clinical pharmacology
Drug–Receptor Interactions
Agonists and antagonists
Agonists activate receptors to produce the desired response. Conventional agonists increase the proportion of activated receptors. Inverse agonists stabilize the receptor in its inactive conformation and act similarly to competitive antagonists. Many hormones, neurotransmitters (eg, acetylcholine, histamine,norepinephrine), and drugs (eg,morphine,phenylephrine,isoproterenol, benzodiazepines, barbiturates) act as agonists. Antagonists prevent receptor activation. The prevention of activation has certain effects. Antagonists increase cellular function if they block the action of a substance that normally decreases cellular function. Antagonists decrease cellular function if they block the action of a substance that normally increases cellular function. Receptor antagonists can be classified as reversible or irreversible. Reversible antagonists readily dissociate from their receptor; irreversible antagonists form a stable, permanent or nearly permanent chemical bond with their receptor (eg, by alkylation). Pseudo-irreversible antagonists slowly dissociate from their receptor. Incompetitive antagonism,binding of the antagonist to the receptor prevents binding of the agonist to the receptor. Innoncompetitive antagonism,agonist and antagonist can be bound simultaneously, but antagonist binding reduces or prevents the action of the agonist. Inreversible competitive antagonism,agonist and antagonist form short-lasting bonds with the receptor, and a steady state among agonist, antagonist, and receptor is reached. Such antagonism can be overcome by increasing the concentration of the agonist. For example,naloxone(an opioid receptor antagonist that is structurally similar tomorphine), when given shortly before or aftermorphine, blocksmorphine’s effects. However, competitive antagonism bynaloxonecan be overcome by giving moremorphine. Structural analogs of agonist molecules frequently have agonist and antagonist properties; such drugs are called partial (low-efficacy) agonists, or agonist-antagonists. For example,pentazocineactivates opioid receptors but blocks their activation by other opioids. Thus,pentazocineprovides opioid effects but blunts the effects of another opioid if the opioid is given whilepentazocineis still bound. A drug that acts as a partial agonist in one tissue may act as a full agonist in another. 