17.10: Drug toxicity: Drug–Drug Interaction

Drug–drug interactions can precipitate toxicity through multiple mechanisms. Absorption interactions alter how drugs enter the body, exemplified when ranitidine increases the absorption of basic drugs, while cholestyramine decreases the levels of propranolol. Protein binding interactions occur when drugs share the same binding sites on plasma proteins. Drugs like aspirin and warfarin, when bound in excess, can lead to increased free drug concentrations, enhancing the potential for toxicity.

Metabolic interactions typically involve the cytochrome P450 enzymes in the liver. For example, ethanol can induce CYP2E1, increasing the conversion of acetaminophen to its toxic metabolite, NAPQI (N-acetyl-p-benzoquinone imine), heightening the risk of liver damage upon overdose. Receptor binding interactions, where one drug blocks or enhances the effect of another at a particular receptor site, can either mitigate or amplify effects, as seen with buprenorphine, which modulates opiate receptor activity and can affect the use of other narcotics.

Therapeutic action interactions involve the pharmacological effects of drugs. For instance, aspirin inhibits platelets, and heparin prevents blood clotting; combined, they heighten bleeding risks. Sulfonylureas stimulate insulin release, reducing blood sugar, while biguanides decrease sugar production by the liver. Used together, they effectively manage high blood sugar in diabetes. Types of interactions include additive, where effects simply sum; synergistic, where effects exceed the sum; and antagonistic, where one drug counteracts another. Functional antagonism arises when drugs produce opposite physiological effects. Chemical antagonism involves direct neutralization, and dispositional antagonism changes the disposition of a drug, reducing its concentration at the target site.

In summary, drug toxicity from drug–drug interactions occurs when the pharmacokinetic and pharmacodynamic properties of drugs are altered. These interactions can increase the active drug concentration, interfere with drug metabolism, or disrupt the intended therapeutic effects, potentially leading to adverse and toxic outcomes.

The use of multiple drugs, over-the-counter medications, and supplements can cause drug interactions, compromising treatment efficacy and potentially causing toxicity.

Drugs can affect each other’s GI absorption. Famotidine increases gut pH, which can reduce the absorption of certain drugs like ketoconazole.

Drugs like aspirin and warfarin undergo plasma protein binding. Their overdose saturates plasma proteins, increasing free drug levels and the risk of toxicity.

Drugs can also alter each other’s metabolism through the hepatic cytochrome P450 system. For example, chronic ethanol intake induces CYP2E1, increasing the conversion of acetaminophen to toxic NAPQI, leading to liver damage.

Coadministration of drugs with different therapeutic actions can enhance efficacy or cause adverse effects.

For example, the sulfonylurea glipizide acts by increasing insulin secretion from the pancreas, and the biguanide metformin reduces hepatic glucose production. Together, they effectively regulate blood sugar levels in diabetes.

On the other hand, combining aspirin, an antiplatelet agent, and heparin, an anticoagulant, increases bleeding risk.