Adverse Drug Reactions - Part I
Course Number: 536
Course Contents
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.
| Type | Mechanisms |
|---|---|
| Receptor alteration | Drug 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 | |
| Pharmacological | Drug 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 |
| Physiological | Drug 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 | |
| Chemical | Drug 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.