Pharmacodynamic Drug-drug Interactions

To produce an effect in target and non-target tissues, a drug must be able to form a complex with its intended and/or unintended receptor. The intended or unintended effect produced by a given plasma level of a drug may result from chronic use or the presence of one or more drugs that lead to (1) changes in the number of available receptors or their ability to respond; or lead to (2) pharmacological, (3) physiological, and (4) chemical drug interactions, which at times may also be used to therapeutic advantage (Table 3).6

Table 3. Pharmacodynamic Drug-drug Interactions.
TypeMechanisms
Receptor alterationDrug A, when administered chronically, decreases the number of its own receptors or alters the adaptability of receptors to physiological events
Drug A, when administered chronically, increase the number of its own receptors or alters the adaptability of receptors to physiological events
PharmacologicalDrug A (an antagonist) and drug B (an agonist) compete for the same receptor site and as a function of their respective concentrations either prevent (antagonist) or produce (agonist) an effect
PhysiologicalDrug A and drug B interact with different receptors and enhance each other’s action via different cellular mechanisms
Drug A and drug B interact with different receptors and produce opposing effects via different cellular mechanisms
ChemicalDrug A interacts with drug B and prevents drug B from interacting with its intended receptor

Consider the pharmacodynamic ADR between NSAIDs and antihypertensive agents. The inhibition of prostaglandin synthesis by NSAIDs increases vascular tone, which decreases the efficacy of antihypertensive drugs. Another example is a pharmacological drug-drug interaction between epinephrine and β1-adrenergic receptor blocking agents. Since the β1-adrenergic receptors are blocked, unopposed α1-adrenergic receptor activation by epinephrine potentially can result in a hypertensive reaction.

Finally, note two examples of beneficial drug-drug interactions. Epinephrine activates α1-adrenergic-receptors causing vasoconstriction, delaying the systemic absorption of LAs, and increasing LAs’ duration of action. Phentolamine mesylate, a competitive α1-adrenergic-receptor antagonist, when injected at the site of LA administration reverses the action of epinephrine as a function of its concentration causing vasodilation, increasing the rate of systemic absorption, and shortening the duration of soft tissues anesthesia.