Chapter: Modern Pharmacology with Clinical Applications: Adrenoceptor Antagonists

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Adrenoceptors

Drugs that produce responses by interacting with adrenoceptors are referred to as adrenoceptor agonists or adrenergic agonists.

ADRENOCEPTORS

Drugs that produce responses by interacting with adrenoceptors are referred to as adrenoceptor agonists or adrenergic agonists. Norepinephrine and isopro-terenol are examples of such compounds. Agents that inhibit responses mediated by adrenoceptor activation are known as adrenoceptor antagonists, adrenergic an-tagonists, or adrenergic blocking agents. Prazosin and propranolol are examples of receptor-blocking drugs.

Norepinephrine is released from the varicosities of the postganglionic sympathetic nerves during neural ac-tivity and interacts with the adrenoceptors of the effec-tor organ, producing the characteristic response of the effector. This occurs because norepinephrine has an affinity for the receptors and possesses intrinsic activity; that is, it has the capacity to activate the receptors. Circulating catecholamines and other directly acting adrenomimetic drugs also interact with these receptors.

The adrenergic blocking agents also have an affinity for the adrenoceptors. The antagonists, however, have only limited or no capacity to activate the receptors; that is, they have little or negligible intrinsic activity. The blocking drugs compete with adrenomimetic substances for access to the receptors. Thus, these agents reduce the effects produced by both sympathetic nerve stimulation and by exogenously administered adrenomimetics. This action forms the basis for their therapeutic and investi-gational use.

Competition for receptors, hence receptor antago-nism, is governed by the law of mass action; that is, the interaction between drug and receptor depends on the concentration of drug in the vicinity of the receptor and the number of receptors present. Because agonist and antagonist have an affinity for the same receptors, the two substances compete for binding to the receptors.

For most adrenoceptor antagonists (and agonists), the attachment of the blocking agent to the adrenocep-tor is by relatively weak forces, such as hydrophobic, hy-drogen, or van der Waals bonding. Because the drug easily dissociates from the receptor, the antagonism ex-hibited by these compounds is readily reversible on re-moval of the antagonists from the biophase. This type of antagonism is referred to as reversibly competitive or equilibrium competitive . However, one group of antagonists, the haloalkylamines, is highly chemically reactive. These compounds are capable of forming covalent bonds with various chemical group-ings on receptors. Removal of these antagonists from the biophase is not sufficient to restore the responsive-ness of the effector to agonists. Full tissue responsive-ness may not occur for several days. Because of the ap-parently irreversible nature of this drug antagonism, it is termed irreversibly competitive or non–equilibrium competitive .

Adrenoceptor-blocking agents do not prevent the release of transmitters from adrenergic nerves as do the neuron-blocking agents, such as guanethidine, and they are not catecholamine-depleting agents, such as reser-pine . They prevent the agonist from in-teracting with its receptor.

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