICIN www.ccjm.orgE on September 27, 2021. For personal use only. All other uses require permission.VOLUME 58 NUMBER 4 ALPHA AND BETA BLOCKERS • PRICHARD Agents that are active at adrenergic receptors may TABLE 3 be classified by their alpha activity. Methoxamine and BETA AGONST AND ANTAGONIST SELECTIVITY phenylephrine are alpha-1 stimulants; clonidine and Receptors its analogues are alpha-2 stimulants; noradrenaline and stimulated or adrenaline stimulate both alpha-1 and alpha-2 recep- Agent blocked tors. Prazosin, doxazosin, terazosin, and urapidil are Agonists alpha-1-blocking agents; yohimbine and rauwolscine Noradrenaline (norepinephrine, neurotransmitter) Adrenaline (epinephrine, neurotransmitter) + + + g, <*2 are alpha-2-blocking drugs; phentolamine blocks both Dobutamine alpha-1 and alpha-2 receptors (Table 2).5,6'11 Isoprenaline (isoproterenol) Orciprenaline (metoproterenol) The beta receptors have also been divided into beta- Fenoterol 1 and beta-2 receptors. More recently, beta-3 receptors Pirbuterol Rimiterol have been described in animal studies.6 Ritodrine As with alpha receptors, beta receptors also differ in Salbutamol Terbutaline their distribution and function. Beta-1 receptors predominate in the human heart. However, beta-2 Antagonists Propranolol" receptors are also present, constituting 35% of the beta Alprenolol and other receptors in the right atrium. For example, beta recep- Pindolol > nonselective beta Oxprenolol + blockers ß, ß2 tors mediate increase in heart rate and force of con- Timolol traction and increase in conductivity. Among the Sotalol Practolol ß,>>ß; many responses mediated by beta-2 receptors are Atenolol relaxation of vascular and bronchial smooth muscle. Metoprolol Acebutolol Adrenergic agonists and antagonists can be distin- guished by their beta reactivity (Table 3). The agonist From van Zweiten." dobutamine is relatively beta-1-selective, although it also stimulates the beta-2 and alpha-1 receptors. strictor impulses needed in the erect posture to main- Xamoterol is a specific but partial agonist for the beta- tain blood pressure are blocked by the irreversible 1 receptor. Noradrenaline is much more effective on binding of the inhibitor to the receptor. the beta-1 receptor, whereas adrenaline stimulates On the other hand, if the block is competitive and both types of beta receptor. The antagonist the dosage is appropriate, the increased sympathetic propranolol is the most widely evaluated nonselective activity associated with standing is likely to result in (beta-1, beta-2) blocking drug and atenolol, the most sufficient reversal of the alpha-receptor inhibition so studied of the beta-1 inhibitory drugs. No beta-2- that a postural fall of blood pressure does not occur. At blocking drug is clinically available. high drug dosage, however, even the competitive block may be sufficient to prevent adequate compensatory