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Chapter: Modern Pharmacology with Clinical Applications: Adrenoceptor Antagonists

Classification of Blocking Drugs

An α-receptor is one that mediates responses for which the adrenomimetic order of potency is epinephrine greater than or equal to norepinephrine greater than iso-proterenol, and that is susceptible to blockade by phen-tolamine and phenoxybenzamine.


An α-receptor is one that mediates responses for which the adrenomimetic order of potency is epinephrine greater than or equal to norepinephrine greater than iso-proterenol, and that is susceptible to blockade by phen-tolamine and phenoxybenzamine. It follows from this definition that phentolamine and phenoxybenzamine are called α-adrenoceptor antagonists or α-blocking agents. A β-receptor mediates responses for which the adreno-mimetic order of potency is isoproterenol greater than epinephrine greater than or equal to norepinephrine, and this receptor is susceptible to blockade by propra-nolol. Propranolol is, therefore, called a β-adrenoceptor antagonist or α-blocking agent.

β-Receptor Subtypes

The two main types of β-receptors have been given the designations β 1 and β 2. Among the responses mediated by β 1-receptors is cardiac stimulation, whereas β 2-receptor stimulation mediates bronchodilation and re- laxation of vascular and uterine smooth muscle. These findings are significant, since a number of both agonists and antagonists have some degree of selectivity for either β 1- or β 2-receptors.

A comparison of the effects produced by propra-nolol, a nonselective β-receptor blocking agent, with those of metoprolol, a relatively selective β 1-receptor blocker, illustrates the clinical utility of such drugs. For example, a patient who is a candidate for β-blocker therapy (angina, hypertension), but who also has ob-structive airway disease probably should not receive a nonselective β-blocking agent such as propranolol be-cause of the possibility of aggravating bronchospasm. In this instance, metoprolol would be advantageous, since β-receptors of the respiratory system are β2, hence less affected by metoprolol than by propranolol. However, metoprolol’s selectivity is only relative, and at high con-centrations the drug will also antagonize 2 responses.

Absolute selectivity of drug action does not exist. Any given effector tissue probably contains more than one receptor subtype, and it is likely that the proportion of receptor subtypes varies within that effector. Nevertheless, the designation of a drug as a selective agent for either a β 1-receptor or a β 2-receptor seems both useful and justified if one keeps in mind that the designation represents a shorthand notation for what is only a predominance of activities.

Molecular genetic techniques have confirmed the existence of multiple subtypes of β-adrenoceptors. β1-Receptors and β2-receptors have been cloned, and recent molecular biological evidence indicates the existence of at least one additional β -receptor sub-type, called the β3-receptor. It is suggested that the β3-receptor may mediate some of the metabolic effects of catecholamines, although no available β-blocker has been shown to rely on β3-receptor antagonism for its therapeutic effectiveness.

β-Receptor Subtypes

There are differences between the receptors on nerves (presynaptic receptors) and those on effector cells (postsynaptic receptors). Furthermore, some α-agonists and antagonists exhibit selectivity for one of these re-ceptor types. Terminology classifies receptors as either α1 or α2. α1-Receptors are those whose stimulation has traditionally been associated with the postsynaptic α- receptors of smooth muscle, while 2-receptors are those originally associated with the presynaptic α-re-ceptors of peripheral nerves. However, the designation of receptors as either α1 or α2 cannot be categorized strictly by anatomical location (i.e., presynaptic or post-synaptic), since evidence now indicates that 2-recep-tors occupy, in addition to peripheral nerves, a variety of sites including smooth muscle, adrenal medullary cells, the brain, and melanocytes.

The existence of -receptor subclasses and the recep-tor selectivity exhibited by certain α β-blocking agents have therapeutic implications. Phentolamine is a disap-pointing antihypertensive drug because its administra-tion results in a reflex increase in both heart rate and con-tractile force; these effects tend to negate the reduction in blood pressure that it produces. In contrast, prazosin is an effective antihypertensive drug because the reflex car-diac stimulation it induces is much less. The differing he-modynamic effects produced by phentolamine and pra-zosin appear to be related to their relative degree of selectivity for α1- and α2- receptors. Phentolamine is a rel-atively nonselective receptor blocking agent, since in ad-dition to blocking postsynaptic α1-receptors, it will block presynaptic α2-receptors; the latter action enhances re-lease of norepinephrine, hence augments cardiac rate and contractile force. Blockade of α2-receptors may actually potentiate the cardiac effects of sympathetic nerve stimulation. Prazosin, in contrast to phentolamine, is relatively selective for α 1-receptors; that is, it preferen-tially blocks responses mediated by the postsynaptic α 1-receptors in the blood vessels without having a substan-tial effect on presynaptic α 2-receptors. Thus, prazosin stimulates the heart less than does phentolamine.

Absolute selectivity of action for α1- or α 2-receptors does not exist for any available  α-agonists and antago-nists. Furthermore, as is the case with α -receptors, a given effector tissue may contain more than one -receptor subtype. Recent evidence suggests that in addition to α 1-receptors, vascular smooth muscle may possess α 2-receptors. Although the functional importance of α 2-re-ceptors in blood vessels seems to be less than that of α 1-receptors, this can account for certain clinical observa-tions, as for example the pressor response that occurs upon initiation of treatment with the α 2-agonist clonidine.

It is becoming increasingly clear that neither α 1- nor α 2-receptors are homogeneous. There seem to be at least three subtypes of both α 1- and α 2-receptors, that is, α 1A, α 1B, α 1D, α 2A, α 2B and α 2C. At this point, the phar-macology and therapeutic usefulness of the major - antagonists can be reasonably well explained by consid-ering their relative selectivity for the two main classes of α -receptors, α 1 and α 2. This is beginning to change, how-ever. For example, tamsulosin (Flomax), a recently in-troduced -antagonist, reportedly exhibits some selec-tivity for α 1A-receptors, which are rich in the prostate, as compared to α 1B-receptors, which are more plentiful in vascular smooth muscle. This may provide some advan-tage to tamsulosin as an agent for treatment of patients with benign prostate hypertrophy.

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